An Efficient One-Pot Synthesis of N-Methoxy-N-methylamides from Carboxylic Acids

Article abstract of DOI:10.1081/SCC-120026336

Several N-methoxy-N-methylamides were prepared by the reaction of the corresponding carboxylic acids with N,O-dimethylhydroxylamine hydrochloride at room temperature using trichloromethyl chloroformate in the presence of triethylamine in excellent yields.

Full text of DOI:10.1081/SCC-120026336

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An Efficient One-Pot Synthesis of N-Methoxy-N-
methylamides from Carboxylic Acids
Associate Professor Misoo Kim a , Hagyoung Lee b , Ki-Jong Han c & Kwang-Yol Kay c
a Department of Basic Science , Hankyong National University , Ansung, Korea
b Department of Chemical Engineering , Hankyong National University , Ansung, Korea
c Department of Molecular Science and Technology , Ajou University , Suwon, Korea
Published online: 16 Aug 2006.
To cite this article: Associate Professor Misoo Kim , Hagyoung Lee , Ki-Jong Han & Kwang-Yol Kay (2003) An Efficient One-Pot
Synthesis of N-Methoxy-N-methylamides from Carboxylic Acids, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 33:23, 4013-4018, DOI: 10.1081/SCC-120026336
To link to this article: http://dx.doi.org/10.1081/SCC-120026336
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 23, pp. 4013–4018, 2003
An Efficient One-Pot Synthesis of
N-Methoxy-N-methylamides from
Carboxylic Acids
2
3
Misoo Kim,1, Hagyoung Lee, Ki-Jong Han,
*
and Kwang-Yol Kay3
1Department of Basic Science, and
2Department of Chemical Engineering,
Hankyong National University, Ansung, Korea
3Department of Molecular Science and Technology,
Ajou University, Suwon, Korea
ABSTRACT
Several N-methoxy-N-methylamides were prepared by the reaction
of the corresponding carboxylic acids with N,O-dimethylhydroxyl-
amine hydrochloride at room temperature using trichloromethyl
chloroformate in the presence of triethylamine in excellent yields.
*Correspondence: Misoo Kim, Associate Professor, Department of Basic
Science, Hankyong National University, 67 Seogjung-Dong, Ansung 456-749,
Korea; E-mail: mkim@hnu.hankyong.ac.kr.
4013
DOI: 10.1081/SCC-120026336
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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4014
Kim et al.
N-Methoxy-N-methylamides;
Weinreb amides; Trichloromethyl chloroformate; N,O-Dimethyl-
Key Words: Carboxylic
acids;
hydroxylamine hydrochloride.
N-methoxy-N-methylamides (Weinreb amides) have widely used as
versatile synthetic intermediates in organic synthesis since they react with
Grignard and organometallic reagents to give ketones.[1–4] Over the last
20 years, a number of methods for the conversion of carboxylic acids to
N-methoxy-N-methylamides have been appeared in Lit.[5–18] In spite
of numerous methods available for the synthesis of N-methoxy-N-
methylamides there still exists scope to develop better synthetic methods.
We wish to report herein a simple one-pot procedure for the conversion
of carboxylic acids to N-methoxy-N-methylamides using trichloromethyl
chloroformate as shown in Sch. 1.
The N-methoxy-N-methylamides can be conveniently prepared from
carboxylic acids and N,O-dimethylhydroxylamine hydrochloride at room
temperature using trichloromethyl chloroformate in the presence of
triethylamine. The carboxylic acid undergoes reaction with trichloro-
methyl chloroformate in the presence of triethylamine to give a mixed
carbonic anhydride as activated intermediate. Nucleophilic attack of the
N-methoxy-N-methyl amine on the carbonyl carbon in the activated
anhydride affords desired Weinreb amide, concomitant with the formation
of phosgene, carbon dioxide, and hydrogen chloride by a concerted
process. As shown in Table 1, excellent yields of the products were
obtained from each of the carboxylic acids examined. The reaction was
found to proceed smoothly at room temperature and usually completed
within 1 h. The reaction mixture was monitored by TLC until the starting
material was consumed. After completion, the triethylamine hydro-
chloride was removed by suction filtration, and the filtrate was concen-
trated under reduced pressure. The crude products were purified by short
path silica gel column chromatography. Not only aliphatic carboxylic
acids but also aromatic carboxylic acids reacted smoothly to afford the
corresponding N-methoxy-N-methylamides in excellent yields. Neither
electron-releasing (Entries 1–3) nor electron-withdrawing substituents
Scheme 1.

