A simple protocol for efficient N-chlorination of amides and carbamates

Article abstract of DOI:10.1055/s-2004-836061

N-Chlorination of various amides, lactams, and carbamates with very cheap trichloroisocyanuric acid proceeds efficiently under very mild conditions. Excellent results were also observed for the N-chlorination of carbamates of free amino acids.

Full text of DOI:10.1055/s-2004-836061

LETTER
223
A Simple Protocol for Efficient N-Chlorination of Amides and Carbamates
Efficient
N-Chli
d
n
of
A
mide
s
i
and
C
a
Dipartimento di di Chimica, Università degli Studi di Sassari, via Vienna 2, 07100 Sassari, Italy
Fax +39(079)212069; E-mail: ggp@uniss.it
Received 11 October 2004
When the starting compound is treated with 1.1 equivalent
of TCCA in dichloromethane at room temperature
(Scheme 1), N-chloroamides and carbamates are obtained
in very good yields (≥ 90%). To avoid any possible de-
composition due to distilling procedures, the chloroam-
ides were recovered by elimination of the solvent at room
temperature and reduced pressure. In all cases, they were
obtained as pure compounds from the reaction mixtures.
Abstract: N-Chlorination of various amides, lactams, and carbam-
ates with very cheap trichloroisocyanuric acid proceeds efficiently
under very mild conditions. Excellent results were also observed for
the N-chlorination of carbamates of free amino acids.
Key words: amides, amino acids, N-chlorination, trichloroisocya-
nuric acid
The reactions were generally fast and were terminated
within 1–3 hours (Table 1), when the starting material was
an amide or a N-Boc protected amino acid derivative. The
rate of the reaction seemed to depend on steric factors. In
fact, carbamates reacted slower than simple amides and in
the presence of sterically bulky groups, such as Cbz or
Fmoc groups, the reaction proceeded slowly (entries 12–
15) and could be accelerated raising the reaction tempera-
ture at the reflux of the solvent.
Trichloroisocyanuric acid, TCCA, belongs to the large
group of N-chloroimides and amides that are used as
bleaching agents, disinfectants, and bactericides owing to
their function as chlorinating agents and oxidants.1 Its
properties are similar to those of N-chlorosuccinimide
(NCS), which, however, is less stable. During our pro-
gram on the use of [1,3,5] triazine derivatives in organic
synthesis2 we were interested to study the possibility to
use TCCA in oxidation3 and chlorination4 reactions. It is
in fact known that N-halo compounds are versatile re-
agents in organic synthesis.5 In particular N-chloroamides
and N-chlorocarbamates are sources of amidyl and
carbamoyl radicals6 and precursors of a,b-dehydro amino
acids.7
It is important to note that, contrary to what observed in
using other methodologies,10–12 the N-chlorination can be
carried out on the carbamates of ‘free’ amino acids, with-
out protecting the carboxylic moiety and with comparable
yields.13
These compounds are generally prepared by N-chlorina-
tion with chlorine,8 commercial bleach,9 t-butyl hypochlo-
rite,6,7,10 and, more recently, with Oxone® in the presence
of NaCl11 or calcium hypochlorite on moist alumina.12
Unfortunately, these methods have certain drawbacks.
The concentration of ‘active’ chlorine in commercial
bleach is time depending, t-butyl hypochlorite is a hazard-
ous reagent owing to its instability and spontaneous com-
bustibility. Oxone® and calcium hypochlorite are more
efficient. However, they require heat and in the last case
long reaction times.
Primary amides yielded N,N-dichloroamides under the
above conditions (entries 1 and 2). However, the reaction
can be carried out to form the mono N-chloroamides, sim-
ply using 0.33 equivalent of TCCA and operating in ace-
tone:chloroform 1:2 (Scheme 2).14
O
O
1/3 equiv TCCA
H
H
R
N
H
R
N
acetone/ CHCl3 = 1:2
4 h
Cl
16, R = Ph yield = 97%
Therefore, in continuing our studies for developing new
methods of transformation of functional groups under
mild conditions, we decided to investigate the use of
TCCA in the conversion of amides and carbamates into
their N-chloro derivatives.
90%
17, R = Bn
Scheme 2
The chlorination reaction is slightly slower in these cases:
the target compounds, 1615 and 17,16 were, however, re-
covered chemically pure and in excellent yields (> 90%).
O
O
1.1 equiv TCCA, CH2Cl2
r.t., 1–3 h
R2(Cl)
R2(H)
In conclusion, this work has shown an easy transforma-
tion of amides, lactams, and carbamates of a-amino acids
into the corresponding N-chlorinated compounds through
reaction with TCCA: in all cases the yields are practically
quantitative and the products recovered in pure form from
the reaction mixtures. This method is characterized by
mild reaction conditions, non-toxic by-products and easy
reaction work-up, making it ideal for both laboratory and
large scale.
R1
N
H
R1
N
Cl
Scheme 1
SYNLETT 2005, No. 2, pp 0223–0226
0
1.
0
2.
2
0
0
5
Advanced online publication: 17.12.2004
DOI: 10.1055/s-2004-836061; Art ID: G34804ST
© Georg Thieme Verlag Stuttgart · New York

