Molecules 28 03379 v2

molecules
Review
Recent Advances in the Synthesis of Propargyl Derivatives, and
Their Application as Synthetic Intermediates and
Building Blocks †
Rodrigo Abonia 1 , Daniel Insuasty 2 and Kenneth K. Laali 3, *
1 Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle,

Cali A.A. 25360, Colombia; [email protected]
2 Grupo de Investigación en Química y Biología, Departamento de Química y Biología, Universidad del Norte,
Barranquilla 081007, Atlántico, Colombia; [email protected]
3 Department of Chemistry, University of North Florida, 1 UNF Drive, Jacksonville, FL 32224, USA
* Correspondence: [email protected]
† Dedicated to Professor Braulio Insuasty on the occasion of his recent retirement.
Abstract: The propargyl group is a highly versatile moiety whose introduction into small-molecule
building blocks opens up new synthetic pathways for further elaboration. The last decade has
witnessed remarkable progress in both the synthesis of propargylation agents and their application
in the synthesis and functionalization of more elaborate/complex building blocks and intermediates.
The goal of this review is to highlight these exciting advances and to underscore their impact.
Keywords: propargylating agents; target substrates; catalysts and catalytic systems; propargylated
building blocks and intermediates; homopropargylic reagents; application in synthesis
1. Introduction
The present review covers relevant literature published from 2010 to present. Accord-
ing to the consulted reports, whereas in the majority of cases the target compounds result
Citation: Abonia, R.; Insuasty, D.; from direct introduction of the propargyl moiety, in many examples, the propargylation
Laali, K.K. Recent Advances in the reaction serves as a strategic step in a reaction sequence that results in the formation of
Synthesis of Propargyl Derivatives, more elaborate/complex structures. In such cases, this review emphasizes the propargyla-
and Their Application as Synthetic tion methodologies rather than the subsequent steps en route to more complex synthetic
Intermediates and Building Blocks. targets. It is noteworthy that tautomerization between the propargyl (I) and allenyl (II)
Molecules 2023, 28, 3379. https:// moieties (Scheme 1) greatly expands the scope of propargylation, since either one may
doi.org/10.3390/molecules28083379
function as a propargylation agent [1,2]. Indeed, in many examples discussed in this review,
Academic Editor: Antonio Massa allenyl derivatives and propargyl derivatives can be employed interchangeably to obtain
the same propargylated derivative, or be applied to different substrates, all leading to the
Received: 11 March 2023
propargylated analogs.
Revised: 5 April 2023
Accepted: 5 April 2023
Published: 11 April 2023
Copyright: © 2023 by the authors.

Licensee MDPI, Basel, Switzerland. Scheme 1. Propargyl–allenyl tautomerization process.
This article is an open access article
distributed under the terms and As depicted in Table 1, this review is organized based on the type of substrate/functional
conditions of the Creative Commons group reacting with various classes of propargylating reagents (propargyl and/or allenyl
Attribution (CC BY) license (https:// derivatives), while also highlighting the catalysts/catalytic systems employed, including
creativecommons.org/licenses/by/ complex catalytic systems formed via catalyst/ligand interactions applied to asymmetric
4.0/). propargylation.
Molecules 2023, 28, 3379. https://doi.org/10.3390/molecules28083379 https://www.mdpi.com/journal/molecules

Molecules 2023, 28, 3379 2 of 61
Table 1. Summary of the types of substrates, propargylating agents, and catalysts/catalytic systems.
Entry Type of Substrates

2.1 (a) Aldehydes and ketones, (b) hemiacetals (involving C=O functionality)
2.2 (a) Imines, (b) iminium, and (c) azo compounds (involving C=N and N=N bonds)
2.3 Aryl and heterocyclic derivatives (involving the =C-H bond)
2.4 Acyl halides (involving both CO-X and C=O bonds)
2.5 Amine/amide derivatives (involving N-H as nucleophilic center)
2.6 Vinylstananes
(a) Alcohols, (b) enol-like precursors, (c) phenols, (d) thiols, and (e) carboxylic acids (involving O-H and S-H as
2.7
nucleophilic centers)
2.8 (a) Alkenes, (b) allenes, and (c) enynes (involving the C=C bond)
Carbanion-like nucleophiles (involving methyl, methyne and methylene-active compounds, enol/enolate, and
2.9
enamine functionalities)
2.10 Carbocationic electrophiles (involving benzylic tosylates, alkyne–Co2 (CO)6 complex, and epoxides)
2.11 Free-radical-like precursors
2.12 Boronic acids (ArB(OH)2 )
2.13 Nitrones
Type of propargylating agents (including propargyl and allenyl derivatives)
a Propargyl-/allenylboron-based reagents (involving borolanes, boronic acids, BF3 K)
b Propargyl-/allenyl-halides (X = Br, Cl, I)
Propargyl ethers, propargyl-ONH3 + Cl- , acid/ester derivatives (involving acetates, phosphates, sulfonates,
c
carboxylates, carboxyls, and -OR)
d Propargylamines
e Organometallic reagents (propargyl-/allenyl-MX, propargyl-M) (M = metal)
f Silyl reagents (involving TMS, SiX3 , SiX3 )
g Propargyl–aryl derivatives
h Propargyl aldehydes
i Propargyl-(SeR2 )+
j Masked propargyl reagents (CaC2 /RCHO, Co-based complex, isoxazolones)
k Propargyl alcohols and cationic-like propargyl intermediates
l Enyne-based reagents
m Methylene-active-based reagents
n Aryl/alkyl acetylenes
Catalysts and catalytic systems
(i) Involving complexed or free metals
Zn, Cu, Ce, Ba, Co, Sc, Mo, Fe, In, Bi, Yb, Ln, Ag, Cr, Ti, Ir, Ru, Al, Sn, Cs, Pd,
Rh, Mn, Au, Ni, Hg
(a) Transition metal-catalyzed reactions:
(ii) Involving combined complexed or free metals
Ir/Sn, Ti/Pd, Pd/Sn, Ni/In, Zn/Pd, Ti/Cu/Zn, Ag/Sb, Co/BF3 , Pd/Ag,
Au/Ag, Cu/Zn, Co/Ag, Ni/Yb, Al/Zn, Cu/Li
K2 CO3 , Cs2 CO3 , NaH, KOH, NaOH, LDA, NH4 OH, n-BuLi, tBuOK, LiHMDS,
(b) Base-catalyzed reactions:
TEA, iPrNH2 , iPr2 NEt, DTBMP, KHCO3 , K2 CO3 /MWI, 2,6-lutidine, tBuOLi
PTSA, TfOH, PPA, HCO2 H, BF3 •OEt2 , combined Lewis/Bronsted acids,
(c) Lewis and Brønsted acid-catalyzed reactions:
B(C6 F5 )3 , Amberlyst-15, [BMIM][BF4 ], BPh3
C6 F5 B(OH)2 , biphenols, pyridium-NO, Tf2 O, PTC/MW, H2 O/MW, clays,
(d) Metal-, base- and acid-free catalyzed conventional heating/solvent, O2 /DDQ, molecular sieves (MS), LEDs/(PhS)2 ,
reactions: enzymes, Hantzsch ester/S-proline, acetone/MW, LiBINOL phosphate;
EDC/H2 O, PhSSPh/blue LEDs.
Molecules 2023, 28, 3379 3 of 61
2. Types of Substrates
2.1. (a) Aldehydes and Ketones and (b) Hemiacetals
A propargylation reaction in carbonyl derivatives (aldehydes and ketones) whereby
the propargylation reagent acts as a nucleophile toward the C=O functionality is a conve-
nient method for the synthesis of chiral and achiral secondary or tertiary homopropargylic
alcohols from aldehydes or ketones, respectively [3]. Significant progress has been made
in the development of chiral propargylation reagents and diastereoselective additions of
propargylic anion equivalents to chiral aldehydes and ketones [4].
Homopropargylic alcohols are present as fundamental structural entities in many
bioactive compounds [5,6], and have also attracted significant interest as useful building
blocks for complex molecule synthesis [7–9]. In this regard, several synthetic strategies and
propargylation reagents have been employed for the synthesis of this interesting family of
alcohols, as summarized below.
(a) Aldehyde and ketones
2.1.1. With Boron-Based Propargyl Reagents

Propargyl–/allenyl–boron-based compounds are a family of propargylation reagents
with easy availability and relatively low costs, and for this reason, they are widely used in
the propargylation processes of diverse organic substrates, as summarized in Table 2 and
Schemes 2–4.
Following the discovery of the highly enantioselective and site-selective copper
alkoxide-catalyzed propargylation of aldehydes 1 (R1 = H) with a propargyl borolane
2a (Table 2, entry 1), a catalytic cycle based on a Cu-alkoxide-mediated B/Cu exchange
with propargyl borolane 2a was proposed, with an allenyl Cu intermediate as a key species.
Additional experiments demonstrated the proposed catalytic cycle [10]. Table 2 also summa-
rizes several other synthetic approaches to the propargylation reaction of diverse aldehydes
and ketones 1 through propargyl/allenyl borolane reagents 2, producing a variety of chiral
and achiral secondary and tertiary homopropargylic alcohols 3.
A simple protocol for the synthesis of homopropargyl alcohols 5, starting with isatin
derivatives 4 under mild reaction conditions, was reported (Scheme 2) [22]. Reactions were
performed in the presence of copper triflate as a Lewis acid catalyst, with allenylboronic
acid pinacol ester 2c as a nucleophile, in aqueous media, producing excellent product 5
yields. The enantioselective synthesis of chiral propargyl alcohols 6 was also explored.
The best regioselectivity was achieved when (S)-SEGPHOS was used as a chiral ligand,
resulting in enantiomeric ratios up to 12:88. Gram-scale synthesis, performed to check the
efficiency of the protocol, showed retention in selectivity [22].
The synthesis of tri- and tetrasubstituted allenylboronic acids was established via
a versatile copper-catalyzed methodology (Scheme 3) [23]. Subsequently, the obtained
allenylboronic acids 7 were subjected to propargylboration reactions with ketones 1 without
any additives, producing homopropargyl alcohols 8 (Scheme 3). Additionally, catalytic
asymmetric propargylboration of the ketones 1 with high stereoselectivity was achieved
when (S)-Br2 -BINOL was used as chiral ligand, allowing for the synthesis of highly enan-
tioenriched tertiary homopropargyl alcohols 9 (Scheme 3). The reaction was suitable for
the kinetic resolution of racemic allenylboronic acids, producing alkynes with adjacent
quaternary stereocenters [23].
The propargylation of aldehydes/ketones 1 using potassium allenyltrifluoroborate 10
promoted by tonsil, an inexpensive and readily available clay, in a chemo- and regioselec-
tive manner was described, leading to homopropargyl alcohols 11 in good to moderate
yields (Scheme 4, entry 1) [24]. The described method is simple and avoids the use of air-
and moisture-sensitive organometallics. In the same way, alcohols 11 were synthesized
under MW irradiation (Scheme 4, entry 2) [17] or by using Amberlyst A-31 (Scheme 4,
entry 3) [25].
Molecules 2023, 28, 3379 4 of 61
Table 2. Propargylation of diversely substituted aldehydes/ketones 1 with propargyl-/allenyl

borolanes 2.
Chiral Number of Yield (%)

Entry Conditions Propargylation Reagent 2 Ref.
Catalyst/Ligand Examples (ee%)
cat. (7%) Cu(II)(isobutyrate)2 , (7%) tBuOLi,

77–99
1 THF, −30 ◦ C, 18 h MeO-BIBOP (9%) 10 [10]
(90–99)
R = Aryl, Het, alkyl; R1 = H; R2 = R3 = TMS
2a
(1) cat. (2–5%) Et2 Zn, THF, 20 ◦ C, 1 h
(2) K2 CO3 , MeOH
2 2a 11 85–99
R = Ph, Aryl, Het, alkyl; Cy; R1 = H, Me;
R2 = TMS; R3 = H
cat. (1.2 equiv.) Et2 Zn, DCM, 20 ◦ C, 1 h

3 R = Aryl, alkyl; R1 = H, Me; R2 = R3 = TMS, —— 7 87–98
SiMe2 Ph, (CH2 )3 Ph [3]
2b
cat. (20%) Et2 Zn, THF, 20 ◦ C, 18 h

4 1 74
R = p-MeOC6 H4 ; R1 = R3 = H
2c
CuOAc (2 mol%), iPrOLi (0.5 equiv.),
iPrOH (1 equiv.), DCM, −75 ◦ C Chiral bisphosphine 65–94
5 2c 15 [11]
R = Ph, Aryl, Het, alkyl, Cy; R1 = Me, Cy; ligand (2.4 mol %) (42–98)
R3 = H
MW
(S)-Br2 -BINOL 60–98
6 R = Ph, Aryl, Het, alkyl, Cy; R1 = Me, Et, Pr, 22 [12]
(10 mol%) (79–99)
Bn, (CH2 )2 Cl, (CH2 )3 Cl, Cy; R3 = H
2d
Cu(isobutyrate)2 (5 mol%), tBuOLi
(8 mol%), THF, −62 ◦ C, 18 h (R)-BINAP 80–98
7 2a 16 [13]
R = Ph, Aryl, Het, alkyl, Cy; R1 = Me, Cy; (7 mol%) (84–98)
R2 = R3 = TMS
AgF (5 mol%), tBuOH (1.1 equiv.), tBuONa
(15 mol%)/MeOH, tBuOMe, −20 ◦ C, 6 h (R,R)-Walphos-8 48–95
8 2c 14 [14]
R = Ph, Aryl, thienyl; R1 = Me, Aryl, (5-6 mol%) (71–97)
tBuCO2 ; R3 = H
Et2 Zn (25 mol%), H2 O (2 mol%), THF,
N-isopropyl-L-
−40 ◦ C, 2 d 70–94
9 2a proline 10 [15]
R = ArC(Me)2 CH2 , Ph(CH2 )2 ; (80–93)
(27 mol%)
R1 = CF3 ; R3 = TMS
CuCl (5 mol%), tBuONa (10 mol%), THF,
−40 ◦ C, 24 h
(S,S,S)-Ph-SKP 58–99
10 R = PhCF2 , ArCF2 , HetCF2 , alkylCF2 ; 2c 25 [16]
(6 mol%) (42–98)
R1 = Me, Et;
R2 = R3 = H
MWI (300 W), 100 ◦ C, 30 min
11 R = Ph, Aryl, furanyl, n-hexyl; R1 = H; 2c —— 20 51–98 [17]
R2 = R3 = H
chiral
12 Computational study; R = Ph; R1 = R3 = H 2c BINOL-phosphoric 1 —— [18]
acid
Computational study; R = Aryl, alkyl;
13 2c (R)-TRIP-PA 2 —— [19]
R1 = R3 = H
2c and
Computational study; R = Ph; R1 = Me; chiral BINOL

14 2 —— [20]
R3 = H catalysts
2e
Computational study; Cu(isobutyrate)2
15 (2.5 mol%), tBuOLi (2.5 mol%), THF, −20 ◦ C 2a Me-BPE (2.5 mol%) —— —— [21]
R = Aryl; R1 = Me; R2 = R3 = TMS
Molecules 2023, 28, 3379 5 of 61
Scheme 2. Synthesis of homopropargyl alcohols 5/6 from isatin derivatives 4 and allenylboronic
ester 2c.
Scheme 3. Synthesis of homopropargyl alcohols 8/9 from ketones 1 and allenylboronic acid 7.
Scheme 4. Synthesis of homopropargyl alcohols 11 from aldehydes/ketones 1 and allenyltrifluorobo-

rate 10.
2.1.2. With Propargyl Silanes

In the context of silane-mediated transformations promoted by chiral Lewis base catal-
ysis, it has been shown that the coupling of a Lewis base with a silane reagent can promote
several synthetically useful reactions, opening up the possibility for further studies [26].
In a recently developed catalytic asymmetric addition process (Scheme 5), optically active
homopropargylic alcohols 13 were synthesized by reacting propargylic silanes 12 with
aldehydes 1 (R = H), using a chiral organosilver species as a pre-catalyst. The catalyst was
formed in situ via an (R)-DM-BINAP·AgBF4 complex. The other additives were TEA (base
pre-catalyst), along with KF and MeOH [27].
Scheme 5. Organosilver-catalyzed asymmetric synthesis of homopropargylic alcohols 13 from

aldehydes 1 and propargylic silane reagents 12.
Allenyltrichlorosilane is an attractive candidate as a nucleophilic partner in C=O and

C=N propargylation reactions because of its mildness, regiospecificity, and low toxicity [28].
It was reported that a new bidentate helical chiral 2,20 -bipyridine N-monoxide Lewis base
Molecules 2023, 28, 3379 6 of 61
can efficiently catalyze the addition of allenyltrichlorosilane 14 to aromatic aldehydes 1

(R = H), producing homopropargylic alcohols 15 with high levels of enantioselectivity
and high yields (Scheme 6, entry 1) [29]. Additionally, extensive computational studies
have made it possible to predict stereoselectivities for the synthesis of alcohols 15 using
axially chiral bipyridine N,N’-dioxides as catalysts (Scheme 6, entries 2 and 3). It was found
that the stereoselectivity of these bidentate catalysts is controlled by well-defined rigid
transition-state structures. It was suggested that N,N’-dioxides are superior platforms for
rational catalyst development for asymmetric propargylation [30,31].
Scheme 6. Asymmetric synthesis of homopropargylic alcohols 15 from allenyltrichlorosilane 14 and

aromatic aldehydes 1.
Xanthones, thioxanthones, and xanthenes are naturally occurring molecules and have
interesting properties due to their special structures [32,33]. With this in mind, gold-
catalyzed bispropargylation of xanthones and thioxanthones 16 (X = O, S, respectively)
was devised (Scheme 7) [34]. In this approach, the use of propargylsilanes 17 permitted de-
oxygenative bispropargylation through the double catalytic addition of the corresponding
allenylgold intermediate to the synergistically activated carbonyl moiety. This methodology
worked in a diastereoselective manner, with either xanthone or thioxanthone derivatives
16, producing the corresponding 9,9-bispropargylxanthenes and thioxanthenes 18 (X = O,
S, respectively) in high yields.
Scheme 7. Gold-catalyzed bispropargylation of xanthones and thioxanthones 16.
2.1.3. With Propargyl Halides

The addition of organochromium reagents to carbonyl compounds is considered an
important tool in contemporary organic synthesis because of a number of unique features,
such as mild reaction conditions, high chemoselectivity, and compatibility with a wide
range of functional groups [35]. Chiral homopropargyl alcohols 3 were envisioned among
the products potentially accessible using this methodology. Most of the asymmetric meth-
ods that provide access to these compounds involve the use of chiral allenyl reagents, for
which catalytic enantioselective NH propargylation was considered a suitable alternative,
owing to the ready availability of propargyl halides 19 as sources of propargyl moieties.
Following the development of a tethered bis-(8-quinolinato) (TBOx) chromium
complex [36], it was successfully used as a highly stereoselective catalyst for several
asymmetric reactions [37–40]. Its application as a catalyst was extended to the asymmetric
NH propargylation of aldehydes. Thus, a highly enantioselective catalytic system for the
NH propargylation of aldehydes 1 (R = H) via a Barbier-type reaction [41] employing
low Mn catalyst loading was developed (Table 3, entry 1). High enantioselectivities, not
Molecules 2023, 28, 3379 7 of 61
previously achievable for aromatic, heteroaromatic, and α,β-unsaturated aldehydes using

NH chemistry, were reported for a range of substrates 1 [42].
Several other approaches to the synthesis of diversely substituted chiral and achiral
homopropargyl alcohols 3, starting with carbonyl compounds 1 and employing halogen-
based propargylation reagents 19, in the presence of a variety of catalytic systems, are
outlined in Table 3 and Scheme 8.
Table 3. Propargylation of diversely substituted aldehydes/ketones 1 with propargyl-/allenyl
halides 19.
Chiral Number of
Entry Conditions Propargylation Reagent 19 Yield (%) Ref.
Catalyst/Ligand Examples
(1) Mn (3 mol%), TESCl, THF, rt, 1h, 1 mol%
H8-
of a tetraarylporphyrin complex 37–91
1 TBOx ligand 19 [42]
(2) TBAF, THF (84–93 ee)
19a (X = Br) (3 mol%)
R = Ph, Aryl, Het, alkyl; Cy; R1 = H; R2 = H
ZnEt2 (220 mol%), DCM (0.1 M), 4Å MS, 19b (X = I) or

2
−78 → 4 ◦ C, 12 h 15
80–99
[43]
R = PhCH=CH, PhCH=CMe Aryl, Naphth, R = 1-Naphthyl, (10 (80–96 ee)
Het, Cy; R1 = H; R2 = H 19c mol%)
CrCl3 •(THF)3 (10 mol%), TEA (20 mol%),

TMSCl (4 equiv.), Mn (4 equiv.), LiCl (1 60–86
3 17 [44]
equiv.), THF, 25 ◦ C, 72 h; R = Ph, Aryl, Het, (85–98 ee)
alkyl, Naphth, Cy; R1 = Me, Et, iPr; R2 = H 19d (X = Cl)
(11 mol%)
[TiCl2 Cp2 ] (0.2 equiv.), Mn dust, Me3 SiCl,
A: 19a (X = Br) A: 16 57–99
2,4,6-collidine A: R = Aryl, alkyl; R1 = R2 = H;
4 B: 19d (X = Cl) —— B: 10 53–99 [45]
B: R = Aryl, alkyl; R1 = Alkyl; R2 = H; C: R =
C: 19a,d (X = Br, Cl) C: 7 19–79
Aryl, alkyl; R1 = Me, H; R2 = Et, pentyl
Electrochemical condition, H2 O-THF (8:2),

5 0.02 M ZnCl2 solution —— 11 35–92 [46]
R = Ph, Aryl, alkyl; R1 = H, CO2 Me; R2 = H, Et
19e (R3 = H, Me)
Computational study; R = tBu, iPr, Bu, Cy,

6 19a,d (X = Cl, Br) 7 —— [47]
iPent; R1 = Me; R2 = H
7 Ligands
A protocol for the total synthesis of (–)-epiquinamide involving the L-proline-catalyzed

one-pot sequential α-amination/propargylation of aldehyde 1 (R = H) was established
(Scheme 8). The synthesis was accomplished in nine steps, with the formation of homo-
propargyl alcohol 20 as a strategic step (entry 1) [48]. In the same way, six-step asymmetric
total synthesis of the natural pyrrole lactone longanlactone was designed. The reaction
involved the formation of propargyl alcohol 22 through the Zn-catalyzed Barbier propargy-
lation of the aldehyde 21 as one of the key steps in this process (Scheme 8, entry 2) [49].
A chemo-enzymatic process was established as a useful method for the derivatization
of galactose unit of spruce galactoglucomannan (GGM) and other galactose-containing
polysaccharides. In this approach, a series of GGMs were selectively formylated at the
C-6 position via enzymatic oxidation by galactose oxidase. The formed aldehydes 23
were further derivatized via an indium-mediated Barbier–Grignard-type reaction using
propargyl bromide 19a, resulting in the formation of homoallylic alcohols 24 (Scheme 8).
All the reaction steps were performed in water in a one-pot reaction. The formation of the
propargylated products was identified via MALDI-TOF–MS. The polysaccharide products
were isolated and further characterized via GC–MS or NMR spectroscopy. The deriva-
tized polysaccharides 24 were considered potential platforms for further functionalization
(entry 3) [50].
Molecules 2023, 28, 3379 8 of 61
A stereospecific Barbier-type reaction of α-hydroxyketones 25 with propargyl

bromide 19a in the presence of indium metal provided (1RS,2SR)-1,2-diarylpent-4-yne-1,2-
diols 26 in good yields as single diastereomers (Scheme 8). The observed high diastere-
oselectivity (>99%) in 1,2-diols 26 was consistent with the Cram’s chelation model [51].
The 1,2-diols 26 were successfully used as precursors for furan synthesis through iodine-
mediated 5-exo-trig cyclization, dehydration, and reductive deiodination (entry 4) [52].
Another study described diastereoselective Zn-mediated propargylation for non-
enolizable norbornyl α-diketones 27. In this approach, the treatment of 27 with zinc
and propargyl bromide 19a in anhydrous THF, using the Barbier procedure under ultra-
sound, produced the corresponding norbornyl homopropargyl alcohols 28 in good yields
(Scheme 8). An analysis of the crude reaction mixtures revealed that 28 was obtained in a
diastereomerically pure form, along with small amounts of allene derivatives as byproducts.
Moreover, the stereochemistry of 28 was confirmed via X-ray crystal structure analysis.
Subsequently, homopropargyl alcohols 28 were used as precursors for an AgI-catalyzed
cycloisomerization toward diversely substituted spirocyclic dihydrofuran derivatives and
produced acceptable to good yields (entry 5) [53].
Scheme 8. Propargylation of carbonyl compounds 1, 21, 23, 25, and 27 with propargyl bromide 19a.
Based on the dual photoredox catalytic strategy [54,55], practical and effective pho-
toredox propargylation of aldehydes 1 (R = H) promoted by [Cp2 TiCl2 ] was developed
(Scheme 9). The reaction did not require stoichiometric metals or scavengers, and employed
a catalytic amount of [Cp2 TiCl2 ], along with the organic dye 3DPAFIPN (as a reductant for
titanium). The reaction displayed a broad scope, producing the desired homopropargylic
alcohols 29 in good yields with both aromatic and aliphatic aldehydes [56].
Molecules 2023, 28, 3379 9 of 61
Scheme 9. Dual photoredox-mediated catalysis with titanium for the propargylation of aldehydes 1
with propargyl bromides 19a.
The synthesis of homopropargyl alcohol 31 with a two-carbon extension was achieved

through the propargylation of aldehydes 1, mediated by zinc(0). This reagent was generated
in situ from the redox coupling of Al and ZnCl2 in 2N HCl and THF, producing products
31 in acceptable to good yields (Scheme 10) [57].
Scheme 10. Zinc(0)-mediated synthesis of homopropargyl alcohols 31.
Aldehydes 1 were transformed into their corresponding homopropargyl alcohols 32

via a reaction with propargyl bromide 19a, with CuCl and Mn powder employed in the
presence of TFA in ACN solvent (Scheme 11). This method proved compatible with a
variety of substrates, leading to diversely substituted products 32 in high yields. A large-
scale reaction was also performed, demonstrating the potential synthetic applications of
this transformation [58].
Scheme 11. Cu-Catalyzed/Mn-mediated chemo-selective synthesis of homopropargyl alcohols 32.
2.1.4. With Organometallic Propargyl Reagents

