A Publication
of Reliable Methods
for the Preparation
of Organic Compounds
Annual Volume
Org. Synth. 2002, 78, 234
DOI: 10.15227/orgsyn.078.0234
[ Carbamic acid, (4-methoxyphenyl)-, methyl ester ]
Submitted by Jeffrey W. Keillor1 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, CDCl3) 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, CDCl3) δ: 52.1, 55.3, 114.1, 120.6, 130.9, 154.5, 155.8 ; FTIR spectrum (CHCl3) cm−1: 3437, 3080, 2963, 1734, 1600, 1511, 1464, 1298, 1226, 1181, 1076, 1035 ; Calcd for C9H11NO3: 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 amides3 (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/Br2,4 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

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.

fOvernight reflux.

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.

iReference 3.

References and Notes
  1. Département de chimie, Université de Montréal, Montréal, Québec, Canada H3C 3J7.
  2. Esch, P. M.; Hiemstra, H.; Speckamp, W. N. Tetrahedron 1992, 48, 3445-3462.
  3. Huang, X.; Seid, M.; Keillor, J. W. J. Org. Chem. 1997, 62, 7495-7496.
  4. Wallis, E .S.; Lane, J. F. Org. React. 1946, 3, 267-306.
  5. Moriarty, R. M.; Chany II, C. J.; Vaid, R. K.; Prakash, O.; Tuladhar, S. M. J. Org. Chem. 1993, 58, 2478-2482.
  6. Baumgarten, H. E.; Smith, H. L.; Staklis, A. J. Org. Chem. 1975, 40, 3554-3561.
  7. Jew, S.-S.; Park, H. G.; Park, H.-J.; Park, M.-S.; Cho, Y.-S. Tetrahedron Lett. 1990, 31, 1559-1562.
  8. Huang, X.; Keillor, J. W. Tetrahedron Lett. 1997, 38, 313-316.

Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)

Methyl N-(p-methoxyphenyl)carbamate:
Carbamic acid, (4-methoxyphenyl)-, methyl ester (9); (14803-72-6)

Benzamide, 4-methoxy- (9); (3424-93-9)

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)