224
L. De Luca et al.
LETTER
Table 1 N-Chlorination of Amides, Lactams, and Carbamates with TCCA
Entry
1
Starting compound
Product
Reaction time (h)
2
Yield (%)
9317
O
O
Cl
NH2
N
Cl
1
2
1
90
O
O
Cl
NH2
N
Cl
2
3
4
2
1
97
O
O
H
N
H
H
N
Cl
3
9618
O
O
N
N
H
Cl
4
5
5
6
1
2
9519
CHO
CHO
N
N
H
Cl
9912
O
O
Cl
N
NH
6
7
8
1
3
3
3
3
9912
9912
90
O
O
Cl
N
NH
7
Ph
Ph
Boc
Boc
Boc
8
N
H
COOMe
COOH
N
COOMe
COOH
Cl
9
Ph
Ph
Boc
9
N
H
N
Cl
10
11
9912
HO
HO
Boc
Boc
Boc
10
Boc
11
N
H
COOMe
COOH
N
COOMe
COOH
Cl
90
HO
HO
N
H
N
Cl
Synlett 2005, No. 2, 223–226 © Thieme Stuttgart · New York

LETTER
Efficient N-Chlorination of Amides and Carbamates
225
Table 1 N-Chlorination of Amides, Lactams, and Carbamates with TCCA (continued)
Entry
12
Starting compound
Product
Reaction time (h)
10
Yield (%)
90
Cbz
N
Cbz
COOMe
COOH
N
H
COOMe
COOH
Cl
12
13
14
15
12
21
7
91
97
91
Cbz
Cbz
N
N
H
Cl
13
Fmoc
Fmoc
N
COOMe
N
COOMe
H
Cl
14
HO
HO
Fmoc
Fmoc
15
N
H
COOH
N
COOH
Cl
(8) Drago, R. S.; Wenz, D. A.; Carlson, R. J. J. Am. Chem. Soc.
1962, 84, 1106.
(9) Bachand, C.; Driguez, H.; Paton, J. M.; Touchard, D.;
Acknowledgment
The University of Sassari (Fondi ex-60%) has financially supported
this work.
Lessard, J. J. Org. Chem. 1974, 39, 3136.
(10) Zimmer, H.; Audrieth, L. F. J. Am. Chem. Soc. 1954, 76,
3856.
(11) Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.;
Tsadjout, A. Synlett 2000, 813.
(12) Larionov, O. V.; Kozhushkov, S. I.; de Meijere, A. Synthesis
2003, 1916.
(13) All solvents and reagents were used as obtained from
commercial source. Standard 1H NMR and 13C NMR were
recorded at 300 MHz and 75.4 MHz, from CDCl3 solutions.
Mass spectra were recorded at 70 eV with a direct probe for
sample introduction. All known compounds have analytical
data corresponding to literature data. All runs were
conducted at least in duplicate.
References
(1) Tilstam, U.; Weinmann, H. Org. Process Res. Dev. 2002, 6,
384.
(2) (a) Falorni, M.; Porcheddu, A.; Taddei, M. Tetrahedron Lett.
1999, 40, 4395. (b) Falorni, M.; Giacomelli, G.; Porcheddu,
A.; Taddei, M. J. Org. Chem. 1999, 64, 8962. (c) Falchi,
