5776 Journal of Medicinal Chemistry, 2010, Vol. 53, No. 15
Solorzano et al.
(R)-(2-Oxo-3-oxetanyl)carbamic Acid tert-Butyl Ester (3b).
White solid; mp 121-122 ꢀC dec (CHCl3/hexane). [R]20D þ26.7
(c 1, MeCN). MS (EI) m/z: 188 (Mþ), 57 (100). 1H NMR
(CDCl3) δ: 1.47 (s, 9H), 4.41-4.51 (m, 2H), 4.85 (br s, 1H),
5.06-5.19 (m, 1H) ppm. IR (Nujol) νmax: 3357, 1844, 1717, 1683
Hz), 2.70 (q, 2H, J = 7.5 Hz), 4.50-4.63 (m, 2H), 5.45-5.55 (m,
1H), 7.31-7.36 (m, 2H), 7.82-7.89 (m, 2H), 8.54 (br s, 1H) ppm.
13C NMR [CD3C(O)CD3] δ: 14.8, 28.4, 58.8, 65.1, 127.4, 128.0,
130.6, 148.6, 166.6, 169.3 ppm. IR (Nujol) νmax: 3298, 1832, 1642
cm-1. Anal. (C12H13NO3) C, H, N.
cm-1
.
(S)-N-(2-Oxo-3-oxetanyl)-1-naphthamide (7i). Off-white
crystals. Yield: 67% (0.161 g); mp 124-126 ꢀC [CH3C(O)-
(S)-2-Oxo-3-oxetanylammonium Toluene-4-sulfonate (4a).28
White solid; mp and 1H NMR are according to the literature.28
(R)-2-Oxo-3-oxetanylammonium Toluene-4-sulfonate (4b).29
White solid. 1H NMR is according to the literature.29
CH3/petroleum ether]. [R]20 -32.2 (c 0.45, MeCN). MS (EI)
D
m/z: 241 (Mþ), 127 (100). 1H NMR [CD3C(O)CD3] δ: 4.63 (dd,
1H, J = 4.6, 6.7 Hz), 4.74 (t, 1H, J = 4.7 Hz), 5.56-5.65 (m,
1H), 7.51-7.62 (m, 3H), 7.78 (dd, 1H, J = 1.3, 7.1 Hz), 7.95-
8.08 (m, 2H), 8.39-8.44 (m, 1H), 8.55 (br s, 1H) ppm. 13C NMR
[CD3C(O)CD3] δ: 58.9, 65.2, 124.7, 125.5, 125.6, 126.4, 127.0,
128.3, 130.3, 130.9, 132.9, 133.8, 169.1, 169.2 ppm. IR (Nujol)
General Procedure for the Synthesis of Amides 7a,b,d-f,i,j,
8a,j. To a stirred mixture of 4a (0.260 g, 1 mmol) in dry CH2Cl2
(4 mL), at 0 ꢀC and under N2 atmosphere, Et3N (0.304 g,
0.42 mL, 3 mmol) and the suitable acyl chloride 6a,b,d-f,i,j
(1.5 mmol) were added. The mixture was stirred at 0 ꢀC for 0.5 h
and at room temperature for 2 h and then concentrated. Purifi-
cation of the residue by column chromatography (cyclohexane/
EtOAc 1:1 for 7d-f,i,j, 8j; 1:1 to 3:7 for 7a,8a; 4:6 for 7b) and
recrystallization gave 7a,b,d-f,i,j, 8a,j.
ν
max: 3291, 1842, 1637 cm-1. Anal. (C14H11NO3) C, H, N.
(S)-N-(2-Oxo-3-oxetanyl)-2-naphthamide (7j). White solid.
Yield: 47% (0.113 g); mp 193-195 ꢀC, decomposition and
shrinkage starting from 180 ꢀC, sealed capillary tube [CH3C(O)-
CH3/petroleum ether]. [R]20D -17 (c 0.1, MeCN). MS (ESI) m/z:
240.5 [M - H]þ. 1H NMR [CD3C(O)CD3] δ: 4.56-4.68 (m, 2H),
5.54-5.64 (m, 1H), 7.56-7.69 (m, 2H), 7.96-8.06 (m, 4H), 8.52
(d, 1H, J = 1 Hz), 8.80 (br d, 1H) ppm. 13C NMR [CD3C(O)-
CD3] δ: 58.8, 65.1, 123.8, 126.9, 127.7, 127.9, 128.3, 129.0, 130.5,
132.6, 135.0, 166.8, 169.3 ppm. IR (Nujol) νmax: 3270, 1825, 1647
cm-1. Anal. (C14H11NO3) C, H, N.