The Barbier type nucleophilic addition of functionalized halides to carbonyls mediated
by metals or metal compounds constitutes an important strategy for carbon–carbon bond
formation in organic synthesis [59–61]. In this context, an operationally simple procedure
for the propargylation of aldehydes 1 in moist solvent (distilled THF) was developed
through the direct addition of propargyl bromide 19a to the aldehyde substrates 1, mediated
by low-valent iron or tin (Scheme 12). The metals were prepared in situ using a bimetal
redox strategy. Using different aldehydes 1 as substrates, both metals proved applicable,
producing homopropargyl alcohols 34 in good yields and with high chemoselectivity in
most cases. Due to its efficacy, operational simplicity, performance in moist solvent, and its
use of inexpensive metal/metal salts, the procedure was claimed to be practically viable
and potentially scalable [62].
Molecules 2023, 28, 3379 10 of 61
Scheme 12. Bimetal redox synthesis of homopropargyl alcohols 34 from aldehydes 1 and propargyl
bromide 19a.
Allenyl boronic acids are widely used as propargylation reagents. These compounds
are usually prepared via the Hg-catalyzed magnesiation of propargyl bromide [63]. How-
ever, the use of mercury, the corrosiveness of propargyl bromide, and the pyrophoric nature
of allenyl boronic acid raise environmental and safety concerns, particularly when using
these reagents for large-scale applications. To circumvent these limitations, the devel-
opment of a mercury-free flow chemistry process for the asymmetric propargylation of
aldehydes using allene gas 35 as a reagent was reported (Scheme 13). The connected contin-
uous processes of allene dissolution, lithiation, Li-Zn transmetalation, and the asymmetric
propargylation of the chiral aldehyde 38 provided a homopropargyl β-amino alcohol 39
with high regio- and diastereoselectivity in high yield. This flow process represents a
practical use for an unstable allenyllithium intermediate 36, using the commercially avail-
able and recyclable (1S,2R)-N-pyrrolidinyl norephedrine (L*) as a ligand to promote the
diastereoselective propargylation of 38 [64].
Scheme 13. Zn-Mediated asymmetric propargylation of aldehydes 38 with allene gas 35 as reagent.
The esters of 4-hydroxybut-2-ynoic acid (alkyl 4-hydroxybut-2-ynoates) 42 are promis-

ing building blocks for organic synthesis. The presence of three important functional groups,
namely the acetylene bond conjugated with the ester moiety, and the hydroxyl group of the
propargyl unit in the structure of these compounds, make them highly versatile and appli-
cable to many useful synthetic transformations [65–70]. With this in mind and based on
previous works on the superelectrophilic activation of acetylene compounds [71], a series of
4-aryl(or 4,4-diaryl)-4-hydroxybut-2-ynoates 42 were obtained for further studies on their
transformations under the action of various acids. The treatment of propynoates 40 with a
solution of BuLi in hexanes produced lithiated intermediates in situ 41. Then, carbonyl com-
pounds 1 were added at low temperature to form the target alkyls 4-hydroxybut-2-ynoates
42 in acceptable to excellent yields (Scheme 14) [72].
Scheme 14. Synthesis of 4-hydroxybut-2-ynoates 42 from carbonyl compounds and lithiated

propynoates 41.
Epoxides serve as both building blocks and synthetic intermediates in various organic
transformations [73,74]. The conjugation of a propargyl group to an epoxide creates
a highly functional small-molecule building block. A series of substituted propargyl
Molecules 2023, 28, 3379 11 of 61
epoxides 45 were prepared via the propargylation of α-bromoketones 43 with an organozinc

reagent 44 (Scheme 15). This method complements existing synthetic methods due to the
advantageous properties of the organozinc reagents, such as their availability, selectivity,
operational simplicity, and low toxicity [75].
Scheme 15. Synthesis of propargyl epoxides 45 via propargylation of α-bromoketones 43 with the
propargylic organozinc reagent 44.
2.1.5. With Propargylic Ethers, Acids, and Esters

The intramolecular propargylation of aldehydes and ketones enables their entry into
cyclic compounds containing a homopropargyl alcohol unit, a structural motif that is
present in a variety of biologically active compounds and is highly useful for synthetic
transformations [76,77]. Due to their ready availability, propargylic esters 46 [78] are log-
ical starting points in these transformations. It has been shown that carbonyl-tethered
propargylic benzoates 46 undergo intramolecular carbonyl propargylation upon treatment
with Et2 Zn in the presence of a catalytic amount of Pd0 to form 2-alkynylcyclopentanol
products 47 (Scheme 16). Diastereoselectivity for the formation of simple homopropargyl-
cycloalkanols 47, generated through the use of Pd0 /Et2 Zn, was examined as a function of
the palladium phosphine ligand in the absence of further structural constraints imposed by
additional substituents or rings. In this approach, a ligand/solvent effect on the cis/trans
selectivity (referring to the relative positions of the alkynyl and OH groups) of ring-closure
was found. In a non-coordinating solvent (benzene), increasing the electron-donating
ability of the phosphine ligand (while decreasing its dissociation ability) led to an increased
tendency towards the trans product, while the combination of a coordinating solvent (THF)
and PPh3 resulted in the exclusive formation of cis products. The experimental and compu-
tational results were compatible with the divergent behavior of an allenyl-ethylpalladium
intermediate that partitions between competitive carbonyl-addition and transmetalation
pathways, each leading to a different diastereoisomers. The results also suggested that the
dissociating ability of the phosphine acted as a regulating factor for this behavior [79].
Scheme 16. Pd0 /Et2 Zn-mediated synthesis of 2-alkynylcyclopentanols 47 from carbonyl-tethered

propargylic benzoates 46.
Isolated in 2008 from the marine sponge Siliquariaspongia mirabilis, mirabalin [80] was
found to inhibit the growth of the tumor cell line HCT-116, with an IC50 value of 0.27 µM.
This compound belongs to the chondropsin family of macrolide lactams, which comprises
chondropsins A−D, 73-deoxychondropsin A, and poecillastrins A−C [81]. Alcohol 50 is
a key intermediate in the convergent and flexible stereoselective synthesis of one isomer
of the C44−C65 fragment of mirabalin [82]. To synthesize alcohol 50, aldehyde 48 was
subjected to stereoselective Marshall allenylation [83] through the addition of a chiral
allenylzinc reagent, prepared in situ via palladozincation of the (S)-propargylic mesylate 49.
This method delivered propargyl alcohol 50 with good diastereoselectivity in favor of
the anti,syn,anti-isomer (Scheme 17). The two diastereomers were separated via flash
chromatography on silica gel.
Molecules 2023, 28, 3379 12 of 61
Scheme 17. Pd-mediated stereoselective Marshall allenylation of aldehyde 48 with (S)-propargylic

mesylate 49.
The transition metal-catalyzed carbonyl propargylation protocol is an elegant approach

to the diastereo- and enantioselective construction of homopropargylic alcohols. Addition
reactions of propargyl metal or metalloid to aldehydes have been widely used as general
synthetic methods. Nevertheless, some limitations exist in this strategy because of its
ambident nucleophile characteristics as propargyl/allenyl organometallic reagents, which
open up new reaction channels and widen their synthetic scope [84,85]. To circumvent
these limitations, researchers have focused on transition metal-free carbonyl propargylation
for the synthesis of 1,2,4-substituted homopropargylic alcohols.
In this regard, a transition metal-free three-component process was developed by
combining aldehydes 1, 3-(tributylstannyl)propargyl acetates 51 formed in situ from readily
available propargyl acetates, and trialkylboranes 52, providing access to a range of 1,2,4-
trisubstituted homopropargylic alcohols 53 (Scheme 18). It was found that the addition
of diisopropylamine played a crucial role in the selective formation of homopropargylic
alcohols 53. Importantly, this methodology could be extended to a single-flask reaction
sequence starting with propargyl acetates [86].
Scheme 18. Three-component synthesis of homopropargylic alcohols 53 mediated by 3-

(tributylstannyl)propargyl acetates 51 as propargylation reagents.
Although propargylic carbonates are readily available compounds that could poten-
tially be used instead of the corresponding propargylic halides in the carbonyl propargyla-
tion process, they are inert under classical Barbier conditions. Whereas notable examples
of the use of propargyl carbonates have been described, their applications were typically
limited to aldehydes as electrophiles [78,87]. To circumvent this limitation, an efficient
protocol for the synthesis of homopropargylic alcohols 55 in moderate to good yields was
reported that utilized propargylic carbonates 54 as pronucleophiles (Scheme 19). This
reaction is based on a combination of transition metal (palladium) and radical (titanium)
chemistry, in which allenyl titanocenes and transient propargylic radicals are formed in situ
as key species for the success of this multimetallic protocol. The reaction took place with
excellent regioselectivity, tolerating a variety of terminal and internal alkyne functionalities
of the starting propargylic carbonates 54 with different substitution patterns, as well as
diverse carbonyl compounds 1 (aldehydes and ketones), thus providing a useful method
for application in synthetic organic chemistry (entry 1) [88].
Molecules 2023, 28, 3379 13 of 61
Scheme 19. Multimetallic protocols for the synthesis of homopropargylic alcohols 55/56 from
propargylic carbonates 54.
In a similar way, low-valent indium(I)-mediated nickel-catalyzed propargylation

of aldehydes 1 with propargylic carbonates 54 was established. In this approach, the
nickel/indium(I)-mediated reaction of the starting materials 54, which possessed different
substitution patterns, produced syn-homopropargylic alcohols 56 in acceptable to high
yields upon coupling with a variety of carbonyl compounds 1 (Scheme 19). Both the nickel
catalyst and the phosphane ligands were found to play a crucial role in this transformation.
Diastereoselectivity was also strongly dependent on the ligand employed. Moreover, a
mechanistic sequence involving an umpolung of propargylnickel intermediates under
the influence of low-valent indium was proposed, to account for the dependence of the
stereochemical characteristics of the phosphane ligands (entry 2) [89].
2.1.6. With Methylene-Active Propargyl Compounds

Despite extensive studies on gold catalysis, σ-allenylgold species have not been in-
voked as catalytic intermediates and their reactivities remain to be studied. In a recent
study, the formation of an in situ-generated σ-allenylgold was proposed via soft propar-
gylic deprotonation of the methylene-active derivatives 57, mediated by the isomerization
of an alkyne to an allene. The σ-allenylgold species formed from 57 underwent nucle-
ophilic addition to the activated aldehydes 1 in bifunctional biphenyl-2-ylphosphine (L1)
ligand-enabled gold catalysis. This development revealed a broad range of opportunities to
achieve the propargylic C−H functionalization of 57 under catalytic and mild conditions,
producing homopropargyl alcohol intermediates 58 (Scheme 20). Subsequently, the result-
ing homopropargyl alcohols 58 underwent ligand-enabled cycloisomerization, involving
an unexpected silyl migration process, to deliver dihydrofurans 59 as isolated products [90].
Scheme 20. Gold-catalyzed synthesis of homopropargyl alcohol intermediates 58 from propargyl

methylene-active derivatives 57 and aldehydes 1.
2.1.7. With 1,3-Enynes

While most methods for enantioselective carbonyl propargylation promote the for-
mation of the parent α-unsubstituted homopropargylic alcohols, less attention has been
devoted to the development of diastereo- and enantioselective propargylation protocols
that generate useful (α-methyl)homopropargyl alcohols [91]. Under the conditions of
ruthenium-catalyzed transfer hydrogenation, employing isopropanol as a source of hydro-
gen, unprotected isopropoxy-substituted enyne 60 and aldehydes 1 engaged in reductive
coupling to provide propargylation product (α-methyl)homopropargyl alcohols 61 with
good to complete levels of anti-diastereoselectivity (Scheme 21). Remarkably, it was found
that the unprotected tertiary hydroxy moiety of isopropoxy enyne 60 is required in or-
der to enforce diastereoselectivity. Moreover, deuterium-labeling studies corroborated
Molecules 2023, 28, 3379 14 of 61
reversible enyne hydrometalation in advance of carbonyl addition. Additionally, it was

demonstrated that the isopropoxy group of products 61 could be readily cleaved upon
exposure to aqueous sodium hydroxide to reveal the terminal alkyne functionality [92].
Scheme 21. Ru-catalyzed synthesis of (α-methyl)homopropargyl alcohols 61 from enyne 60 and

aldehydes 1.
2.1.8. With Aryl-Acetylenes

The Favorskii reaction, which involves the nucleophilic addition of alkynes to alde-
hydes in the presence of a strong base, has been recognized as an efficient synthetic
strategy to produce propargyl alcohols and α,β-unsaturated ketones [93]. Direct propargy-
lation/alkenylation via the allenol-enone isomerization sequence through the activation
of the C-H bond in terminal alkynes, without a transition metal and employing a weak
base, represents a challenging research area. In response to this, a fast and efficient tran-
sition metal-free, modified Favorskii-type direct alkynylation protocol for the synthesis
of propargyl alcohols 63/65 was developed using a combination of Cs2 CO3 and TEA as
weak bases (Scheme 22). Aliphatic aldehydes 1 (R1 = H) produced propargyl alcohols 63,
while cyclic ketones 64 furnished propargyl alcohols 65. The operationally simple protocol,
wide substrate scope, and gram-scale synthesis represent key aspects of this methodol-
ogy. A plausible mechanism for this transformation involving the weak base-assisted
propargylation of carbonyl compounds 1 was suggested [94].
Scheme 22. Favorskii-type direct propargylation of carbonyl compounds 1 for the synthesis of
propargyl alcohols 63/65 using a combination of Cs2 CO3 and TEA as weak bases.
(b) Hemiacetals
The development of copper(I)-catalyzed stereodivergent anomeric propargylation of
unprotected aldose 66 was established as a facile synthetic pathway to a broad variety
of sialic acid derivatives 69, via a key propargylation intermediate 68 (Scheme 23). The
reaction proceeded with the in situ formation of a soft allenylcopper(I) species, catalytically
generated from the stable allenylboronic acid pinacolate 2c. It was also observed that the
addition of B(OMe)3 facilitated the ring-opening of the non-electrophilic cyclic hemiacetal
form of aldose 66 to reach its corresponding open-chain reactive aldehyde form 67, subse-
quently leading to the formation of the key intermediate 68. This synthetic method, which
required no protecting groups, could be performed at the gram-scale, offering general and
practical access to various sialic acid derivatives from unprotected-type aldoses 66 [95].
Molecules 2023, 28, 3379 15 of 61
Scheme 23. Copper(I)-catalyzed stereodivergent anomeric propargylation of unprotected aldose 66

with allenylboronic acid pinacolate 2c.
In a similar way, copper(I)-catalyzed stereodivergent nucleophilic propargylation

at the anomeric carbon of unprotected N-acetyl mannosamine 70 was devised using 3-
substituted allenylboronates 2c as nucleophiles (Scheme 24). The homopropargylic alcohol
products 71 and 72 containing two contiguous stereocenters, and two stereoisomers out
of the four possible isomers, were selectively obtained in a catalyst-controlled manner by
applying either basic conditions (a MesCu/(R,R,R)-Ph-SKP catalyst with a B(OiPr)3 addi-
tive) or acidic conditions (a CuBF4 /(S,S,S)-Ph-SKP catalyst with an MeB(OiPr)2 additive).
In the following two steps, the propargylation products 71 and 72 were transformed into
C3-substituted sialic acids without the use of protecting groups [96].
Scheme 24. Copper(I)-catalyzed stereodivergent nucleophilic propargylation of the unprotected

N-acetyl mannosamine 70 using 3-substituted allenylboronates 2c as nucleophiles.
2.2. (a) Imines, (b) Iminium, and (c) Azo Compounds

(a) Imines
The addition of organometallic reagents to imines is one of the most useful and
versatile methodologies for creating both a new carbon–carbon bond and new amine
functionality [97]. When a propargyl organometallic reagent is used [98], via diverse
synthetic strategies, the process offers the possibility for further transformation of the
unsaturation to form more carbon–carbon or carbon–heteroatom bonds [99], thus giving
practical use to this synthetic approach.
2.2.1. With Propargyl Halide/Metal Reagents

The enantio- and/or diastereoselective version of the propargylation of imines is
of additional interest because at least one new stereogenic center is created [100]. More-
over, α- or γ-substitution in the imine reagent could also induce chemoselectivity in this
process because the propargyl moiety could be selectively added to the structure of the
product [101]. Using this approach, the diastereoselective Barbier-type addition of allyl
halides to chiral sulfinylimines 73, promoted by indium metal [102], resulted in the forma-
tion of chiral N-protected homoallylic amines in good yields and % dr. More specifically, the
reaction of different chiral imines 73, derived from aldehydes or ketones, with the silylated
propargyl bromide 19a under sonication, in the presence of indium metal, led mainly or
exclusively to the formation of protected homopropargylamines 74 in a diastereoselective
manner (Scheme 25, entry 1). Of special interest in this process are the ketimine derivatives
Molecules 2023, 28, 3379 16 of 61
73 (derived from ketones) because the new stereocenter has a quaternary configuration.
Further, selective deprotection of the two protecting groups (TMS and sulfinyl moieties)
was accomplished using conventional methods [103].
Scheme 25. Diverse synthetic approaches of homopropargylamines 74 to the reaction of chiral

sulfinylimines 73 and the silylated propargyl bromide 19a.
In another approach, a highly efficient method for the asymmetric synthesis of a

wide range of quaternary carbon-containing homopropargylic amines 74 via the Zn-
mediated asymmetric propargylation of N-tert-butanesulfinyl ketimines 73 was reported
(Scheme 25, entry 2). In this approach, the ketimines 73 were readily prepared accord-
ing to known procedures [104], producing products 74 in good yields and with high
diastereoselectivities [105].
A series of enantioenriched homopropargylic amines 74 were obtained in good yields
and with excellent diastereomeric ratios via the indium-mediated N-propargylation of
chiral N-tert-butanesulfinyl ketimines 73 using trimethylsilylpropargyl bromide 19a, in
the presence of indium metal, under sonication (Scheme 25, entry 3). Further, the chi-
ral amines 74 were used as starting materials to obtain access to 3-substituted 1,2,3,4-
tetrahydroisoquinoline derivatives in their enantioenriched form [106].
A Zn-mediated propargylation/lactamization cascade reaction with chiral
2-formylbenzoate-derived N-tert-butanesulfinyl imines 73 (R = aryl, R1 = H) was real-
ized, as described in Scheme 26. In this strategy, sulfinyl amines 75 were obtained as
intermediates, providing a practical and efficient method for the synthesis of chiral isoin-
dolinones 76. Moreover, high diastereoselectivities and good reaction yields were observed
for the majority of the examined cases [107].
Scheme 26. Zn-mediated propargylation/lactamization cascade reaction of chiral 2-formylbenzoate-

derived N-tert-butanesulfinyl imines 73 and silylated propargyl bromide 19a.
An efficient approach to the synthesis of α,α-bispropargyl-substituted amines 78 in ac-

ceptable yields was achieved via Zn-promoted aza-Barbier-type reactions of N-sulfonyl im-
idates 77 with various propargyl reagents 19a (Scheme 27, entry 1). The synthetic utility of
this approach was demonstrated via the rapid construction of pyrrolidine derivatives [108].
In a similar way, a one-pot method for the synthesis of homopropargylic N-sulfonylamines
79 from aldehydes catalyzed by zinc powder was described. The imine derivatives 77 were
obtained in situ as intermediates from a reaction between the corresponding aldehydes 1
and TsNH2 in the presence of BnBr and Zn. This procedure offers simplicity, good yields,
and was shown to be applicable to a variety of aldehydes (Scheme 27, entry 2) [109].
Molecules 2023, 28, 3379 17 of 61
Scheme 27. Zn-promoted synthesis of mono and α,α-bispropargyl-substituted amines 79/78 from
N-sulfonyl imidates 77 and various propargyl reagents 19a.
The synthesis of 3-propargylated 3-aminooxindoles 81 was carried out via the zinc-
mediated propargylation of isatin-derived imines 80 (Scheme 28). This approach avoided
the use of catalysts, severe reaction conditions, multistep procedures, and reaction addi-
tives. To demonstrate its synthetic utility, different isatin-derived imines 80 and propargyl
bromide 19a were used to obtain products 81 in good yields [110].
Scheme 28. Zinc-mediated propargylation of isatin-derived imines 80 using propargyl bromide 19a
as propargylation reagent.
2.2.2. With Propargyl/Allenyl Boron Reagents

Expanding the available methods for the synthesis of homopropargylic amines, zinc-
catalyzed diastereoselective propargylation of tert-butanesulfinyl imines 73 using propargyl
borolanes 2a was reported (Scheme 29, entry 1). This method produced both aliphatic and
aryl homopropargylic amines 74 in acceptable to good yields and with good stereoselectiv-
ity. The utility of the homopropargylic amines 74 was demonstrated in the synthesis of a
cis-substituted pyrido-indole through diastereoselective Pictet-Spengler cyclization [111].
Scheme 29. Propargyl-/allenylboron-mediated synthesis of diverse propargyl derivatives 74/83/85/87

from imine substrates 73/82/84/86. In entries 2 and 3, the synthetic equivalent allenyl-Bpin 2c was
used instead propargyl-Bpin 2a.
Allenylborolane 2c (instead of propargyl borolane 2a) was employed in the enan-

tioselective Ag-catalyzed propargylation of N-sulfonylketimines 82 (Scheme 29, entry 2).
The reaction was compatible with a wide variety of diaryl- and alkylketimines 82, pro-
ducing their respective homopropargylic sulfonamides 83 in high yields and in excellent
enantiomeric ratios. It was also found that both propargyl and allenylborolane reagents
Molecules 2023, 28, 3379 18 of 61
(2a and 2c) could be used to obtain homopropargylic products 83, and a mechanism in-
volving transmetalation of the borolane reagent 2c with a silver catalyst was proposed.
Further, the homopropargylic products 83 were used as starting materials to elaborate
diverse products of higher complexity with high stereochemical fidelity, including enyne
ring-closing metathesis, Sonogashira cross-coupling, and reduction reactions [112].
The catalytic asymmetric propargylation of 3,4-dihydro-β-carboline 84 with allenyl-
borolane 2c (instead of propargyl borolane 2a) was investigated (Scheme 29, entry 3).
Optimization of the reaction conditions in the presence of CuCl and (R)-DTBM-SEGPHOS
ligands gave chiral scaffolds 85 with reproducible results, good yields, and high ee values.
Further transformations of 85 via designed Au(I)/Ag(I)-mediated 6-endo-dig cyclization
directly delivered the indolenine-fused methanoquinolizidine core of the akuammiline
alkaloid strictamine in its native oxidation state [113].
The copper-catalyzed asymmetric propargylation of cyclic aldimines 86 was also re-
ported. Asymmetric propargylation of a diverse series of N-alkyl and N-aryl aldimines
86 with propargyl borolanes 2a was achieved, producing the corresponding chiral propar-
gylamine scaffolds 87 with good to high asymmetric induction (Scheme 29, entry 4). The
utility of products 87 was further demonstrated via titanium-catalyzed hydroamination and
reduction to generate the chiral indolizidines (−)-crispine A and (−)-harmicine alkaloids.
Moreover, the influence of the trimers of imines 86 on inhibiting the reaction was identified,
and equilibrium constants between the monomers 86 and their trimers were determined
for general classes of imines [114].
2.2.3. With Propargyl/Allenyl-MX reagents

The diastereoselective synthesis of enantiopure homopropargylic amines 74 via the
propargylation of various N-tert-butylsulfinylimines 73 with 1-trimethylsilyl allenylzinc
bromides 88 was achieved (Scheme 30, entry 1). In this approach, the full conversion of
imines 73 was observed when two equivalents of Zn derivatives 88 were used, giving
homopropargylic amines 74 as single isomers in very good isolated yields [115].
The fluorinated analogs of tert-butanesulfinyl imines 73 were considered convenient
precursors for a synthetic route to obtaining enantioenriched fluorinated monoterpenic
alkaloid analogues via a Pauson–Khand cyclization reaction [116]. In this approach, di-
astereoselective propargylation of 73 was implemented as the key step to introducing
the chiral information necessary for the rest of the synthetic sequence to be performed.
In the first assay, the addition of propargyl magnesium bromide 89 to sulfinyl imine 73
(R = CF3 ) in DCM resulted in the formation of homopropargylamine 74 (R = CF3 ) with
low diastereoselectivity. When DCM was replaced with THF, not only was the diastereose-
lectivity vastly improved, but the major diastereoisomer was actually the opposite of the
one observed in DCM. Following the latter reaction conditions, sulfinyl amines 74 were
obtained in good yields with high diastereoselectivity (Scheme 30, entry 2).
The dramatic effect of the solvent in this type of transformation was attributed to
differing transition states depending on the nature of the solvent, but it was also suspected
that the strong electron-withdrawing characteristics of the fluorinated groups of substrates
73 played a role in increasing the reactivity of the imines 73 and decreasing the difference in
energy between the two transition states in non-coordinating solvents such as DCM [116].
Scheme 30. Diastereoselective synthesis of enantiopure homopropargylic amines 74 via propargyla-

tion of sulfinylimines 73 with allenylzinc/propargylmagnesium bromides 88/89.
Molecules 2023, 28, 3379 19 of 61
2.2.4. With Imino-Masked Propargyl Reagents

