Mandelamide-Zinc Catalyzed Alkyne Addition to Heteroaromatic Aldehydes

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1 1 Mandelamide-Zinc Catalyzed Alkyne Addition to Heteroaromatic Aldehydes Gonzalo Blay, Isabel Fernández, Alícia Marco-Aleixandre, and José R. Pedro Departament de Química Orgànica, Facultat de Química, Universitat de València, Dr. Moliner, 50, E Burjassot (València), Spain SUPPORTING INFORMATION Table of Contents: General Experimental Methods Characterization data for compounds 3aa-3ce and for mandelamide V S1 S2-S8 1 H NMR and 13 C NMR for compounds 3aa-3ce and for mandelamide V S9-S40 General Experimental Methods: Glassware was oven-dried overnight at 120 C. Reactions were monitored by TLC analysis. Flash column chromatography was performed on silica gel 60, ( mm). 1 H NMR were run at MHz for 1 H and at 50.3 MHz for 13 C NMR in CDCl 3 and referenced to the solvent as internal standard. Specific optical rotations were measured in CHCl 3 using sodium light (D line 589 nm). IR spectra were recorded as thin films in NaCl disks. HPLC analyses were performed in a chromatograph equipped with a refraction index detector using chiral stationary phase columns. All alkynes 1 and aldehydes 2 were commercially available and used as purchuased without further purification. Toluene was distilled from CaH 2 and stored on 4 Å molecular sieves. Mandelamides were prepared according to procedures described in the literature. 1

2 2 (R)-(+)-1,3-Diphenyl-2-propyn-1-ol (3aa). 2,3,4 Ph 3aa Obtained in 95% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 13.1 min, minor enantiomer t r = 21.7 min, to be 25 89%; [α] D +6.7 (c 0.54, CHCl 3, ee 89%); MS(EI) 208 (M +, 100), 191 (30), 179 (61); HRMS , C 15 H 12 O required ; 1 H NMR (CDCl 3 ) δ 7.61 (d, J = 6.3 Hz, 2H), (m, 8H), 5.68 (s, 1H), 2.27 (br s, 1H); 13 C NMR (CDCl 3 ) δ (C), (CH), (CH), (CH), (CH), (CH), (CH), (C), 88.6 (C), 86.6 (C), 65.1 (CH). (S)-(+)-1-(Furan-2-yl)-3-phenyl-2-propyn-1-ol (3ab). 4 Ph O 3ab Obtained in 88% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 10.3 min, minor enantiomer t r = 21.1 min, to be 25 83%; [α] D +34 (c 0.58, CHCl 3, ee 83%); MS(EI) 198 (M +, 19), 181 (26), 141 (100); HRMS , C 13 H 10 O 2 required ; 1 H NMR (CDCl 3 ) δ (m, 3H), (m, 3H), 6.51 (d, J = 3.0 Hz, 1H), 6.36 (dd, J = 5.4, 3.0 Hz, 1H), 5.68 (s, 1H), 2.50 (br s, 1H); 13 C NMR (CDCl 3 ) δ (C), (CH), (CH), (CH), (CH), (C), (CH), (CH), 86.1 (C), 85.8 (C), 58.6 (CH). (S)-(+)-1-(Furan-3-yl)-3-phenyl-2-propyn-1-ol (3ac). 2 Ph 3ac O Obtained in 94% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 9.6 min, minor enantiomer t r = 24.7 min, to be 89%; [α] D (c 0.53, CHCl 3, ee 89%); MS(EI) 198 (M +, 57), 181 (24), 169 (42), 141 (100);

