Title: Synthesis of Nitrogen-Containing Heterocycles and

Cyclopentenone Derivatives via Phosphine-Catalyzed Michael

Addition/Intramolecular Wittig Reaction

Authors: Nidal Saleh, Florent Blanchard, and Arnaud Voituriez

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))

Synthesis of Nitrogen-Containing Heterocycles and

Cyclopentenone Derivatives via Phosphine-Catalyzed Michael
Addition/Intramolecular Wittig Reaction
Nidal Saleh, Florent Blanchard and Arnaud Voituriez*
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, 1 av. de la
Terrasse, 91198 Gif-sur-Yvette, France. E-mail: [email protected]; Fax : +33 (0)1 69 07 72 47.

Received: ((will be filled in by the editorial staff))

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.

Abstract. The phosphine-catalyzed Michael Either classical heating or microwave conditions give
addition/intramolecular Wittig reaction between dialkyl access to the desired products in good yields (15 examples,
acetylenedicarboxylate and amino-carbaldehyde or amino- 60-99% yields). This catalytic methodology is further
ester derivatives has been developped. This reaction can be applicable to the synthesis of enantioenriched 1H-pyrrole
rendered catalytic in phosphine by the in situ chemoselective derivatives, with the use of chiral phosphines. Finally, we
reduction of the phosphine oxide with silane. This successfully extended the reaction to the synthesis of
methodology enables rapid access to a variety of nitrogen- polysubstituted cyclopentenone, starting from butane-2,3-
containing heterocycles, which are present in numerous dione as substrate.
natural products and/or bioactive compounds.
Keywords: Phosphine; Organocatalysis; In situ reduction;
Cyclization; Wittig reaction

molecular Wittig reaction between dialkylacetylene-

Introduction dicarboxylate (DAAD) and indole-2-carboxaldehyde
derivatives, for the synthesis of highly functionalized
Stoichiometric phosphine-promoted processes, 9H-pyrrolo[1,2-a]indoles (Scheme 1a).[9]
such as the Wittig, Staudinger, and Mitsunobu
reactions are widely used in organic synthesis.[1] In
addition to these well-known transformations, some
interesting phosphine-mediated annulation reactions
have been recently described, giving access to a wide
range of heterocycles.[2] Despite their usefulness,
these reactions possess a major drawback, namely the
concomitant formation of a stoichiometric quantity of
phosphine oxide, which often complicates the
purification of large-scale processes and globally
decreases the atom economy.[3] With the aim of
developing a more environmentally friendly
chemistry, a substoichiometric amount of phosphine
should be ideally employed. To reach this goal,
different strategies have been undertaken, such as the
activation of the phosphine oxide with isocyanates[4]
or oxalyl chloride,[5] and the in situ chemoselective
reduction of the phosphine oxide formed during the
reaction. The latter strategy is the most popular,[6] and
consequently many reactions were already rendered
catalytic in phosphine (catalytic loading of 5-20
mol%) upon using a stoichiometric quantity of a Scheme 1. Phosphine-catalyzed synthesis of nitrogen-
reducing agent, such as silane.[7] containing heterocycles and cyclopentenone derivatives.
Relying on this strategy, we have developed the
first catalytic cyclization reactions between the so-
called Huisgen zwitterion and ketoester Herein, we propose to fully explore the scope of
derivatives.[8] Recently, we also reported the first the catalytic addition/intramolecular Wittig reaction
phosphine-catalyzed sequential addition/intra- between DAAD, amino-carbaldehyde and amino-

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

ester derivatives, and therefore expand our the possibility of developing the first catalytic and
methodology towards an easy access to plenty of N- asymmetric version of such tandem
containing condensed heterocycles (Scheme 1b). addition/intramolecular Wittig reaction. To further
Although few of these structures have already been validate the synthetic flexibility of this methodology,
obtained by using stoichiometric amounts of we envisioned applying it to a wide range of
phosphine,[10] other products were directly substrates, and the main results of these studies are
synthesized with this catalytic methodology. The summarized hereafter.
process proved to be very efficient for developing
quickly a library of various heterocyclic scaffolds
well known for their biological properties and their Results and Discussion
presence in many drugs.[11] For example, as shown in
Figure 1, mitomycin A (I) based on a pyrrolo[1,2- I) Phosphine-catalyzed synthesis of diverse
a]indole core is an effective anti-tumor agent.[12] nitrogen-containing condensed heterocycles.
Licofelone (II) based on a pyrrolizine core is an
analgesic, an anti-inflammatory agent, and considered The major challenges to circumvent during the
as a treatment for osteoarthritis.[13] Vinpocetine (III), development of phosphine-catalyzed reactions are: i)
based on an indole-naphthyridine backbone, enhances the choice of an appropriate reducing agent to
the cerebral blood-flow, has neuroprotective effects chemoselectively reduce in situ the phosphine oxide
and was used as a drug for the treatment of without altering the starting materials, intermediates,
cerebrovascular disorders.[14] and/or products; ii) the phosphine oxide should be
easily reduced and iii) the trivalent phosphine should
exhibit a good nucleophilicity. It is well known
nowadays that the 5-membered ring cyclic phosphines
possess these features and that [R3SiH/Brønsted acid]
as a reducing system can tolerate a wide range of
functional groups.[6a,7c,8,9] Moreover, the mixture
phenylsilane/bis(4-nitrophenyl)phosphate is known to
reduce efficiently five-membered ring cyclic
phosphine oxide at 60°C in toluene. Indeed, the 4-
methyl-1-phenyl-2,3-dihydrophosphole P1 catalyst
proved to be very efficient in the synthesis of pyrrolo-
indole and pyrrolizine derivatives (scheme 1a).[9]
So, we decided to fully explore the substrate scope
of this reaction, by using different amino-
carbaldehydes (Table 1). Using the catalytic system
{P1 (5 mol %) as pre-catalyst, 5 mol % of bis(4-
nitrophenyl)phosphate, phenylsilane (1 equiv.), for 16
hours at 60°C}, a wide range of umpolung
addition/Wittig reactions was developed, giving
access to a variety of N-containing condensed
heterocycles. First of all, the diethyl 7-bromo-9H-
pyrrolo[1,2-a]indole-2,3-dicarboxylate product 3a
was synthesized in 92% yield (Table 1, entry 1).[9]
Figure 1. Some natural and bioactive products containing The structural assignment of this molecule was
the targeted heterocycles and carbocycles. ascertained by single crystal X-ray analysis (Figure
2a), that verified the double bond migration after the
intramolecular Wittig reaction (see the mechanism
In addition to N-containing heterocycles, the Scheme 2). Similarly, we were able to generalize the
“catalytic addition/intramolecular Wittig synthesis of dialkyl 3H-pyrrolizine-5,6-dicarboxylate
reaction“ methodology can be interestingly extended derivatives 3ba-3bc from 1b. Starting from
towards the synthesis of 4-oxocyclopent-2-ene-1,2- commercially available pyrrole-2-carbaldehyde and
dicarboxylate derivatives. This skeleton was found in dimethyl, diethyl, and di-tert-butyl acetylene
several drugs such as alprostadil[15] (IV) dicarboxylate 2a-c, the corresponding 3H-pyrrolizines
(Prostaglandin E1 (PGE1)), used in the continuous 3ba-3bc were obtained in 83-90% yields (entries 2-4).
treatment of erectile dysfunction,[16] as well as in It is worth noting that the structure of this bicyclic
natural products such as Jasmone (V) which is a backbone was confirmed by X-ray diffraction study
volatile portion of the oil from jasmine flowers. on crystals of 3ba (Figure 2b). The more stable 3H-
Trilobolide (VI), a bioactive compound possessing pyrrolizine isomer was isolated, contrary to the
anticancer activities, could be synthesized also from chemical structure of 1H-pyrrolizine, reported by
this key builduing block.[17] In addition, our Yavari et al.[10c] By 1H and 13C NMR analysis, we
methodology gives access to products containing have the characteristic signals of the -NCH2- moiety
stereogenic centers, thus we were interested to assess of 3ba [4.66 (CH2); 55.4 (CH2)] [ 4.76 (CH2); 55.1