Whereas the development of methods for the α-alkylation of carbonyl compounds
has advanced tremendously in recent years, catalytic enantioselective α-propargylation is
relatively less developed [117,118]. In response to this, a two-step reaction sequence for the
asymmetric formal α-propargylation of ketones was introduced (Scheme 31). This approach
took advantage of the amino-catalyzed conjugate addition of ketones to alkylidene isoxazol-
Molecules 2023, 28, x FOR PEER REVIEW 20 of 65
5-ones, producing intermediates 90/91, which, through a controlled nitrosative degradation
event, produced α-propargyl ketones 92/93 in moderate to good yields, with perfect di-
astereocontrol, good to excellent enantioselectivity, and broad structural scope [119].
O Ph O Ph 8 examples
Ph
O Ph O Ph (41–66%)
8 examples
R Ph R
N Aryl; R1 = H, Me
R = Alkyl,(41–66%)
R R1 O N
R R1 Ph R = Alkyl, Aryl; R1 = H, Me
R1O O FeSO4 7H2O, NaNO2 92R1 Ph
90O 15 examples
FeSO 92
90 AcOH,4 7H 2O,min
rt, 30 NaNO2
(10–82%)
O R 15 examples
O R R1 AcOH, rt, 30 min
R X = CH2, (CH(10–82%)
2)2, (CH2)3, CH2NCO2Et,
O R R1 O
X =CH
CH22CMe
, (CH )2, (CH
2,2CH 2C(O2)23C
, 2CH
H42)NCO2Et,
N
X X R1 R = Ph,CH 2CMe
Aryl, 2, CH2C(O
2-Naphth, 2C2H4)
cyclopropyl,
O N
X O X 93 R1 R =2-furanyl
Ph, Aryl, 2-Naphth, cyclopropyl,
91 O
O 93 R1 = Ph,
2-furanyl
Aryl, 2-Naphth, iPr
91
R1 = Ph, Aryl, 2-Naphth, iPr
Scheme 31. Fe-catalyzed enantioselective synthesis of α-propargyl ketones 92/93 via controlled ni-
Scheme31.
Scheme
trosative 31. Fe-catalyzed
degradation enantioselective
enantioselective
of the synthesis
synthesisofof90/91.
alkylidene isoxazol-5-ones α-propargyl
α-propargylketones
ketones92/93 viavia
92/93 controlled ni-
controlled
trosative degradation of the alkylidene isoxazol-5-ones 90/91.
nitrosative degradation of the alkylidene isoxazol-5-ones 90/91.
(b) Iminium Compounds
(b) Iminium
(b) IminiumCompounds
Compounds
2.2.5. With Propiolic Acids
2.2.5.
2.2.5.With
WithPropiolic
PropiolicAcidsAcids
Thermal-induced transition metal-catalyzed decarboxylative coupling reactions are
Thermal-induced
Thermal-induced
recognized as a powerful transition
tool in metal-catalyzed
transition metal-catalyzed
organic synthesis decarboxylative
and medicinalcoupling
decarboxylative chemistryreactions
coupling as they are
reactions are
re-
recognized
recognized
quire as
simpleas a powerful
a powerful
operation tool
andtool in organic
in organic
produce CO2 as synthesis
synthesis and medicinal
and medicinal
a byproduct chemistry
[120–122].chemistry as they
Based onasprevious re-
they re-
quire
quire simple
simple operation
operation and
and produce
produce CO
CO 2 2as
asa abyproduct
byproduct [120–122].
[120–122].
works in which dipropargylic amines were obtained as side products mediated by isobu- Based
Based onon previous
previous
works
worksininwhich dipropargylic
tylboronic which
acid reagents [123],amines
dipropargylic amines
the were
were
expansion obtained
of thisas
obtained side
as products
side
chemistry led tomediated
products mediated
the by by
isobutyl-
development isobu-
of
boronic acidacid
reagents [123], thetheexpansion of this chemistry ledled to the development of a
a more flexible approach for the synthesis of dipropargylic amines from primary amines,of
tylboronic reagents [123], expansion of this chemistry to the development
more
a moreflexible approach
flexible approach forfor
the
the synthesis
synthesis ofofdipropargylic
amines from
from primary
primary amines,
amines,
formaldehyde, and propiolic acids under metal-free conditions. After assaying different
formaldehyde,
formaldehyde, and propiolic
andapropiolic acids
acids under
under metal-free
metal-free conditions.
conditions. After assaying different
reaction conditions, method in which a mixture of amine 94 (R1 = After
H), assaying different
1 = formaldehyde, and
reaction
reaction conditions,
conditions, aa method
method in inwhich
whichaamixture
mixtureofofamine
amine94 94
(R 1(R= H), H), formaldehyde,
formaldehyde, and
propiolic acid 95 in DCE was heated in a sealed tube produced optimal yields of the target
and propiolic
propiolic acid acid
95 in95
DCE in was
DCEheated
was heated
in a in a tube
sealed sealed tube produced
produced optimal optimal
yields of yields
the of
target
dipropargylic amines 96 (Scheme 32). The method exhibited a broad range of functional
the target dipropargylic
dipropargylic amines amines 96 (Scheme 32). The method exhibited a broad range of
group compatibility for96 (Scheme
primary 32). The
amines method
94 and exhibited
propiolic acidsa95,
broad and range of functional
produced the cor-
functional group compatibility
group compatibility forin primary for primary94 amines 94 and propiolic acids 95, and produced
responding products 96 low to amines and propiolic
excellent yields [124]. acids 95, and produced the cor-
the
responding products 96 in low to excellent yields [124]. [124].
corresponding products 96 in low to excellent yields
Scheme 32. Three-component

Three-componentsynthesis
synthesisofof
dipropargylic 96 mediated
amines by aby
96 mediated thermally induced
a thermally in-
Scheme
duced 32. Three-component
metal-free
metal-free decarboxylative
decarboxylative synthesis ofprocess.
transition
transition process.dipropargylic amines 96 mediated by a thermally in-
duced metal-free decarboxylative transition process.
2.2.6. With
2.2.6. With Acetylene
Acetylene Derivatives
Derivatives
2.2.6.AWith Acetylene Derivatives
series
A series of N-heterocyclic
of silylene-stabilized monocoordinated
N-heterocyclic silylene-stabilized monocoordinated Ag(I) Ag(I) cationic
cationic com-
com-
plexes weakly
plexesAweakly bound
series of to free arene
N-heterocyclic
bound rings (C H ,
silylene-stabilized
to free arene C Me
rings (C66H66, C66Me , and C H
monocoordinated ) were
66, and C77H88) were synthesized,
Ag(I) and
cationic com-
synthesized, and
the
the efficacy
plexes
efficacyweaklyof these
bound
of these electrophilic
to free arene
electrophilic Ag(I)
Ag(I) complexes
rings (C6H6, C
complexes as
as6Me catalysts was investigated toward
6, and C7H8) were synthesized, and
catalysts was investigated toward A3-
3 -coupling reactions, producing a series of propargylamines 97 in good to excellent yields3
Athe
coupling reactions, producing a series of propargylamines 97 was
efficacy of these electrophilic Ag(I) complexes as catalysts in goodinvestigated toward
to excellent A-
yields
in a tricomponent
coupling reaction
reactions, of amines
producing a series acetylenes
94, of 62, and polyformaldehyde
propargylamines 97 in good to (Scheme
excellent 33).
yields
in a tricomponent reaction of amines 94, acetylenes 62, and polyformaldehyde (Scheme
The process
in aThe was accompanied
tricomponent ofby the in94,
situ formation62, of an iminium species from(Scheme
94 and
33). process wasreaction
accompanied amines
by the inacetylenes
situ formationand polyformaldehyde
of an iminium species from 94
polyformaldehyde.
33).polyformaldehyde. The best
The process was accompanied results were obtained
by thewere
in situ when
formation catalyst
of an A was
iminium used, with
species low
from 94
and The best results obtained when catalyst A was used, with
catalyst
and loading under solvent-free
polyformaldehyde. The best conditions
results were [125].
obtained when catalyst A was used, with
low catalyst loading under solvent-free conditions [125].
plexes weakly bound to free arene rings (C6H6, C6Me6, and C7H8) were synthesized, and
the efficacy of these electrophilic Ag(I) complexes as catalysts was investigated toward A3
coupling reactions, producing a series of propargylamines 97 in good to excellent yield
in a tricomponent reaction of amines 94, acetylenes 62, and polyformaldehyde (Schem
33). The process was accompanied by the in situ formation of an iminium species from 9
Molecules 2023, 28, 3379 and polyformaldehyde. The best results were obtained when catalyst A was 20 of 61
used, with

Scheme 33.Scheme
of 33.
Synthesis
A library Synthesis
of ofoxazolidines
propargylamines
propargylamines
N-propargyl and97N,N-dipropargyl
97 mediated bymediated by N-heterocyclic
N-heterocyclic silylene-stabilized
silylene-stabilized
vicinal amino monoco-
alcohols mono
ordinated coordinated
Ag(I) cationicAg(I) cationicunder
complexed complexed under conditions.
solvent-free solvent-free conditions.
was prepared through a multicomponent reaction of formaldehyde, β-aminoalcohols 98,
and A library of62
acetylenes N-propargyl oxazolidines and A
using a copper-catalyzed N,N-dipropargyl
3-type-coupling vicinal
processamino alcohols
(Scheme 34).
was A library
prepared of N-propargyl
throughof oxazolidines
a multicomponent and N,N-dipropargyl
reaction vicinal amino alcohols
Whereas the presence bromide and chloride ionsofaccelerated
formaldehyde, β-aminoalcohols
the process toward open-98,
was
and prepared
acetylenesthrough a multicomponent
62producing
using reaction
a copper-catalyzed of formaldehyde,
A3-type-coupling β-aminoalcohols
process (Scheme 34).
ring alkynylation, dipropargylated products 99, the presence of the catalytic
98, and acetylenes 62 using a copper-catalyzed A3 -type-coupling process (Scheme 34).
Whereas
system Cu/Ithe favored
presencethe
of formation
bromide and chloride ions
of propargyl accelerated
oxazolidines 100the process toward open-
[126].
Whereas the presence of bromide and chloride ions accelerated the process toward open-
ring alkynylation, producing dipropargylated products 99, the presence of the catalytic
ring alkynylation, producing dipropargylated products 99, the presence of the catalytic
system Cu/I favored the formation of propargyl oxazolidines 100 [126].
system Cu/I favored the formation of propargyl oxazolidines 100 [126].
Scheme 34. Synthesis of N,N-dipropargyl aminoalcohols 99 and N-propargyl oxazolidines100 via

copper-catalyzed A3-type-coupling.
Scheme 34. Synthesis of N,N-dipropargyl
N,N-dipropargyl aminoalcohols 99 and N-propargyl
N-propargyl oxazolidines100 via
(c) Azo compounds
copper-catalyzed A33-type-coupling.
-type-coupling.
(c)
2.2.7.Azo
(c) Azo compounds
compounds
With Propargyl Halides
The addition of propargylic or allenylic metal reagents to azo compounds is a con-
2.2.7.
2.2.7. With Propargyl
With Propargyl Halides
Halides
venient method for the preparation of propargylic hydrazines [127,128]. Expanding on
The
The
earlier addition
theof
addition
studies, propargylic
ofBarbier-type or
orallenylic
allenylicmetal
propargylicpropargylation of reagents
metal reagents
azo totoazo
compounds azocompounds
compounds
101 is is
a conve-
a con-
with propargylic
nient
venientmethod
methodfor the preparation
for thereactive of
preparation propargylic hydrazines
of propargylic [127,128].
hydrazines Expanding on earlier
halides 19 that utilizes barium as a low-valent metal in[127,128]. Expanding
THF as solvent on
was re-
studies,
earlier the Barbier-type propargylation of azo compounds 101 with101propargylic halides
ported studies,
(Schemethe 35),Barbier-type
providing propargylation of azohydrazines
diverse propargylic compounds with propargylic
102 regioselectively in
19 that utilizes
halides 19tothat reactivereactive
utilizes barium barium
as a low-valent metal in
as a low-valent THFinasTHF
metal solvent was reported
as solvent was not
re-
moderate high yields. The corresponding α-adducts 102 were exclusively formed
(Scheme
ported 35), providing
(Scheme diverse propargylic
35), providing hydrazines
diverse propargylic 102 regioselectively
hydrazines in moderate
102 regioselectively in
only from azobenzenes (diaryldiazenes) but also from dialkyl azodicarboxylates. The
to high
moderate yields.
to The
high corresponding
yields. The α-adducts
corresponding 102 were
α-adducts exclusively
102 were formed not
exclusively only from
formed not
method was also applicable to γ-alkylated and γ-phenylated propargylic bromides 19.
azobenzenes
only fromthe (diaryldiazenes)
azobenzenes but also from
(diaryldiazenes) butdialkyl azodicarboxylates.
also from The method was
dialkyl azodicarboxylates. The
Notably, ester moieties of dialkyl azodicarboxylates remained unaffected by the bar-
also applicable
method was thus to applicable
also γ-alkylatedtoand γ-phenylated
γ-alkylated propargylic bromides
andpropargylated
γ-phenylated propargylic Notably, the
19. bromides 19.
ium reagent, providing the corresponding compounds 102 as unique
ester moieties of dialkyl azodicarboxylates remained unaffected by the barium reagent,
Notably,
products the ester moieties of dialkyl azodicarboxylates remained unaffected by the bar-
[129].
thus providing the corresponding propargylated compounds 102 as unique products [129].
ium reagent, thus providing the corresponding propargylated compounds 102 as unique
products [129].
Scheme 35. Barium-induced Barbier-type propargylation of azo compounds 101 with propargylic
halides 19.
Scheme 35. Barium-induced Barbier-type propargylation of azo compounds 101 with propargylic
2.3. Aryl
2.3. Aryl
halides and Heterocyclic
19.and Heterocyclic Derivatives
Derivatives
(a)
(a) Aryl
Aryl derivatives
derivatives
2.3. Aryl and Heterocyclic Derivatives
2.3.1.
(a) Withderivatives
2.3.1.Aryl
With Propargyl-TMS
Propargyl-TMS
Haloarenes
Haloarenes are
are of
ofgreat
greatsynthetic
syntheticinterest,
interest,since
sincethey
theyare used
are asas
used structural scaffolds
structural scaffoldsof
2.3.1. With
different
of different Propargyl-TMS
compounds
compoundsemployed in catalytic
employed chemistry,
in catalytic medicalmedical
chemistry, chemistry, and agrochemistry.
chemistry, and agro-
Due to this,
Haloarenesnew strategies
are of great have emerged
synthetic to
interest,obtain
since various
they are halogenated
used as
chemistry. Due to this, new strategies have emerged to obtain various halogenated aromatics,
structural for
scaffolds
aro-
example,
of differentthe insertion
compounds of a substituent in the ortho-position with respect to a pre-existing
matics, for example, the employed
insertion ofina catalytic chemistry,
substituent medical chemistry,
in the ortho-position and agro-
with respect to a
chemistry.
pre-existingDue to this,
halogen new In
group. strategies havethe
this context, emerged to obtain
synthesis various halogenated
of ortho-propargyl aro-
iodobenzenes
matics, for example,
104 represents the insertion
a desirable goal. Aofviable
a substituent in the
procedure ortho-position
to synthesize with
these respect toin-
derivatives a
pre-existing halogen group. In this context, the synthesis of ortho-propargyl iodobenzenes
volves reacting (diacetoxyiodo)arenes 103, previously activated with BF3, with a propar-
104 represents
gyl metalate 12 ausing
desirable goal. A viable
an ACN/DCM mixtureprocedure to synthesize
as solvent, these derivatives
to furnish ortho-propargyl in-
iodo-
volves reacting (diacetoxyiodo)arenes 103, previously activated with BF3, with a propar-
Molecules 2023, 28, 3379 21 of 61
halogen group. In this context, the synthesis of ortho-propargyl iodobenzenes 104 represents
a desirable
Molecules 2023, 28, x FOR PEER REVIEW goal. A viable procedure to synthesize these derivatives involves reacting 22 of 65
(diacetoxyiodo)arenes 103, previously activated with BF3 , with a propargyl metalate 12
using an ACN/DCM mixture as solvent, to furnish ortho-propargyl iodobenzenes 104 in
substrate
moderate 103 bearing
to high yieldsa (Scheme
single type36),ofasortho-CH
describedsite. The regioselectivity
in [130]. A striking featureis affected by the
of this protocol
substrate
electronic 103 bearing
environment a single type of
of propargylated ortho-CH
the iodoarene nucleus site. The regioselectivity is affected by the
is that it generates a singly product 103, andeach
104 for the substrate
method is103applicable
bearing atosingle
elec-
electronic environment
tron-deficient iodoarenes of the iodoarene nucleus 103, and the method is applicable to elec-
type of ortho-CH site. The103.
regioselectivity is affected by the electronic environment of the
tron-deficient iodoarenes 103.
iodoarene nucleus 103, and the method is applicable to electron-deficient iodoarenes 103.
Scheme 36. BF3-catalyzed synthesis of ortho-propargyl iodobenzenes 104 from (diacetoxy-

Scheme 36.
Scheme 36.BF
iodo)arenes BF
103 3-catalyzed
3 -catalyzed
and synthesis
synthesis
propargyl metalates of12.ortho-propargyl
of ortho-propargyl iodobenzenes
iodobenzenes 104 from104 from (diacetoxy-
(diacetoxyiodo)arenes
iodo)arenes 103 and propargyl
103 and propargyl metalates 12. metalates 12.
Synthetic access to ortho-propargylated arylsulfides, as in compounds 106, is also of
greatSynthetic
Synthetic accessa to
interest, since to ortho-propargylated
ortho-propargylated
variety arylsulfides,
of synthetic derivatives withasa in compounds
wide catalog of106, is also
also of
applicationsof
great
great
can interest,
beinterest,
produced since
since
froma variety
a variety of synthetic
of synthetic
these types derivatives
derivatives
of structures. with
Compoundswide a wide catalog
catalog
106 have of
been applications
of applications
synthesized
can
can be
be produced
produced from
from these
these types
types of
of structures.
structures. Compounds
Compounds
in good to excellent yields via a cross-coupling reaction between aryl-sulfoxide 106
106 have
have been
been synthesized
synthesized
105 and
in
in good
good to
to excellent
excellent yields
yields via
via a
a cross-coupling
cross-coupling reaction
reaction between
propargylsilanes 17, using Tf2O as an electrophilic activator and 2,6-lutidine as 105
between aryl-sulfoxide
aryl-sulfoxide baseand
and
in
propargylsilanes
propargylsilanes 17,
17,using
usingTfTf
2 O2Oas an
as electrophilic
an electrophilicactivator and
activator 2,6-lutidine
and
ACN (Scheme 37). The addition of 2,6-lutidine improved their reaction yields and pre- as
2,6-lutidinebaseas in ACN
base in
(Scheme
ACN 37).
(Scheme The
37).addition
The of
addition 2,6-lutidine
of improved
2,6-lutidine their
improved reaction
their
vented the formation of undesirable products via acid-mediated cyclization. A plausible yields
reaction and
yieldsprevented
and pre-
the formation
vented of undesirable
the formation productsproducts
via acid-mediated cyclization. A plausible mecha-
mechanism for this ofmetal-free
undesirable cross-couplingvia acid-mediated
process involves cyclization. A plausible
an interrupted
nism for this
mechanism for thismetal-free cross-coupling
metal-free process involves
cross-coupling an interrupted Pummerer/allenyl
Pummerer/allenyl thio-Claisen rearrangement, whereprocess involves
the formation an interrupted
of classic Pummerer
thio-Claisen rearrangement, where the formation of classic Pummerer products did not
products did not occur, even in the presence of electron-scavenging alkyl chainsPummerer
Pummerer/allenyl thio-Claisen rearrangement, where the formation of classic on sulfur.
occur,
products evendid in the presence
not occur, even of electron-scavenging
in the alkyl chains on sulfur. Hence, this
Hence, this methodology allows forpresence of electron-scavenging
the formation
2 3 of sp2-sp3 C-C bonds alkylinchains on sulfur.
products 106 in
methodology
Hence, this and allows for the
methodology formation
allows for theof sp -sp C-C
formation bonds
of sp 2-sp3 in products
C-C bonds in 106 in an efficient
products 106 in
an efficient regioselective manner [131].
and regioselective manner [131].
an efficient and regioselective manner [131].
Scheme 37. Synthesis ofo-propargylated

Synthesisof o-propargylatedarylsulfide derivatives
arylsulfide viavia
106106
derivatives sulfoxide-directed, metal-free
sulfoxide-directed, metal-
Scheme
free 37. Synthesis of
ortho-propargylation o-propargylated
of sulfoxides
ortho-propargylation of sulfoxides 105. arylsulfide
105. derivatives 106 via sulfoxide-directed, metal-
free ortho-propargylation of sulfoxides 105.
2.3.2. With
Propargyl Alcohols
Alcohols
2.3.2.The
With Propargyl Alcohols
nucleophilic substitution ofof the
the -OH
-OH group
group inin propargyl alcohols is is an
The nucleophilic substitution propargyl alcohols an efficient
efficient
methodology
The for the
nucleophilic preparation
substitutionof synthetic
of the -OH precursors,
group in which, due
propargyl to its
alcohols
methodology for the preparation of synthetic precursors, which, due to its versatility, versatility,
is an could
efficient
be further
methodology implemented
for the in synthetic
preparation of schemes
synthetic via alkyne
precursors, functionality
which, due
could be further implemented in synthetic schemes via alkyne functionality and the pos- and
to the
its possible
versatility,
addition
sible be of
couldaddition acetylides
further to different
of implemented
acetylides carbonyls.
in synthetic
to different However,
schemes
carbonyls. this type
via alkyne
However, of substitution
functionality
this type and theis chal-
of substitution pos-
is
lenging in aryl-propargyl
sible addition
challenging alcohols
of acetylides toalcohols
in aryl-propargyl due
differentdueto the low
carbonyls. reactivity
to the low However, of the
reactivitythis hydroxyl
type
of the as a leaving
of substitution
hydroxyl as a leav-is
group and the
challenging in formation of unwanted side
aryl-propargyl products,
lowasreactivity
well as polymers originating
as a from
ing group and the formation ofalcohols
unwanted dueside
to the
products, as wellofasthe hydroxyl
polymers leav-
originating
unstable/highly
ing group and the reactive carbocationic
formation intermediates. Theasviable alternative methods for
from unstable/highly reactive of unwanted
carbocationic side products,
intermediates. well
The as
viable polymers
alternative originating
methods
the
from preparation of propargyl derivatives, such as 108, via the nucleophilic substitution of
for theunstable/highly
preparation of reactive
propargylcarbocationic
derivatives,intermediates.
such as 108, via The
theviable alternative
nucleophilic methods
substitution
aryl-propargyl
foraryl-propargyl alcohols
the preparation 63 are highlighted
of propargyl in Scheme 38. via the nucleophilic substitution
of alcohols 63 are derivatives,
highlighted such as 108,
in Scheme 38.
of aryl-propargyl alcohols 63 are highlighted in Scheme 38.
Molecules 2023,
Molecules 2023, 28,
28, 3379
x FOR PEER REVIEW 2322of
of 65
61
Scheme 38. Metal- and heterobimetallic-catalyzed synthesis of diverse aryl-propargylated products