(S)-N-(2-Oxo-3-oxetanyl)-3-phenylpropionamide (7a).23 White
solid. Yield: 60% (0.132 g); mp 104-106 ꢀC [CH3C(O)CH3/
D
petroleum ether]. [R]20 -13 (c 0.5, MeOH); ee > 98% [Chiral
HPLC: AD-H; flow: 1 mL/min; λmax: 220 nm; eluent: n-hexane/2-
propanol 85:15; tS: 8.9 min]. MS (EI) m/z: 219 (Mþ), 91 (100). 1H
NMR (CDCl3) δ:2.57(t, 2H, J= 7.5 Hz), 2.99 (t, 2H, J=7.5Hz),
4.34 (t, 1H, J = 4.9 Hz), 4.43 (dd, 1H, J1 = 5.2 Hz, J2 = 6.5),
5.10-5.19 (m, 1H), 5.97 (br d, 1H), 7.18-7.36 (m, 5H) ppm. 13C
NMR (CDCl3) δ: 31.2, 37.7, 58.4, 66.1, 126.5, 128.3, 128.7, 140.2,
168.4, 172.5 ppm. IR (Nujol) νmax: 3333, 1832, 1652 cm-1. Anal.
(C12H13NO3) C, H, N.
(R)-N-(2-Oxo-3-oxetanyl)-2-naphthamide (8j). White solid.
Yield: 20% (0.048 g); mp 195 ꢀC, decomposition and shrinkage
starting from 175 ꢀC [CH3C(O)CH3/petroleum ether]. [R]20
D
þ17 (c 0.1, MeCN). MS (EI) m/z: 241 (Mþ), 141 (100). 1H NMR
[CD3C(O)CD3] δ: 4.56-4.68 (m, 2H), 5.54-5.64 (m, 1H),
7.57-7.68 (m, 2H), 7.96-8.06 (m, 4H), 8.52 (d, 1H, J = 1
Hz), 8.80 (br d, 1H) ppm. 13C NMR [CD3C(O)CD3] δ: 58.8,
65.1, 123.8, 126.9, 127.7, 127.9, 128.3, 129.0, 130.5, 132.6, 135.0,
166.8, 169.3 ppm. IR (Nujol) νmax: 3262, 1824, 1645 cm-1. Anal.
(C14H11NO3) C, H, N.
(R)-N-(2-Oxo-3-oxetanyl)-3-phenylpropionamide (8a). White
solid. Yield: 33% (0.072 g); mp 100-103 ꢀC [CH3C(O)CH3/
D
petroleum ether]. [R]20 þ11 (c 1, MeOH); ee > 98% (experi-
mental conditions are identical with those for 7a; tR: 12.3 min).
MS (EI) m/z: 219 (Mþ), 91 (100). 1H NMR (CDCl3) δ: 2.57 (t,
2H, J = 7.5 Hz), 2.99 (t, 2H, J = 7.5 Hz), 4.34 (t, 1H, J = 4.9
Hz), 4.43 (dd, 1H, J1 = 5.2 Hz, J2 = 6.5), 5.08-5.18 (m, 1H),
6.11 (br d, 1H), 7.17-7.34 (m, 5H) ppm. 13C NMR (CDCl3) δ:
31.2, 37.7, 58.4, 66.1, 126.5, 128.3, 128.7, 140.2, 168.4, 172.5
ppm. IR (Nujol) νmax: 3349, 1845, 1646 cm-1. Anal. (C12H13-
NO3) C, H, N.
General Procedure for the Synthesis of Amides 7c,g,h,k-n. To
a stirred solution of the suitable acid 9c,g,h,k-n (2 mmol) in dry
CH2Cl2 (5 mL), at 0 ꢀC and under N2 atmosphere, (COCl)2
(0.381 g, 0.26 mL, 3 mmol) and a catalytic amount of DMF were
added. After gas evolution, the mixture was stirred at room
temperature for 3 h (16 h, 7l; 6 h, 7m) and concentrated; the
resulting crude acid chloride was used as such in the next step. A
mixture of the acid chloride (2 mmol), 4a (0.337 g, 1.3 mmol),
Et3N (6.7 mmol, 7c,g; 8 mmol, 7 h,k; 5.5 mmol, 7n; 3.6 mmol, 7l,
m) (a catalytic amount of 4-dimethylaminopyridine in the case
of 7c,g is necessary) in dry CH2Cl2 (8 mL, 7c,g,k; 4 mL, 7l,m) or
dry THF (20 mL, 7h; 8 mL, 7n) was stirred at 0 ꢀC for 0.5 h and at
room temperature for 3 h under N2 atmosphere and then
concentrated. In the case of 7m, further amounts of 4a (0.168
g, 0.65 mmol) and Et3N (0.101 g, 0.14 mL, 1 mmol) were added
and the mixture was stirred for further 3 h and then concen-
trated. Purification of the residue by column chromatography
(cyclohexane/EtOAc 1:1 for 7c,g,h,n; CH2Cl2/EtOAc 9:1 for
7k-m) and recrystallization gave 7c,g,h,k-n.