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

(CH2)][10c] and 3bc [4.70 (CH2); 55.1 (CH2)] [ 4.69 solubility problems of the starting material 1e
(CH2); 55.1 (CH2)].[10c] occurred, forcing the use of THF as a co-solvent to
Diethyl 4H-pyrrolo[3,2,1-ij]quinoline-4,5- ensure a decent yield. Similarly, 1-Boc-2,3-diethyl
dicarboxylate derivatives 3c,d (entries 5,6) were quinoline-1,2,3(2H)-dicarboxylate 3f was obtained in
obtained in 96% and 94% yield, respectively, from 73% yield (entry 8) and the tricyclic diethyl 1-tosyl-
commercially available 1H-indole-7-carbaldehydes. 1,2-dihydrobenzo[4,5]thieno[3,2-b]pyridine-2,3-
Once more, the structure of 3c was confirmed by X- dicarboxylate 3g in 60% yield (entry 9).
ray diffraction studies (Figure 2c).
Table 1. Scope of different classes of N-containing
condensed heterocycles.

Figure 2. ORTEP-3 plot of a) 3a (CCDC 1489491); b) 3ba

(CCDC 1489494); c) 3c (CCDC 1489495) and d) 5d
(CCDC 1489493). Ellipsoids are drawn at the 50%
probability level and H atoms are shown as spheres of
arbitrary radius.

Inspired by Werner and coworkers, who developed

the first microwave-assisted catalytic Wittig reaction
(CWR),[18] we decided to switch from classical
heating conditions (oil bath, 60°C, 16h) to microwave
heating (100°C, 2h). Keeping the reaction conditions
developed previously, we studied the microwave-
assisted performance of the addition/intramolecular
CWR on the same substrates. Interestingly, all the
reactions in table 1 (except for entry 7) were finished
just after 2 hours while heating at 100°C, without
decreasing the yields. On the contrary, the yields were
even enhanced with some substrates (entries 3, 5, 6).
Increasing the reaction temperature did not have any
influences in the reaction time or in the reaction
yields. The only disappointing result came from the
substrate 1e (entry 7), due to the low solubility of
pyrido[3,4-b]indole-aldehyde substrate in toluene.
This catalytic system showed to be very efficient
and allows an easy access to a wide library of
different N-containing condensed heterocycles with
very high yields and faster reaction rates.
a)
Isolated yields. b) Classical heating, using an oil bath,
60°C, 16h. c) Microwave reactor, 100°C, 2h. d) Results from II) Phosphine-catalyzed synthesis of chiral
ref. [9]. tetrahydropyridine and 2,5-dihydro-1H-pyrrole
derivatives.
Moreover, a highly complex N-containing Interestingly, this methodology can be also
heterocycle 3e could be obtained in 86% yield, extended to acyclic amino-aldehyde and amino-ester
starting from the 1-formyl-9H-pyrido[3,4-b]indole-3- substrates, as shown in Table 2, to prepare the
carboxylate substrate 1e (entry 7). In this case, some

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

corresponding tetrahydropyridine and 2,5-dihydro- DAAD (entries 3-4). In the latter case, the
1H-pyrrole heterocycles. intramolecular Wittig reaction with ester group
requires to increase the reaction temperature to 120°C,
Table 2. Synthesis of diverse N-containing heterocycles. to obtain a total conversion.
We can note that 5d was obtained as a mixture of
two rotamers, due to the Cbz group. The structural
assignment of this molecule was ascertained by single
crystal X-ray analysis (Figure 2d). Finally, the higher
reactivities of Cbz-protected substrates, compared to
the tosyl-protected one can be explained by the lower
nucleophilicity of the nitrogen atom in the case of
NTs, compared to the NCbz substrate.
Diastereoselective reaction could be also performed,
starting from enantiopure D-phenylalanine ethyl ester
and DAAD (entry 5). A mixture of 2 diastereoisomers
5e and 5e’ in 2:1 ratio was obtained, in 82% overall
yield. With the L-proline ethyl ester substrate, only
one diastereoisomer 5f was synthesized in 83% yield
(entry 6).
Moreover, the microwave-assisted reaction of the
umpolung addition/CWR with acyclic amino-
aldehydes worked properly at 100°C for 2 hours, to
furnish 5a and 5b in 81-92% yield (entries 1-2).
Concerning the use of amino-esters, the reaction
temperature was at 120°C for 2h, giving access to the
dihydropyrroles 5c-5f in 82-97% isolated yields
(entries 3-6). The microwave heating condition has
not modified and/or altered the diastereomeric ratio in
the case of products 5e and 5f.
As previously reported and according to the
accepted mechanism,[10a-b] the trivalent phosphine
adds to the DAAD to form the zwitterionic species A
(Scheme 2).[19] The latter is subsequently protonated
by the NH proton of the substrate, to give the
corresponding vinylphosphonium salt B. The addition
of the conjugate base of the substrate to B furnishes
the ylide C, which undergoes an intramolecular
Wittig reaction to form D. In some cases, migration of
the double bonds formed the product E. Finally, the
phosphine oxide generated by the Wittig olefination is
reduced in situ by silane to the corresponding trivalent
phosphine, to realize the PV=O/PIII redox cycling.
Both trivalent phosphine or the corresponding
phosphine oxide can be used indifferently at the
beginning of the reaction. In the latter case the first
step is the reduction of the P=O bond.

a)
Isolated yields. b) Classical heating, using an oil bath,
120°C, 16h. c) Microwave reactor, 120°C, 2h. d) Classical
heating, using an oil bath, 60°C, 16h. e) Microwave reactor,
100°C, 2h.

Diethyl tetrahydro-pyridine dicarboxylate

derivatives with tosyl (5a) and Cbz (5b) protecting
groups were obtained in 79% and 90% yields
respectively, starting from N-protected 3-
aminopropanal substrates (entries 1-2). Diethyl-4-
ethoxy-2,5-dihydro-1H-pyrrole dicarboxylate with
tosyl (5c) and Cbz (5d) as protecting groups were
obtained in 80% and 92% yields, respectively, from
protected commercially available amino-esters and

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

commercially available chiral phosphines to prove the

concept of a catalytic and asymmetric tandem
reaction. To the best of our knowledge, there is only
one precedent in the literature of a catalytic and
asymmetric Wittig reaction, with the use of (S,S)-Me-
DuPhos (10 mol%) as chiral catalyst, in presence of
HSi(OMe)3. The conversion was less than 10%, but
the enantiomeric excess was about 90% ee.[21]
Contrary to this seminal example, where the
enantioselective step occurred during the Wittig
reaction, via a desymmetrisation reaction of a
prochiral diketone substrate with the phosphorus ylide,
in our case the enantioselective step is the addition of
the nitrogen anion to the vinylphosphonium
intermediate B, to furnish the ylide C (Scheme 2).[22]
The best results are reported in Table 3.

