Advanced
A New Synthesis of N-Methoxy-N-methylamides from S-2-Pyridyl Thiocarbamate and Grignard Reagents
A New Synthesis of N-Methoxy-N-methylamides from S-2-Pyridyl Thiocarbamate and Grignard Reagents
Journal of the Korean Chemical Society. 2005. Dec, 49(6): 609-612
Copyright © 2005, The Korean Chemical Society
  • Received : September 20, 2005
  • Published : December 20, 2005
Download
PDF
e-PUB
PubReader
PPT
Export by style
Article
Author
Metrics
Cited by
TagCloud
About the Authors
재인 이
혜진 정

Abstract
Keywords
EXPERIMENTAL
- Preparation of S-2-pyridyl thiocarbamate (1).
To a solution of S,S-di(2-pyridyl)dithiocarbonate (1.24 g, 5.0 mmol) in dichloromethane (20 mL) was added N , O -dimethylhydroxylamine hydrochloride (487.8 mg, 5.0 mmol) and triethylamine (697 μL, 5.0 mmol) at 0 ℃. After being stirred for 1 h, the mixture was poured into brine (40 mL) and extracted with dichloromethane (3×25 mL). The combined organic phases were dried over MgSO 4 , filtered, and concentrated in vacuo . The residue was purified by silica gel column chromatography using 50% EtOAc/ n -hexane as an eluant to give 1 (902.4 mg, 91%). 1 H NMR (300 MHz, CDCl 3 ) δ 8.60-8.63 (m, 1H), 7.70-7.72 (m, 2H), 7.25-7.30 (m, 1H), 3.83 (s, 3H), 3.24 (s, 3H); 13 C NMR (75 MHz, CDCl 3 ) δ 169.5, 152.6, 150.5, 137.3, 131.2, 123.7, 62.4, 34.8; FT-IR (film) 3050, 2977, 2937, 1672 (C=O), 1573, 1451, 1341, 1175, 1073, 985, 771 cm -1 ; Ms m/z (%) 198 (M + , 1), 167 (47), 138 (58), 110 (14), 78 (C 5 H 4 N + , 100).
Preparation of N-methoxy-N-methyl-p-methoxybenzamide (4g) . To a solution of 1 (396.7 mg, 2.0 mmol) in THF (6 mL) cooled to 0 ℃ was slowly added p -methoxyphenyl-magnesium bromide (0.25 M in THF, 8.0 mL, 2.0 mmol) over 10 min under argon atmosphere. After being stirred for 10 min, the mixture was quenched with sat. NH 4 Cl (3 mL) and THF was evaporated in vacuo . The mixture was poured into sat. NH 4 Cl (30 mL) and extracted with dichloromethane (3×25 mL). The combined organic phases were dried over MgSO 4 , filtered, and evaporated to dryness in vacuo . The crude product was purified by silica gel column chromatography using 30% EtOAc/ n -hexane as an eluant to give 4g (351.4 mg, 90%) as a colorless liquid. 1 H NMR (300 MHz, CDCl 3 ) δ 7.73 (d, J =8.7 Hz, 2H), 6.90 (d, J =8.7 Hz, 2H), 3.83 (s, 3H), 3.56 (s, 3H), 3.35 (s, 3H); FT-IR (film) 3055, 2966, 2935, 1637 (C=O), 1607, 1374, 1254, 1029, 842 cm -1 ; Ms m/z (%) 195 (M + , 1), 136 (10), 135 ( p -CH 3 O-C 6 H 4 CO + , 100), 92 (12), 77 (14).
N-Methoxy-N-methylnonamide (4a): 1 H NMR (300 MHz, CDCl 3 ) δ 3.68 (s, 3H), 3.18 (s, 3H), 2.41 (t, J =7.6 Hz, 2H), 1.56-1.68 (m, 2H), 1.19-1.38 (m, 10H), 0.88 (t, J =6.7 Hz, 3H); FT-IR (film) 2928, 2855, 1668 (C=O), 1465, 1385, 1179, 1121 cm -1 ; Ms m/z (%) 141 [CH 3 (CH 2 ) 7 CO + , 100], 71 (66), 61 (71), 57 (72), 55 (30).
N-Methoxy-N-methylcyclohexanecarboxamide (4b): 1 H NMR (300 MHz, CDCl 3 ) δ 3.70 (s, 3H), 3.18 (s, 3H), 2.64-2.72 (m, 1H), 1.73-1.81 (m, 5H), 1.46-1.50 (m, 2H), 1.25-1.28 (m, 3H); FT-IR (film) 2931, 2855, 1658 (C=O), 1449, 1177, 1116, 994 cm -1 ; Ms m/z (%) 171 (M + , 2), 111 (39), 83 ( c -C 6 H 11 + , 100), 55 (44).
