L-Proline: An efficient catalyst for transamidation of carboxamides with amines

Article abstract of DOI:10.1021/ol4002625

In the presence of a catalytic amount of l-proline (10 mol %), transamidations of carboxamides with amines were achieved under solvent-free conditions. The transamidation process is compatible with a wide range of amines.

Full text of DOI:10.1021/ol4002625

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
L‑Proline: An Efficient Catalyst for
Transamidation of Carboxamides
with Amines
Sadu Nageswara Rao, Darapaneni Chandra Mohan, and Subbarayappa Adimurthy*
CSIR-Central Salt & Marine Chemicals Research Institute, G. B. Marg,
Bhavnagar-364 002, Gujarat, India
adimurthy@csmcri.org
Received January 29, 2013
ABSTRACT
In the presence of a catalytic amount of L-proline (10 mol %), transamidations of carboxamides with amines were achieved under solvent-free
conditions. The transamidation process is compatible with a wide range of amines.
The amide bond is one of the most important linkages in
natureduetoitspresenceinpeptidesandproteinstructures
and has been well recognized in chemistry and biology.1 In
addition, amides serve as versatile intermediates for the
preparation of pharmaceuticals, agrochemicals, polymers,
and materials.2 Traditionally amides have been prepared
by the reaction of amines with carboxylic acid derivatives,3
alcohols,4 or aldehydes,5 hydroamination of alkynes,6 and
hydration of nitriles.7 Alternatively, transamidation is an
attractive tool and represents one of the most convenient
and straightforward methods for exchanging the constitu-
ents of two different amide groups. Transamidation is
a distinct biochemical activity8 associated with several
neurodegenerative disorders such as Alzheimer’s and
Hungtinton’s disease.9
(1) (a) Larock, R. C. Comprehensive Organic Transformations, 2nd
ed.; Wiley-VCH: Weinheim, 1999. (b) Sewald, N.; Jakubke, H. D. Peptides:
Chemistry and Biology; Wiley-VCH: Weinheim, 2002. (c) Bray, B. L. Nat.
Rev. Drug Discovery 2003, 2, 587. (d) Cupido, T.; Tulla-Puche, J.;
Spengler, J.; Albericio, F. Curr. Opin. Drug Discovery Dev. 2007, 10,
768. (e) Bode, J. W. Curr. Opin. Drug Discovery Dev. 2006, 9, 765. (f)
Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243. (f)
Greenberg, A.; Breneman, C. M.; Liebman, J. F. Amide Linkage:
Selected Structural Aspects in Chemistry, Biochemistry, and Materials
Science; Wiley-Interscience: New York, 2000.
(2) (a) Wang, G. W.; Yuan, T. T.; Li, D. D. Angew. Chem., Int. Ed.
2011, 50, 1380. (b) Zhang, X. X.; Teo, W. T.; Chan, P. W. H. J. Organomet.
Chem. 2011, 696, 331. (c) Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009,
38, 606.
(3) (a) Roughley, S. D.; Jordan, A. M. J. Med. Chem. 2011, 54, 3451.
(b) Allen, C. L.; Chhatwal, R. A.; Williams, J. M. J. Chem. Commun.
2012, 48, 666. (c) Ishihara, K.; Ohara, S.; Yamamoto, H. J. Org. Chem.
1996, 61, 4196. (d) Charville, H.; Jackson, D.; Hodges, G.; Whiting, A.
Chem. Commun. 2010, 46, 1813. (e) Arnold, K.; Davies, B.; Herault, D.;
Whiting, A. Angew. Chem., Int. Ed. 2008, 47, 2673.
(5) (a) For representative examples, see: (a) Ishihara, K.; Yano, T.
Org. Lett. 2004, 6, 1983. (b) Yoo, W. J.; Li, C. J. J. Am. Chem. Soc. 2006,
128, 13064. (c) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129,
13798. (d) Sakakura, A.; Ohkubo, T.; Yamashita, R.; Akakura, M.;
Ishihara, K. Org. Lett. 2011, 13, 892. (e) Sakakura, A.; Yamashita, R.;
Ohkubo, T.; Akakura, M.; Ishihara, K. Aust. J. Chem. 2011, 64, 1458.
(F) Ghosh, S. C.; Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D. H.; Chai,
C. L. L.; Chen, A. J. Org. Chem. 2012, 77, 8007.
(6) (a) Cho, S.; Yoo, E.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005,
127, 16046. (b) Chen, Z.-W.; Jiang, H.-F.; Pan, X.-Y.; He, Z.-J. Tetra-
hedron 2011, 67, 5920.