108 from38.
Scheme propargyl alcohols
Metal- and 63.
heterobimetallic-catalyzed synthesis of diverse aryl-propargylated products
from propargyl
108 from propargyl alcohols
alcohols 63.
63.
There is currently considerable interest in multi-metallic catalysis since it allows for
the design
There of specifically
is currently homogeneous
considerable hetero-bimetallic
interest in multi-metallic catalysts
catalysisthatsince
can facilitate
it allows thefor
activation
the design of different
design ofspecifically electrophiles
specificallyhomogeneous through
homogeneoushetero-bimetallic the stereoelectronic
hetero-bimetallic catalysts
catalysts characteristics
that cancan
that facilitate of
thetwo
facilitate ac-
the
metals
tivation
activationpresent in a single
of different
of different compound,
electrophiles
electrophiles throughthus promoting
the
through selective
stereoelectronic
the stereoelectronic binding
characteristics to aofsubstrate.
characteristics two ofmetals
twoIn
this
metalssense,
present in athe
present use
single ofsingle
hetero-bimetallic
in acompound, catalysts
thus promoting
compound, thus constitutes
selective
promoting bindingan alternative
selective tobinding tomethod
a substrate. In thisfor
a substrate. the
sense,
In
functionalization
the use of of
hetero-bimetallicpropargyl alcohols.
catalysts For
constitutes example,
an using
alternative an IrIII-SnI
method
this sense, the use of hetero-bimetallic catalysts constitutes an alternative method for the V catalyst
for the in 1,2-di-
functionaliza-
tion of propargyl
chloroethane
functionalization (DCE) alcohols. For alcohols.
as a solvent
of propargyl example,
enabledFor using an IrIII -SnI
theexample,
activation ofVpropargyl
using catalyst
an IrIII-SnIinalcohols
1,2-dichloroethane
V catalyst 63in(electro-
1,2-di-
(DCE)
philes), as
chloroethane a solvent
which(DCE)reactedenabled
aswith the activation
a series
a solvent of
of aromatic
enabled propargyl
nucleophiles
the activation alcohols 63
(Nu-H) 107
of propargyl (electrophiles), which
regioselectively,
alcohols 63 (electro-
reacted
to furnish
philes), with a series ofwith
aryl-propargylated
which reacted aromatic nucleophiles
derivatives
a series 108(Nu-H)
of aromatic with high
nucleophiles regioselectively,
107 turnover
(Nu-H)frequency to furnish
(TOF) aryl-
107 regioselectively, and
propargylated
with moderate derivatives
to good 108
yields with
(Scheme high turnover
38, entry 1)frequency
[132].
to furnish aryl-propargylated derivatives 108 with high turnover frequency (TOF) and (TOF)
Furthermore, and with
the moderate
direct propar- to
good
gylationyields
of (Scheme
arenes 107 38, entry
with 1)
propargyl[132]. Furthermore,
alcohols 63 was the direct
promoted
with moderate to good yields (Scheme 38, entry 1) [132]. Furthermore, the direct propar- propargylation
by SnCl 2 or of
Ce(OTf)arenes
3 in
107
MeNO with
gylation propargyl
2 as
ofaarenes
solvent. alcohols
107These 63 was promoted
withtransformations
propargyl by63
resulted
alcohols SnCl or
in2 high
was Ce(OTf)
selectivity
promoted 3byinSnCl
MeNO
toward
2 or2 as
thea propar-
solvent.
Ce(OTf) 3 in
These
gylated transformations
MeNO2 products
as a solvent. 108Theseresulted
(Scheme in high selectivity
38, entry 2 and
transformations toward
entry 3)
resulted the
in [133,134].propargylated products
high selectivity toward the propar- 108
(Scheme 38, entry108
gylated products 2 and entry 3)
(Scheme 38,[133,134].
entry 2 and entry 3) [133,134].
2.3.3. With Propargyl Fluorides
2.3.3. With Propargyl Fluorides
2.3.3.The
With Propargyl
Nicholas Fluorides
reaction has been employed as an alternative to circumvent the chal-
lenges The Nicholas
involved reaction
in reaction has been employed
the propargylation of arenes,as as
butan alternative to circumvent the chal-
The Nicholas has been employed anthis method has
alternative drawbacksthe
to circumvent because
chal-
lenges involved in the propargylation of arenes, but this method has drawbacks because
it uses involved
lenges Co2(CO6),inrequires several steps,
the propargylation ofand gives
arenes, butlowthisyields
method with has electron-poor
drawbacks because arenes.
it uses Co2 (CO6 ), requires several steps, and gives low yields with electron-poor arenes.
The ionization
it uses Co2(COof of propargyl fluorides 19 (X = F) in trifluoroacetic acid
6), requires several steps, and gives low yields with electron-poor arenes. (TFA) in a mixture
The ionization propargyl fluorides 19 (X = F) in trifluoroacetic acid (TFA) in a mixture of
of
TheDCM/HFIP
ionization asofsolvents
propargyl produced
fluorides products
19 (X108=108F) intrifluoroacetic
acceptable to excellent yieldsa(Scheme
DCM/HFIP as solvents produced products in in
acceptable acid (TFA)
to excellent yields in mixture
(Scheme 39),
39),
of thus providing
DCM/HFIP as a viable
solvents method to
produced directly108
products obtain
in a variety of
acceptable to substituted
excellent aryl-propar-
yields (Scheme
thus providing a viable method to directly obtain a variety of substituted aryl-propargyl
gyl
39),derivatives
thus providing 108 inviable
a Friedel–Crafts-type propargylation reaction [135].
derivatives 108 in a aFriedel–Crafts-type
method to directly obtain a variety
propargylation reactionof[135].
substituted aryl-propar-
gyl derivatives 108 in a Friedel–Crafts-type propargylation reaction [135].
Scheme 39. TFA-catalyzed synthesis of diverse aryl-propargyl

aryl-propargyl derivatives
derivatives 108
108 from
from the reaction of
propargyl fluorides 19 with arenes 107 in DCM/HFIP
DCM/HFIP solvent.
solvent.
Scheme 39. TFA-catalyzed synthesis of diverse aryl-propargyl derivatives 108 from the reaction of
propargyl fluorides 19 with arenes 107 in DCM/HFIP solvent.
2.3.4. With
Propargyl Phosphates
Phosphates
The
2.3.4.The copper-catalyzed
With direct
direct propargylation
Propargyl Phosphates
copper-catalyzed propargylationof of polyfluoroarenes
polyfluoroarenes107107(n(n== 44 and
and 5)
5) with
with
secondary
secondary propargyl phosphates
propargyl phosphates 109 that uses a
109 that uses a of strong
strong base, such as,
base, such as,tBuOLi
tBuOLi or THF,
or THF,asasa
The copper-catalyzed direct propargylation polyfluoroarenes 107 (n = 4 and 5) with
solvent has
asecondary been described.
solvent propargyl Using
has beenphosphates this method,
described.109Using a series
thisa strong of
method, propargylated
a such
series polyfluoroarenes
of propargylated
that uses base, as, tBuOLi or THF, as
108 were synthesized
polyfluoroarenes 108 in moderate
were to good
synthesized in yields, with
moderate to highyields,
good chemo- andhigh
with regioselectivity
chemo- and
a solvent has been described. Using this method, a series of propargylated
(Scheme 40). Furthermore, this reaction could also be extended to triethylsilyl- and tert-
polyfluoroarenes 108 were synthesized in moderate to good yields, with high chemo- and
butyl substituted alkynes [136].
Molecules 2023, 28, x FOR PEER REVIEW
ethylsilyl- and tert-butyl substituted alkynes [136].
Molecules 2023, 28, 3379

regioselectivity (Scheme 40). Furthermore, this reaction could also
23 of 61
be exte
ethylsilyl- and tert-butyl substituted alkynes [136].
Scheme 40. Synthesis of propargylated polyfluoroarenes 108 from secondary prop

109 in the presence of tBuOLi/CuOAc.
2.3.5. With Propargyl Cation Equivalents

Scheme 40. Synthesis of propargylated polyfluoroarenes 108 from secondary propargyl phosphates
Scheme 40. Synthesis of propargylated polyfluoroarenes 108 from secondary proparg
109 in Given
109 in the presencethe
the presenceprevalence
of tBuOLi/CuOAc. of the phenol motif in bioactive molecules, p
of tBuOLi/CuOAc.
and With
2.3.5. functional
Propargylmaterials [137],
Cation Equivalents a series of ortho-propargyl phenols 111 w
via Given
2.3.5.aWith
boron-catalyzed
thePropargyl
prevalence of sequential
the
Cationphenol procedure
motif
Equivalents in bioactivethrough
molecules,the addition of term
pharmaceuticals,
and2functional materials [137], a series of ortho-propargyl phenols 111 were synthesized
(R =Given
Aryl) theto substituted
prevalence phenols 110, bearing in
of the phenol congested quaternary carbo
via a boron-catalyzed sequential procedure through motif
the additionbioactive
of terminalmolecules,
alkynes 62 phar
Control
(R experiments
2 = Aryl) to
and functional materials
substituted combined
[137],
phenols with
a series
110, bearing DFT
of calculations
ortho-propargyl
congested quaternary suggested
phenols
carbons 111that
(Scheme 41). th
were
ceeds
Control
via via a sequential
experiments
a boron-catalyzedcombinedphenol
with DFTalkenylation/hydroalkynylation
sequential procedure through the additionprocess
calculations suggested that the reaction proceeds [13
of termina
via a sequential phenol alkenylation/hydroalkynylation process [138].
(R2 = Aryl) to substituted phenols 110, bearing congested quaternary carbons
Control experiments combined with DFT calculations suggested that the r
ceeds via a sequential phenol alkenylation/hydroalkynylation process [138].
Scheme 41. Boron-catalyzed sequential procedure for the synthesis of congested o-propargyl
Scheme 41. Boron-catalyzed sequential procedure for the synthesis of congested
phenols 111.
nols 111.
(b) Heterocyclic derivatives
(b) Indoles
(i)
Scheme Heterocyclic derivatives
41. Boron-catalyzed sequential procedure for the synthesis of congested o-p
nols 111.
(i) Indoles
2.3.6. With Propargyl Alcohols, Ethers, and Esters
N-Heterocyclic systems are important as building blocks of natural products, drugs,
(b)
2.3.6.
and Heterocyclic
With organic
functional Propargylderivatives
Alcohols,
materials, Ethers, and
and the development of Esters
mild and selective methods for
(i) Indoles
the direct introduction of propargyl groups into heterocyclic rings is highly desirable in
N-Heterocyclic systems are important as building blocks of natural p
order to access important and novel organic precursors.
andFocusing
functional organic
on indoles, Table materials, and theofdevelopment
4 provides a summary available methodsof formild and select
the synthe-
2.3.6.
sis
With Propargyl
of propargyl–indole
Alcohols,
hybrids 113
Ethers, and Esters
the direct introduction of via the reactiongroups
propargyl of indole into
derivatives 112 with diversely
heterocyclic rings is hig
N-Heterocyclic
substituted systems
propargyl derivatives are
54/63, important as
employing various
order to access important and novel organic precursors. building blocks
Lewis acids, of natural
zeolites, and prod
superacids, in molecular solvents, as well in ionic liquids (entries 1-7) [134,139–144].
and functional organic materials, and the development of mild and selective
Focusing onpropargylation
Enantioselective indoles, Table between 4 provides
indoles 112a andsummary
propargylof available
esters 54, cat- metho
the
alyzeddirect
by theintroduction
transition metal of propargyl
CuOTf • 1/2C H groups
, was into
reported heterocyclic
in the presence rings
of a is highly
chiral
thesis of propargyl–indole hybrids 6 6113 via the reaction of indole derivativ
order to access important
ligand ((4S,5R)-diPh-Pybox) and novel organic
in 4-methylmorpholine and precursors.
MeOH, leading to products 113
versely
in moderate substituted
to high propargyl derivatives 54/63,anemploying various Lewis
Focusing onyields, (TableTable
indoles, 4, entry 8) [145]. Likewise,
4 provides a summary asymmetric procedure
of available methods
anddescribed,
was superacids, in molecular
consisting of Friedel–Craftssolvents,
alkylationas well in
between ionic liquids
substituted indoles 112(entries
and 1-7)
thesis
propargyl ofcarbonates
propargyl–indole
54, in the hybrids
presence of 113 via
Ni(cod) andthethe reaction
chiral of(R)-BINAP
ligand indole derivatives
and
Enantioselective propargylation between indoles 112 and propargyl
2
versely substituted
a base, in toluene, forming propargyl derivatives
propargyl–indole derivatives54/63, employing
113 with various Lewis ac
high enantioselectivity
lyzed
and by the transition
regioselectively and in metal
moderate to CuOTf•1/2C
good yields (entry 6H6, was reported in the pres
9) [146].
and superacids, in molecular solvents, as well in ionic liquids (entries 1-7) [1
ligand ((4S,5R)-diPh-Pybox) in 4-methylmorpholine and MeOH, leading
Enantioselective propargylation between indoles 112 and propargyl es
in moderate to high yields,
lyzed by the transition metal (Table
CuOTf•1/2C4, entry 8) [145]. Likewise, an asymm
6H6, was reported in the presenc
was described,
ligand consisting of
((4S,5R)-diPh-Pybox) in Friedel–Crafts
4-methylmorpholine alkylation between
and MeOH, substitu
leading to
and propargyl carbonates 54, in the presence
in moderate to high yields, (Table 4, entry 8) [145]. Likewise, an asymmetrof Ni(cod) 2 and the chiral lig
and described,
was a base, in toluene,
consisting forming propargyl–indole
of Friedel–Crafts alkylationderivatives
between113 with hig
substituted
tivity
and and regioselectively
propargyl carbonates 54, and in moderate
in the presence of to Ni(cod)
good yields (entry 9) [146].
2 and the chiral ligan
Table 4. Diverse methodologies for the synthesis of propargyl–indole hybrids 113 from substituted
Molecules 2023, 28, 3379 propargyl derivatives 54/63 and indoles 112. 24 of 61
Table 4. Diverse methodologies for the synthesis of propargyl–indole hybrids 113 from substituted
propargyl derivatives 54/63 and indoles 112.
Chiral
Entry Conditions Number of Examples Yield (%) Ref.
Catalyst/Ligand
CeCl3 (30 mol%), ZnO (1 equiv.), MeNO2, reflux.
1 R = H, Me; R1 = H, R2 = H, OMe, Br, Aryl, R3 = Aryl; R4 = Me; R5 = ---- 12 28–88 [139]
Ph, alkyl; R6 = H
BF3•Et2O (5 mol%), ACN, rt 3 h. Chiral
Entry Conditions Number of Examples Yield (%) Ref.
2 ----
Catalyst/Ligand 1 91 [140]
R = Me; R1 = alkyl; R2 = H, R3 = Ph; R4: H, R5 = Ph; R6 = H
CeCl3 (30 mol%), ZnO (1 equiv.), MeNO2 , reflux.
Ce(OTf)3 (30 mol%)
1 R = H, Me; R1 = H, R2 = H, OMe, Br, Aryl, R3 = Aryl; R4 = Me; —- 12 28–88 [139]
3 MeNO 2, 40
R5 = Ph, °C, R
alkyl; R6 == H;
H R1 = H, R2 = H, R3 = Ph, M; R4 = Me; R5 = Ph; ---- 3 45–83 [134]
= H•Et O (5 mol%), ACN, rt 3 h.
R6BF
3 2
2 —- 1 91 [140]
Al(OTf)
R = Me; 3 (2R1 mol%),
= alkyl; R 2
ACN, R3 = Ph; R4 : H, R5 = Ph; R6 = H
= H, reflux.
4 R Ce(OTf)
= H, Me; R = H, Me; R = H, OMe, Cl; R = H, alkyl; R = Ph,
1
3 (30 mol%)
2 3 4 ---- 20 54–94 [141]
3 MeNO
Aryl; Ph,◦ C,
R5 2=, 40 R = H;RR
Butyl; 6 1==HH, R2 = H, R3 = Ph, M; R4 = Me; —- 3 45–83 [134]
R5 = Ph; R6 = H
Bi(NO3)3•5H2O, (10 mol%), (bmim)PF6.
5 R Al(OTf)
= H; R13=(2H, mol%),
Me; RACN,
2 = H,reflux.
F, Br, CN, NO2, OMe; R3 = H; R4 = Ph; ---- 15 81–94 [142]
4 R = H, Me; R1 = H, Me; R2 = H, OMe, Cl; R3 = H, alkyl; —- 20 54–94 [141]
R5R=4 H, Ph, SiCH 53; R6 = H
= Ph, Aryl; R = Ph, Butyl; R = H 6
Montmorillonite K-10, benzene, rt, 4 h.

Bi(NO3 )3 •5H2 O, (10 mol%), (bmim)PF6.
65 RR= H,
= H;Me;
R1 =RH, 1 = Ph, Aryl;
Me; R2 = H,RF,2 =Br,H, Cl,NO
CN, Me; R3 = H;3 R4 = Ph; R5 = Ph;
2 , OMe; R = H; —- ---- 15 8 81–9460–71 [143]
[142]
R6R=4 H= Ph; R5 = H, Ph, SiCH3; R6 = H
TfOH, dioxane. K-10, benzene, rt, 4 h.
Montmorillonite
76 1
R2R=3 =H,Ph; 3 4 ---- 1 60–71 92 [144]
RR = H, R
= 5Me; Me;1 =R
6
CHO;= Ph,RAryl;
2 = H, Cl, R
Me;
4= R
H, =RH;5 =R
Ph;= Ph;
R6 = H —- 8 [143]
R = Ph; R = H
7
CuOTf•1/2 C6H6, 4-methylmorpholine, MeOH, 0 °C.
TfOH, dioxane.
—- 1 92 54–93 [144]
8 RR = Me;
= H, R1 =Het;
alkyl, CHO; 2
R1R: H;
= H,
R2R
3
= Ph;
: Me, R4 = Cl;
OMe, H, RR53:=CF 6
Ph;3,RH,=alkyl,
H Ph; 26 [145]
(80–97% ee)
R = Aryl, Het; R = H; R = OC(O)C6F5
4 5 6
◦
CuOTf•1/2 C6 H6 , 4-methylmorpholine, MeOH, 0 C.
54–93
8 R = H, alkyl, Het; R1 : H; R2 : Me, OMe, Cl; R3 : CF3 , H, alkyl, 26 [145]
(80–97% ee)
Ph; R4 = Aryl, Het; R5 = H; R6 = OC(O)C6 F5
Ni(cod)2, iPr2NEt, toluene, 40 °C, 24 h.

41−89%
9 R = H; R1 = H; Ph, alkyl; R2 = ◦H, Br; R3 = Me, Et, PhCH2CH2; R4 = 24 [146]
Ni(cod)2 , iPr2 NEt, toluene, 40 C, 24 h. (97–99% ee)
9
= Aryl,
H,RR=5 H; alkyl, Het, Ph; R6 = Boc
R1 = H; Ph, alkyl; R2 = H, Br; R3 = Me, Et, PhCH CH ; 24
41−89%
[146]
2 2
(97–99% ee)
R4 = H, R5 = Aryl, alkyl, Het, Ph; R6 = Boc
2.3.7. With Allenyl Bromides

2.3.7. With Allenyl Bromides
A direct method for a C-H propargylation reaction of indole derivatives 112 using
A direct method
bromoallenes 19c (X =for
Br)a C-H propargylation
was reported, whichreaction of indole
employed derivatives
Mn(I)/Lewis acid112 using bro-
as cocatalyst
moallenes 19c (X = Br) was reported, which employed Mn(I)/Lewis acid as cocatalyst [147].
[147]. The presence of BPh3 not only promoted reactivity, but also enhanced selectivity.
The presence of BPh3 not only promoted reactivity, but also enhanced selectivity. Using
Using this method, secondary, tertiary, and even quaternary carbon centers in the propar-
this method, secondary, tertiary, and even quaternary carbon centers in the propargylic
gylic position could be directly constructed, leading to diversely substituted propargyl–
position could be directly constructed, leading to diversely substituted propargyl–indoles
indoles 114 in moderate to high yields (Scheme 42) [147].
114 in moderate to high yields (Scheme 42) [147].
Scheme 42. Direct Mn(I)/BPh co-catalyzedsynthesis

Mn(I)/BPh33co-catalyzed synthesisof
ofpropargyl–indoles
propargyl–indoles 114 using bromoallenes
114 using
19c as propargylating reagents.
reagents.
(ii) Other heterocyclic substrates
2.3.8. With Propargyl-TMS

The same approach as that described in Scheme 37 was adopted for the direct metal-
free ortho-propargylation of heteroaromatics 115 to produce o-propargylated heteroaromatic
Molecules 2023, 28, 3379 The same approach as that described in Scheme 37 was adopted for the direct metal- 25 of 61
The same approach as that described in Scheme 37 was adopted for the direct metal-
free ortho-propargylation of heteroaromatics 115 to produce o-propargylated heteroaro-
free ortho-propargylation of heteroaromatics 115 to produce o-propargylated heteroaro-
matic sulfides 116. Thus, mixtures of thiophenyl or furanyl sulfoxide 115, propargyl-TMS
matic sulfides 116. Thus, mixtures of thiophenyl or furanyl sulfoxide 115, propargyl-TMS
derivatives
sulfides 116.17, andmixtures
Thus, Tf2O were reacted in ACN
of thiophenyl as a solvent
or furanyl to 115,
sulfoxide produce products 116
propargyl-TMS regi-
deriva-
derivatives 17, and Tf2O were reacted in ACN as a solvent to produce products 116 regi-
oselectively
tives and
17, and Tf 2 Oin good
were to excellent
reacted in ACNyields (Scheme
as a solvent 43) [131].products 116 regioselectively
to produce
oselectively and in good to excellent yields (Scheme 43) [131].
and in good to excellent yields (Scheme 43) [131].
Scheme 43. Synthesis of o-propargylated heteroaromatic sulfides 116 via sulfoxide-directed, metal-
Scheme o-propargylated heteroaromatic
43. Synthesis of o-propargylated heteroaromatic sulfides
sulfides 116 via sulfoxide-directed,
116 via sulfoxide-directed, metal-
metal-
free ortho-propargylation of heteroaromatic sulfoxides 115.
free ortho-propargylation of heteroaromatic
heteroaromatic sulfoxides
sulfoxides 115.
115.
Following the approach described in Scheme 36, a method for the synthesis of ortho-
described in
Following the approach described in Scheme
Scheme 36,
36, aa method
method forfor the
the synthesis
synthesis of ortho-
of ortho-
propargyl iodothiophenes 119/120 was described [130]. In this case, a mixture of propar-
propargyl iodothiophenes
propargyl 119/120 was
iodothiophenes119/120 wasdescribed
described[130].
[130].InInthis
thiscase,
case,a mixture
a mixtureof of
propargyl-
propar-
gyl-TMS derivative 12, thiophenyliodine diacetates 117/118, and BF3•OEt2 in ACN/DCM
TMS derivative
gyl-TMS 12, thiophenyliodine
derivative 12, thiophenyliodine diacetates 117/118,
diacetates and BF
117/118, and3 •BF
OEt 2 in ACN/DCM
3•OEt 2 in ACN/DCM as a
as a solvent
solvent was was allowed
allowed to to react
react at at low
low temperature
temperature to to produce
produce products
products 119/120
119/120 regiose-
regioselec-
as a solvent was allowed to react at low temperature to produce products 119/120 regiose-
lectively,
tively, and
andand in good
in good yields
yields (Scheme
(Scheme 44)
44)44) [130].
[130].
lectively, in good yields (Scheme [130].
Scheme 44. BF
Scheme 44. BF33-catalyzed synthesis of ortho-propargyl
synthesis of ortho-propargyl iodothiophenes 119/120 from thiophenylio-
iodothiophenes 119/120
Scheme
dine 44. BF
dine diacetates 3-catalyzed synthesis of ortho-propargyl iodothiophenes 119/120 from thiophenylio-
diacetates 117/118
117/118 and propargyl metalates 12.
dine diacetates 117/118 and propargyl metalates 12.
2.3.9.
2.3.9. With
With Allenyl
Allenyl Bromide
Bromide
2.3.9.Following
With Allenyl Bromide
Following the proceduredescribed
the procedure describedin Scheme 42, propargylated
in Scheme pyrrole
42, propargylated and thiphene
pyrrole and thi-
Molecules 2023, 28, x FOR PEER REVIEW Following
derivatives the procedure
125–128 described
were obtained in Scheme
in acceptable 42, propargylated
to good pyrrole and
yields from bromoallenes thi-
19c
27 of 65
phene derivatives 125–128 were obtained in acceptable to good yields from bromoallenes
phene
(X derivatives
= Br), and the125–128 were obtained
corresponding in acceptable
heteroaromatic to good yields
precursors fromare
121–124 bromoallenes
shown in
19c (X = Br), and the corresponding heteroaromatic precursors 121–124 are shown in
19c (X =45Br),
Scheme and the corresponding heteroaromatic precursors 121–124 are shown in
[147].
Scheme 45 [147].
Scheme 45 [147].
DirectMn(I)/BPh
Scheme 45. Direct Mn(I)/BPh 3 co-catalyzed
3 co-catalyzed synthesis
synthesis of propargyl-heterocycles
of propargyl-heterocycles usingusing
125–128
125–128 bro-
moallenes 19c19c
bromoallenes as propargylating reagents.
as propargylating reagents.
2.3.10. With Propargyl Alcohols

Scheme 46 gives an overview of the reported methods for the synthesis of propar-
gylated heterocycles 134–139 using propargyl alcohols 63. A wide variety of catalytic sys-
tems have been employed, including hetero-bimetallic catalysts of IrIII-SnIV (entry 1) [132],
Pd-Sn bimetallic catalysts (entry 2) [148], Ce(OTf)3 (entry 3) [134], and boron Lewis acids
(entry 4) [149]. Doubly propargylated N-methylcarbazoles 136 were synthesized in
Molecules 2023, 28, 3379 Scheme 45. Direct Mn(I)/BPh3 co-catalyzed synthesis of propargyl-heterocycles 125–128 using bro-
26 of 61
moallenes 19c as propargylating reagents.

