Convenient synthesis of N-hydroxysuccinimide esters from carboxylic acids using triphosgene

Article abstract of DOI:10.1080/00397910902906628

A simple and convenient method for the synthesis of N-hydroxysuccinimide ester is developed using triphosgene as an acid activator. Several aromatic and aliphatic N-hydroxysuccinimide esters are prepared from their corresponding carboxylic acids at room temperature in good yields in a rapid process using triphosgene. Some of the major advantages are mild conditions, good yields, and easy operation.

Full text of DOI:10.1080/00397910902906628

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Convenient Synthesis of N-
Hydroxysuccinimide Esters
from Carboxylic Acids Using
Triphosgene
Misoo Kim a & Ki-Jong Han b
a Department of Basic Science , Hankyong National
University , Ansung, Korea
b Department of Molecular Science and Technology ,
Ajou University , Suwon, Korea
Published online: 12 Nov 2009.
To cite this article: Misoo Kim & Ki-Jong Han (2009) Convenient Synthesis of N-
Hydroxysuccinimide Esters from Carboxylic Acids Using Triphosgene, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:24, 4467-4472, DOI: 10.1080/00397910902906628
To link to this article: http://dx.doi.org/10.1080/00397910902906628
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Synthetic Communications1, 39: 4467–4472, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910902906628
Convenient Synthesis of N-Hydroxysuccinimide
Esters from Carboxylic Acids Using Triphosgene
Misoo Kim1 and Ki-Jong Han2
1Department of Basic Science, Hankyong National University,
Ansung, Korea
2Department of Molecular Science and Technology, Ajou University,
Suwon, Korea
Abstract: A simple and convenient method for the synthesis of N-hydroxysucci-
nimide ester is developed using triphosgene as an acid activator. Several aromatic
and aliphatic N-hydroxysuccinimide esters are prepared from their corresponding
carboxylic acids at room temperature in good yields in a rapid process using
triphosgene. Some of the major advantages are mild conditions, good yields,
and easy operation.
Keywords: Carboxylic acids, N-hydroxysuccinimide, N-hydroxysuccinimide
esters, triphosgene
Carboxylic acid esters of N-hydroxysuccinimide have been widely used as
valuable intermediates in peptide synthesis because they acylate primary
amines to give the corresponding amides.[1] For example, several methods
have been developed using dicyclohexylcarbodiimide,[2] Ph3P=diethyl azo-
dicarboxylate,[3] bis(N-succinimidyl) carbonate,[4] 2-pyridyl carbonate,[5]
N,N,N0,N0-tetramethyl(succinimido)uronium tetrafluoroborate,[6] chloro
phosphate,[7] 3-(dimethylamino)propylcarbodiimide,[8] O-succinimidyl-1,3-
dimethyl-1,3-trimethyleneuronium salts,[9] and 1-ethyl-3-(30-dimethyl-
aminopropyl) carbodiimide.[10] However, these are not free from some
Received January 14, 2009.
Address correspondence to Dr. Misoo Kim, Professor, Department of Basic
Science, Hankyong National University, 67 Seogjung-Dong, Ansung 456-749,
Republic of Korea. E-mail: mkim@hknu.ac.kr
4467

4468
M. Kim and K.-J. Han
Scheme 1.
drawbacks such as by-product formation, limited availability, inconvenient
handling, or poor stability.
Triphosgene is commercially available as a white solid. The synthetic
utility of triphosgene has been extensively investigated over the past 20
years.[11] During the past few years, we have been interested in the use
of triphosgene in organic synthesis.[12] In continuation of our research
to develop new methods using triphosgene as an acid activator, we report
herein a simple and convenient method for the preparation of N-
hydroxysuccinimide esters from their corresponding carboxylic acids
using triphosgene, as shown in Scheme 1.
In this procedure, carboxylic acids were first converted into
carboxylic acid anhydrides by triphosgene in the presence of triethyla-
mine.[13] N-Hydroxysuccinimide esters were formed after addition of N-
hydroxysuccinimide to the intermediate carboxylic acid anhydrides. In
all cases, the reactions proceeded rapidly in methylene chloride at room
temperature. As shown in Table 1, a variety of N-hydroxysuccinimide
esters were prepared from carboxylic acids. Aromatic carboxylic acids
containing both electron-donating and electron-withdrawing groups were
Table 1. Synthesis of N-hydroxysuccinimide esters
Entry
Acid
Product
Yielda (%)
1
95
2
96
(Continued )

Synthesis of N-Hydroxysuccinimide Esters
Table 1. Continued
4469
Yielda (%)
92
Entry
Acid
Product
3
4
91
5
6
7
93
92
93
8
9
93
91
10
87
aYields refer to isolated products.

