Direct synthesis of acyl azides from carboxylic acids using 2-azido-l,3-dimethylimidazolinium chloride

Article abstract of DOI:10.1246/cl.2010.732

Acyl azides were directly synthesized from carboxylic acids by the treatment with 2-azido-l,3-dimethylimidazolinium chloride (ADMC, 1) and amine. This procedure resulted in acyl azides in good yields and was applied to the amidation of amino acid derivatives without racemization of the products.

Full text of DOI:10.1246/cl.2010.732

doi:10.1246/cl.2010.732
732
Published on the web June 5, 2010
Direct Synthesis of Acyl Azides from Carboxylic Acids
Using 2-Azido-1,3-dimethylimidazolinium Chloride
Mitsuru Kitamura,* Norifumi Tashiro, Yusuke Takamoto, and Tatsuo Okauchi
Department of Applied Chemistry, Kyushu Institute of Technology,
1-1 Sensui-cho, Tobata-ku, Kitakyushu, Fukuoka, 804-8550
(Received April 30, 2010; CL-100418; E-mail: kita@che.kyutech.ac.jp)
Acyl azides were directly synthesized from carboxylic acids
added to ADMC 1 if the thermodynamic stability of 1,3-
dimethyl-2-imidazolidinone (DMI, 3) is driving force
by the treatment with 2-azido-1,3-dimethylimidazolinium chlo-
ride (ADMC, 1) and amine. This procedure resulted in acyl
azides in good yields and was applied to the amidation of amino
acid derivatives without racemization of the products.
a
(path B). In fact, acyl azides were found to be synthesized by
the reaction of ADMC 1 and carboxylic acid in the presence of
a base. This procedure was subsequently utilized in amide
formation. In this letter, we describe the outcome of the
investigation.
Acyl azides are useful in organic synthesis because of their
unique reactivity.1 For example, the Curtius rearrangement is
used as a key reaction for the synthesis of nitrogen-containing
compounds such as amides and aza-heterocycles. Furthermore,
acyl azides are used as appropriately activated acid derivatives
for the synthesis of peptides.
Acyl azides were synthesized by the reaction of ADMC 1
and carboxylic acid in the presence of Et3N as shown in Table 1.
To a solution of ADMC 1 prepared by the reaction of
commercially available chloroimidazolinium salt 4 and sodium
azide in acetonitrile at 0 °C for 30 min, a carboxylic acid and
triethylamine in THF were added at 0 °C.
Previously acyl azides were prepared by N-nitrosation of
acyl hydrazides, while they are now more commonly prepared
from the corresponding carboxylic acids by the following
two-step sequence: i) transformation of the carboxylic acid
to activated acid such as acid chloride or acid anhydride, ii)
substitution with an azide ion.2 To avoid the need for isolation
of activated acid, a one-pot procedure has been developed.2b,3
Direct transformation from carboxylic acids has also been
investigated for the synthesis of acyl azides, in which commer-
cially available diphenylphosphoryl azide (DPPA) is commonly
used.4 However, the development of alternate reagents is desired
from the viewpoint of atom economy.5
Recently, we reported that 2-azido-1,3-dimethylimidazoli-
nium chloride (ADMC, 1) is an efficient diazo-transfer reagent
for 1,3-dicarbonyl compounds (Scheme 1, path A).6 Nucleo-
philes attack 1 either at the terminal nitrogen atom (position a)
or at the carbon position connected to three nitrogen atoms
(position b). In the diazo-transfer reaction, the products are
formed via the intermediate A, which is formed by nucleophilic
attack at position a. We had anticipated that azide transfer would
proceed when an oxygen nucleophile such as carboxylate was
Benzoic acid was quantitatively transformed to the corre-
sponding acyl azide (Run 1). In this reaction, the formation of
DMI 3 was observed, which suggested that the reaction
proceeded in the expected manner, as shown in Scheme 1.
Various aroyl azides could be synthesized at a faster rate in good
yields regardless of the substituent on ortho-, meta-, or para-
position of the aryl group (Runs 2-9).
Table 1. Synthesis of various acyl azides with ADMC 1
−
+
N
Cl−
N
N
Cl−
Cl
NaN3
+
+
MeN
NMe
MeN
NMe
CH3CN
4
0 °C, 30 min
ADMC 1
O
O
O
R
OH
R
N3
RHN
NHR
Et3N, THF
0 °C, 30 min
5
6
Run
R
Time/h
Yield/%b
1
2
3
4
5
6
7
8
9
Ph
0.5
0.5
1.5
3
0.5
0.5
0.5
1
100
61
97
86
95
86
58
61
41
4-MeC6H4
W
path A: diazo-transfer
W
4-MeOC6H4
4-NO2C6H4
3-MeOC6H4
2-MeC6H4
2-MeOC6H4
2-NO2C6H4
2,6-(MeO)2C6H3
PhCH2CH2
Ph2CH
N
H
N
W
W
N
−
W
W
MeN
NMe
attack at a
N2
2
−
+
N
N
W = -C(O)R
A
b
N
a
Y
Cl−
NMe
0.5
0.5
0.5
+
2: Y = NH
NMe
MeN
10
11
48c [91]d
30e
O
MeN
3: Y = O (DMI)
R
O
RCO−
ADMC 1
O
N3
O
aMolar ratio of 4/NaN3/carboxylic acid/Et3N = 1.2/1.2/1/2.
MeN
NMe
R
N3
c
bIsolated yield. Urea 6 was isolated in 43% yield. dDeter-
attack at b
3
1
B
mined by H NMR of crude compounds. 1,1,2,2-Tetrachloro-
path B: azide-transfer
e
ethane was used as an internal standard. Urea 6 was isolated
Scheme 1. Diazo/azide-transfer with ADMC 1.
in 50% yield.
Chem. Lett. 2010, 39, 732-733
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

