N,N′-Dichloro bis(2,4,6-trichlorophenyl)urea (CC-2): an efficient reagent for the synthesis of α-chloro-nitroso compounds

Article abstract of DOI:10.1016/j.tetlet.2006.12.001

A simple, efficient, rapid, and mild method for the synthesis of α-chloro-nitroso compounds is described using bis(2,4,6-trichlorophenyl)urea (CC-2).

Full text of DOI:10.1016/j.tetlet.2006.12.001

Tetrahedron Letters 48 (2007) 767–770
N,N0-Dichloro bis(2,4,6-trichlorophenyl)urea (CC-2): an
efficient reagent for the synthesis of a-chloro-nitroso compounds
A. K. Gupta, J. Acharya, D. Pardasani and D. K. Dubey*
Vertox Laboratory, Defence R&D Establishment, Jhansi Road, Gwalior 474 002, MP, India
Received 3 October 2006; revised 22 November 2006; accepted 1 December 2006
Available online 19 December 2006
Abstract—A simple, efficient, rapid, and mild method for the synthesis of a-chloro-nitroso compounds is described using bis(2,4,6-
trichlorophenyl)urea (CC-2).
ꢀ 2006 Elsevier Ltd. All rights reserved.
a-Chloro-nitroso compounds are versatile intermediates
for the synthesis of various organic compounds, and dif-
ferences in their chemical and biological properties is
governed by reactions in which either one or more of
the functional groups take part in the reactions.1–5 Sev-
eral methods have been developed to prepare aliphatic
and cyclic a-halo-nitroso compounds from their corre-
sponding oximes, by using various halogenating agents
such as elemental chlorine,6 aqueous hypochlorous
acids,6 nitrosyl chloride,7 alkylhypochlorites,8 N-bromo-
succinimide,9 and N-bromoacetamide.10 These methods
often result in the formation of undesired side products
such as over-oxidized nitro- and/or keto-derivatives,11,12
mixtures of gem-dichloro alkanes and dimerized prod-
ucts of a-chloro-nitroso compounds. Since the reaction
of ketoximes with elemental chlorine is reversible, con-
tinuous removal of HCl is necessary to drive the reac-
tion to completion. On the other hand, the reactions
of ketoximes with other halogenating agents need to
be controlled at the a-chloro-nitroso stage only to avoid
the formation of over-oxidized products. Control of the
reaction could either be governed by manipulating the
reaction conditions or by using selective reagents.
Quenching the reaction at the a-chloro-nitroso stage
would entail a study of the kinetic profile of the reaction.
The use of selective reagents has also been reported but
many of them have drawbacks such as the use of haz-
ardous solvents, long reaction times, involve tedious
work-ups and result in poor to moderate yields.12,13
Due to these limitations, there is a need to develop effi-
cient reagents and synthetic methods that would afford
better yields in shorter reaction times.
The use of recyclable reagents in organic synthesis has
received considerable attention due to stringent environ-
mental rules.14 We have investigated the possibility of
Cl
HO
Cl
Cl
Cl
N
Cl
Cl
Cl
Cl
CH3CN, r.t.
15-45 min
Cl
ON
R
N
C
O
C
O
C
C
+
+
R'
N
H
N
H
N
Cl
R
Cl
Cl
Cl
Cl
Cl
1
2
3
4
Scheme 1.
Keywords: N,N0-Dichloro bis(2,4,6-trichlorophenyl)urea; CC-2; Bis-(2,4,6-trichlorophenyl)urea; a-Chloro-nitroso alkanes; Oximes; tert-Butyl
hypochlorite.
*
Corresponding author. Tel.: +91 7512233488; fax: +91 7512341148; e-mail: dkdubey@rediffmail.com
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.12.001

768
A. K. Gupta et al. / Tetrahedron Letters 48 (2007) 767–770
Table 1. Preparation of a-chloro-nitroso compounds from ketoximes using CC-2
Entry
1
Substrate
Producta
Time (min)
15
Yieldb
96
NOH
Cl
ON
H3C
C2H5
Cl
C2H5
NOH
C3H7
H3C
H3C
ON
2
3
4
5
6
7
15
20
30
15
20
30
94
95
96
92
94
89
H3C
C3H7
NOH
iC4H9
Cl
ON
iC4H9
H3C
H3C
H3C
NOH
tC4H9
Cl
ON
tC4H9
H3C
NOH
Cl
Cl
ON
ON
NOH
Cl
NOH
ON
Cl
NOH
NOH
NO
NO
8
9
35
25
30
45
85
88
89
82
Cl
NO2
NO2
10
11
Cl
NO
NOH
Cl
NO
NOH
NOH
Cl
ON
12
13
40
45
80
80
O
O
Cl
Cl
NOH
ON
NOH
NO
a All the products were compared with authentic sample and gave satisfactory IR, NMR, and MS data.
b Isolated yields.