N-Methoxy-N-methylphenylpropiolamide (4c): M.p. 37 ℃; 1 H NMR (300 MHz, CDCl 3 ) δ 7.56-7.64 (m, 2H), 7.34-7.44 (m, 3H), 3.85 (s, 3H), 3.30 (s, 3H); FT-IR (KBr) 3063, 2974, 2936, 2219, 1642 (C=O), 1382, 1101, 759, 690 cm -1 ; Ms m/z (%) 189 (M + , 2), 130 (14), 129 (C 6 H 5 C 2 CO + , 100), 101 (6), 75 (10).
N-Methoxy-N-methylbenzamide (4d): 1 H NMR (300 MHz, CDCl 3 ) δ 7.65-7.68 (m, 2H), 7.39-7.45 (m, 3H), 3.55 (s, 3H), 3.36 (s, 3H); FT-IR (film) 3060, 2971, 2936, 1644 (C=O), 1380, 1214, 788, 707 cm -1 ; Ms m/z (%) 165 (M + , 2), 106 (8), 105 (C 6 H 5 CO + , 100), 77 (50).
N-Methoxy-N-methyl-o-methylbenzamide (4e): 1 H NMR (300 MHz, CDCl 3 ) δ 7.17-7.32 (m, 4H), 3.53 (s, 3H), 3.30 (s, 3H), 2.34 (s, 3H); FT-IR (film) 3063, 2970, 2935, 1650 (C=O), 1380, 1063, 773 cm -1 ; Ms m/z (%) 179 (M + , 2), 120 (10), 119 ( o -CH 3 -C 6 H 4 CO + , 100), 91 (53), 65 (14).
N-Methoxy-N-methyl-p-methylbenzamide (4f): 1 H NMR (300 MHz, CDCl 3 ) δ 7.59 (d, J =8.0 Hz, 2H), 7.19 (d, J =8.0 Hz, 2H), 3.55 (s, 3H), 3.34 (s, 3H), 2.38 (s, 3H); FT-IR (film) 3029, 2967, 2934, 1643 (C=O), 1613, 1377, 1181, 830 cm -1 ; Ms m/z (%) 179 (M + , 2), 120 (10), 119 ( p -CH 3 -C 6 H 4 CO + , 100), 91 (44).
N-Methoxy-N-methyl-p-chlorobenzamide (4h): 1 H NMR (300 MHz, CDCl 3 ) δ 7.65 (d, J =6.8 Hz, 2H), 7.27 (d, J =6.8 Hz, 2H), 3.53 (s, 3H), 3.35 (s, 3H); FT-IR (film) 3067, 2971, 2935, 1646 (C=O), 1594, 1380, 1091, 840 cm -1 ; Ms m/z (%) 199 (M + , 2), 141 (34), 139 ( p -Cl-C 6 H 4 CO + , 100), 113 (11), 111 (34), 75 (16).
N-Methoxy-N-methyl-α-naphthamide (4i): M.p. 38 ℃; 1 H NMR (300 MHz, CDCl 3 ) δ 7.86-7.91 (m, 3H), 7.46-7.56 (m, 4H), 3.52 (s, 3H), 3.42 (s, 3H); FT-IR (KBr) 3056, 2971, 2934, 1650 (C=O), 1592, 1374, 1102, 800, 778 cm -1 ; Ms m/z (%) 215 (M + , 8), 156 (13), 155 (C 10 H 7 CO + , 100), 128 (9), 127 (70).
N-Methoxy-N-methyl-2-thiophenecarboxamide (4j): 1 H NMR (300 MHz, CDCl 3 ) δ 7.97 (dd, J 1 =3.8 Hz, J 2 =1.1 Hz, 1H), 7.56 (dd, J 1 =5.0 Hz, J 2 =1.1 Hz, 1H), 7.11 (dd, J 1 =5.0 Hz, J 2 =3.8 Hz, 1H), 3.78 (s, 3H), 3.38 (s, 3H); FT-IR (film) 3096, 2974, 2936, 1633 (C=O), 1423, 1383, 1208, 979, 728 cm -1 ; Ms m/z (%) 171 (M + , 10), 112 (7), 111 (C 4 H 3 SCO + , 100), 83 (8).
RESULTS AND DISCUSSION
S-2-Pyridyl thiocarbamate ( 1 ) was prepared by the addition of N , O -dimethylhydroxylamine hydrochloride ( 3 ) and triethylamine to a solution of S,Sdi(2-pyridyl)dithiocarbonate ( 2 ) in dichloromethane at 0 ℃ ( 1 ). The reaction proceeded smoothly with the selective substitution of 2-thiopyridyl group by 3 within 1 h at 0 ℃. After usual aqueous workup, the condensed residue was purified by silica gel column chromatography using 50% EtOAc/ n -hex-ane as an eluant to give 1 in 91% yield. The reagent 1 could be stored in a refrigerator for several months without any decomposition.