A.; Giacomelli, G.; Porcheddu, A.; Taddei, M. Synlett 2000,
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Chem. 2001, 66, 2534. (e) De Luca, L.; Giacomelli, G.;
Porcheddu, A. Org. Lett. 2001, 3, 1519. (f) De Luca, L.;
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Chem. 2002, 67, 5152. (h) De Luca, L.; Giacomelli, G.;
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Typical Procedure for the Preparation of N-Chloro-
amides.
Trichloroisocyanuric acid (5.25 mmol) was added at 0 °C to
a well stirred solution of the amide (5 mmol) in CH2Cl2 (30
mL) and the mixture was kept at r.t. for the required time,
monitoring (TLC) till completion. Then the mixture was
filtered on Celite and the solution evaporated under reduced
pressure affording the N-chloro derivative.
Spectroscopic Data of Selected Compounds:
(S)-2-(N-Chloroamino-N-tert-butoxycarbonyl)-3-
phenylpropanoic Acid (9): [a]D25 –54.98 (c 1, CH2Cl2). 1H
NMR: d = 10.51 (s, 1 H), 7.35–7.05 (m, 5 H), 4.60 (m, 1 H),
3.35–2.92 (m, 2 H), 1.40 (s, 9 H) ppm. 13C NMR: d = 174.9,
156.0, 139.4, 128.9, 128.5, 127.1, 79.5, 54.4, 37.7, 28.2 ppm.
MS (ES+): m/e (relative intensity) = 301 (32), 300(1), 299
(100). IR (film): 1255 cm–1.
(4) De Luca, L.; Giacomelli, G. Synlett 2004, 2180.
(5) (a) Fieser, M.; Fieser, L. F. Reagents for Organic Synthesis;
John Wiley and Sons: New York, 1967, 78. (b) Barton, D.
R. H.; Ollis, W. D. Comprehensive Organic Chemistry, Vol.
2; Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1979, 1030.
(6) Daoust, B.; Lessard, J. Tetrahedron 1999, 55, 3495; and
references therein.
(S)-Methyl 2-(N-Chloramino-N-benzyloxycarbonyl)-4-
methylpentanoate (12): [a]D20 –19.81 (c 0.5, CH2Cl2). 1H
NMR: d = 7.40–7.30 (m, 5 H), 5.27 (s, 2 H), 4.99 (dd,
J = 3.90, 11.70 Hz, 1 H), 3.70 (s, 3 H), 2.06–1.85 (m, 1 H),
1.77–1.59 (m, 2 H), 0.94 (d, 6 H) ppm. 13C NMR: d = 170.3,
(7) (a) Poisel, H.; Schmidt, U. Angew. Chem., Int. Ed. Engl.
1976, 15, 294. (b) Poisel, H. Chem. Ber. 1977, 110, 948.
(c) Kolar, A. J.; Olsen, R. K. Synthesis 1977, 457.
Synlett 2005, No. 2, 223–226 © Thieme Stuttgart · New York

