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. TLC (SiO2): Rf = 0.32 (10% EtOAc/ carried out with magnetic stirring and if air or Hexanes); IR (neat): 3426, 2923, 1582, 1480, 1443, moisture sensitive, in flame-dried glassware under −1 1 1301, 1085, 1055, 740, 696 cm ; H NMR (CDCl3, nitrogen. Syringes used to transfer reagents and 300 MHz): δ 7.32 (d, J = 7.1 Hz, 2H), 7.24 (t, J = 7.1 solvents were purged with nitrogen prior to use. 1H 13 Hz, 2H), 7.16 (t, J = 7.1 Hz, 1H), 3.64-3.56 (m, 1H), and C NMR spectra were recorded at 200, 300, 400 3.06 (dd, J = 13.5, 3.3 Hz, 1H), 2.80 (dd, J = 13.5, 8.6 and 50, 75, 100 MHz respectively in CDCl3. Reactions Hz, 1H), 1.49-1.40 (m, 2H), 1.36-1.22 (m, 8H), 0.87 were monitored by thin layer chromatography (TLC). 13 (t, J = 6.7 Hz, 3H); C NMR (CDCl3, 75 MHz): δ Before use, all the Grignard reagents were titrated 135.8, 128.9, 128.3, 125.5, 69.2, 41.0, 35.7, 31.4, with salicylaldehyde phenylhydrazone indicator. + 28.9, 25.2, 22.2, 13.7; ESI-MS: m/z 238 [M] . 1-(Phenylthio)octan-2-ol, 9a To a solution of the mixture of thioanisole 7 4-Methyl-1-(phenylthio)pentan-2-ol, 9b: Following (1.2 mL, 10 mmol), DABCO (1.1 g, 10 mmol) the procedure detailed above, thioanisole 7 (1.2 mL, in anhydrous THF (16 mL) was added n-BuLi 10 mmol) and isovaleraldehde 8b (1.1 mL, 10 mmol) (7.3 mL, 1.5 M in Hexanes, 11 mmol) at 0°C. The furnished the alcohol 9b (1.79 g, 8.5 mmol) in 85% mixture was gradually allowed to warm to RT and yield as a liquid. TLC (SiO2): Rf = 0.39 (10% EtOAc/ stirred for 2 h. The reaction mixture was then Hexanes); IR (neat): 3448, 2926, 2855, 1630, 1462, cooled to 0°C, a solution of heptaldehyde 8a (1.4 mL, 1254, 1217, 1060, 837, 767, 687 cm−1; 1H NMR 10 mmol) in anhydrous THF (10 mL) was added and (CDCl3, 300 MHz): δ 7.34 (d, J = 7.9 Hz, 2H), 7.25 the mixture stirred at the same temperature for 1 h. (t, J = 7.9 Hz, 2H), 7.16 (t, J = 7.9 Hz, 1H), 3.74-3.65 The reaction mixture was quenched with saturated aq. (m, 1H), 3.06 (dd, J = 13.4, 3.5 Hz, 1H), 2.80 (dd, NH4Cl, the layers were separated and the aqueous J = 13.4, 8.4 Hz, 1H), 2.32 (s, 1H), 1.85-1.72 (m, 1H), layer was extracted with EtOAc (3×10 mL). The 1.31-1.24 (m, 2H) 0.95-0.85 (m, 6H); 13C NMR 332 INDIAN J. CHEM., SEC B, MARCH 2018
(CDCl3, 75 MHz): δ 136.0, 129.6, 128.9, 126.2, 67.7, the product 3a (2.9 g, 8.2 mmol) in 97% yield as a + 45.3, 24.7, 23.4, 22.1, 14.2; ESI-MS: m/z 234 [M+Na] . liquid. TLC (SiO2): Rf = 0.81 (Hexanes); IR (neat): 2953, 2927, 2855, 1582, 1470, 1252, 1094, 1008, 755, −1 1 3-Methyl-1-(phenylthio)butan-2-ol, 9c: Following 737, 694 cm ; H NMR (CDCl3, 500 MHz): δ 7.28 (d, the procedure detailed above for the preparation 9a, J = 7.8 Hz, 2H), 7.19 (t, J = 7.8 Hz, 2H), 7.08 (t, thioanisole 7 (1.2 mL, 10 mmol) and isobutanal 8c J = 7.8 Hz, 1H), 3.77 (m, 1H), 2.95 (dd, J = 13.6, 5.8 (0.9 mL, 10 mmol) furnished sulfide 9c (1.5 g, 8.0 Hz, 1H), 2.90 (dd, J = 13.6, 5.8 Hz, 1H), 1.71-1.62 mmol) in 80% yield as a liquid. TLC (SiO2): Rf = 0.35 (m, 1H), 1.51-1.44 (m, 1H), 1.32-1.24 (m, 8H), (10% EtOAc/Hexanes); IR (neat): 3426, 2923, 1582, 0.91-0.86 (bs, 12H), 0.03 (s, 3H), 0.00 (s, 3H); −1 13 1480, 1443, 1301, 1085, 1055, 740, 696 cm ; C NMR (CDCl3, 75 MHz): δ 137.3, 129.3, 128.6, 1 H NMR (CDCl3, 500 MHz): δ 7.34 (d, J = 7.8 Hz, 125.7, 71.4, 40.9, 36.4, 31.9, 29.4, 25.9, 25.8, 22.8, 2H), 7.28 (t, J = 7.8 Hz, 2H), 7.18 (d, J = 7.8 Hz, 1H), 18.1, 14.2, -4.3, -4.5; ESI-MS: m/z 369 [M+O+H]+. 3.40-3.34 (m, 1H), 3.15 (dd, J = 13.6, 2.9 Hz, 1H), Note: The sulfide was oxidized to the sulfoxide while 2.80 (dd, J = 13.6, 5.8 Hz, 1H), 2.32 (s, 1H), recording the mass spectrum. 1.79-1.72 (m, 1H), 0.95 (d, J = 7.8 Hz, 3H), 0.94 (d, 13 J = 6.8 Hz, 3H); C NMR (CDCl3, 75 MHz): δ 135.5, tert-Butyldimethyl(4-methyl-1-(phenylthio)pentan- 130.1, 129.2, 126.7, 73.9, 40.0, 34.0, 17.8, 17.2; 2-yloxy)silane, 3b: Following the procedure detailed ESI-MS: m/z 234 [M+O+Na]+; ESI-HRMS: m/z above for the preparation of sulfide 3a, the alcohol 9b Calcd for C11H16O2SNa 235.0763. Found: 235.0756. (1.79 g, 8.9 mmol) furnished sulfide 3b (2.6 g, 8.2 Note: The sulfide was oxidized to the sulfoxide while mmol) in 92% yield as a liquid. TLC (SiO2): Rf = 0.82 recording the mass spectrum. (Hexanes); IR (neat): 2955, 2925, 2857, 1580, 1472, 1250, 1090, 1012, 758, 735, 697 cm−1; 1H NMR 3,3-Dimethyl-1-(phenylthio)butan-2-ol, 9d: Following (CDCl3, 500 MHz): δ 7.31 (d, J = 7.9 Hz, 2H), 7.22 the general procedure thioanisole 7 (1.2 mL, 10 (t, J = 7.9 Hz, 2H), 7.12 (t, J = 7.9 Hz, 1H), 3.85-3.79 mmol) and trimethylacetaldehyde 8d (1.1 mL, 