Pd-catalyzed one-pot chemoselective hydrogenation protocol for the preparation of carboxamides directly from azides

Article abstract of DOI:10.1016/j.tetlet.2010.05.066

Carboxamides were obtained efficiently in high yields from azides on reaction with the corresponding pre-formed activated carboxylic acids in a single-step reductive transformation using hydrogen atmosphere (balloon) under Pd/BaSO4 or Pd/CaCO3 catalysis. The method is highly chemoselective and compatible with extremely labile functional groups such as benzyl carbamates, benzyl ethers, benzyl esters, and olefins.

Full text of DOI:10.1016/j.tetlet.2010.05.066

Tetrahedron Letters 51 (2010) 3815–3819
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed one-pot chemoselective hydrogenation protocol
for the preparation of carboxamides directly from azides
a
Sudhir N. Bavikar a, , Deepak B. Salunke a,b, , Braja G. Hazra a, , Vandana S. Pore ,
*
Josiane Thierry b, Robert H. Dodd b,
*
a Division of Organic Chemistry, National Chemical Laboratory, Pune, India
b Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 15 February 2010
Revised 8 May 2010
Accepted 17 May 2010
Available online 21 May 2010
Carboxamides were obtained efficiently in high yields from azides on reaction with the corresponding
pre-formed activated carboxylic acids in a single-step reductive transformation using hydrogen atmo-
sphere (balloon) under Pd/BaSO4 or Pd/CaCO3 catalysis. The method is highly chemoselective and com-
patible with extremely labile functional groups such as benzyl carbamates, benzyl ethers, benzyl
esters, and olefins.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Azide
Carboxamide
Succinimide ester
Chemoselective
Palladium
Catalytic hydrogenation
The conversion of azides to amines is an important transforma-
tion in organic synthesis.1 Amines are further utilized for the syn-
thesis of the corresponding carboxamides which is one of the most
common functionalities in many biologically interesting mole-
cules. Several methods have been developed for amide bond for-
mation using carboxylic acids and amines.2 To overcome the
situation where free amines cannot be used because of structural
wavering, azides have been used to directly form an amide bond
(Fig. 1). The classical method of conversion of azide to amide in-
cludes Staudinger-type ligation involving the acylation of an imi-
acid/azide amidation,7 which was also documented as an improved
method for the synthesis of N-acyl sulfonamides.8 A chemical liga-
tion method was also reported by Raines and co-workers, in which
phosphinobenzenethiol was used to link a thioester and an azide to
form an amide bond.9
As part of our ongoing program on the synthesis of biologically
interesting bile acid-amino acid conjugates,10 we required an effi-
cient method for the chemoselective transformation of azides to
carboxamides. There are several reports on the reduction of azides
by hydrogenation followed by acylation with activated carboxylic
acids.11 However, this two-step classical protocol suffers from
the potential problem of inadequate chemoselectivity and instabil-
ity of the intermediate amine formed. The major drawback of the
Staudinger-type ligation involves the difficult purification of prod-
ucts whereas the Williams thioacid/azide amidation and seleno-
carboxylate/azide amidation require the conversion of acids to
thio acids and selenocarboxylates, respectively. This scenario de-
mands an exceptionally chemoselective and operationally simple
protocol for the synthesis of carboxamides directly from azides.
For our purposes, we were particularly attracted to the reduc-
tive transformation of azides to N-(tert-butoxycarbonyl)amines
via catalytic hydrogenation described by Saito et al.12 and Baskaran
and co-workers.13 Various methods have been developed for such a
type of transformation using triethylsilane14 or polymethyl-hydro-
siloxane15,16 as hydrogen source. Based on these observations
we describe herein a new and efficient ‘one-pot’ chemoselective
nophosphorane.3
A one-pot self-regulated approach for the
synthesis of amides based on two redox reactions has been
described earlier by Ghosh et al.4 By treatment with Woollins’ re-
agent in toluene, carboxylic acids were converted to selenocarb-
oxylic acids and further reacted with azides to form amides by
Knapp and Darout.5 A one-pot procedure for the similar seleno-
carboxylate/azide amidation was documented by Hu and Wu.6
In their protocol, selenocarboxylates are prepared by the reaction
of carboxylic acids with LiAlHSeH and exposed in situ to azides
to form amides. Other attractive methods include the Williams thio
* Corresponding authors. Tel.: +91 20 25898164; fax: +91 20 25902629 (B.G.H.);
tel.: +33 1 69824594; fax: +33 1 69077247 (R.H.D.).