Scheme 46 gives an overview of the reported methods for the synthesis of propar-
Scheme
gylated 46 gives134–139
heterocycles an overview of the reported
using propargyl methods
alcohols for the
63. A wide synthesis
variety of propar-
of catalytic sys-
gylated heterocycles 134–139 using propargyl alcohols 63. A wideIII variety of catalytic
tems have been employed, including hetero-bimetallic catalysts of Ir -SnI (entry 1)
V [132],
systems have been employed, including hetero-bimetallic catalysts of IrIII -SnIV
Pd-Sn bimetallic catalysts (entry 2) [148], Ce(OTf)3 (entry 3) [134], and boron Lewis acids
(entry 1) [132], Pd-Sn bimetallic catalysts (entry 2) [148], Ce(OTf)3 (entry 3) [134], and
(entry 4) [149]. Doubly propargylated N-methylcarbazoles 136 were synthesized in
boron Lewis acids (entry 4) [149]. Doubly propargylated N-methylcarbazoles 136 were syn-
[BMIM][PF6]/TfOH (entry 5) [150], and [BMIM][BF4]/Sc(OTf)3 proved effective for the pro-
thesized in [BMIM][PF6 ]/TfOH (entry 5) [150], and [BMIM][BF4 ]/Sc(OTf)3 proved effective
pargylation of various classes of heterocycles under mild reaction conditions (entry 6)
for the propargylation of various classes of heterocycles under mild reaction conditions
[151].
(entry 6) [151].
1 1
R R R R
Het R2 R2
139 S
3 examples 134
R = H; R1 = Ph;
R = H; R1 = Ph; R2 = Ph; (74–89%) 72%
S R2 = Ph
Het = pyrrole, furan,
Het
[BMIM][BF 4]/ [Pd(COD)Cl–SnCl3] (2
130 129
Sc(OTf)3 mol%), MeNO2, 85 oC
Entry 6
1 Entry 2
R R O
Het 1
133 R R
R2 R1 130
R
O 138 Het R2
C6F5B(OH)2 HO [Ir(ì-Cl)(COD)Cl(SnCl 3)]2,
12 examples 135
(10 mol%), 4 Å MS, 63 R2 DCE (1 mL), 60 oC, 3 h 9 examples
(10–96%) DCM, rt, 16 h
Entry 1 (52–90%)
R = H; R1 = Aryl, Alkyl; Entry 4 R = H, Me; R1 = Me, Et;
R2 = Alkyl R2 = Ph; Het = pyrrole,
Ce(OTf)3 (30 mol%) TfOH (10 mol% ), N furan, thiophene
O 131
MeNO2, 40 °C (bmim)PF6, rt, 4–6 h
132 R
Entry 5 R1 R1
Molecules 2023, 28, x FOR PEER REVIEW R R
1
Entry 3
R2 R2
R2
O 137
R = Me; R1 = N
R = H, Me; R1 = Ph; R2 = Ph R 136
Aryl;
2 examples 14 examples
2.4. Acyl Halides R2 = Ph, Bu
(60–67%) (70–92%)
With Propargyl-Organolithium
Scheme 46. Different
46. Different synthetic Reagent
synthetic approaches to propargylated
propargylated heterocycles 134–139 using
using propargyl
propargyl
alcohols 63.
alcohols 63.
Homopropargyl and bis-homopropargyl alcohols are convenient interm
2.4. Acyl Halides
ganic synthesis [152]. Previous studies have established that the controlle
With Propargyl-Organolithium Reagent
allenes forms operational equivalents of propargyl dianions (C3H2Li2, 1,3-dil
Homopropargyl and bis-homopropargyl alcohols are convenient intermediates in
143 [153,154].
organic In this
synthesis [152]. vein,studies
Previous controlled dilithiation
have established ofcontrolled
that the propargyl bromide
lithiation of wit
lents forms
allenes of n-butyllithium, in the
operational equivalents presence
of propargyl of TMEDA,
dianions was reported to be
(C3 H2 Li2 , 1,3-dilithiopropyne)
143 [153,154]. In this vein, controlled dilithiation of propargyl bromide with two equivalents
method for the synthesis of bis-homopropargylic alcohols 142 (Scheme 4
of n-butyllithium, in the presence of TMEDA, was reported to be a productive method for
proach,
the dianion
synthesis 141 underwent
of bis-homopropargylic in situ
alcohols reactions
142 (Scheme 47). with
In this acid chlorides
approach, dianion 140 to
hols
141 142 in moderate
underwent yields
in situ reactions with
with acid high regioselectivity
chlorides 140 to produce alcohols [155].
142 in moderate
yields with high regioselectivity [155].
Scheme
Scheme Synthesis
47. 47. of bis-homopropargylic
Synthesis alcohols 142 from
of bis-homopropargylic 1,3-dilithiopropyne
alcohols 141 and acid
142 from 1,3-dilithiopropyn
chlorides 140.
chlorides 140.
2.5. Amine/Amide Derivatives

Scheme 48 gives an overview of the reported methods for the synthesi
gylamines 97/144 from secondary propargyl alcohols 63, utilizing SnCl2 in C
Scheme 47. Synthesis of bis-homopropargylic alcohols 142 from 1,3-dilithiopropyne 141 and acid
Molecules 2023, 28, 3379 Scheme 47.
chlorides Synthesis of bis-homopropargylic alcohols 142 from 1,3-dilithiopropyne 141 and
140. acid
27 of 61
chlorides 140.
2.5. Amine/Amide Alcohols
Derivatives
2.5.1.Scheme
With Propargyl
48 gives anAlcohols
overview of the reported methods for the synthesis of N-propar-
Scheme
gylamines 48 gives
97/144 an overviewpropargyl
from secondary of the reported methods for theSnCl
synthesisCHof3NO
N-propar-
Scheme 48 gives an overview of the alcohols
reported63,methods
utilizing 2 insynthesis
for the 2 (entry
of N-
gylamines 97/144
1) [133] and Sc(OTf)from secondary
3 in [BMIM][BF
propargyl
4] (entry
alcohols 63, utilizing
2) [151]alcohols
as catalysts. SnCl 2 in CH3NO2 (entry
propargylamines 97/144 from secondary propargyl 63, utilizing SnCl2 in CH3 NO2
1) [133]1)and
(entry Sc(OTf)
[133] 3 in [BMIM][BF4] (entry 2) [151] as catalysts.
and Sc(OTf) 3 in [BMIM][BF4 ] (entry 2) [151] as catalysts.
Scheme 48. Synthesis of N-propargylamines 97/144 from secondary propargyl alcohols 63.
Scheme 48. Synthesis of N-propargylamines 97/144 from secondary
secondary propargyl
propargyl alcohols
alcohols 63.
63.
Scheme 49 highlights an efficient tandem propargylation–cyclization–oxidation pro-
Scheme
Scheme 49 highlights an efficient
efficient tandem
tandem propargylation–cyclization–oxidation
propargylation–cyclization–oxidation pro-
pro-
cedure for the49synthesis
highlights
of an
diversely substituted pyrimidines 147 via propargylamine in-
cedure
cedure for the
for the synthesis
synthesisofofdiversely
diverselysubstituted
substituted pyrimidines
pyrimidines 147
147 viavia propargylamine
propargylamine in-
termediates 146, by reacting propargylic alcohols 63 with amidine 145 using copper(II)
intermediates
termediates 146, by reacting
146, by[156]. propargylic alcohols 63 with amidine 145 using copper(II)
reacting propargylic alcohols 63 with amidine 145 using copper(II)
triflate as a catalyst
triflate
triflate as
as aa catalyst
catalyst [156].
[156].
Scheme 49.
Scheme Cu-catalyzed
49.Cu-catalyzed synthesis
synthesis of propargylamine
of propargylamine intermediates
intermediates 146
146 from from propargylic
propargylic alcohols
Scheme
alcohols 49.
63 Cu-catalyzed
and amidine
63 and amidine 145. synthesis
145. of propargylamine intermediates 146 from propargylic alcohols
63 and amidine 145.
2.5.2. With Propargyl Bromide
2.5.2.Among
Molecules 2023, 28, x FOR PEER REVIEW With Propargyl Bromide
the nitrogen-containing fused heterocycles, quinoline, azepine, and triazole 29 of 65
Among the nitrogen-containing fused heterocycles, quinoline, azepine, and triazole
moieties are considered
Among privileged scaffolds,
the nitrogen-containing are present in quinoline,
fused heterocycles, numerous natural
azepine, products,
and and
triazole
moieties are considered privileged scaffolds, are present in numerous natural products,
are among
moieties arethe most widely
considered exploited
privileged heterocyclic
scaffolds, are rings for
present inthe development
numerous naturalof products,
bioactive
and are among the most widely exploited heterocyclic rings for the development of bio-
molecules
and are [157–159].
among the The widely
most propargylation
exploitedof heterocyclic
secondary amines
rings prepared
149,the
for via the of
development reduc-
reductive
active amination
molecules of 2-chloro-3-formylquinolines
[157–159]. The propargylation 148,
of secondary produced
amines tertiary
149, prepared viabio-
propargyla-the
tive amination
active 150
moleculesof 2-chloro-3-formylquinolines
[157–159]. Thefor
propargylation 148, produced tertiary propargylamines 150
mines as key intermediates the synthesisof ofsecondary amines 149,
fused-heterocyclic prepared
products 151,via the
incor-
as key intermediates for the synthesis of fused-heterocyclic products 151, incorporating
porating three active pharmacophores (quinoline, azepine and triazole) in a single molec-
three active pharmacophores (quinoline, azepine and triazole) in a single molecular frame-
ular framework [160]; this illustrates the potential of the N-propargyl moiety in heterocy-
work [160]; this illustrates the potential of the N-propargyl moiety in heterocyclic synthesis
clic synthesis (Scheme 50).
(Scheme 50).
Scheme
Scheme 50.
50. Synthesis
Synthesisofof
tertiary propargylamine
tertiary propargylamineintermediates 150150
intermediates through propargylation
through of sec-
propargylation of
ondary amines 149 with propargyl bromide 19a in the presence of calcium carbonate.
secondary amines 149 with propargyl bromide 19a in the presence of calcium carbonate.
Chiral N-tert-butanesulfinyl imines are important for the stereoselective synthesis of

nitrogen-containing heterocyclicsystems
nitrogen-containing heterocyclic systems[161].
[161].With
Withthethe
goalgoal of synthesizing
of synthesizing 3-substi-
3-substituted
tuted 1,2,3,4-tetrahydroisoquinolines
1,2,3,4-tetrahydroisoquinolines 153 in153 in an enantioenriched
an enantioenriched form, form, the N-propargyla-
the N-propargylation of
tion of enantioenriched
enantioenriched homopropargylic
homopropargylic amines 74amines 74 was performed
was performed under basicunder basic to
conditions condi-
give
tions to give the corresponding
the corresponding 4-azaocta-1,7-diyne
4-azaocta-1,7-diyne intermediates 152 intermediates
in fair to good152 in fair
yields to good
(Scheme 51).
yields (Scheme 51). An oxidation step, followed by [2+2+2] cyclotrimerization promoted
by a Wilkinson catalyst, produced the target structure 153 which contained substituents
at the 3-, 6- and 7-positions in high yields [106]. This illustrative example highlights the
efficacy of bis-homopropargylamine in heterocyclic synthesis.
ondary amines
Chiral 149 with propargyl bromide
N-tert-butanesulfinyl imines 19a
are in the presence
important for of
thecalcium carbonate. synthesis of
stereoselective
ondary amines 149 with propargyl bromide 19a in the presence of calcium carbonate.
nitrogen-containing heterocyclic systems [161]. With the goal of synthesizing 3-substi-
Chiral N-tert-butanesulfinyl imines are important for the stereoselective synthesis of
tutedChiral
1,2,3,4-tetrahydroisoquinolines
N-tert-butanesulfinyl imines 153are
in an enantioenriched
important form, the N-propargyla-
for the stereoselective synthesis of
nitrogen-containing heterocyclic systems [161]. With the goal of synthesizing 3-substi-
tion of enantioenriched
nitrogen-containing homopropargylic
heterocyclic systems amines 74 was
[161]. With the performed under basic3-substi-
goal of synthesizing condi-
tuted 1,2,3,4-tetrahydroisoquinolines 153 in an enantioenriched form, the N-propargyla-
Molecules 2023, 28, 3379 tions to give the corresponding 4-azaocta-1,7-diyne intermediates 152 in
tuted 1,2,3,4-tetrahydroisoquinolines 153 in an enantioenriched form, the N-propargyla- fair to good
28 of 61
tion of enantioenriched homopropargylic amines 74 was performed under basic condi-
yields
tion of(Scheme 51). An oxidation
enantioenriched step, followed
homopropargylic aminesby74[2+2+2] cyclotrimerization
was performed promoted
under basic condi-
tions to give the corresponding 4-azaocta-1,7-diyne intermediates 152 in fair to good
by a Wilkinson
tions to give the catalyst, produced4-azaocta-1,7-diyne
corresponding the target structureintermediates
153 which contained substituents
152 in fair to good
yields (Scheme 51). An oxidation step, followed by [2+2+2] cyclotrimerization promoted
at the 3-,
yields 6- and 51).
(Scheme 7-positions in high
An oxidation yields
step, [106]. This
followed illustrative
by [2+2+2] example highlights
cyclotrimerization promotedthe
An
by aoxidation
Wilkinson step, followed
catalyst, by [2+2+2]
produced cyclotrimerization
the target structure 153 promoted by a Wilkinson
which contained cat-
substituents
efficacy of bis-homopropargylamine
by a Wilkinson catalyst, produced the in heterocyclic synthesis.
target structure 153 which contained substituents
alyst,
at the produced the target structure
3-, 6- and 7-positions 153 which
in high yields [106].contained substituents
This illustrative exampleat highlights
the 3-, 6- andthe
at the 3-, 6- and 7-positions in high yields [106]. This illustrative example highlights the
7-positions in high yields [106]. This
efficacy of bis-homopropargylamine inillustrative
heterocyclicexample
synthesis.highlights the efficacy of bis-
efficacy of bis-homopropargylamine
homopropargylamine in heterocyclicin heterocyclic synthesis.
synthesis.
Scheme 51. Synthesis of 4-azaocta-1,7-diyne intermediates 152 through propargylation of homopro-

pargylic amines 74 with propargyl bromide 19a.
Scheme 51. Synthesis of 4-azaocta-1,7-diyne intermediates 152 through propargylation of homopro-
Synthesisofof4-azaocta-1,7-diyne
Scheme 51. Synthesis 4-azaocta-1,7-diyne intermediates
intermediates 152152 through
through propargylation
propargylation of homo-
of homopro-
pargylic
The amines 74 with propargyl
N-propargylation of bromide
vinyl 19a.
sulfoximines 154 with propargyl bromide 19a pro-
pargylic amines 74 with propargyl bromide 19a.
propargylic amines 74 with propargyl bromide 19a.
duced N-propargyl-sulfoximines 155 as highly functionalized biologically promising
The N-propargylation
N-propargylation of vinyl sulfoximines
sulfoximines 154
154 with
with propargyl
propargyl bromide
bromide 19a
19a pro-
smallThe
molecules (Scheme 52)of[162].
vinyl sulfoximines 154 with propargyl bromide 19a pro-
pro-
duced
duced N-propargyl-sulfoximines
N-propargyl-sulfoximines 155155
as as highly
highly functionalized
functionalized biologically
biologically promising
promising small
duced N-propargyl-sulfoximines 155 as highly functionalized biologically promising
small molecules
molecules (Scheme
(Scheme 52) [162].
52) [162].
small molecules (Scheme 52) [162].
Scheme 52. NaH-Catalyzed synthesis of N-propargyl-sulfoximines 155 via treatment of sul-

foximines 154 with propargyl bromide 19a.
Scheme 52.52.NaH-Catalyzed
NaH-Catalyzed synthesis of N-propargyl-sulfoximines
synthesis 155 via
of N-propargyl-sulfoximines treatment
155 of sulfoximines
via treatment of sul-
Scheme 52. NaH-Catalyzed synthesis of N-propargyl-sulfoximines 155 via treatment of sul-
foximines
154 with 154 with
propargyl propargyl
bromide
The N-propargylation bromide
19a. 19a.
foximines 154 with propargyl of substituted
bromide 19a. isatins 4 (R = H) was accomplished via a micro-
wave-assisted reaction using anhydrous K2CO3 as base in DMF solvent, according to
The N-propargylation
N-propargylationofofsubstituted isatins
substituted 4 (R
isatins 4=(RH) waswas
= H) accomplished via avia
accomplished microwave-
a micro-
SchemeThe53, to produce a setofofsubstituted
N-propargylation diversely substituted
isatins 4 (R =N-propargyl
H) was isatins 156via
accomplished in agood to
micro-
assisted reactionreaction
wave-assisted using anhydrous K2 CO3 as K
using anhydrous base
2COin DMF
3 as solvent,
base in DMFaccording to Scheme
solvent, according53, to
to
excellent yields
wave-assisted [163].
reaction
produce
Scheme a53, diverselyausing
settoofproduce anhydrous
substituted
set of diversely
K2CO3isatins
N-propargyl
substituted
as base
156in DMF tosolvent,
in good
N-propargyl
according
excellent
isatins 156 yields
to
[163].
in good to
Scheme 53, to produce a set of diversely substituted N-propargyl isatins 156 in good to
excellentOyields [163]. O
excellent yields [163]. Br
K2CO3
R1 R1
Molecules 2023, 28, x FOR PEER REVIEW O O
+ O O 30 of 65
NO Br MWI, DMF NO
R Br K2CO
5–7 min3
R1 4 O + 19a K2CO3 R1 156 O
R1 N O + (79–99%)
MWI, DMF R1 N O
1
R = H; R = RH, Me, Et, iPr, Cl, F, Br, I MWI, DMF 12 examples
N 5–7 min N
4 53.R 19a 156
Scheme 4 Microwave-assisted
19a 5–7 min
synthesis of substituted
156 N-propargyl isatins 156.
(79–99%)
Scheme
R = H; R1 =53. Microwave-assisted
H, Me, synthesis of12substituted
Et, iPr, Cl, F, Br, I (79–99%) examples N-propargyl isatins 156.
R = H; R1 = H, Me, Et, iPr, Cl, F, Br, I 12 examples
Similarly, a library of N-propargyl 4H-pyrano[2,3-d]pyrimidine derivatives 158 was
Similarly, a library of N-propargyl 4H-pyrano[2,3-d]pyrimidine derivatives 158 was
prepared through the N-propargylation of pyrano derivatives 157, under ultrasound-as-
prepared through the N-propargylation of pyrano derivatives 157, under ultrasound-
sisted reaction conditions via phase transfer catalysis, according to Scheme 54 [164].
assisted reaction conditions via phase transfer catalysis, according to Scheme 54 [164].
Scheme 54. Ultrasound-assisted synthesis of N-propargyl 4H-pyrano[2,3-d]pyrimidine derivatives

158 using TBAB as phase-transfer catalyst.
A procedure for the synthesis of a series of N-propargylated compounds 160a–f was

conducted, according
accordingto
toScheme
Scheme5555[165],
[165],using azazerumbone
using azazerumbone (159a), azazerumbone
(159a), azazerumbone oxides
ox-
(159b,c),
ides acridin-9(10H)-one
(159b,c), (159d), 7-methoxy-6-[3-(morpholin-4-yl)propoxy]quinazolin-
acridin-9(10H)-one (159d), 7-methoxy-6-[3-(morpholin-4-
4(3H)-one (159e), and murrayafoline
yl)propoxy]quinazolin-4(3H)-one A (159f)
(159e), as substrates. A (159f) as substrates.
and murrayafoline
Scheme 54. Ultrasound-assisted synthesis of N-propargyl 4H-pyrano[2,3-d]pyrimidine derivatives
158 using TBAB as phase-transfer catalyst.
A procedure for the synthesis of a series of N-propargylated compounds 160a–f was

conducted, according to Scheme 55 [165], using azazerumbone (159a), azazerumbone ox-
Molecules 2023, 28, 3379 29 of 61
ides (159b,c), acridin-9(10H)-one (159d), 7-methoxy-6-[3-(morpholin-4-
yl)propoxy]quinazolin-4(3H)-one (159e), and murrayafoline A (159f) as substrates.
Scheme 55. NaH-catalyzed

Scheme 55. synthesisofofN-propargylated
NaH-catalyzedsynthesis N-propargylatedheterocyclic compounds
heterocyclic using
160160
compounds propar-
using pro-
pargyl
gyl bromide
bromide 19a 19a as propargylating
as propargylating agent.
agent.
A
A series
series of
of nucleobase
nucleobase derivatives 165–168 were
derivatives 165–168 were synthesized
synthesized via
via the
the propargylation
propargylation
of
of DNA nucleobases 161–164 according to Scheme 56, with the goal of
DNA nucleobases 161–164 according to Scheme 56, with the goal of extending
extending their
their
functionality
functionality to
to obtain
obtain biofunctional
biofunctional materials.
materials. The
The in
in vitro
vitro biocompatibility
biocompatibility of of the
the native
native
161–164 and
161–164
Molecules 2023, 28, x FOR PEER REVIEW and nucleobase
nucleobase derivatives 165–168 was
derivatives 165–168 was assessed
assessed using
using primary
primary human
human dermal
dermal
31 of 65
fibroblasts (HF), showing
fibroblasts (HF), showingthat
thatthey
theywere
werenon-toxic,
non-toxic, and
and hence,
hence, suitable
suitable for for biomedical
biomedical ap-
applications [166].
plications [166].
Scheme 56. One-pot

Scheme 56. One-pot synthesis
synthesis of
of nucleobase
nucleobase derivatives 165–168 via regioselective N-H functional-
ization of
ization of the
the DNA
DNA nucleobases
nucleobases 161–164
161–164with
withpropargyl
propargylbromide
bromide19a.
19a.
2.5.3.
2.5.3. With
With Propargylic
Propargylic Cation
Cation Intermediates
Intermediates
The
The nucleophilic addition of
nucleophilic addition of the
the primary
primary amino-ester
amino-ester 169169 to to cobalt-stabilized
cobalt-stabilized propar-
propar-
gylic carbocation 170—initially in the presence of BF 3
gylic carbocation 170—initially in the presence of BF3•OEt • OEt 2 , followed
2, followed
by CAN, as cat-
by CAN, as catalytic
systems—generated the corresponding dipropargylamino-ester 171 according to Scheme
57 [167].
Scheme 56. One-pot synthesis of nucleobase derivatives 165–168 via regioselective N-H functional-
ization of the DNA nucleobases 161–164 with propargyl bromide 19a.
2.5.3. With Propargylic Cation Intermediates

Molecules 2023, 28, 3379 30 of 61
The nucleophilic addition of the primary amino-ester 169 to cobalt-stabilized propar-
gylic carbocation 170—initially in the presence of BF3•OEt2, followed by CAN, as catalytic
systems—generated the corresponding dipropargylamino-ester 171 according to Scheme
alytic systems—generated the corresponding dipropargylamino-ester 171 according to
57 [167].
Scheme 57 [167].
Scheme 57. Synthesis of dipropargylamino-ester 171 using co-stabilized propargylic carbocation 170
Scheme 57. Synthesis of dipropargylamino-ester 171 using co-stabilized propargylic carbocation 170
as aa propargylating
as propargylating agent,
agent, in
in the
the presence
presence of
of BF •OEt22/CAN
BF33•OEt /CANasasaacatalytic
catalyticsystem.
system.
2.6. Vinylstananes
2.6. Vinylstananes
With Propargyl Bromide
A methodology involving the coupling of vinyl-stannanes (β-trifluoromethyl (Z)-α-
A methodology involving
and (Z)-β-stannylacrylates) 172the coupling of vinyl-stannanes
to propargylic (β-trifluoromethyl
bromides 19a catalyzed by copper(I)(Z)-α-
pro-
and (Z)-β-stannylacrylates) 172 to propargylic bromides 19a catalyzed by copper(I)
vided access to the corresponding propargylated products 173 without allenic transposition pro-
vided access 32 of 65
(Scheme
Molecules 2023, 28, x FOR PEER REVIEW 58). to thePd-free
This corresponding propargylated
cross-coupling productsvarious
process tolerated 173 without allenic
R-groups, andtransposi-
occurred
32 of 65
tion
with(Scheme
retention58).
of This Pd-free cross-coupling
the configuration process
at the double tolerated
bond; varioushomocoupling
furthermore, R-groups, andandoc-
curred
allenic with retention
products wereof thedetected
not configuration
[168]. at the double bond; furthermore, homocoupling
and allenic products were not detected [168].
Scheme 58. Copper(I)-catalyzed synthesis of propargylated products 173 from trifluoromethyl

Scheme 58. Copper(I)-catalyzed synthesis
58. Copper(I)-catalyzed synthesis of
of propargylated
propargylated products
products 173 from trifluoromethyl
trifluoromethyl
stannylacrylates 172 and propargylic bromides 19a.
stannylacrylates 172 and propargylic bromides
bromides 19a.
19a.
2.7.
2.7. (a)
(a) Alcohols,
Alcohols, (b)
(b) Enol-Like
Enol-Like Precursors,
Precursors, (c)
(c) Phenols, (d) Thiols, and (e) Carboxylic Acids
2.7. (a) Alcohols, (b) Enol-Like Precursors, (c) Phenols,
Phenols, (d)
(d) Thiols,
Thiols, and
and (e)
(e) Carboxylic
Carboxylic Acids
Acids
(a) Alcohols
(a) Alcohols
(a) Alcohols
2.7.1. With Propargyl Bromides
The propargylation of hydroxyl-amides 174, synthesized via a Passerini reaction me-
The propargylation
propargylationofofhydroxyl-amides
hydroxyl-amides174, synthesized
174, synthesizedviavia
a Passerini reaction
a Passerini me-
reaction
diated by boric acid, generated O-propargyloxyamides 175 as key intermediates (Scheme
diated by boric
mediated acid, acid,
by boric generated O-propargyloxyamides
generated 175 as key
O-propargyloxyamides 175 intermediates (Scheme
as key intermediates
59) [169], whose cyclization in the presence of potassium tert-butoxide via a 5-endo-dig
59) [169],59)
(Scheme whose
[169],cyclization in the presence
whose cyclization of potassium
in the presence tert-butoxide
of potassium via a 5-endo-dig
tert-butoxide via a 5-
process produced a series of 2,5-dihydrofurans 176 of synthetic interest [170–173].
endo-dig process produced
process produced a series
a series of of 2,5-dihydrofurans
2,5-dihydrofurans 176 of synthetic
176 of synthetic interestinterest [170–173].
[170–173].
Scheme 59.
Scheme The synthesis
59. The of O-propargyloxyamide
synthesis of intermediates 175
O-propargyloxyamide intermediates from hydroxyl-amides
175 from 174
hydroxyl-amides 174
Scheme 59. The synthesis of O-propargyloxyamide intermediates 175 from hydroxyl-amides 174
potassium tert-butoxide
and propargyl bromide 19a in the presence of potassium tert-butoxide as
as aa base.
base.
and propargyl bromide 19a in the presence of potassium tert-butoxide as a base.
Expanding on
Expanding on the
the strategy
strategy for
for the
the synthesis
synthesis of
ofquinoline/azepine
quinoline/azepine pharmacophores
pharmacophores
Expanding
fused to on
to aa triazole the strategy
triazole moiety
moiety (see for
(see Scheme the
Scheme 50), synthesis of quinoline/azepine
50), hetero-polycyclic
hetero-polycyclic products 179
179pharmacophores
were obtained
obtained
fused products were
fused
from to a triazole moiety (see Scheme
(2-chloroquinolin-3-yl)methanol 50), hetero-polycyclic
derivatives 177 via theproducts 179 were obtained
O-propargylation of 177 to
177 to
from (2-chloroquinolin-3-yl)methanol derivatives 177 via the O-propargylation of
fromthe
give (2-chloroquinolin-3-yl)methanol
key propargyl intermediates derivatives
178, followed177
byvia
a the O-propargylation
click reaction and of 177 to
Pd-catalyzed
give the key propargyl intermediates 178, followed by a click reaction and Pd-catalyzed
give functionalization
C-H the key propargyl(Scheme
intermediates 178, followed by a click reaction and Pd-catalyzed
60) [160].
C-H functionalization (Scheme 60) [160].
Scheme 60. Synthesis of O-propargyl intermediates 178 from the propargylation of (2-chloroquino-
and propargyl bromide 19a in the presence of potassium tert-butoxide as a base.
Expanding on the strategy for the synthesis of quinoline/azepine pharmacophores

fused to a triazole moiety (see Scheme 50), hetero-polycyclic products 179 were obtained
from (2-chloroquinolin-3-yl)methanol derivatives 177 via the O-propargylation of 177 to
Molecules 2023, 28, 3379 31 of 61
give the key propargyl intermediates 178, followed by a click reaction and Pd-catalyzed
Scheme 60. Synthesis of O-propargyl

O-propargylintermediates 178from
intermediates178 fromthe
thepropargylation
propargylationofof
(2-chloroquinolin-
(2-chloroquino-
lin-3-yl)methanol
3-yl)methanol derivatives 177 with propargyl bromide 19a in the presence of calcium carbonate
derivatives 177 with propargyl bromide 19a in the presence of calcium
as
as aa base.
base.
Molecules 2023, 28, x FOR PEER REVIEW The O-Propargylation

