N,N′-dichlorobis(2,4,6-trichlorophenyl)urea (CC-2): An efficient reagent for N-chlorination of amino esters, amide, and peptides

Article abstract of DOI:10.1246/cl.2007.996

A simple, efficient, and rapid protocol for N-chlorination of various protected amino esters, amides, and peptides has been described. N,N′-dichlorobis(2,4,6-trichlorophenyl)urea has been used as a chlorinating agent and transformation takes place rapidly in mild conditions with quantitative yields. Copyright

Full text of DOI:10.1246/cl.2007.996

996
Chemistry Letters Vol.36, No.8 (2007)
N,N0-Dichlorobis(2,4,6-trichlorophenyl)urea (CC-2):
An Efficient Reagent for N-Chlorination of Amino Esters, Amide, and Peptides
Manisha Sathe, Hitendra Karade, and Mahabir Parshad Kaushikꢀ
Discovery Centre, Process Technology Development Division, Defence R & D Establishment,
Jhansi Road, Gwalior-474002, (M P), India
(Received May 7, 2007; CL-070489; E-mail: mpkaushik@rediffmail.com)
A simple, efficient, and rapid protocol for N-chlorination of
Treatment of various amino esters, amides and dipeptides
1 (1–12) in the presence of 2 at room temperature afforded the
corresponding N-chloro compounds 3 (1–12) in 10 min with
quantitative yields Table 1. It is also evident from Table 1, that
2 does bring about a smooth N-chlorination of various ꢀ as
well as ꢁ amino esters, carbamate, protected amino esters,
tolerating sensitive functionalities such as, unprotected primary
hydroxy group in N-Boc-protected serine methyl ester (Table 1,
Entry 9). Similarly, this method can also be extended for the
chlorination of highly strained bicyclic ꢁ-lactam (Table 1,
Entry 4) and peptide7 (Table 1, Entries 11 and 12). A number
of previously unknown N-protected N-chlorinated amino acid
various protected amino esters, amides, and peptides has been
described. N,N0-dichlorobis(2,4,6-trichlorophenyl)urea has been
used as a chlorinating agent and transformation takes place
rapidly in mild conditions with quantitative yields.
Halogenation in general and chlorination in particular, is
one of the important biochemical mechanism used by mamma-
lians as protection from pathogens.1 N-chlorinated amino esters,
are also of fundamental chemical interest as they show distinct
physical, chemical, and biological properties.2 These com-
pounds exhibit pharmacological activity, because of their oxidiz-
ing action in aqueous, partial aqueous and non-aqueous media,
which has further stimulated recent interest in their chemistry.
Therefore, an understanding of the synthesis, properties and re-
actions of N-chloro derivatives of amino esters are of importance
in medicinal chemistry. Although, myriad reagent3 employed for
the synthesis of N-chloro derivatives of amino esters have been
reported, there is still scope for improvement, as the existing
chlorinating methods suffers from one or more drawbacks, like
use of toxic and hazardous reagent, long reaction time, harsh
reaction conditions, short shelf life, difficulties in isolation of
products, and formation of by-products leading to low yields.
Moreover, N-chlorinated products so formed are unstable in
the aqueous basic media. Advantages such as cleaner reactions,
short reaction times and easy work up have kindled a special in-
terest in the synthesis of N-chloro compounds of amino esters.
During the course of our study on chlorination, we encountered
a reagent namely N,N0-dichlorobis(2,4,6-trichlorophenyl)urea,4
which is, mild, non-toxic, stable, safe, and efficient chlorine re-
leasing reagent. It also has high concentration of active chlorine
and previously has been used for the synthesis of ꢀ-chloro-
nitoso compounds5 and selective oxidation of sulfides to sulfox-
ides.6 To the best of our knowledge, the reagent has also not been
reported in the literature as chlorinating agent. Herein, we de-
scribe a convenient, rapid, environmental friendly and scaleable,
method for the synthesis of N-chloro compounds of amino
esters, amides, and peptides using N,N0-dichlorobis(2,4,6-tri-
chlorophenyl)urea (2) in non-aqueous media. This method has
allowed us to obtain excellent yields of N-chlorinated com-
pounds 3 (1–12) in the reduced reaction time. The general syn-
thetic method is given in Scheme 1.
Table 1. N-chlorination of amino esters, amides, and peptides
using CC-2
Entry
1.
Substrate (1)
Producta (3)
Yield/%b
92
(1–12)
(1–12)
C6H5CONClCH2C6H5
Cl
C6H5CONHCH2C6H5
H
N
O
N
O
95
90
2.
3.
Cl
N
NH
O
O
O
N
O
89
90
4.
5.
6.
NH
Cl
Cl
NHBoc
NBoc
COOCH3
NHBoc
COOCH3
Cl
NBoc
86
94
COOCH3
O
COOCH3
O
CH2COOCH3
CH2COOCH3
C6H5
O2N
7.
8.
C6H5
O2N
N
N
Cl
H
COOCH3
COOCH3
NHBoc
OH
88
85
NBoc
Cl
OH
9.
BocN
BocHN
COOCH3
COOCH3
COOCH3
Cl
90
10.
BocHN