226
L. De Luca et al.
LETTER
156.2, 135.3, 128.9, 128.5, 127.8, 66.9, 53.4, 52.4, 41.6,
24.2, 23.0, 20.7 ppm. MS (ES+): m/e (relative intensity) =
315 (34), 314 (15), 313 (100). IR (film): 1243 cm–1.
(2S,3S)-2-N-Chloramino-N-benzyloxycarbonyl)-3-
methylpentanoic Acid (13): [a]D20 –4.52 (c 0.5, CH2Cl2).
1H NMR d = 7.37–7.29 (m, 5 H), 5.08 (s, 2 H), 4.43–4.33 (m,
1 H), 2.02–1.80 (m, 1 H), 1.62–1.39 (m, 1 H), 1.28–1.13 (m,
1 H), 0.92 (m, 6 H) ppm. 13C NMR: d = 173.8, 156.3, 135.1,
128.8, 128.4, 128.2, 69.4, 58.2, 37.5, 24.6, 15.4, 10.3 ppm.
MS (ES+): m/e (relative intensity) = 301 (32), 300(6), 299
(100). IR (film): 1267 cm–1.
(S)-Methyl 2-[N-Chloramino-N-(9H-fluoren-9-yl)meth-
oxycarbonyl]-3-methylbutanoate (14): [a ]D20 –4.13 (c 0.1,
CH2Cl2). 1H NMR: d = 7.62 (d, 2 H), 7.56 (d, 2 H), 7.26–7.13
(m, 4 H), 4.47–4.35 (m, 2 H), 4.30 (m, 1 H), 4.19 (t, 1 H),
3.76 (s, 3 H), 2.25–2.10 (m, 1 H), 0.97 (d, 3 H), 0.92 (d, 3 H)
ppm. 13C NMR: d = 172.6, 156.0, 145.4, 138.7, 128.9, 128.1,
125.4, 120.9, 67.8, 59.0, 53.4, 52.2, 31.1, 18.8, 17.5 ppm.
MS (ES+): m/e (relative intensity) = 389 (35), 387 (100), 388
(19), 390 (5). IR (film): 1216 cm–1. Anal. Calcd for
C21H22ClNO4 (387.86): C, 65.03; H, 5.72; Cl, 9.14; N, 3.61.
Found: C, 65.05; H, 5.78; Cl, 9.18; N, 3.64.
7.27–7.12 (m, 6 H), 6.47 (br s, 1 H), 4.46 (s, 2 H), 4.18–3.70
(m, 4 H) ppm. 13C NMR: d = 173.8, 156.6, 145.2, 144.8,
129.0, 128.2, 125.2, 120.8, 67.9, 55.9, 46.8 ppm. MS (ES+):
m/e (relative intensity) = 363 (28), 361 (100), 336 (19), 364
(5). IR (film): 1230 cm–1. Anal. Calcd for C18H16ClNO5
(361.07): C, 59.76; H, 4.46; Cl, 9.80; N, 3.87. Found: C,
59.72; H, 4.48; Cl, 9.80; N, 3.84.
(14) Typical Procedure for the Preparation of N-
Chloroamides from Primary Amides.
Trichloroisocyanuric acid (1.60 mmol) was added slowly, in
small portions, and at 0 °C to a well stirred solution of the
amide (5 mmol) in dry acetone:CHCl3 (1:2 solution, 30 mL)
and the mixture was kept at r.t. for the required time,
monitoring (TLC) till completion. Then the mixture was
filtered on Celite and the solution evaporated under reduced
pressure affording the N-chloro derivatives 16 and 17.13,16
(15) De Rosa, M.; Brown, K.; McCoy, M.; Ong, K.; Sanford, K.
J. Chem. Soc., Perkin Trans. 2 1993, 1787.
(16) De Sarlo, F.; Guarna, A.; Brandi, A.; Mascagni, P. Gazz.
Chim. Ital. 1980, 110, 341.
(17) Roberts, J. T.; Rittberg, B. R.; Kovacic, P. J. Org. Chem.
1981, 46, 3988.
(S)-2-[N-Chloramino-N-(9H-fluoren-9-yl)methoxy-
carbonyl]-3-hydroxypropanoic Acid (15): [a]D20 –11.96 (c
0.2, CH2Cl2). 1H NMR: d = 10.41 (s, 1 H), 7.43 (d, 2 H),
(18) Johnson, R. A.; Greene, F. D. J. Org. Chem. 1975, 40, 2186.
(19) Goosen, A.; McCleland, C. W.; Merrifield, A. J. J. Chem.
Soc., Perkin Trans. 1 1992, 627.
Synlett 2005, No. 2, 223–226 © Thieme Stuttgart · New York