Table 3. Asymmetric and catalytic process.

Scheme 2. Mechanism proposal for the phosphine-

catalyzed addition/intramolecular CWR.

This mechanism was supported by the isolation of

the stable phosphorus ylide 6 (Scheme 3). The
reaction of ethyl 2-(benzyloxycarbonylamino)acetate
4d and DAAD 2a at room temperature, in presence of
a stoichiometric quantity of triphenylphosphine,
afforded the compound 6 in 80% yield. The 1H and
31
P NMR spectra showed two series of signals
ascribed to the respective two rotamers (see the
Supporting Information).[20] Afterwards, the isolated
phosphorus ylide 6 undergoes an intramolecular
Wittig reaction with the carbonyl of the ester group,
upon refluxing in toluene. The corresponding product
5d and triphenyl phosphine oxide are formed
quantitatively. The reaction can be followed by 31P
NMR: we observed the disappearance of the two
peaks of 6 ( = 26 and 27 ppm) and the formation of
Ph3P=O ( = 30 ppm) (See Supporting Information).

a) b)
Isolated yields. Determined by HPLC on a chiral
stationary phase.

(1R,1′R,2S,2′S)-DuanPhos P2 and 2-{2-[(2R,5R)-

Scheme 3. Synthesis of the phosphorus ylide 6 and
2,5-diethyl-1-phospholano]phenyl}1,3-dioxolane P3
subsequent intramolecular Wittig reaction.
(Table 3, entries 1 and 2) gave the best
enantioselectivities with 70% and 81% ee, but in
relatively low yields, in presence nevertheless of
respectively 75 mol% and 150 mol% of phosphine
III) Catalytic and asymmetric umpolung addition/ (50% and 30% yields). Unfortunately, incorporation
intramolecular Wittig reaction. of 5-20 mol% of these chiral phosphines in the
reaction mixture resulted in the formation of traces of
In the following, one of our biggest interests, as the desired product 5d after refluxing in toluene for
well as the most challenging goal, was to develop a 24 hours, and thereby does not allow the development
catalytic and asymmetric reaction, mediated by a of the catalytic and asymmetric reaction. That proved
chiral phosphine. At first, we screened several

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

the difficulties to find a chiral phosphine which is Initially, we examined the outcome of the reaction of
easily reducible, but also nucleophilic enough to acetylene dicarboxylate 2c (1-3 equiv.) with butane-
catalyse the reaction. In general, cyclic phosphines, 2,3-dione 7, in the presence of sub-stoichiometric
such as phenylphospholane oxide, are more easily amounts of phosphine and silane. The reaction was
reducible by silanes than acyclic phosphines. And this conducted with 20 mol% of 4-methyl-1-phenyl-2,3-
particularity of cyclic phosphine is especially true for dihydrophosphole 1-oxide, 20 mol % of (p-
the five-membered rings, such as catalyst P1-5. On NO2PhO)2PO2H and 2.8 equiv. of Me(EtO)2SiH for
the other hand, the steric hindrance around the 16 hours at 70°C in toluene. Only traces of 8a were
phosphorus atom could explain the lower reactivity of observed with 1 equiv. of substrate 7, independently
P2 and P3. Fortunately, the use of 5 mol% of of the concentration used (table 2, entries 1-2). To our
(1S,4S,5R)-5-phenyl-2-tosyl-2-aza-5 phosphabicyclo delight, 8a was formed in 33% yield, with the use of 2
[2.2.1]heptane P4 (Kwon bicyclic phosphine equiv. of substrate 7 (entry 3). The use of other
catalyst)[23] gave the desired product in 67% yield, but solvents (dioxane, dichloroethane; entries 4-5) did not
with a moderate enantiomeric excess (17% ee, entry improve the reaction rate. Surprisingly, the yield was
3). Finally, the new chiral catalyst P5, a increased to 48% while adding 20 mol% of DIPEA
phosphindole-1-oxide bearing a chiral menthyl group, (entry 6), but the addition of 100 mol% of DIPEA had
showed the best catalytic activity (94% yield, entry 4) a negative effect on the catalytic activity (18% yield,
and significant enantioselectivities (30% ee), with entry 7). Enhanced yields were obtained at 90°C and
only a catalyst loading of 5 mol%. These interesting 110°C (50% and 66% yields, respectively, entries 8-
preliminary results showed the development of a 9). Traces of 8a were produced by using PPh3 as
catalytic and enantioselective tandem addition/CWR, catalyst, and 54% yield was obtained with the P-
previously known as racemic and stoichiometric in phenyl-dibenzophosphole P6 (entries 10-11).
phosphine. Interestingly, best reaction conditions were reached,
as reported in entry 12, while using 3 equiv. of
IV) Synthesis of 4-oxocyclopent-2-ene-1,2- biacetyl 7. The desired product 8a was obtained in
dicarboxylate derivatives 83% NMR yield (77% isolated yield). Decreasing the
amounts of Me(EtO)2SiH to two equivalents had a
In the continuity of this work concerning the negative impact on the reaction rate (50% yield, entry
catalytic development of new reactions, we wondered 13).
whether it was possible to spread the reactivity of Table 4. Optimization of the reaction conditions.
DAAD to other substrates, to obtain carbocycles. In
2004, Yavari et al. firstly reported the synthesis of di-
tert-butyl 3-methyl-4-oxocyclopent-2-ene-1,2-
dicarboxylate 8a (Scheme 4a) using stoichiometric
amount of PPh3 as a promoter for the reaction
between di-tert-butyl acetylene dicarboxylate 2c and
butane-2,3-dione 7.[24] In the literature, 8a proved to
be an essential building block in the synthesis of
natural products of trilobolide (see structure (VI) in
Figure 1).[17] However, on bigger scale, Férézou et al. DIPEA
proved to have some difficulties to reproduce the Entr 7 T Yield
(x solvent, [c]
synthesis of 8a, following the Yavari’s procedure. On y (n equiv.)
mol%)
(°C) (%)a)
20g scale reaction, 1 equiv. of PPh3 was used with 20
equiv. of 7 to obtain 8a in 63% yield, as summarized 1 1 - Toluene, [0.1] 70 5
in scheme 4a. Hence, large amounts of wastes were 2 1 - Toluene, [0.2] 70 5
produced, and therefore developing a catalytic version 3 2 - Toluene, [0.2] 70 33
of this reaction could be very interesting (Scheme 4b). 4 2 - Dioxane, [0.2] 70 20
5 2 - DCE, [0.2] 70 15
6 2 20 Toluene, [0.2] 70 48
7 2 100 Toluene, [0.2] 70 18
8 2 20 Toluene, [0.2] 90 50
9 2 20 Toluene, [0.2] 110 66
10b) 2 20 Toluene, [0.2] 110 <5
11c) 2 20 Toluene, [0.2] 110 54
83
12 3 20 Toluene, [0.2] 110
(77)d)
13e) 3 20 Toluene, [0.2] 110 50
14f) 3 20 Toluene, [0.2] 110 39

Scheme 4. Synthesis of cyclopentenone derivatives.

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

a)
NMR yields were determined using trimethoxybenzene DIPEA seems to have an important role by avoiding
as an internal standard. b) Use of PPh3 instead of the protonation of the enol intermediate.
phospholene catalyst. c) Use of P6 instead of phospholene
catalyst. d) Isolated yield. e) Me(OEt)2SiH (2.0 equiv.
instead of 2.8 equiv.). f) Without (ArO)2PO2H. DIPEA =
N,N-diisopropylethylamine; DCE = 1,2-dichloroethane.

