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1 Mild rganocatalytic α-methylenation of Aldehydes Anniina Erkkilä and Petri M. Pihko* Laboratory of rganic Chemistry, elsinki University of Technology, P..B. 61, FI-215 TKK, Finland Supporting Information Table of Contents Table of Contents... S1 General Methods... S2 Procedures for the Preparation of Starting Materials... S2 Synthesis of Catalyst 13 (L-Pro-β-Ala)... S4 α-methylenation of Aldehydes, General Procedures and Characterization Data... S5 Copies of 1 and 13 C Spectra... S8

2 S2 General Methods All aqueous reactions were carried out under ambient atmosphere in capped vials, unless otherwise noted. Under nonaqueous conditions, the reactions were performed under argon, and reagents were dried prior to use and transferred under argon via syringe. TF was distilled from Na/benzophenone. DMS was distilled from Ca 2. Me was distilled from Mg(Me) 2. C 2 Cl 2 was distilled from Ca 2. N-Methyl morpholine was distilled over sodium chips. ther solvents and reagents were used as obtained from the supplier, unless otherwise noted. Temperatures refer to bath temperatures. Analytical TLC was performed using Merck silica gel F254 (23-4 mesh) plates and analyzed by UV light or by staining upon heating with vanillin solution (6 g vanillin, 5 ml conc. 2 S 4, 3 ml glacial acetic acid, 25 ml Et) or ninhydrin solution (1 g ninhydrin, 1 ml isopropanol, 5 drops glacial acetic acid). For silica gel chromatography, the flash chromatography technique was used, with Merck silica gel 6 (23-4 mesh) and p.a. grade solvents unless otherwise noted. The 1 NMR and 13 C NMR spectra were recorded in either CDCl 3 or 2 /D 2 on a 4 Mz ( Mz; 13 C 1.59 Mz) spectrometer. The chemical shifts are reported in ppm relative to residual CCl 3 (δ 7.26) or TMS (δ ) signals for 1 NMR spectra. The coupling constants are reported in z. For the 13 C NMR spectra, the residual CDCl 3 (δ 77.) was used as the internal standard. The enantiomeric excess (ee) of 15 was determined by GC in comparison to the corresponding racemic samples using Chiraldex β-p cyclodextrin column (3 m x.25 mm, 11 C isotherm, carrier pressure 32 psi, FID detection (28 C)). Procedures for the Preparation of Starting Materials Swern oxid. S1 28 Aldehyde 28 was obtained by Swern oxidation of the commercially available alcohol S1. Data obtained correlates with literature data. 1 1 NMR (CDCl 3, 4 Mz): δ (CDCl 3, 4 Mz): δ 9.8 (dd, 1, J = 1.2, 2.); 4.55 (tt, 1, J = 6., 6.8 z); 4.18 (dd, 1, J = 6.; 8.4); 3.58 (dd, 1, J = 6.8, 8.4 z); 2.85 (ddd, 1, J = 2., 6.8, 17.2 z); 2.65 (ddd, 1, J = 1.2, 6., 17.2 z) 1.41 (s, 3); 1.36 (s, 3); 13 C NMR (CDCl 3, 1 Mz): δ 2, 19.2, 7.6, 69.1, 47.8, 26.8, 25.4; [α] 2 D +6.1 (c = 2., CCl 3 ). S2 n-buli; TBDPSCl S3 TBDPS Alcohol S3. To a solution of S2 (3.5 ml, 3.56 g, 39.5 mmol, 1 mol%) in TF (6 ml) at -78 C was added dropwise BuLi (1.58 M, 2 ml, 39.5 mmol, 1 mol%, followed by TBDPSCl (1.1 ml, 1.85 g, 39.5 mmol, 1 mol%). The reaction mixture was allowed to warm to rt during 25 min., then brought to reflux for 4 h. The reaction mixture was allowed to cool to rt, then quenched with 7% aq NaC 3 solution (6 ml). The mixture was extracted with Et 2 (2 x 3 ml). The combined extracts were dried (Na 2 S 4 ) and concentrated in vacuo. The crude product was purified with flash chromatography (5% EtAc in hexanes) to yield 9.4 g (73%) of alcohol S3 as yellowish oil. Data obtained correlates with literature data. 2 1 NMR (CDCl 3, 4 Mz): δ (m, 4); (m, 6); 3.7 (t, 2, J = 5.7 z); 3.66 (t, 2, J = 5.7 z); 2.3 (br s, 1); (m, 4), 1.6 (s, 9); 13 C NMR (CDCl 3, 1 Mz): δ 135.5, 133.6, 129.6, 127.6, 64., 62.8, 29.8, 29.4, 26.8, Arroyo-Gómez, Y.; López-Sastre, J. A.; Rodríguez-Amo, J. F.; Santos-García, M.; Sanz-Tejedor M. A. Tetrahedron Asymmetry 1999, 1, Nacro, K.; Baltas, M.; Gorrichon, L. Tetrahedron, 1999, 55,

