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Ru-Catalyzed Benzannulation of Vinyl Sulfoxonium Ylide with

Electron-Deficient Alkynes and Alkenes
Daksh Singh Davas, Dinesh Kumar Gopalakrishnan, Deepesh Kumar, and Janakiram Vaitla*
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ABSTRACT: Herein, we report carbene-mediated benzannulation of

vinyl sulfoxonium ylides with electron-deficient alkynes and alkenes to
synthesize oxygenated arenes. This protocol features excellent
regioselectivity, a broad substrate scope, and mild reaction conditions.
Mechanistic studies revealed that the reaction proceeds through furan
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generation, cycloaddition, ring cleavage, and aromatization cascades.

The synthesized arenes have been utilized in diverse product
transformations and arene ring homologation.

O xygenated arenes are present in various biologically

active natural products, pharmaceuticals, synthetic
reagents, and functional materials (Figure 1).1 The substitution
Scheme 1. Synthesis of Oxygenated Arenes

Figure 1. Natural products and biologically important compounds

containing oxygenated arene moiety.

on the aromatic ring significantly influenced the properties of

these molecules. 1a Therefore, the synthesis of highly
substituted oxygenated arenes has received considerable
attention from the synthetic community.2
Most of the reported approaches involve multistep func-
tional group installation to preexisting arene units by classical
organic transformations. The major issue with these
approaches is the regioselectivity. The use of a convergent-
based approach represents a more attractive step-economical
strategy to obtain oxygenated arenes.
In this context, several anionic annulations such as Hauser,3 Received: October 5, 2022
van Leusen,4 Staunton−Weinreb,5 Sammes,6 Hauser−Kraus,7 Published: November 7, 2022
and Tamura annulations8 are effective strategies for the rapid
generation of various oxygenated aromatic compounds by
controlling the regioselectivity (Scheme 1a). The potential of
these approaches has been demonstrated in the synthesis of

