FeCl36H2O-Catalyzed acceleration of the acylation of sodium azide with n-acylbenzotriazoles

Article abstract of DOI:10.1080/00397911.2010.505698

Catalyzed by ferric chloride hexahydrate (FeCl₃6H₂O), the acylation of sodium azide with N-acylbenzotriazoles was greatly accelerated in a mixed solvent of acetone and water. Thus, good to excellent yields of a variety of acyl azides were obtained at room temperature in a short time. Furthermore, because of the complete conversion of N-acylbenzotriazoles and the easy removal of the by-product, purification by column chromatography was no longer required, which made the protocol suitable for large-scale preparation.

Full text of DOI:10.1080/00397911.2010.505698

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FeCl · 6H O-Catalyzed Acceleration of
3
2
the Acylation of Sodium Azide with N-
Acylbenzotriazoles
a
a
a
a
Zhiyun Zhong , Jieling Hu , Xiaoxia Wang , Junhua Liu
&
a
Longfeng Zhang
a
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces,
College of Chemistry and Life Sciences, Zhejiang Normal University,
Jinhua, China
Published online: 14 Jun 2011.
To cite this article: Zhiyun Zhong , Jieling Hu , Xiaoxia Wang , Junhua Liu & Longfeng Zhang (2011)
FeCl · 6H O-Catalyzed Acceleration of the Acylation of Sodium Azide with N-Acylbenzotriazoles,
3
2
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 41:16, 2461-2467, DOI: 10.1080/00397911.2010.505698
To link to this article: http://dx.doi.org/10.1080/00397911.2010.505698
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1
Synthetic Communications , 41: 2461–2467, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.505698
FeCl ꢀ 6H O-CATALYZED ACCELERATION
3
2
OF THE ACYLATION OF SODIUM AZIDE
WITH N-ACYLBENZOTRIAZOLES
Zhiyun Zhong, Jieling Hu, Xiaoxia Wang, Junhua Liu, and
Longfeng Zhang
Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, College
of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, China
GRAPHICAL ABSTRACT
Abstract Catalyzed by ferric chloride hexahydrate (FeCl
3
ꢀ 6H
2
O), the acylation of sodium
azide with N-acylbenzotriazoles was greatly accelerated in a mixed solvent of acetone and
water. Thus, good to excellent yields of a variety of acyl azides were obtained at room tem-
perature in a short time. Furthermore, because of the complete conversion of N-acylbenzo-
triazoles and the easy removal of the by-product, purification by column chromatography
was no longer required, which made the protocol suitable for large-scale preparation.
Keywords Acylation; acyl azides; N-acylbenzotriazoles; ferric chloride hexahydrate
(
FeCl
3
2
ꢀ 6H O); sodium azide
INTRODUCTION
Acyl azides are valuable reactive intermediates in organic synthesis. Among the
existing methods for the preparation of acyl azides, the acylation of azide anion
provides a straightforward and simple approach. A number of reagent combinations
have been developed for the direct transformation of acid to acid azides, such as cyan-
[
1a]
[1b]
[1c]
uric chloride,
ethyl)aminosulfur trifluoride,
3,4,5-trifuobenzeneboronic acid,
triphosgene,
bis(2-methoxy-
[1e]
and trichloroacetonitrile=triphenylphosphine.
[1d]
It should be mentioned that the one-pot procedure sometimes involved long reaction
Received August 22, 2009.
Address correspondence to Xiaoxia Wang, Zhejiang Key Laboratory for Reactive Chemistry on
Solid Surfaces, College of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua 321004,
China. E-mail: wangxiaoxia@zjnu.cn
2
461

