Here, it is important to note that as mentioned earlier while
optimization of the reaction conditions, when N,N′-
Dimethylformamide was used as a solvent, corresponding N-
formylated product was obtained in excellent yield (Table 5).
The examples for transamidation of formamide or N,N′-
dimethylformamide with various arylamines and alkyl amines are
presented in Table 5. Different kinds of amines were used for N-
formylation reaction; all were found to give excellent yields.
Typically, an amino acid i.e. L-phenylalanine methylester
hydrochloride was subjected for transamidation using present
protocol (Table 5, entry 10), the transamidated N-formyl product
was formed and there was no change in configuration and optical
purity, thus this method can be useful in asymmetric synthesis
also. Similarly, many other amino acids can also be tranamidated
using this method. In case of secondary amines, 4-
benzylpiperidine was subjected for this reaction; the
transamidated product with excellent yield was obtained (Table
In view of the applications in peptide synthesis, a reaction
with protected glutamine i.e. methyl (((9H-fluoren-9-
yl)methoxy)carbonyl)-L-glutaminate 11 was conducted, which
was prepared from its N-trityl protected form 10, this compound
11 could be transamidated with aniline to give 12 as shown in
scheme 4. The reaction of this protected glutamine 11 was tried
with glycine methyl ester, amazingly, which could not undergo
this transformation. Further studies are planned to explore the
details about this reactions.
Scheme 4. Transamidation reaction of protected glutamine with
aniline
5
, entry 12) and also diphenylamine has given the desired
In conclusion, we have demonstrated
K
2
S
2
O
8
mediated
product (Table 5, entry 4) in excellent yields. Some examples of
aryl amines or aliphatic amines are shown in Table 5.
transamidation protocol of amides with amines using greener and
mild approach in aqueous media by following conventional heating
and microwave irradiation strategy. As illustrated by variety of the
examples, present reaction is applicable for transamidation of
acetamide, formamide and phthalimide substrates with various alkyl
or arylamines. The scope of present reaction is shown by application
in the synthesis of representative examples of drugs or natural
products. The present method can find applications in various fields
of organic synthesis, medicinal chemistry or drug discovery.
Scheme 3. Plausible mechanism for the formation transamidated
product from amide with aniline
From the mechanistic point of view, the time monitored
experiment was conducted. In this study, various intermediates
were observed along with the product formation in good amount
at the time of 30 min in conventional heating reaction. At very
Acknowledgments
MS, GLR, VV thanks UGC/CSIR for the award of fellowship.
The funding support from CSIR funded project BSC0108 is
gratefully acknowledged.
2 2 8
first instance, there is a cleavage of peroxy bond of K S O by
mixing an amide with this reagent and forms adduct i.e.
intermediate 1, as shown in scheme 3. By addition of aniline on
intermediate 1, it gets converted to intermediate 2. This finally
References and notes
releases the ammonia and gives KHSO
required transamidated product 5a.
4
and further forms the
1. (a) Carey, F.; Giuliano, R. Organic Chemistry, 8th ed., McGraw-
Hill, 2010; (b) Solomons, T. W. G.; Fryhle, C. Organic Chemistry,
9
th ed., Wiley, New York 2007.
(a) Wang, G. W.; Yuan, T. T.; Li, D. D. Angew. Chem., 2011, 123,
416; Angew. Chem. Int. Ed., 2011, 50, 1380; (b) Kung, P. P.;
2
.
1
Huang, B. W.; Zhang, G.; Zhou, J. Z.; Wang, J.; Digits, J. A.;
Skaptason, J.; Yamazaki, S.; Neul, D.; Zientek, M.; Elleraas, J.;
Mehta, P.; Yin, M. J.; Hickey, M. J.; Gajiwala, K. S.; Rodgers, C.;
Davies, J. F.; Gehring, M. R. J. Med. Chem., 2010, 53, 499; (c)
Zhang, X. X.; Teo, W. T.; Chan, P. W. H. J. Organomet. Chem.,
2
011, 696, 331.
3
.
(a) Cupido, T.; Tulla-Puche, J.; Spengler, J.; Albericio, F. Curr.
Opin. Drug Discovery Dev., 2007, 10, 768; (b) Humphrey, J. M.;
Chamberlin, A. R. Chem. Rev., 1997, 97, 2243.
4
5
6
.
.
.
Alcaide, B.; Almendros, P.; Aragoncillo, C. Chem. Rev., 2007,
1
07, 4437.
Beckwith, A. L. J. Chemistry of Amides; Zabicky, J. Ed.; Wiley:
New York, 1970, 73-185.
(a) Larock, R. C. Comprehensive Organic Transformations, VCH,
New York, 1999; (b) Han, S.-Y.; Kim, Y.-A. Tetrahedron, 2004,
6
0, 2447; (c) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron,
2005, 61, 10827; (d) Valeur, E.; Bradley, M. Chem. Soc. Rev.,
009, 38, 606; (e) Gunanathan, C.; David Y. B.; Milstein, D.
Figure 2. Application of present reaction for synthesis of various
drugs and natural products
2
Science, 2007, 317, 790; (f) Sakakura, A.; Ohkubo, T.; Yamashita,
R.; Akakura, M.; Ishihara, K. Org. Lett., 2011, 13, 892.
Galat, A.; Elion, G. J. Am. Chem. Soc. 1943, 1566.
To further expand the scope of present reaction, application
study for the synthesis of various drugs and natural products was
carried out. In this direction, different drugs such as
7
8
.
.
Plagens, A.; Laue, T. M. 2005 Named organic reactions (2nd ed).
Chichester: John Wiley & Sons. ISBN 0-470-01041-X; (b) Kaim,
L. E.; Grimaud, L.; Oble, J. Angew. Chem. Int. Ed., 2005, 44,
7961; (c) Tanaka, Y.; Hasui, T.; Suginome, M. Org. Lett., 2007, 9,
5
,14a
6,14a
7,14b
phenacetin
synthesized. However, natural product like piperine
paracetamol
and lidocaine
8
were
was also
,14c
4
1
407; (d) Passerini, M.; Simone, L. Gazz. Chim. Ital., 1921, 51,
26; (e) Schulenberg, J. W.; Archer, S. Org. React. 2011
synthesized using present approach, as shown in fig. 2. Several
other drugs/drug intermediates or natural products can also be
synthesized using present method.
doi:10.1002/0471264180.or014.01; (f) Chapman, A. W. J. Chem.
Soc., Trans., 1925, 127, 1992; (g) Bodroux, F. Bull. Soc. Chim.
France, 1905, 33, 831.