A. K. Gupta et al. / Tetrahedron Letters 48 (2007) 767–770
769
using a stable, nontoxic, and efficient chlorine releasing
References and notes
reagent namely, N,N0-dichloro bis(2,4,6-trichlorophen-
yl)urea (CC-2) 2.15 CC-2 has been incorporated as a
reactive ingredient in a formulation developed in our
laboratory to decontaminate bis-(2-chloroethyl)sulfide
(sulfur mustard), a cytotoxic, alkylating vesicant chemi-
cal warfare agent.16 Having established a commercially
viable synthetic procedure for CC-2, we explored its
application in the synthesis of dialkyl chloro phosphate
from dialkyl phosphates.17 In continuation of this work,
we have explored the use of CC-2 as an alternative re-
agent for the conversion of ketoximes to a-chloro-nitro-
so compounds. Herein, we describe a convenient, rapid,
economic, environmentally friendly, and scaleable meth-
od for the synthesis of a-chloro-nitroso compounds
from their corresponding ketoximes at room tempera-
ture.18 This method has allowed us to obtain excellent
yields of the products in reduced reaction times. The
general synthetic method is given in Scheme 1.
1. (a) Cecherelli, P.; Curini, M.; Epifano, F.; Marcotullio, M.
C.; Rosati, O. Tetrahedron Lett. 1998, 39, 4385; (b)
Tordeux, M.; Boumizane, K.; Wakselman, C. J. Org.
Chem. 1993, 58, 1939.
2. (a) Sabuni, M.; Kresz, G.; Braun, H. Tetrahedron Lett.
1984, 25, 5377; (b) Walters, T. R.; Zajac, W., Jr.; Woods,
J. M. J. Org. Chem. 1991, 56, 316.
3. Yamamoto, M.; Momiyama, N. Chem. Commun. 2005,
3514.
4. Martynov, I. V.; Chepakova, L. A.; Brel, V. K.; Sokolov,
V. B. Zh. Obshch. Khim. 1986, 56, 2020.
5. (a) Kruglyak, Yu. L.; Landau, M. A.; Leibovskaya, G. A.;
Martynov, I. V.; Saltykova, L. I. Zh. Obshch. Khim. 1971,
41, 2338; (b) Kayen, A. H. M.; De Boer, Th. Recl. Trav.
Chim. Phys. Bas. 1977, 96, 8.
6. (a) Archibald, T. G.; Garver, L. G.; Baum, K.; Cohen, M.
C. J. Org. Chem. 1989, 54, 2869; (b) Labaziewicz, H. L.;
Riddell, F. G. J. Chem. Soc., Perkin Trans. 1 1979, 2926;
(c) Diekmann, H.; Luttke, W. Angew. Chem., Int. Ed.
Engl. 1968, 7, 388; (d) Barnes, M. W.; Patterson, J. M. J.
Org. Chem. 1976, 41, 733.
7. (a) Kugelman, M.; Mallams, A. K.; Vernay, H. F. J.
Chem. Soc., Perkin Trans. 1 1976, 1113; (b) Bozzi, E. G.;
Shiue, Ch. Y.; Clapp, L. B. J. Org. Chem. 1973, 38, 56.
8. (a) Diekmann, H.; Luttke, W. Angew. Chem., Int. Ed.
Engl. 1968, 7, 387; (b) Corey, E. J.; Estreicher, H.
Tetrahedron Lett. 1980, 21, 1117; (c) Felber, H.; Kresze,
G.; Brau, H.; Vasella, A. Tetrahedron Lett. 1984, 25, 5381.
9. Bull, J. R.; Jones, E. R. H.; Meakins, G. D. J. Chem. Soc.
1965, 2601.
To demonstrate the versatility of this reagent, a variety
of ketoximes were chlorinated (Table 1). It is evident
from Table 1, that changing the alkyl chain length does
not influence significantly the reaction time (entries 1–4).
Aliphatic/alicyclic ketoximes reacted a little faster than
aromatic ketoximes, while aromatic and bicyclic ketoxi-
mes required longer times which could be attributed to
steric hindrance. We also examined the role of other fac-
tors such as temperature and solvents and found that
these also influenced the course of the reaction to some
extent. Although the reactions were exothermic, external
cooling was not necessary. Amongst various solvents,
dichloromethane and acetonitrile were found to be the
most suitable in terms of reaction time, yield and
work-up. One of the unique features of this method is
convenient isolation of the reaction products. The by-
product, bis-(2,4,6-trichlorophenyl)urea (4) was insolu-
ble and hence could be removed by filtration.
10. Iffland, D. C.; Fu-Yen, T. J. Am. Chem. Soc. 1954, 76,
4083.
11. Wichterle, O.; Hudlicky, M. Collect. Czech. Chem. Com-
mun. 1947, 12, 661.
12. (a) Cuthbertson, F.; Musgrave, W. K. R. J. Appl. Chem.
1957, 7, 99; (b) Doering, W. Von.; Henderson, W. A., Jr.
J. Am. Chem. Soc. 1958, 80, 5274; (c) Orazi, O. O.; Corral,
R. A.; Schuttenberg, H. J. Chem. Soc., Perkin Trans. 1
1974, 2087; (d) Olah, G. A.; Welch, J. Synthesis 1974,
2087; (e) Seyferth, D.; Murphy, G. J.; Mauze, B. J. Am.
Chem. Soc. 1977, 99, 5317; (f) Villieras, J.; Perriot, P.;
Normant, J. F. Bull. Soc. Chim. Fr. 1977, 765; (g)
Kruglova, N. V.; Freidline, R. K. Bull. Acad. Sci. USSR,
Engl. Trans. 1984, 346; (h) Lee, G. M.; Weinreb, S. M.
J. Org. Chem. 1990, 55, 1281.
Both aliphatic and aromatic a-chloro-nitroso com-
pounds were stable for several days if stored below
5 ꢁC. Tertiary nitroso compounds, on the other hand,
were quite stable.
13. Migrdiechian, V. Organic Synthesis. In Open Chain
Saturated Compounds; Chapman and Hall: London,
1960; Vol. 1, p 702.
14. Laszlo, P. Organic Reactions: Simplicity and Logic; Wiley:
New York, 1995.
15. Dubey, D. K.; Malhotra, R. C.; Vaidyanathaswamy, R.;
Vijayraghavan, R. J. Org. Chem. 1993, 64, 8301.
16. Vijayraghavan, R.; Praveen Kumar; Dubey, D. K.; Ram
Singh Biomed. Enviro. Sci. 2002, 15, 25.
17. Shakya, P. D.; Dubey, D. K.; Pardasani, D.; Palit, M.;
Gupta, A. K. J. Chem. Res. 2005, 821–823.
18. (a) Typical experimental procedure: A solution of 2,2,6,6-
tetramethylcyclohexanone oxime, (8.45 g, 0.05 mol) in
50 mL dry acetonitrile was added slowly to a suspension
of CC-2, (12.2 g, 0.025 mol) in 25 mL acetonitrile with
stirring at room temperature. A blue color appeared after
mixing the reactants which indicated formation of the
product. The flask was wrapped with black carbon paper
to avoid photochemical reactions. Progress of the reaction
was monitored by TLC and GC analysis. The reaction
mixture was filtered under suction and washed with
acetonitrile (3 · 10 mL). The solvent was evaporated and
Caution: gem-Chloro-nitroso compounds are thermally
unstable. Great caution should be exercised especially
when distilling them, if the pressure is allowed to rise,
explosion may occur.6
In conclusion, we have reported a highly efficient meth-
od for the preparation of aliphatic as well as aromatic
a-chloro-nitroso compounds in excellent yields. This
method has advantages over earlier reported methods
in terms of versatility, easy work-up, recyclability of
the reagent (4 was collected after filtration, re-chlori-
nated and used for further reactions) and reaction time.
Acknowledgement
We thank Shri K. Sekhar, Director, DRDE Gwalior, for
his keen interest and encouragement.