O-Propargylation of oxime
of oxime 180 propargyl
180 with with propargyl
bromidebromide 19a, according
19a, according to Scheme to
33 of61,
65
provided
Scheme 61,facile access tofacile
provided the perylenediimide compound 181, whose
access to the perylenediimide main 181,
compound characteristic
whose mainwas
its capability to
characteristic detect
was Cu2+ and to
its capability +2 ions in 2+
Pddetect Cu water [174].
and Pd +2 ions in water [174].
Scheme 61.
Scheme 61. NaH-mediated
NaH-mediated synthesis
synthesis of
of propargyl-perylenediimide
propargyl-perylenediimide 181
181 from
from the
the reaction
reaction of
of oxime
oxime
Scheme 61. NaH-mediated synthesis of propargyl-perylenediimide 181 from the reaction of oxime
180 with
180 withpropargyl
propargylbromide
bromide19a.
19a.
180 with propargyl bromide 19a.
Scheme highlightstwo
Scheme 62 highlights twosynthetic
syntheticstrategies
strategies forfor access
access to propargylated
to propargylated ethers
ethers 183
Scheme 62 highlights two synthetic strategies for access to propargylated ethers 183
andand
183 186.186. The process
The first first process involves
involves the cyclization
the cyclization of L-glutamic
of L-glutamic acid toacid to the
obtain obtain the
lactone
and 186. The first process involves the cyclization of L-glutamic acid to obtain the lactone
lactone
182, which which
182,was was with
reacted reacted with propargyl
propargyl bromide 19abromide 19a inmedium
in alkaline alkalineinmedium
a mixture in of
a
182, which was reacted with propargyl bromide 19a in alkaline medium in a mixture of
mixture of polar
polar aprotic aprotic
solvents to solvents
obtain thetopropargylated
obtain the propargylated
lactone 183 inlactone 183 in
moderate moderate
yields [175].
polar aprotic solvents to obtain the propargylated lactone 183 in moderate yields [175].
yields
Compound[175]. 183
Compound 183 was
was then used as athen used
starting as afor
point starting point
multistep for multistep
synthesis, leadingsynthesis,
to poly-
Compound 183 was then used as a starting point for multistep synthesis, leading to poly-
leading
cyclic compound 184. The goal of the second etherification process was to generate was
to polycyclic compound 184. The goal of the second etherification process pro-
cyclic compound 184. The goal of the second etherification process was to generate pro-
to generate disaccharides.
pargylated propargylatedIndisaccharides. In this
this case, glycoside 185 case,
wasglycoside was reacted
185propargyl
reacted with with
bromide
pargylated disaccharides. In this case, glycoside 185 was reacted with propargyl bromide
propargyl bromide
19a to produce 19a to produce the arabino-3,6-galactane
the tetra-propargylated tetra-propargylated arabino-3,6-galactane
186 in good yields [176].186 in
19a to produce the tetra-propargylated arabino-3,6-galactane 186 in good yields [176].
good yields [176].
OH
OH OH
O OH
O
HO
HO O
OH HO O
OH O HO O
O
OO O
O O
OH O CO tBu
CO22tBu
O O O O O
O OH O OH O
185 OH 182
O O 185 Br 182
O O 186186 Br O
O KOH/H O/toluene 19a NaH 183 O O
KOH/H22O/toluene 19a NaH 183 O O O
O 20–25 oC DMF/THF O O
O 20–25 oC DMF/THF
O 38% O
O 87% O
87% 38% 184
184
Scheme 62. Alternative routes to propargylated ethers 183 and 186 via hydroxyderivatives 182 and
Scheme
Scheme 62.
62. Alternative
Alternativeroutes
routestoto
propargylated ethers
propargylated 183183
ethers andand
186186
via via
hydroxyderivatives 182 and
hydroxyderivatives 182
185.
185.
and 185.
Scheme 63 highlights a method for the synthesis of terminal gem-difluoropropargyl
Scheme 63 highlights a method for the synthesis of terminal gem-difluoropropargyl
ethers 190 from gem-difluoropropargyl bromide dicobalt complex 188 in the presence of
ethers 190 from gem-difluoropropargyl bromide dicobalt
dicobalt complex
complex 188 in the presence of
silver triflate and TEA in toluene. Complex 188 reacted selectively with aliphatic alcohols
silver triflate and TEA in toluene. Complex 188 reacted selectively with aliphatic alcohols
187, even if the substrates 187 contained other nucleophilic functional groups, producing
propargyl ether complexes 189. Decomplexation of the resulting dicobalt complexes 189
propargyl ether complexes 189. Decomplexation
Decomplexation of the resulting dicobalt complexes 189
using cerium ammonium nitrate (CAN) or N,N,N′-trimethylethylenediamine, followed by
using cerium ammonium nitrate (CAN) or N,N,N′-trimethylethylenediamine, followed by
desilylation by TBAF, produced compound 190 [177].
desilylation by TBAF, produced compound 190 [177].
Scheme 62. Alternative routes to propargylated ethers 183 and 186 via hydroxyderivatives 182 and
185.
Scheme 63 highlights a method for the synthesis of terminal gem-difluoropropargy

ethers 190 from gem-difluoropropargyl bromide dicobalt complex 188 in the presence o
Molecules 2023, 28, 3379 silver triflate and TEA in toluene. Complex 188 reacted selectively with aliphatic
32 of 61 alcohols
propargyl ether complexes 189. Decomplexation of the resulting dicobalt complexes 189
usingammonium
using cerium cerium ammonium nitrate
nitrate (CAN) or(CAN)
N,N,Nor N,N,N′-trimethylethylenediamine,
0 -trimethylethylenediamine, followed followed
by by
desilylation by TBAF, produced compound
desilylation by TBAF, produced compound 190 [177]. 190 [177].

Scheme 63. AgOTf-mediated

Scheme synthesis ofsynthesis
63. AgOTf-mediated propargylofand both dicobalt
propargyl complexes
and both from the reaction
189complexes
dicobalt 189 from the re
Implementing the strategy outlined in Scheme 55, a series of O-propargylated com-
action of gem-difluoropropargyl
the strategy outlined in Scheme 55, a series of O-propargylated com- alcohols
of gem-difluoropropargyl
Implementing bromide dicobalt bromide
complex dicobalt
188 with complex
diversely 188 with diversely
substituted substituted
alcohols 187.
pounds 191a-d
187. bearing one or two propargyl groups in their structures were synthesized
pounds 191a-d bearing one or two(187a),
usingImplementing
3-methyl-9H-carbazol-1-ol propargyl groups in their structures and
4-hydroxycoumarin wereα-mangostin
synthesized
the strategy outlined in Scheme 55, a series(187b),
of O-propargylated com-
using
pounds 3-methyl-9H-carbazol-1-ol
(187c) as191a-d
substrates (Scheme
bearing one or64). (187a),
twoThese
propargyl 4-hydroxycoumarin
compounds
groups inwere (187b),
evaluated
their structuresfor and
their
were α-mangostin
in vitro cyto-
synthesized us-
(187c)
ing asagainst
toxicity substrates (Scheme
three human64).
3-methyl-9H-carbazol-1-ol These
cancer cell
(187a), compounds were evaluated
lines, the HepG2,
4-hydroxycoumarin LU-1,
(187b),and for
andHelatheir
cellinlines.
α-mangostin vitro(187c)
cyto-
Com-
toxicity
pound
as against
191c
substrates threemost
proved
(Scheme human cancer
64).active,
These cell lines,
showing
compounds the HepG2,
IC50were
values LU-1,
of 1.02,
evaluated for and
2.19, andHela
their 2.55 cell
µg/mL,
in vitro lines.respec-
Com-
cytotoxicity
pound 191c
tively [165].
against proved most active, showing IC 50 values of 1.02, 2.19, and 2.55 µg/mL, respec-
three human cancer cell lines, the HepG2, LU-1, and Hela cell lines. Compound 191c
tively [165].
proved most active, showing IC values of 1.02, 2.19, and 2.55 µg/mL, respectively [165].
50
Scheme 64. K2CO3-catalyzed synthesis of O-propargylated compounds 191 from propargyl bromide
Scheme
19a and 64. K
K22CO
hydroxy 3-catalyzed
-catalyzedsynthesis
CO3derivatives synthesisof
187. ofO-propargylated
O-propargylatedcompounds
compounds 191
191 from
from propargyl
propargyl bromide
bromide
19a and
19a and hydroxy
hydroxy derivatives
derivatives 187.
187.
2.7.2. With Propargyl Esters
2.7.2. With
Propargyl Esters
Esters
Compounds 194/195 and 196 were synthesized via O-propargylation of the monosac-
Compounds
Compounds 194/195 and 196
194/195 and were synthesized
196 were synthesized via O-propargylation of
via O-propargylation of the
the monosac-
monosac-
charide 194 and hydroxylic precursors 193 with propargyl esters 54, employing dual ca-
charide 194
charide andhydroxylic
194 and hydroxylicprecursors
precursors193 with
193with propargyl
propargyl esters
esters 54,54, employing
employing dualdual
ca-
talysis between [Cu(ACN)4]BF 4 and boronic acid (B), and using a chiral ligand ((S,S)-L) in
catalysis
talysis between
between [Cu(ACN)
[Cu(ACN) 4]BF4 ]BF 4 and
4 and
boronic
boronic acid
acid (B),
(B), andand using
using a a chiral
chiral ligand
ligand ((S,S)-L)
((S,S)-L) in
the presence of a weak base (TEA) in THF (Scheme 65). A notable feature of this approach
in
thethe presence
presence of
of aofa weak
weak base (TEA)
basestereocentersin
(TEA) in THF THF (Scheme 65). A notable feature of this approach
is the formation several in(Scheme
a chemo-65).andAstereoselective
notable featuremanner
of this approach
[178,179].
is the
is the formation
formation of of several
several stereocenters
stereocenters in in aa chemo-
chemo- and
and stereoselective
stereoselective manner
manner[178,179].
[178,179].
Scheme 65. Propargylation

Propargylation of the monosaccharides 192 and the hydroxylic precursors 193 from their
Scheme 65.
reactions Propargylation
with of the
propargyl esters
reactions with propargyl esters monosaccharides 192 and the hydroxylic precursors 193 from their
54.
54.
reactions with propargyl esters 54.
2.7.3. With Propargyl Alcohol/Ethers
Alcohol/Ethers
2.7.3.An
With Propargyl Alcohol/Ethers
An efficient
efficient method
method for for the
the synthesis
synthesis ofof end-functionalized
end-functionalized oligosaccharides
oligosaccharides from
from
An efficient
unprotected method
monosaccharides for the synthesis
using a of end-functionalized
one-pot/two-step oligosaccharides
approach
unprotected monosaccharides using a one-pot/two-step approach was developed was from
developed
unprotected
(Scheme
(Scheme 66) monosaccharides
66) [180].
[180]. In
Inthe
thefirst
firststep,using
step, a one-pot/two-step
mannose
mannose 197was
197 approach
wasfunctionalized
functionalized with was developed
propargyl
with alcohol
propargyl alco-
(Scheme 66) [180]. In the first step, mannose 197 was functionalized with propargyl
hol 63 (R = R = H) at the anomeric position through Fisher glycosylation using Amberlyst-
1 alco-
hol 63 (R = R1 =aH)
15, producing at the anomeric
propargyl position through
monosaccharide 198. In aFisher
secondglycosylation usingmixture
step, the reaction Amberlyst-
was
15, producing
heated a propargyl
under vacuum monosaccharide
at 100 °C in order to198. In a second
increase step,of
the degree thepolymerization
reaction mixture
of was
198,
heated
leadingunder vacuum
to a fully at 100 °C in
functionalized order to increase
propargylated the degree
glycoside of polymerization
199, with of 198,
a degree of polymeri-
Molecules 2023, 28, 3379 33 of 61
63 (R = R1 = H) at the anomeric position through Fisher glycosylation using Amberlyst-

15, producing a propargyl monosaccharide 198. 35 of 65
In a second step, the reaction mixture
was heated under vacuum at 100 ◦ C in order to
35 of 65
increase the degree of polymerization
35 of 65
of 198, leading to a fully functionalized propargylated glycoside 199, with a degree of
polymerization (n) up to 8 [180].
Scheme 66. Amberlyst-15-mediated synthesis of end-propargylated glycosides 199.

Scheme 66.
Scheme 66. Amberlyst-15-mediated
Amberlyst-15-mediated synthesis of
synthesis of end-propargylated
end-propargylated glycosides
glycosides 199.
199.
Propargyl ethers 200 were synthesized by reacting propargylic alcohols 63 and dif-
Propargyl
ferent primary and
Propargyl ethers 200 were
werealcohols
secondary
ethers 200 synthesized by
187 inby
synthesized reacting
thereacting propargylic
presencepropargylic alcohols
of catalytic alcohols
amounts6363 and dif-
dif-
of aqueous
and
ferentPropargyl
primary ethers
ethers
and 200were
200 were
secondary synthesized
synthesized
alcohols 187 inby
by
thereacting
reactingpropargylic
presencepropargylic
of alcohols
catalytic alcohols
amounts and
63of
63 differ-
and dif-
aqueous
HBF4 as
ferent a catalyst
primary and (Scheme 67)alcohols
secondary [181]. 187 in the presence of catalytic amounts of aqueous
ent primary
ferent
HBF and secondary alcohols 187 in the presence of catalytic amounts
primary and secondary alcohols 187 in the presence of catalytic amounts of
4 as a catalyst (Scheme 67) [181].
of aqueous
HBF
HBF44 as
as aa catalyst
catalyst (Scheme
(Scheme 67)
67) [181].
[181].
Scheme 67. HBF4-catalyzed synthesis of propargyl ethers 200 using propargylic alcohols 63 as pro-
Scheme 67. HBF
pargylating 4-catalyzed synthesis of propargyl ethers 200 using propargylic alcohols 63 as pro-
agents.
Scheme 67.
67. HBF
HBF4-catalyzed synthesis
4 -catalyzed of of
synthesis propargyl ethers
propargyl 200200
ethers using propargylic
using alcohols
propargylic 63 as63
alcohols pro-
as
Scheme 67. agents.
pargylating HBF4-catalyzed synthesis of propargyl ethers 200 using propargylic alcohols 63 as pro-
pargylating agents.
propargylating agents.
pargylating agents.
Implementing the procedure described in Scheme 57, the corresponding propar-
Implementing
gylated amino-ethers
Implementing the203
the
the procedure
procedure
procedure described
were synthesized
described
described inaScheme
invia Scheme
Scheme
in reaction 57,
57, the
57, the corresponding
corresponding
ofcorresponding
dicobalt
the propar-
hexacarbonyl-com-
propargylated
propar-
gylatedImplementing
amino-ethers the
203procedure
were described
synthesized viaina Scheme
reaction 57,
of the corresponding
dicobalt propar-
hexacarbonyl-com-
plexed (Co
amino-ethers
gylated 2(CO)
2036)-propargyl
amino-ethers were
203 weremethyl
synthesized ether
via 202 with
a reaction
synthesized via a aminoalcohols
of dicobalt
reaction of 201hexacarbonyl-com-
in the presence of
hexacarbonyl-complexed
dicobalt
gylated(Co
plexed amino-ethers 203 were synthesized via a reaction of dicobalt hexacarbonyl-com-
2(CO)6)-propargyl methyl ether 202 with aminoalcohols 201 in the presence of
BF3•OEt
(Co 2 (CO)
plexed 26and
(Co CAN
)-propargyl
2(CO) asmethyl
catalytic
6)-propargyl systems
ether
methyl202 (Scheme
with
ether 68)aminoalcohols
[167].201 in the201
aminoalcohols
202 with presence
in the of BF3 •OEt
presence of2
plexed
BF 3•OEt
(Co 2(CO)6)-propargyl methyl ether 202 with aminoalcohols 201 in the presence of
2 and CAN as catalytic systems (Scheme 68) [167].
and
BF CAN as catalytic systems (Scheme 68) [167].
3•OEt2 and CAN as catalytic systems (Scheme 68) [167].
BF3•OEt2 and CAN as catalytic systems (Scheme 68) [167].
Scheme 68. Synthesis of the propargylated amino-ethers 203 from aminoalcohols 201 with
Scheme
(Co2(CO)68. Synthesis ofof the
Synthesis
6)-propargyl
the propargylated
propargylated amino-ethers
amino-ethers 203
203 from
from aminoalcohols
aminoalcohols 201
201 with
Scheme 68. Synthesisether complex
of the 202 as propargylating
propargylated agent.
amino-ethers 203 from aminoalcohols 201 with
Scheme
(Co (CO) 68. Synthesis
)-propargyl of
ether the propargylated
complex 202 as amino-ethers
propargylating
2(CO)6)-propargyl ether complex 202 as propargylating agent. 203
agent. from aminoalcohols 201 with
(Co22(CO)66)-propargyl ether complex 202 as propargylating agent.
(Co2(CO)6)-propargyl ether complex 202 as propargylating agent.
(b) Enolic substrates
(b)
(b) Enolic substrates
Enolic substrates
(b)
(b) Enolic
Enolic substrates
substrates
2.7.4. With
With Propargyl Bromides
Propargyl Bromides
Bromides
2.7.4.The
2.7.4.The
Withreaction
Propargylof difluoropropargyl–bromide–dicobalt
Bromides complexes 188 with enolizable
The reaction of
reaction of difluoropropargyl–bromide–dicobalt
difluoropropargyl–bromide–dicobalt complexes 188
complexes with enolizable
188 with enolizable
ketones
The and aldehydes
reaction of 204, in the presence of AgNTf2 and
difluoropropargyl–bromide–dicobalt with iPr2NEt
complexes 188 or DTBMP
with as a
enolizable
ketones
The
ketones and aldehydes
reaction
and of
aldehydes 204, in the presence of AgNTf
difluoropropargyl–bromide–dicobalt
204, in the
the presence
presence of
ofvinyl
AgNTf and with iPr
complexes NEt
188 or
withDTBMP
22 and with iPr22NEt or DTBMP as aa
enolizable
as
base, ledand
ketones to the synthesis204,
aldehydes of difluoropropargyl
in AgNTf ether–dicobalt
2 and with iPr complexes 205 bearing
2NEt or DTBMP as
base,
ketones
base, ledand
led to the
to the synthesis204,
aldehydes
synthesis of difluoropropargyl
of difluoropropargyl vinyl
in the presence ofvinyl
AgNTf ether–dicobalt
2 and with iPr
ether–dicobalt complexes
2NEt or DTBMP
complexes 205 as aa
bearing
205 bearing
diverse
base, ledsubstituents
to the (Scheme
synthesis of 69). These compounds
difluoropropargyl vinyl were then utilized
ether–dicobalt as convenient
complexes 205 pre-
bearing
diverse
diverse substituents
base, ledsubstituents (Scheme
to the synthesis 69).These
These compounds
of difluoropropargyl
(Scheme 69). were
thenthen
vinyl ether–dicobalt
compounds were utilized
complexes
utilized as 205
convenient
bearing
as convenient
convenient pre-
cursors
diverse
precursorsfor the
for synthesis
substituents
the synthesisof
(Scheme difluorodienone
69).
of These and
compounds
difluorodienone difluoroallene
and were then derivatives
utilized
difluoroallene as [182].
derivatives [182]. pre-
diverse substituents
cursors for
for the synthesis(Scheme 69). These
synthesis of difluorodienone compounds were
difluorodienone and difluoroallenethen utilized as convenient
difluoroallene derivatives [182].
[182]. pre-
cursors
cursors for thethe synthesis of of difluorodienone and
and difluoroallene derivatives
derivatives [182].
Scheme 69. Synthesis of difluoropropargyl vinyl ether–dicobalt complexes 205 from carbonyl
carbonyl com-
com-
Scheme 69. Synthesis
pounds 188 mediated of
mediated of
by difluoropropargyl vinyl
AgNTf22 and iPr22NEt
bydifluoropropargyl NEt or ether–dicobalt
or DTBMP
DTBMP bases. complexes 205 from carbonyl com-
bases. complexes
Scheme 69. Synthesis vinyl ether–dicobalt 205 from carbonyl com-
Scheme188
pounds 69. mediated
Synthesis by
of difluoropropargyl
AgNTf2 and iPr2NEt vinyl ether–dicobalt
or DTBMP bases. complexes 205 from carbonyl com-
pounds 188 mediated by AgNTf2 and iPr2NEt or DTBMP bases.
pounds 188 mediated by AgNTf2 and iPr2NEt or DTBMP bases.
Molecules 2023, 28, 3379 34 of 61
(c) Phenolic substrates

2.7.5. The
Withpropargylation
Propargyl Bromidesof phenolic hydroxyl groups is important because of its potential
The propargylation of phenolic hydroxyl groups is important because of its potential
as starting material for the preparation
The propargylation of phenolic of high-molecular-weight
hydroxyl synthetic
groups is important because and
of its natural
potential
as starting material for the preparation of high-molecular-weight synthetic and natural
polymers. The reaction of propargyl bromide 19a with the phenolic OHs of
as starting material for the preparation of high-molecular-weight synthetic and natural the lignin de-
polymers. The reaction of propargyl bromide 19a with the phenolic OHs of the lignin de-
rivative 206,
polymers. Thein reaction
the presence of an aqueous
of propargyl base,
bromide yielded
19a a propargylated-lignin
with the phenolic OHs of theproductlignin
rivative 206, in the presence of an aqueous base, yielded a propargylated-lignin product
210 (entry 206,
derivative 1) [183]. Inpresence
in the other studies,
of an the propargylation
aqueous of phenols
base, yielded 207, 208, and 209,
a propargylated-lignin in the
product
210 (entry 1) [183]. In other studies, the propargylation of phenols 207, 208, and 209, in the
presence
210 (entryof1)K[183].
2CO3 asIn catalysts in acetone
other studies, the or DMF and under
propargylation MW irradiation,
of phenols 207, 208, produced
and 209,
presence of K2CO3 as catalysts in acetone or DMF and under MW irradiation, produced
thethe
in corresponding
presence of K propargylated ethersin211
2 CO3 as catalysts (entryor2)DMF
acetone [184],and
212 under
(entry MW
3) [185], and 213
irradiation,
the corresponding propargylated ethers 211 (entry 2) [184], 212 (entry 3) [185], and 213
produced the corresponding propargylated ethers 211 (entry 2) [184], 212
(entry 4) [186] (Scheme 70). These compounds were further functionalized via “click” (entry 3) [185],
(entry 4) [186] (Scheme 70). These compounds were further functionalized via “click”
and 213 (entry 4) [186] (Scheme 70). These compounds were further functionalized via
chemistry.
chemistry.
“click” chemistry.
Scheme 70. Propargylation of phenolic hydroxyl groups in precursors 206–209 using propargyl bro-
Scheme 70. Propargylation ofofphenolic
phenolichydroxyl groups in precursors 206–209 using propargyl bro-
Scheme as Propargylation
mide 19a70. propargylating agent. hydroxyl groups in precursors 206–209 using propargyl
mide 19a as propargylating agent.
bromide 19a as propargylating agent.
2.7.6. With
2.7.6. With PropargylAlcohols/Ethers
Alcohols/Ethers
2.7.6. WithPropargyl
Propargyl Alcohols/Ethers
Following
Following the procedure describedin
in Scheme57, 57, propargylatedtyrosine
tyrosine derivatives
Followingthe
theprocedure
proceduredescribed
described inScheme
Scheme 57,propargylated
propargylated tyrosinederivatives
derivatives
215, were
were prepared starting
starting from with
with dicobalt complexes
complexes 202 as as propargylating agents,
agents,
215, were prepared
215, prepared starting from
from with dicobalt
dicobalt complexes 202202 as propargylating
propargylating agents,
according to Scheme 71, and employing BF 3•OEt2 and CAN as catalytic systems [167].
according
accordingto toScheme
Scheme71,
71,and
andemploying
employingBFBF33••OEt
OEt22 and
and CAN
CAN as
as catalytic
catalytic systems
systems [167].
[167].
Scheme
Scheme71.71. Synthesis
Synthesis of
of the
the propargylated
propargylatedtyrosine
tyrosinederivatives 215from
derivatives215 fromtyrosine
tyrosineanalogues 214and
analogues214 and
Scheme 71. Synthesis of the propargylated tyrosine derivatives 215 from tyrosine analogues 214 and
(Co22(CO)
(Co (CO)66)-propargylated complexes 202
202 as
as propargylating
propargylating agents.
agents.
(Co2(CO)6)-propargylated complexes 202 as propargylating agents.
(d) Thiolic substrates

Thiobenzimidazole- 216 and cysteine-containing peptides 217 were S-propargylated
using a mild base, according to Scheme 72, to produce propargylated thiobenzimidazole
218 (entry 1) [187] and propargylated peptides 219 (entry 2) [188].
(c) Thiolic substrates
(c) Thiolic substrates
Thiobenzimidazole- 216 and cysteine-containing peptides 217 were S-propargylated
using Thiobenzimidazole- 216 and
a mild base, according cysteine-containing
to Scheme peptides
72, to produce 217 were
propargylated S-propargylated
thiobenzimidazole
Molecules 2023, 28, 3379 using a mild base, according to Scheme 72, to produce propargylated 35 of 61
thiobenzimidazole
Scheme 72. Propargylation reactions of thiobenzimidazole- 216 and cysteine-containing peptides

Scheme
Scheme 72. Propargylation reactions ofofthiobenzimidazole- andand
216216 cysteine-containing peptides 217
217 with72. Propargylation
propargyl bromidereactions thiobenzimidazole-
19a as propargylating agent. cysteine-containing peptides
with propargyl bromide 19a as propargylating agent.
217 with propargyl bromide 19a as propargylating agent.
2.7.8. Propargylic
2.7.8. Propargylic Cation
2.7.8. Propargylic Cation Intermediates
Intermediates
S-propargylated
S-propargylated cysteine ethyl
cysteine ethyl ester
ester derivatives
derivatives 221
221 were
were prepared
prepared according
according to
to the
the
S-propargylated
conditionsestablished cysteine
establishedininSchemeethyl ester
Scheme57,57, derivatives
starting with 221 were prepared
propargyl–dicobalt according
complexes to the
conditions starting with propargyl–dicobalt complexes 170 170
in thein
conditions
the presenceestablished
of BF in2 and
•OEt Scheme
CAN 57,asstarting with
catalytic propargyl–dicobalt
systems (Scheme 73) complexes 170 in
[167].
presence of BF3 •OEt2 and CAN as catalytic systems (Scheme 73) [167].
3
the presence of BF3•OEt2 and CAN as catalytic systems (Scheme 73) [167].
Scheme 73. Synthesis