10 mmol) (m, 1H), 2.97 (dd, J = 12.8, 4.9, Hz, 1H), 2.89 (dd, furnished the alcohol 9d (1.26 g, 6.0 mmol) in 60% J = 12.8, 6.9, Hz, 1H), 1.75-1.65 (m, 1H), 1.55-1.48 yield as a liquid. TLC (SiO2): Rf = 0.35 (10% EtOAc/ (m, 2H) 0.95-0.82 (m, 15H), 0.04 (s, 3H), 0.03 (s, 13 Hexanes); IR (neat); 3448, 2926, 2855, 1630, 1462, 3H); C NMR (CDCl3, 75 MHz): δ 137.2, 129.7, 1254, 1217, 1060, 837, 767, 697 cm−1; 1H NMR 128.8, 126.0, 69.9, 46.1, 27.4, 26.1, 24.5, 23.7, 22.5, + (CDCl3, 500 MHz): δ 7.34 (d, J = 7.4 Hz, 2H), 7.26 18.4, -4.0, -4.4; ESI-MS: m/z 341[M+O+H] . Note: (t, J = 7.4 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 3.25 The sulfide was oxidized to the sulfoxide while (dd, J = 11.7, 1.9 Hz, 1H), 3.22 (dd, J = 13.6, 1.9 Hz, recording the mass spectrum. 1H), 2.70 (dd, J = 13.6, 11.7 Hz, 1H), 0.90 (bs, 9H); 13 C NMR (CDCl3, 75 MHz): δ 135.3, 129.8, 129.0, tert-Butyldimethyl(3-methyl-1-(phenylthio)butan- 126.5, 76.3, 38.0, 34.7, 25.9; ESI-MS: m/z 249 2-yloxy)silane, 3c: Following the procedure detailed + [M+O+Na] ; ESI-HRMS: m/z Calcd for C12H18O2SNa for the preparation 3a, the alcohol 9c (1.5 g, 7.9 mmol) 249.0919. Found: 249.0931. Note: The sulfide was oxidized furnished the product 3c (2.2 g, 7.3 mmol) in 92% to the sulfoxide while recording the mass spectrum. yield as a liquid. TLC (SiO2): Rf = 0.81 (Hexanes); IR (neat): 2953, 2927, 2855, 1582, 1470, 1252, 1094, −1 1 tert-Butyldimethyl(1-(phenylthio)octan-2-yloxy) 1008, 755, 737, 694 cm ; H NMR (CDCl3, 300 silane, 3a: To a solution of the alcohol 9a (2.0 g, 8.5 MHz): δ 7.24 (d, J = 7.5 Hz, 2H), 7.28 (t, J = 7.5 Hz, mmol) in anhydrous DCM (34 mL) cooled to 0°C was 2H), 7.18 (t, J = 7.5 Hz, 1H), 3.45-3.44 (m, 1H), 3.14 added imidazole (867 mg, 12.7 mmol, 1.5 eq) followed (dd, J = 9.2, 3.1 Hz, 1H), 2.80 (dd, J = 9.2, 3.1 Hz, by TBS-Cl (1.4 g, 9.35 mmol, 1.1 eq). The mixture 1H), 1.81-1.67 (m, 1H), 0.93 (d, J = 6.7 Hz, 3H), 0.9 was stirred at RT for a period of 2 h, then diluted (s, 9H), 0.79 (d, J = 6.7 Hz, 3H), 0.06 (s, 3H), 0.00 (s, 13 with DCM (30 mL), washed successively with 3H); C NMR (CDCl3, 75 MHz): δ 137.4, 129.2, water (10 mL), brine (10 mL), dried over anhyd. 128.9, 125.9, 75.6, 38.1, 32.5 26.0, 25.8, 18.9, 16.4, + Na2SO4 and the solvent evaporated under reduced -4.0, -4.5; ESI-MS: m/z 362 [M+O2+NH4] . Note: The pressure to yield the crude product which was purified sulfide was oxidized to the sulfone while recording by column chromatography using hexanes to furnish the mass spectrum. RAGHAVAN & CHOWHAN: ASYMMETRIC INDUCTION BY β-SUBSTITUENT 333
tert-Butyl(3,3-dimethyl-1-(phenylthio)butan-2-yloxy) tert-Butyldimethyl((3RS,4RS)-3-(phenylthio)dec- dimethylsilane, 3d: Following the procedure detailed 1-en-4-yloxy)silane, 4ab: Following the general for the preparation of 3a, the alcohol 9d (1.18 g, 5.6 procedure detailed above, the α-chlorosulfide derived mmol) furnished the product 3d (1.55 g, 4.8 mmol) in from sulfide 3a (176 mg, 0.5 mmol) was reacted with 85% yield as a liquid. TLC (SiO2): Rf = 0.86 vinylzinc bromide (1.5 mmol) at RT (6 h) to afford (Hexanes); IR (neat): 2953, 2927, 2855, 1582, 1470, the crude product which was purified by column 1252, 1094, 1008, 755, 737, 694 cm−1; 1H NMR chromatography using hexanes as the eluent to furnish (CDCl3, 500 MHz): δ 7.38 (d, J = 7.5 Hz, 2H), 7.33 the pure product 4ab (141 mg, 0.37 mmol) in 75% (t, J = 7.5 Hz, 2H), 7.22 (t, J = 7.5 Hz, 1H), 3.54 yield as a liquid. TLC (SiO2): Rf = 0.84 (Hexanes); IR (dd, J = 6.5, 3.1 Hz, 1H), 3.31 (dd, J = 13.0, 3.1 Hz, 1H), (neat): 3067, 2930, 2856, 1468, 1254, 1094, 840, 776 −1 1 2.86 (dd, J = 13.0, 6.5 Hz, 1H), 1.01 (bs, 9H), 0.97 cm ; H NMR (CDCl3, 300 MHz): δ 7.40 (d, J = 6.9 (bs, 9H), 0.12 (s, 6H); ESI-MS: m/z 325 [M+H]+. Hz, 2H), 7.30-7.16 (m, 3H), 5.90 (ddd J = 17.0, 10.2, 8.5 Hz, 1H), 5.15-5.01 (m, 2H), 3.87-3.8 (m, 1H), 3.60 tert-Butyldimethyl((7R,8RS)-8-(phenylthio)hexadec- (dd, J = 8.5, 4.1 Hz, 1H), 1.82-1.60 (m, 2H), 1.40-1.20 9-yn-7-yloxy)silane, 4aa (bs, 8H), 0.90 (bs, 12H), 0.06 (s, 3H), 0.05 (s, 3H); 13 To a solution of 1-octyne (165 mg, 1.5 mmol) in C NMR (CDCl3, 75 MHz): δ 135.7, 132.2, 129.5, anhydrous THF (0.8 mL) cooled to −10°C was added 128.7, 126.8, 116.7, 74.5, 43.8, 33.6, 29.3, 25.9, 25.7, i-PrMgCl·LiCl (1 mL, 1.5 mmol, 1.5 M in THF) and 25.6, 22.6, 18.2, 14.1, -3.6, -4.4; ESI-MS: m/z 417 stirred for 30 min at the same temperature. To the [M+O+Na]+. Note: The sulfide was oxidized to the so generated Grignard reagent, ZnBr2 (1.1 mL, 1.65 sulfoxide while recording the mass spectrum. mmol, 1.5 M in THF) was added at 0°C and stirred