Preparation of methyl N-substituted carbamates from amides through N-chloroamides

Article abstract of DOI:10.1081/SCC-200066695

Amides are chlorinated on the nitrogen using trichloroisocyanuric acid, and the N-chloroamides are then rearranged to the corresponding methyl N-substituted carbamates by sodium methoxide in methanol. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200066695

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Preparation of Methyl
N‐Substituted Carbamates
from Amides through
N‐Chloroamides
Gene A. Hiegel a & Tyrone J. Hogenauer 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 (2005): Preparation of
Methyl N‐Substituted Carbamates from Amides through N‐Chloroamides, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 35:15, 2091-2098
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Synthetic Communicationsw, 35: 2091–2098, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200066695
Preparation of Methyl N-Substituted
Carbamates from Amides through
N-Chloroamides
Gene A. Hiegel and Tyrone J. Hogenauer
Department of Chemistry and Biochemistry, California State University,
Fullerton, California, USA
Abstract: Amides are chlorinated on the nitrogen using trichloroisocyanuric acid, and
the N-chloroamides are then rearranged to the corresponding methyl N-substituted car-
bamates by sodium methoxide in methanol.
Keywords: Amides, N-chloroamides, methyl N-substituted carbamates, preparation,
rearrangement, synthesis, trichloroisocyanuric acid
N-Chloramides are easily prepared from amides using trichloroisocyanuric
acid [TCICA; 1,3,5-trichloro-1,3,5-triazine-2,4,6-(1H,3H,5H)-trione; C3Cl3N3O3],
a stable solid.[1] Treatment of N-chloroamides with aqueous hydroxide
gives amines with one less carbon in a reaction known as the Hofmann
degradation.[2] An intermediate in this reaction is the isocyanate, and that
reacts with hydroxide followed by decarboxylation to give the corresponding
amine (Scheme 1). We report that treatment of N-chloroamides with sodium
methoxide in methanol gives the corresponding methyl N-substituted
carbamates (Scheme 2). Although similar reactions have been reported
using N-bromoamides,[3] a search of the chemical literature did not turn up
previous examples using N-chloroamides. The results are summarized in
Table 1. Carbamates can be hydrolyzed to the corresponding amines,
reduced to N-methylamines with lithium aluminum hydride,[4] converted
Received in the USA March 28, 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
2091

2092
G. A. Hiegel and T. J. Hogenauer
Scheme 1.
into the corresponding isocyanates with chlorocatecholborane and triethyl-
amine,[5] and converted to dimethyl acetals by anodic methoxylation.[6]
1
All carbamates were characterized by their FT-IR and H NMR spectra
1
and by comparison with carbamate standards through FT-IR and H NMR
spectra and by mixture melting points when appropriate. Carbamate
standards were prepared from the amines by reaction with dimethyl
carbonate and sodium methoxide in methanol (Scheme 3).[7] The data for
carbamates prepared from the amines are shown in Table 2.
EXPERIMENTAL
All reagents were used as received unless otherwise stated. Reagent-grade
acetone, anhydrous methanol, anhydrous acetonitrile, p-toluamide, cyclohex-
anecarboxamide, dimethyl carbonate, benzylamine, and cyclohexylamine
were obtained from Aldrich Chemical Co. Hexanamide, octanamide, decanamide,
propylamine, pentylamine, heptylamine, nonylamine, 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 from benzene (mp 112.0–112.88C).
Aniline was obtained from Spectrum Chemical Co. Trichloroisocyanuric
acid (99%) was obtained from Chem Lab Products.
1H FT-NMR spectra were recorded in CDCl3 using an Anasazi-modified
Varian EFT 90 MHz spectrometer. FT-IR spectra were recorded using a
Perkin Elmer 1650 spectrometer. GC analyses were carried out with a
Hewlett-Packard 5890 Series II instrument on a 6 ft  1/8 in 10%
Carbowax 20M column. Melting points were taken using a Thomas Hoover
Uni-Melt capillary melting-point apparatus and are uncorrected.
Scheme 2.