Scheme 73. Synthesis ofof the
the propargylated
propargylated cysteine
cysteine ethyl
ethyl ester
ester derivatives 221 from cysteine
derivatives 221 cysteine ana-
Scheme
logues 73.and
Synthesis
the (Coof
the(Co the 6propargylated cysteine ethyl ester derivatives 221 from cysteine ana-
logues 220
220 and 22(CO)
(CO) 6 )-propargylated complex 170 as propargylating agent.
agent.
logues 220 and the (Co2(CO)6)-propargylated complex 170 as propargylating agent.
(e)
(d) Carboxylic
Carboxylicacids
acids
(d) Carboxylic acids
2.7.9.
2.7.9. With
With Propargyl
Propargyl Bromide
Bromideand andPropargylamine
Propargylamine
2.7.9.The
With Propargyl Bromide and Propargylamine
The propargylamides 224 were synthesized
propargylamides 224 were synthesized through
through aa reaction
reactionbetween
between indoloacids
indoloacids
224 The
with propargylamides
propargylamine 222224
(R
224 with propargylamine 222 (R = NH were
= NH synthesized
) via an acyl through
chloride a reaction
intermediate
2 2) via an acyl chloride intermediate between indoloacids
(generated
(generatedin situin
224
by
Molecules 2023, 28, x FOR PEER REVIEW with propargylamine
reacting 223 with oxalyl 222 (R =
chloride) NH 2) via an
(Scheme 74,acyl
entry chloride
1) [189].intermediate
Using the
situ by reacting 223 with oxalyl chloride) (Scheme 74, entry 1) [189]. Using the same ap- (generated
same approach,
38 of in
65
situ by reacting
propargylation
proach, of223 withofmaslinic
natural
propargylation oxalyl
natural chloride)
acid 225(Scheme
maslinic with 22574,
acidpropargyl entry
with 1) [189].
bromide
propargyl 19a Using the
(R = Br)
bromide 19asame
(R = ap-
produced Br)
the desired
proach, propargyl
propargylation derivative
of natural 226 (entry
maslinic 2) [190].
acid 225
produced the desired propargyl derivative 226 (entry 2) [190]. with propargyl bromide 19a (R = Br)
produced the desired propargyl
The preparation derivative
of C-propargylic 226228
esters (entry
was2)carried
[190]. out via a reaction between
N-protected amino acids 227 and propargyl bromide 19a (R = out
The preparation of C-propargylic esters 228 was carried viaDMF
Br) in a reaction
in the between
presence
N-protected amino acids 227 and propargyl bromide
of anhydrous potassium carbonate (Scheme 74, entry 3) [191]. 19a (R = Br) in DMF in the presence
of anhydrous potassium carbonate (Scheme 74, entry 3) [191].
Scheme 74. Propargylation

Scheme Propargylationofofthe
thehydroxyl
hydroxylgroups in in
groups carboxylic acids
carboxylic 223,223,
acids 225,225,
and and
227 using pro-
227 using
pargyl bromide 19a and propargylamine 222.
propargyl bromide 19a and propargylamine 222.
2.7.10.
TheWith O-Propargylated
preparation Hydroxylamine
of C-propargylic esters 228 was carried out via a reaction between
N-protected amino acids 227 and propargyl bromide
A novel bio-orthogonal prodrug 231 of the HDACi (R = Br) in DMF
19apanobinostat was in the presence
developed that
of anhydrous potassium carbonate (Scheme 74, entry 3) [191].
was harmless to cells and could be converted back into the cytotoxic panobinostat via Au
catalysis. The key propargylated product 231 was obtained from O-propargylated hydrox-
ylamine 230 with β-substituted-acrylic acid 229 using N-(3-dimethylaminopropyl)-N′-
ethylcarbodiimide hydrochloride (EDC) in H2O, according to Scheme 75 [192].
Scheme 74. Propargylation of the hydroxyl groups in carboxylic acids 223, 225, and 227 using pro-
Molecules 2023, 28, 3379 Schemebromide
pargyl 74. Propargylation of the hydroxyl
19a and propargylamine groups in carboxylic acids 223, 225, and 227 using
222. 36 pro-
of 61
pargyl bromide 19a and propargylamine 222.
2.7.10. With O-Propargylated Hydroxylamine
2.7.10. With O-Propargylated Hydroxylamine
2.7.10.A With
novelO-Propargylated
bio-orthogonal prodrug 231 of the HDACi panobinostat was developed that
Hydroxylamine
A novel bio-orthogonal
was harmless to cells and prodrug
could be 231 of the
converted HDACi
back panobinostat
into the was developed
cytotoxic panobinostat viathat
Au
A novel bio-orthogonal prodrug 231 of the HDACi panobinostat was developed that
was harmless
catalysis. to
The key cells and could
propargylated be converted back into the cytotoxic panobinostat via Au
was harmless to cells and couldproduct 231 wasback
be converted obtained from
into the O-propargylated
cytotoxic hydrox-
panobinostat via
catalysis.
ylamine The key
230 with propargylated product
β-substituted-acrylic 231 was
acid 229 obtained from O-propargylated hydrox-
Au catalysis. The key propargylated product 231using N-(3-dimethylaminopropyl)-N′-
was obtained from O-propargylated
ylamine 230 with hydrochloride
ethylcarbodiimide β-substituted-acrylic
(EDC) acid
in H 229according
2O, using N-(3-dimethylaminopropyl)-N′-
toN-(3-dimethylaminopropyl)-
Scheme 75 [192].
hydroxylamine 230 with β-substituted-acrylic acid 229 using
ethylcarbodiimide hydrochloride (EDC) in H2O, according to Scheme 75 [192].
N 0 -ethylcarbodiimide hydrochloride (EDC) in H2 O, according to Scheme 75 [192].
Scheme 75. EDC-catalyzed synthesis of the propargylated prodrug 231 from O-propargylated hy-
Scheme
Scheme 75.
75. EDC-catalyzed
droxylamine 230 synthesis of of
thethe
and β-substituted-acrylic
EDC-catalyzed synthesis propargylated
acid 229. prodrug
propargylated 231231
prodrug from O-propargylated
from hy-
O-propargylated
droxylamine
hydroxylamine230230
and β-substituted-acrylic
and acid
β-substituted-acrylic 229.
acid 229.
2.7.11. With Propargylic Cation Intermediates
2.7.11. With
2.7.11. With Propargylic
Propargylic Cation
Intermediates
Following a similar procedure to that described in Scheme 57, the propargylated N-
Following aa similar
Following similarprocedure
proceduretotothat
thatdescribed
described inin Scheme
Scheme 57,257, the propargylated
Bz-D-phenylalanine 232 was synthesized through its carboxyl–CO Hthe propargylated
functionality, N-
by re-
N-Bz-D-phenylalanine
Bz-D-phenylalanine 232 was synthesized
232 was synthesized through
through its carboxyl–CO H functionality, by
acting the propargyl–dicobalt complex 170 with a its carboxyl–COderivative
phenylalanine 2H functionality,
2
227 (R11 by re-
= Bn)
reacting
acting the propargyl–dicobalt
the propargyl–dicobalt complex
complex 170 with
170 with76)a phenylalanine
a phenylalanine derivative 227 (R =
derivative 227 (R = Bn)
1 Bn)
in the presence of BF3•OEt2 and CAN (Scheme [167].
in the
in the presence
presence of
of BF •OEt22 and
BF33•OEt and CAN
CAN (Scheme
(Scheme 76)
76) [167].
[167].
Scheme 76.
Scheme Synthesisofofthe
76. Synthesis thepropargylated
propargylated N-Bz-D-phenylalanine
N-Bz-D-phenylalanine 232232 from
from the the phenylalanine
phenylalanine de-
Scheme
derivative
rivative 76.227
227 Synthesis
andand of the propargylated
propargyl–dicobalt
propargyl–dicobalt N-Bz-D-phenylalanine
complex
complex 170.
170. 232 from the phenylalanine de-
rivative 227 and propargyl–dicobalt
2.8. (a) Alkenes, (b) Allenes, and (c)complex
Enynes 170.
2.8. (a) Alkenes, (b) Allenes, and (c) Enynes
(a) Alkenes
(a) Alkenes
2.8.1. With Propargyl-/Allenylboron
2.8.1. With Propargyl-/Allenylboron
Catalytic enantioselective allylic substitution is a widely used strategy in organic syn-
Catalytic
thesis, becauseenantioselective allylic substitution
it transforms an alkenyl is aanew
substrate into widely used strategy
unsaturated in organic
compound bear-
synthesis, because it transforms an
ing an allylic stereogenic center [193]. alkenyl substrate into a new unsaturated compound
bearing an allylic stereogenic
Transformations center
of acyclic, or[193].
aryl-, heteroaryl-, and alkyl-substituted penta-2,4-
dienyl phosphates 233, as well as cyclicheteroaryl-,
Transformations of acyclic, or aryl-, and alkyl-substituted
dienyl phosphates penta-2,4-dienyl
234, were carried out in the
phosphates 233, as well as cyclic dienyl phosphates 234, were carried out in the
presence of commercially available allenyl-B-(pinacolato) 2c, mediated by a sulfonate-con- presence
of commercially available allenyl-B-(pinacolato) 2c, mediated by a sulfonate-containing
taining NHC-Cu complex (NHC = imidazolyl carbene). Products 235/236 were obtained
NHC-Cu complex (NHC = imidazolyl carbene). Products 235/236 were obtained that
that contained, in addition to a 1,3-dienyl group, a readily functionalizable propargyl moi-
contained, in addition to a 1,3-dienyl group, a readily functionalizable propargyl moiety
ety (Scheme 77). The positive attributes of this reaction were high yields, high E:Z ratios,
(Scheme 77). The positive attributes of this reaction were high yields, high E:Z ratios,
and impressive enantiomeric ratios (er). Kinetic isotope effect measurements and DFT
and impressive enantiomeric ratios (er). Kinetic isotope effect measurements and DFT
computations provided mechanistic insights into this catalytic process [194].
computations provided mechanistic insights into this catalytic process [194].
Scheme 77.
Scheme 77.Synthesis
Synthesisofofpropargyl-containing
propargyl-containing 1,3-dienyl
1,3-dienyl derivatives
derivatives 235/236
235/236 fromfrom
dienyldienyl phos-
phosphates
phates 233/234
233/234 and allenyl-B-(pinacolato)
and allenyl-B-(pinacolato) 2c mediated
2c mediated by a sulfonate-containing
by a sulfonate-containing NHC-Cu NHC-Cu
complex.complex.
Focusing on allylic substitution, in another study, 1,5-enynes 238 were synthesized

via a silver-catalyzed allylic substitution by reacting a propargylic organoboron com-
pound 2a with allylic phosphates 237, using a chiral N-heterocyclic carbene (NHC) ligand
Molecules 2023, 28, 3379 Scheme
Scheme 77. 77. Synthesis
Synthesis of of propargyl-containing
propargyl-containing 1,3-dienyl
1,3-dienyl derivatives
derivatives 235/236
235/236 from
from dienyl
dienyl
37 phos-
phos-
of 61
phates
phates 233/234
233/234 andand allenyl-B-(pinacolato)
allenyl-B-(pinacolato) 2c mediated
2c mediated by by a sulfonate-containing
a sulfonate-containing NHC-Cu
NHC-Cu complex.
complex.
Focusing
Focusing on on allylic
allylic substitution,
substitution, in in another
another study,
study, 1,5-enynes
1,5-enynes 238238 were
were synthesized
synthesized
Focusing on allylic substitution, in another study, 1,5-enynes 238 were synthesized via
viavia a silver-catalyzed
a silver-catalyzed allylic
allylic substitution
substitution by by reacting
reacting a propargylic
a propargylic organoboron
organoboron com-
com-
a silver-catalyzed allylic substitution by reacting a propargylic organoboron compound
pound
pound 2a 2a with
with allylic
allylic phosphates
phosphates 237, 237, using
using a chiral
a chiral N-heterocyclic
N-heterocyclic carbene
carbene (NHC)
(NHC) ligand
ligand
2a with allylic phosphates 237, using a chiral N-heterocyclic carbene (NHC) ligand and
andand a silver
a silver catalyst
catalyst complexed
complexed to atocopper
a copper chloride
chloride saltsalt (Scheme
(Scheme 78)78) [195].
[195]. In all
In all cases,
cases, thethe
a silver catalyst complexed to a copper chloride salt (Scheme 78) [195]. In all cases, the
incorporation
incorporation of the
of the propargylic
propargylic groupgroup
waswas favored
favored overover allenyl
allenyl addition.
addition.
incorporation of the propargylic group was favored over allenyl addition.
Scheme 78. Ag-Catalyzed

Scheme
Scheme 78. 78. synthesis
Ag-Catalyzed
Ag-Catalyzed of the
synthesis of 1,5-enynes
synthesis of the
the 238 from
1,5-enynes
1,5-enynes 238238the
from reaction
from
thethe of allylic
reaction
reaction ofphosphates
allylic
of allylic 237 237237
phosphates
phosphates
with
withwith propargyl
propargyl
propargyl organoboron
organoboron
organoboron compound
compound
compound 2a. 2a. 2a.

2.8.2.
2.8.2. With
With Propargyl
Propargyl Alcohols
Alcohols
The 1,5-enynes 240 were synthesized via the reaction of allyltrimethylsilane 239
TheThe 1,5-enynes
1,5-enynes 240240 were
were synthesized
synthesized viavia
thethe reaction
reaction of allyltrimethylsilane
of allyltrimethylsilane 239239 with
with
with propargylic alcohols 63 in the presence of Bi(OTf)3 in [bmim][BF4 ] ionic liquid (IL)
propargylic
alcohols 63 63 in the
in the presence
presence of Bi(OTf)
of Bi(OTf) in [bmim][BF
3 in3 [bmim][BF 4] ionic
4] ionic liquid
liquid (IL)(IL) (Scheme
(Scheme
(Scheme 79). The reaction exhibited a broad substrate scope, with the possibility for the
79).79).
TheThe reaction
reaction exhibited
exhibited a broad
a broad substrate
substrate scope,
scope, with
with thethe possibility
possibility forfor
thethe recov-
recov-
recovery/reuse of the IL solvent with a minimal decrease in isolated yields, after six
ery/reuse
ery/reuse of the
of the IL solvent
IL solvent with
with a minimal
a minimal decrease
decrease in isolated
in isolated yields,
yields, after
after sixsix cycles
cycles [196].
[196].
cycles [196].
Scheme Scheme
Scheme 79. 79.
79. Synthesis Synthesis
Synthesis of the
the 1,5-enynes
of theof1,5-enynes
1,5-enynes 240240
240 from fromfrom allyltrimethylsilane
allyltrimethylsilane
allyltrimethylsilane 239
239 and 239
andand propargylic
propargylic
alcohols
alcohols 63
in the 63 the
in in the
63presence presence
presence
of of Bi(OTf)
of Bi(OTf)
Bi(OTf) 3/[bmim][BF
3/[bmim][BF
3 /[bmim][BF 4] system.
catalytic
4] catalytic
4 ] catalytic system.
system.
In another approach, diarylalkenyl propargylic frameworks 242 were synthesized via
In another approach,
an Fe-catalyzed reaction of diarylalkenyl propargylic
propargylic alcohols 63 withframeworks 242 wereand
various symmetric synthesized
asymmet-
via an Fe-catalyzed reaction of propargylic alcohols 63 with various symmetric
ric 1,1-diarylethylenes 241 (Scheme 80). The reaction worked well for a wide range and of
asym-
eth-
metric 1,1-diarylethylenes 241 (Scheme 80). The reaction worked well for a wide
ylenes 241 bearing electron-donating or electron-withdrawing groups (as R2 or R3 substit-range
of ethylenes 2 3
uents) [197]. 241 bearing electron-donating or electron-withdrawing groups (as R or R
substituents) [197].
Scheme
Scheme 80.
80. FeCl •6H2O-catalyzed
FeCl33•6H 2 O-catalyzed synthesis
synthesis of of diarylalkenyl
diarylalkenyl propargylic
propargylic derivatives
derivatives 242 using
242 using pro-
pargylic alcohols
propargylic 63 63
alcohols as propargylating agents.
as propargylating agents.
An
Anefficient
efficientcatalytic
catalyticmethod
method forfor
thethe
propargylation
propargylationof quinones 243 that
of quinones 243 benefits from
that benefits
the cooperative effect of Sc(OTf) 3 and Hantzsch ester (HE) has been reported, yielding
from the cooperative effect of Sc(OTf)3 and Hantzsch ester (HE) has been reported, yield- the
corresponding propargylated quinone derivatives 244 (Scheme 81). Using this
ing the corresponding propargylated quinone derivatives 244 (Scheme 81). Using this ap-approach,
aproach,
broad range ofrange
a broad propargylic alcoholsalcohols
of propargylic 63 were63converted into theinto
were converted appropriate propargyl
the appropriate pro-
derivatives 244 in acceptable to excellent yields [198].
pargyl derivatives 244 in acceptable to excellent yields [198].
Scheme 81. Cooperative catalytic propargylation of quinones 243 mediated by Sc(OTf)3 and Hantzsch
Scheme
ester (HE).81. Cooperative catalytic propargylation of quinones 243 mediated by Sc(OTf)3 and
Hantzsch ester (HE).

The development of enantioselective alkyl–alkyl cross-couplings with the formation
Molecules 2023, 28, 3379 38 of 61

The development of enantioselective alkyl–alkyl cross-couplings with the formation
of a stereogenic center is significant and highly desirable. In this context, the regio- and
enantioselective Ni-catalyzed hydropropargylation of acrylamides 245 yielded propargy-
lamides 246 bearing a tertiary stereogenic carbon center (Scheme 82). This protocol was
carried out using propargyl bromides with alkyl, aryl, and silyl substituents 19a in the
presence of a NiBr2 glyme, an (R,R)-L12 chiral ligand, trimethoxylsilane, potassium phos-
phate monohydrate, and tert-butanol in diethyl ether, producing Csp3 –Csp3 cross-coupling
products 246 in good yields and with excellent enantioselectivities [199].
Scheme 82. Regio- and enantioselective Ni-catalyzed synthesis of chiral propargylamides 246.
(b) Alkenes
2.8.4. With Propargyl Ethers/Esters

Allenamides have received increasing attention in recent decades due to their diverse
reactivity. In this context, highly diastereoselective oxy-propargylamination of allenamides
248 with C-alkynyl N-Boc-acetals as difunctionalization reagents 247 has been described,
which employs XPhosAu-(MeCN)PF6 as a catalyst. This methodology provided highly
functionalized propargyl-1,3-amino alcohol derivatives 249 in acceptable to good yields
and with good to excellent diastereoselectivities (Scheme 83) [200].
Scheme 83. Gold-catalyzed synthesis of propargyl-1,3-amino ether derivatives 249 from C-alkynyl
N-Boc-acetals 248 and allenamides 247.

A series of (E/Z)-3-amidodienynes 251 were synthesized via a tandem α-propargylation–
1,3-H isomerization reaction of chiral allenamides 250 and propargyl bromides 19a with
moderate E/Z ratios. Subsequently, the reactivities of these E/Z-isomers 251 were exam-
ined via thermal Diels–Alder cycloaddition reactions. The results showed that only the
(Z)-3-amidodienynes (Z)-251 reacted to provide endo-II products 253 (Scheme 84) [201].
Molecules 2023, 28, 3379 39 of 61
Scheme 84. Synthesis of (E/Z)-3-amidodienynes 251 via tandem α-propargylation–1,3-H isomeriza-

tion reaction of chiral allenamides 250 and propargyl bromides 19a and their Diels–Alder cycloaddi-
tions to produce cyclo-adducts 253.
(c) Enynes

The chemoselectivity in the 1,4-carbooxygenations of 3-en-1-ynamides 254 with propar-
gylic alcohols 63 was examined using a gold catalyst via non-Claisen pathways. The reac-
tions were performed with electron-rich propargylic alcohols 63, using Ph3 PAuCl/AgOTf
as a catalytic system in toluene, producing 1,4-oxopropargylation products 255 in good
yields and with high E-selectivity (Scheme 85) [202].
Scheme 85. Synthesis of 1,4-oxopropargylated products 255 from propargylic alcohols 63 using
Ph3 PAuCl/AgOTf as catalytic system.
A chiral ruthenium-based complex was prepared from (TFA)2 Ru(CO)(PPh3 )2 and

(R)-BINAP in order to catalyze the enantioselective C−C coupling of diverse-type primary
alcohols 187 with conjugated enyne 60. This approach produced secondary homopropargyl
alcohols 256 bearing gem-dimethyl groups in their structures (Scheme 86) [203].
Scheme 86. Ruthenium-mediated synthesis of secondary homopropargyl alcohols 256 from conju-
gated enyne substrate 60.
2.9. Carbanionic-Like Nucleophiles

Propargylations of 1,3-diketones 257 were achieved with propargylic alcohols 63
mediated by Lewis and Brønsted acidic ILs in the presence of the metallic triflate Sc(OTf)3
or Bi(NO3 )3 as catalysts, and produced products 258 (Scheme 87, entry 1). The scope of this
condensation reaction was investigated using a variety of propargylic alcohols and a host
of β-ketoesters 259 and cyclic dicarbonyl compounds 260, producing the corresponding
adducts 261 and 262, respectively. The [BMIM][PF6 ]/Bi(NO3 )3 •5H2 O catalytic system
Molecules 2023, 28, 3379 40 of 61
proved superior for propargylation reactions, and the IL solvent could be recycled and
reused [204].
Scheme 87. Propargylations of diverse dicarbonylic/dicarboxylic compounds

257/259/260/263/265/266 with propargylic alcohols 63 mediated by Lewis and Brønsted
acidic ILs using Sc(OTf)3 or Bi(NO3 )3 •5H2 O as catalysts.
Using Sc(OTf)3 as catalysts, alkynyl diesters 264 were synthesized via propargylations
of 1,3-diesters 263 using 3-sulfanyl and 3-selanylpropargyl alcohols 63 (R1 = SPh, SePh)
in MeNO2 –H2 O. Cyclic alkynyl diketones 265 and ketoesters 266 were similarly propar-
gylated, (Scheme 87, entry 2). Further, under the action of bases such as Bu4 NF, CsCO3 ,
K2 CO3 and NaH, some of the obtained propargylated derivatives 264, 267–268 underwent
intramolecular cyclization to give diversely substituted tetrahydro-benzofurans [205].
Propargylic alcohols can be activated towards SN 1-type reactions with nucleophiles
using a variety of Lewis acids or Brønsted acids as catalysts [206]. In this process, the highly
stereoselective organocatalytic alkylation of internal propargylic alcohols with aldehydes
has been described, with water used as a solvent, using a mixture of In(OTf)3 and the
MacMillan organocatalyst L*; these worked in a cooperative manner to produce propargyl
aldehydes 270 regioselectively (Scheme 88). The reported method is versatile and tolerates
diverse functional groups, allowing for the use of highly functionalized internal alkynes
63 and aldehydes 269 as precursors. According to the reaction conditions, the formation
of 270 proceeds via an SN 1-type reaction involving a stabilized propargylic cation species
formed via the ionization of propargylic alcohols 63 [207].
Scheme 88. Indium-mediated regioselective synthesis of propargyl aldehydes 270 from propargyl
alcohols 63 using MacMillan reagent L* as chiral organocatalyst.
Expanding on propargylation reactions mediated by Lewis and Brønsted acidic ILs

(in Scheme 87), a [BMIM][PF6 ]/Bi(NO3 )3 •5H2 O catalytic system proved efficient for the
Molecules 2023, 28, 3379 41 of 61
propargylation of 4-hydroxycoumarins 187b, producing the corresponding propargylated

4-hydroxycoumarins 271 (Scheme 89) [204].
Scheme 89. IL/Bi-mediated synthesis of C-propargylated 4-hydroxycoumarins 271 from propargyl

alcohols 63.
2.9.2. With Propargyl Halides/Phosphoesters

With the goal of synthesizing the bicyclic fragment (i.e., AE rings) of the Daphniphyl-
lum alkaloid yuzurine, the key intermediate 272 was synthesized via the diastereoselec-
tive propargylation of the α-position of lactone 271 with propargyl bromide 19a (X = Et)
(Scheme 90, entry 1) [208]. In other approach, the propargylation of Ugi adducts 273 with
propargyl bromide 19a (X = H), under the addition of excess sodium hydride in DMSO, led
to the direct formation of pyrrolidinone enamides 275. Products 275 were produced via the
intermediate formation of the propargyl derivatives 274, and cyclized in situ through the
action of NaH (Scheme 90, entry 2). The latter compounds 275 were identified as useful pre-
cursors of iminium intermediates, and were applied to the formation of benzoindolizidine
alkaloids via Ugi/propargylation/Pictet−Spengler cyclization [209].
Scheme 90. Propargylation reactions of diverse methyne/methylene-active compounds