3 3 HRMS , C 13 H 10 O 2 required ; 1 H NMR (CDCl 3 ) δ 7.58 (s, 1H), (m, 3H), (m, 3H), 6.56 (s, 1H), 5.61 (s, 1H), 2.11 (br s, 1H); 13 C NMR (CDCl 3 ) δ (CH), (CH), (CH), (CH), (C), (C), (CH), 88.1 (C), 85.1 (C), 57.7 (CH). (S)-(+)-3-Phenyl-1-(thiophen-2-yl)-2-propyn-1-ol (3ad). This compound has been described in racemic form. 5 Ph 3ad S Obtained in 91% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 11.2 min, minor enantiomer t r = 23.2 min, to be 90%; [α] 25 D +20 (c 0.53, CHCl 3, ee 90%); MS(EI) 214 (M +, 23), 197 (15), 185 (30), 102 (100); HRMS , C 13 H 10 OS required ; 1 H NMR (CDCl 3 ) δ (m, 2H), (m, 3H), 7.23 (dt, J = Hz), 7.00 (dd, J = 5.0, 3.5 Hz, 1H), 5.88 (br d, J = 6.0 Hz, 1H), 2.53 (br d, J = 6.0 Hz, 1H); 13 C NMR (CDCl 3 ) δ (C), (CH), (CH), (CH), (CH), (CH), (CH), (C), 87.9 (C), 86.0 (C), 60.7 (CH). (S)-(+)-3-Phenyl-1-(thiophen-3-yl)-2-propyn-1-ol (3ae). 2 Ph 3ae S Obtained in 86% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 11.5 min, minor enantiomer t r = 30.8 min, to be 88%; [α] 25 D +20 (c 0.53, CHCl 3, ee 88%); MS(EI) 214 (M +, 23), 197 (15), 185 (30), 102 (100); HRMS , C 13 H 10 OS required ; 1 H NMR (CDCl 3 ) δ (m, 2H), (m, 5H), 5.71 (s, 1H), 2.18 (br s, 1H); 13 C NMR (CDCl 3 ) δ (C), (CH), (CH), (CH), (CH), (CH), (CH), (C), 88.5 (C), 85.8 (C), 61.0 (CH).

4 4 (R)-(+)-1,5-Diphenyl-2-pentyn-1-ol (3ba). 2,3 PhH 2 CH 2 C 3ba Obtained in 96% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 15.7 min, minor enantiomer t r = 27.4 min, to be 25 88%; [α] D (c 0.52, CHCl 3, ee 88%); MS(EI) 236 (M +, 98), 218 (61), 91 (100); HRMS , C 17 H 16 O required ; 1 H NMR (CDCl 3 ) δ 7.45 (dd, J = 7.8, 2.2 Hz, 2H), (m, 8H), 5.41 (s, 1H), 2.85 (t, J = 7.5 HZ, 2H), 2.56 (td, J = 7.5, 1.8 Hz, 2H), 2.13 (br s, 1H); 13 C NMR (CDCl 3 ) δ (C), (C), (CH), (CH), (CH), (CH), (CH), 86.7 (C), 80.7 (C), 64.7 (CH), 34.8 (CH 2 ), 20.9 (CH 2 ). (S)-(+)-1-(Furan-2-yl)-5-phenyl-2-pentyn-1-ol (3bb). PhH 2 CH 2 C 3bb O Obtained in 96% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 13.9 min, minor enantiomer t r = 21.7 min, to be 90%; [α] 25 D (c 0.54, CHCl 3, ee 90%); IR (thin film) 3397, 3120, 3062, 3028, 2927, 2227, 1603, 1497, 1453, 1008, 744 cm -1 ; MS(EI) 226 (M +, 6), 208 (3), 91 (100); HRMS , C 15 H 14 O 2 required ; 1 H NMR (CDCl 3 ) δ 7.32 (s, 1H), (m, 5H), 6.25 (s, 2H), 5.34 (d, J = 6.0 Hz, 1H), 2.79 (t, J = 7.5 Hz, 2H), 2.49 (td, J = 7.5, 1.8 Hz, 2H), 2.21 (d, J = 6.0 Hz); 13 C NMR (CDCl 3 ) δ (C), 142.8(CH), (C), (CH), (CH), (CH), (CH), (CH), 86.0 (C), 78.2 (C), 58.2 (CH), 34.7 (CH 2 ), 20.9 (CH 2 ).