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various complex natural products.9 Although these annulations initially adding both ylide 1a and alkyne 2a in the presence of a
have extensive utility, some drawbacks still persist. (1) These metal catalyst. Treatment of 1a and 2a in the presence of an Ir-
annulations proceed via organolithiated intermediates which catalyst at 40 °C led to the formation of both arene 3a and
limits the functional group tolerance in the reaction. (2) The furanone 4a in an ∼3:1 mixture (Table 1, entry 2). The
preparation of the reactants requires toxic reagents such as reaction afforded diminished yields in the presence of the Rh-
sodium or potassium cyanide. (3) These annulations require based catalysts (Table 1, entries 3−4). No reaction was
an arene ring adjacent to the ester group to generate selective observed with cheap iron-based catalysts such as FeBr2 and
γ-lithiation; thus, they are restricted to naphthalene scaffolds hemin (Table 1, entries 5−6), which are capable of generating
and difficult to afford monocyclic oxygenated arenes. In the metal carbenes. Interestingly, the reaction was successful with
case of α,β-unsaturated esters, lithiation can afford both kinetic the ruthenium complex [Ru(p-cymene)Cl2]2 and afforded a
and thermodynamic enolates (α and γ-lithiation), which may 5:1 ratio of 3a (49%) and 4a (10%) (Table 1, entry 7). To our
not give monocyclic oxygenated arenes selectively (Scheme delight, the arene 3a was obtained in 78% isolated yield when
1c).10 In 2020, Newton’s group developed a method for the the reaction was performed at 70 °C (Table 1, entry 8). At
synthesis of monocyclic oxygenated arenes from the [4 + 2]- higher temperature, the intermolecular reaction between in situ
cycloaddition of 2,5-Bis(tert-butyldimethylsilyloxy)furans with generated 2-ethoxyfuran 4a′ and alkyne 2a dominating the
dienophiles via a one-pot Diels−Alder/ring-opening/tautome- intramolecular side reaction for furanone 4a. The sequential
rization cascade (Scheme 1b).11 However, in this method addition of reactants (similar to entry 1) under Ru-catalyzed
regioselectivity is a major issue for unsymmetrical dienophiles. conditions at 70 °C did not improve the yield. No reaction was
In our continuing interest in sulfur ylides,12 we envisioned that observed in the presence of 455 nm light and also Co(II)
vinyl sulfoxonium ylide reacts with the metal complex under catalyzed conditions, which are suitable conditions for
metal-catalyzed conditions to generate a carbenoid (Scheme generating carbenes from diazo compounds.14 Hence, entry
1d),13 which is analogous to the lithiated intermediate of 8 was chosen as the optimum condition for this benzannula-
Hauser annulation as shown in Scheme 1a. Thus, we would tion.15
like to utilize this intermediate for the catalytic regioselective Having the optimized reaction conditions (Table 1, entry 8),
synthesis of oxygenated arenes. Herein, we report the metal- the substrate scope of this benzannulation was evaluated. First,
catalyzed benzannulation of vinyl sulfoxonium ylides with we examined the scope of substitution at the aryl ring of vinyl
activated alkynes and alkenes to synthesize the oxygenated sulfoxonium ylide (Scheme 2a). A series of ylides bearing
biaryl compounds that can be used as a disinfectant, electron-releasing, electron-neutral, and electron-withdrawing
bactericide, and virucide (Scheme 1e). substituents at the 3- and 4-position of the benzene ring of the
In our previous study, we observed that the reaction of vinyl
vinylsulfoxonium ylide underwent smooth benzannulation to
sulfoxoium ylide 1a with an iridium complex led to 2-ethoxy
afford the corresponding biaryl phenols in good yields (3a−
furan 4a′.13 In the present study, we initially generated 2-
3g). The structure of the benzannulated product 3a was
ethoxyfuran 4a′ from 1a (1 equiv) in the presence of an Ir(I)
confirmed using X-ray analysis (CCDC2209249). The syn-
catalyst, and the addition of diethyl acetylenedicarboxylate 2a
thesis of hexasubstituted arenes, an important scaffold in
(1.2 equiv) to the generated furan 4a′ in CH2Cl2 at 40 °C
pharmaceutical and natural product synthesis, is a major
afforded arene 3a in 48% yield (Table 1, entry 1). Instead of
sequential addition, we intended to perform the reaction by challenge. Using the present method, the treatment of α,β-
substituted vinyl sulfoxonium ylide with 2a afforded hexasub-
stituted arene 3h in 72% yield. Next, we evaluated the variation
Table 1. Optimization of the Reaction Conditionsa
in the acid derivative part of the ylide (Scheme 2b). Vinyl
sulfoxonium ylide containing the amide group afforded para-
aminophenol derivative 3i in 68% yield. The ester group
containing benzyl and the substituted benzyl groups of ylide
also afforded the corresponding arenes 3j (70%) and 3k
(52%). When the reaction was performed with ylide containing
Entry Cat. (mol %) Solvent T (°C) Yield (3a:4a)b,c methyl ester, the corresponding benzannulated product 3la
1d
[Ir(COD)Cl]2 (2) CH2Cl2 40 48:trace (52%) and also methyl deprotected quinol 3lb (31%) were
2 [Ir(COD)Cl]2 (2) CH2Cl2 40 56:21 obtained.
3 [Rh(COD)Cl]2 (2) CH2Cl2 40 44:18 Next, we focused on the regioselective benzannulation of
4 [Rh2(OAc)]4 (2) CH2Cl2 40 21:10 vinyl sulfoxonium ylides with unsymmetrically substituted
5 FeBr2 (5) CH2Cl2 40 NR activated alkyne (Scheme 2c). Treatment of p-haloaryl ynones
6 Hemin (5) CH2Cl2 40 NR with ylide afforded oxygenated terphenyls in good yields (3m−
7 [Ru(p-cymene)Cl)2]2 (2) CH2Cl2 40 49:10 3n). Oxygenated terphenyls and their derivatives are naturally
8e,f [Ru(p-cymene)Cl)2]2 (2) C2H4Cl2 70 83(78):trace occurring compounds, and their synthesis required several
9 Blue LED CH2Cl2 rt NR steps via cross-coupling reactions.16 The present method is an
10 Co(II)TPP (5) C2H4Cl2 70 NR alternate approach for quickly accessing these molecules. The
a
reaction of ylide with methyl propiolate and methyl 3-
Standard conditions: 1a (0.2 mmol), 2a (0.24 mmol), solvent (2.0 bromopropiolate afforded expected regioisomers of biaryl
mL), 2 h. bThe yield was determined by 1H NMR analysis of crude
products using CH2Br2 as the internal standard. cFor entries 8−10, 4
phenols 3o (78%) and 3p (69%).
Å molecular sieves were added. d2a was added after 30 min to the Bromo substituted arene 3p can be used as a precursor for
reaction mixture. eIsolated yield at 0.2 mmol scale in parentheses. various metal-mediated coupling reactions to obtain pharma-
f
Same yield was observed when 2a was added after 30 min to the ceutically important compounds.17 The benzannulation
reaction mixture. reaction performed using alkyne containing both keto and
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Org. Lett. 2022, 24, 8359−8363
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Scheme 2. Synthesis of Oxygenated Arenes Using Sulfoxonium Ylide Derived Vinyl Carbenes

