A mild and efficient method for the synthesis of vinylogous carbamates from alkyl azides

Article abstract of DOI:10.1016/j.tetlet.2004.12.047

A mild and efficient one-pot method for the synthesis of vinylogous carbamates is reported starting from alkyl azides under a hydrogen atmosphere using 10% Pd/C. The resulting products are useful intermediates for the synthesis of heterocyclic compounds, natural products, and in peptidomimetics.

Full text of DOI:10.1016/j.tetlet.2004.12.047

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 979–982
A mild and efficient method for the synthesis of
vinylogous carbamates from alkyl azidesq
D. Srinivasa Reddy,* Trideep V. Rajale, K. Shivakumar and Javed Iqbal
Discovery Research, Dr. ReddyÕs Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500 049, India
Received 20 October 2004; revised 29 November 2004; accepted 8 December 2004
Abstract—A mild and efficient one-pot method for the synthesis of vinylogous carbamates is reported starting from alkyl azides
under a hydrogen atmosphere using 10% Pd/C. The resulting products are useful intermediates for the synthesis of heterocyclic com-
pounds, natural products, and in peptidomimetics.
Ó 2004 Elsevier Ltd. All rights reserved.
Vinylogous carbamates also known as enaminoesters
are versatile building blocks in the synthesis of various
heterocycles,1 natural products2 and are often endowed
with useful pharmacological properties.3 Recent reports
show that these compounds are useful in peptidomimet-
ics4 and also in the preparation of b-amino acids.5 Vinyl-
ogous carbamates are generally prepared by
condensation of amines with b-ketoesters, with azeotro-
pic removal of water, use expensive reagents, and some
of these suffer from incomplete reaction, long reaction
times, and the use of hazardous solvents.6 In this Letter,
we describe the synthesis of various vinylogous carb-
amates starting from alkyl azides and b-ketoesters in a
one-pot procedure.
aqueous work-up was needed, the catalyst was simply
filtered off, and on evaporation of all volatiles the prod-
uct 3 was obtained in high yield. This method has not
previously been documented.8 Hence, we decided to gen-
eralize this simple and efficient procedure to access other
useful vinylogous carbamates.
A variety of alkyl azides were treated with methyl aceto-
acetate 2 in the presence of 10% Pd/C under hydrogen to
furnish the corresponding vinylogous carbamates in
high yields and these are summarized in Table 1.9 It is
noteworthy that in all cases we did not observe any sig-
nificant amounts of over reduced products or the inter-
mediate amines. Although a competitive debenzylation
would be possible under these reaction conditions, reac-
tions involving benzyl azides (entries 5–7, Table 1) did
not undergo loss of the benzyl group, the corresponding
vinylogous carbamates being obtained in good yields. In
all cases the products were isolated as mixtures of Z,E-
isomers. In general the isomers were not separable.
During the synthesis of aza-cyclic peptides for b-turn
´
mimics in the laboratory of Professor Aube, one of us
(D.S.R.) observed that hydrogenation of the alkyl azide
1 in the presence of methyl acetoacetate 2 furnished the
vinylogous carbamate 3 in high yield (Scheme 1).7 No
10% Pd/C, H2
O
O
EtOAc
BocHN
BocHN
NH
O
+
N3
OMe
rt, 10 min.
92%
OMe
1
3
2
Scheme 1.
Keywords: Alkyl azide; Enaminone; Hydrogenation.
q DRL Publication No. 455.
*
Corresponding author. Tel.: +91 402304 5439; fax: +91 402304 5438; e-mail:
dsreddy@drreddys.com
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.047

980
D. S. Reddy et al. / Tetrahedron Letters 46 (2005) 979–982
Table 1.
R
O
O
NH
O
O
10% Pd/C, H2
EtOAc
R-N3
+
OMe
OMe
2
Entry
1
Azide
Product
Yield (%)
100
NH
NH
N3
OMe
OMe
HO
Cl
O
2
3
4
5
6
84
82
64
75
67
HO
Cl
N3
N3
NH
O
OMe
O
NH
O
N3
OMe
NH
NH
N3
OMe
O
N3
OMe
N3
NH
O
7
8
9
71
55
48
MeO
MeO
OMe
EtOOC
NH
O
N3
EtOOC
OMe
OMe
NH
O
N3
Table 2.
Ph
10% Pd/C, H2
NH
O
N3
Ph
R1
OR
O
O
O
R2
R1
OR
4
R2
Entry
1
Keto ester
Product
Yield (%)
60
Ph
O
O
NH
NH
O
O
O
Ph
O
O
2
3
62
67
F3C
O
OMe
F3C
Ph
OMe
NH
O
O
OEt
OEt
Ph
O
O
O
O
HN
4
5
66
45
O
Ph
O
O
NH
O
OEt
OEt
Ph
EtO
EtO
O
O
O
HN