E-mail addresses: bg.hazra@ncl.res.in (B.G. Hazra), robert.dodd@icsn.cnrs-gif.fr
(R.H. Dodd).
These authors contributed equally in this work.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.066

3816
S. N. Bavikar et al. / Tetrahedron Letters 51 (2010) 3815–3819
AcO
AcO
Z-Asp-(SPy)-OBn
CuCl2-2H2O
AcO
AcO
O
O
PPh3
AcO
AcO
O
AcO
AcO
N3
O
AcO
O
AcO
HN
OAc
N
OBn
Staudinger type ligation3h
O
NHZ
nBu3P
Boc-Asp-OBn
BnO
BnO
BnO
BnO
BnO
BnO
H
N
O
O
O
N3
NHAc
-78 oC to 25 oC
54%
NHAc
Boc-Asp-OBn
Amidation of carboxylic acid with an azide3e
O
N3-R'
Se- THF
O
Cl
O
LiAlHSeH
O
O
O
O
R'
THF, 0 oC
R
N
R
OH
R
O
O
R
H
CO2
+
HO
Selenocarboxylate/azide amidation6
-H+
N3
N
+H+
O
O
S
O
-O
N
R'
R'
R
SH
R
S-
R
N
H
N
R'
R
Williams thio acid/azide amidation7
SH
PPh2
O
O
H
N
H
N
H
H
N
N
Ph
S
N
H
H
N
O
O
O
O
Ph
Ph
Ph
N3
O
Peptide from thioester and azide9
Figure 1. Literature reports on the conversion of azides to carboxamides.
protocol for the preparation of carboxamides directly from azides.
With this procedure, carboxamides were obtained efficiently in
high yields from azides on reaction with the corresponding
pre-formed activated carboxylic acids in a single-step reductive
transformation using hydrogen atmosphere (balloon) under Pd/BaSO4
or Pd/CaCO3 catalysis (Scheme 1).
The first successful result for the amidation of benzyl azide 1a
with Boc-Gly-OSu 2a was obtained using Pd/BaSO4 in THF to fur-
nish Boc-protected 2-amino-benzylacetamide 3 in 86% yield. Con-
tinuous 18 h of H2 (balloon) atmosphere was required for the
complete consumption of the starting materials at 25 °C (Table 1,
entry 1), whereas at 0 °C no reaction was observed even after
20 h. Under these reaction conditions, compound 4 was obtained
in good yield when benzyl azide 1a was treated with Boc-Glu(Ot-
Bu)-OSu 2b (entry 2). Similarly, compound 5 was obtained in
82% yield when benzyl azide 1a was treated with Boc-Thr(Bzl)-
OSu 2c (entry 3). This was our first evidence for chemoselective
reductive transformation of azides to carboxamides in the pres-
ence of a benzyl ether functionality. Unfortunately, we could not
achieve the required chemoselectivity for the reduction of azides
in the presence of benzyl esters (entry 4), as the benzyl ester func-
tionality in compound Boc-Asp(OBzl)-OSu 2d was hydrogenolyzed
under the present reaction conditions to give 6 in 79% yield and the
desired product 7 was not realized. The longer reaction time may
be one of the reasons for the observed hydrogenolysis of the benzyl
ester functionality. To reduce the reaction time we used polar-
protic solvents such as ethanol instead of THF. The succinimide es-
ters (–COOSu) are known to undergo cross esterification in alcohol
solvents; therefore the stability of N-hydroxy succinimide (NHS)
ester functionality of compound 2a in EtOH at room temperature
was verified. Under the present reaction conditions (EtOH solvent
and Pd catalyst at room temperature) the activated ester was found
to be stable for 12 h. Ethanolysis of compound 2a was observed at
elevated temperatures as well as when the reaction time was more
than 12 h. This suggests that EtOH can be utilized for the reaction
at room temperature provided the reaction is complete within 10–
12 h.
