PAPER
One-pot Conversion of t-Butyl Carbamates to Amides with Acyl Halide–Methanol Mixtures
205
N-(Bromoacetyl)glycine Isopropyl Ester (14)
Prepared according to procedure A from 5c (208 mg, 0.96 mmol) to
give 229 mg (100%) of 14 as a colourless oil.
IR (neat): 3281, 3092, 1742, 1667, 1570, 1224 cm–1.
1H NMR (CDCl3): = 7.01 (br s, 1 H, NH), 5.08 (sept, J = 6.3 Hz,
1 H, CH), 4.02 (d, J = 5.2 Hz, 2 H, CH2), 3.90 (s, 2 H, CH2), 1.26
[d, J = 6.3 Hz, 6 H, (CH3)2].
mixture of acetyl chloride (4 equiv), sodium iodide (2
equiv) and methanol (2 equiv) in acetonitrile for 20 min-
utes at room temperature followed by treatment with di-
isopropylethyl amine (4 equiv) for 1 hour at room
temperature
In summary, we have demonstrated that the combination
of acyl halides with methanol is an efficient procedure for
promoting the direct conversion of t-butyl carbamates to
the corresponding amides. This procedure avoids the iso-
lation of the intermediate amines, which are unstable in
some cases. Conditions for the chemoselective conversion
of Boc groups in the presence of Cbz groups, which
should be of use in amine and peptide chemistry, have
also been established.
13C NMR (CDCl3): = 168.8, 165.7, 69.7, 42.2, 28.6, 21.8.
Anal. Calcd for C7H12BrNO3: C, 35.31; H, 5.08; N, 5.88. Found: C,
35.37; H, 5.02; N, 5.88.
N-Tetradecanoylglycine Methyl Ester (15)
Prepared according to procedure B from 5d (200 mg, 1.06 mmol)
and chromatographed on a silica gel column (Et2O–hexanes, 30:70
60:40) to give 197 mg (62%) of 15 as a white powder.
Mp 54 °C.
IR (KBr): 3309, 3075, 1737, 1636, 1548, 1216 cm–1.
Compounds 5a–d were prepared by N-protection of the correspond-
ing amines with di-tert-butyl dicarbonate. 5e was prepared from 3-
aminopropanol by N-protection with di-tert-butyl dicarbonate fol-
lowed by O-acetylation with acetyl chloride. Dipeptide 17 was pre-
pared from glycine methyl ester hydrochloride and N-
hydroxysuccinimidyl ester of N2-Boc-N6-Cbz-L-lysine. Melting
points were measured in capillary tubes with a Büchi SMP-20 appa-
ratus and were not corrected. Infrared spectra were recorded on a
Perkin-Elmer 881 spectrometer. 1H and 13C NMR spectra were re-
corded at 200 MHz and 50 MHz respectively on a Bruker AC 200
instrument in CDCl3. Amides 6,6 7,7 8,8 9,9 10,10 11,11 12,12 16,5 are
known in the literature.
1H NMR (CDCl3): = 5.94 (br s, 1 H, NH), 4.06 (d, J = 5.1 Hz, 2
H, CH2), 3.77 (s, 3 H, CH3), 2.24 (t, J = 7.5 Hz, 2 H, CH2), 1.64 (m,
2 H, CH2), 1.25 (br s, 20 H, CH2), 0.88 (t, J = 6.4 Hz, 3 H, CH3).
13C NMR (CDCl3): = 173.3, 170.6, 52.3, 41.2, 36.4, 31.9, 29.6,
29.4, 29.3, 29.2, 25.5, 22.7, 14.1.
Anal. Calcd for C17H33NO3: C, 68.19; H, 11.11; N, 4.68. Found: C,
68.12; H, 11.12; N, 4.60.
N-[N2-Acetyl-N6-(benzyloxycarbonyl)-L-lysyl]glycine Methyl
Ester (20)
Prepared according to procedure B from dipeptide 17 (226 mg, 0.50
mmol) and purified on a silica gel column (MeOH–CH2Cl2, 8:92
15:95) to give 153 mg (78%) of 20 as a white solid.
Synthesis of N-benzyl Acetamide; Procedure A
AcBr (0.29 mL, 3.86 mmol) was added to a solution of tert-butyl
benzylcarbamate (5a) (0.20 g, 0.97 mmol) and MeOH (0.08 mL,
1.93 mmol) in CH2Cl2 (10 mL). After stirring for 20 min at r.t.,
K2CO3 (0.40 g, 2.89 mmol) was added and the reaction was moni-
tored by TLC until completion (1 h). The medium was filtered on
celite® and concentrated under vacuum to give 144 mg (100%) of
N-benzyl acetamide 6.6
Mp 132 °C.