COOCH3
BocN
Cl
O
H
O
H
N
CH3
CH3
CH3
CH3
11.
12.
N
92
90
BocHN
BocHN
O
O
BocN
Cl
O
O
O
O
O
H
N
O
H
N
O
Cl
R2
Cl Cl
Cl
Cl
Cl
Cl Cl
Cl
O
O
O
CH3CN
BocN
Cl
R1
N
N
N
N
H
N
H
rt, 10 min
O
O
NH
R1
Cl
Cl
Cl
Cl
Cl
Cl
R2
3
1
4
2
(1-12)
(1-12)
aAll compounds have been characterized by IR, NMR, and MS.
bIsolated yield.
Scheme 1.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.8 (2007)
997
esters containing a cyclopropane moiety (Table 1, Entry 8) could
be prepared by this method.8 Effect of solvents was studied on
the chlorination of substrates and acetonitrile was found to be
the most suitable solvent in terms of reaction time, yield, and
work-up. Substituents present on the nitrogen atom of the
substrate also did not have any effect on the chlorination. Most
of the compounds have been found to be stable for 3 months
at 25 ꢁC except peptides (Table 1, Entries 11 and 12). Most
probably, the chlorination takes place via the transfer of chlorine
from 2 to the nitrogen of the various substrates used 1 (1–12).
The important advantage of this reaction is its occurrence
at room temperature.9 The noteworthy feature of this reagent
is that the monitoring of the reaction is very easy; completion
of reaction was confirmed by the precipitation of 1,3-bis(2,4,6-
trichlorophenyl)urea (4), within 10 min, from the homogenous
reaction medium. Furthermore, the reaction does not require
any additional work up except filteration. The important applica-
tion of these N-chloro compounds lies in their mild oxidizing
properties; hence it can be used for the oxidative decontamina-
tion of hazardous chemicals.10 Moreover, large number of
pharmacologically active compounds can also be synthesized
by following this method/reagent. In conclusion, we have
exploited the chlorinating property of N,N0-dichlorobis(2,4,6-tri-
chlorophenyl)urea (2) for the preparation of various N-chloro
compounds. The striking features of the reagent are: short
reaction time, wide applicability, easy work up procedures,
recyclability (4 was recovered, re-chlorinated and used for
further reactions) and quantitative yields.
Vijayraghavan, J. Org. Chem. 1999, 64, 8031.
A. K. Gupta, J. Acharya, D. Pardasani, D. K. Dubey, Tetra-
hedron Lett. 2007, 48, 767.
R. Vijayraghavan, Praveen Kumar, D. K. Dubey, R. Singh,
Biomed. Enviro. Sci. 2002, 15, 25.
5
6
7
8
N-Chloro-dipeptides are not stable for long, and undergo
base-promoted decomposition.
N-Chlorination of the cyclopropyl-containing amino acid
derivatives (Entry 8) with any of the other known reagents
was hampered to a greater extent by some side processes
furnishing the corresponding N-chlorinated products in low
yield and purity.
9
(a) Typical experimental procedure: To a stirred solution of
cyclic amide (Entry 2) (0.8 g, 0.01 mol) in acetonitrile
(15 mL) N,N0-dichlorobis(2,4,6-trichlorophenyl)urea was
added (2.4 g, 0.005 mol) at room temperature. The resulting
mixture was stirred at room temperature for 10 min. The
progress of reaction has been monitored by TLC (EtOAc:
hexane 2:8). After the completion of reaction 1,3-bis(2,4,6-
trichlorophenyl)urea precipitated indicating the completion
of reaction. It was then filtered to remove the precipitate
followed by the removal of solvent under vacuum to afford
the pure products. Typical spectral data: 3(5): Viscous oil,
IR (film), ꢂmax 1737, 1236, 1260 cmꢂ1 1H NMR (CDCl3,
;
400 MHz) ꢃ 1.40 (s, 9H), 1.44 (m, 4H), 1.66 (m, 2H), 1.79
(m, 2H), 2.87 (dd, 1H, J ¼ 4:66, 6.0 Hz), 3.67 (s, 3H),
4.17 (m, 1H); 13C NMR (CDCl3, 100 MHz) ꢃ 21.3, 21.5,
24.2, 25.2, 28.7, 37.6, 49.3, 56.7, 70.1, 157, 176; ESI-MS
292 (M + H). Anal. Calcd for C13H22ClNO4: C, 53.51; H,
7.60; N, 4.80%. Found: C, 53.47; H, 7.55; N, 4.76%. 3(6):
Viscous oil, IR (film) ꢂmax: 1735, 1239, 1266 cmꢂ1: 1H NMR
(CDCl3; 400 MHz) ꢃ 1.26–1.29 (m, 8H), 1.40 (s, 9H), 1.50–
1.64 (m, 4H), 2.87 (dd, 1H, J ¼ 4:1, 6.6 Hz), 3.25 (m, 1H),
3.67 (s, 3H); 13C NMR (CDCl3; 100 MHz) ꢃ 24.7, 24.9,
26.2, 27.2, 28.7, 30, 33.2, 45, 47, 50.7, 70.6, 157, 176.
ESI-MS 320 (M + H). Anal. Calcd for C15H26ClNO4: C,
56.33; H, 8.19; N, 4.38%. Found: C, 56.28; H, 8.10; N,
4.33%.
References and Notes
1
2
3
S. T. Test, S. J. Weiss, Adv. Free Radical Biol. Med. 1986, 2,
91.
a) A. J. Kolar, R. K. Olsen, Synthesis 1977, 457. b) B.
Daoust, J. Lessard, Tetrahedron 1999, 55, 3495.
a) C. Bachand, H. Driguez, J. M. Patson, D. Touchard,
J. Lessard, J. Org. Chem. 1974, 39, 3136. b) M. Curini, F.
Epifano, M. C. Marcotullio, O. Rosati, A. Tsadjust, Synlett
2000, 813.
4
D. K. Dubey, R. C. Malhotra, R. Vaidyanathaswamy, R.
10 R. S. Neale, N. L. Marcus, J. Org. Chem. 1969, 34, 1808.
Published on the web (Advance View) June 30, 2007; doi:10.1246/cl.2007.996