Supporting Information Configurational Assignments

Supporting Information Configurational Assignments Symmetric Diaryl Sulfoxides as Asymmetric Sulfinylating Reagents for Dialkylmagnesium Compounds Simon Ruppenthal and Reinhard Brückner* Institut für Organische Chemie Albert-Ludwigs-Universität Freiburg Albertstraße 21, 79104 Freiburg im Breisgau, Germany reinhard.brueckner@organik.chemie.uni-freiburg.de

Table of Content 1. Preparation of Alkyl (4-Chlorophenyl) Sulfoxides...2 1.1 (4-Chlorophenyl) Ethyl Sulfoxide (58): (S)-( )-Enantiomer and Racemic...2 1.2 Butyl (4-Chlorophenyl) Sulfoxide (59): (S)-( )-Enantiomer and Racemic...3 1.3 (4-Chlorophenyl) Isobutyl Sulfoxide (60): (S)-( )-Enantiomer and Racemic...4 2. Configurational Assignments of Non-Racemic Sulfoxides...6 2.1 Assignment of the Aryl Ethyl Sulfoxides ( )-22, ( )-31, and ( )-34 by Chemical Correlations With the Corresponding Aryl Isopropyl Sulfoxides...8 2.2 Configurational Assignment of the Chlorine-Free Alkyl Aryl Sulfoxides ( )-32, ( )- 39, ( )-40, and ( )-47 by Independent Syntheses From Alkyl (4-Chlorophenyl) Sulfoxides...9 2.3 Configurational Assignment of the Alkyl (2-Bromophenyl) Sulfoxides ( )-52, ( )-53, and ( )-54 by Debrominations to the Corresponding Alkyl Phenyl Sulfoxides...10 1

1. Preparation of Alkyl (4-Chlorophenyl) Sulfoxides 1.1 (4-Chlorophenyl) Ethyl Sulfoxide (58): (S)-( )-Enantiomer and Racemic This compound was used to assign the configuration of the S-stereocenter of (S)-( )-32. The racemic synthesis followed the General Procedure for the Preparation of Racemic Alkyl Aryl Sulfoxides (cf. Experimental Section of our proper manuscript) using bis(4-chlorophenyl) sulfoxide (53.5 mg, 0.197 mmol) with Et 2 Mg (0.33 M in Et 2 O, 0.33 ml, 0.109 mmol, 0.55 equiv.) within 30 min. Flash chromatography on silica gel 1 (c-c 6 H 12 :EtOAc 55:45, Fr. 31-44) delivered rac-58 (25.8 mg, 69%) as a colorless oil. The asymmetric synthesis followed the Procedure for the Asymmetric Sulfinylations of Dialkylmagnesium Compounds by Symmetric Diaryl Sulfoxides (cf. Section 3.2) using bis(4- chlorophenyl) sulfoxide (53.4 mg, 0.197 mmol). After 10 s this delivered (S)-( )-58 (29.1 mg, 78%; <51% ee 2 ) as a colorless oil. 1 H NMR (300.1 MHz, CDCl 3 ): δ = 1.20 (dd, J 2,1 -A = J 2,1 -B = 7.5 Hz, 3 H, 2 -H 3 ), AB signal (δ A = 2.74, δ B = 2.89, J A,B = 13.3 Hz, A part additionally split by q, J 1 -A,2 = 7.5 Hz, 1 -H A ; B part additionally split by q, J 1 -B,2 = 7.4 Hz, 1 -H B ), AA BB signal with signal centers at δ A = 7.50 and δ B = 7.55 ppm (4 H, 2 2-H and 2 3-H). The preceding data are consistent with those reported in the literature. 3 The ee was determined by chiral HPLC (Chiralcel OD-H, n-heptane/etoh 98:2, 1 ml/min, λ detector = 221 nm): t r (R) = 16.56 min, t r (S) = 19.31 min. [ α ] 20 365 = 190.0, [ α ] 20 = 92.8, [ α ] 20 = 47.0, [ α ] 20 = 40.9, [ ] 20 436 546 578 α = 37.7 (c = 0.53 in EtOH; the respective sample had <51% ee 2 ); Lit. 4 : [ α ] 20 589 = 142.5 [c = 0.47 in MeOH, a sample of the (S)-enantiomer, the ee is not stated in ref. 4]. The absolute configuration was determined by comparing the sense of the optical rotation with literature data. 4 589 2