Table 1. Preparation of methyl N-substituted carbamates from amides
Mixture mpb/
GC purity
Amide
Carbamate
Yield
85%
Mpa/bp (press)
46.0–46.88C
45.0–45.58C
85%
97.5–98.28C
97.2–97.88C
92%
94%
63.9–64.58C
74.0–74.68C
64.3–65.08C
74.0–74.68C
(continued)

Table 1. Continued
Mixture mpb/
GC purity
Amide
Carbamate
Yield
Mpa/bp (press)
98%c
68%d
137.58C (6.5 torr)
97.7%
99.6%
95%c
89%d
178.58C (15.6 torr)
205.18C (6.7 torr)
195.08C (1.82 torr)
103%c
90%d
99.6%
95.9%
84%c
92%d
aMelting points are uncorrected.
bMixture mp with carbamate standards.
cCrude yield.
dPercent recovery of distilled carbamate (Hickman apparatus).

Methyl N-Substituted Carbamates
2095
Scheme 3.
Conversion of p-toluamide to methyl N-p-tolylcarbamate: In a 250-mL,
round-bottom flask were placed 50 mL of methanol and 9.187 g
(67.96 mmol) of p-toluamide. The mixture was allowed to stir until the
solid dissolved. TCICA, 5.791 g (24.92 mmol, 74.76 meq), was added and a
precipitate of cyanuric acid formed in 4 min. After stirring for 1 h, the
mixture was vacuum filtered and the solid was washed with methanol. The
filtrate was transferred to a dry, 250-mL, round-bottom flask, and the
solvent was removed using a rotary evaporator to give 11.811 g (102.5%) of
crude solid N-chloroamide product. A magnetic stir bar and 10 mL of
methanol were added to the crude product, and the flask was fitted with a
Claisen adapter containing condenser and a 50-mL addition funnel. A
nitrogen line was attached to the addition funnel and the system was flushed
with nitrogen. The apparatus was placed in an ice-water bath, then 55 mL
(137.5 mmol) of 2.5 N sodium methoxide in methanol was added through
the addition funnel at a rate of 5 mL every 5 min while stirring. The
addition funnel was rinsed into the flask with 10 mL of methanol, and
stirring was continued for 20 h at room temperature. The reaction mixture
was concentrated using a rotary evaporator and then 100 mL of ether and
50 mL of water were added. After shaking and separation, the aqueous layer
was extracted further with ether (3 Â 50 mL). The combined ether solution
was washed with saturated NaCl solution (50 mL) and dried over
MgSO4. After filtration and evaporation, the crude product was recrysta-
llized from cyclohexane to give 9.573 g (85.3%) of methyl N-p-tolylcarba-
mate: mp 97.5–98.28C; mmp 97.2–97.88C; FT-IR (mull) 3322
(m, NH), 1700 (s, C55O), 1600 (m), 1540 (m), 1512 (m), 1317 (m), 1236
(s, C–O), 1073 (m), 816 (m) cm21 1H NMR (CDCl3) d 7.39 (m, 2H,
;
ArH), 7.06 (m, 2H, ArH), 6.71 (s, br, 1H, NH), 3.75 (s, 3H, OCH3), 2.29
(s, 3H, CH3).
Preparation of methyl N-p-tolylcarbamate from p-toluidine: In a 15-mL,
round-bottom flask with condenser and nitrogen line were placed 2 mL of
methanol, 1.015 g (9.476 mmol) of p-toluidine, and 0.973 g (10.80 mmol) of
dimethylcarbonate. Sodium methoxide in methanol, 4.1 mL of 2.5 N
(10.25 mmol), was added over 1 min. After refluxing for 24 h under N2, the
mixture was concentrated to a solid using a rotary evaporator. The solid
crude product was mixed with 10 mL of water and 10 mL of ether. After
shaking and separation, the aqueous layer was further extracted with ether
(3 Â 10 mL). The combined ether solution was washed with 1 N HCl
(25 mL) and saturated NaCl solution (25 mL) and then dried over MgSO4.

2096
G. A. Hiegel and T. J. Hogenauer
Table 2. Preparation of methyl n-substituted carbamates from amines
Mpa/bp
GC
purity
Amine
Carbamate
Yield
(press)
52%
46.0–46.88C
46%
80%
97.2–97.88C
64.3–65.08C
83%
74.0–74.68C
76%b
88%c
155.18C
(13.4 torr)
99.6%
99.8%
85%b
91%c
184.98C
(11.5 torr)
91%b
88%c
199.28C
(4.1 torr)
99.5%
99.7%
94%b
84%c
185.18C
(0.68 torr)
aMelting points are uncorrected.
bCrude yield.
cPercent recovery of distilled carbamate (Hickman apparatus).
After filtration and evaporation, the crude product was recrystallized from
cyclohexane to give 0.735 g (46.9%) of methyl N-p-tolylcarbamate: mp
97.2–97.88C; FT-IR (mull) 3322 (m, NH), 1700 (s, C55O), 1600 (m), 1540
1
(m), 1512 (m), 1317 (m), 1236 (s, C-O), 1073 (m), 830 cm21; H NMR
(CDCl3) d 7.16 (m, 4H, ArH), 6.67 (s, br, 1H, NH), 3.75 (s, 3H, OCH3),
2.29 (s, 3H, ArCH3).
Conversion of benzamide to methyl N-phenylcarbamate: From 8.633 g of
the amide were obtained 9.451 g (85.5%) of methyl N-phenylcarbamate after

