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