1.2 Butyl (4-Chlorophenyl) Sulfoxide (59): (S)-( )-Enantiomer and Racemic This compound was used to assign the configuration of the S-stereocenter of (S)-( )-39 and (S)-( )-40. The racemic synthesis followed the General Procedure for the Preparation of Racemic Alkyl Aryl Sulfoxides (cf. Experimental Section of our proper manuscript) using bis(4-chlorophenyl) sulfoxide (53.4 mg, 0.197 mmol) with Bu 2 Mg (0.75 M in Et 2 O, 0.14 ml, 0.11 mmol, 0.55 equiv.) within 30 min. Flash chromatography on silica gel 1 (c-c 6 H 12 :EtOAc 80:20, F. 22-33) delivered rac-59 (25.1 mg, 59%) as a colorless oil. The asymmetric synthesis followed the Procedure for the Asymmetric Sulfinylations of Dialkylmagnesium Compounds by Symmetric Diaryl Sulfoxides (cf. Section 3.2) using bis(4- chlorophenyl) sulfoxide (53.4 mg, 0.197 mmol). After 10 s this delivered (S)-( )-59 (36.6 mg, 86%; 29% ee) as a colorless oil. 1 H NMR (300.1 MHz, CDCl 3 ): δ = 0.92 (t, J 4,3 = 7.6 Hz, 3 H, 4 -H 3 ), 1.35-1.81 (m, 4 H, 2 - and 3 -H 2 ), AB signal (δ A = 2.77, δ B = 2.78, J A,B = 8.3 Hz, 2 H, 1 -H A and 1 -H B ), AA BB signal with signal centers at δ A = 7.50 and δ B = 7.56 ppm (2 2-H and 2 3-H). The preceding data are consistent with those reported in the literature. 5 The ee was determined by chiral HPLC (Chiralcel OD-3, n-heptane/i-proh 98:2, 1 ml/min, λ detector = 205 nm): t r (R) = 12.21 min, t r (S) = 15.35 min. [ α ] 20 365 = 304.0, [ α ] 20 = 150.2, [ α ] 20 = 76.3, [ α ] 20 = 65.8, [ ] 20 436 546 EtOH; the respective sample had 29% ee). 3 578 α = 61.1 (c = 0.90 in The absolute configuration was assigned by chemical correlation: At room temperature phenyl magnesium bromide (0.78 M in THF, 0.28 ml, 0.22 mmol, 2.5 equiv.) was added to ( )-butyl (4-chlorophenyl) sulfoxide (19.1 mg, 0.088 mmol) in THF (0.5 ml). After 3.5 h the reaction was quenched by the addition of aqueous saturated NH 4 Cl solution (1 ml). The layers were separated and the aqueous layer was extracted with t-buome (3 2 ml). The combined organic layers were dried over MgSO 4 and evaporated. The residue was purified by flash chromatography on silica gel 1 (c-c 6 H 12 :EtOAc 90:10, Fr. 103-112). The product (R)- 589