(7) (a) Yamaguchi, K.; Matsushita, M.; Mizuno, N. Angew. Chem.,
Int. Ed. 2004, 43, 1576. (b) Goto, A.; Endo, K.; Saito, S. Angew. Chem.,
Int. Ed. 2008, 47, 3607. (c) Ramon, R. S.; Marion, N.; Nolan, S. P.
Chem.;Eur. J. 2009, 15, 8695. (d) Mitsu-dome, T.; Mikami, Y.; Mori,
H.; Arita, S.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem. Commun.
2009, 3258.
(8) (a) Jeon, J. H.; Cho, S. Y.; Kim, C. W.; Shin, D. M.; Kweon, J. C.;
Choi, K. H.; Park, S. M. C.; Kim, I. G. Biochem. Biophy. Res. Commun.
2002, 294, 818. (b) Rossin, F.; D’Eletto, Macdonald, D.; Farrace, M. G.;
Piacentini, M. Amino Acids 2012, 42, 1793.
(9) (a) Anderson, R. P.; Degano, P.; Godkin, A. J.; Jewell, D. P.; Hill,
A. V. Nat. Med. 2000, 6, 337. (b) Green, H. Cell 1993, 74, 955. (c)
Lorand, L. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14310.
(4) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007,
317, 790. (b) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc.
€
2008, 130, 17672. (c) Zweifel, T.; Naubron, J.-V.; Grutzmacher, H.
Angew. Chem., Int. Ed. 2009, 48, 559. (d) Watson, A. J. A.; Maxwell,
A. C.; Williams, J. M. J. Org. Lett. 2009, 11, 2667. (e) Soule, J. F.;
Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc. 2011, 133, 18550. (f)
Yamaguchi, K.; Kobayashi, H.; Oishi, T.; Mizuno, N. Angew. Chem.,
Int. Ed. 2012, 51, 544.
r
10.1021/ol4002625
XXXX American Chemical Society

Recently, Stahl,10 Williams,11 Myers,12 Beller,13 and
other groups14 have developed elegant methods for trans-
amidation. Yet, despite the advances achieved, most of
these methods require transition metal10À13 or lanthanide
metal14a catalysts to promote this transformation effi-
ciently. Thus, the separation of the metal catalyst from
products is a central issue to consider. This separation is of
particular importance for the synthesis of pharmaceutical
fine chemicals, because of metal residual toxicity in the
target compounds. Moreover, transition-metal-catalyzed
reactions also generate hazardous waste which is environ-
mentally problematic and hence should be avoided wher-
ever possible. Also, these catalysts are active only in
organic solvents. Few reports are available for a complete-
ly solvent-free transamidation process.14c
Recently, organocatalysis emerged as an area of very
rapid growth for chemical synthesis due to environmental-
friendliness.15 Particularly, L-proline has received much
attention due to its dual role as a ligand and catalyst.16 In
view of the above perceptions, the development of benign
and metal-free transamidation procedures with high yield
and selectivity is desirable. In continuation of our efforts to
develop green and sustainable methods,17 herein, we wish
to report a general solvent-free L-proline catalyzed transa-
midation of carboxamides with amines. To the best of
our knowledge, this is the first convenient procedure for
efficient transamidation using L-proline as the catalyst.
We started our studies on transamidation of acetamide
with benzylamine as a model system (Table 1). First, the
reaction was performed without a catalyst and solvent;
a complete lack of reactivity was observed at 100 °C
(Table 1, entry 1). The reaction was carried out in the
presence of L-proline as an inexpensive catalyst (10 mol %);
it resulted in 14% of transamidation product 3a, but the
conditions were not sufficiently efficient to achieve the
desired conversion (Table 1, entry 2). When the reaction
was performed in toluene at 100 °C, an 88% conversion
was observed (Table 1, entry 3). Further, no improvements
were observed when the reaction was carried out in other
solvents (Table 1, entries 4À7). To our delight, when the
reaction was performed under neat conditions it resulted
in >99% conversion (Table 1, entry 8). Transamidation
slightly dropped when the catalyst loading was decreased
to 5 mol % (Table 1, entry 9). Upon varying the tempera-
ture of the reaction between rt and 80 °C, conversion also
declined (Table 1, entries 10À12). Transamidation was not
efficient with other amino acid catalysts tested (Table 1,
entries 13À18).
Table 1. Optimization of Reaction Conditions for 3aa
catalyst
(mol %)
temp
yield
(%)b
entry
solvent
(°C)
1
_
_
100
100
100
100
100
100
100
100
100
80
0
2
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (10)
L-proline (5)
H2O
14
88
19
65
36
60
99
96
81
30
9
3
toluene
4
DMF
5
DMSO
6
EtOH
7
iPrOH
8
À
À
À
À
À
À
À
À
À
À
À
(10) Stahl group: (a) Stephenson, N. A.; Zhu, J.; Gellman, S. H.;
Stahl, S. S. J. Am. Chem. Soc. 2009, 131, 10003. (b) Hoerter, J. M.; Otte,
K. M.; Gellman, S. H.; Cui, Q.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130,
647. (c) Kissounko, D. A.; Hoerter, J. M.; Guzei, L. A.; Cui, Q.;
Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 1776. (d)
Hoerter, J. M.; Otte, K. M.; Gellman, S. H.; Stahl, S. S. J. Am. Chem.