for 30 min. To the above organozinc reagent cooled tert-Butyldimethyl((5RS,6RS)-5-(phenylthio)dodecan- to 0°C was added the solution of chloro sulfide 6-yloxy)silane, 4ac: Following the general procedure, (0.5 mmol) in anhydrous benzene (5 mL), generated the α-chloro sulfide derived from sulfide 3a (176 mg, from sulfide 3a (176 mg, 0.5 mmol). The reaction 0.5 mmol) was reacted with n-butylzinc bromide mixture was stirred, gradually allowing it to attain (1.5 mmol) at RT (6 h) to afford the crude product RT, and stirred further for a period of 7 h when TLC which was purified by column chromatography examination indicated complete consumption of the using hexanes as the eluent to furnish the pure product chlorosulfide. The reaction mixture was cooled to 0°C 4ac (101 mg, 0.25 mmol) in 50% yield as a liquid. and quenched by the addition of an aq. saturated TLC (SiO2): Rf = 0.85 (Hexanes); IR (neat): 3063, −1 NH4Cl solution. It was allowed to warm to RT and 2954, 2930, 2857, 1468, 1253, 1089, 837 cm ; 1 diluted with Et2O (5 mL), the layers were separated H NMR (CDCl3, 500 MHz): δ 7.38 (d, J = 8.0 Hz, and aqueous layer was extracted with Et2O (3×10 mL). 2H), 7.24 (t, J = 8.0 Hz, 2H), 7.18 (t, J = 8.0 Hz, 1H), The combined organic layers were washed with brine 3.69-3.64 (m, 1H), 3.12 (dt, J = 6.0, 3.0 Hz, 1H), (5 mL), dried over anhyd. Na2SO4. The solvent was 1.92-1.84 (m, 1H), 1.83-1.77 (m, 1H), 1.67-1.58 (m, evaporated under reduced pressure to afford a crude 1H), 1.44-1.20 (m, 13H), 0.94-0.88 (m, 6H), 0.85 (s, 13 compound which was purified by column chromatography 9H), -0.09 (s, 3H), -0.10 (s, 3H); C NMR (CDCl3, using hexanes as the eluent to afford the pure product 75 MHz): δ 136.6, 132.0, 128.8, 126.7, 74.1, 55.7, 4aa (179 mg, 0.39 mmol) in 78% yield as a liquid. 32.0, 31.5, 30.4, 29.8, 29.4, 28.7, 26.7, 26.0, 22.8, + TLC (SiO2): Rf = 0.88 (Hexanes); IR (neat): 3063, 18.0, 14.3, 14.2, -4.3, -4.4; ESI-MS: m/z 380 [M] . 2954, 2928, 2857, 1586, 1463, 1384, 1253, 1094, 837, −1 1 777, 695 cm ; H NMR (CDCl3, 300 MHz): δ 7.45 (d, tert-Butyldimethyl((4RS,5RS)-2-methyl-5-(phenylthio) J = 6.9 Hz, 2H), 7.30-7.18 (m, 3H), 3.87 (dt, J = 4.5, tridec-6-yn-4-yloxy)silane, 4ba: Following the 2.2 Hz, 1H), 3.75-3.73 (m, 1H), 2.16 (dt, J = 6.7, 2.2 general procedure, the α-chlorosulfide prepared from Hz, 2H), 1.78-1.69 (m, 2H), 1.50-1.20 (m, 16H), 0.92- sulfide 3b (162 mg, 0.5 mmol) was reacted with 0.87 (bs, 15H), 0.01 (s, 3H), 0.0 (s, 3H); 13C NMR 1-octynylzinc bromide (1.5 mmol) at RT (6 h) to (CDCl3, 75 MHz): δ 135.3, 132.1, 128.7, 127.1, 86.1, afford the crude product which was purified by 77.5, 74.0, 46.3, 33.6, 31.8, 31.3, 29.3, 28.6, 28.4, column chromatography using hexanes as the eluent 25.8, 25.1, 22.6, 22.5, 18.9, 18.1, 14.1, 14.0, −4.5, to furnish the pure product 4ba (172 mg, 0.4 mmol) in + −4.6; ESI-MS: m/z 483 [M+Na] . 80% yield as a liquid. TLC (SiO2): Rf = 0.86 334 INDIAN J. CHEM., SEC B, MARCH 2018
(Hexanes); IR (neat): 3063, 2954, 2928, 2857, 1586, 419 [M+O+Na]+. Note: The sulfide was oxidized to 1463, 1384, 1253, 1094, 837, 777, 695 cm−1; 1H NMR the sulfoxide while recording the mass spectrum. (CDCl3, 500 MHz): δ 7.49 (d, J = 6.7 Hz, 2H), 7.30-7.20 (m, 3H), 3.89 (dt, J = 4.5, 2.2 Hz, 1H), 3.78 (td, J = 7.5, tert-Butyldimethyl((3RS,4RS)-2-methyl-4-(phenylthio) 5.2 Hz, 1H), 2.15 (dt, J = 5.2, 2.2 Hz, 2H), 1.80-1.70 dodec-5-yn-3-yloxy)silane, 4ca: Following the general (m, 2H), 1.52-1.25 (m, 12H), 0.97-0.91 (bs, 15H), procedure, the α-chlorosulfide prepared from 3c (156 13 0.02 (s, 6H); C NMR (CDCl3, 75 MHz): δ 135.5, mg, 0.5 mmol) was reacted with the 1-octynylzinc 132.3, 128.8, 127.2, 86.3, 77.5, 74.2, 46.5, 33.8, 32.0, bromide at RT (6 h) to afford the crude product which 31.5, 29.5, 28.8, 28.6, 26.0, 25.3, 22.8, 19.1, 18.3, was purified by column chromatography using 14.2, −4.3, −4.4; ESI-MS: m/z 455 [M+Na]+; hexanes as the eluent to furnish the pure product 4ca ESI-HRMS: m/z Calcd for C26H44OSSiNa 455.2779. (156 mg, 0.37 mmol) in 75% yield as a liquid. TLC Found: 455.2765. (SiO2): Rf = 0.85 (Hexanes); IR (neat): 3062, 2955, 2926, 2855, 1587, 1462, 1385, 1252, 1090, 835, 776, −1 1 tert-Butyldimethyl((3RS,4RS)-6-methyl-3-(phenylthio) 693 cm ; H NMR (CDCl3, 300 MHz): δ 7.46 (d, hept-1-en-4-yloxy)silane, 4bb: Following the general J = 7.5 Hz, 2H), 7.30-7.10 (m, 3H), 3.89 (dt, J = 4.9, procedure, the α-chloro sulfide prepared from sulfide 2.4 Hz, 1H), 3.62 (dd, J = 4.7, 2.4 Hz, 1H), 2.20-2.0 3b (162 mg, 0.5 mmol) was reacted vinylzinc bromide (m, 2H), 1.40-1.20 (m, 8H), 0.91-0.72 (m, 19H), 0.10 13 (1.5 mmol) at RT (6 h) to afford the crude product (s, 3H), 0.01 (s, 3H); C NMR (CDCl3, 75 MHz): δ which was purified by column chromatography using 136.1, 131.9, 128.8, 126.9, 86.3, 79.3, 78.9, 45.7, hexanes as the eluent to furnish the pure product 4bb 32.2, 31.5, 29.8, 28.7, 26.3, 22.7, 20.8, 19.1, 18.6, (148 mg, 0.42 mmol) in 85% yield as a liquid. TLC 17.5, 14.2, -3.6, -4.0; ESI-MS: m/z 441 [M+Na]+. 