(+)-butyl phenyl sulfoxide 6 (36, 8.8 mg, 55%) was obtained as a colourless oil. Under the proviso that this sulfinylation takes place with inversion of configuration (which is the bottom-line of the stereoselectivities compiled in Figure 1 of the proper manuscript), the conclusion is that the sulfinylating agent ( )-59 is (S)-configured. 1.3 (4-Chlorophenyl) Isobutyl Sulfoxide (60): (S)-( )-Enantiomer and Racemic This compound was used to assign the configuration of the S-stereocenter of (S)-( )-47. The racemic synthesis followed the General Procedure for the Preparation of Racemic Alkyl Aryl Sulfoxides (cf. Experimental Section of our proper manuscript) using bis(4-chlorophenyl) sulfoxide (70.1 mg, 0.259 mmol) with i-bu 2 Mg (0.8 M in Et 2 O, 0.18 ml, 0.14 mmol, 0.55 equiv.) within 1.5 h. Flash chromatography on silica gel 1 (c-c 6 H 12 :EtOAc 80:20, Fr. 17-29) delivered rac-60 (48.0 mg, 86%) as a colorless oil. The asymmetric synthesis followed the Procedure for the Asymmetric Sulfinylations of Dialkylmagnesium Compounds by Symmetric Diaryl Sulfoxides (cf. Experimental Section of our proper manuscript) using bis(4-chlorophenyl) sulfoxide (53.2 mg, 0.196 mmol). After 30 min this delivered (S)-( )-60 (32.9 mg, 77%; 44% ee) as a colorless oil. 1 H NMR (400.1 MHz, CDCl 3 ): δ = 1.07 (d, J 3,2 = 6.4 Hz, 3 H, 3 -H 3 ), 1.15 (d, J 3,2 = 6.8 Hz, 3 H, 3 -H 3 ), 2.23 (m c, 1 H, 2 -H), 2.45 (dd, J 1 -A,1 -B = 11.0 Hz, J 1 -A,2 = 9.0 Hz, 1 H, 1 -H A ), 2.79 (dd, J 1 -B,1 -A = 12.9 Hz, J 1 -B,2 = 5.4 Hz, 1 H, 1 -H B ), AA BB signal with signal centers at δ A = 7.50 and δ b = 7.57 ppm (2 2-H and 2 3-H). 13 C NMR (100.6 MHz, CDCl 3 ): δ = 21.8 (C-3 ), 22.9 (C-3 ), 24.4 (C-2 ), 67.8 (C-1 ), 152.4 (C-2), 129.8 (C-3), 137.2, 143.4 ppm (C-1 and C-4). IR (CDCl 3 ): ν = 3475, 3080, 3060, 3015, 2960, 2930, 2960, 2930, 2900, 2870, 2665, 2405, 2070, 1640, 1575, 1575, 1465, 1390, 1370, 1340, 1290, 1275, 1235, 1210, 1170, 1090, 1080, 1040, 1010, 945, 925, 860, 830, 810, 740, 710, 695 cm -1. 4

HRMS (CI, NH 4 Cl): C 10 H 14 OSCl (M + H + ), calculated: 217.04550, found: 217.04539 ( = +0.5 ppm). The ee was determined by chiral HPLC (Chiralpak AD-H, n-heptane/i-proh 96:4, 1 ml/min, 22 C, λ detector = 221 nm): t r (R) = 12.63 min, t r (S) = 14.19 min. [ α ] 20 365 = 574.9, [ α ] 20 = 288.3, [ α ] 20 = 147.0, [ α ] 20 = 126.9, [ ] 20 436 546 EtOH; the respective sample had 44% ee). 578 α = 120.2 (c = 1.78 in The absolute configuration was assigned by chemical correlation: At room temperature phenyl magnesium bromide (0.78 M in THF, 0.89 ml, 0.69 mmol, 2.5 equiv.) was added to ( )-isobutyl (4-chlorophenyl) sulfoxide (60.0 mg, 0.277 mmol) in THF (1 ml). After 3.5 h the reaction was quenched by the addition of aqueous saturated NH 4 Cl solution (1 ml). The layers were separated and the aqueous layer was extracted with t-buome (3 5 ml). The combined organic layers were dried over MgSO 4 and evaporated. The residue was purified by flash chromatography on silica gel 1 (c-c 6 H 12 :EtOAc 90:10, F. 72-90). The product (R)-(+)- isobutyl phenyl sulfoxide 7 (42, 26.9 mg, 53%) was obtained as a colourless oil. Under the proviso that this sulfinylation takes place with inversion of configuration (which is the bottom-line of the stereoselectivities compiled in Figure 1 of the proper manuscript), the conclusion is that the sulfinylating agent ( )-60 is (S)-configured. 589 5

2. Configurational Assignments of Non-Racemic Sulfoxides The configurations attributed in Scheme 2 of our manuscript (pertinent extract: next line) were assigned as follows: O S ( )-21 21 8 : comparison of the sign of the specific rotation with literature data. ( )-22 was carried on to the known (Supporting Information of ref. 9) sulfoxide (S)-( )-19 by successive treatments with LDA and MeI (cf. Section 2.1 of this document). The configurations attributed in Scheme 3 of our manuscript (pertinent extract: next line) were assigned as follows: 29, 5 30, 5 33, 4 and 35 6 : comparison of the signs of the specific rotations with literature data. ( )-31 and ( )-34 were carried on to their known 9,10 isopropyl analogues (S)-( )-61, and (S)-( )-62, respectively, by successive treatments with LDA and MeI (cf. Section 2.1 of this document). ( )-22 was identified analogously (Supporting Information of ref. 9). ( )-32: comparison of the sign of the specific rotation with that of a sample of (R)-(+)-32, which we synthesized from the known 4 (4-chlorophenyl) ethyl (S)-( )-sulfoxide [58, cf. 6