5 5 (S)-(+)-1-(Furan-3-yl)-5-phenyl-2-pentyn-1-ol (33bc). PhH 2 CH 2 C 3bc O Obtained in 93% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 11.9 min, minor enantiomer t r = 22.6 min, to be 92%; [α] 25 D (c 0.52, CHCl 3, ee 92%); IR (thin film) 3383, 3132, 3062, 3022, 2933, 2216, 1597, 1494, 1453, 1002, 745 cm -1 ; MS(EI) 226 (M +, 50), 208 (11), 91 (100); HRMS , C 15 H 14 O 2 required ; 1 H NMR (CDCl 3 ) δ 7.32 (d, J = 2.1 Hz, 1H), 7.30 (s, 2H), (m, 5H), 6.37 (s, 2H), 5.27 (unresolved t, J = 1.5 Hz, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.49 (td, J = 7.5, 1.8 Hz, 2H), 1.88 (br s, 1H); 13 C NMR (CDCl 3 ) δ (CH), (C), 140.1(CH), (CH), (CH), (C), (CH), (CH), 85.1 (C), 80.2 (C), 57.4 (CH), 34.8 (CH 2 ), 20.8 (CH 2 ). (S)-(+)-5-Phenyl-1-(thiophen-2-yl)-2-pentyn-1-ol (3bd) PhH 2 CH 2 C S 3bd Obtained in 89% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 14.7 min, minor enantiomer t r = 30.6 min, to be 91%; [α] 25 D (c 0.57, CHCl 3, ee 91%); IR (thin film) 3390, 3062, 3026, 2927, 2229, 1603, 1495, 1452, 1015, 699 cm -1 ; MS(EI) 242 (M +, 10), 110 (100); HRMS , C 15 H 14 OS required ; 1 H NMR (CDCl 3 ) δ (m, 6H), 6.99 (d, J = 3.3 Hz, 1H), 6.87 (dd, J = 5.4, 3.3 Hz, 1H), 5.54 (s, 1H), 2.79 (t, J = 7.5 Hz, 2H), 2.50 (td, J = 7.5, 1.8 Hz, 2H), 2.28 (d, J = 6.0 Hz); 13 C NMR (CDCl 3 ) δ (C), (C), (CH), (CH), (CH), (CH), (CH), (CH), 86.2 (C), 80.2 (C), 60.4 (CH), 34.7 (CH 2 ), 20.8 (CH 2 ).

6 6 (S)-(+)-5-Phenyl-1-(thiophen-3-yl)-2-pentyn-1-ol (3be) PhH 2 CH 2 C S 3be Obtained in 94% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 14.7 min, minor enantiomer t r = 29.9 min, to be 89%; [α] 25 D (c 0.51, CHCl 3, ee 89%); IR (thin film) 3385, 3100, 3062, 3024, 2930, 2225, 1600, 1494, 1452, 1013, 701 cm -1 ; MS(EI) 242 (M +, 100), 224 (10), 91 (61); HRMS , C 15 H 14 OS required ; 1 H NMR (CDCl 3 ) δ (m, 7H), 7.05 (d, J = 5.1 Hz 1H), 5.37 (s, 1H), 2.79 (t, J = 7.5 Hz, 2H), 2.50 (td, J = 7.5, 1.8 Hz, 2H), 1.96 (br s, 1H); 13 C NMR (CDCl 3 ) δ (C), (C), (CH), (CH), (CH), (CH), (CH), 85.8 (C), 80.6 (C), 60.6 (CH), 34.8 (CH 2 ), 20.8 (CH 2 ). (+)-4,4-Dimethyl-1-phenyl-2-pentyn-1-ol (3ca). This compound has been described in racemic form. 5 t-bu 3ca Obtained in 93% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 5.8 min, minor enantiomer t r = 4.7 min, to be 67%; [α] 25 D (c 0.51, CHCl 3, ee 67%); MS(EI) 188 (M +, 100), 173 (16), 158 (21); HRMS , C 13 H 16 O required ; 1 H NMR (CDCl 3 ) δ 7.53 (d, J = 6.3, Hz, 2H), (m, 3H, 5.42 (s, 1H), 2.08 (br s, 1H), 1.24 (s, 9H); 13 C NMR (CDCl 3 ) δ (C), (CH), (CH), (CH), 95.8 (C), 78.3 (C), 64.7 (CH), 30.9 (CH 3 ), 27.5 (C). (+)-1-(Furan-2-yl)-4,4-dimethyl-2-pentyn-1-ol (3cb) t-bu 3cb O