D. S. Reddy et al. / Tetrahedron Letters 46 (2005) 979–982
981
The Chemistry of Enamines Part 1; Rappoport, Z., Ed.;
John Wiley and Sons: Chichester, New York, Brisbane,
Toronto, Singapore, 1994.
O
O
Ph
OMe
Me
10% Pd/C, H2
N3
Ph
2
2. Michael, J. P.; De Koning, C. B.; Gravestock, D.; Hosken,
G. D.; Howard, A. S.; Jungmann, C. M.; Krause, R. W.
M.; Parsons, A. S.; Pelly, S. C.; Stanbury, T. V. Pure Appl.
Chem. 1999, 71, 979–988.
N
H
6
(56%)
5
3. (a) Scott, K. R.; Rankin, G. O.; Stables, J. P.; Alexander,
M. S.; Edafiogho, I. O.; Farrar, V. A.; Kolen, K. R.;
Moore, J. A.; Sims, L. D.; Tonnu, A. D. J. Med. Chem.
1995, 38, 4033–4043; (b) Edafiogho, I. O.; Alexander, M.
S.; Moore, J. A.; Farrar, V. A.; Scott, K. R. Curr. Med.
Chem. 1994, 1, 159–175; (c) Edafiogho, I. O.; Moore, J. A.;
Alexander, M. S.; Scott, K. R. J. Pharm. Sci. 1994, 83,
1155–1170; (d) Eddington, N. D.; Cox, D. S.; Roberts, R.
R.; Stables, J. P.; Powell, C. B.; Scott, K. R. Curr. Med.
Chem. 2000, 7, 417–436.
Scheme 2.
Products with Z double bond geometry were favoured
over the E-isomers. It is postulated that intramolecular
hydrogen bonding could be responsible for the observed
equilibrium shift toward Z-isomers.10 In Table 2, we
have summarized the results obtained from the reaction
of phenethyl azide 4 with different b-ketoesters.11
4. (a) Smith, A. B.; Guzman, M. C.; Sprengeler, P. A.;
Keenan, T. P.; Holcomb, R. C.; Wood, J. L.; Carroll, P.
J.; Hirschmann, R. J. Am. Chem. Soc. 1994, 116, 9947–
9962; (b) Smith, A. B.; Hirschmann, R.; Pasternak, A.;
Akaishi, R.; Guzman, M. C.; Jones, D. R.; Keenan, T. P.;
Sprengeler, P. A.; Darke, P. L.; Emini, E. A.; Holloway,
M. K.; Schleif, W. A. J. Med. Chem. 1994, 37, 215–218; (c)
Smith, A. B.; Holcomb, R. C.; Guzman, M. C.; Keenan,
T. P.; Sprengeler, P. A.; Hirschmann, R. Tetrahedron Lett.
1993, 34, 63–66; (d) Smith, A. B.; Keenan, T. P.;
Holcomb, R. C.; Sprengeler, P. A.; Guzman, M. C.;
Wood, J. L.; Carroll, P. J.; Hirschmann, R. J. Am. Chem.
Soc. 1992, 114, 10672–10674; (e) Hagihara, M.; Anthony,
N. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L. J. Am. Chem.
Soc. 1992, 114, 6568–6570.
5. (a) Hsiao, Y.; Rivera, N. R.; Rosner, T.; Krska, S. W.;
Njolito, E.; Wang, F.; Sun, Y.; Armstrong, J. D., III;
Grabowski, E. J. J.; Tillyer, R. D.; Spindler, F.; Malan, C.
J. Am. Chem. Soc. 2004, 126, 9918–9919; (b) Ikemoto, N.;
Tellers, D. M.; Dreher, S. D.; Liu, J.; Huang, A.; Rivera,
N. R.; Njolito, E.; Hsiao, Y.; McWilliams, J. C.; Williams,
J. M.; Armstrong, J. D., III; Sun, Y.; Mathre, D. J.;
Grabowski, E. J. J.; Tillyer, R. D. J. Am. Chem. Soc. 2004,
126, 3048–3049; Review: (c) Drexler, H.-J.; You, J.;
Zhang, S.; Fischer, C.; Baumann, W.; Spannenberg, A.;
Heller, D. Org. Process Res. Dev. 2003, 7, 355–361; (d)
Tang, W.; Wang, W.; Yongxiang, C.; Zhang, X. Angew.
Chem., Int. Ed. 2003, 42, 3509–3511; (e) You, J.; Drexler,
H.-J.; Zhang, S.; Fischer, C.; Heller, D. Angew. Chem.,
Int. Ed. 2003, 42, 913–916; (f) Tang, W.; Wu, S.; Zhang, X.
J. Am. Chem. Soc. 2003, 125, 9570–9571; (g) Pena, D.;
Minnaard, A. J.; de Vries, J. G.; Feringa, B. L. J. Am.
Chem. Soc. 2002, 124, 14552–14553; (h) Wu, J.; Chen, X.;
Guo, R.; Yeung, C.; Chan, A. S. C. J. Org. Chem. 2003,
68, 2490–2493; (i) Tararov, V. I.; Kadyrov, R.; Riermeier,
T. H.; Holz, J.; Borner, A. Tetrahedron Lett. 2000, 41,
2351–2355; (j) Burk, M. J.; Casy, G.; Johnson, N. B. J.
Org. Chem. 1998, 63, 6084–6085; (k) Lee, N. E.; Buch-
wald, S. L. J. Am. Chem. Soc. 1994, 116, 5985–5986.
6. (a) Ferraz, H. M. C.; Pereira, e. F. L. C. Quim. Nova 2004,
27, 89–95, and references cited therein; (b) Brandt, C. A.;
da Silva, A. C. M. P.; Pancote, C. G.; Brito, C. L.; da
Silvaria, M. A. B. Synthesis 2004, 1557–1559; (c) Ahmad,
R.; Khosropour, A. R.; Khodaei, M. M.; Kookhazadeh,
M. Tetrahedron Lett. 2004, 41, 1725–1728; (d) Azzaro, M.;
Geribaldi, S.; Videau, B. Synthesis 1981, 880–881; (e)
Baraldi, P. G.; Simoni, D.; Manfredini, S. Synthesis 1983,
902–903; (f) Valduga, C. J.; Squizani, A.; Braibante, H. S.;
Braibante, M. E. F. Synthesis 1998, 1019–1022; (g)
Stefane, B.; Polanc, S. New J. Chem. 2002, 26, 28–32.
7. Reddy, D. S.; Vander Velde, D.; Aube, J. J. Org. Chem.
2004, 69, 1716–1719.
Interestingly, trisubstituted pyrrole 612 was isolated in
moderate yield when we reacted a-azido acetophenone
5 with methyl acetoacetate under the same reaction con-
ditions (Scheme 2).13 Although we do not have support
for the mechanism, we believe that formation of the
pyrrole involves the vinylogous carbamate as an
intermediate.
In short, we have developed a simple and environmen-
tally friendly procedure for the synthesis of vinylogous
carbamates starting from alkyl azides and b-ketoesters
using 10% Pd/C catalyst and hydrogen. In one example,
we also showed that one can access trisubstituted pyr-
roles starting from b-ketoesters and a-azido ketones in
a one-pot procedure. New applications of these impor-
tant vinylogous carbamates in the synthesis of natural
products and heterocycles will be the subject of future
work from our laboratory.
Acknowledgements
We thank Dr. ReddyÕs Laboratories Ltd for financial
´
support and encouragement and Professors J. Aube
and A. Dutta of the University of Kansas for useful dis-
cussions. Help from the analytical department in record-
ing spectral data is appreciated.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2004.
12.047.
References and notes
1. (a) Elassar, A-Z. A.; El-Khai, A. A. Tetrahedron 2003, 59,
8463–8480; (b) Alan, C.; Spivey, A. C.; Srikaran, R.;
Diaper, C. M.; David, J.; Turner, D. J. Org. Biomol.
Chem. 2003, 1, 1638; (c) Greenhill, J. V. Chem. Soc. Rev.
1977, 6, 277–294; (d) Lue, P.; Greenhill, J. V. Adv.
Heterocycl. Chem. 1997, 67, 207–343; (e) Cimarelli, C.;
Palmieri, G. Recent Res. Dev. Org. Chem. 1997, 1, 179–
189; (f) Pawlak, J. M.; Khau, V. V.; Hutchinson, D. R.;
Martinelli, M. J. J. Org. Chem. 1996, 61, 9055–9059; (g)

