Article pubs.acs.org/joc
Catalytic Enantioselective Synthesis of 3,4-Unsubstituted Thiochromenes through Sulfa-Michael/Julia−Kocienski Olefination Cascade Reaction Amit Kumar Simlandy and Santanu Mukherjee* Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India S Supporting Information *
ABSTRACT: A highly enantioselective cascade sulfa-Michael/Julia−Kocienski olefination reaction between 2-mercaptobenzaldehydes and β-substituted vinyl PT-sulfones has been realized for the synthesis of 3,4-unsubstituted 2H-thiochromenes. This reaction, catalyzed by diphenylprolinol TMS ether, proceeds through an aromatic iminium intermediate and furnishes a wide range of 2-substiuted 2H-thiochromenes with excellent enantioselectivities (up to 99:1 er).
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INTRODUCTION Thiochromenes, thiochromanes and their derivatives are valuable compounds due to their potential applications in pharmaceutical industries (Figure 1).1 As a result, a number of
Scheme 1. Catalytic Enantioselective Routes to 2-Substituted Thiochromenes
Figure 1. Bioactive thiochromenes and thiochromanes.
strategies have been devised for the enantioselective synthesis of such heterocycles.2−4 Catalytic enantioselective sulfaMichael-initiated cascade reactions are possibly the most efficient ways of constructing these and related heterocycles.2−5 The first report by Wang et al. in 20062 triggered the development of a large number of sulfa-Michael-initiated cascade reactions. However, in all these reactions, 2Hthiochromenes are formed invariably containing an electronwithdrawing substituent at the C3 position (Scheme 1A).4 Enantioselective synthesis of 3,4-unsubstituted 2H-thiochromenes remained an unmet challenge until very recently. While the present study was nearing completion, Birman et al. reported an elegant strategy for the first enantioselective synthesis of 3,4-unsubstituted thiochromenes via an acyltransfer-initiated cascade reaction (Scheme 1B).6 With our interest in thiochromenes, we aimed to develop a facile and enantioselective route to 3,4-unsubstituted thiochromenes. In 2013, our laboratory has reported a sulfa-Michael/ Horner−Wadsworth−Emmons cascade reaction between 2© 2017 American Chemical Society
mercaptobenzaldehydes and α-carboxylato vinylphosphonates for the enantioselective synthesis of 2H-thiochromenes bearing an ester moiety at C3 (Scheme 1A).4c While the phosphonate group acts as a traceless activator of α,β-unsaturated ester in this reaction, vinyl phosphonate itself was found to be unreactive under our reaction conditions and thereby eliminates the possibility of constructing 3,4-unsubstituted 2H-thiochromenes through this route. Nucleophilic addition to vinyl sulfones followed by JuliaKocienski (JK) olefination as a metal-free strategy for formal allylic alkylation is known through the seminal works of Cid and co-workers.7 We reasoned that a related sulfa-Michael addition of 2-mercaptobenzaldehyde to vinyl sulfones could set the stage for a JK olefination8 (Scheme 1B). Controlling enantioselectivity of the initial sulfa-Michael step would of Received: March 10, 2017 Published: April 7, 2017 4851
DOI: 10.1021/acs.joc.7b00579 J. Org. Chem. 2017, 82, 4851−4858
Article
The Journal of Organic Chemistry
subsequent ring closure through intramolecular JK olefination13 should then generate the desired thiochromene 3aa. The reaction between 1a and 2a, when carried out in the presence of 10 mol % of diphenylprolinol TMS ether14 (I) in toluene at room temperature, 2-phenyl-2H-thiochromene 3aa was indeed found to form, albeit in rather low yield and with modest enantioselectivity (Table 1, entry 2). Variation of the aryl group or the silyl protecting group on oxygen of the catalyst (II−VII) either did not improve the enantioselectivity or did so marginally at the expense of the reaction rate (entries 3−8). Likewise, nearly racemic product was obtained using bifunctional secondary amino-thiourea VIII15 as the catalyst. Product with