Scheme 3. Applications of Oxygenated Arenes Obtained from Benzannulation

ester groups with ylide afforded an equal amount of biaryl and propargyl-substituted propiolates also underwent effective
phenol regiomers 3q and 3q′ in 76% yield. benzannulation to afford the biaryl phenols 3ac−3ae in good
Thereafter, we evaluated the benzannulation of ylides with yields (Scheme 2e).
alkene-based dienophiles such as acrylate, maleic anhydride, To demonstrate the practicality and scalability of this
and N-phenyl maleimide which gave the biaryl products 3r method, we performed a scale-up reaction on a 4.5 mmol scale
(71%), 3s (82%), and 3t (77%) respectively (Scheme 2d). The under standard reaction conditions, and arene 3o was obtained
benzannulation of ylide 1a with 2,2-disubstituted 1,3-cyclo- in 74% yield (0.91 g) (Scheme 3a). Hypervalent iodine-
pentenedione afforded 3u (77%), which is the core structure of mediated dearomatization of arene 3o followed by treatment
the bioactive natural product meroindenon.18 The benzannu- with β-naphthol under 10 mol % of Lewis acid afforded biaryl
lation of ylide with ynones also gave good yields of arenes 3v− diol 6 (91%). The same reaction with 10 mol % of Brønsted
3ab. Moreover, the reaction of ylide with steroid-, terpenoid-, acid at 80 °C yielded benzo-3,4-coumarin 7 (84%) which is a
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Org. Lett. 2022, 24, 8359−8363
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core structure of natural products and pharmaceuticals such as 1722 cm−1). When the reaction mixture was heated at 70 °C, a
defucogilvocarcin M, gilvocarcin M, deacetylravidomycin M, gradual increase in the arene formation was noticed and we
and arnottin I.19 In addition, we examined the gram scale have not detected a possible conjugate addition product. This
benzannulation of methyl substituted sulfoxonium ylide with is further confirmed by HRMS analysis of the crude reaction
alkyne 2a, which yielded arene 8 in 71% yield (Scheme 3b). mixture of benzannulation (see the SI for full details).
Treatment of 8 with BBr3 led to the formation of quinol 9, Based on the mechanistic experiments and literature
which is a precursor for the synthesis of the neuroprotective precedents,13 a plausible mechanism was proposed (Scheme
compound indanostatin.20 Next, considering the importance of 5). First, vinyl sulfoxonium ylide reacts with the Ru-complex to
polyarene synthesis by arene homologation,21 we focused on
the one unit homologation of benzannulated arene 3a. Adding Scheme 5. Plausible Mechanism for the Benzannulation
a 1,4-hydroquinone unit to arene scaffold 3a can lead to
oxygenated naphthalenes, which are the basic scaffolds of
various natural products and pharmaceuticals (Scheme 3c).22
Treating benzyl-protected arene 10 with dimethyl succinate
followed by benzyl protection yielded oxygenated naphtha-
lenes 11.23
Several mechanistic experiments were conducted to
elucidate the benzannulation mechanism (Scheme 4). In the