Methyl N-Substituted Carbamates
2097
recrystallization from cyclohexane: mp 46.0–46.88C; mmp 45.0–45.58C; FT-
IR (mull) 3322 (m, NH), 1709 (s, C55O), 1615 (m), 1605 (s), 1543 (s), 1503
(m), 1451 (s), 1324 (s), 1248 (s, C–O), 1072 (s), 1031 (m), 905 (m), 730 (m),
1
710 (m) cm21; H NMR (CDCl3) d 7.46–6.92 (m, 5H, ArH; 1H, NH), 3.74
(s, 3H, OCH3).
Conversion of 2-phenylacetamide to methyl N-benzylcarbamate: From
2.428 g of the amide were obtained 1.824 g (66.0%) of methyl N-phenylcarba-
mate after recrystallization from cyclohexane: mp 63.9–64.58C; mmp
64.0–64.68C; FT-IR (mull) 3344 (m, NH), 1692 (s, C55O), 1536 (s), 1495
1
(m), 1273 (s, C-O), 1144 (w), 999 (w), 739 (w), 704 (w) cm21; H NMR
(CDCl3) d 7.26 (s, 5H, ArH), 5.21 (s, br, 1H, NH), 4.32 (d, J ¼ 5.9 Hz, 2H,
CH2), 3.65 (s, 3H, CH3).
Conversion of cyclohexanecarboxamide to methyl N-cyclohexylcarba-
mate: From 5.105 g of the amide were obtained 5.528 g (94.9%) of methyl
N-cyclohexylcarbamate after recrystallization from cyclohexane: mp 74.0–
74.68C; mmp 74.0–74.68C; FT-IR (mull) 3333 (m, NH), 1694 (s, C55O),
1533 (s), 1451 (s), 1351 (s), 1282 (s), 1233 (s, C–O), 1053 (s), 893 (m),
;
778 (m) cm21 1H NMR (CDCl3) d 4.81 (s, br, 1H, NH), 3.65 (s, 3H,
OCH3), 1.41 [m, 11H, (ring CH, CH2)].
Conversion of butanamide into methyl N-propylcarbamate: From 4.193 g
of the amide, 5.567 g (98.9%) of crude liquid carbamate were obtained. A
1.402-g portion was distilled using a Hickman apparatus to give 1.090
(77.8% recovery) of methyl N-propylcarbamate: bath temp. 137.58C (6.5
torr); 97.7% pure by GC; FT-IR (film) 3333 (m, NH), 2949 (s, CH), 2865
(m, CH), 1697 (s, C55O), 1538 (s), 1466 (m), 1371 (w), 1267 (s, C-O), 1193
1
(m), 1146 (m), 1117 (m), 1051 (m), 1011 (m), 981 (w), 781 cm21; H NMR
(CDCl3) d 5.29 (s, br, 1H, NH), 3.67 (s, 3H, OCH3), 3.12 (m, 2H, CH2N),
1.47 (m, 2H, CH2CH3), 0.91 (t, J ¼ 7.3 Hz, 3H, CH3).
Conversion of hexanamide into methyl N-pentylcarbamate: From 0.955 g
of the amide, 1.151 g (95.6%) of crude liquid carbamate were obtained. A
1.084-g portion was distilled using a Hickman apparatus to give 0.966
(89.1% recovery) of methyl N-pentylcarbamate: bath temp. 178.58C (15.6
torr); 99.6% pure by GC; FT-IR (film) 3333 (m, NH), 2949 (s, CH), 2865
(m, CH), 1697 (s, C55O), 1540 (s), 1472 (m), 1379 (w), 1265 (s, C-O), 1197
1
(m), 1149 (m), 1100 (m), 781 cm21; H NMR (CDCl3) d 5.21 (s, br, 1H,
NH), 3.65 (s, 3H, OCH3), 3.15 (m, 2H, CH2N), 1.37 (m, 6H, CH CH3),
2
0.89 (t, J ¼ 5.8 Hz, 3H, CH3).
Conversion of octanamide into methyl N-heptylcarbamate: From 0.722 g
of the amide, 0.908 g (103.9%) of crude liquid carbamate was obtained. A
0.799-g portion was distilled using a Hickman apparatus to give 0.722
(90.5% recovery) of methyl N-heptylcarbamate: bath temp. 205.18C

2098
G. A. Hiegel and T. J. Hogenauer
(6.7 torr); 99.6% pure by GC; FT-IR (film) 3344 (m, NH), 2941 (s, CH), 2849
(m, CH), 1697 (s, C55O), 1540 (s), 1470 (m), 1383 (w), 1262 (s, C-O), 1195
1
(m), 1092 (w), 781 cm21; H NMR (CDCl3) d 4.99 (s, br, 1H, NH), 3.66
(s, 3H, OCH3), 3.15 (m, 2H, CH2N), 1.29 (m, 10H, CH2CH3), 0.88
(t, J ¼ 5.7 Hz, 3H, CH3).
Conversion of decanamide into methyl N-nonylcarbamate: From 0.950 g
of the amide, 0.946 g (84.7%) of crude liquid carbamate was obtained. A
0.766-g portion was distilled using a Hickman apparatus to give 0.711
(92.9% recovery) of methyl N-nonylcarbamate: bath temp 195.08C (1.82
torr); 95.9% pure by GC; FT-IR (film) 3333 (m, NH), 2898 (s, CH), 2816
(m, CH), 1700 (s, C55O), 1540 (s), 1470 (m), 1383 (w), 1262 (s, C–O),
1
1196 (m), 1149 (w), 1040 (w) 781 cm21; H NMR (CDCl3) d 4.81 (s, br,
1H, NH), 3.66 (s, 3H, OCH3), 3.15 (m, 2H, CH2N), 1.27 (m, 14H,
CH2CH3), 0.88 (t, J ¼ 6.1 Hz, 3H, CH3).
ACKNOWLEDGMENT
This research was supported in part by a grant from the CSU Special Fund for
Research, Scholarship, and Creative Activity.
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