Article
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 22 7245
2H), 5.38-5.5 (br s, 1H), 5.6-5.8 (br s, 1H). Anal. (C7H15NO)
C, H, N. Yield 65%.
2-Ethylbutanamide (10). White crystals. Mp 113-115 °C.
MS-EI, m/z (%): 100 (Mþ - 15, 7), 87 (85), 86 (44), 72 (100),
55 (25). 1H NMR (300 MHz, CDCl3, δ TMS): 0.88-1.0 (t, J =
9, 6H), 1.4-1.68 (br m, 4H), 1.9-2.4 (br m, 1H), 5.4-5.6 (br s,
1H), 5.8-6.0 (br s, 1H). Anal. (C6H13NO) C, H, N. Yield 60%.
2-Methylbutanamide (11). Silver crystals. Mp 112-114 °C.
MS-EI, m/z (%): 86 (Mþ - 15, 26), 73 (100), 72 (17), 57 (30), 55
(12). 1H NMR (300 MHz, CDCl3, δ TMS): 0.9-1.0 (t, J = 9,
3H), 1.14-1.22 (d, J = 6.3, 3H), 1.38-1.54 (m, 1H), 1.6-1.78
(m, 1H), 2.12-2.28 (m, 1H), 5.4-5.8 (br s, 2H). Anal.
(C5H11NO) C, H, N. Yield 65%.
3,3-Dimethylbutanamide (12). Silver crystals. Mp 135-
137 °C. MS-EI, m/z (%): 115 (Mþ, 0.43), 59 (100), 58 (8), 57
(33), 55 (4). 1H NMR (300 MHz, CDCl3, δ TMS): 1.0 (s, 9H),
2.04 (s, 2H), 1.9-2.4 (br m, 1H), 5.4-5.6 (br s, 1H), 5.8-6.0 (br
s, 1H). Anal. (C6H13NO) C, H, N. Yield 60%.
2,3-Dimethylbutanamide (9). Silver powder. Mp 131-133 °C.
MS-EI, m/z (%): 115 (Mþ, 0.35), 100 (15), 73 (100), 72 (24), 55
(14). 1H NMR (300 MHz, CDCl3, δ TMS): 0.95 (dt, J = 6.6, 8.1
6H), 1.12 (d, J = 6.9 3H), 1.76-1.9 (m, 1H), 1.94-2.04 (m, 1H),
5.4-5.7 (br s, 1H), 5.7-6.0 (br s, 1H). Anal. (C6H13NO) C, H,
N. Yield 62%.
2-Ethyl-4-methylpentanamide (15). White needles. Mp 86-
88 °C. MS-EI, m/z (%): 128 (Mþ - 15, 2.5), 100 (19), 87 (51), 72
(100), 57 (27). 1H NMR (300 MHz, CDCl3, δ TMS): 0.86-1.0
(m, 9H), 1.18-1.3 (m, 1H), 1.4-1.66 (br m, 4H), 2.1-2.2 (m,
1H), 5.38-5.62 (br d, J = 36, 2H). Anal. (C8H17NO) C, H, N.
Yield 65%.
2-Ethyl-3,3,-dimethylbutanamide (16). White powder. Mp
136-138 °C. MS-EI, m/z (%): 128 (Mþ - 15, 1), 87 (71), 72
1
(100), 57 (23), 55 (11). H NMR (300 MHz, CDCl3, δ TMS):
Pivalamide (13). Silver crystals. Mp 156-158 °C. MS-EI, m/z
(%): 101 (Mþ, 65), 100 (84), 86 (52), 85 (60), 68 (100). 1H NMR
(300 MHz, CDCl3, δ TMS): 1.0 (s, 9H), 5.4-5.8 (br s, 2H). Anal.
(C5H11NO) C, H, N. Yield 65%.
0.91 (t, J = 7.2, 3H), 0.98 (s, 9H), 1.46-1.7 (br m, 2H),
1.72-1.79 (dd, J = 97.5, 3, 1H), 5.3-5.6 (br d, J = 36, 1H).
Anal. (C8H17NO) C, H, N. Yield 56%.