1 (SiO2): Rf = 0.85 (Hexanes); H NMR (CDCl3, 500 MHz): δ 7.36 (d, J = 7.0 Hz, 2H), 7.24 (t, J = 7.0 Hz, tert-Butyldimethyl((3RS,4RS)-2-methyl-4-(phenylthio) 2H), 7.19 (t, J = 7.0 Hz, 1H), 5.92 (ddd, J = 17.0, 10.0, hex-5-en-3-yloxy)silane, 4cb: Following the general 8.0 Hz, 1H), 5.10-5.01 (m, 2H), 3.91 (td, J = 8.0, 4.0 procedure, the α-chlorosulfide prepared from 3c (156 Hz, 1H), 3.65 (dd, J = 8.0, 4.0 Hz, 1H), 1.73-1.65 mg, 0.5 mmol) was reacted with vinylzinc bromide (m, 1H), 1.59-1.53 (m, 1H), 1.44-1.38 (m, 1H), 0.94 (1.5 mmol) at RT (6 h) to afford the crude product (d, J = 7.0 Hz, 6H), 0.89 (bs, 9H), 0.02 (s, 3H), 0.01 which was purified by column chromatography using 13 (s, 3H); C NMR (CDCl3, 75 MHz): δ 135.6, 135.5, hexanes as the eluent to furnish the pure product 4cb 132.4, 128.8, 126.9, 117.0, 72.7, 58.7, 42.6, 26.1, (126 mg, 0.37 mmol) in 75% yield as a liquid. TLC 1 24.4, 23.8, 22.2, 18.3, −4.1, −4.3; ESI-MS: m/z 373 (SiO2): Rf = 0.82 (Hexanes); H NMR (CDCl3, 500 + [M+Na] ; ESI-HRMS: m/z Calcd for C20H34OSSiNa MHz): δ 7.34 (d, J = 6.8 Hz, 2H), 7.27-7.16 (m, 3H), 373.1997. Found: 373.1986. 5.86 (ddd, J = 16.6, 9.7, 8.7 Hz, 1H), 4.94 (d, J = 9.7 Hz, 1H), 4.86 (d, J = 16.6 Hz, 1H), 3.65 (dd, J = 8.7, tert-Butyldimethyl((4RS,5RS)-2-methyl-5-(phenylthio) 4.8 Hz, 1H), 3.59 (t, J = 4.8 Hz, 1H), 2.04 (m, 1H), nonan-4-yloxy)silane, 4bc: Following the general 0.99-0.93 (m, 15H). 0.10 (s, 3H), 0.05 (s, 3H); 13 procedure, the α-chloro sulfide prepared from sulfide C NMR (CDCl3, 75 MHz): δ 136.9, 135.4, 132.3, 3b (162 mg, 0.5 mmol) was reacted with n-butylzinc 128.5, 126.7, 115.6, 79.5, 59.0, 32.1, 29.8, 26.3, 20.7, bromide (1.5 mmol) at RT (6 h) to afford the crude product 17.9, −3.5, −3.8. which was purified by column chromatography using hexanes as the eluent to furnish the pure product 4bc tert-Butyldimethyl((3RS,4RS)-2-methyl-4-(phenylthio) (95 mg, 0.25 mmol) in 50% yield as a liquid. TLC octan-3-yloxy)silane, 4cc: Following the general procedure, 1 (SiO2): Rf = 0.85 (Hexanes); H NMR (CDCl3, 500 the α-chlorosulfide prepared from 3c (156 mg, 0.5 MHz): δ 7.52 (d, J = 7.5 Hz, 2H), 7.42-7.31 (m, 3H), mmol) was reacted with n-butylzinc bromide (1.5 mmol) 3.87 (td, J = 5.2, 3.0, Hz, 1H), 3.14 (td, J = 6.0, 3.0 at RT (6 h) to afford the crude product which was Hz, 1H), 2.08-1.95 (m, 1H), 1.84-1.66 (m, 2H), purified by column chromatography using hexanes as 1.53-1.33 (m, 4H), 1.15-0.97 (m, 20H), 0.0 (s, 3H), the eluent to furnish the pure product 4cc (81 mg, 13 -0.01 (s, 3H); C NMR (CDCl3, 75 MHz): δ 132.5, 0.23 mmol) in 45% yield as a liquid. TLC (SiO2): 1 129.2, 129.0, 127.0, 71.9, 40.6, 30.6, 28.5, 26.0, 24.5, Rf = 0.83 (Hexanes); H NMR (CDCl3, 500 MHz): δ 24.2, 22.9, 21.8, 18.2, 14.3, -4.3, -4.5; ESI-MS: m/z 7.38 (d, J = 7.1 Hz, 2H), 7.30-7.18 (m, 3H), 3.56 (dd, RAGHAVAN & CHOWHAN: ASYMMETRIC INDUCTION BY β-SUBSTITUENT 335
J = 4.9, 3.2 Hz, 1H), 3.12-3.06 (m, 1H), 1.90-1.80 chromatography using hexanes as the eluent to furnish (m, 1H), 1.40-1.20 (m, 2H), 1.02-0.85 (m, 22H), the pure product 4dc (92 mg, 0.28 mmol) in 48% 13 −0.01 (s, 3H), −0.03 (s, 3H); C NMR (CDCl3, 75 yield as a liquid. TLC (SiO2): Rf = 0.84 (Hexanes); 1 MHz): δ 137.3, 131.2, 128.8, 126.2, 78.4, 55.4, 31.2, H NMR (CDCl3, 500 MHz): δ 7.26 (d, J = 7.5 Hz, 30.4, 29.7, 26.0, 25.6, 22.6, 21.5, 19.0, 14.0, −4.1, −4.2. 2H), 7.19 (t, J = 7.5 Hz, 2H), 7.06 (t, J = 7.5 Hz, 1H), 3.49 (s, 1H), 3.20 (dd, J = 8.8, 5.4 Hz, 1H), 1.82-1.72 tert-Butyl((3RS,4RS)-2,2-dimethyl-4-(phenylthio)dodec- (m, 1H), 1.69-1.56 (m, 2H), 1.28-1.20 (m, 6H) 0.98 5-yn-3-yloxy)dimethylsilane, 4da: Following the (s, 12H), 0.94 (s, 9H), 0.10 (s, 3H), 0.03 (s, 3H); 13 general procedure, the α-chlorosulfide prepared from C NMR (CDCl3, 75 MHz): δ 138.3, 130.4, 128.8, sulfide 3d (162 mg, 0.5 mmol) was reacted with 125.7, 81.1, 51.8, 36.8, 35.8, 30.6, 27.8, 26.6, 22.7, octynylzinc bromide (1.5 mmol) at RT (6 h) to afford 19.1, 14.2, −2.9, −3.8. the crude product which was purified by column chromatography using hexanes as the eluent to furnish (2-Methylpentyl)(phenyl)sulfane, 5a the pure product 4da (140 mg, 0.32 mmol) in 65% To the mixture of the alcohol 11a (510 mg, 5 mmol) and diphenyl