PPT Slide
Lager Image
As shown in 1 , various N -methoxy- N -methylamides were synthesized in high yields (74-91%) by this method. The reaction proceeded smoothly for both aliphatic ( 4a-4c ) and aromatic Grignard reagents ( 4d-4j ). Furthermore, the kind of electron donating ( 4f, 4g ) and electron withdrawing group ( 4h ) in p -substituted phenylmagnesium bromide didn't influence on the selective substitution of 2-thiopyridyl group. However, the reaction of 1 with phenylethynylmagnesium bromide ( 4c ), o -methylphenylmagnesium bromide ( 4e ), and α-naphthylmagnesium bromide ( 4i ) required 1.5 equiv of Grignard reagent due to the decreased nucleophi-licity or steric effect for the high yield formation of the corresponding N -methoxy- N -methylamides.
Preparation ofN-methoxy-N-methylamides from S-2-pyridyl thiocarbamate and Grignard reagentsa
PPT Slide
Lager Image
aThe Grignard reagents were added at 0 ℃ over 10 min. bRMgCl was used. c1.5 equiv was used. dThe reaction was carried out between 0 ℃ and room temperature.
The successful preparation of N -methoxy- N -methylamides ( 4 ) using 1 depends largely on the selective substitution of 2-thiopyridyl group. We anticipated that 2-thiopyridyl group capable of forming 6-membered chelate would be more reactive than N -methoxy- N -methylamino group toward Grignard reagent. Thus, the treatment of 1 with 1 equiv of p -methoxyphenylmagnesium bromide at 0 ℃ over a period of 10 min gave N -methoxy- N -methyl- p -methoxybenzamide ( 4g ) in 90% yield without appreciable side products. The preferential formation of 4 is presumably due to the stability of 6-membered chelate between magnesium atom of Grignard reagent and carbonyl oxygen/ring nitrogen atom of 1 , which dissociates to give 4 after hydrolysis.
In conclusion, the present method provides a new synthesis of N -methoxy- N -methylamides using 1 from alkyl halides in connection with (i) availability of starting material (ii) convenience of one step operation (iii) high yield of 4 and may be utilized in many synthetic applications.
Acknowledgements
We are very grateful to Duksung Women’s University for its financial support (2005).
References
Sibi M. P. 1993 Org. Prep. Proced. Int. 25 15 -    DOI : 10.1080/00304949309457931
Einhorn J. , Einhorn C. , Luche J. L. 1990 Synth. Comm. 20 1105 -    DOI : 10.1080/00397919008052817
Poss M. A. , Reid J. A. 1992 Tetrahedron Lett. 33 1411 -    DOI : 10.1016/S0040-4039(00)91634-4
Brenner-Weiß G. , Giannis A. , Sandhoff K. 1992 Tetrahedron 48 5855 -    DOI : 10.1016/S0040-4020(01)90177-2
Sibi M. P. , Stessman C. C. , Schultz J. A. , Christensen J. W. , Lu J. , Marvin M. 1995 Synth. Comm. 25 1255 -    DOI : 10.1080/00397919508012689
Fehrentz J. A. , Castro B. 1983 Synthesis 676
Wen J. J. , Crews C. M. 1998 Tetrahedron: Asymmetry 9 1855 -    DOI : 10.1016/S0957-4166(98)00183-9
Luca L. D. , Giacomelli G. , Taddei M. 2001 J. Org. Chem. 66 2534 -    DOI : 10.1021/jo015524b
Raghuram T. , Vijaysaradhi S. , Singh I. , Singh J. 1999 Synth. Comm. 29 3215 -    DOI : 10.1080/00397919908085946
Lucet D. , Gall T. L. , Mioskowski C. , Ploux O. , Marquet A. 1996 Tetrahedron: Asymmetry 7 985 -    DOI : 10.1016/0957-4166(96)00098-5
Irako N. , Hamada Y. , Shioiri T. 1992 Tetrahedron 48 7251 -    DOI : 10.1016/S0040-4020(01)88264-8
Woo J. C. S. , Fenster E. , Dake G. R. 2004 J. Org. Chem. 69 8984 -    DOI : 10.1021/jo048385h
Aidhen I. S. , Ahuja J. R. 1992 Tetrahedron Lett. 33 5431 -    DOI : 10.1016/S0040-4039(00)79113-1
Williams J. M. , Jobson R. B. , Yasuda N. , Marchesini G. , Dolling U. H. , Grabowski E. J. J. 1995 Tetrahedron Lett. 36 5461 -
Shimizu T. , Osako K. , Nakata T. 1997 Tetrahedron Lett. 38 2685 -    DOI : 10.1016/S0040-4039(97)00429-2
Davis F. A. , Kasu P. V. N. 1998 Tetrahedron Lett. 39 6135 -    DOI : 10.1016/S0040-4039(98)01296-9
Lee J. I. , Park H. 2001 Bull. Korean Chem. Soc. 22 421 -