3 S3 TBDPS Aldehyde 24. A solution of oxalyl chloride (1.9 ml, 2.76 g, 21.8 mmol, 11 mol%) in C 2 Cl 2 (5 ml) at -6 C, was added DMS (3.1 ml, 3.41 g, 43.6 mmol, 22 mol%). After 3 min, a solution of alcohol S3 (6.5 g, 19.8 mmol, 1 mol%) in C 2 Cl 2 (2 ml) was added and the mixture was stirred for 5 min. Et 3 N was then added dropwise. The reaction mixture was allowed to warm to rt and stirred for 7 min. 2 (1 ml) was added and the separated aqueous phase was extracted with C 2 Cl 2 (5 ml). The combined organic phases were washed with brine, dried (Na 2 S 4 ) and filtered through thin silica pad. The solution was concentrated in vacuo to afford 5 g (78%) of aldehyde 24 as yellowish oil. Data obtained correlates with literature data. 3 1 NMR (CDCl 3, 4 Mz): δ 9.81 (t, 1, J = 1.6 z); (m, 4), (m, 6); 3.7 (t, 2, J = 6. z); 2.55 (td, 2, J = 1.6 z, 7.1 z); 1.9 (tt, 2, J = 6. z, 7.1 z); 1.6 (s, 9) 13 C NMR (CDCl 3, 1 Mz): δ 22.5, 135.5, 133.5, 129.6, 127.6, 62.9, 4.7, 26.8, 25.2, Keto Aldehyde 26. A solution of methyl cyclohexene (1.2 ml,.96 g, mmol, 1 mol%) in C 2 Cl 2 (7 ml) was cooled to -78 C. A stream of 3 was bubbled through the solution until a blue colour persisted. A stream of 2 was then bubbled through the reaction mixture to remove excess ozone. Dimethyl sulfide (1.2 ml,.99 g, 16. mmol, 16 mol%) was then added. The reaction mixture was stirred for an additional 23 h. 2 was then added and the mixture was extracted with DCM (2 x 5 ml). The combined extracts were washed with brine, dried (Na 2 S 4 ) and concentrated in vacuo. The crude product was purified with flash chromatography (4% MTBE in hexanes) to yield.38 g (3%) of 26 as pale yellow oil. IR 3419, 2943, 2726, 1712, 1411, 1365, 1161, 186, 1, 734 cm -1 ; 1 NMR (CDCl 3, 4 Mz): δ 9.73 (t, 1, J = 1.2 z); 2.45 (m, 4), 2.14 (s, 3); 1.61 (m, 4); 13 C NMR (CDCl 3, 1 Mz): δ 28.4, 22.2, 43.7, 43.2, 29.9, 23.1, RMS (ESI+) calc for [C Na] , obsd Freeman, F.; Kim, D. S.. L. J. rg. Chem. 1992, 57,