IR (KBr): 3305, 3068, 1735, 1690, 1636, 1547, 1270 cm–1.
1H NMR (CDCl3): = 7.34 (m, 5 H, Ph), 6.83 (m, 1 H, NH), 6.38
(br d, J = 7.6 Hz, 1 H, NH), 5.08 (s, 2 H, CH2), 5.03 (m, 1 H, NH),
4.45 (dt, J = 7.6, 6.0 Hz, 1 H, CH), 4.07 (dd, J = 18.1, 5.6 Hz, 1 H,
CH2), 3.94 (dd, J = 18.1, 5.4 Hz, 1 H, CH2), 3.71 (s, 3 H, CH3), 3.19
(q, J = 6.3 Hz, 2 H, CH2), 2.00 (s, 3 H, CH3), 1.90–1.20 (m, 6 H,
CH2).
Synthesis of N-benzyl Dichloroacetamide; Procedure B
Dichloroacetyl chloride (0.44 mL, 4.55 mmol) was added to a solu-
tion of tert-butyl benzylcarbamate (5a) (0.22 g, 1.14 mmol), MeOH
(0.09 mL, 2.28 mmol) and NaI (0.34 g, 2.28 mmol) in CH3CN (11
mL). The yellow heterogeneous mixture was stirred for 20 min at
r.t. N,N-Diisopropylethylamine (0.59 g, 4.55 mmol) was added at
0 °C and the white heterogeneous mixture was stirred at r.t. for 1 h.
It was quenched with 10% aq HCl (15 mL) and extracted with Et2O
(30 mL). The organic layer was washed with aq NaHCO3 (15 mL),
dried over Na2SO4, concentrated under vacuum and chromato-
graphed on a silica gel column (CH2Cl2–hexanes, 1:1) to give 0.23
g (95%) of amide 8.8
13C NMR (CDCl3): = 172.3, 170.6, 170.2, 156.8, 136.7, 128.6,
128.1, 66.6, 52.8, 52.4, 41.1, 40.4, 31.7, 29.4, 23.1, 22.3.
Anal. Calcd for C19H27N3O6: C, 58.00; H, 6.92; N, 10.68. Found: C,
57.69; H, 6.78; N, 10.46.
Acknowledgments
This work was carried out at the Unité Mixte de Recherche 7509.
Spectral Data of Compounds 13–15 and 20
N-Acetylglycine Isopropyl Ester (13)
References
Prepared according to procedure A from 5c (113 mg, 0.55 mmol) to
give 86 mg (98%) of 13 as a colourless oil.
(1) Nazih, A.; Cordier, Y.; Kolbe, H.; Heissler, D. Synlett 2000,
635.
(2) Ihara, M.; Hirabayashi, A.; Taniguchi, N.; Fukumoto, K.
Heterocycles 1992, 33, 851.
Bp 184 °C (0.25 Torr).
IR (neat): 3299, 3080, 1746, 1662, 1557, 1207 cm–1.
1H NMR (CDCl3): = 5.95 (br s, 1 H, NH), 5.08 (sept, J = 6.3 Hz,
1 H, CH), 4.00 (d, J = 5.0 Hz, 2 H, CH2), 2.04 (s, 3 H, CH3), 1.26
[d, J = 6.3 Hz, 6 H, (CH3)2].
(3) Nudelman, A.; Bechor, Y.; Falb, E.; Fisher, B.; Wexler, B.;
Nudelman, A. Synth. Commun. 1998, 28, 471.
(4) Lesk, A.; Nudelman, A. Synth. Commun. 1999, 29, 1405.
(5) Arai, K.; Tamura, S.; Masumizu, T.; Kawai, K.; Nakajima,
S. Can. J. Chem. 1990, 68, 903.
13C NMR (CDCl3): = 170.1, 169.6, 69.4, 41.7, 22.9, 21.7.
(6) Keck, G.; Wager, T.; McHardy, S. Tetrahedron 1999, 55,
11755.
Anal. Calcd for C7H13NO3: C, 52.82; H, 8.23; N, 8.80. Found: C,
52.40; H, 8.50; N, 8.70.
Synthesis 2002, No. 2, 203–206 ISSN 0039-7881 © Thieme Stuttgart · New York