7 7 Obtained in 79% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 5.6 min, minor enantiomer t r = 5.3 min, to be 85%; [α] 25 D (c 0.53, CHCl 3, ee 85%); IR (thin film) 3425, 2968, 2239, 1643, 1081, 1009 cm - 1 ;MS(EI) 178 (M +, 85), 163 (82), 135 (66) 121 (97), 91 (100); HRMS , C 11 H 14 O 2 required ; 1 H NMR (CDCl 3 ) δ 7.38 (m, 1H), 6.40 (d, J = 3.0 Hz), 6.32 (dd, J = 3.0, 2.1 Hz, 1H), 5.41 (s, 1H), 2.23 (br s, 1H), 1.24 (s, 9H); 13 C NMR (CDCl 3 ) δ (C), (CH), (CH), (CH), 94.8 (C), 75.9 (C), 58.2 (CH), 30.8 (CH 3 ), 27.4 (C). (+)-1-(Furan-3-yl)-4,4-dimethyl-2-pentyn-1-ol (3cc) t-bu O 3cc Obtained in 98% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 0.5 ml/min, major enantiomer t r = 9.5 min, minor enantiomer t r = 9.1 min, to be 90%; [α] 25 D (c 0.56, CHCl 3, ee 90%); IR (thin film) 3366, 2970, 2235, 1027, 753 cm -1 ; MS(EI) 178 (M +, 84), 163 (1), 121 (72), 91 (100); HRMS , C 11 H 14 O 2 required ; 1 H NMR (CDCl 3 ) δ 7.47 (s, 1H), 7.36 (unresolved t, 1H), 6.47 (unresolved d, 1H), 5.34 (s, 1H), 1.94 (br s, 1H), 1.23 (s, 9H); 13 C NMR (CDCl 3 ) δ (CH), (CH), (C), (CH), 94.1 (C), 77.9 (C), 57.4 (CH), 30.8 (CH 3 ), 27.4 (C). (+)-1-(Thiophen-2-yl)-4,4-dimethyl-2-pentyn-1-ol (3cd) S t-bu 3cd Obtained in 95% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 5.7 min, minor enantiomer t r = 5.1 min, to be 90%; [α] 25 D (c 0.51, CHCl 3, ee 90%); IR (thin film) 3381, 3105, 2969, 2238, 976, 702 cm -1, MS(EI) 194 (M +, 100), 179 (17); HRMS , C 11 H 14 OS required ; 1 H NMR (CDCl 3 ) δ 7.26 (dd, J = 4.8, 1.5 Hz, 1H), 7.13 (dt, J = 3.5, 1.5 Hz, 1H), 6.95 (dd, J = 4.8, 3.5 Hz, 1H), 5.60 (d, J = 5.6 Hz), 2.33 (d, J = 5.6Hz, 1H), 1.25 (s, 9H); 13 C NMR (CDCl 3 ) δ (C), (CH), (CH), (CH), 95.1 (C), 78.0 (C), 60.3 (CH), 30.7 (CH 3 ), 27.4 (C).