Finally, the importance of bis(4-nitrophenyl)

hydrogen phosphate in the reaction mixture was
proved (only 39% yield without (ArO)2PO2H, entry
14). This result demonstrated the pivotal role of the
phosphate in the P(V)/P(III) redox catalytic cycle.
Under these reaction conditions, no better isolated
yields were obtained with PhSiH3 or Ph2SiH2.
The practicability of our catalytic protocol was further
demonstrated by a 2.2-mmol-scale synthesis of
product 8a. The desired product was obtained in 77%
isolated yield (0.50 g). This scalability proves the
robustness of our catalytic methodology and
applications in the synthesis of key building blocks
can be now envisaged.
This methodolgy was also extended to the synthesis Scheme 6. Proposed mechanism for the synthesis of
of di-tert-butyl 4-oxo-3-phenylcyclopent-2-ene-1,2- products 8a,b.
dicarboxylate 8b in 51% (Scheme 5). Moreover, 8a
and 8b were obtained in 65% and 53% yields,
respectively, while performing these reactions in Conclusion
microwave at 120°C for 2 hours.
The phosphine-catalyzed Michael addition/Wittig
reactions tolerate a wide range of substrates, giving
access to the corresponding heterocycles and
cyclopentenone derivatives in good yields, either
using classical heating or microwave conditions (17
examples, 60-99% yields). We are confident that our
methodology could find applications in organic
chemistry, particularly in medicinal chemistry, where
people are interested in obtaining a large number of
Scheme 5. Application of the catalytic methodology to the molecules, structurally varied, in minimum time.
synthesis of substrate 8b. Finally, the use of a catalytic quantity of phosphine is
even more relevant in the case of the use of a chiral
Concerning the reaction mechanism (Scheme 6), phosphine. Given the prohibitive cost of these chiral
nucleophilic addition of the phosphine to DAAD 2c catalysts, it is inconceivable to use in these reactions a
produces the zwitterionic species F, which reacts as a stoichiometric quantity. The use of our method allows
base to deprotonate the diketone substrate 7 or 9. The now to use of small quantity of catalyst, to obtain
enol intermediate subsequently adds on easily an enantioenriched product. Even if the results
vinylphosphonium G to form the oxaphosphetane H, described here are preliminary, they are the first
which produced the desired product 8a,b and significant results in the domain. In the future, our
phosphine oxide as a concomitant by-product. In situ work is going to concentrate on the discovery of new
reduction of this phosphine oxide with silane such as phosphine-catalyzed reactions, and in the
phenylsilane allowed the regeneration of the active development of asymmetric reactions. The synthesis
catalyst and close the catalytic cycle. During the of new chiral phosphines, especially designed to
phosphine oxide reduction, the phosphate proved to improve the current results will be reported in due
be necessary to facilitate this process (as showed in course.
Table 4, entry 14). Thus, it is postulated that the in
situ formed phosphoric silyl ester I (Scheme 6) acts as
a bifunctional catalyst.[25] Both the oxygen atom of
the phosphine oxide and the silane are activated by
the Lewis acid/Lewis base properties of this
organocatalyst. In this process the tertiary amine base

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

Experimental Section In a Standard Vial G10, amino-aldehydes or amino-esters

(0.15 mmol, 1 equiv.), phospholene (5 mol %) bis(4-
I. General information: nitrophenyl)phosphate (5 mol %), and freshly distilled
degassed toluene (0.15 M) were added. Dialkyl acetylene
All non-aqueous reactions were run under a positive dicarboxylate (0.15 mmol, 1 equiv.) and phenylsilane (1
pressure of argon, by using standard techniques for equiv.) were then added using microsyringes. The vial was
manipulating air-sensitive compounds. Microwave assisted sealed by reusable snap-cap with PTFE coated silicone
reactions were performed in Anton-Par Monowave 300 septum and the reaction mixture was then heated at 100°C
microwave in Borosilicate glass standard vial G10. Toluene for the aldehyde derivatives and 120°C for the ester
was distilled over CaH2 under an argon atmosphere. derivatives for 2 hours. The crude reaction mixture was
Tetrahydrofuran was distilled over sodium/benzophenone concentrated and purified by flash chromatography using
under an argon atmosphere. All other reagents and solvents 4g GraceResolv™ silica gel pre-packed column and
were of commercial quality and used without further EtOAc/heptanes as eluent (0 to 40% of EtOAc over 25 min,
purification (substrates 1b, 2, 7, 9 and chiral phosphines). 18 mL/min).