disulfide (1.2 g, 5.5 mmol) in yield as a liquid. TLC (SiO2): Rf = 0.88 (Hexanes); IR (neat): 3064, 2952, 2928, 2857, 1586, 1463, 1384, anhydrous THF (20 mL) cooled to 0°C was added −1 1 Bu3P (7.5 mL, 7.5 mmol, 1.5 M in EtOAc) drop-wise 1253, 1094, 837, 777, 695 cm ; H NMR (CDCl3, 500 MHz): δ 7.46 (d, J = 7.7 Hz, 2H), 7.25-7.15 (m, 3H), and the mixture stirred for 4 h while allowing it to 4.02 (dt, J = 3.7, 2.2 Hz, 1H), 3.71 (d, J = 3.7 Hz, warm to RT gradually. The reaction mixture was then 1H), 2.16 (td, J = 6.0, 2.2 Hz, 2H), 1.49-1.42 (m, 2H), diluted with water (5 mL). The aqueous layer was 1.32-1.23 (m, 6H), 1.02 (s, 9H), 1.00 (s, 9H), 0.90 separated and extracted with EtOAc (3×15 mL). The (t, J = 6.7 Hz, 3H), 0.27 (s, 3H), 0.11 (s, 3H); combined organic layer were washed with brine 13 (5 mL), dried over anhyd. Na2SO4 and concentrated C NMR (CDCl3, 75 MHz): δ 137.0, 131.4, 128.6, 126.4, 84.6, 83.3, 82.2, 43.4, 37.0, 31.6, 29.9, 28.7, under reduced pressure to afford the crude sulfide 27.2, 26.5, 22.8, 19.1, 14.3, −2.9, −4.5; ESI-MS: m/z which was purified by column chromatography using 455 [M+Na]+; ESI-HRMS: m/z Calcd for 2% EtOAc/Hexanes (v/v) as the eluent to afford the pure sulfide 5a as a viscous oil (824 mg, 4.25 mmol) C26H44OSSiNa 455.2779. Found: 455.2765. in 85% yield; TLC (SiO2): Rf = 0.81 (Hexanes); IR tert-Butyl((3RS,4RS)-2,2-dimethyl-4-(phenylthio) (neat): 3445, 2955, 2927, 2855, 1580, 1470, 1252, −1 1 hex-5-en-3-yloxy)dimethylsilane, 4db: Following 1094, 1006, 775, 694 cm ; H NMR (CDCl3, 500 the general procedure, the α-chlorosulfide prepared MHz): δ 7.26 (d, J = 7.4 Hz, 2H), 7.21 (t, J = 7.4 Hz, from sulfide 3d (162 mg, 0.5 mmol) was reacted with 2H), 7.09 (t, J = 7.4 Hz, 1H), 2.89 (dd, J = 12.8, 5.9 vinylzinc bromide (1.5 mmol) at RT (6 h) to afford Hz, 1H), 2.74 (dd, J = 12.8, 7.9 Hz, 1H), 1.75-1.70 the crude product which was purified by column (m, 1H), 1.50-1.43 (m, 1H), 1.40-1.19 (m, 3H), chromatography using hexanes as the eluent to furnish 1.10 (d, J = 6.6 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H); 13 the pure product 4db (127 mg, 0.36 mmol) in 73% C NMR (CDCl3, 75 MHz): δ 135.2, 128.9, 128.8, yield as a liquid. TLC (SiO2): Rf = 0.83 (Hexanes); 125.6, 41.1, 38.6, 32.8, 20.1, 19.5, 14.4. ESI-MS: m/z 1 + H NMR (CDCl3, 500 MHz): δ 7.35-7.11 (m, 5H), 194 [M] . 5.95 (ddd, J = 17.3, 10.5, 9.0 Hz, 1H), 4.88 (d, J = 10.5 Hz, 1H), 4.72 (d, J = 17.3 Hz, 1H), 3.75 (dd, J = 9.0, (2,3-Dimethylbutyl)(phenyl)sulfane, 5b: The 2.2 Hz, 1H), 3.52 (d, J = 2.2 Hz, 1H), 0.97 (s, 9H), alcohol 11b (510 mg, 5 mmol) was converted into the 0.92 (s, 9H), 0.15 (s, 3H), 0.04 (s, 3H); 13C NMR sulfide 5b by following the procedure detailed above. The crude sulfide was purified by column (CDCl3, 75 MHz): δ 139.8, 132.4, 129.1, 128.8, 126.7, 114.8, 82.8, 57.2, 37.5, 27.6, 26.7, 19.1, −2.7, −3.8. chromatography using 2% EtOAc/Hexanes (v/v) as the eluent to afford the pure sulfide 5b as a viscous tert-Butyl((3RS,4RS)-2,2-dimethyl-4-(phenylthio) oil (824 mg, 4.25 mmol) in 85% yield as a liquid. octan-3-yloxy)dimethylsilane, 4dc: Following the TLC (SiO2): Rf = 0.84 (Hexanes); 3063, 2955, 2927, general procedure, the α-chlorosulfide prepared from 2855, 1580, 1470, 1252, 1094, 1006, 775, 694 cm−1; sulfide 3d (162 mg, 0.5 mmol) was reacted with 1H NMR (CDCl3, 500 MHz): δ 7.31 (d, J = 7.2 Hz, n-butylzinc bromide (1.5 mmol) at RT (6 h) to afford 2H), 7.25 (t, J = 7.2 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), the crude product which was purified by column 3.01 (dd, J = 12.7, 5.4 Hz, 1H), 2.71 (dd, J = 12.7, 8.2 336 INDIAN J. CHEM., SEC B, MARCH 2018
Hz, 1H), 1.85-1.78 (m, 1H), 1.68-1.62 (m, 1H), 1.01 (t, J = 1.9 Hz, 1H), 2.16 (dt, J = 6.9, 1.9 Hz, 4H), (d, J = 6.3 Hz, 3H) 0.95 (d, J = 7.2, Hz, 3H), 0.90 1.82-1.76 (m, 2H), 1.72-1.66 (m, 2H), 1.50-1.42 13 (d, J = 6.3 Hz, 3H); C NMR (CDCl3, 75 MHz): δ (m, 6H), 1.38-1.22 (m, 16H), 1.09 (d, J = 5.9 Hz, 6H), 137.8, 129.0, 128.8, 125.5, 39.0, 38.6, 31.6, 20.5, 0.92 (t, J = 6.9, 6H), 0.89 (t, J = 6.9 Hz, 6H); + 13 18.0, 15.4; ESI-MS: m/z 194 [M] . C NMR (CDCl3, 75 MHz) 137.0, 136.4*, 132.0, 131.8*, 128.7*, 128.6, 127.1, 126.9*, 86.0*, 85.6, Phenyl(2-phenylpropyl)sulfane, 5c: Sulfide 5c 78.8, 77.6*, 46.2, 45.2*, 37.6, 37.5*, 37.4, 36.9, 35.2, was prepared by from alcohol 11c (680 mg, 5 mmol) 31.4, 29.8, 28.8*, 28.5, 22.7, 20.5, 20.4*, 18.9, 14.4*, following the general procedure. The crude sulfide 14.2. Note: The signals for the minor diastereoisomer was purified by column chromatography using are indicated by an asterisk mark. 2% EtOAc/Hexanes (v/v) as