4 S4 Synthesis of Catalyst 13 (L-Pro-β-Ala) N Cbz S4 C 3 N 2 Me S5 Cl ibu NMM N Cbz N S6 C 2 Me 1M Na N N Pd/C N Cbz N 13 C 2 S7 C 2 Cbz-L-prolyl-β-alanine methyl ester S6. To Cbz-L-proline (S4) (3. g, 12. mmol, 1 mol%) in dry TF (12 ml) at 25 C, N-methyl morpholine (NMM) (1.4 ml, 12.6 mmol, 15 mol%) and isobutyl chloroformate (1.7 ml, 12.6 mmol, 15 mol%) were added with stirring. A cloudy mixture was formed. After 1 min, S5 (1.76 g, 12.6 mmol, 15 mol%) was added, followed by NMM (1.5 ml, 13.2 mmol, 11 mol%). The mixture was allowed to stir for additional 2 h at 25 C, then quenched with sat. NaC 3 (18 ml) and extracted with EtAc (3 x 1 ml). The combined organic extracts were dried (Na 2 S 4 ), filtered and concentrated. The crude product was recrystallized from Et 2 /hexanes to afford 4. g (quant.) of the dipeptide S6 as white amorphous crystals. R f.93 (5% Me in C 2 Cl 2 ) [α] 2 D = (c = 1. in CCl 3 ); mp C, IR 332, 366, 2953, 2882, 1736, 174, 1538, 1416, 1356, 1176, 112, 752, 698; 1 NMR (CDCl 3, 4 Mz) δ (m, 5); 7.2 (br s,.5); 6.49 (br s,.5); (m, 2); (m, 1); (m, 7); (m, 7); 13 C NMR (CDCl 3, 1 Mz): δ 191.9, 172.6, 151.3, 136.3, 128.5, 128.1, 127.8, 67.2, 6.7, 51.7, 46.9, 34.8, 33.6, 28.6; RMS (ESI+) calc for [C N Na] , obsd ; Anal. calc. for C N 2 5 : C, 61.7;, 6.63; N, Found: C, 61.;, 6.49; N, Cbz-L-prolyl-β-alanine S7. To the methyl ester S6 (4.25 g, 12.7 mmol, 1 mol%) in 1:1 Me/TF (5 ml), was added 1 M Na (19. ml, 19. mmol, 15 mol%) at ambient temperature. The reaction mixture was stirred 3 h, then solvents were evaporated to afford 3.22 g (79%) of S7 as white crystals. Spectroscopic data obtained obtained for this compound correlates with literature data. 4 R f.68 (5% Me in DCM) [α] 2 D = (c = 1. in DMF); mp C. L-prolyl-β-alanine 13. To S7 (2.73 g, 8.5 mmol, 1 mol%) in Me (5 ml) under Ar was added 5% Pd/C (.27 g, 1 w-%). The reaction mixture was then purged with argon and finally with hydrogen, and the mixture was stirred under 2 for 1.5 h. After an argon purge, the reaction mixture was filtered through a thin celite pad and washed with Me to remove Pd/C. Evaporation of solvents afforded 1.32 g (83%) of 13 as white powder. R f 5 (5% Me in C 2 Cl 2 ). Data obtained correlates with literature data. 4 mp C; [α] 2 D = -5.8 (c = 1. in 2 ); 1 NMR ( 2, 4 Mz): δ (m, 1), (m, 4), (m, 3), (m, 3) 13 C NMR ( 2, 1 Mz): δ 179.9, 169.2, 59.7, 46.3, 36.9, 36.4, 29.6, Ienaga, K; igashiura, K.; Kimura,. Chem. Pharm. Bull. 1987, 35,

5 S5 α-methylenation of Aldehydes, General Procedures and Characterization Data General procedure A for the α-methylenation of aldehydes. To a mixture of aqueous formaldehyde solution (37% formaldehyde in water, 1. mmol, 1 mol%) and aldehyde (1. mmol) in i-pr (1 µl) was added propionic acid (.1 mmol, 1 mol%) and pyrrolidine (.1 mmol, 1 mol%). The reaction mixture was stirred at 45 C for 1-25 h. NaC 3 was added and the mixture was extracted with C 2 Cl 2 (3 x 5 ml). The combined extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. If necessary, the crude product thus obtained was purified by a passage through a short pad of silica gel using Et 2 as the eluent. General procedure B for the α-methylenation of aldehydes. To catalyst 13 (L-Pro-β-Ala) (.1 mmol, 1 mol%) in i- Pr (1 µl) in a 5 ml vial was added aqueous formaldehyde solution (37% formaldehyde in water, 1. mmol, 1 mol%) and aldehyde (1. mmol, 1 mol%) at rt. The mixture was stirred at 45 C for 1-25 h. 2 (5 ml) was then added and the mixture was extracted with C 2 Cl 2 (3 x 5 ml). The combined extracts were washed with brine, dried (Na 2 S 4 ), and concentrated in vacuo. If necessary, the crude product thus obtained was purified by a passage through a short pad of silica gel using Et 2 as the eluent. Characterization Data for the α-methylenation Products: 17 2-methyleneoctanal (17). The reaction was carried out following the General Procedure A to yield 129 mg (92 %) of 17 as a pale yellow oil. Data obtained match the literature data. 5 1 NMR (CDCl 3, 4 Mz): δ 9.48 (s, 1), 6.19 (s, 1), 5.93 (s, 1); 2.18 (t, 2, J = 7.6 z), (br m, 8 ),.87 (t, 3, J = 7 z); 13 C NMR (CDCl 3, 1 Mz): δ 194.6, 15.4, 133.7, 31.5, 28.8, 27.7, 27.6, 22.4, tert-butylacrolein/3,3-dimethyl-2-methylenebutanal (19). The reaction was carried out following the General Procedure A to yield 97 mg (86%) of 19 as a colorless oil. IR 338, 2961, 2872, 172, 146, 1364, 136, 1195, 953, 848, 67; 1 NMR (CDCl 3, 4 Mz): δ 9.54 (s, 1); 6.3 (s, 1); 5.9 (s, 1); 1.19 (s, 9); 13 C NMR (CDCl 3, 1 Mz): δ 19, 158.1, 133.6, 33.8, RMS (ESI+) calc for [C 7 13 ] , obsd (S)-3,7-Dimethyl-2-methylene-6-octanal (15). The reaction was carried out following the General Procedure A to yield 147 mg (89%) of 15 as a pale yellow oil. Data obtained correlates with literature data. 6 [α] 2 D = +5.2 (c = 13.4 in CCl 3 ); 1 NMR (CDCl 3, 4 Mz): δ 9.53 (s, 1); 6.23 (s, 1); 5.98 (s, 1); 7 (tt, 1, J = 1.2, 7.2 z); 2.7 (sext., 1, J = 6.8 z); 1.92 (m, 2); 1.67 (s, 3); 1.56 (s, 3); 1.51 (m, 1); 1.37 (m, 1) 1.6 (d, 3, J = 6.8 z) 13 C NMR (CDCl 3, 1 Mz): δ 194.7; 155.5; 133.2; 124.1; 35.6; 3.9; 25.7; 25.6; 19.5; GC analysis (β-p cyclodextrin, flow rate 32 psi, 11 C isotherm) t R = 3 (minor), 5.13 (major) reveals this material to be 99% ee. 5 Fearnley, S. P.; Funk, R. L.; Gregg, R. J. Tetrahedron 2 56, White, J. D.; Amedio, J. C.; Gut, S.; hira, S. Jayasinghe, L. R. J. rg. Chem. 1992, 57,