2462
Z. ZHONG ET AL.
times, strictly controlled conditions (anhydrous conditions and inert gas protection),
or the use of expensive reagents. Besides, column chromatographic purification was
generally employed to isolate the products, which may limit their application in
obtaining chromatography-sensitive acyl azides.
Acyl chlorides are the most frequently used acid derivatives in the preparation
of acyl azides. The acylation of azide anion with acyl chlorides were carried out in
[2]
[3]
either anhydrous or aqueous conditions; however, anhydrous conditions were
frequently employed because acyl chlorides were sensitive to moisture and may
undergo hydrolysis.
The Katritzky group recently introduced readily available and stable N-acyl-
[4]
benzotriazoles as alternatives to acid chlorides for the acylation of sodium azide
at room temperature, where a drop of water was added to the acetonitrile solution
to facilitate the solubility of sodium azide. However, 16–20 h were required for the
reaction to reach completion.
We herein report an optimized procedure by using FeCl ꢀ 6H O as a catalyst
3
2
for the synthesis of acyl azides as compared with Katritzky group’s original pro-
cedure. This brought on remarkably greater efficiency (greatly shortened reaction
time and comparable or improved yields), avoidance of column chromatographic
purification, and large-scale preparation.
[
5]
We have previously found that with SmI as a catalyst, N-acylbenzotriazoles
3
could acylate active methylene compounds efficiently, which provided us with a hint
that the presence of a Lewis acid may play a significant role in enhancing the
reactivity of N-acylbenzotriazoles. Herein, we disclose that the cheap and environ-
mentally friendly FeCl ꢀ 6H O could catalyze the reaction between N-acylylbenzo
3
2
triazoles and sodium azide with remarkable efficiency.
Initially, a variety of solvents were screened to optimize the conditions for the
acylation of sodium azide with N-benzoyl benzotriazole in the presence of 5 mol% of
FeCl ꢀ 6H O (Scheme 1 and Table 1). A sufficient amount of water was used in all
3
2
the runs as a cosolvent to ensure complete dissolution of sodium azide.
As listed in Table 1, dichloromethane (DCM) and ethyl acetate required longer
times for the complete conversion of N-benzoyl benzotriazole due to the hetero-
geneous conditions (Table 1, entries 2 and 7). The use of dimethylformamide
(DMF), ethanol, or butanol could give improved results (Table 1, entries 3, 4, and 6).
However, acetonitile and acetone showed the greatest efficiency (Table 1, entries 1
and 5). Finally, acetone was employed as the ideal solvent for the reaction because
it has a lower boiling point (it is better to remove the solvent at lower temperatures
because acyl azides are sensitive to heat) and is less toxic. It should be mentioned
that under the optimized conditions, 92% yield of benzoyl azide with the purity
1
99% [determined by high-performance liquid chromatography (HPLC) and H
>
NMR] were isolated by simple workup consisting of extraction with diethyl ether,
Scheme 1. Screening of the co-solvent for the FeCl
benzotriazole.
3
ꢀ 6H
2 3
O-catalyzed acylation of NaN with N-benzoyl

FeCl
3
ꢀ 6H
2
O-CATALYZED ACYLATION
2463
Table 1. Screening of the solvents for the FeCl
3
-catalyzed acylation
a
b
Entry
Solvent
Time
Conversion
c
1
2
3
4
5
6
7
CH
CH
3
CN
Cl
5 min (16–20 h)
4.5 h
100
74.5
100
100
100
90
2
2
DMF
30 min
40 min
5 min
CH
CH
3
2
CH OH
3
COCH
3
BuOH
CH COOEt
40 min
24 h
3
100
a
All the runs were carried out with 1 mmol of N-benzoyl benzotriazole in 3 mL of the solvent, fresh
sodium azide solution (3 mmol of sodium azide in 1 mL of water) and 5 mol% of FeCl
b
3
2
ꢀ 6H O.
The conversion of N-benzoyl benzotriazole was determined by HPLC.
c
The time required in the absence of FeCl
3
2
ꢀ 6H O as reported in Ref. [4].
washing with aqueous Na CO solution, drying over sodium sulfate, and evapor-
3
2
ating the solvent.
We next applied a variety of N-acylbenzotriazoles, including a variety of aroyl,
cinnamoyl, crotonoyl, and aliphatic N-acylbenzotriazoles, as the substrates to inves-
tigate the scope of the protocol (Scheme 2). The results are presented in Table 2.
The reaction catalyzed with FeCl ꢀ 6H O gave remarkably greater efficiency
3
2
[
4]
for the acylation reaction as compared with Katritzky’s original procedure, where
a much longer reaction time was involved. N-Benzoyl benoztriazole and N-aroyl
benoztriazoles with electron-withdrawing groups or moderate electron-releasing
groups on the aryl afforded the acyl azides in excellent isolated yields in 5 min with
5
mol% of FeCl ꢀ 6H O (Table 2, entries 1, 2, 6, 8–10). The same efficacy was also
3
2
observed for N-(2-furoyl), N-(1-naphthoyl), and N-adamantanoyl benzotriazole
Table 2, entries 11, 12, 17). For N-aroyl benoztriazoles with strong electron-
(
releasing groups or o-substituents on the aryl, such as N-(2-methylbenzoyl) benzo-
triazole and N-(2-chlorobenzoyl) benzotriazole, more catalyst loading (20 mol% of
FeCl ꢀ 6H O) was required to ensure the same reaction rate (Table 2, entries 3, 5,
3
2
7
). This protocol was also efficient for a,b-unsaturated N-acyl benzotriazoles, from
which good to excellent yields of the acyl azides could be obtained with 20 mol% of
FeCl ꢀ 6H O in 10 min to 2 h (entries 13–16). It is worth mentioning that we have
3
2
previously attempted to synthesize N-crotonoyl azide using the reported procedure
Scheme 2. Acylation of NaN
3
with N-acylbenzotriazoles promoted by FeCl
3
ꢀ 6H
2
O in acetone-water.

2464
Z. ZHONG ET AL.
Table 2. Synthesis of acyl azides from N-acyl benzotriazoles and sodium azide catalyzed by FeCl
3
ꢀ 6H
2
O
a
Catalyst
loading
Yields
(lit.) (%)
ꢁ
b
Entry
R
Products
Time
Mp (lit.) ( C)
[
6]
1
2
2a
2b
5
5
5 min
5 min
Oil (25–27)
90 (82)
89 (82)
[
6]
32–34 (35)
3
2c
20
5 min
Oil (—)
81
[
6]
6]
6]
c
4
5
6
2d
2d
2e
5
20
5
30 min
5 min
5 min
68–70 (70–71)
71
[
68–70 (70–71)
85
90
[
43–45 (42–43)
[7]
7
2f
20
5 min
Oil
81
8
9
2g
2h
5
5
5 min
5 min
63–65 (—)
71–72 (70–72)
91
94
[8]
[
9]
10
11
12
2i
2j
5
5
5
5 min
5 min
5 min
64–66 (68)
92
80 (75)
88
[4]
52–54 (60–62)
1
30–133
124–126 dec.)
2k
[10]
(
[
4]
1
3
4
2l
20
20
20 min
1 h
83–85 (82–83)
71–73 dec. (—)
82 (72)
85
[2]
1
2m
[2]
1
1
5
6
2n
2o
20
20
2 h
85–87 dec. (—)
Oil
90
10 min
74 (43)
1
7
8
2p
2q
5
5 min
5 min
68–70
84
[7]
d
53
1
n-C
6
H13 1q
20
Oil
a
b
c
Yields were isolated yields and based on N-acylbenzotriazoles.
The yields using the methods reported in Ref. [4] were listed in the parentheses.
With 5 mol% of catalyst, incomplete conversion of 1d was observed, which would lead to the isolation
of product 2c by column chromatography.
d
1
Product 2q was determined by H NMR, but it was contaminated by 1q.

FeCl
3
ꢀ 6H
2
O-CATALYZED ACYLATION
2465
(Table 2, entry 16). In that case, besides the long reaction time (18 h), several
by-products were observed. In addition, product 2o underwent partial decompo-
sition on the silica column, which made the yield even lower. However, with
FeCl ꢀ 6H O as a catalyst, the reaction time was reduced to 10 min, no side reactions
3
2
were detected, column chromatography purification was avoided, and the yield of
the product was greatly increased. Besides, 1-adamantanoyl azide 2p was prepared
and isolated in good yields by the present method (Table 2, entry 17). As has been
[
11]
reported,
readily obtained in its pure form otherwise.
2p readily decomposed upon flash chromatography and could not be
Thus the unique advantage of the improved procedure was demonstrated.
Finally, it should be pointed out that the method appeared to be limited to N-alka-
noyl benzotriazoles because the use of N-heptanoyl benzotriazole 1q did not produce
encouraging results under the same conditions (entry 18). Although 100% conversion
of the starting material 1q was observed after completion of the reaction, it was
regenerated in the workup process by reversible attack of benzotriazole anion on
acyl azide 2q.
In view of the simple workup procedure, its potential for large-scale prep-
aration was explored. As expected, the acylation with 60 mmol of N-benzoyl benzo-
triazoles proceeded equally smoothly at room temperature. The by-product
(
which afforded 8.0 g (91% yield) of benzoyl azide in its pure form (>99% purity by
benzotriazole) could be easily removed by simply washing it with aqueous Na CO ,
2 3
[
12]
HPLC). It is possible to recover benzotriazole
from the aqueous Na CO
2 3
solution by neutralization with condensed hydrochloric acid and extraction with
ethyl acetate.
The improved efficiency in the presence of FeCl ꢀ 6H O may be rationalized in
3
2
two aspects: (1) the complexation of the iron(III) with the oxygen atom of the acyl
enhanced the reactivity of N-acylbenzotriazoles and accelerated the reaction rate; (2)
the lesser sensitivity of N-acyl benzotriazoles to moisture allows the presence of a
sufficient amount of water as cosolvent, ensuring homogeneous conditions where
both sodium azide and N-acylbenzotriazoles could be soluble.
In conclusion, the protocol provided an improved synthesis of acyl azides form
N-acylbenzotriazoles and sodium azide. The acylation proceeded efficiently with
FeCl ꢀ 6H O as catalyst. Furthermore, the complete conversion of the starting
3
2
N-acylbenzotriazoles and easy removal of the catalyst and by-product made the
protocol suitable for large-scale preparation, demonstrating its distinct advantage
over a number of existing methods.
EXPERIMENTAL
Melting points were uncorrected. Infrared (IR) spectra were recorded using
KBr disks or film with a Nexus 670 Fourier transform (FTIR)–spectrometer with
ꢂ1
1
absorption in cm . H NMR and C NMR spectra were determined in a Bruker
13
AC-400 spectrometer as CDCl solutions. J values are in hertz. Chemical shifts
3
are expressed in parts per million (ppm) downfield from internal tetramethylsilane
(TMS). Elemental analysis was carried out on a EA 1110 instrument. HPLC was per-
formed on ODS-BP (200 mm ꢃ 4.6 mm, 5 mm) column with methanol–water (50:50)
as mobile phase at a flow rate of 0.5 mL=min.

2466
Z. ZHONG ET AL.
General Procedure for the Preparation of Acyl Azides
Ferric chloride hexahydrate (0.05 mmol, 13.5 mg or 0.2 mmol, 54.1 mg) was
added to a solution of N-acylbenzotriazole (1 mmol) in acetone (3 mL). Fresh
sodium azide solution (3 mmol, 0.195 g of sodium azide dissolved in 1 mL of water)
was added over a period of 5 min. The mixture was stirred at room temperature for
5
min or the period as indicated in Table 1 [monitored by thin-layer chromatography
TLC], and then extracted with diethyl ether (3 ꢃ 10 mL). The organic layer was
washed successively with saturated sodium carbonate solution (1 ꢃ 10 mL) and brine
(
1 ꢃ 10 mL). After being dried over anhydrous sodium sulfate, the solvent was
removed in vacuo to give pure acyl azids 2a–2p.
Selected Data
ꢂ1
Azido(2-tolyl)methanone 2c. Colorless oil. nmax(KBr)=cm : 3430, 3039,
2
7
923, 2164, 1687, 1590, 1212. dH (CDCl ): 7.91 (d, J ¼ 7.9 Hz, 1H, ArH),
3
1
3
.42–7.44 (m, 1H, ArH), 7.25–7.26 (m, 2H, ArH), 2.63 (s, 3H, CH ). C NMR
3
(CDCl ): 173.1, 141.4, 133.4, 132.1, 131.0, 126.9, 22.0. Anal. calcd. for C H N O:
C, 59.62; H, 4.38; N, 26.07. Found C, 59.73; H, 4.40; N, 26.12%.
3
8
7
3
ꢂ1
Azido(4-iodophenyl)methanone 2g. White solid. nmax (KBr)=cm : 3364,
923, 2140, 1694, 1580, 1259. d (CDCl ): 7.83 (d, J ¼ 8.0 Hz, 2H, ArH), 7.73 (d,
2
H
3
1
3
J ¼ 8.0 Hz, 2H, ArH). C NMR (CDCl ): 172.1, 138.1, 130.7, 130.1, 102.7. Anal.
3
calcd. for C H IN O: C, 30.79; H, 1.48; N, 15.39. Found: C, 30.85; H, 1.49; N,
3
7
4
1
5.33%.
ꢂ1
1
-Azidobut-2-en-1-one 2o. White solid. nmax (KBr)=cm : 3355, 2919, 2145,
1
691, 1646, 1232. dH (CDCl ): 7.05–7.07 (m, 1H, C=CH), 5.86 (d, J ¼ 8.0 Hz, 1H,
3
13
C=CH), 1.93 (d, J ¼ 8.0 Hz, 3H, CH ). C NMR (CDCl ): 172.1, 147.6, 122.2,
3
3
1
4
8.1. Anal. calcd. for C H N O: C, 43.24; H, 4.54; N, 37.82. Found: C, 43.37; H,
4 5 3
.52; N, 37.96%.
ꢂ1
(KBr)=cm :
Azido(1-adamantanyl)methanone 2p. White solid. n
max
ꢂ1
3
397, 2906, 2851, 2141, 1705, 1451, 1220, 1010 cm . dH (CDCl ): 2.05 (br s, 3H,
3
1
3
CH), 1.85 (d, J ¼ 2.4 Hz, 6H, CH), 1.72–1.66 (m, 6H, CH). C NMR (CDCl3):
1
2
85.3, 45.2, 38.5, 36.3, 27.8. Anal. calcd. for C H N O: C, 64.37; H, 7.37; N,
11 15 3
0.47. Found: C, 64.57; H, 7.38; N, 20.38%.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China
No. 20802070) for financial support.
(
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