4470
M. Kim and K.-J. Han
cleanly converted to the corresponding N-hydroxysuccinimide esters
(entries 1–5). Aliphatic and N-Cbz-protected amino acids also afforded
the desired products in good yields under these reaction conditions
(entries 6–10). The reaction conditions are mild, and the experimental
procedure is operationally simple. The products were formed in good
yields (87–96%). The structures of all the products were confirmed by
1H and 13C NMR spectroscopy.
In summary, we have developed a simple and convenient method for
the conversion of various carboxylic acids to their corresponding N-
hydroxysuccinimide esters using triphosgene as an acid activator. This
method is operationally simple and provides the products in good yields.
EXPERIMENTAL
Triphosgene was purchased from Aldrich Company. Analytical
thin-layer chromatography (TLC) was performed on precoated Merck
silica-gel 60 F254 TLC plate. Purification was performed by flash-column
chromatography using Merck silica gel (230–400 mesh). Melting points
were determined in capillary tubes on a Bibby Sterilin apparatus and
1
are corrected. H NMR and 13C NMR spectral data were obtained on
a Jeol JNM-ECP 400-MHz NMR spectrometer. Identification of the
products was ascertained by 1H and 13C NMR spectroscopy and by
comparison with published values.[6,8,14]
General Procedure
Triphosgene (1 mmol) and triethylamine (10 mmol) were added at 0ꢀC to
a stirred solution of the carboxylic acid (2 mmol) in dichloromethane
(10 ml). Then N-hydroxysuccinimide (2 mmol) was added to the reaction
mixture. The reaction mixture was stirred for 30 min at room tempera-
ture. After completion of the reaction, the reaction mixture was filtered
by suction filtration. Removal of the filtrate by rotary evaporation fol-
lowed by short-path silica-gel column chromatography using 20% ethyl
acetate in hexane as the mobile phase afforded the pure product.
Selected Spectral Data
N-Hydroxysuccinimide Ester of 3-Toluic Acid (entry 3)
Mp 116–117ꢀC (lit.[14a] 117–118ꢀC); TLC Rf 0.35 (40% ethyl acetate in
hexane); IR (KBr): n, 3445, 3012, 2938, 1768, 1734, 1603, 1587, 1464,

Synthesis of N-Hydroxysuccinimide Esters
4471
1435, 1374, 1265, 1184, 1069, 988, 883 cmꢁ1
;
1H NMR (400 MHz,
CDCl3): d 7.93 (d, J ¼ 8.00 Hz, 2H), 7.47 (d, J ¼ 7.60 Hz, 1H), 7.39 (t,
J ¼ 7.60 Hz, 1H), 2.87 (s, 4H) 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 169.6, 162.1, 139.0, 135.8, 131.0, 128.9, 127.8, 125.1, 25.8, 21.3.
N-Hydroxysuccinimide Ester of N-Benzyloxycarbonyl-L-isoleucine
(entry 10)
Mp 115–116ꢀC (lit.[14c] 115.5–116ꢀC); TLC Rf 0.48 (20% ethyl acetate in
25
25
chloroform); ½aꢂD ꢁ15.0ꢀ (c ¼ 2.0, dioxane); lit.[14c] ½aꢂD ꢁ15.5ꢀ (c ¼ 2.0,
dioxane); IR (KBr): n, 3292, 2958, 1732, 1657, 1543, 1456, 1337, 1274,
1195, 1098, 985 cmꢁ1
;
1H NMR (400 MHz, CDCl3): d 8.12 (d,
J ¼ 8.40 Hz, 1H), 7.41–7.30 (m, 5H), 5.07 (s, 2H), 4.47–4.39 (m, 1H),
2.81 (s, 4H), 1.81–1.69 (m, 2H), 1.67–1.58 (m, 1H), 0.91 (m, 6H); 13C
NMR (100 MHz, CDCl3): d 170.1, 169.2, 156.1, 136.7, 128.5, 128.1,
127.9, 66.0, 50.7, 25.6, 24.3, 22.7, 21.1.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from Hankyong National
University.
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