6 S6 Ph 21 2-benzylacrolein/2-methylene-3-phenylpropanal (21). The reaction was carried out following the General Procedure A or General Procedure B to yield 146 mg (99%) of 21 as a pale yellow oil. Data obtained correlates with literature data. 7 1 NMR (CDCl 3, 4 Mz): δ 9.61 (s, 1); (m, 5); 6.11 (s, 1); 6.7 (s, 1); 3.57 (s, 2); 13 C NMR (CDCl 3, 1 Mz) δ 193.9, 149.7, 138.1, 135.2, 129.1, 128.5, 126.4, Ph 23 α-phenylethylacrolein / 2-(1-phenyl-ethyl)-propenal (23). The reaction was carried out following either the General Procedure A to yield 144 mg (9%) or General Procedure B to provide 122 mg (76%) of 23 as a pale yellow oil. IR: 2986, 235, 1693, 1421, 1265, 95, 896, 741, 75, 49; 1 NMR (CDCl 3, 4 Mz): 9.54 (s, 1); δ (m, 5); 6.24 (s, 1); 6.8 (s, 1); 4.6 (q, 1, J = 7.2 z); 1.43 (d, 3, J = 7.2 z); 13 C NMR (CDCl 3, 1 Mz): δ 193.8; 154.4; 143.6; 133.6; 128.4; 127.5; 126.4; 37.2; 2. RMS (ESI+) calc for [C Na] , obsd TBDPS 2-(2 -(tert- Butyldiphenylsilyloxy)ethyl)propenal (25). The reaction was carried out following the General Procedure A to yield 284 mg (83%) as a pale yellow oil. Data obtained correlates with literature data. 8 1 NMR (CDCl 3, 4 Mz): δ 9.49 (s, 1); δ (m, 4); (m, 6); 6.35 (s, 1); 6.5 (s, 1), 3.77 (t, 2, J = 6.4 z); 2.51 (t, 2,. J = 6.4 z); 1.3 (s, 9); 13 C NMR (CDCl 3, 1 Mz): δ 194.4, 147., 135.8, 135.5, 133.7, 129.6, 127.6, 61.7, 31., 26.8, methylene-6-oxo-heptanal (27). The reaction was carried out following the General Procedure A to yield 99 mg (74%) of 27 as a pale yellow oil. IR 3412, 2943, 1713, 1691, 1411, 1367, 1143, 953 cm -1 ; 1 NMR (CDCl 3, 4 Mz): δ 9.49 (s, 1); 6.26 (s, 1); 6. (s, 1); 2.42 (t, 2, J = 7.2 z); 2.2 (t, 2, J = 7.2 z); 2.1 (s, 3); 1.7 (qn, J = 7.2 z); 13 C NMR (CDCl 3, 1 Mz): δ 28.5, 194.5, 149.4, 134.5, 42.8, 29.9, 26.9, 21.7; RMS (ESI+) calc for [C Na] , obsd (S)-2-(2,2-dimethyl-[1,3]dioxolan-4-yl)-propenal (29). The reaction was carried out following the General Procedure B to yield 126 mg (8%) of 29 as a colorless oil. [α] 2 D +21. (c = 1., CCl 3 ); IR 3435, 2987, 1687, 1372, 1217, 1155, 167, 852 cm -1 ; 1 NMR (CDCl 3, 4 Mz): δ 9.57 (s, 1); 6.59 (dd, 1, J = 1.4 z); 6.11 (dd, 1, J = 2 x 1.4 z); 4.83 (dddd, 1, J = 2 x 1.4, 2 x 6.8 z); 4.34 (dd, 1, J = 6.8, 8.4 z); 3.49 (dd, 1, J = 6.8, 8.4 z); 1.42 (s, 3); 1.39 (s, 3); 13 C NMR (CDCl 3, 1 Mz): δ 193.3, 149., 133.2, 19.2, 72.5, 69.5, 26.2, 25.3; RMS (ESI+) calc for [C Na] , obsd Nakahira,.; Ryu, I.; Ikebe, M.; ku, Y.; gawa, A.; Kambe, N.; Sonoda, N.; Murai, S. J. rg. Chem. 1992, 57, Myers, A. G.; Dragovich, P. S.; Kuox, E. Y. J. Am. Chem. Soc. 1992, 114,