O
O
H
N
N
O
O
O
H
N
O
O
2a
O
N3
N
H
O
Pd Catalyst
The first trial experiment for the amidation of benzyl azide 1a
with Boc-Gly-OSu 2a in EtOH at 25 °C using H2 balloon and Pd/
BaSO4 catalysis produced the desired amide 3 within 30 min (entry
1).17 In a similar fashion, the reaction time for the synthesis of
3
1a
Hydrogen Atmosphere
(balloon pressure)
Scheme 1. Typical example for the conversion of azide to carboxamide.

S. N. Bavikar et al. / Tetrahedron Letters 51 (2010) 3815–3819
3817
Table 1
Single-step reductive transformation of azides to carboxamides using pre-formed activated carboxylic acids
Entry
Azide
NHS ester
Product
Catalysta
Yield
A
B
89/86b
91
O
O
N3
O
NHBoc
N
H
1
N
O
NHBoc
1a
1a
O
2a
O
3
A
B
85/83b
87
O
O
N3
NHBoc
O
N
H
N
O
NHBoc
O
2
O
4
2b
O
O
A
B
82/82b
81
O
O
N3
O
NHBoc
O
N
H
N
O
NHBoc
O
1a
3
O
5
2c
O
O
O
N3
O
O
NHBoc
OH
NHBoc
N
H
N
N
N
O
4
5
A
B
86/79b
1a
1a
O
O
O
O
O
6
2d
O
O
N3
NHBoc
NHBoc
N
H
O
81
O
O
O
O
2d
7
A
B
85
84
O
O
N3
O
NHBoc
N
H
NHBoc
NHCbz
6
7
8
O
1b
2a
8
A
B
88
87
O
O
N3
O
NHCbz
O
N
H
N
N
O
1a
O
O
9
2e
A
B
77
80
O
N3
O
NHCbz
N
H
NHCbz
O
1b
2e
10
A
B
87
83
O
O
N3
H
N
O
O
H
N
H
N
N
N
O
9
O
1a
11
NHBoc
O
O
2f
NHBoc
A
B
79
76
O
O
O
OH
OH
O
OH
NHBoc
OH
O
10
2a
12
N3
OH 1c
HN
OH
H
H
BocHN
O
(continued on next page)

3818
S. N. Bavikar et al. / Tetrahedron Letters 51 (2010) 3815–3819
Table 1 (continued)
Entry
Azide
NHS ester
Product
Catalysta
Yield
73
70
A
B
O
O
O
OH
OH
O
OH
N
O
NHBoc
O
OH
O
11
N3
OH 1c
2c
HN
O
OH
H
H
BocHN
O
13
a
A—Palladium, 5 wt % on barium sulfate; B—Palladium, 5 wt % on calcium carbonate (purchased from Aldrich and used as received).
Yields for the reactions carried out in THF (reaction time: 18 h), all other yields are for the reactions carried out in EtOH (reaction time: 30 min).
b
carboxamides 4 and 5 in ethanol was drastically reduced to 30 min,
compared to the 18 h required for the reaction to be complete in
THF. Even using this modified protocol, we could not realize the
synthesis of the desired carboxamide 7, compound 6 being formed
instead from 2d in 86% yield (entry 4). After surveying several cat-
alytic systems for this transformation the best result was achieved
using Lindlar catalyst18 (Pd/CaCO3) in EtOH.17
Supplementary data
Supplementary data (general experimental methods, analytical
data for compounds 4–13, selected 1H, 13C NMR and DEPT spectra)
associated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2010.05.066.
In a typical experimental procedure, benzyl azide 1a treated
with Boc-Asp(OBzl)-OSu 2d in EtOH at 25 °C using H2 balloon
and Pd/CaCO3 catalysis produced the desired amide 7 in 81% yield
within 30 min (entry 5). The successful result obtained with sub-
strate 2d encouraged us to investigate the scope of the procedure.