8 8 (+)-1-(Thiophen-3-yl)-4,4-dimethyl-2-pentyn-1-ol (3ce) t-bu S 3ce Obtained in 90% yield; enantiomeric excess was determined by HPLC (Chiralcel OD-H), hexane:i- Pr 90:10, 1 ml/min, major enantiomer t r = 5.5 min, minor enantiomer t r = 5.0 min, to be 77%; [α] 25 D (c 0.57, CHCl 3, ee 77%); IR (thin film) 3351, 3106, 2969, 2238, 995, 793 cm - 1, MS(EI) 194 (M +, 100), 179 (24), 164 (13); HRMS , C 11 H 14 OS required ; 1 H NMR (CDCl 3 ) δ 7.35 (dt, J = 3.0, 1.2 Hz, 1H), 7.28 (dd, J = 4.8, 3.0 Hz, 1H), 7.17 (dd, J = 4.8, 1.2 Hz, 1H), 5.44 (s, 1H), 1.25 (s, 9H); 13 C NMR (CDCl 3 ) δ (C), (CH), (CH), (CH), 94.9 (C), 78.3 (C), 60.6 (CH), 30.9 (CH 3 ), 27.4 (C). (S)-N-(2-methoxybenzyl)-2-hydroxy-2-phenylacetamide (V) O HO V HN MeO [α] 25 D (c 0.53, CHCl 3 ); IR (thin film) 3338, 3064, 2938, 1659, 1531, 1494, 1244, 754 cm - 1 MS(EI) 271 (M +, 16), 253 (20), 121 (100); HRMS , C 16 H 17 NO 3 required ; 1 H NMR (CDCl 3 ) δ (m, 5H); 7.26 (td, J = 7.6, 1.6 Hz, 1H), 7.17 (dd, J = 7.5, 1.6 Hz, 1H), 6.88 (t, J = 7.5 Hz, 1H), 6.83 (d, J = 7.5 Hz, 1H), 6.52 (br s, 1H), 5.00 (d, J = 3.3 Hz, 1H), 4.42 (AB system, 2H), 3.73 (s, 3H); 13 C NMR (CDCl 3 ) δ (C), (C), (C), (CH), (CH), (2 x CH), (CH), (2 x CH), (C), (CH), (CH), 74.0 (CH), 55.1 (CH 3 ), 39.6 (CH 2 ). 1. Blay, G.; Fernández, I.; Hernández-Olmos, V.; Marco-Aleixandre, A.; Pedro, J. R. Tetrahedron: Asymmetry 2005, 16, Takita, R.; Yakura, K.; Ohshima, T.; Shibashaki, M. J. Am. Chem. Soc. 2005, 127, Frantz, D. E.; Fässler, R.; Carreira, E. M. J. Am. Chem. Soc. 2000, 122, Li. Z. B.; Pu, L. Org. Lett. 2004, 6, Sakai, N.; Kanada, R.; Hirasawa, M.; Konakahara, T. Tetrahedron 2005, 61,

9 9 Ph 3aa

10 10 Ph 3aa

11 11 Ph 3ab O

12 12 Ph 3ab O

13 13 Ph 3ac O

14 14 Ph 3ac O

15 15 Ph 3ad S

16 16 Ph 3ad S

17 17 Ph 3ae S

18 18 Ph 3ae S

19 19 PhH 2 CH 2 C 3ba

20 20 PhH 2 CH 2 C 3ba

21 21 PhH 2 CH 2 C 3bb O

22 22 PhH 2 CH 2 C 3bb O

23 23 PhH 2 CH 2 C 3bc O

24 24 PhH 2 CH 2 C 3bc O

25 25 PhH 2 CH 2 C 3bd S

26 26 PhH 2 CH 2 C 3bd S

27 27 PhH 2 CH 2 C 3be S

28 28 PhH 2 CH 2 C 3be S

29 29 t-bu 3ca

30 30 t-bu 3ca

31 31 t-bu 3cb O

32 32 t-bu 3cb O

33 33 t-bu 3cc O

34 34 t-bu 3cc O

35 35 t- Bu 3cd S

36 36 t- Bu 3cd S

37 37 t-bu 3ce S

38 38 t-bu 3ce S

39 39 O HO V HN MeO

40 40 O HO V HN MeO