the eluent to afford the pure sulfide 5c as a viscous oil (969 mg, 4.25 mmol) ((3SR,4SR)-4-Methylhept-1-en-3-yl)(phenyl)sulfane, in 85% yield as a liquid. TLC (SiO2): Rf = 0.84 6ab: Following the general procedure, the α-chlorosulfide (Hexanes); 3063, 2955, 2927, 2855, 1580, 1470, prepared from sulfide 5a (97 mg, 0.5 mmol) was −1 1 1252, 1094, 1006, 775, 694 cm ; H NMR (CDCl3, reacted with vinylzinc bromide (1.5 mmol) at RT 500 MHz): δ 7.28-7.09 (m, 10H), 3.18 (dd, J = 12.8, (6 h) to afford the crude product which was purified 5.4 Hz, 1H), 3.12-2.92 (m, 2H), 1.39 (d, J = 6.4 Hz, by column chromatography using hexanes as the 13 3H); C NMR (CDCl3, 125 MHz): δ 145.3, 136.8, eluent to furnish the pure product 6ab as a viscous 128.8, 128.7, 128.3, 126.8, 126.4, 125.6, 41.8, 39.2, oil (80 mg, 0.36 mmol) in 73% yield; TLC (SiO2): Rf 20.8; ESI-MS: m/z 245 [M+O+H]+. = 0.90 (Hexanes); IR (neat): 3067, 2930, 2856, 1468, −1 1 1254, 1094, 840, 776 cm ; H NMR (CDCl3, 500 Phenyl(2,3,3-trimethylbutyl)sulfane, 5d: Sulfide MHz): δ 7.29-7.21 (m, 10H), 5.78-5.70 (m, 2H), 4.94 5d was prepared by from alcohol 11d (580 mg, (d, J = 9.0 Hz, 2H), 4.88 (d, J = 16.2 Hz, 1H), 4.84* 5 mmol) following the general procedure. The crude (d, J = 16.2 Hz, 1H), 3.55* (dd, J = 9.0, 5.0 1H), 3.51 sulfide was purified by column chromatography using (dd, J = 9.0, 5.0 Hz, 1H), 1.30-1.20 (m, 10H), 1.02 2% EtOAc/Hexanes (v/v) as the eluent to afford the (d, J = 7.0 Hz, 3H), 1.00* (d, J = 7.0 Hz, 3H), 0.90 13 pure sulfide 5d as a viscous oil (884 mg, 4.25 mmol) (t, J = 7.0, 6H); C NMR (CDCl3, 75 MHz): δ 137.4, in 85% yield as a liquid. TLC (SiO2): Rf = 0.84 132.5*, 132.3, 129.0*, 128.6, 127.5, 127.1*, 126.8, (Hexanes); 3065, 2955, 2927, 2855, 1580, 1470, 126.6*, 116.4*, 115.9, 59.4, 58.4*, 37.0, 35.9*, 29.7, −1 1 1252, 1094, 1006, 775, 694 cm ; H NMR (CDCl3, 20.4, 20.2*, 17.2, 16.2*, 14.2. Note: The signals for 300 MHz): δ 7.30-7.17 (m, 4H), 7.10 (t, J = 6.9 Hz, the minor diastereoisomer are indicated by an asterisk 1H), 3.20 (d, J = 12.2 Hz, 1H), 2.40 (dd, J = 12.5, 1.8 mark. Hz, 1H), 1.49-1.39 (m, 1H), 1.02 (d, J = 6.6 Hz, 3H), 13 0.91-0.88 (bs, 9H); C NMR (CDCl3, 75 MHz): δ ((4SR,5SR)-4-Methylnonan-5-yl)(phenyl)sulfane, 137.7, 128.8, 128.6, 125.4, 42.7, 36.9, 33.2, 27.3, 6ac: Following the general procedure, the α-chlorosulfide 14.2; ESI-MS: m/z 208 [M]+. prepared from sulfide 5a (97 mg, 0.5 mmol) was reacted with n-butylzinc bromide (1.5 mmol) at RT ((4SR,5RS)-4-Methyltridec-6-yn-5-yl)(phenyl)sulfane, (6 h) to afford the crude product which was purified 6aa: Following the general procedure, the α- by column chromatography using hexanes as the chlorosulfide prepared from sulfide 5a (97 mg, 0.5 eluent to furnish the pure product 6ac as a viscous oil mmol) was reacted with 1-octynylzinc bromide (100 mg, 0.45 mmol) in 90% yield in 40:45 ratio of (1.5 mmol) at RT (6 h) to afford the crude product sulfide 6ac and vinyl sulfide; TLC (SiO2): Rf = 0.90 which was purified by column chromatography using (Hexanes); IR (neat): 3063, 2954, 2930, 2857, 1468, −1 1 hexanes as the eluent to furnish the pure product 6aa 1253, 1089, 837 cm ; H NMR (CDCl3, 500 MHz): δ as a viscous oil (123 mg, 0.41 mmol) in 82% yield; 7.39 (t, J= 7.7 Hz, 4H), 7.26 (t, J = 7.7 Hz, 4H), 7.28 TLC (SiO2): Rf = 0.90 (Hexanes); IR (neat): 3063, (t, J = 7.7 Hz, 2H), 3.12-3.07 (m, 2H) 1.70-1.44 2954, 2928, 2857, 1586, 1463, 1384, 1253, 1094, 837, (m, 8H) 1.40-1.20 (m, 17H), 0.96 (d, J= 6.8 Hz, 6H), −1 1 13 777, 695 cm ; H NMR (CDCl3, 500 MHz): δ 7.45 0.89 (t, J= 6.8 Hz, 12H); C NMR (CDCl3, 75 MHz): (d, J = 6.9 Hz, 4H), 7.25 (t, J = 7.9 Hz, 4H), 7.19 δ 137.5, 128.7, 128.6, 125.4, 41.0, 38.4, 32.6, 29.9, (t, J = 6.9 Hz, 4H), 3.84* (t, J = 1.9 Hz,1H), 3.75 20.0, 19.9, 19.3, 19.2, 14.3, 14.2. RAGHAVAN & CHOWHAN: ASYMMETRIC INDUCTION BY β-SUBSTITUENT 337
−1 1 ((3SR,4RS)-2,3-Dimethyldodec-5-yn-4-yl)(phenyl) 1253, 1089, 837 cm ; H NMR (CDCl3, 500 MHz): δ sulfane, 6ba: Following the general procedure, the 7.30-7.10 (m, 5H), 3.25-3.10 (m, 1H), 1.70-1.40 α-chlorosulfide prepared from sulfide 5b (97 mg, (m, 8H), 1.10 (d, J = 6.7 Hz, 3H), 1.05 (d, J = 6.7 Hz, 0.5 mmol) was reacted with 1-octynylzinc bromide 3H), 0.99-0.85 (m, 6H). (1.5 mmol) at RT (6 h) to afford the crude product which was purified by column chromatography using Phenyl((2SR,3RS)-2-phenylundec-4-yn-3-yl)sulfane, hexanes as the eluent to furnish the pure product 6ba 6ca: Following the general procedure, the α-chlorosulfide as a viscous oil (113 mg, 0.37 mmol) in 80% yield; from sulfide 5c (114 mg, 0.5 mmol) was reacted with TLC (SiO2): Rf = 0.90 (Hexanes); IR (neat): 3063, 1-octynylzinc bromide (1.5 mmol) at RT (6 h) to 2954, 2928, 2857, 1586, 1463, 1384, 1253, 1094, 837, afford the crude product which was purified by −1 1 777, 695 cm ; H NMR (CDCl3, 500 MHz): δ 7.4 column chromatography using hexanes as the (d, J = 7.1, 4H), 7.29-7.18 (m, 6H), 4.0-3.96* (m, 1H), eluent to furnish the pure product 6ca as a viscous oil 3.75-3.69 (m, 1H), 2.13 (td, J = 6.8, 2.2 Hz, 2H), 1.3-1.2 (134 mg, 0.4 mmol) in 80% yield; TLC (SiO2): (m, 20H), 1.06 (d, J = 6.8 Hz, 6H), 0.95 (d, J = 6.7 Rf = 0.91 (Hexanes); IR (neat): 3065, 2956, 2930, Hz, 6H), 0.90 (t, J = 6.7 Hz, 6H), 0.85 (d, J = 6.7 Hz, 2855, 1584, 1462, 1384, 1253, 1094, 837, 777, 695 13 −1 1 6H); C NMR (CDCl3, 75 MHz): δ 134.5, 132.3, cm ; H NMR (CDCl3, 500 MHz): δ 7.43-7.36 131.9*, 129.2, 128.6, 128.1*, 127.5*, 127.0, 85.5, (m, 8H), 7.29-7.15 (m, 12H), 4.01 (dt, J = 4.5, 2.2 Hz, 79.8, 44.9, 43.6, 43.4*, 31.6, 31.3*, 29.8, 28.7, 28.5, 1H), 3.95* (dt, J = 4.5, 2.2 Hz, 1H), 3.07 (q, J = 6.7 22.6, 22.5*, 21.7, 21.1*, 19.3*, 18.9, 18.0*, 17.6, Hz, 1H), 2.98* (m, 1H), 2.17 (td, J = 6.7, 2.2 Hz, 2H), 14.5*, 14.1, 12.9*, 12.8; ESI-MS: m/z 302 [M]+. 2.08* (dt, J = 6.7, 2.2 Hz, 2H), 1.48 (d, J = 6.7 Hz, Note: The signals for the minor diastereoisomer are 6H), 1.37-1.18 (m, 16H), 0.9 (t, J = 6.0 Hz, 3H), 13 indicated by an asterisk mark. 0.80* (t, J = 6.7 Hz, 3H); C NMR (CDCl3, 75 MHz): δ 144.1*, 143.0, 135.2*, 134.6, 132.4, 132.2*, ((3SR,4SR)-4,5-Dimethylhex-1-en-3-yl)(phenyl) 129.4, 129.2*, 128.9, 128.8*, 128.4, 128.0*, 127.7, sulfane, 6bb: Following the general procedure, the 127.3*, 127.1, 126.9, 87.2, 86.9*, 78.7, 77.4*, 46.7, α-chlorosulfide prepared from sulfide 5b (97 mg, 46.6*, 44.0, 43.4*, 31.5, 28.8*, 28.7, 28.6, 22.7, 19.7, 0.5 mmol) was reacted with vinylzinc bromide 19.1, 19.0, 17.3, 14.3; ESI-MS: m/z 336[M]+. Note: (1.5 mmol) at RT (6 h) to afford the crude product The signals for the minor diastereoisomer are indicated which was purified by column chromatography using by an asterisk mark. hexanes as the eluent to furnish the pure product 6bb as a viscous oil (88 mg, 0.4 mmol) in 80% yield; TLC Phenyl((3SR,4SR)-4-phenylpent-1-en-3-yl)sulfane, (SiO ): R = 0.90 (Hexanes); IR (neat): 3064, 2932, 2 f 6cb: Following the general procedure the the 2858, 1468, 1256, 1094, 842, 774 cm−1; 1H NMR α-chlorosulfide prepared from sulfide 5c (114 mg, (CDCl 500 MHz): δ 7.27 (d, J = 6.9 Hz, 2H), 7.20-7.10 3, 0.5 mmol) was reacted with the organozinc reagent (m, 3H), 5.63 (ddd, J = 17.0, 9.8, 9.4 Hz, 1H), 4.78 prepared from vinylmagnesium bromide (1.5 mmol) (d, J = 9.8 Hz, 1H), 4.66 (J = 17.0 Hz, 1H), 3.42 (dd, at RT (6 h) to afford the crude product which was J = 9.4, 8.3 Hz, 1H) 1.90-1.80 (m, 1H) 1.50-1.40 (m, purified by column chromatography using hexanes as 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.9 (d, J = 6.7 Hz, 3H), the eluent to furnish the pure product 6cb as a viscous 0.74 (d, J = 6.6 Hz, 3H); 13C NMR (CDCl , 75 MHz): 3 oil (82 mg, 0.39 mmol) in 78% yield; TLC (SiO ): R δ 138.7, 133.0, 128.7, 128.6, 126.9, 115.1, 58.7, 43.1, 2 f + = 0.91 (Hexanes); IR (neat): 3064, 2932, 2856, 1468, 29.9, 22.0, 17.2, 12.4; ESI-MS: m/z 237 [M+O+H] . −1 1 1254, 1094, 840, 776 cm ; H NMR (CDCl3, 500 ((3SR,4SR)-2,3-Dimethyloctan-4-yl)(phenyl)sulfane, MHz): δ 7.42-7.21 (m, 20H), 5.75* (ddd, J = 16.9, 6bc: Following the general procedure, the α-chlorosulfide 9.9, 9.0 Hz, 1H), 5.56 (ddd, J = 16.9, 9.9, 7.0 Hz, 1H), prepared from sulfide 5b (97 mg, 0.5 mmol) was 4.95* (d, J = 9.9 Hz, 1H), 4.81 (d, J = 10.0 Hz, 1H), reacted with n-butylzinc bromide (1.5 mmol) at RT 4.77* (d, J = 16.9 Hz 1H), 4.68 (d, J = 16.9 Hz, 1H), (6 h) to afford the crude product which was purified by 3.75* (dd, J = 6.7, 9.0 Hz, 1H), 3.71 (dd, J = 9.3, 7.0 column chromatography using hexanes as the eluent to Hz, 1H), 3.22* (q, J = 6.7 Hz, 1H), 3.01-3.11 (m, 1H), furnish the pure product 6bc as a viscous oil (116 mg, 1.48 (d, J = 6.7 Hz, 3H), 1.39* (d, J = 6.7 Hz, 3H); 13 0.47 mmol) in 40% yield, TLC (SiO2): Rf = 0.90 C NMR (CDCl3, 75 MHz): δ 137.2*, 136.7, 132.9, (Hexanes); IR (neat): 3063, 2954, 2930, 2857, 1468, 132.8, 128.9, 128.8, 128.3*, 128.2, 127.9*, 127.86, 338 INDIAN J. CHEM., SEC B, MARCH 2018