Thus, the simplicity, remarkable chemoselectivity, and mildness of
this catalytic transformation were exhaustively studied with com-
pounds bearing different sensitive functional groups such as ben-
zyl ethers (entries 3 and 11), olefins (entries 6 and 8), and benzyl
carbamates (entries 7 and 8) all of which survived the hydrogeno-
lytic conditions to give the corresponding carboxamides. In partic-
ular, synthesis of compound 10 (entry 8) was realized when the
azide-bearing olefin 1b and the NHS ester 2e bearing an N-Cbz pro-
tecting group were exposed to the present modified protocol. As
expected, the azide was smoothly converted into the correspond-
ing carboxamide 10 in excellent yield (80%) without affecting the
carbon–carbon double bond and N-Cbz protecting group. In the
context of our current research,10 the generality of this protocol
was demonstrated by the high yielding synthesis of peptide 11 (en-
try 9) and steroidal carboxamides 12 as well as 13 (entries 10 and
11, respectively). This also suggested that the method is tolerant to
the presence of free carboxylic acids.
In the present Letter, we have demonstrated a new, robust, and
efficient ‘one-pot’ chemoselective protocol for the preparation of
carboxamides. Using this protocol, carboxamides were obtained
in high yields from azides on reaction with the corresponding
pre-formed activated carboxylic acids in a single-step reductive
transformation using hydrogen atmosphere (balloon pressure) un-
der Pd/BaSO4 or Pd/CaCO3 catalysis. The simplicity and remarkable
chemoselectivity of this catalytic transformation were studied
with compounds bearing different sensitive functional groups such
as benzyl ethers, olefins, benzyl carbamates, and benzyl esters
which remained untouched.
References and notes
1. (a) Scriven, E. F. V.; Turnbull, K. Chem. Rev. 1988, 88, 298–368; (b) Amantini, D.;
Fringuelli, F.; Pizzo, F.; Vaccaro, L. Org. Prep. Proc. Int. 2002, 34, 111–147.
2. Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827–10852.
3. (a) Garcia, J.; Urpf, F.; Vilarrasa, J. Tetrahedron Lett. 1984, 25, 4841–4844; (b)
Inazu, T.; Kobayashi, K. Synlett 1993, 869–870; (c) Bosch, I.; Urpi, F.; Vilarrasa, J.
J. Chem. Soc., Chem. Commun. 1995, 91–92; (d) Maunier, V.; Boullanger, P.;
Lafont, D. J. Carbohydr. Chem. 1997, 16, 231–235; (e) Mizuno, M.; Haneda, K.;
Iguchi, R.; Muramoto, I.; Kawakami, T.; Aimoto, S.; Yamamoto, K.; Inazu, T. J.
Am. Chem. Soc. 1999, 121, 284–290; (f) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R.
Org. Lett. 2000, 2, 2141–2143; (g) Boullanger, P.; Maunier, V.; Lafont, D.
Carbohydr. Res. 2000, 324, 97–106; (h) Damkaci, F.; DeShong, P. J. Am. Chem. Soc.
2003, 125, 4408–4409; (i) Bures, J.; Martin, M.; Urpi, F.; Vilarrasa, J. J. Org. Chem.
2009, 74, 2203–2206.
4. Ghosh, S. K.; Verma, R.; Ghosh, U.; Mamdapur, V. R. Bull. Chem. Soc. Jpn. 1996,
69, 1705–1711.
5. Knapp, S.; Darout, E. Org. Lett. 2005, 7, 203–206.
6. Wu, X.; Hu, L. J. Org. Chem. 2007, 72, 765–774.
7. Kolawski, R. V.; Shangguan, N.; Sauers, R. R.; Williams, L. J. J. Am. Chem. Soc.
2006, 128, 5695–5702.
8. Barlett, K. N.; Kolakowski, R. V.; Katukojvala, S.; Williams, L. J. Org. Lett. 2006, 8,
823–826.
9. Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000, 2, 1939–1941.
10. Bavikar, S. N.; Salunke, D. B.; Hazra, B. G.; Pore, V. S.; Dodd, R. H.; Thierry, J.;
Shirazi, F.; Deshpande, M. V.; Srinath, K.; Chattopadhyay, S. Bioorg. Med. Chem.
Lett. 2008, 18, 5512–5517.
