A New Synthesis of N-Methoxy-N-methylamides from S-2-Pyridyl Thiocarbamate and Grignard Reagents

S-2-피리딜 싸이오카바메이트와 Grignard 시약으로부터 N-메톡시-N-메틸 아마이드의 새로운 합성

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 MgSO4, 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%). 1H NMR (300 MHz, CDCl3) 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); 13C NMR (75 MHz, CDCl3) 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 (C5H4N+, 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. NH4Cl (3 mL) and THF was evaporated in vacuo. The mixture was poured into sat. NH4Cl (30 mL) and extracted with dichloromethane (3×25 mL). The combined organic phases were dried over MgSO4, 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. 1H NMR (300 MHz, CDCl3) 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-CH3O-C6H4CO+, 100), 92 (12), 77 (14).

N-Methoxy-N-methylnonamide (4a): 1H NMR (300 MHz, CDCl3) 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 [CH3(CH2)7CO+, 100], 71 (66), 61 (71), 57 (72), 55 (30).

N-Methoxy-N-methylcyclohexanecarboxamide (4b): 1H NMR (300 MHz, CDCl3) 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-C6H11+, 100), 55 (44).

N-Methoxy-N-methylphenylpropiolamide (4c): M.p. 37 ℃; 1H NMR (300 MHz, CDCl3) 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 (C6H5C2CO+, 100), 101 (6), 75 (10).

N-Methoxy-N-methylbenzamide (4d): 1H NMR (300 MHz, CDCl3) 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 (C6H5CO+, 100), 77 (50).

N-Methoxy-N-methyl-o-methylbenzamide (4e): 1H NMR (300 MHz, CDCl3) 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-CH3-C6H4CO+, 100), 91 (53), 65 (14).

N-Methoxy-N-methyl-p-methylbenzamide (4f): 1H NMR (300 MHz, CDCl3) 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-CH3-C6H4CO+, 100), 91 (44).

N-Methoxy-N-methyl-p-chlorobenzamide (4h): 1H NMR (300 MHz, CDCl3) 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-C6H4CO+, 100), 113 (11), 111 (34), 75 (16).

N-Methoxy-N-methyl-α-naphthamide (4i): M.p. 38 ℃; 1H NMR (300 MHz, CDCl3) 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 (C10H7CO+, 100), 128 (9), 127 (70).

N-Methoxy-N-methyl-2-thiophenecarboxamide (4j): 1H NMR (300 MHz, CDCl3) δ 7.97 (dd, J1=3.8 Hz, J2=1.1 Hz, 1H), 7.56 (dd, J1=5.0 Hz, J2=1.1 Hz, 1H), 7.11 (dd, J1=5.0 Hz, J2=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 (C4H3SCO+, 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 ℃ (Scheme 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.

Scheme 1

As shown in Table 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.

Table 1aThe 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.