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IJCB 57B(3) 327-339.Pdf Indian Journal of Chemistry Vol. 57B, March 2018, pp. 327-339 Stereoselective carbon–carbon bond formation via 1,2-asymmetric induction by a β-substituent in the reaction of α-chloro sulfides with organozinc reagents S Raghavan*a & L Raju Chowhana,b a Natural Product Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India b School of Chemistry, University of Hyderabad, Hyderabad 500 046, India E-mail: [email protected] Received 8 October 2016; accepted (revised) 8 May 2017 The stereoselectivity of C–C bond formation in the reaction of α-chlorosulfides with a variety of organozinc reagents has been investigated. The study reveals excellent 1,2-asymmetric induction by a β-siloxy substituent and moderate 1,2-induction by the β-methyl substituent. The stereoselectivity is a function of the size of the organozinc reagents. Keywords: α-Chlorosulfide, organozinc reagents, 1,2-asymmetric induction, chiral α-substituted sulfides α-Chloro sulfides are versatile intermediates for the 3 in the reaction of the derived chloro sulfides, with stereocontrolled formation of C–C bonds. Normant1 various organozinc reagents. Also the stereoselectivity reported the preparation of organomagnesium reagent of C–C bond formation by 1,2-asymmetric induction from α-chloro- sulfides for C–C bond formation. as a function of the size of the alkyl group in β-methyl Takai and co-workers reported on the reaction of α-chloro sulfides derived from sulfides 5 is explored. organochromium reagents2, derived from α-chloro The siloxy substrates 3a-d were readily prepared sulfides, with aldehydes. More recently, Mitzel and by reaction of phenythiomethyl lithium15 obtained co-workers have prepared organoindium reagents3 from from 7 with commercially available aldehydes 8a-d, chloro sulfides and utilized them for the preparation followed by silylation (Scheme II). of epoxy alkynes. α-Chloro sulfides are valuable as The α-chloro sulfides, prepared from sulfides 3 by reactive electrophiles for the alkylation of aromatics4, reaction with N-chlorosuccinimide, were reacted with alkenes5, enolates6, and silyl ethers of aldehydes, ketones7, octynylzinc bromide 10a, vinylzinc bromide 10b and esters and lactones8. Chiral α-substituted sulfides are butylzinc bromide 10c to furnish syn-siloxy sulfides 4 useful synthons for the preparation of epoxydiynes9, in synthetically useful yields and diastereoselectivity. α,β-unsaturated acids10, allylic alcohols11, and allylic The results are collected in Table I. The structures amino derivatives12. The stereoselective synthesis of were assigned to the products based on the J values α-substituted sulfides therefore assumes importance. of the methine protons of the diastereoisomers and by comparison with product 2 (Ref 9,14). The Results and Discussion stereoselecitvity of the reaction was determined by The reaction of the simplest α-chloro sulfide with integration of the peaks of the diastereomers in the phenylmagnesium bromide was reported as early as crude 1H NMR spectrum. An inspection of Table I 1936 by Bohme13. The generality of the reaction was reveals that sterically bulky sp2 (10b) and sp3 (10c) demonstrated by introducing α-alkyl/aryl substituents hybridized nucleophiles reacted with substrates 3a-d on simple cyclic and acyclic chloro sulfides. There uniformly with high selectivity to furnish the syn- were no reports however, on the diastereoselective isomers as the sole product. With the less bulky sp preparation of α-substituted sulfides prior to our hybridized reagent 10a, the influence of the β-alkyl preliminary report, utilizing organozinc reagents for substituent could be discerned. The sulfide 3d with a stereoselective C–C bond formation from β-siloxy bulky t-butyl substituent afforded propargylic sulfide α-chloro sulfides, Scheme I (Ref 14). Herein, we 4da as the sole product. Moderate selectivity only was provide details of the steric influence of alkyl observed in the case of substrates 3b and 3c (dr = 3:1), substituents attached to the β-carbon of siloxy sulfides which was poorer than that observed for sulfide 1 (dr = 9:1). 