Section 1.1, page 4 of this document; e.r. 75:25] and 4-phenylphenyl magnesium bromide (assuming an inversion of the configuration at the S-atom; cf. Section 2.2 of this document). The configurations attributed in Scheme 4 of our manuscript (pertinent extract: next line) were assigned as follows: 36, 6 37, 11 and 42 6 : comparison of the signs of the specific rotations with literature data. (S)-( )-39 and (S)-( )-40: comparison of the signs of the specific rotations with those of samples of (R)-(+)-39 and (R)-(+)-40, respectively, which we synthesized from (S)-( )-butyl (4-chlorophenyl) sulfoxide [59, cf. Section 1.2, page 5 of this document; e.r. = 64.5:35.5] and 4-phenylphenyl magnesium bromide and 4-methoxyphenyl magnesium bromide, respectively (assuming an inversion of the configuration at the S-atom; cf. Section 2.2 of this document). The configurations attributed in Scheme 5 of our manuscript (pertinent extract: next line) were assigned as follows: 43 7 and 44 7 : comparison of the signs of the specific rotations with literature data. 46: X-ray single crystal structure analysis (Bijvoet method 12 ). 7

(S)-( )-47: comparison of the sign of the specific rotation with that of a sample of (R)-(+)-47, which we synthesized from (S)-( )-(4-chlorophenyl) isobutyl sulfoxide [60, cf. Section 1.3, page 6 of this document; e.r. = 72:28] and 4-methoxyphenyl magnesium bromide (assuming an inversion of the configuration at the S-atom; cf. Section 2.2 of this document). The (S)-configurations of the sulfoxides 52-54 in Scheme 6 of our manuscript (pertinent extract: next paragraph) were assigned after performing Br Li exchanges with n-buli and subsequent protolyses of the C Li bonds. This rendered the known (S)-configured sulfoxides 29, 5 36, 6 and 43, 7 respectively (cf. Section 2.3 of this document). 2.1 Assignment of the Aryl Ethyl Sulfoxides ( )-22, ( )-31, and ( )-34 by Chemical Correlations With the Corresponding Aryl Isopropyl Sulfoxides Scheme 1: α-methylation of the Aryl Ethyl Sulfoxides ( )-22, ( )-31, and ( )-34 to the Corresponding Aryl Isopropyl Sulfoxides (S)-( )-61, (S)-( )-62, and (S)-( )-63. At 78 C a solution of the aryl ethyl sulfoxides (0.05-0.23 mmol, 1.0 equiv.) in THF (1 ml) was added dropwise to a solution of LDA (1.0 equiv.) in THF (0.5 ml). After 30 min MeI (1.0 equiv.) was added. After 10 min the mixture was allowed to warm to room temperature. After 1 h the reaction was quenched by the addition of aqueous saturated NH 4 Cl solution (1 ml). The layers were separated. The aqueous layer was extracted with t-buome (3 5 ml). The combined organic layers were dried over MgSO 4 and evaporated. The residue was purified by flash chromatography on silica gel 1. This delivered the aryl isopropyl sulfoxides ( )-19, 9 ( )-61, 9 and ( )-62, 9 respectively, as colorless oils; the levorotatory enantiomer of each of these compounds is known to be (S)-configured. 9 Since these alkylations affect no 8