770
A. K. Gupta et al. / Tetrahedron Letters 48 (2007) 767–770
the residue was crystallized from acetonitrile–hexane
dissolved in 200 mL of acetic acid and 20 mL of pyridine
was added followed by stirring at 70 ꢁC. Chlorine gas was
bubbled into the reaction for 4 h with stirring. Absorption
of chlorine ceased with complete precipitation of bis(2,4,6-
trichlorophenyl)urea. The mixture was cooled to 10 ꢁC in
an ice bath, and solid NaOH (7 g) was added in portions
to bring the pH of the mixture to almost neutral. Chlorine
gas was passed through until all the organic matter had re-
dissolved. The mixture was poured into water to precip-
itate the CC-2, which was washed with water, filtered and
re-crystallized from toluene. After drying, the yield was
56 g, 98%, mp 179–180 ꢁC. The chlorine content of CC-2
was checked by standard iodometric titration and was
found to be 14.51% (theoretical value 14.54%).
(70:30 by volume) mixture to afford a-chloro-nitroso-
2,2,6,6-tetramethylcyclohexane as blue crystals; yield:
9.06 g (89%), mp 115–116 ꢁC (Table 1, entry 7). 1H
NMR (400 MHz, CDCl3): d = 2.75 (m, 2H), 2.40 (m, 1H),
2.18 (m, 1H), 1.86 (m, 2H), 1.21 (s, 6H), 0.28 (s, 6H). 13C
NMR (100.62 MHz, CDCl3): 136.51, 42.15, 40.25, 27.56,
20.06. MS; m/z (%) = 168 (8), 158 (14), 145 (15), 143 (48),
137 (54), 131 (13), 123 (26), 107 (17), 105 (20), 107 (18), 97
(16), 91 (14), 95 (42), 83 (25), 81 (38), 79 (19), 69 (100), 67
(38), 57 (36), 55 (46), 43 (24), 41 (73). IR (KBr): 2961,
2925, 2875, 1592, 1478, 1381, 1367, 1212, 638 cmꢀ1
.
(b) Preparation of N,N0-dichloro bis(2,4,6-trichlorophen-
yl)urea (CC-2): Bis(diphenyl)urea (25 g, 0.117 mol) was