328 INDIAN J. CHEM., SEC B, MARCH 2018 Scheme I — Stereoselective synthesis of α-substituted sulfides by asymmetric induction Scheme II — Synthesis of β-siloxy sulfides 3a-d The diastereoselectivity in the reaction of the inferior compared to the siloxy group. While substrate chloro sulfide derived from 3a with 10a could not be 3d afforded 4da as the only product even in the determined by examination of the 1H NMR of crude reaction with the least bulky of the nucleophiles product mixture. Thus a branching at the α- or even at 10a, the chloro sulfide derived from 5d afforded the β-position of the alkyl group is sufficient to 6da as a 9:1 mixture of isomers. Likewise, while furnish substituted sulfides in good to excellent sulfide 1 afforded products in the reaction with diastereoselectivity. organozinc reagents 10a-c in excellent selectivity, 5c furnished syn-propargylic sulfide 6ca in a 56:44 Synthesis and reactions of β-methyl sulfides 5 ratio. The allylic and alkyl sulfides 6cb and 6cc The substrate 5a was prepared from the known16 were obtained as roughly 3:1 ratio of isomers. alcohol 11a, by reaction with diphenyl disulfide using Interestingly, relative to 5c, sulfide 5b possesing an Hata's protocol17 (Scheme III). The sulfide 5b, 5c and isopropyl substituent, afforded products with a 5d were prepared using Hata's protocol from the better stereoseectivity; allylic sulfide 6bb and alkyl known alcohols 11b, 11c and 11d (Ref 18). To sulfide 6bc were obtained as sole products and comprehend the influence of the β-methyl substituent propargylic sulfide 6ba was obtained in a 3:1 ratio. relative to the siloxy substituent in the 1,2-asymmetric The superior induction by the OTBS group is evident induction, sulfides 5a-d were reacted with reagents by comparing entry 2, Table I with entry 1, Table II; 10a-c and the results are collected in Table II. the alkyl sulfide 6ac is obtained in a 7:3 ratio A cursory examination of Table II reveals that while 6ac was obtained as the sole product. The the asymmetric induction by the β-methyl group is influence of the size of the alkyl substituent at the RAGHAVAN & CHOWHAN: ASYMMETRIC INDUCTION BY β-SUBSTITUENT 329 Table I Entry Substrate Propargylic sulfide, Yield (dr) Allylic sulfide, Yield (dr) Alkyl sulfide, Yield (dr) 1 64%a (>95:<5) 86% (90:10) 80% (>95:<5) 2 50%a (>95:<5) 78% (70:30) 75% (>95:<5) 3 a 80% (78:22) 85% (>95:<5) 50% (>95:<5) 4 45%a (>95:<5) 75% (75:25) 75% (>95:<5) 5 65% (>95:<5) 73% (>95:<5) 48%a (>95:<5) a: Vinyl sulfide side product also obtained resulting in poor yields. β-position is evident in the methyl series as in the Assignment of structure OTBS series. The branching at the α-position of The observed stereoselectivity of products can be the alkyl substituent is required for efficient rationalized by invoking a model depicted in chiral induction. As observed with substrates 3, Scheme IV, wherein the nucleophile (R3M) attacks vinyl sulfides were obtained in the reaction of the sulfenium ion from the face opposite to the larger chlorosulfides prepared from 5 with butylzinc reagent. alkyl group (R1), R2 being OTBS/Me groups. The ratio of alkylated to eliminated products was The relative stereochemistry of the compound 5ca lower due to lower reactivity. It can be concluded has been assigned as shown in Scheme V, on the that an alkyl group with α-branching (5b) is required basis of preferred conformations. Acyclic compounds for obtaining substituted sulfides with good selectivity having vicinal stereogenic centers, each bearing in the β-Me series. one hydrogen, normally exist predominantly in the 330 INDIAN J. CHEM., SEC B, MARCH 2018 Scheme III — Synthesis of β-methyl sulfides 5a-d Table II Entry Substrate Propargylic sulfide, Yield (dr) Allylic sulfide, Yield (dr) Alkyl sulfide, Yield (dr) 1 73% (75:25) 40% a (68:32) 82% (64:36) 2 a 80% (75:25) 80% (>95:<5) 44% (70:30) 3 a 80% (56:44) 78% (80:20) 40% (70:30) 4 a 73% (90:10) 70% (>95:<5) 55% (>95:<5) a: Vinyl sulfide side product also obtained resulting in poor yields. conformation having the hydrogens anti to minimize observed at δ 2.18 (dt, J = 6.7, 2.2 Hz, 2H). The gauche interactions19. The preferred conformations signals for the vinyl group in 5cb appeared at δ 5.56 of 5ca and its anti-diastereomer is depicted in (m, 1H), 4.80 (d, 1H), 4.68 (d, 1H) and for the anti- Scheme V. The substituent gauche to the phenyl group isomer the signals were observed at δ 5.71 (m, 1H), resonates upfield due to the net shielding effect of 4.94 (d, 1H) and 4.76 (d, 1H). The chemical shift the aromatic ring. The observed chemical shifts for values for the major isomer were upfield relative to –CH2-C≡C- of 5ca is δ 2.10 (dt, J = 6.7, 2.2 Hz, 2H) the minor isomer. Based on the above, the relative and for the minor anti-diastereomer the signal is orientation of the Me- and -SPh groups in the major RAGHAVAN & CHOWHAN: ASYMMETRIC INDUCTION BY β-SUBSTITUENT 331 Scheme IV — Model to rationalize stereoselectivity Scheme V — Assignment of relative configuration product 5ca-5cc were assigned as syn- and anti- in the combined organic layers were washed with brine minor isomers. relation. The stereochemistry of other (10 mL), dried over anhyd. Na2SO4, concentrated under compounds were assigned based on analogy. reduced pressure and purified by column chromatography using 10% EtOAc/Hexanes (v/v) as the eluent to Experimental Section afford the alcohol 9a (2.0 g, 8.5 mmol) in 85% yield as Unless otherwise indicated, all reactions were a colourless oil.
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