11. (a) Sugimoto, T.; Wada, Y.; Yamamura, S.; Ueda, M. Tetrahedron 2001, 57,
9817–9825; (b) Ballard, T. E.; Richards, J. J.; Aquino, A.; Reed, C. S.; Melander, C.
J. Org. Chem. 2009, 74, 1755–1758.
12. Saito, S.; Nakajima, M.; Inaba, M.; Moriwake, T. Tetrahedron Lett. 1989, 30, 837–
838.
13. Reddy, P. G.; Pratap, T. V.; Kumar, G. D. K.; Mohanty, S. K.; Baskaran, S. Eur. J.
Org. Chem. 2002, 3740–3743.
14. Kotsuki, H.; Ohishi, T.; Araki, T. Tetrahedron Lett. 1997, 38, 2129–2132.
15. Chandrasekhar, S.; Chandraiah, L.; Reddy, C. R.; Reddy, M. V. Chem. Lett. 2000,
780–781.
16. Chandrasekhar, S.; Babu, B. N.; Reddy, C. R. Tetrahedron Lett. 2003, 44, 2057–
2059.
17. Typical experimental procedure: Compound 3: Palladium (5 wt % on barium
sulfate or 5 wt % on calcium carbonate, poisoned with lead: 30 mg, 15% by wt)
was added to a stirred solution of Boc-Gly-OSu 2a (200 mg, 0.73 mmol) and
benzyl azide 1a (108
lL, 0.87 mmol) in EtOH (5 mL). The reaction flask was
evacuated and flushed with hydrogen gas. The resulting mixture was stirred
(stirring rate of ꢀ500 RPM, to maintain the uniformity of the suspension)
under a hydrogen atmosphere (balloon) at 25 °C for 30 min. After completion
of the reaction, the catalyst was filtered through a pad of Celite, the filter cake
was washed with EtOH (20 mL), and the filtrate was concentrated under
reduced pressure. This crude product was dissolved in EtOAc (100 mL) washed
with 10% citric acid (2 Â 10 mL), 20% NaHCO3 (2 Â 10 mL), cold water
(2 Â 10 mL), brine (10 mL), and was dried over Na2SO4. The residue was
purified by chromatography on silica gel (100–200 mesh) using 2% MeOH/
CH2Cl2 to afford compound 3 as a white solid (176 mg, 91% yield); mp 65–66 °C
(lit.19 mp 64–68 °C); Anal. Calcd for C14H20N2O3: C, 63.62; H, 7.63; N, 10.60.
Acknowledgments
S.N.B. thanks the University Grant Commission (UGC, New Del-
hi) for the Senior Research Fellowship. D.B.S. thanks Embassy of
France in India, New Delhi, for a Sandwich Thesis Scholarship.
Emeritus Scientist Scheme awarded to B.G.H. by the CSIR, New Del-
hi, is gratefully acknowledged.

S. N. Bavikar et al. / Tetrahedron Letters 51 (2010) 3815–3819
3819
Found: C, 63.84; H, 7.51; N, 10.97; IR mmax (Nujol) 3308, 1703, 1658,
18. Selective hydrogenation of azides in presence of double bond and carbonyl
group was earlier demonstrated using Lindlar catalyst. Corey, E. J.; Nicolaou, K.
C.; Balanson, R. D.; Machida, Y. Synthesis 1975, 590–591.
19. Jeganathan, A.; Richardson, S. K.; Mani, R. S.; Haley, B. E.; Watt, D. S. J. Org.
Chem. 1986, 51, 5362–5367.
1530 cmÀ1 1H NMR (CDCl3, 200 MHz) d 1.41 (s, 9H), 3.82 (d, 2H, J = 6 Hz),
;
4.45 (d, 2H, J = 6 Hz), 5.30 (br s, 1H), 6.67 (br s, 1H), 7.24–7.37 (m, 5H); 13C
NMR (CDCl3, 50 MHz) d 28.1 (3C), 43.1, 44.2, 80.0, 127.3, 127.5 (2C), 128.5 (2C),
137.9, 156.1, 169.5; MS (LCMS) m/z 265.23 [M+H]+, 287.21 [M+Na]+.