1764
Z. Chen et al.
LETTER
a
b
Not only excellent regioselectivity, N-cumyl a-diazo acet-
amide 1b also exhibited extremely high acitivity towards
dirhodium catalysts. With 1 mol% of Rh2(OAc)4, the C-H
insertion was complete in 15 minutes at room temperature
in CH2Cl2 to give product 2b in 96% isolated yield. Even
with the catalyst loading of as low as 0.01 mol%, 91% iso-
lated yield of 2b was obtained from the reaction at room
temperature for 24 hours.
OH
Br
Ph
Ph
O
O
Ph
O
10
9
Ph
Ph
N
N2
c
d
N
Ph
O
H
H
O
11
13
12
Ph
Application of this method was further examined in the
synthesis of pregabalin (8). Deprotection of g-lactam 2b
was achieved with CF3COOH9 to give g-lactam 7 in 97%
isolated yield. Hydrolysis of g-lactam 7 under refluxing 6
N HCl afforded pregabalin (8) in 90% yield as corre-
sponding hydrochloride salt (Scheme 3).
NH
N
e
f
Ph
O
Ph
Ph
O
O
O
14
NH
O
15
Ph
Ph
N
N2
Scheme 4 a) NBS, Ph3P, CH2Cl2, r.t., 12 h, 77%; b) cumylamine,
K2CO3, KI, DMF, 90 °C, 8 h, 77%; c) 1) diketene, THF, r.t., 8 h; 2)
p-ABSA, DBU, THF, r.t., 8 h; 3) LiOH, H2O, THF, r.t., 8 h, 70%
(overall yield); d) 1 mol% Rh2(OAc)4, CH2Cl2, r.t., 15 min, 88%; e)
CF3COOH, 40 °C–50 °C, 2 h, 74%; f) LiAlH4, THF, reflux, 4 h, 78%.
N
a
b
H
O
O
2b
1b
H
NH2.HCl
COOH
N
c
O
8
7
References
Pregabalin
(1) (a) Ye, T.; Mckervey, M. A. Chem. Rev. 1994, 94, 1091.
(b) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo
Compounds; Wiley: New York, 1998, 129. (c) Doyle, M.
P.; Forbes, D. C. Chem. Rev. 1998, 98, 911. (d) Merlic, C.
A.; Zechman, A. L. Synthesis 2003, 1137. (e) Davies, H. M.
L.; Beckwith, R. E. J. Chem. Rev. 2003, 103, 2861.
(2) Zhenliang, C.; Zhiyong, C.; Yaozhong, J.; Wenhao, H.
Synlett 2003, 1965.
(3) (a) Padwa, A.; Austin, D. J.; Hornbuckle, S. F.; Semenes, M.
A. J. Am. Chem. Soc. 1992, 114, 1874. (b) Padwa, A.;
Austin, D. J.; Price, A. T.; Semones, M. A.; Doyle, M. P.;
Protopopova, M. N.; Winchester, W. R.; Tran, A. J. Am.
Chem. Soc. 1993, 115, 8669. (c) Watanabe, N.; Anada, M.;
Hashimoto, S.; Ikegami, S. Synlett 1994, 1031. (d)Yoon, C.
H.; Zaworotho, M. J.; Moulton, B.; Jung, K. W. Org. Lett.
2001, 3, 3539. (e) Yoon, C. H.; Nagle, A.; Chen, C.; Gandhi,
D.; Jung, K. W. Org. Lett. 2003, 5, 2259.
(4) Anada, M.; Mita, O.; Watanabe, H.; Kitagaki, S.;
Hashimoto, S. Synlett 1999, 1775.
(5) Wee, A. G. H.; Liu, B.; Zhang, L. J. Org. Chem. 1992, 57,
4404.
(6) Doyle, M. P.; Hu, W.; Wee, A. G. H.; Wang, Z.; Duncan, C.
Org. Lett. 2003, 5, 407.
(7) Yuen, P.; Kanter, G. D.; Taylor, C. P.; Vartanian, M. G.
Bioorg. Med. Chem. Lett. 1994, 4, 823.
Scheme 3 a) 0.01 mol% Rh2(OAc)4, CH2Cl2, r.t., 24 h, 91%;
b) CF3COOH, reflux, 2 h, 87%; c) 6 N HCl, reflux, 2 h, 90%.
We were delighted to see that the g-lactam ring remained
unattached during the deprotection of the cumyl group.
Thus, b-substituted pyrrolidine building blocks could be
synthesized from this method. For an example, with 1
mol% Rh2(OAc)4, C-H insertion of N-cumyl a-diazo ace-
tamide 12 gave N-cumyl g-lactam 13 in 88% isolated
yield. Deprotection of g-lactam 13 with CF3COOH gave
g-lactam 14 in 74% isolated yield. The reduction of g-lac-
tam 14 with LiAlH4 afforded 3-benzyloxy pyrrolidine
(15) in 78% yield (Scheme 4).
In summary, cumyl is a readily removable amide N-pro-
tecting group, which provides excellent regioselectivity in
the intramolecular C-H insertion of a-diazo acetamides
1b and 12. Pregabalin and 3-benzyloxy pyrrolidine build-
ing block have been synthesized in 79% and 21% overall
yield by applying this method. Application of this method
for general synthesis of other N-hetero cycle compounds
is in progress.
(8) Wee, A. G. H.; Duncan, S. C. Tetrahedron Lett. 2002, 43,
6173.
Acknowledgment
(9) Clayden, J.; Menet, C. J.; Tchabanenko, K. Tetrahedron
2002, 58, 4727.
We acknowledge the financial support from the Chinese Academy
of Sciences and the National Science Foundation of China (Grant
No. 20202011).
Synlett 2004, No. 10, 1763–1764 © Thieme Stuttgart · New York