271/273/276/278/280 with propargyl bromides 19a.
1,3-diester 276 was propargylated with propargyl bromide 19a (X = H) using metallic
zinc in DMF, producing the corresponding propargyl 1,3-diester 277 (Scheme 90,
entry 3) [210]. In the context of multistep asymmetric total synthesis, the propargyl in-
termediate 279 was synthesized in a highly stereoselective fashion via LDA-mediated
Molecules 2023, 28, 3379 42 of 61
propargylation of the 1,3-dioxolanone 278 with propargyl bromide 19a (X = H), producing
intermediate 279 (Scheme 90, entry 4) [211].
With the aim of evaluating the influence of ultrasound in association with a new phase-
transfer catalyst (PTC) for synthetic purposes, 2,2-di(prop-2-ynyl)-1H-indene-1,3(2H)-dione
281 was synthesized via the propargylation of indene-1,3-dione 280 with propargyl bromide
19a (X = H) using aqueous potassium hydroxide under phase-transfer catalysis, employing
N-benzyl-N-ethyl-N-isopropylpropan-2-ammonium bromide and ultrasonic irradiation in
chlorobenzene (Scheme 90, entry 5). Based on a kinetic study, it was established that the
overall reaction rate can be greatly enhanced with ultrasound irradiation [212].
Scheme 91 illustrates the reported synthesis of γ-ketoacetylene 284 via a conden-
sation reaction between propargyl chloride 282 and β-keto ester 283 in the presence of
sodium hydride [213]. This compound is a key intermediate in the biomimetic synthesis of
plumarellide, a polycyclic diterpene [214].
Scheme 91. Synthesis of the γ-ketoacetylene 284 via a condensation reaction between propargyl
chloride 282 and β-keto ester 283 in the presence of sodium hydride.
1,4-Diynes are valuable and versatile synthons for natural products, organometallic
complexes, and the synthesis of novel molecules [215]. Scheme 92 illustrates a reported
method for the catalytic synthesis of difluorinated compounds 286, difluoromethylene
(CF2 )-skipped 1,4-diynes, via palladium-catalyzed cross-coupling between terminal alkynes
62 and gem-difluoropropargyl bromide 285 in toluene. The method exhibited high func-
tional group tolerance and a broad substrate scope [216].
Scheme 92. Pd-catalyzed synthesis of difluoromethylene (CF2 )-skipped 1,4-diynes 286 from reaction
of gem-difluoropropargyl bromide 285 with terminal alkynes 62.
Compounds bearing a quaternary carbon stereocenter are important building blocks

in medicinal chemistry, and are found in biologically active compounds such as pharma-
ceuticals and agrochemicals. Scheme 93 illustrates an efficient enantioselective method
for the asymmetric α-alkylation of α-branched aldehydes 204 with propargyl bromide 19a
to generate products 287 bearing a chiral quaternary carbon stereocenter. The reaction
proceeds through enamine-based organocatalysis using a chiral primary amino acid as a
catalyst [217].
Scheme 93. Asymmetric α-propargylation of α-branched aldehydes 204 mediated via primary amino
acid catalyst.
Molecules 2023, 28, 3379 43 of 61
Propargylated products 289 were synthesized via the Suzuki-type coupling of propar-
gylic electrophiles 19d/109 with diborylmethane 288, using CuI/PPh3 as the catalytic
system and tBuOLi as a base, under mild conditions with good functional group tolerance
(Scheme 94) [218].
Scheme 94. CuI/PPh3 -mediated Suzuki–Miyaura-type cross-coupling reaction for the synthesis of
propargylated products 289 from propargyl electrophiles 19d/109 and diborylmethane 288.
2.9.3. With Propargyl Ethers or Esters

The diastereo- and enantioselective synthesis of 2,2-disubstituted benzofuran-3(2H)-
ones 291 was achieved via a “copper-pybox”-catalyzed reaction between 2-substituted
benzofuran-3(2H)-ones 290 and propargyl acetates 200 (R = Ac), as outlined in Scheme 95,
entry 1. The positive attributes of the method were good functional group tolerance and
broad substrate scope. The utility of the method was demonstrated by further transfor-
mation of the terminal alkyne of 291 into a methyl ketone without loss of enantiomeric
purity [219]. Using a similar approach, propargyl tricarboxylate derivatives 293 were
synthesized via the copper-catalyzed enantioselective propargylation of triethylmethanet-
ricarboxylate 292 with propargylic alcohol derivatives 200. The active catalyst “copper-
pybox” was generated by combining the copper complex Cu(CH3 CN)4 BF4 with (S)-sec-
butyl-Pybox (Ligand L1*) at low temperatures in methanol, with DIPEA as base, as out-
lined in Scheme 95, entry 2. The scope of the methodology was demonstrated using
phenyl-substituted propargylic substrates 200 bearing electron-donating as well as electron-
withdrawing groups at the para-position of the phenyl ring [220].
Scheme 95. Copper-catalyzed diastereo- and enantioselective synthesis of propargylated compounds

291/293 using propargyl acetates 200 as propargylation reagents.
The efficacy of the copper–ligand complexes in stereoselective synthesis with propar-

gyl esters are showcased here with the following examples, sketched in Scheme 96:
Molecules 2023, 28, 3379 44 of 61
Scheme 96. Efficacy of the copper–ligand complexes in stereoselective α-propargylation of diverse

carbonylic/carboxylic compound 294/296/298/301/302 with propargyl esters 200.
(i) The synthesis of a series of optically active 3,3-disubstituted oxindole skeletons 295
bearing vicinal tertiary and all-carbon quaternary stereocenters via the propargyla-
tion of 3-substituted oxindoles 294 with propargylic acetates 200, using Cu(ACN)4 PF6
combined with a chiral tridentate ferrocenyl, P,N,N-ligand L1*, in methanol,
entry 1 [221].
(ii) The synthesis of a series of propargyl nitro derivatives 297 bearing two contiguous
stereogenic centers by reacting propargylic carbonates 200 with α-substituted nitroac-
etates 296 using Cu−pybox as catalyst. The most striking features of these reactions
are the observed high diastereo- and enantioselectivities. Products 297 were further
employed as precursors of non-proteinogenic quaternary α-amino acids after the
reduction of their nitro groups, entry 2 [222].
(iii) The synthesis of highly functionalized chiral propargylated P-ylides 299 via the copper-
catalyzed asymmetric propargylation of phosphonium salts 298 with racemic propar-
gylic esters 200, in the presence of the chiral ligand L*, and further Wittig reactions of
299 with aliphatic aldehydes; this led to the synthesis of diversely substituted chiral
propargylated alkene building blocks 300 (Scheme 96, entry 3), with a wide substrate
scope and satisfactory functional group compatibility [223].
(iv) The synthesis of terminal alkyne-containing products 303 and 304 bearing two vicinal
stereocenters via an asymmetric propargylic substitution (APS) reaction of thiazolones
301 (A = S) and oxazolones 302 (A = O) with propargyl esters 200 (X = H) medi-
ated by Cu/Zn and Cu/Ti dual metal catalytic systems (Scheme 96, entry 4). The
resulting functional group-rich products exhibited good to excellent diastereo- and
enantioselectivities [224].
(v) The enantioselective synthesis of propargylic diesters 305 via a nickel/Lewis acid-
catalyzed asymmetric propargyl substitution, by reacting achiral starting-type mate-
rials 263 and 54 under mild conditions. The introduction of a Lewis acid cocatalyst
such as Yb(OTf)3 was crucial in transforming the mixture of 263 and 54 into products
Molecules 2023, 28, 3379 45 of 61
305 (Scheme 97). Further, this asymmetric propargylic substitution reaction was in-
vestigated for the development of a range of structurally diverse natural products
and seven biologically active compounds, namely, (−)-thiohexital, (+)-thiopental,
(+)-pentobarbital, (−)-AMG 837, (+)-phenoxanol, (+)-citralis, and (−)-citralis, demon-
strating the efficacy of this asymmetric strategy [225].
Scheme 97. Nickel/Lewis acid-catalyzed asymmetric synthesis of propargylic diesters 305.
(vi) Enantioselective copper-catalyzed vinylogous propargylic substitution with coumarin

derivatives. In this approach, aromatic and aliphatic propargylic esters 200 reacted
with substituted coumarins 306 under mild conditions to yield propargylated coumarin
derivatives 307 with impressive enantioselectivities (Scheme 98). Further, biological
studies on the compounds 307 led to the discovery of a novel class of autophagy
inhibitors [226].
Scheme 98. Copper-catalyzed synthesis of propargyl-substituted coumarins 307 from propargylic

esters 200.
A catalytic system based on bis(triphenylphosphine)palladium (II) dichloride, Ag2 CO3 ,

and phosphine-based ligand L was developed for the one-pot selective synthesis of di-
versely substituted dihydrofuro[3,2-c]coumarins 308. The synthetic strategy involved
a propargylation reaction between propargylic carbonates 54 and 4-hydroxycoumarins
187b, mediated by the aforementioned catalytic system (Scheme 99). Mechanistic studies
have suggested that 4-hydroxycoumarins 187b react with an η 1 –(propargyl)palladium
complex, formed in situ, to generate the key terminal alkyne intermediate 271, which
undergoes selective intramolecular 5-exo-dig cyclization to give the isolated products 308 in
one pot [227].
Scheme 99. Use of the bis(triphenylphosphine)palladium(II) dichloride-/Ag2 CO3 -/phosphine-based

ligand L catalytic system for propargylation of 4-hydroxycoumarins 187b with propargylic carbonates 54.
Molecules 2023, 28, 3379 46 of 61
A series of substituted pyrrole derivatives 310 were synthesized via a zinc(II) chloride-
catalyzed regioselective propargylation/amination/cycloisomerization process by reacting
enoxysilanes 309 with propargylic acetates 200 and primary amines 94. This method was
applicable to a variety of aromatic and aliphatic propargylic acetates 200 without the
necessity of isolating intermediates such as 258 (Scheme 100) [228].
Scheme 100. Zinc(II) chloride-catalyzed three-component and regioselective propargylation of

enoxysilanes 309 with propargylic acetates 200.
A series of diversely substituted propargyl ethers 311 were obtained via a Re(I)-
catalyzed hydropropargylation reaction between silyl enol ethers 309 and propargyl ether
191 (Scheme 101). Mechanistic studies suggested that the reaction proceeded via the
intermediacy of vinylidene–alkenyl metal intermediates undergoing a 1,5-hydride transfer
to generate the isolated products 311 [229].
Scheme 101. Re(I)- catalyzed synthesis of propargyl ethers 311 from hydropropargylation reaction
between silyl enol ethers 309 and propargyl ether 191.
Fully substituted pyrroles are important bioactive motifs, and are widely presented in
many biologically active compounds and natural products [230]. In this context, a copper-
catalyzed and microwave-assisted tandem propargylation/alkyne azacyclization/isomerization
sequence between propargyl acetates 200 and β-enamino compounds 312 was established
(Scheme 102). Through this process, a series of pentasubstituted pyrroles 314 were synthe-
sized. This transformation was characterized by a broad substrate scope that tolerated diverse
substituents in its starting materials 200 and 312, and could be scaled up for further biomed-
ical research. A mechanistic sequence in which an enyne-like structure 313 acts as a key
intermediate in the catalytic cycle was proposed [231].
Scheme 102. Copper-catalyzed and microwave-assisted synthesis of propargyl intermediates 313 via
propargylation of β-enamino compounds 312 with propargyl acetates 200.
A highly diastereo- and enantioselective method for the synthesis of compounds

316/317 bearing vicinal tertiary stereocenters was devised by reacting propargylic acetates
200 with morpholine-derived cyclic enamine 315, in the presence of a copper catalyst, a
chiral tridentate P,N,N-ligand ((R)-L*), and iPr2 NEt in MeOH. This approach was compati-
ble with a wide range of substrates 200, producing chiral propargylated cyclohexanones
316/317 in good yields and with excellent diastereoselectivity (Scheme 103) [232].
Molecules 2023, 28, 3379 47 of 61
Scheme 103. Copper-mediated diastereoselective synthesis of chiral propargylated cyclohexanones

316/317 from propargyl acetates 200 in the presence of the chiral tridentate P,N,N-ligand ((R)-L*).
2.9.4. With 1,3-Diarylpropynes

Direct C–C coupling from Csp3 –H bonds with molecular oxygen as the terminal
oxidant continues to be a challenging task. In this context, diversely substituted propargyl
adducts 318 were synthesized via a coupling reaction between 1,3-dicarbonyl compounds
257/259 and 1,3-diarylpropynes 57 in the presence of molecular oxygen, DDQ, and sodium
nitrite (Scheme 104). The addition of HCO2 H dramatically increased the speed of the
process [233].
Scheme 104. Synthesis of propargyl adducts 318 from a coupling reaction between 1,3-dicarbonyl
compounds 257/259 and 1,3-diarylpropynes 57 in the presence of molecular oxygen, DDQ, and
sodium nitrite.
2.9.5. With Propargyl Aldehydes

The metal-free, amino acid-catalyzed, three-component reductive coupling of propar-
gyl aldehydes 319 and cyclic/acyclic methylene-active compounds 320/321, in the presence
of Hantzsch ester and (S)-proline as catalysts, produced diversely substituted and gram-
scalable propargylated cyclic/acyclic systems 322/323 (Scheme 105). To demonstrate the
synthetic value of this protocol, in selected cases, adducts 322/323 were further transformed
into dihydropyran derivatives through an annulative etherification reaction using AgOTf
as a catalyst [234].
Scheme 105. (S)-Proline-catalyzed three-component reductive coupling of propargyl aldehydes 319

with methylene-active compounds 320/321 in the presence of Hantzsch ester.
Molecules 2023, 28, 3379 48 of 61
The propargylated alcohol 325 was synthesized via catalytic asymmetric propargyla-
tion of the highly enolizable β-keto-lactone 324 with propargyl aldehyde 319 (Scheme 106).
The reaction was mediated by an Evans aldol type reaction [235], promoted by rigorously
acid-free Sn(OTf)2 . Notably, the synthesis of this compound was a key step in the total
synthesis of leiodermatolide, a natural product derived from a deep-sea sponge with potent
cytotoxic activity (Scheme 106) [236].
Scheme 106. Synthesis of propargylated alcohol 325 via catalytic asymmetric propargylation of the
enolizable β-keto-lactone 324 with propargyl aldehyde 319.
2.10. Carbocationic Electrophiles

With Propargyl Organometallic-Based Reagents
A series of diversely substituted o-propargylated phenols 327 were obtained through
the transition metal-free alkynylation of substituted 2-(tosylmethyl)phenols 326 with
bromo(alkynyl)zinc reagents 89, generated from the corresponding terminal alkyne with
BuLi and ZnBr2 , under N2 at room temperature. This efficient strategy exhibited good func-
tional group compatibility (Scheme 107). The products were further used as intermediates
for the synthesis of 2,3-disubstituted benzofurans [237].
Scheme 107. Bromo(alkynyl)zinc-mediated synthesis of o-propargylated phenols 327 from 2-

(tosylmethyl)phenols 326.
A method for the synthesis of spiroketals 329 bearing a five-membered and a seven-
or eight-membered ring was described. In this approach, initially, the alkyne 328 was
treated with Co2 (CO)8 in DCM at room temperature to form the corresponding alkyne–
Co2 (CO)6 complex intermediates, which were subsequently exposed to BF3 •OEt2 at low
temperature to produce the desired dioxaspiro[4.7]-compounds 329 (Scheme 108). This
method was applicable to cyclopropanes possessing gem-disubstituents, as well as mono-
aryl substituents [238].
Scheme 108. Synthesis of spiroketal derivatives 329 from propargyl derivatives 328 mediated by
Co2 (CO)6 /BF3 •OEt2 complex.
The synthesis of a series of propargylic and homopropargylic alcohols 331/332 was

accomplished via the reaction of epoxides 330 with 3,3,4,4-tetraethoxybut-1-yne acetylide
89 (M = Mg). The use of a MgBr counterion in the acetylide proved superior for the selective
formation of propargylic alcohol 331, while the use of a lithium acetylide and BF3, followed
by hydrolysis, gave homopropargylic alcohols 332 (Scheme 109) [239].
Molecules 2023, 28, 3379 49 of 61
Scheme 109. Synthesis of propargylic and homopropargylic alcohols 331/332 from the reaction of
acetylide 89 with epoxides 330.
2.11. Free-Radical-like Precursors

2.11.1. With Propargyl Halides
Among the metal catalysts that promote alcohol C-H functionalization via C-X bond
reductive cleavage pathways, rhodium-based catalysts were shown to be promising can-
didates [240]. In this sense, the carbinol C-propargylation of alcohols 187 with propargyl
chlorides 19d in basic media, under rhodium-catalyzed transfer hydrogenation, enabled the
direct conversion of primary alcohols 187 into propargylated alcohols 13. Interestingly, this
methodology tolerated benzylic and heteroaromatic benzylic alcohols, as well as aliphatic
and allylic alcohols 187, producing the expected homopropargyl alcohols 13 in good yields
(Scheme 110) [241].
Scheme 110. Synthesis of homopropargyl alcohols 13 via Rh-catalyzed C-C coupling of primary
alcohols 187 with propargyl chlorides 19d.
A radical hydrodifluoropropargylation method in which alkenes 241 are reacted

with silyl-protected bromodifluoropropyne 285 in DMF, at room temperature and under
irradiation with blue LEDs, has been described [242]. The method employed diphenyld-
isulfide and benzothiazoline 333 as reductants, yielding silyl-protected difluoropropar-
gylated products 334 in acceptable to good yields, with wide functional group tolerance
(Scheme 111) [242].
Scheme 111. Blue LED-catalyzed synthesis of difluoropropargylated products 334 from alkenes 241
and silyl-protected bromodifluoropropyne 285 as propargylating agent.
Molecules 2023, 28, 3379 50 of 61
2.11.2. With 1,3-Enynes

The 1,3-enyne moiety has been recognized as an alternative pronucleophile for the
carbonyl propargylation process [243]. Radical carbonyl propargylation via dual chromium/
photoredox catalysis was recently reported [244]. Using this approach, a library of homo-
propargylic alcohols 336 bearing all-carbon quaternary centers was synthesized (Scheme 112)
via the catalytic radical tricomponent coupling of 1,3-enynes 60 (R2 = Me, CH2 OH), alde-
hydes 1, and suitable radical precursors (Hantzsch ester) 335 in the presence of an iridium-
based photocatalyst (PC). This redox-neutral multi-component reaction occurred under
mild conditions and showed high functional group tolerance, producing products 336 with
acceptable diastereomeric ratios [244].
Scheme 112. Enyne-mediated synthesis of homopropargylic alcohols 336 through radical carbonyl
propargylation via dual chromium/photoredox catalysis.
2.12. Boronic Acids (ArB(OH)2 )

With Propargyl Bromides
The efficient microwave-assisted (MW), two-step synthesis of N-aryl propargylamines
144 from aromatic boronic acids 337, aqueous ammonia, and propargyl bromide 19a was
reported. The first step involved copper-catalyzed coupling of aromatic boronic acids 337
with aqueous ammonia, which reacted with propargyl bromide 19a in the second step to
give a propargylamine derivative 144 (Scheme 113, entry 1) [245]. In another approach, gem-
difluoropropargyl derivatives 190 were prepared via the difluoropropargylation of boronic
acids 337 with gem-difluoropropargyl bromide 285, by employing [Pd2 (dba)3 ]/P(o-Tol)3
(L1) as a catalyst in the presence of K2 CO3 in dioxane (Scheme 113, entry 2) [246].
Scheme 113. Synthesis of propargyl derivatives 190 and 144 from coupling reactions of propargyl
bromides 285 and 19a with boronic acid reagents 337.
2.13. Nitrones
The propargylation of chiral nonracemic mono- and poly-hydroxylated cyclic nitrone
derivatives 338–340 with Grignard reagents (generated in situ) was established as an
efficient method for preparing building blocks containing an alkyne moiety 341–343. These
compounds were then employed in copper-catalyzed azide alkyne cycloaddition click
chemistry [247]. The synthesis of 341–343 was accompanied, in most cases, by the formation
of diastereomeric mixtures, and also required the use of (trimethylsilyl)propargyl bromide
19a as a precursor for the formation of the Grignard reagent, in order to avoid the formation
of undesired allene derivatives (Scheme 114).
Molecules 2023, 28, 3379 51 of 61
Scheme 114. Propargylation of chiral nonracemic mono- and poly-hydroxylated cyclic nitrones
338–340 with propargylated Grignard reagents (generated in situ) from TMS-propargyl bromide 19a.
3. Conclusions and Outlook

This review has underscored the importance of the propargyl moiety as a highly versa-
tile and powerful building block in organic synthesis. Propargylic and homopropargylic
reagents have been synthesized from a variety of precursors and applied to a highly diverse
array of substrates to synthesize propargylated derivatives. Judicious selections of catalysts,
co-catalysts, and chiral ligands have resulted in the development the stereo- and enantio-
selective synthesis of numerous functional small molecules, with applications in natural
products and medicinal chemistry. The progress in this area during the last decade has been
nothing short of astonishing. Clearly, this is a highly dynamic and continuously evolving
research area, and we are confident that it will continue to advance in the coming decade.
Author Contributions: K.K.L. conceived the project and worked with R.A. and D.I. through various
stages of manuscript, including organization/development, writing/rewriting, reviewing, and edit-
ing. R.A. constructed the project, organized the material, and wrote various drafts of the manuscript
with D.I., R.A. and D.I. performed the literature searches, assembled the references, and prepared the
graphics and tables. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Acknowledgments: D.I. thanks the Universidad del Norte for their partial financial support of this
work. R.A. thanks Minciencias, the Universidad del Valle, and CIBioFi for their partial financial
support. We are thankful to the reviewer of this paper for bringing to our attention references to
shorter, more focused reviews within the topic, which we have cited as [248–250].
Conflicts of Interest: The authors declare no conflict of interest.
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molecules

1 Research Group of Heterocyclic Compounds, Department of Chemistry, Universidad del Valle,

Copyright: © 2023 by the authors.

Molecules 2023, 28, 3379. https://doi.org/10.3390/molecules28083379 https://www.mdpi.com/journal/molecules

Entry Type of Substrates

2.1.1. With Boron-Based Propargyl Reagents

Table 2. Propargylation of diversely substituted aldehydes/ketones 1 with propargyl-/allenyl

Chiral Number of Yield (%)

cat. (7%) Cu(II)(isobutyrate)2 , (7%) tBuOLi,

cat. (1.2 equiv.) Et2 Zn, DCM, 20 ◦ C, 1 h

cat. (20%) Et2 Zn, THF, 20 ◦ C, 18 h

Computational study; R = Ph; R1 = Me; chiral BINOL

Scheme 4. Synthesis of homopropargyl alcohols 11 from aldehydes/ketones 1 and allenyltrifluorobo-

2.1.2. With Propargyl Silanes

Scheme 5. Organosilver-catalyzed asymmetric synthesis of homopropargylic alcohols 13 from

Allenyltrichlorosilane is an attractive candidate as a nucleophilic partner in C=O and

can efficiently catalyze the addition of allenyltrichlorosilane 14 to aromatic aldehydes 1

Scheme 6. Asymmetric synthesis of homopropargylic alcohols 15 from allenyltrichlorosilane 14 and

Scheme 7. Gold-catalyzed bispropargylation of xanthones and thioxanthones 16.

2.1.3. With Propargyl Halides

previously achievable for aromatic, heteroaromatic, and α,β-unsaturated aldehydes using

ZnEt2 (220 mol%), DCM (0.1 M), 4Å MS, 19b (X = I) or

CrCl3 •(THF)3 (10 mol%), TEA (20 mol%),

Electrochemical condition, H2 O-THF (8:2),

Computational study; R = tBu, iPr, Bu, Cy,

A protocol for the total synthesis of (–)-epiquinamide involving the L-proline-catalyzed

A stereospecific Barbier-type reaction of α-hydroxyketones 25 with propargyl

The synthesis of homopropargyl alcohol 31 with a two-carbon extension was achieved

Scheme 10. Zinc(0)-mediated synthesis of homopropargyl alcohols 31.

Aldehydes 1 were transformed into their corresponding homopropargyl alcohols 32

Scheme 11. Cu-Catalyzed/Mn-mediated chemo-selective synthesis of homopropargyl alcohols 32.

2.1.4. With Organometallic Propargyl Reagents

The esters of 4-hydroxybut-2-ynoic acid (alkyl 4-hydroxybut-2-ynoates) 42 are promis-

Scheme 14. Synthesis of 4-hydroxybut-2-ynoates 42 from carbonyl compounds and lithiated

epoxides 45 were prepared via the propargylation of α-bromoketones 43 with an organozinc

2.1.5. With Propargylic Ethers, Acids, and Esters

Scheme 16. Pd0 /Et2 Zn-mediated synthesis of 2-alkynylcyclopentanols 47 from carbonyl-tethered

Scheme 17. Pd-mediated stereoselective Marshall allenylation of aldehyde 48 with (S)-propargylic

The transition metal-catalyzed carbonyl propargylation protocol is an elegant approach

Scheme 18. Three-component synthesis of homopropargylic alcohols 53 mediated by 3-

In a similar way, low-valent indium(I)-mediated nickel-catalyzed propargylation

2.1.6. With Methylene-Active Propargyl Compounds

Scheme 20. Gold-catalyzed synthesis of homopropargyl alcohol intermediates 58 from propargyl

2.1.7. With 1,3-Enynes

reversible enyne hydrometalation in advance of carbonyl addition. Additionally, it was

Scheme 21. Ru-catalyzed synthesis of (α-methyl)homopropargyl alcohols 61 from enyne 60 and

2.1.8. With Aryl-Acetylenes

Scheme 23. Copper(I)-catalyzed stereodivergent anomeric propargylation of unprotected aldose 66

In a similar way, copper(I)-catalyzed stereodivergent nucleophilic propargylation

Scheme 24. Copper(I)-catalyzed stereodivergent nucleophilic propargylation of the unprotected

2.2. (a) Imines, (b) Iminium, and (c) Azo Compounds

2.2.1. With Propargyl Halide/Metal Reagents

Scheme 25. Diverse synthetic approaches of homopropargylamines 74 to the reaction of chiral

In another approach, a highly efficient method for the asymmetric synthesis of a

Scheme 26. Zn-mediated propargylation/lactamization cascade reaction of chiral 2-formylbenzoate-

An efficient approach to the synthesis of α,α-bispropargyl-substituted amines 78 in ac-

2.2.2. With Propargyl/Allenyl Boron Reagents

Scheme 29. Propargyl-/allenylboron-mediated synthesis of diverse propargyl derivatives 74/83/85/87

Allenylborolane 2c (instead of propargyl borolane 2a) was employed in the enan-