982
D. S. Reddy et al. / Tetrahedron Letters 46 (2005) 979–982
´
8. There are three examples of an intramolecular version.
10. (a) Reddy, D. S.; Judd, W. R.; Aube, J. Org. Lett. 2003, 5,
3899–3902; (b) Gilli, P.; Bertolasi, V.; Pretto, L.; Lycka,
A.; Gilli, G. J. Am. Chem. Soc. 2002, 124, 13554–13567;
(c) Zhuo, J.-C. Magn. Reson. Chem. 1997, 35, 311–322; (d)
Zhuo, J. C.; Schenk, K. Helv. Chim. Acta 1997, 80, 2137–
2147.
See: (a) Lambert, P. H.; Vaultier, M.; Carrie, R. J. Org.
Chem. 1985, 50, 5352–5356; (b) Langer, P.; Freifeld, I.
Chem. Commun. 2002, 2668–2669; (c) Shaw, K. J.;
Luly, J. R.; Rapoport, H. J. Org. Chem. 1985, 50, 4515–
4523.
9. To a solution of alkyl azide (1 equiv) and methyl aceto-
acetate (2 equiv) in EtOAc was added a catalytic amount
of 10% Pd/C (ꢀ10% weight) and the reaction mixture was
stirred under hydrogen (balloon) at room temperature.
After 0.5–2 h, the catalyst was filtered off and the residue
obtained after the removal of all volatiles, passed through
a small silica gel plug to furnish the desired products as a
Z:E mixture.
11. See supporting information for characterization of all new
compounds characterization.
12. (a) Gomez-Sanchez, A.; Stiefel, B. M.; Fernandez-
Fernandez, R.; Pascual, C.; Bellanato, J. J. Chem. Soc.,
Perkin Trans. 1 1982, 441–447; (b) Montforts, F.-P.;
Schwartz, U. M.; Maib, P.; Mai, G. Liebigs Ann. Chem.
1990, 1037–1043.
13. This reaction was not optimised.