(S)-N-(2-Oxo-3-oxetanyl)-2-phenylacetamide (7b).31 White
solid. Yield: 10% (0.021 g); mp 112-114 ꢀC dec (CHCl3/hexane)
(lit. 122-123 ꢀC).31 [R]20D -14.1 (c 0.34, MeOH). MS (EI) m/z:
205 (Mþ), 91 (100). 1H NMR (CDCl3) δ: 3.67 (s, 2H), 4.41-4.46
(m, 2H), 5.06-5.16 (m, 1H), 6.00 (br s, 1H), 7.25-7.43 (m, 5H)
ppm. 13C NMR (CDCl3) δ: 43.1, 58.5, 65.9, 127.9, 129.3, 129.5,
133.6, 168.2, 171.3 ppm. IR (Nujol) νmax: 3321, 1845, 1814, 1651
cm-1. Anal. (C11H11NO3) C, H, N.
(S)-N-(2-Oxo-3-oxetanyl)heptanamide (7d). White fluffy
crystals. Yield: 49% (0.097 g); mp 103-105 ꢀC (CHCl3/n-
hexane). [R]20 -16.0 (c 0.45, MeOH). MS (ESI) m/z: 200.5
D
[M þ H]þ. 1H NMR [CD3C(O)CD3] δ: 0.88 (t, 3H, J = 6.5 Hz),
1.25-1.36 (m, 6H), 1.52-1.67 (m, 2H), 2.24 (t, 2H, J = 7.4 Hz),
4.43 (d, 2H, J = 5.8 Hz), 5.21-5.31 (m, 1H), 7.86 (br s, 1H) ppm.
13C NMR [CD3C(O)CD3] δ: 13.4, 22.2, 25.1, 28.6, 31.4, 35.1,
58.5, 65.1, 169.3, 172.9 ppm. IR (Nujol) νmax: 3275, 1861, 1648,
1534 cm-1. Anal. (C10H17NO3) C, H, N.
(S)-N-(2-Oxo-3-oxetanyl)-7-phenylheptanamide (7c). White
fluffy solid. Yield: 39% (0.139 g); mp 98-99 ꢀC [CH3C(O)-
CH3/petroleum ether]. [R]20 -16.2 (c 0.5, MeOH). MS (ESI)
D
m/z: 274.6 [M - H]þ. 1H NMR (CDCl3) δ: 1.32-1.39 (m, 4H),
1.55-1.73 (m, 4H), 2.25 (t, 2H, J = 7.5 Hz), 2.61 (t, 2H, J = 7.6
Hz), 4.40-4.50 (m, 2H), 5.15-5.24 (m, 1H), 6.14 (br d, 1H, J =
7.5 Hz), 7.14-7.33 (m, 5H) ppm. 13C NMR (CDCl3) δ: 25.1,
28.8, 29.0, 31.2, 35.8, 58.4, 66.3, 125.6, 128.2, 128.4, 142.6, 168.5,
173.3 ppm. IR (Nujol) νmax: 3331, 1853, 1833, 1649 cm-1. Anal.
(C16H21NO3) C, H, N.
(S)-N-(2-Oxo-3-oxetanyl)benzamide (7e). White crystals.
Yield: 41% (0.078 g); mp 113-114 ꢀC [CH3C(O)CH3/petroleum
ether]. [R]20D -28.4 (c 0.5, MeCN). MS (EI) m/z: 191 (Mþ), 77
(100). 1H NMR [CD3C(O)CD3] δ: 4.52-4.63 (m, 2H),
5.47-5.57 (m, 1H), 7.46-7.60 (m, 3H), 7.91-7.97 (m, 2H),
8.63 (br s, 1H) ppm. 13C NMR [CD3C(O)CD3] δ: 58.8, 65.1,
127.3, 128.5, 131.9, 133.2, 166.7, 169.2 ppm. IR (Nujol) νmax
:
(S)-N-(2-Oxo-3-oxetanyl)biphenyl-3-carboxamide (7g). White
fluffy solid. Yield: 68% (0.236 g); mp 116-117 ꢀC [CH3C(O)-
CH3/petroleum ether]. [R]20D -20 (c 0.55, MeCN). MS (ESI) m/z:
268.0 [M þ H]þ. 1H NMR [CD3C(O)CD3] δ: 4.54-4.66 (m, 2H),
5.51-5.61 (m, 1H), 7.37-7.74 (m, 6H), 7.86-7.96 (m, 2H), 8.20-
8.22 (m, 1H), 8.75 (br s, 1H) ppm. 13C NMR [CD3C(O)CD3]
3272, 1849, 1827, 1647 cm-1. Anal. (C10H9NO3) C, H, N.
(S)-4-Ethyl-N-(2-oxo-3-oxetanyl)benzamide (7f). White fluffy
crystals. Yield: 40% (0.088 g); mp 118-119 ꢀC [CH3C(O)CH3/
petroleum ether]. [R]20D -9.5 (c 0.6, MeOH). MS (EI) m/z: 219
(Mþ), 133 (100). 1H NMR [CD3C(O)CD3] δ: 1.23 (t, 3H, J = 7.5