2-Isopropyl-4-methylpentanamide (17). White powder. Mp
108-110 °C. MS-EI, m/z (%): 142 (Mþ - 15, 2), 115 (21), 101
2-Ethylhexanamide (14). White crystals. Mp 79-80 °C. MS-
EI, m/z (%): 143 (Mþ, 0.2), 115 (11), 87 (58), 72 (100), 57 (25). 1H
NMR (300 MHz, CDCl3, δ TMS): 0.8-0.98 (m, 5H), 1.2-1.38
(m, 4H), 1.4-1.68 (m, 4H), 1.96-2.8 (m, 1H), 5.36-5.7 (ds, 2H).
Anal. (C8H17NO) C, H, N. Yield 95%.
1
(28), 86 (67), 72 (100). H NMR (300 MHz, CDCl3, δ TMS):
0.89 (t, J = 6.6, 6H), 0.94-0.98 (dd, J = 6.6, 1.2 6H), 1.18-1.3
(m, 1H), 1.5-1.64 (br m, 2H), 1.7-1.82 (m, 1H), 1.88-1.96 (m,
1H), 5.38-5.45 (br s, 1H), 5.6-5.7 (br s, 1H). Anal. (C9H19NO)
C, H, N. Yield 50%.
General Procedure for the Synthesis of Compounds 23-27.
The corresponding acids were prepared according to the above-
mentioned procedure for compounds 2-5 and 15-22. The
corresponding acids (propyl isopropylacetic acid, diisopropyla-
cetic acid, valnoctic acid, ethyl butylacetic acid, and tert-buty-
lacetic acid, corresponding to compounds 23-27, respectively)
were chlorinated with thionyl chloride according to a previously
published method.59 The obtained acyl chloride (33 mmol) was
dissolved in 10 mL of dry DCM and 5 mL of a 41% methylamine
solution in water, and was left to stir for 2 h. The reaction
mixture was extracted with ethyl acetate (3 ꢀ 30 mL), the
organic phase was washed with 2 N HCl, dried over MgSO4,
and evaporated, and the product was recrystallized with ethyl
acetate/petroleum ether (3:1) to obtain the desired product.
2-Ethyl-N,3-dimethylpentanamide (23). White powder. Mp
69-72 °C. MS-EI, m/z (%): 157 (Mþ, 0.33), 101 (72), 86 (100),
58 (42), 57 (36). 1H NMR (300 MHz, CDCl3, δ TMS): 0.76-0.94
(m, 9H), 1.0-1.2 (m, 2H), 1.4-1.62 (br m, 3H), 1.7-1.8 (m, 1H),
2.79 (d, J = 4.8, 3H), 5.6-5.8 (br s, 1H). Anal. (C9H19NO) C, H,
N. Yield 75%.
4-Methyl-2-propylpentanamide (18). White “needle-like” powder.
Mp 120-121 °C. MS-EI, m/z (%): 142 (Mþ - 15, 1), 114 (12), 101
1
(17), 72 (100), 55 (13). H NMR (300 MHz, CDCl3, δ TMS):
0.8-0.96 (m, 9H), 1.16-1.42 (br m, 4H), 1.5-1.68 (br m, 3H),
2.18-2.28 (m, 1H), 5.4-5.6 (br s, 1H), 5.7-5.9 (br s, 1H). Anal.
(C9H19NO) C, H, N. Yield 67%.
2-Isopropyl-3-methylpentanamide (19). White “cotton-like”
crystals. Mp 105-107 °C. MS-EI, m/z (%): 128 (Mþ - 29,
0.4), 115 (8), 101 (24), 86 (100), 69 (11). H NMR (300 MHz,
1
CDCl3, δ TMS): 0.84-1.0 (m, 12H), 1.00-1.3 (br m, 1H),
1.36-1.62 (br dm, 1H), 1.66-1.82 (m, 2H), 1.94-2.1 (br m,
1H), 5.4-5.6 (br s, 1H), 5.7-5.9 (br s, 1H). Anal. (C9H19NO) C,
H, N. Yield 35%.
3-Methyl-2-propylpentanamide (20). White “needle-like” pow-
der. Mp 120-121 °C. MS-EI, m/z (%): 142 (Mþ - 15, 0.35), 101
1
(35), 86 (32), 72 (100), 55 (16). H NMR (300 MHz, CDCl3, δ
TMS): 0.8-0.96 (m, 9H), 1.06-1.3 (br m, 2H), 1.3-1.64 (br m,
5H), 0.9-2.0 (m, 1H), 5.4-5.54 (br s, 1H), 5.7-5.9 (br s, 1H).
Anal. (C9H19NO) C, H, N. Yield 45%.