127.1, 126.7, 116.9*, 116.3, 60.0, 59.8*, 43.9, 43.7*, 500 MHz): δ 7.30-7.08 (m, 5H), 5.85 (ddd J = 15.8, 29.8; 19.8; ESI-MS: m/z 254 [M]+. 9.8, 8.3 Hz, 1H), 4.78 (m, 2H), 3.76 (dd, J = 8.3, 1.7 Hz, 1H), 1.66-1.56 (m, 1H), 1.10-1.04 (m, 12H); Phenyl((2SR,3SR)-2-phenylheptan-3-yl)sulfane, 6cc: 13C NMR (CDCl , 75 MHz): δ 140.0, 136.2, 132.1, Following the general procedure the α-chlorosulfide 3 128.7, 126.6, 113.9, 55.5, 47.7, 29.2, 28.8, 27.5; ESI- prepared from sulfide 5c (114 mg, 0.5 mmol) was MS: m/z 234 [M]+. reacted with the organozinc reagent prepared from n- butyl bromide (1.5 mmol) at RT (6 h) to afford the Phenyl((3SR,4SR)-2,2,3-trimethyloctan-4-yl)sulfane, crude product which was purified by column 6dc: Following the general procedure, the chromatography using hexanes as the eluent to furnish α-chlorosulfide prepared from 5d (104 mg, 0.5 mmol) the pure product 6cc as a viscous oil (113 mg, 0.4 was reacted with n-butylzinc bromide (1.5 mmol) at mmol) in 40% yield; TLC (SiO2): Rf = 0.90 RT (6 h) to afford the crude product which was (Hexanes); IR (neat): 30635, 2954, 2930, 2857, 1468, −1 1 purified by column chromatography using hexanes as 1253, 1089, 837 cm ; H NMR (CDCl3, 500 MHz): δ the eluent to furnish the pure product 6dc as a viscous 7.5-7.2 (m, 20H), 3.39-3.34* (m, 1H), 3.14 (q, J = 6.7 oil (72 mg, 0.27 mmol) in 55% yield of sulfide 6dc; Hz, 1H), 3.04* (q, J = 6.7 Hz, 1H), 2.95-2.85 (m, 1H), TLC (SiO2): Rf = 0.91 (Hexanes); IR (neat): 3063, 1.65-1.60* (m, 1H), 1.55-1.47 (m, 1H), 1.42 (d, J = 6.7 2954, 2930, 2857, 1468, 1253, 1089, 837 cm−1; Hz, 3H), 1.40 (d, J = 6.7 Hz, 3H), 1.25-1.15 (m, 12H), 1 H NMR (CDCl3, 500 MHz) 7.33-7.10 (m, 5H), 3.37 0.97* (t, J = 6.7 Hz, 3H), 0.80 (t, J = 6.7 Hz, 3H); 13 (m, 1H), 1.65-1.55 (m, 7H), 1.13 (s, 9H), 1.01 (s, 3H), C NMR (CDCl3, 75 MHz): δ 131.7, 129.2, 129.0, 13 1.0 (t, J = 6.6 Hz, 3H); C NMR (CDCl3, 75 MHz): 128.5, 128.2, 127.9, 127.6, 126.5, 57.6, 44.0, 42.5*, δ 137.5, 129.0, 128.9, 128.3, 44.9, 36.9, 30.0, 29.1, 33.2, 29.9*, 29.6, 25.3, 17.9*, 18.9, 14.1. 28.5, 27.4, 22.7, 15.2, 14.1. Phenyl((3SR,4RS)-2,2,3-trimethyldodec-5-yn-4-yl) Conclusion sulfane, 6da: Following the general procedure, the A general stereoselective route to α-substituted α-chlorosulfide prepared from 5d (104 mg, 0.5 mmol) sulfides has been developed taking advantage of was reacted with 1-octynylzinc bromide (1.5 mmol) at 1,2-asymmetric induction. The asymmetric induction RT (6 h) to afford the crude product which was by a β-siloxy substituent is better than the β-methyl purified by column chromatography using hexanes as substituent. The products have useful handles for the eluent to furnish the pure product 6da as a viscous further functionalization to synthetic intermediates. oil (115 mg, 0.36 mmol) in 73% yield; TLC (SiO ): R 2 f = 0.93 (Hexanes); IR (neat): 3063, 2954, 2928, 2857, Acknowledgements 1586, 1463, 1384, 1253, 1094, 837, 777, 695 cm−1; LRC is thankful to CSIR, New Delhi for 1H NMR (CDCl 500 MHz): δ 7.44 (d, J = 7.2 Hz, 3, fellowship. SR acknowledges funding from DST 2H), 7.25-7.21 (m, 3H), 4.05 (d, J = 2.0 Hz, 1H), 2.10 (SR/S1/OC-5/2011) and CSIR, New Delhi as a part of (dt, J = 7.2, 2.0 Hz, 2H), 1.86-1.82 (m, 1H), 1.42-1.34 the XII five year plan programme under the title (m, 2H) 1.3-1.2 (m, 6H), 1.18 (d J = 7.2 Hz, 3H), 1.04 13 ORIGIN (CSC-108). (bs, 9H), 0.88 (t, J = 7.2 Hz, 3H); C NMR (CDCl3, 75 MHz): δ 136.2, 131.9, 128.6, 126.8, 84.1, 81.9, References 48.6, 43.0, 33.9, 31.5, 28.8, 28.8, 27.4, 22.7, 19.0, 1 (a) Normant H & Castro C R, C R Hebd Seances Acad Sci, 14.2, 12.1; ESI-MS: m/z 316 [M]+. 259 (1964) 830; (b) Gross H & Hoft E, Angew Chem Int Ed Engl, 6 (1967) 335; (c) Ogura K, Fujitha M, Takahashi K & Phenyl((3SR,4SR)-4,5,5-trimethylhex-1-en-3-yl) Iida H, Chem Lett, 11 (1982) 1697; (d) Cohen T & Matz J R, sulfane, 6db: Following the general procedure, the J Am Chem Soc, 106 (1985) 6902. α-chlorosulfide prepared from 5d (104 mg, 0.5 mmol) 2 Nakatsuka S, Takai K & Utimoto K, J Org Chem, 51 (1986) 5045. was reacted with vinylzinc bromide (1.5 mmol) at RT 3 (a) Mitzel T M, Palomo C & Jendza K, J Org Chem, 67 (6 h) to afford the crude product which was purified (2002) 136; (b) Frimpong K, Wzorek J, Lawlor C, Spencer K by column chromatography using hexanes as the & Mitzel, T, J Org Chem, 74 (2009) 5861. eluent to furnish the pure product 6db as a viscous 4 Ishibashi H, Mita N, Matsuba N, Kubo T, Nakanishi M & oil (82 mg, 0.35 mmol) in 70% yield; TLC (SiO ): Ikeda M, J Chem Soc Perkins Trans 1, (1992) 2821. 2 5 (a) Ishibashi H, Kitano Y, Nakatani H, Okada M & Ikeda M, Rf = 0.92 (Hexanes); IR (neat): 3067, 2930, 2856, Tetrahedron Lett, 25 (1984) 4231; (b) Tsai Y, Chang Chang F, −1 1 1468, 1254, 1094, 840, 776 cm ; H NMR (CDCl3, Huang J & Shiu C, Tetrahedron Lett, 30 (1989) 2121; (c) RAGHAVAN & CHOWHAN: ASYMMETRIC INDUCTION BY β-SUBSTITUENT 339
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