Org. Synth. 2002, 78, 234
DOI: 10.15227/orgsyn.078.0234
METHYL CARBAMATE FORMATION VIA MODIFIED HOFMANN REARRANGEMENT REACTIONS: METHYL
N-(p-METHOXYPHENYL)CARBAMATE
[
Carbamic acid, (4-methoxyphenyl)-, methyl ester
]
Submitted by Jeffrey W. Keillor
1
and Xicai Huang.
Checked by Scott Ceglia and Edward J. J. Grabowski.
1. Procedure
To a 1-L, round-bottomed flask equipped with a stirring
bar are added
p-methoxybenzamide
(10 g, 66 mmol),
N-bromosuccinimide
(NBS) (11.9 g, 66 mmol),
1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) (22 mL, 150 mmol) and
methanol
(300 mL)
(Note 1). The solution is
heated at reflux for 15 min (Note 2), at which point an additional
aliquot of NBS (11.9 g, 66 mmol)
is added slowly. The reaction is allowed to continue for another 30 min (Note 3).
Methanol is removed by rotary evaporation and the residue is
dissolved in
500 mL of ethyl acetate
(EtOAc). The EtOAc solution is washed with 6 N
hydrochloric acid (HCl) (2 × 100 mL),
1 N sodium hydroxide (NaOH) (2
× 100 mL) and saturated
sodium
chloride (NaCl), and then dried over
magnesium
sulfate (MgSO4). The solvent is removed by rotary
evaporation and the product,
methyl N-(p-methoxyphenyl)carbamate,
is purified
by flash column chromatography [
50 g of silica
gel, EtOAc / hexane
(1:1)] to give a pale yellow solid
(11.1 g, 93%), which is further purified by recrystallization from
500 mL of hexane
(Note 4). Another 1.4
g of product (total 8.8 g,
73%) is obtained from the mother
liquor by recrystallization from
100 mL
of hexane
.
2. Notes
1.
p-Methoxybenzamide,
NBS and DBU were purchased from the Aldrich Chemical Company, Inc.
2.
The reaction mixture is heated using an
oil bath.
3.
Reaction progress can be followed by thin layer chromatography
using EM Science silica gel 60 F254 aluminum-backed plates, eluted with EtOAc/
hexane
(1:1) and visualized using a
254 nm UV lamp.
4.
Methyl N-(p-methoxyphenyl)carbamate
prepared by this procedure was characterized as follows:
mp (uncorr.) 88.5-89.5°C (lit.
2
mp 88-89°C);
1H NMR (500 MHz, CDCl
3) δ:
3.77 (s, 3 H), 3.78 (s, 3 H), 6.50 (bs, 1 H),
6.90 (m, 2 H), 7.26 (m, 2 H)
;
13C NMR (100 MHz, CDCl
3) δ:
52.1, 55.3, 114.1, 120.6, 130.9,
154.5, 155.8
; FTIR
spectrum (CHCl
3) cm
−1: 3437, 3080,
2963, 1734, 1600, 1511, 1464,
1298, 1226, 1181, 1076, 1035
;
Calcd for C
9H
11NO
3: C, 59.7; H, 6.1; N, 7.7. Found:
C, 59.6; H, 6.3; N, 7.7.
Handling and Disposal of Hazardous Chemicals
The procedures in this article are intended for use only by persons with prior training in experimental organic chemistry. All hazardous materials should be handled using the standard procedures for work with chemicals described in references such as "Prudent Practices in the Laboratory" (The National Academies Press, Washington, D.C., 2011 www.nap.edu). All chemical waste should be disposed of in accordance with local regulations. For general guidelines for the management of chemical waste, see Chapter 8 of Prudent Practices.
These procedures must be conducted at one's own risk. Organic Syntheses, Inc., its Editors, and its Board of Directors do not warrant or guarantee the safety of individuals using these procedures and hereby disclaim any liability for any injuries or damages claimed to have resulted from or related in any way to the procedures herein.
3. Discussion
This method offers a rapid, efficient and particularly mild preparation of methyl
carbamates,
and has been used with success with a variety of primary amides
3
(see Table).
These carbamates are easily hydrolyzed to free amines, making this method particularly
useful for making
15N-labeled anilines containing electron-donating substituents,
such as
p-anisidine
,
2,4-dimethoxyaniline
and
4-dimethylaminoaniline
. Although other
methods are available for the preparation of methyl carbamates, including the use
of NaOH/Br
2,
4 iodine(III)
species,
5
lead tetraacetate
,
6 and NBS-Hg(OAc)
2,
7
none of these methods are mild enough to permit the clean conversion of
p-methoxybenzamide
, since they cause
further oxidation of the product. Currently, the best alternative method is the use
of NBS/NaOMe reported earlier by this laboratory.
8
TABLE
CONVERSION OF AMIDES TO METHYL CARBAMATES
WITH NBS/DBU
|
|
|
| Ra
|
Yield,b (%) |
Obs. mp,c (°C) |
Lit. mp, (°C) |
|
|
3,4-(MeO)2C6H3-
|
89
|
80-81
|
81
d
|
|
p-MeC6H4-
|
84
|
98-99
|
99-101
e
|
|
C6H5-
|
95
|
45-46
|
47-48.5
e
|
|
p-ClC6H4-
|
94
|
113-115
|
115-117
e
|
|
p-NO2C6H4-
|
70
f
|
177-178
|
177.5-178
g
|
|
C6H5CH2-
|
95
|
64-65
|
65
h
|
|
CH3(CH2)8-
|
90
|
< r.t. |
– |
|
CH3(CH2)14-
|
73
|
61-62
|
61-62
i
|
|
aPrepared from the corresponding carboxylic
acid or acid chloride.
|
bRefers to pure isolated and characterized
product.
|
cDetermined in capillary tubes and uncorrected.
|
dBrunner, O.; Wöhrl, R. Monatsh.
1933, 63, 374-384.
|
eFujisaki, S.; Tomiyasu, K.; Nishida, A.;
Kajigaeshi, S. Bull. Chem. Soc. Jpn.
1988, 61, 1401-1403.
|
|
|
gHegarty, A. F.; Frost, L. N. J. Chem.
Soc., Perkin Trans. 2
1973, 1719-1728.
|
hChabrier de la Saulnière, P. Ann. Chim.
1942, 17, 353-370.
|
|
|
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
Methyl N-(p-methoxyphenyl)carbamate:
Carbamic
acid, (4-methoxyphenyl)-, methyl ester (9); (14803-72-6)
p-Methoxybenzamide:
Benzamide, 4-methoxy-
(9); (3424-93-9)
N-Bromosuccinimide:
Succinimide, N-bromo-
(8);
2,5-Pyrrolidinedione, 1-bromo- (9); (128-08-5)
1,8-Diazabicyclo[5.4.0]undec-7-ene: DBU:
Pyrimido[1,2-a]azepine,
2,3,4,6,7,8,9,10-octahydro- (8,9); (6674-22-2)
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