7 S7 Bn 31 3-benzyloxy-2-methylenepropanal (31). The reaction was carried out following the general General Procedure B to yield 156 mg (89%) of 31 as a pale yellow oil. IR 3436, 388, 364, 331, 2863, 1954, 1693, 1496, 1454, 1368, 111, 96, 739 cm -1 ; 1 NMR (CDCl 3, 4 Mz): δ 9.6 (s, 1); (m, 5); 6.58 (s, 1); 6.16 (d, 1, J = 1.6 z); 4.59 (s, 2), 4.26 (t, 2, J = 1.6 z); 13 C NMR (CDCl 3, 1 Mz): δ 193.3, 146.7, 137.8, 134., 128.4, 127.7, 127.6, 73., 65.8; RMS (ESI+) calc for [C Na] , obsd Bn 33 2-Benzyloxyprop-2-enal/2-benzyloxy-2-methylene-ethanal (33). The reaction was carried out following the General Procedure A to yield 161 mg (98%) of 33 or General Procedure B to yield 13 mg (64%) of 33 as a pale yellow oil. Data obtained correlates with literature data. 9 1 NMR (CDCl 3, 4 Mz): δ 9.3 (s, 1); (m, 5); 5.25 (d, 1, J = 3.); 5.14 (d, 1, J = 3.); 4.93 (s, 2); 13 C NMR (CDCl 3, 1 Mz): δ 188., 158.1, 135.5, 128.6, 128.1, 127.3, 13.8, 7.1. N Boc 35 Tert-Butyl-1-formylvinylcarbamate / N-Boc-dehydroalaninal (35): The reaction was carried out following the General Procedure A to yield 146 mg (85%) of 35 or General Procedure B to yield 147 mg (86%) of 35 as a pale yellow oil. Data obtained correlates with literature data: 1 1 NMR (CDCl 3, 4 Mz): δ 9.12 (s, 1); 6.97 (s, 1); 6.7 (s, 1); 5.35 (s, 1); 1.46 (s, 9) 13 C NMR (CDCl 3, 1 Mz): δ 188.6, 152.3, 14.2, 114.8, 81., on, Y.-S.; Chang, F.-J.; Lu, L.; Lin, W.-C. Tetrahedron 1998, 54, Chem. Pharm. Bull., 1996, 44,

8 e33.1as8 Copies of 1 and 13 C Spectra 14a

9 S9 TBDPS S ae164a ae164a

10 S1 TBDPS ae165a ae165a

11 S ae3126b ae3126b

12 S12 N N C ae267a ae267a

13 S ae44a ae44a

14 e39.19as e a

15 S ae315ppm (t1) ae315

16 e3138s16 Ph a

17 S17 Ph ae313ppm (t1) ae313

18 S18 TBDPS ae ae3134

19 S ae ae43

20 S ae ae3131

21 S21 Bn ae461a ae461a

22 S22 Bn ae ae3115

23 S23 N Boc ae312a ae312a