Soc. 2006, 128, 5177. (e) Kissounko, D. A.; Guzei, L. A.; Gellman, S. H.;
Stahl, S. S. Organometallics 2005, 24, 5208. (f) Eldred, S. E.; Stone,
D. A.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2003, 125, 3422.
(11) Williams group: (a) Allen, C. L.; Atkinson, B. N.; Williams,
J. M. J. Angew. Chem., Int. Ed. 2012, 51, 1383. (b) Atkinson, B. N.;
Chhatwal, A. R.; Lomax, H. V.; Walton, J. W.; Williams, J. M. J. Chem.
Commun. 2012, 48, 11626.
9
10
11
12
13
14
15
16
17
18
L-proline (10)
L-proline (10)
L-proline (10)
L-lysine (10)
60
rt
100
100
100
100
100
100
90
87
74
77
82
88
L-histidine (10)
L-leucine (10)
L-glutamic acid (10)
L-alanine (10)
L-glycine (10)
(12) Dineen, T. A.; Zajac, M. A.; Myers, A. G. J. Am. Chem. Soc.
2006, 128, 16406.
(13) Zhang, M.; Imm, S.; Bahn, S.; Neubert, L.; Neumann, H.; Beller,
M. Angew. Chem., Int. Ed. 2012, 51, 3905.
a Conditions: 1a (10 mmol), 2a (10 mmol), and L-proline (10 mol %)
in a sealed tube at 100 °C for 36 h, unless otherwise stated. b Determined
by GC-MS.
(14) (a) Tamura, M.; Tonomura, T.; Shimizu, K.; Satsuma, A. Green
Chem. 2012, 14, 717. (b) Nguyen, T. B.; Sorres, J.; Tran, M. Q.;
Ermolenko, L.; Al-Mourabit, A. Org. Lett. 2012, 14, 3202. (c) During
the preparation of the current manuscript, a hypervalent iodine cata-
lyzed transamidation was reported: Vanjari, R.; Allam, B. K.; Singh,
K. N. RSC Adv. 2013, 3, 1691.
(15) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43,
5138. (b) MacMillan, D. W. C. Nature 2008, 455, 304. (c) Kotsuki, H.;
Ikishima, H.; kuyama, A. Heterocycles 2008, 75, 757. (d) Bertelsen, S.;
Jorgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178.
(16) (a) Tanimoro, T.; Ueno, M.; Takeda, K.; Kirihata, M.; Tanimori,
S. J. Org. Chem. 2012, 77, 7844. (b) Tanimori, S.; Kobayashi, Y.; Iesaki, Y.;
Ozaki, Y.; Kirihata, M. Org. Biomol. Chem. 2012, 10, 1381. (c) Nezhad,
A. K.; Sarikhani, S.; Shahidzadeh, E. S.; Panahi, F. Green Chem. 2012,
14, 2876.
(17) (a) Chunavala, K. C.; Joshi, G.; Suresh, E.; Adimurthy, S.
Synthesis 2011, 635. (b) Patil, R. D.; Adimurthy, S. Adv. Synth. Catal.
2011, 353, 1695. (c) Mohan, D. C.; Rao, S. N.; Adimurthy, S. J. Org.
Chem. 2013, 78, 1266.
Under these optimized conditions (Table 1, entry 8), the
transamidation of acetamide with various amines was
examined (Scheme 1). The results in Scheme 1 demonstrate
that the reaction has a high degree of functional group
tolerance. Benzlyamines with electron-rich and -deficient
(p/m/o) substituents were reacted smoothly and produced
corresponding transamidation products in good to excel-
lent yields (3bÀ3h). The less nucleophilic anilines, p-methyl
aniline and m-chloroaniline, provided good to moderate
yields (3iÀ3k). This may be due to the delocalization of the
nitrogen lone pair of electrons on the aromatic ring, which
is apparent according to the literature.14b Notably, alkyl
B
Org. Lett., Vol. XX, No. XX, XXXX

aromatic, aliphatic, and secondary amines proceeded
smoothly (3lÀ3p) under these conditions.