Analytical thin-layer chromatography (TLC) was
performed on plates precoated with silica gel layers. The Diethyl 7-bromo-9H-pyrrolo[1,2-a]indole-2,3-
developed chromatogram was visualized by UV dicarboxylate (3a)[9] (52 mg, 92 % yield; Microwave: 53
absorbance and/or vanillin stain. Flash column mg, 93% yield). Yellow solid; mp 101–104°C; Rf 0.32
chromatography was performed using a GraceResolv™ (20% EtOAc/heptanes); 1H NMR (300 MHz, CDCl3):  =
silica gel column on a Combi Flash® companion®. 7.91 (d, J = 8.5 Hz, 1H), 7.50-7.46 (1H, m), 7.39 (dd, J =
Nuclear magnetic resonance spectra (1H, 13C, 31P) were 8.5, 2.1 Hz, 1H), 6.44-6.41 (m, 1H), 4.35 (q, J = 7.1 Hz,
recorded at 500 or 300 MHz spectrometers. Chemical shifts 2H), 4.25 (q, J = 7.1 Hz, 2H), 3.79 (s, 2H), 1.33 (t, J = 7.1
are reported in parts per million relative to an internal Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz,
standard of residual chloroform (δ= 7.19 ppm for 1H NMR CDCl3): = 164.6 (CO), 161.2 (CO), 139.8 (C), 138.6 (C),
and 77.16 ppm for 13C NMR). IR spectra were recorded on 137.1 (C), 130.8 (CH), 128.7 (CH), 125.4 (C), 119.0 (C),
a Perkin-Elmer FT-IR spectrophotometer and are reported 118.2 (C), 116.2 (CH), 104.6 (CH), 61.5 (CH2), 60.8 (CH2),
in reciprocal centimeters (cm-1). High-resolution mass 28.9 (CH2), 14.3 (CH3), 14.1 (CH3); IR: νmax = 2980, 1706,
spectrometry (HRMS) was performed using electrospray 1479, 1467, 1270, 1212, 1181, 1113, 1053, 751 cm-1;
ionization (ESI) and time-of-flight (TOF) analyzer, in HRMS (ESI) calcd. for C17H17BrNO4 [M+H]+: 378.0341,
positive-ion or negative-ion detection mode. HPLC was found: 378.0312.
performed at a column temperature of 20°C on a Waters
2695 Separations Module equipped with a diode array UV Dimethyl 3H-pyrrolizine-5,6-dicarboxylate (3ba) (29 mg,
detector. Data are reported as follows: column type, eluent, 90 % yield; Microwave: 30 mg, 91% yield). White solid;
flow rate, retention time (tr). Substrates 1H-indole-7- mp 63–65°C; Rf 0.41 (30% EtOAc/PE); 1H NMR (300
carbaldehyde 1c,[26] 3-bromo-1H-indole-7-carbaldehyde MHz, CDCl3):  = 6.55 (dt, J = 6.0, 2.1 Hz, 1H), 6.46 (dt, J
1d,[26] methyl 1-formyl-9H-pyrido[3,4-b]indole-3- = 6.0, 1.9 Hz, 1H), 6.35 (bs, 1H), 4.68-4.64 (m, 2H), 3.82
carboxylate 1e, [27] tert-butyl (2-formylphenyl)carbamate 1f, (s, 3H), 3.78 (s, 3H); 13C NMR (75 MHz, CDCl3):
164.9 (CO), 160.8 (CO), 143.6 (C), 132.6 (CH), 124.0
[28]
4-methyl-N-(3-oxopropyl)benzenesulfonamide 4a,
[29]
benzyl (3-oxopropyl)carbamate 4b,[30] ethyl (C), 122.2 (CH), 120.4 (C), 102.3 (CH), 55.4 (CH2), 51.8
tosylglycinate 4c,[31] ethyl (benzyloxy)carbonyl)glycinate (CH3), 51.7 (CH3); IR: νmax = 2997, 2952, 1730, 1693, 1486,
4d,[32] ethyl L-prolinate 4f,[33] and P5,[34] were prepared 1447, 1317, 1290, 1252, 1206, 1184, 1151, 1138, 1079,
according to literature. Synthesis of 1g and 1-((2S,5R)-2- 1055, 951, 777 cm-1; HRMS (ESI) calcd. for C11H12NO4
isopropyl-5-methylcyclohexyl)phosphindole 1-oxide are [M+H]+: 222.0766, found: 222.0760.
described in the supporting information.
Diethyl 3H-pyrrolizine-5,6-dicarboxylate (3bb) (31 mg,
II. Experimental Procedures: 83 % yield; Microwave: 36 mg, 85% yield). Yellow solid;
mp 48–50 °C; Rf 0.39 (20% EtOAc/heptanes); 1H NMR
General procedure for the reaction in Schlenk Line. (300 MHz, CDCl3):  6.56 (dt, J = 6.0, 2.1 Hz, 1H), 6.46
In a Schlenk tube, amino-aldehydes or amino-esters (0.15 (dt, J = 6.0, 1.9 Hz, 1H), 6.35 (bs, 1H), 4.68-4.64 (m, 2H),
mmol, 1 equiv.), phospholene (5 mol %) bis(4- 4.34-4.21 (m, 4H), 1.33-1.26 (m, 6H); 13C NMR (75 MHz,
nitrophenyl)phosphate (5 mol %), and freshly distilled CDCl3): 164.7 (CO), 160.4 (CO), 143.5 (C), 132.4
degassed toluene (0.15 M) were added. Dialkyl acetylene (CH), 124.6 (C), 122.3 (CH), 120.3 (C), 101.9 (CH), 60.6
dicarboxylate (0.15 mmol, 1 equiv.) and phenylsilane (1 (CH2), 55.3 (CH2), 14.33 (CH3), 14.30 (CH3); IR: νmax =
equiv.) were then added using microsyringes and the 2982, 1725, 1688, 1487, 1442, 1286, 1250, 1210, 1151,
reaction mixture was heated at 60°C for the aldehyde 1077, 1054, 766 cm-1; HRMS (ESI) calcd. for C13H16NO4
derivatives and 120°C for the ester derivatives for 16 hours. [M+H]+: 250.1079, found: 250.1066.
The crude reaction mixture was concentrated and purified
by flash chromatography using 4g GraceResolv™ silica gel Di-tert-butyl 3H-pyrrolizine-5,6-dicarboxylate (3bc) (41
pre-packed column and EtOAc/heptanes as eluent (0 to mg, 89% yield; Microwave: 41 mg, 89% yield). Orange oil;
40% of EtOAc over 25 min, 18 mL/min). Rf 0.82 (30% EtOAc/PE); 1H NMR (300 MHz, CDCl3):
6.61 (dt, J = 6.0, 2.1 Hz, 1H), 6.48 (dt, J = 6.0, 1.9 Hz,
General procedure for the Microwave assisted reaction. 1H), 6.31 (bs, 1H), 4.75-4.62 (m, 2H), 1.60 (s, 9H), 1.58 (s,