improved er was observed when the reaction was carried out at higher concentration (entry 10). Solvent, however, was found to play the vital role: the reaction in tertbutylbenzene using I as the catalyst furnished the product with significantly improved er of 94:6 (entry 12). Enantioselectivity could be further improved by using 10 mol % an acid cocatalyst, with diphenyl phosphate proved to be the optimum (entries 13−15).16 Susceptibility of 1a toward oxidation appeared to be the reason for low yield, which could be overcome by using an excess of 1a (entry 16). Finally, superior product yield was obtained in the presence of 4 Å molecular sieves: under these conditions, 3aa was formed in 79% yield with 99:1 er (entry 17). Considering the operational simplicity, we decided to carry out the reaction at 0.1 M concentration when the same level of yield and enantioselectivity was maintained (entry 18). Application of reaction conditions optimized for 2mercaptobenzaldehyde 1a and vinyl PT-sulfone 2a (Table 1, entry 18) to a range of similar substrates was then undertaken. The scope of vinyl sulfones (2) was first examined and the results are outlined in Table 2. Our reaction conditions proved to be general for a range of vinyl PT sulfones bearing both aromatic and aliphatic substituents at the β-position. Irrespective of the steric or electronic nature of the substituents on different positions of the aryl ring, 2H-thiochromenes (3) were obtained with excellent enantioselectivities in moderate to high yields (entries 2−15). The same selectivity trend was observed for β-heteroaryl or β-alkenyl substituted vinyl PTsulfones, although in the latter case the product was formed with low yield (entries 16−17). We were delighted to find that β-alkyl substituted vinyl PT sulfones were not only tolerated, but furnished the products with good to excellent enantioselectivities (entries 18−20). In addition to the examples shown in Table 2, we surveyed the scope of the aldehyde component (1) with respect to the substituents on the aryl ring. As portrayed in Table 3, various substituents on either 4- or 5-position of the aryl ring could be accommodated. In all these cases, the products were obtained with good to excellent enantioselectivities. Absolute configuration of 3ai and 3ak was established by Xray crystallography and found to be R (Figure 2).17 The stereochemistry of the remaining examples was assigned by analogy. Having successfully demonstrated the scope of the sulfaMichael/JK olefination cascade reaction, the product 2-phenyl2H-thiochromene 3aa was subjected to a few synthetic elaborations (Scheme 2). Hydrogenation under Pd/C afforded (R)-2-phenylthiochromane 4 in excellent yield. Enantioselective synthesis of 3,4-unsubstituted thiochromanes has not been explored previously except for a solitary report by Pfaltz et al.18 Therefore, ours is only the second example of the
course be the key to success of this cascade reaction, which would result in 3,4-unsubstituted 2H-thiochromenes containing a stereogenic center at the C2 position. The successful implementation of this strategy is presented here.
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RESULTS AND DISCUSSION Earlier studies by our group9 and the Cid group7a confirmed vinyl(1-phenyl-1H-tetrazol-5-yl)sulfone7 (vinyl PT-sulfone) to be more reactive compared to the corresponding vinyl phenyl sulfone. Accordingly, the reaction between 2-mercaptobenzaldehyde 1a and vinyl PT-sulfone 2a was chosen for the optimization of catalyst and reaction conditions (Table 1). The Table 1. Reaction Optimizationa
entry
cat.
solvent
co-cat.
t/h
yield (%)b
erc
1 2 3d 4 5 6 7 8 9 10e 11e 12e 13e 14e 15e 16e,f 17e,f,g 18f,g
− I II III IV V VI VII VIII I I I I I I I I I
PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhMe PhCF3 t-BuPh t-BuPh t-BuPh t-BuPh t-BuPh t-BuPh t-BuPh
− − − − − − − − − − − − PhCO2H 2-FC6H4CO2H (PhO)2PO2H (PhO)2PO2H (PhO)2PO2H (PhO)2PO2H
24 48 72 96 48 48 48 48 72 48 48 46 48 48 48 48 48 48