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One-Pot Synthesis of N-Methoxy-N-methylamides
4015
Table 1. Preparation of N-methoxy-N-methylamides from carboxylic acids.
Entry
Acid
Product
Yielda (%)
97
1
2
3
4
5
6
94
92
96
98
95
7
8
93
96
9
92
93
10
aYields refer to isolated products.
(Entries 4 and 5) on the benzoic acids disturbed the facile formation of
N-methoxy-N-methylamides. The reaction of saturated aliphatic, unsatu-
rated aliphatic, and cyclic acids (Entries 6–10) gave the corresponding
N-methoxy-N-methylamides in excellent yields.
The N-methoxy-N-methylamides can be also prepared from the mixed
carbonic anhydride generated from the treatment of carboxylic acids with

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4016
Kim et al.
alkyl chloroformates in the presence of base followed by subsequent addi-
tion of N,O-dimethylhydroxylamine hydrochloride.[19] Even though the
trichloromethyl chloroformate used here is somewhat more expensive
reagent than other acid activating agents such as alkyl chloroformates,
the use of this reagent offers some significant advantages compared to
the use of routine alkyl chloroformates. Perhaps the advantage of the
procedure is the fact that pure Weinreb amides can be obtained without
the need to separate by-product. The reaction took place in shorter reac-
tion times and better yields compared to the alkyl chloroformates.[19b,d]
Although trichloromethyl chloroformate has been used to be an
excellent activating reagent in several organic reactions such as dehydra-
tion of formamides,[20] dehydration of aldoximimes,[21] oxidation of
alcohols,[22] acylation of a-aminoalcohols,[23] and formation of
isocyanates[24] and dioxolanediones,[25] we did not find where this reagent
was used to prepare Weinreb amides from carboxylic acids.
In summary, we have developed an efficient one-pot procedure for the
conversion of various carboxylic acids to their corresponding N-methoxy-
N-methylamides using trichloromethyl chloroformate. The present
procedure described here has the advantages of mild reaction condition,
high yields of products, shorter reaction times, and operational simplicity.
EXPERIMENTAL SECTION
Trichloromethyl chloroformate was purchased from Fluka and used
as received. Analytical thin layer chromatography was performed on
pre-coated Merck silica gel 60 F254 TLC plate. Purification was performed
by flash column chromatography by using Merck 230–400 mesh silica gel.
1H NMR and 13C NMR spectral data were obtained on a Jeol JNM-ECP
400 MHz NMR spectrometer. Infrared spectra were recorded using a
Jasco FT/IR-410 spectrophotometer with internal calibration. Mass
spectra were recorded on a Jeol JMS-700 High Resolution mass
spectrometer. The products were characterized by comparison of their
1H NMR spectra with those of known compounds (Entries 1–6 and
8–10).[9,17,26–28] Otherwise, an unknown product was fully characterized
by IR, 1H NMR, 13C NMR, and HRMS analysis (Entry 7).
General Procedure
To a stirred solution of the carboxylic acid (2 mmol) in CH2Cl2
(10 mL) at 0ꢀC were added trichloromethyl chloroformate (2 mmol)

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One-Pot Synthesis of N-Methoxy-N-methylamides
4017
and triethylamine (6 mmol). Then N,O-dimethylhydroxylamine hydro-
chloride (2 mmol) was added to the solution and the ice bath was
removed. The reaction mixture was stirred at room temperature until
completion. The triethylamine hydrochloride was removed by suction
filtration. Removal of the filtrate by rotary evaporation followed by
short path silica gel column chromatography purification using 20%
ethyl acetate in hexane as the mobile phase afforded the pure product.
The characterization of N-methoxy-N-methyldecanamide (Entry 7).
IR (thin film): 2925, 2854, 1670, 1465, 1412, 1382, 1177, 1124, 1003,
764 cmꢁ1 1H NMR (400 MHz, CDCl3): ꢀ 3.68 (s, 3H), 3.18 (s, 3H),
.
2.41 (t, J ¼ 7.32 Hz, 2H), 1.63 (t, J ¼ 7.32 Hz, 2H), 1.20–1.35 (br, 12H),
0.88 (t, J ¼ 6.96 Hz, 3H). 13C NMR (100 MHz, CDCl3): ꢀ 175.0, 61.3,
32.2, 32.0, 29.6, 29.5, 29.3, 24.7, 22.7, 14.2. HRMS (EI) m/z: Calcd. for
(C12H25NO2): 215.1885. Found: 215.1880 [Mþ].
ACKNOWLEDGMENT
We thank Hankyong National University Analysis Center for using
NMR and mass facilities.
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Received in India June 23, 2003