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

9H); 13C NMR (75 MHz, CDCl3):163.7 (CO), 159.4 1H), 4.42-4.29 (m, 2H), 4.15-3.99 (m, 2H), 1.58 (s, 9H)
(CO), 142.7 (C), 131.9 (CH), 126.2 (C), 122.4 (CH), 121.7 1.39 (t, J = 7.0 Hz, 3H), 1.16 (t, J = 7.3 Hz, 3H); 13C NMR
(C), 101.4 (CH), 81.3 (C), 80.4 (C), 55.1 (CH2), 28.4 (CH3), (75 MHz, CDCl3): 169.3 (CO), 164.8 (CO), 152.4 (C),
28.2 (CH3); HRMS (ESI) calcd. for C17H23NNaO4 136.7 (C), 134.1 (CH), 130.3 (CH), 128.6 (CH), 124.8 (C),
[M+Na]+: 328.1525, found: 328.1522. 124.1 (CH), 123.8 (CH), 82.5 (C), 61.5 (CH2), 61.1 (CH2),
53.3 (CH), 28.2 (CH3), 14.2 (CH3), 13.9 (CH3); IR: νmax =
Diethyl 4H-pyrrolo[3,2,1-ij]quinoline-4,5-dicarboxylate 2980, 2936, 2908, 1744, 1710, 1368, 1290, 1247, 1230,
(3c) (43 mg, 96 % yield; Microwave: 44 mg, 99% yield). 1202, 1156, 1128, 1025, 946, 856, 765 cm-1; HRMS (ESI)
Yellow solid; mp 93–95 °C; Rf 0.76 (30% EtOAc/PE); 1H calcd. for C20H25NNaO6 [M+Na]+: 398.1580, found:
NMR (300 MHz, CDCl3): 7.80 (d, J = 1.1 Hz, 1H), 398.1573.
7.48 (dd, J = 7.7, 1.0 Hz, 1H), 7.22 (d, J = 3.4 Hz, 1H),
7.07-6.91 (m, 2H), 6.47 (d, J = 3.0 Hz, 1H), 6.04 (s, 1H), Diethyl 1-tosyl-1,2-dihydrobenzo[4,5]thieno[3,2-
4.30-4.20 (m, 2H), 4.19-4.01 (m, 2H), 1.29 (t, J = 7.2 Hz, b]pyridine-2,3-dicarboxylate (3g) (44 mg, 60% yield;
3H), 1.17 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): Microwave: 44 mg, 60% yield). Yellow solid; mp 173–
168.3 (CO), 165.3 (CO), 134.6 (CH), 133.4 (C), 126.2 176 °C; Rf 0.67 (30% EtOAc/PE); 1H NMR (300 MHz,
(CH), 125.1 (C), 124.3 (CH), 122.1 (C), 121.5 (CH), 120.9 CDCl3): 8.32 (dd, J = 8.5, 1.0 Hz, 1H), 7.69 (dd, J =
(CH), 116.0 (C), 103.7 (CH), 62.1 (CH2), 61.1 (CH2), 58.4 7.9, 0.8 Hz, 1H), 7.48-7.31 (m, 2H), 7.19-7.13 (m, 2H),
(CH), 14.3 (CH3), 14.0 (CH3); IR: νmax = 2982, 2931, 1743, 7.02-6.89 (m, 3H), 6.05 (s, 1H), 4.26-4.09 (m, 2H), 4.03-
1699, 1598, 1370, 1288, 1248, 1212, 1058, 1024, 1151, 3.85 (m, 2H), 2.27 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H), 0.99 (t,
794 cm-1; HRMS (ESI) calcd. for C17H18NO4 [M+H]+: J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): 167.8
300.1236, found: 300.1223. (CO), 163.7 (CO), 144.5 (C), 138.9 (C), 134.7 (C), 134.1
(C), 131.3 (C), 129.0 (CH), 128.1 (C), 127.2 (CH), 127.0
Diethyl 1-bromo-4H-pyrrolo[3,2,1-ij]quinoline-4,5- (CH), 126.5 (CH), 125.6 (CH), 125.3 (CH), 123.2 (C),
dicarboxylate (3d) (53 mg, 94 % yield; Microwave: 56 mg, 122.4 (CH), 62.1 (CH2), 61.1 (CH2), 57.4 (CH), 21.5 (CH3),
99% yield). Green solid; mp 67–70 °C; Rf 0.67 (30% 14.3 (CH3), 13.8 (CH3); IR: νmax = 3068, 2982, 2940, 1739,
EtOAc/PE); 1H NMR (300 MHz, CDCl3): 7.77 (d, J = 1703, 1608, 1500, 1365, 1292, 1258, 1236, 1185, 1170,
1.1 Hz, 1H), 7.40 (dd, J = 7.2, 1.5 Hz, 1H), 7.24 (s, 1H), 1145, 1089, 1020, 769, 731 cm-1; HRMS (ESI) calcd. for
7.10-6.98 (m, 2H), 5.96 (bs, 1H), 4.24 (qd, J = 7.2, 1.1 Hz, C24H24NO6S2 [M+H]+: 486.1045, found: 486.1037.
2H), 4.19-4.03 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.19 (t, J
= 7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): 167.8 (CO), Diethyl 1-tosyl-1,2,5,6-tetrahydropyridine-2,3-
165.0 (CO), 133.8 (CH), 132.8 (C), 125.1 (CH), 124.5 (C), dicarboxylate (5a) (45 mg, 79 % yield; Microwave: 46 mg,
122.6 (CH), 122.4 (CH), 121.9 (C), 121.6 (CH), 116.2 (C), 81% yield). Colorless oil; Rf 0.5 (30% EtOAc/PE); 1H
92.7 (C), 62.3(CH2), 61.4 (CH2), 58.2 (CH), 14.2 (CH3), NMR (300 MHz, CDCl3):  7.73 (d, J = 8.5 Hz, 2H),
14.0 (CH3); IR: νmax = 2982, 2931, 1743, 1602, 1598, 1368, 7.28 (d, J = 8.5 Hz, 2H), 7.13-7.04 (m, 1H), 5.43 (s, 1H),
1289, 1244, 1214, 1179, 1069, 1023, 790, 742 cm-1; HRMS 4.30-4.17 (m, 2H), 4.14-3.97 (m, 2H), 3.89 (dd, J = 14.0,
(ESI) calcd. for C17H17BrNO4 [M+H]+: 378.0341, found: 7.0 Hz, 1H), 3.30-3.19 (m, 1H), 2.42 (s, 3H), 2.39-2.28 (m,
378.0342. 1H), 2.26-2.14 (m, 1H), 1.29 (t, J = 7.3 Hz, 3H), 1.19 (t, J
= 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): 168.8 (CO),
5,6-diethyl 2-methyl 6H-indolo[3,2,1-de][1,5] 164.5 (CO), 143.6 (C), 139.3 (CH), 137.1 (C), 129.5 (2CH),
naphthyridine-2,5,6-tricarboxylate (3e) (53 mg, 86 % 127.2 (CH), 127.1 (C), 61.6 (CH2), 61.0 (CH2), 54.2 (CH),
yield; Microwave: no reaction). Yellow-orange solid; mp 38.5 (CH2), 24.5 (CH2), 21.5 (CH3), 14.1 (CH3), 13.9
167–170 °C; Rf 0.17 (30% EtOAc/PE); 1H NMR (300 MHz, (CH3); IR: νmax = 2982, 2937, 2905, 1732, 1712, 1345,
CDCl3): 8.67 (s, 1H), 8.14 (s, 1H), 8.09 (d, J = 7.9 Hz, 1263, 1160, 1102, 1047, 1025, 996, 816, 716 cm-1; HRMS
1H), 7.65 (d, J = 8.5 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.34 (ESI) calcd. for C18H24NO6S [M+H]+: 382.1324, found:
(t, J = 7.3 Hz, 1H), 6.27 (s, 1H), 4.37-4.23 (m, 2H), 4.03- 382.1319.
4.15 (m, 2H), 3.99 (s, 3H), 1.32 (t, J = 7.3 Hz, 3H), 1.08 (t,
J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3): 166.7 1-benzyl 2,3-diethyl 5,6-dihydropyridine-1,2,3(2H)-
(CO), 166.3 (CO), 164.5 (CO), 141.0 (C), 139.4 (C), 135.9 tricarboxylate (5b) (49 mg, 90% yield; Microwave: 50 mg,
(C), 135.6 (C), 135.2 (CH), 129.1 (CH), 128.4 (C), 125.9 92% yield). Orange oil; Rf 0.53 (30% EtOAc/PE); 1H NMR
(C), 122.8 (CH), 122.3 (C), 122.1 (CH), 119.8 (CH), 111.6 (300 MHz, CDCl3, rotamers): 7.46-7.28 (m, 5H), 7.12
(CH), 62.5 (CH2), 61.8 (CH2), 57.3 (CH), 52.8 (CH3), 14.1 (m, 1H), 5.63 (s, 0.4H), 5.52 (s, 0.6H), 5.34-5.08 (m, 2H),
(CH3), 13.9 (CH3); IR: νmax = 2982, 2949, 1740, 1707, 1635, 4.37-4.08 (m, 5H), 3.23-2.92 (m, 1H), 2.52-2.18 (m, 2H),
1435, 1373, 1269, 1248, 1223, 1192, 1165, 1116, 1020, 1.36-1.14 (m, 6H); 13C NMR (75 MHz, CDCl3, rotamers):
767, 750 cm-1; HRMS (ESI) calcd. for C22H21N2O6 165.0 (CO), 139.1 (CH), 138.4 (CH), 136.4 (C), 128.5
[M+H]+: 409.1400, found: 409.1389. (CH), 128.4 (CH), 128.1 (CH), 128.0 (CH), 127.7 (CH),
127.5 (C), 67.6 (CH2), 67.5 (CH2), 61.6 (CH2), 60.9 (CH2),
1-tert-butyl- 2,3-diethyl quinoline-1,2,3(2H)- 54.0 (CH), 53.8 (CH), 37.8(CH2), 37.2 (CH2), 25.2 (CH2),
tricarboxylate (3f) (41 mg, 73% yield (formation of a by- 24.9 (CH2), 14.1 (CH3), 14.0 (CH3); IR: νmax = 2982, 2937,
product (10%)); Microwave: 39 mg, 70% yield). White 2902, 1736, 1706, 1657, 1422, 1367, 1337, 1285, 1236,
solid; mp 131–134 °C; Rf 0.76 (30% EtOAc/PE); 1H NMR 1210, 1192, 1108, 1051, 1024, 762, 699 cm-1; HRMS (ESI)
(300 MHz, CDCl3): 7.81 (bs, 1H), 7.57 (s, 1H), 7.39- calcd. for C19H24NO6 [M+H]+: 362.1604, found: 362.1605.
7.33 (m, 1H), 7.30-7.26 (m, 2H), 7.13-7.08 (m, 1H), 6.31 (s,