2-Isopropyl-N,3-dimethylbutanamide (24). White needles. Mp
2-Isopropyl-3,3-dimethylbutanamide (21). White powder. Mp
128-130 °C. MS-EI, m/z (%): 142 (Mþ - 15, 0.68), 101 (36), 100
102-104 °C. MS-EI, m/z (%): 157 (Mþ, 0.14), 115 (39), 100
1
(100), 58 (24), 57 (25). H NMR (300 MHz, CDCl3, δ TMS):
1
(30), 86 (100), 57 (22). H NMR (300 MHz, CDCl3, δ TMS):
0.86-0.96 (dd, J = 6.75, 12H), 1.549 (t, J = 15, 1H), 1.9-2.6
(m, 2H), 2.77 (d, J = 4.8, 3H), 5.6 (br s, 1H). Anal. (C9H19NO)
C, H, N. Yield 73%.
0.9-1.1 (m, 15H), 1.7 (d, J = 6, 1H) 2.0-2.1 (m, 1H), 5.3-5.5
(br s, 1H). Anal. (C9H19NO) C, H, N. Yield 45%.
2-tert-Butylpentanamide (22). White powder. Mp 118-
119 °C. MS-EI, m/z (%): 142 (Mþ - 15, 0.88), 101 (35), 100 (9),
72 (100), 57 (21). 1H NMR (300 MHz, CDCl3, δ TMS): 0.86-0.94
(t, 3H), 0.94-1.0 (s, 9H), 1.1-1.22 (m, 1H), 1.3-1.44 (m, 2H),
1.56-1.78 (m, 1H), 1.8-1.86 (dd, J = 12, 1H), 5.4-5.6 (br s,
1H), 5.8-6.0 (br s, 1H). Anal. (C9H19NO) C, H, N. Yield 40%.
General Procedure for the Syntheis of Compounds 10-14. The
corresponding acid (ethylbutyric acid, methylbutyic acid, tert-
butylacetic acid, and pivalic acid corresponding to compounds
6-9, respectively) was chlorinated with thionyl chloride accord-
ing to a previously published method.59 The acyl chloride
(44 mmol) obtained was dissolved in 20 mL of dry ACN
and was added dropwise to a 50 mL ammonium hydroxide
solution (28-30% in water) at 0 °C and then left to stir for 2 h.
Reaction mixture was extracted with ethyl acetate (3 ꢀ 30 mL),
the organic phase was washed with 2 N NaOH, dried over
MgSO4, and evaporated, and the oily product was recrystallized
with ethyl acetate petroleum ether (3:1) to obtain the desired
product.
2-Isopropyl-N-methylpentanamide (25). White powder. Mp
97-99 °C. MS-EI, m/z (%): 157 (Mþ, 0.40), 115 (56), 100 (53),
86 (100), 58 (45). 1H NMR (300 MHz, CDCl3, δ TMS): 0.8-0.96
(m, 9H), 1.06-1.26 (br m, 2H), 1.4-1.6 (br m, 2H), 1.6-1.82 (br
m, 2H), 2.8 (d, J = 4.5, 3H), 5.44-5.6 (br s, 1H). Anal.
(C9H19NO) C, H, N. Yield 70%.
2-Ethyl-N-methylhexanamide (26). White powder. Mp 73-
76 °C. MS-EI, m/z (%): 157 (Mþ, 0.74), 101 (59), 86 (100), 58
(53), 57 (37). 1H NMR (300 MHz, CDCl3, δ TMS): 0.86-0.96
(dd, J = 6.75, 12H), 1.549 (t, J = 15, 1H), 1.9-2.6 (m, 2H), 2.77
(d, J = 4.8, 3H), 5.6 (br s, 1H). Anal. (C9H19NO) C, H, N. Yield
70%.
N,3,3-Trimethylbutanamide (27). White needles. Mp 73-
75 °C. MS-EI, m/z (%): 129 (Mþ, 0.33), 114 (2.2), 73 (100), 58
(42), 57 (42). 1H NMR (300 MHz, CDCl3, δ TMS): 1.0 (s,
9H), 2.04 (s, 2H), 2.8 (d, J = 4.5, 3H), 5.4 (br s, 1H). Anal.
(C7H16NO) C, H, N. Yield 70%.
General Procedure for the Synthesis of Compounds 28-34.
The chemical synthesis for compounds 28-34 was identical to