bond at the stereocenter, it was concluded that the respective substrates ( )-22, 9 ( )-31, 9 and ( )-34 9 are (S)-configured as well. 2.2 Configurational Assignment of the Chlorine-Free Alkyl Aryl Sulfoxides ( )-32, ( )- 39, ( )-40, and ( )-47 by Independent Syntheses From Alkyl (4-Chlorophenyl) Sulfoxides Scheme 2: Sulfoxide-Magnesium Exchanges of Alkyl (4-Chlorophenyl) Sulfoxides Leading to Alkyl (4- Phenylphenyl) Sulfoxides (Top Half) and to Alkyl (4-Methoxyphenyl) Sulfoxides (Bottom Half). At room temperature (4-phenylphenyl) magnesium bromide or (4-methoxyphenyl) magnesium bromide (Solutions in THF, 2.5 equiv.) was added to the (S)-( )-alkyl (4- chlorophenyl) sulfoxides [which we synthesized and of which we assigned the configuration independently cf. Section 1 of this document; for ee s cf. Scheme 2 of this document (0.044-0.144 mmol, 1.0 equiv.)] in THF (0.5-1 ml). After full conversion was observed by TLC, the reaction was stopped by the addition of aqueous saturated NH 4 Cl solution (1 ml). The layers were separated and the aqueous layer was extracted with t-buome (3 2 ml). The combined organic layers were dried over MgSO 4 and evaporated. The residue was purified by flash chromatography on silica gel 1. The sign of the specific rotation of each of the resulting alkyl aryl sulfoxides 32, 39, 40, and 47 was (+). The starting materials for these sulfinylations were (S)-( )-configured. Under the proviso that these sulfinylations take place with inversion of configuration (which is the bottom-line of the stereoselectivities compiled in Figure 1 of the proper manuscript), the conclusion is that the sulfoxides (+)-32, (+)-39, (+)-40, and (+)-47 in Scheme 2 of this document are (R)-configured. Therefore, ( )-32, ( )-39, ( )- 40, and ( )-47 derived from our asymmetric sulfinylation reactions in the proper manuscript are (S)-configured. 9

2.3 Configurational Assignment of the Alkyl (2-Bromophenyl) Sulfoxides ( )-52, ( )- 53, and ( )-54 by Debrominations to the Corresponding Alkyl Phenyl Sulfoxides Scheme 3: Defunctionalizations by Br/Li-Exchange / Protolysis of the Bromine-Containing Sulfoxides ( )-52, ( )-53, and ( )-54 to the analogous Bromine-Free Sulfoxides (S)-( )-29, (S)-( )-36, and (S)-( )-43. At 78 C n-buli (2.35 M in hexane, 1.3 equiv.) was added to a solution of the alkyl (2- bromophenyl) sulfoxides (0.037-0.055 mmol) in THF (2 ml) and stirred for further 30 min. MeOH (2 ml) and a saturated aqeueos solution of NH 4 Cl (1 ml) were added. The layers were separated. The aqueous layer was extracted with t-buome (3 2 ml). The combined organic layers were dried over MgSO 4 and evaporated. The residue was purified by flash chromatography on silica gel 1 which delivered the known (S)-( )-alkyl phenyl sulfoxides 29, 5 36, 6 and 43 7 as colorless oils. Since these defunctionalizations affect no bond at the stereocenter, it was concluded that the respective substrates ( )-52, 5 ( )-53, 6 and ( )-54 7 are (S)-configured as well. 1 W. C. Still, M. Kahn, A. Mitra, J. Org. Chem. 1978, 43, 2923-2925. 2 This compound contained a small amount of an impurity, which we concluded since the HPLC chromatogram revealed a shoulder at the peak of the major enantiomer. 3 P. R. Blakemore, M. S. Burge, M. A. Sephton, Tetrahedron Lett. 2007, 48, 3999-4002. 4 H. Takeuchi, H. Minato late, M. Kobayashi, M. Yoshida, H. Matsuyama, N. Kamigata, Phosphorus, Sulfur, Silicon Relat. Elem. 1990, 47, 165-172. 5 P. R. Blakemore, M. S. Burge, J. Am. Chem. Soc. 2007, 129, 3068-3069. 6 P. Gogoi, T. Kotipalli, K. Indukuri, S. Bondalapati, P. Saha, A. K. Saikia, Tetrahedron Lett. 2012, 53, 2726-2729. 7 G. E. O Mahony, A. Ford, A. R. Maguire, J. Org. Chem. 2012, 77, 3288-3296. Erratum: J. Org. Chem. 2013, 78, 791. 8 P. Malik, D. Chakraborty, Tetrahedron Lett. 2012, 53, 5652-5655. 9 T. Hampel, S. Ruppenthal, D. Sälinger, R. Brückner, Chem. Eur. J. 2012, 18, 3136-3140. 10 D. D. Ridley, M. A. Smal, Austr. J. Chem. 1982, 35, 495-507. 11 A. A. Lindén, M. Johansson, N. Hermanns, J.-E. Bäckvall, J. Org. Chem. 2006, 71, 3849-3853. 12 J. M. Bijvoet, A. F. Peerdeman, A. J. Vanbommel, Nature 1951, 168, 271-272; b) E. L. Eliel, S. H. Wilen, in: Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, 113-115. 10