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

Diethyl 4-ethoxy-1-tosyl-2,5-dihydro-1H-pyrrole-2,3- 1.5H), 4.02-3.91 (m, 2.5H), 3.89-3.69 (m, 1.5H), 3.47 (dd,
dicarboxylate (5c) (49 mg, 80 % yield; Microwave: 51 mg, J = 13.8, 5.5 Hz, 0.5H), 3.17 (dd, J = 13.9, 5.3 Hz, 0.5H),
83 % yield). Yellow oil; Rf 0.67 (40% EtOAc/PE); 1H 2.97-2.85 (m, 1.2H), 1.34-1.26 (m, 3.8H), 1.18 (t, J = 7.2
NMR (300 MHz, CDCl3):  7.67 (d, J = 8.7 Hz, 2H), Hz, 2H), 1.13-1.05 (m, 3.8H), 0.95 (t, J = 7.16 Hz, 2H); 13C
7.27 (d, J = 8.7 Hz, 2H), 4.92 (dd, J = 4.5, 1.5 Hz, 1H), NMR (75 MHz, CDCl3, rotamers): 171.4 (CO), 171.1
4.41 (dd, J = 15.1, 4.5 Hz, 1H), 4.26 (dd, J = 15, 1.7 Hz, (CO), 164.1 (CO), 164.0 (CO), 161.6 (CO), 153.6 (C),
1H), 4.16-3.95 (m, 6H), 2.37 (s, 3H), 1.29 (t, J = 7.1 Hz, 153.2 (C), 136.0 (C), 135.9 (C), 135.3 (C), 135.1 (C), 129.8
3H), 1.17 (m, 6H); 13C NMR (75 MHz, CDCl3): 170.3 (CH), 129.7 (CH), 128.6 (CH), 128.5 (CH), 128.4 (CH),
(CO), 163.3 (CO), 161.6 (CO), 144.3 (C), 134.1 (CO), 128.2 (CH), 128.2 (CH), 128.1 (CH), 127.9 (CH), 126.7
129.9 (CH), 127.5 (CH), 101.0 (C), 68.3 (CH2), 65.1 (CH), (CH), 126.1 (CH), 102.8 (C), 69.6 (CH2), 69.3 (CH2), 67.7
61.5 (CH2), 60.2 (CH2), 52.1 (CH2), 21.5 (CH3), 15.2 (CH3), (CH2), 67.2 (CH2), 65.0 (CH), 64.6 (CH), 64.2 (CH), 63.8
14.1 (CH3), 14.0 (CH3); IR: νmax = 2984, 2943, 2908, 1741, (CH), 61.3 (CH2), 61.1 (CH2), 60.2 (CH2), 36.8 (CH2), 35.3
1644, 1369, 1333, 1211, 1163, 1090, 1027, 815, 764 cm-1; (CH2), 15.4 (CH3), 14.0 (CH3), 13.8 (CH3); IR: νmax = 2982,
HRMS (ESI) calcd. for C19H26NO7S [M+H]+: 412.1430, 2936, 2905, 1742, 1710, 1639, 1404, 1338, 1312, 1215,
found: 412.1425. 1198, 1118, 1062, 1027, 768, 700 cm-1; HRMS (ESI) calcd.
for C27H32NO7 [M+H]+: 482.2179, found: 482.2181.
1-benzyl 2,3-diethyl 4-ethoxy-1H-pyrrole-1,2,3(2H,5H)-
tricarboxylate (5d) (54 mg, 92 % yield, Microwave: 57 (7S)-diethyl 7-ethoxy-2,3,5,7a-tetrahydro-1H-
mg, 97% yield). Light yellow solid; mp 95–98 °C; Rf 0.43 pyrrolizine-5,6-dicarboxylate (5f) (35 mg, 83% yield;
(40% EtOAc/PE); 1H NMR (300 MHz, CDCl3, rotamers): Microwave: 36 mg, 84% yield). Yellow oil; Rf 0.27 (30%
7.37-7.20 (m, 5H), 5.18-4.96 (m, 3H), 4.54-4.27 (m, EtOAc/PE); 1H NMR (300 MHz, CDCl3): 4.5 (s, 1H),
2H), 4.19-4.01 (m, 5H), 4.00-3.82 (m, 1H), 1.37-1.28 (m, 4.33-4.22 (m, 2H), 4.16-4.05 (m, 2H), 4.01 (dd, J = 14.0,
3H), 1.25-1.14 (m, 4H), 1.02 (t, J = 7.2 Hz, 2H); 13C NMR 7.0 Hz, 2H), 3.42-3.33 (m, 1H), 3.29-3.17 (m, 1H), 2.22-
(75 MHz, CDCl3, rotamers): 171.4 (CO), 171.1 (CO), 2.11 (m, 1H), 2.05-1.88 (m, 3H), 1.27 (t, J = 7.2 Hz, 3H),
164.1 (CO), 163.9 (CO), 161.9 (CO), 153.7 (C), 136.0 (C), 1.20 (t, J = 7.2 Hz, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR
135.8 (C), 128.5 (CH), 128.4 (CH), 128.3 (CH), 128.2 (75 MHz, CDCl3): (C167.3 (CO), 165.2 (CO),
(CH), 128.1 (CH), 128.0 (CH), 100.9 (C), 100.7 (C), 68.0 151.4 (C), 86.8 (CH), 62.1 (CH2), 61.4 (CH2), 61.0 (CH),
(CH2), 67.6 (CH2), 64.0 (CH), 63.6 (CH), 61.4 (CH2), 61.2 59.3 (CH2), 48.4 (CH2), 30.5 (CH2), 23.1 (CH2), 14.4 (CH3),
(CH2), 60.0 (CH2), 50.9 (CH2), 50.6 (CH2), 15.2 (CH3), 14.1 (CH3), 13.8 (CH3); IR: νmax = 2981, 2935, 2901, 1736,
14.2 (CH3), 14.1 (CH3), 13.9 (CH3); IR: νmax = 2983, 2934, 1692, 1574, 1434, 1378, 1339, 1269, 1219, 1182, 1140,
2908, 1737, 1717, 1640, 1410, 1354, 1240, 1212, 1113, 1093, 1045, 1022, 792 cm-1.
1059, 1028, 768 cm-1; HRMS (ESI) calcd. for C20H26NO7
[M+H]+: 392.1709, found: 392.1713. Synthesis of ylide 6.
In a round bottom flask, 4d (50 mg, 0.21 mmol) and PPh3
(2R,5S)-1-benzyl 2,3-diethyl 5-benzyl-4-ethoxy-1H- (55 mg, 0.21 mmol) were dissolved in DCM. 2a (0.21
pyrrole-1,2,3(2H,5H)-tricarboxylate (5e) (40 mg, 55% mmol, 34 µL) was added and the reaction was stirred
yield). Yellow oil; Rf 0.82 (40% EtOAc/PE); 1H NMR (300 overnight at room temperature. The crude reaction mixture
MHz, CDCl3, rotamers): 7.35-7.19 (m, 5H), 7.18-7.01 was concentrated and purified by flash chromatography
(m, 4.2H), 5.24-4.99 (m, 2.8H), 4.76 (dd, J = 7.5, 3.8 Hz, using 4g GraceResolv™ silica gel pre-packed column and
0.5H), 4.66-4.52 (m, 1.1H), 4.21-3.94 (m, 5.7H), 3.80 (q, J EtOAc/heptanes as eluent (0 to 70% of EtOAc over 25 min,
= 7.3 Hz, 1.1H), 3.36 (dd, J = 13.9, 4.1 Hz, 0.5H), 3.17 (dd, 18 mL/min) to obtain 141 mg (80 %) of the ylide 6 in two
J = 13.6, 6.0 Hz, 0.5H), 3.04 (dd, J = 13.6, 6.8 Hz, 1.5H), geometrical isomers as a yellow oil.
1.28-1.14 (m, 5.3H), 1.14-0.96 (m, 5H);13C NMR (75 MHz, 31
P NMR (202 MHz, CDCl3):  ppm 27.0, 26.0; HRMS
CDCl3, rotamers): 171.0 (CO), 170.8 (CO), 166.2 (CO), (ESI) calcd. for C38H41NaO8P [M+H]+: 670.2570 found:
165.4 (CO), 162.3 (CO), 154.2 (C), 153.6 (C), 137.8 (C), 670.2570.
137.6 (C), 136.2 (C), 135.9 (C), 129.7 (CH), 129.5 (CH),
128.4 (CH), 128.2 (CH), 128.0 (CH), 127.8 (CH), 126.4 General procedure for the synthesis of cyclopentan-2-
(CH), 102.5 (C), 101.71 (C), 69.4 (CH2), 69.2 (CH2), 67.5 ene-1-one derivatives.
(CH2), 67.3 (CH2), 64.9 (CH), 64.7 (CH), 64.6 (CH), 64.0 In a Schlenk tube, biacetyl or 1-phenylpropane-1,2-dione
(CH), 61.4 (CH2), 61.3 (CH2), 60.4 (CH2), 41.3 (CH2), 40.6 (0.6 mmol, 3 equiv.), phospholene (20 mol %) bis(4-
(CH2), 15.0 (CH3), 14.1 (CH3), 13.9 (CH3); IR: νmax = 2981, nitrophenyl)phosphate (20 mol %), DIPEA (20 mol%), and
2934, 2905, 1739, 1711, 1634, 1407, 1345, 1270, 1213, freshly distilled degassed toluene (0.2 M) were added. Di-
1109, 1062, 1027, 742, 700 cm-1;HRMS (ESI) calcd. for tert-butyl acetylene dicarboxylate (0.2 mmol, 1 equiv.) and
C27H32NO7 [M+H]+: 482.2179, found: 482.2199. Me(EtO)2SiH (2.8 equiv.) were then added using
microsyringes and the reaction mixture was heated at
(2S,5S)-1-benzyl 2,3-diethyl 5-benzyl-4-ethoxy-1H- 110 °C for 18 hours. The crude reaction mixture was
pyrrole-1,2,3(2H,5H)-tricarboxylate (5e‘) (20 mg, 27% concentrated and purified by flash chromatography using
yield). Yellow oil; Rf 0.75 (40% EtOAc/PE); 1H NMR (300 4g GraceResolv™ silica gel pre-packed column and
MHz, CDCl3, rotamers): 7.41-7.21 (m, 6.3H), 7.14-7.05 EtOAc/heptanes as eluent (30 to 40% of EtOAc over 25
(m, 3.7H), 6.97-6.91 (m, 1.4H), 6.84-6.77 (m, 1H), 5.32- min, 18 mL/min).
5.21 (m, 0.5H), 5.15-5.01 (m, 2H), 4.97-4.90 (m, 0.5H),
4.87-4.81 (m, 0.5H), 4.32-4.18 (m, 3.6H), 4.18-4.02 (m,