Scheme 4. Mechanistic Studies

afford vinyl carbenoid 15a which undergoes intramolecular

cyclization, leading to the formation of furan 4a′. The Diels−
Alder reaction between furan and alkyne leads to the formation
of cycloadduct 16a which can undergo ring cleavage in the
presence of the Ru-complex to afford 16c. Finally, the
aromatization of 16c led to the formation of arene 3a.
In conclusion, we have presented a facile benzannulation of
sulfoxonium ylide derived vinyl carbenes with alkynes and
alkenes. The mild reaction conditions, broad scope, and one-
step synthesis of highly substituted arenes with high
regioselectivity are the important features of this reaction.
We believe that similar to the notable Wulff−Dötz reaction,
which involves the benzannulation of vinyl carbenes with
alkynes to synthesize oxygenated arenes, our simple and
presence of a catalyst, vinyl sulfoxonium ylide afforded 2- convenient method will be useful in the preparation of various
ethoxy furan 12 in 88% yield (Scheme 4A). In the absence of a pharmacologically important oxygenated arenes.
catalyst, no possible conjugate addition of ylide to the methyl
acrylate was observed;24 instead, the ylide underwent a known
[2,3]-sigmatropic rearrangement (Scheme 4B).25 Treating of
■ ASSOCIATED CONTENT
Data Availability Statement
vinyl sulfoxonium ylide with methyl acrylate in the presence of
The data underlying this study are available in the published
a Ru-catalyst at 40 °C afforded a mixture of bridge bicyclic
article and its online Supporting Information.
compounds 14a (44%) and 14b (41%) (Scheme 4C). When
the mixture of cycloadducts (14a and 14b) was heated at 70 *
sı Supporting Information

°C, a trace amount of arene 3r′ is observed. The similar The Supporting Information is available free of charge at
reaction in the presence of 2 mol % Ru-catalyst afforded the https://pubs.acs.org/doi/10.1021/acs.orglett.2c03388.
arene 3r′ in 91% yield (Scheme 4E). This suggests that the Ru- Representative experimental procedures, characteriza-
catalyst assists as a Lewis acid to cleave the strained C−O bond tion data, and spectra for all new compounds (PDF)
of the ketal group of the cycloadduct.26 To gain more insights
into the mechanism, the benzannulation of vinyl sulfoxonium Accession Codes
ylide with alkyne was monitored using reaction IR studies CCDC 2209249−2209250 contain the supplementary crys-
(Scheme 4F). At rt, the reaction yielded furan 4a′ in 30 min tallographic data for this paper. These data can be obtained
(band at 1607 cm−1) and conversion of arene is slow (band at free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
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Org. Lett. 2022, 24, 8359−8363
Organic Letters pubs.acs.org/OrgLett Letter

emailing [email protected], or by contacting The (9) Mal, D. Anionic Annulations in Organic Synthesis: A Versatile and
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Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 2018.
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■ AUTHOR INFORMATION
Corresponding Author
K. N.; Njardarson, J. T. J. Am. Chem. Soc. 2021, 143, 5793.
(11) Dissanayake, I.; Hart, J. D.; Becroft, E. C.; Sumby, C. J.;
Newton, C. G. J. Am. Chem. Soc. 2020, 142, 13328.
Janakiram Vaitla − Department of Chemistry, Indian Institute (12) (a) Vaitla, J.; Bayer, A.; Hopmann, K. H. Angew. Chem., Int. Ed.
of Technology Delhi, New Delhi 110016, India; 2017, 56, 4277. (b) Vaitla, J.; Bayer, A. Synthesis 2019, 51, 612.
orcid.org/0000-0003-4068-5916; Email: vaitla@ (c) Vaitla, J.; Hopmann, K. H.; Bayer, A. Org. Lett. 2017, 19, 6688.
chemistry.iitd.ac.in (d) Vaitla, J.; Bayer, A.; Hopmann, K. H. Synlett 2019, 30, 1377.
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Authors 2018, 57, 16180.
(14) (a) Durka, J.; Turkowska, J.; Gryko, D. ACS Sustainable Chem.
Daksh Singh Davas − Department of Chemistry, Indian Eng. 2021, 9, 8895. (b) de Bruin, B.; te Grotenhuis, C. Synlett 2018,
Institute of Technology Delhi, New Delhi 110016, India 29, 2238.
Dinesh Kumar Gopalakrishnan − Department of Chemistry, (15) See the Supporting Information for details.
Indian Institute of Technology Delhi, New Delhi 110016, (16) Adrio, L. A.; Míguez, J. M. A.; Hii, K. K. Org. Prep. Proced. Int.
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Complete contact information is available at: Fenical, W. Org. Lett. 2019, 21, 5779.
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■ ACKNOWLEDGMENTS
J.V. acknowledges the financial support from CSIR (02(0418)/
(21) Zhang, K.; Cai, L.; Jiang, X.; Garcia-Garibay, M. A.; Kwon, O. J.
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for the institute fellowship. (23) Kelly, T. R.; Bell, S. H.; Ohashi, N.; Armstrong-Chong, R. J. J.
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