733
SiO2
H2O
dimethylimidazolinium chloride (ADMC, 1) which surpasses
DPPA from the view-point of reagent atom economy. Further-
more, we demonstrated the racemization-free amidation of
amino acid derivatives using salt 1.
O
SiO2
Curtius
R−N=C=O
R
N3
−CO2
5
7
Rearrangement
O
7
R−NH2
RHN
NHR
This research was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Culture,
Sports, Science and Technology.
8
6
Scheme 2. Formation of urea 6.
References and Notes
1
Table 2. Amidation of amino acids with ADMC 1a
For the reviews see: a) E. F. V. Scriven, K. Turnbull, Chem.
Rev. 1988, 88, 297. b) S. Bräse, C. Gil, K. Knepper, V.
Zimmermann, Angew. Chem., Int. Ed. 2005, 44, 5188. c) S.
Bräse, K. Banert, Organic Azides, Wiley, Wiltshire, 2010.
Various synthetic methods of organic acyl azides are cited in
Ref. 1. Recent selected reports, see: a) A. R. Katritzky, K.
Widyan, K. Kirichenko, J. Org. Chem. 2007, 72, 5802. b) V. V.
Sureshbabu, H. S. Lalithamba, N. Narendra, H. P. Hemantha,
Org. Biomol. Chem. 2010, 8, 835.
O
H
N
P
OH
NaN3
H
R
9
4
ADMC 1
2
CH3CN
0 °C
30 min
base, THF
0 °C, 30 min
O
O
H
H
BnNH2
3
a) J. Chambers, C. B. Reese, Tetrahedron Lett. 1975, 16, 2783.
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R. Butler, R. F. Schlemmer, Jr., C. P. VanderMaelen, J. A.
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Int. Ed. 2000, 39, 4308. f) A. Bhattacharjee, O. R. Seguil, J. K.
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1408.
N
N
P
N3
P
NHBn
0 °C, 15 min
H
R
H
R
10
9
10
Time
/h
Run
Base
Et3N
P
R
Yieldb/% ee/%c
1
2
9a Cbz CH3
9b Boc CH2OBn i-Pr2NEt
4
1
10a
10b
90
80
>99
>99
aMolar ratio of 4/NaN3/9/base/BnNH2 = 1.3/1.3/1/2/1.2.
bIsolated yield. Enantiomeric excess (ee) was determined by
4
c
HPLC analysis, see Ref. 8.
In the case of aliphatic acids, the corresponding acyl azides
were formed, while urea 6 was formed in the isolation step. For
example, in the reaction of 3-phenylpropionic acid, acyl azide
was detected in 91% yield in the crude product (Run 10).
However, pure acyl azide 5 was obtained in only 48% yield after
purification using silica gel column chromatography, and urea 6
was obtained in 43% yield. Urea 6 was formed by the reaction of
isocyanate 7 formed by the Curtius rearrangement of 5 and
amine 8 following hydrolysis of the isocyanate 7 using silica
gel, as shown Scheme 2.
Acyl azides are often used as intermediates for synthesizing
peptides, and the azide coupling procedure is regarded as a low
racemization method.4,7 The racemization could occur at the
stage of acyl azide preparation and/or at the amidation step. We
examined the amidation of amino acid derivatives using ADMC
1 (Table 2). First the amidation of Cbz-Ala-OH 9a and
benzylamine was examined (Run 1). To a solution of ADMC
1 in CH3CN, 9a was added. After stirring the mixture for 4 h,
monitoring consumption of 9a using TLC, benzyl amine was
added to the reaction mixture. After further stirring for 15 min,
amide 10a was obtained in 90% yield without racemization.8,9
Next, Boc-Ser(OBn)-OH 9b, which has the highest suscepti-
bility to racemization, was employed for the amidation.7,10
Although racemization of the product 10b was observed when
Et3N was used as a base, amide 10b was obtained as an
enantiomerically pure form in 80% yield when i-Pr2NEt was
used.8
5
a) B. M. Trost, Science 1991, 254, 1471. b) B. M. Trost,
Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
6
7
M. Kitamura, N. Tashiro, T. Okauchi, Synlett 2009, 2943.
For a reviews, see: a) C. A. G. N. Montalbetti, V. Falque,
Tetrahedron 2005, 61, 10827. b) J. Lutz, H.-J. Musiol, L.
Moroder, in Houben-Weyl: Synthesis of Peptides & Peptido-
mimetics, ed. by M. Goodman, A. Felix, L. Moroder, C.
Toniolo, Georg Thieme Verlag, Stuttgart, 2002, Vol. E22a,
p. 427. c) J. Meienhofer, in The Peptides, ed. by E. Gross, J.
Meinenhofer, Academic, New York, 1979, Vol. 1, Chap. 4.
Enantiomeric excess (ee) of 10 was determined by HPLC
analysis using a chiral column [DAICEL CHIRALCEL AD-
H].
Similar peptide coupling reagent including imidazolinium
core, see: a) K. Akaji, N. Kuriyama, T. Kimura, Y. Fujiwara,
Y. Kiso, Tetrahedron Lett. 1992, 33, 3177. b) Y. Kiso, Y.
Fujiwara, T. Kimura, A. Nishitani, K. Akaji, Int. J. Pept.
Protein Res. 1992, 40, 308.
8
9
10 H. Li, X. Jiang, Y. Ye, C. Fan, T. Romoff, M. Goodman, Org.
Lett. 1999, 1, 91.
In conclusion, we have developed a new direct synthetic
route to acyl azides from carboxylic acids using 2-azido-1,3-
Chem. Lett. 2010, 39, 732-733
© 2010 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/