10

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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

Di-tert-butyl 3-methyl-4-oxocyclopent-2-ene-1,2- A. J. Holohan, B. J. Doonan, Chem. Eur. J. 2013, 19,

dicarboxylate (8a)[24] (46 mg, 77% yield; Microwave: 39 5854-5858; d) E. E. Coyle, B. J. Doonan, A. J. Holohan,
mg, 65% yield). 1H NMR (300 MHz, CDCl3): 3.82 (m, K. A. Walsh, F. Lavigne, E. H. Krenske, C. J. O'Brien,
1 H) 2.75 (dd, J=18.9, 7.9 Hz, 1 H) 2.48 (dd, J=18.9, 2.4 Angew. Chem. Int. Ed. 2014, 53, 12907-12911; e) M.-L.
Hz, 1 H) 2.07 (d, J=2.4 Hz, 3 H) 1.56 (s, 9 H) 1.46 (s, 9 H) Schirmer, S. Adomeit, T. Werner, Org. Lett. 2015, 17,
3078-3081; f) H. A. van Kalkeren, C. te Grotenhuis, F.
Di-tert-butyl 4-oxo-3-phenylcyclopent-2-ene-1,2- S. Haasjes, C. A. Hommersom, F. Rutjes, F. L. van
dicarboxylate (8b) (37 mg, 51 % yield; Microwave: 38 mg, Delft, Eur. J. Org. Chem. 2013, 7059-7066; g) L. Wang,
53% yield). Yellow oil; Rf 0.76 (30% EtOAc/PE); 1H NMR Y. Wang, M. Chen, M.-W. Ding, Adv. Synth. Catal.
(300 MHz, CDCl3): 7.34-7.29 (m, 3H), 7.27-7.20 (m, 2014, 356, 1098-1104; Staudinger reaction: h) H. A.
2H), 3.93 (dd, J = 7.6, 2.8 Hz, 1H), 2.82 (dd, J = 18.9, 7.9 van Kalkeren, J. J. Bruins, F. P. J. T. Rutjes, F. L. van
Hz, 1H), 2.65 (dd, J = 18.9, 3.1 Hz, 1H), 1.41 (s, 9H), 1.28 Delft, Adv. Synth. Catal. 2012, 354, 1417-1421; i) A. D.
(s, 9H); 13C NMR (75 MHz, CDCl3): 205.2 (CO), 170.4 Kosal, E. E. Wilson, B. L. Ashfeld, Angew. Chem. Int.
(CO), 163.9 (CO), 155.8 (C), 146.2 (CO), 130.0 (CO), Ed. 2012, 51, 12036-12040; Appel reaction: j) H. A.
129.1 (CH), 128.8 (CH), 127.8 (CH), 82.9 (C), 82.1 (C), van Kalkeren, S. H. A. M. Leenders, C. R. A.
45.5 (CH), 38.8 (CH2), 27.9 (CH2), 27.7 (CH2); IR: νmax = Hommersom, F. P. J. T. Rutjes, F. L. van Delft, Chem.
2979, 2928, 1722, 1368, 1251, 1146, 844, 764, 697 cm-1; Eur. J. 2011, 17, 11290-11295; Mitsunobu reaction: k)
HRMS (ESI) calcd. for C21H26NaO5 [M+Na]+: 381.1678, C. J. O’Brien (Univ. Texas, USA), US Patent 8901365,
found: 381.1680. 2014; l) J. A. Buonomo, C. C. Aldrich, Angew. Chem.
Int. Ed. 2015, 54, 13041-13044; Miscellaneous : m) J.
R. Harris, M. T. Haynes, II, A. M. Thomas, K. A.
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Advanced Synthesis & Catalysis 10.1002/adsc.201700313

FULL PAPER
Synthesis of Nitrogen-Containing Heterocycles and
Cyclopentenone Derivatives via Phosphine-
Catalyzed Michael Addition/Intramolecular Wittig
Reaction

Adv. Synth. Catal. Year, Volume, Page – Page

Nidal Saleh, Florent Blanchard and Arnaud

Voituriez*

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