Scheme 2. Expanded Substrate Scope of Transamidation
Methoda
To examine the scope of transamidation, a variety of
benzylic, aromatic, aliphatic, propargylic, heteroaromatic,
and secondary amines were reacted with other amides
(Scheme 2). In general, the transamidation of benzamide
with benzyl amines (electron-neutral, -rich, -deficient),
aliphatic, alkyl aromatic, and cyclic secondary amines gave
corresponding transamidation products in good to moder-
ate yields (5aÀ5i). Similarly, transamidation of formamide
with a variety of amines including morpholine, propargylic
amine, 2-aminopyridine, piperidine, and cyclic secondary
Scheme 1. Transamidation of Acetamide with Various Aminesa
a Conditions unless otherwise stated: 4 (10 mmol), 2 (10 mmol), and
L-proline (10 mol %) in a sealed tube at 150 °C, 36 h; isolated yield.
b Reactions carried out at rt (27 °C).
Table 2. L-Proline Catalyzed Transamidation of Phthalimide
with Aminesa
a Conditions unless otherwise stated: 1a (10 mmol), 2 (10 mmol),
L-proline (10 mol %) in a sealed tube at 100 °C for 36 h, isolated yield.
b Reactions carried out at 150 °C.
amines also gave good to moderate yields (5jÀ5r). How-
ever, the present method is not suitable for acyclic second-
ary (dibenzyl and diisopropyl) amines. Further, it should
be noted that transamidation products 5m, 5n, and 5pÀ5r
were obtained from corresponding amines at rt. The
change of temperature may be due to the high electro-
philicity of formamide.
Finally, the L-proline catalyzed transamidation of
phthalimide was examined with various primary amines
(Table 2). All primary amines reacted smoothly to provide
corresponding N-substituted phthalimides in good to ex-
cellent yields. The tansamidation of phthalimide can be
assumed to be similar to what has been proposed by
Nguyen et al.14b To our delight, we found this transforma-
tion to be very general for a wide range of amines.
Transamidation of the secondary and tertiary amides
resulted in low to moderate yields, compared to primary
amides (Scheme 3).
a Conditions: 6 (10 mmol), amine (10 mmol), in a sealed tube.
b Isolated yield.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Transamidation of 2° and 3° Amidesa
Scheme 5
a Conditions unless otherwise stated: amide (10 mmol) and 2a
(10 mmol) in a sealed tube; isolated yield. b 150 °C.
Scheme 4. Experiments for Mechanistic Studiesa
intermediate A,19 which further undergoes nucleophilic
addition with an amine to generate tetrahedral intermedi-
ate B. Subsequently, elimination of ammonia results in
another intermediate, C. Finally its hydrolysis provides the
transamidation product.
In summary, we have developed a novel L-proline-
catalyzed transamidation process that can be selectively
transaminated in an efficient manner. Compared to
previously known transamidation catalysts, L-proline is
inexpensive, is readily available, and can be used conve-
niently. A wide range of benzylic, aromatic, aliphatic,
propargylic, and heteroaromatic amines can be effectively
usedtoproducecorrespondingtransamidationproductsin
good to excellent yields.
a Conditions: 1a (10 mmol) and 2a (10 mmol) in a sealed tube, 36 h;
isolated yield.
Acknowledgment. We thank Dr. A. V. Boricha, Mr.
B. M. Bhil, Ms. Bumika, and Mr. A. K. Das of this institute
for recording NMR and GC/HR-MS respectively. S.N.R.
and D.C.M. are thankful to CSIR and UGC-New Delhi,
India for their fellowships. DST, Govt. India (SR/S1/
OC-13/2011), CSIR (Indus Magic-CS-0123). and CSIR-
CSMCRI (OLP-0042) are greatly acknowledged for finan-
cial support.
To gain insight into the reaction mechanism, we per-
formed some additional experiments (Scheme 4). To check
the effect of both the carboxylic and NÀH group of
L-proline, the reactions were performed using pyrrolidine
as well as the N-methyl and ethyl ester of L-proline as
catalysts. However, the latter two catalysts showed some
activity but were not efficient. These studies indicate that
both free NÀH and ÀCOOH groups of L-proline are
essential for efficient transamidation.
Supporting Information Available. Detailed experimen-
tal procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Based on experimental observations and literature
reports18 a plausible reaction mechanism for an L-proline
catalyzed transamidation is proposed (Scheme 5). We
assume that L-proline reacts with an amide to form
(19) Khalafi-Nezhad, A.; Sarikhani, S.; Shahidzadeh, E. S.; Panahi,
F. Green Chem. 2012, 14, 2876.
(18) (a) Lerner, R. A.; Barbas, C. F., III. J. Am. Chem. Soc. 2000, 122,
2395. (b) Northrup, A. B.; Mangion, F. H.; Macmillan, D. W. C. Angew.
Chem., Int. Ed. 2004, 43, 2152. (c) Pojarliev, P.; Biller, W. T.; Martin,
H. J. J. Am. Chem. Soc. 2002, 124, 827.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX