Preparation of N-chloroamides using trichloroisocyanuric acid

Article abstract of DOI:10.1081/SCC-200066703

Amides are efficiently converted to N-chloroamides by trichloroisocyanuric acid in methanol. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200066703

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Preparation of N‐Chloroamides
Using Trichloroisocyanuric Acid
Gene A. Hiegel a , Tyrone J. Hogenauer a & Justin C.
Lewis a
a Department of Chemistry and Biochemistry,
California State University, Fullerton, California,
USA
Version of record first published: 16 Aug 2006.
To cite this article: Gene A. Hiegel, Tyrone J. Hogenauer & Justin C. Lewis
(2005): Preparation of N‐Chloroamides Using Trichloroisocyanuric Acid, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:15, 2099-2105
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Synthetic Communicationsw, 35: 2099–2105, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200066703
Preparation of N-Chloroamides Using
Trichloroisocyanuric Acid
Gene A. Hiegel, Tyrone J. Hogenauer, and Justin C. Lewis
Department of Chemistry and Biochemistry, California State University,
Fullerton, California, USA
Abstract: Amides are efficiently converted to N-chloroamides by trichloroisocyanuric
acid in methanol.
Keywords: Amides, chlorination, N-chloroamides, preparation, trichloroisocyanuric
acid, synthesis
N-Chloramides can be an intermediate in the familiar Hoffmann degradation
for the conversion of amides into amines containing one less carbon
(Scheme 1).[1] The N-chloroamides used in the Hoffmann degradation were
often prepared utilizing a high concentration of hypochlorite solution, which
was made from chlorine gas generated by reacting hydrochloric acid with
potassium permanganate.[2] N-Chloroamides have also been prepared using
t-butyl hypochlorite,[3,4] calcium hypochlorite,[5] N-chlorobenzotriazole with
microwave radiation,[6] N-chlorosuccinimide with n-butyllithium,[7] and
chlorine gas.[8]
Several N-chloroamides and imides that are used as chlorinating agents[9]
and N-chloro-D1-4-azasteroids[10] were prepared using trichloroisocyanuric
acid [TCICA; 1,3,5-trichloro-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione; C3Cl3N3O3].
However, no general procedure for the preparation of N-chloroamides using
Received in the USA April 11, 2005
Address correspondence to Gene A. Hiegel, Department of Chemistry and Bio-
chemistry, California State University, Fullerton, CA 92834, USA. E-mail: ghiegel@
fullerton.edu
2099

2100
G. A. Hiegel, T. J. Hogenauer, and J. C. Lewis
Scheme 1.
TCICA, a stable solid, has been developed. Consequently, we undertook an
investigation of the reaction between amides and TCICA.
First, a study of the effect of solvent on the N-chlorination of p-toluamide
was carried out using acetonitrile, methylene chloride, methyl acetate,
acetone, and methanol. As determined by TLC, complete conversion at
room temperature took 1.5 h, 24 h, 6 h, 5 h, and 0.5 h, respectively. Then,
using a 1-h reaction time and methanol as the solvent, it was determined
that an equivalent ratio of amide to TCICA of 1 to 1.10 gave a high yield
of crude product of high purity (Scheme 2). Although preliminary studies
with p-toluamide in methanol showed that the reaction was complete in
30 min, a 1-h reaction time was used for subsequent reactions.
A simple general procedure was developed for the preparation of
N-chloroamides. After the amide dissolved in methanol, TCICA was added
and the solution stirred for 1 h at room temperature. The solid cyanuric acid
that formed was removed by filtration, and after evaporation of the
methanol, the crude product was purified by flash chromatography or recrys-
tallization. The results for a number of N-chloroamides are shown in Table 1.
EXPERIMENTAL
All reagents were used as received unless otherwise stated. Reagent-grade
acetone, anhydrous methanol, anhydrous acetonitrile, p-toluamide, and cyclo-
hexanecarboxamide were obtained from Aldrich Chemical Co. Hexanamide,
octanamide, decanamide, and 2-phenylacetamide were obtained from TCI
Chemical Co. Anhydrous diethyl ether and reagent-grade dichloromethane
were obtained from EM Science. Benzamide (practical) was obtained from
Acros Chemical Co. and was recrystallized from benzene (mp 125.0–
125.88C). p-Toluidine was obtained from Avocado Chemical Co. Butanamide
(practical) was obtained from Eastman Chemical Co. and was recrystallized
Scheme 2.

N-Chloroamides
2101
Table 1. Preparation of N-chloroamides from amides
Purified
yield
Amide
N-Chloroamide
Melting pointa
95%b
92%c
114.0–115.08C
115.0–116.08C
95%b
94%c
146.0–146.88C
147.0–147.88C
97%b
75%c
129.0–130.08C
129.5–130.08C
68%c
139.0–140.08C
94%b
89%b
86%b
97%c
One spot on TLCd
One spot on TLCd
One spot on TLCd
40.5–41.58C
aMelting points are uncorrected.
bPurified by flash chromatography.
cPurified by recrystallization.
dLiquid.
from benzene (mp 112.0–112.88C). Trichloroisocyanuric acid (99%) was
obtained from Chem Lab Products.
1H FT-NMR spectra were recorded in CDCl3, CD3CN, or CD3COCD3
using an Anasazi-modified Varian EFT 90-MHz spectrometer. FT-IR
spectra were recorded using a Perkin Elmer 1650 spectrometer. TLC was
performed using Bakerflex silica-gel IB-F plates, 2.5 Â 7.5 cm from J. T.

2102
G. A. Hiegel, T. J. Hogenauer, and J. C. Lewis
Baker using diethyl ether as the solvent. Melting points were taken using a
Thomas Hoover Uni-Melt capillary melting-point apparatus and are uncor-
rected. Flash chromatography was performed using silica gel, grade 9385,
˚
230–400 mesh, 60 A from Aldrich Chemical Co.
1
N-Chloroamides were characterized by FT-IR and H FT-NMR spectra
and by comparison of the melting point with the literature data or by conver-
sion back to the amide using sodium hydrogen sulfite. The recovered amides
were then compared with the starting amides by mixture melting points and
1
FT-IR and H FT-NMR spectra. IR bands characteristic of the N-Cl linkage
in benzamide derivatives occur at 1250–1272 and 882–910 cm21 [4]
.
N-Chlorination of p-toluamide: In a 200-mL, round-bottom flask were
placed 100 mL methanol and 7.576 (56.05 mmol) of p-toluamide, and the
mixture was allowed to stir until the solid dissolved. TCICA, 4.780 g
(20.57 mmol, 61.70 meq), was added and a precipitate of cyanuric acid
formed in 8 min. After stirring for 1 h, the mixture was vacuum filtered and
the solid was washed with methylene chloride. The solvent was removed
from the filtrate using a rotary evaporator to give 9.857 g (103.7%) of crude
solid product. Recrystallization from benzene gave 8.938 g (94.0%) of N-
chloro-p-toluamide: mp 147.0–147.88C (Lit.[4] mp 1478C); FT-IR (mull)
1
3125 (m, br, NH), 1661 (s, C55O), 1267 (m, NCl), 894 (m, NCl) cm21; H
NMR d 7.69 (m, 2H, ArH), 7.24 (m, 2H, ArH, 1H, NH), 2.39 (s, 3H, CH3).
N-Chlorination of hexanamide: In a 15-mL, round-bottom flask were placed
5 mL of methanol and 0.5154 g (4.475 mmol) of hexanamide, and the mixture
was allowed to stir until the solid dissolved. TCICA, 0.3811 g (1.604 mmol,
4.919 meq), was added and a precipitate formed in 3 min. After stirring for
1 h, the mixture was filtered and the solid was washed with methylene
chloride. The solvent was removed from the filtrate using a rotary evaporator
to give a solid/liquid crude product. The mixture was vacuum filtered and the
solid washed with methylene chloride. The solvent was removed from the
filtrated using a rotary evaporator to give 0.6836 g (102.2%) of liquid crude
product. Flash chromatography with 1:1 pentane–ether gave 0.5936 g
(89.2%) of N-chlorohexanamide: FT-IR (film) 3134 (s, br, NH), 2942
(s, CH), 2840 (s, CH), 1664 (s, C55O), 1468 (s), 1250 (m, NCl), 1099 (w),
1
913 (w), 910 (w, NCl) 745 (w) cm21; H NMR (CDCl3) d 9.06 (s, br 1H,
NH), 2.43 (t, J ¼ 7.4, 2H, CH2CO), 1.69 (m, 2H, CH2CH2CO), 1.35
(m, 4H, CH2), 0.89 (t, J ¼ 5.7, 3H, CH3). For conversion back to the
amide, 0.309 g (2.06 mmol) of N-chloroamide was dissolved in 3 mL of
methanol and 2 mL of water, and 0.292 g (2.80 mmol) of NaHSO3 was
added. After stirring for 50 min, a negative test for oxidizing power was
obtained using wet KI-starch test paper. The methanol was removed with a
rotary evaporator, the water was saturated with NaCl, and the solution was
extracted with ether (4 Â 10 mL). After drying and removal of the ether, the
crude amide was recrystallized from cyclohexane to give 0.192 g (65.2%) of

N-Chloroamides
2103
hexanamide: mp 98.8–99.68C; mmp 98.5–99.98C. The melting point of the
1
starting amide was 100.2–100.88C. The FT-IR and H FT-NMR spectra of
the recovered and the starting amides were identical.
N-Chlorination of benzamide: The reaction of 4.764 g (39.328 mmol) of
benzamide with 3.352 g (14.423 mmol, 43.27 meq) of TCICA gave 5.630 g
(92.0%) of N-chlorobenzamide after recrystallization from benzene: mp
115.0–116.08C (Lit.[7] mp 117–1188C); FT-IR (mull) 3134 (m, br, NH),
1
1663 (s, C55O), 1270 (m, NCl), 887 (m, NCl) cm21; H NMR (CDCl3) d
8.09 (s, br, 1H, NH), 7.84 (m, 2H, ArH), 7.44 (m, 3H, ArH).
N-Chlorination of 2-phenylacetamide: The reaction of 0.3966 g
(2.934 mmol) of 2-phenylacetamide with 0.2495 g (1.074 mmol, 3.221 meq)
of TCICA gave 0.4977 g (97.5%) of N-chloro-2-phenylacetamide after flash
chromatography using 1:1 methylene chloride–diethyl ether: mp 129.0–
130.08C; FT-IR (mull) 3115 (m, br, NH), 1663 (s, C55O), 1314 (w), 1129
(w), 1266 (w, NCl), 1088 (w), 966 (m), 935 (w), 917 (w), 764 (m), 729
1
(m), 695 (m) cm21; H NMR (CDCl3) d 7.33 (s, br, 5H, ArH), 7.26 (s, 1H,
NH), 3.72 (s, 2H, CH2). Reaction with NaHSO3 followed by recrystallization
from ethyl acetate gave 61.0% 2-phenylacetamide: mp 158.2–158.68C; mmp
158.1–158.68C; mp of starting amide 158.4–158.88C.
N-Chlorination of cyclohexanecarboxamide: Reaction of 0.4090 g
(3.22 mmol) of cyclohexanecarboxamide with 0.2747 g (1.18 mmol,
3.55 meq) of TCICA gave 0.3545 g (68.2%) of N-chlorocyclohexanecarboxamide:
mp 139.0–140.08C; FT-IR (mull) 3174 (s, NH), 1664 (s, C55O), 1250
1
(w, NCl), 1189 (m), 1134 (m), 951 (m), 898 (m, NCl) cm21; H NMR
(CDCl3) d 8.28 (s, 1H, NH), 2.20–2.66 (m, 1H, CHCO), 1.04–2.11 [m,
10H, (CH2)5]. Reaction with NaHSO3 followed by recrystallization from
benzene gave 83.6% cyclohexanecarboxamide: mp 186.0–186.48C; mmp
186.0–186.58C; mp of starting amide 186.0–186.88C.
N-Chlorination of butanamide: Reaction of 0.3943 g (4.526 mmol)
of butanamide with 0.3873 g (1.666 mmol, 4.999 meq) of TCICA gave
0.5182 g (94.2%) of liquid N-chlorobutanamide after flash chromatography
with 1:2 pentane–ether: FT-IR (film) 3134 (m, br, NH), 2949 (s, CH),
2865 (s, CH), 1669 (s, C55O), 1466 (m), 1391 (w), 1274 (w), 1258 (m, sh,
NCl), 1198 (m), 1098 (w), 905 (m, NCl) 793 (w) cm21 1H NMR
;
(CDCl3) d 9.56 (s, br 1H, NH), 2.45 (t, J ¼ 7.0, 2H, CH2CO), 1.73 (sex,
J ¼ 7.0, 2H, CH2), 0.98 (t, J ¼ 7.3, 3H, CH3). Reaction with NaHSO3
followed by recrystallization from ethyl acetate/cyclohexane gave 95.8%
butanamide: mp 112.5–112.88C; mmp 112.6–112.88C; mp of starting
amide 112.5–112.98C.
N-Chlorination of octanamide: Reaction of 0.4280 g (2.988 mmol) of octa-
namide with 0.2546 g (1.095 mmol, 3.286 meq) of TCICA gave 0.4590 g

2104
G. A. Hiegel, T. J. Hogenauer, and J. C. Lewis
(86.5%) of liquid N-chlorooctanamide after flash chromatography using 1:1
pentane–ether: FT-IR (film) 3134 (s, br, NH), 2906 (s, CH), 2824 (s, CH),
1669 (s, C55O), 1468 (s), 1269 (m, NCl), 1105 (w), 971 (w), 886 (w, NCl),
1
745 (w) cm21; H NMR (CDCl3) d 8.90 (s, br 1H, NH), 2.44 (t, J ¼ 7.3 Hz,
2H, CH2CO), 1.74 (m, 2H, CH2CH2CO), 1.31 (m, 8H, CH2), 0.89
(t, J ¼ 5.1 Hz, 3H, CH3). Reaction with NaHSO3 followed by recrystallization
from ethyl acetate/cyclohexane gave 61.6% octanamide: mp 104.5–105.28C;
mmp 104.8–105.48C; mp of starting amide 105.1–105.68C.
N-Chlorination of decanamide: Reaction of 0.8484 g (4.953 mmol) of
decanamide with 0.4217 g (1.814 mmol, 5.443 meq) of TCICA gave
0.9926 g (97.5%) of N-chlorodecanamide after recrystallization from
pentane: mp 40.5–41.58C; FT-IR (mull) 3205 (m, NH), 2932 (s, CH), 2849
(s, CH), 1664 (s, C55O), 1267 (w, NCl), 1105 (w), 962 (m), 893 (w, NCl),
719 (m) cm21
;
1H NMR (CDCl3) d 8.15 (s, br 1H, NH), 2.36
(t, J ¼ 7.1 Hz, 2H, CH2CO), 1.69 (m, 2H, CH2CH2CO), 1.26 (m, 12H,
CH2), 0.87 (t, J ¼ 6.1 Hz, 3H, CH3). Reaction with NaHSO3 followed by
recrystallization from hexane/cyclohexane gave 77.2 % decanamide: mp
97.8–98.28C; mmp 97.9–98.28C.; mp of starting amide 97.8–98.18C.
ACKNOWLEDGMENT
This research was supported in part by a grant from the California State
University Special Fund for Research, Scholarship, and Creative Activity
and by an award from Rohm and Haas Company: Otto Hass Award for
Technical Excellence (courtesy of Robert K. Barr).
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