Synthesis of trifluoromethyltetrazoles via building block strategy

Article abstract of DOI:10.1016/S0022-1139(99)00122-0

A series of 1-substituted-5-trifluoromethyltetrazoles was conveniently prepared from N-substituted trifluoroacetimidoyl chlorides via nucleophilic replacement with azide anion followed by subsequent cyclization in moderate to excellent yield by building b

Full text of DOI:10.1016/S0022-1139(99)00122-0

Journal of Fluorine Chemistry 99 (1999) 83±85
Synthesis of tri¯uoromethyltetrazoles via
building block strategy
Jingbo Xiao, Xiaomei Zhang, Deying Wang, Chengye Yuan*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 20 April 1999; accepted 31 May 1999
Abstract
A series of 1-substituted-5-tri¯uoromethyltetrazoles was conveniently prepared from N-substituted tri¯uoroacetimidoyl chlorides via
nucleophilic replacement with azide anion followed by subsequent cyclization in moderate to excellent yield by building block strategy.
# 1999 Elsevier Science S.A. All rights reserved.
Keywords: Tri¯uoromethyltetrazole; Tri¯uoromethylated building block; Nucleophilic replacement; Cyclization
1. Introduction
2. Results and discussion
Awide range of tetrazole derivatives has been patented for
antihypertension activity and as angiotensin II receptor
antagonists [1±3]. These are claimed to be useful for treating
congestive heart failure [4] and preventing cardiac hyper-
trophy [5]. The tetrazole ring also features in a range of
antiallergic substances which act by inhibiting the allergic
histamine release [6,7]. Tetrazoles, due to their pharmaceu-
tical importance and extensive application in organic synth-
esis, have aroused the interests of many synthetic chemists.
On the other hand, tri¯uoromethylated compounds have
received an increasing attention in recent years because
of their enhancement effect on the biological activity of
the parent molecules [8±10]. Much current effort has been
devoted to the development of methods for synthesis of
tri¯uoromethylated heterocycles, most of them are based on
the building block strategy [11,12]. N-substituted tri¯uor-
oacetimidoyl chloride was found to be useful in the forma-
tion of tri¯uoromethylated nitrogen heterocycles [13].
Herein we wish to report a facile synthetic method leading
to tri¯uoromethylated tetrazoles 3 based on building block
strategy. These compounds are expected to show some
potential biological activities. To the best of our knowledge,
these title compounds have not been reported to date.
As shown in Scheme 1, N-substituted tri¯uoroacetimidoyl
chlorides 1 upon nucleophilic replacement by azide ion 2
followed by subsequent cyclization give tri¯uoromethylated
tetrazoles, namely 1-substituted-5-tri¯uoromethyltetrazoles
3.
Our experimental data demonstrated that the cyclization
of 2±3 proceeded smoothly in moderate to excellent yield
depending on the nature of substituents on imino nitrogen. It
seems that there are two structural requirements for the
cyclization process. First, the lone pair of the imino nitrogen
and azido group should be in cis con®guration since some
imidoyl azides in trans con®guration were not easily
cyclized to corresponding tetrazoles [14,15]. Second, a
suf®cient electron density is necessary on the imino nitrogen
in order to form the electron withdrawing tetrazole ring. It is
clear that this indirect [1±3] dipolar cycloaddition leading to
the formation of the aromatic system is the driving force of
this cyclization process. As shown in Table 1, the presence
of an electron donating group on the N-substituent of 1
increases the yield dramatically, although the yield of 3c is
not so high as expected. It is necessary to point out that
although Carpenter et al. [16], in their paper on ¯uorinated
1,2,3-triazolines, described a reaction leading to 1-benzyl-5-
tri¯uoromethyltetrazole starting from N-benzyltri¯uoroace-
timidoyl ¯uoride, our method is distinguished by its avail-
ability and its wide scope of applications (see Table 2).
In summary, we describe a method for the preparation of
1-aryl(alkyl)-5-tri¯uoromethyltetrazoles starting from tri-
*Corresponding author.
E-mail address: yuancy@pub.sioc.ac.cn (C. Yuan)
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 1 2 2 - 0

84
J. Xiao et al. / Journal of Fluorine Chemistry 99 (1999) 83±85
recorded on a JEOL FX-90Q Spectrometer. Chemical shifts
for 1H NMR spectra are reported in ꢀ values down®eld from
TMS. 19F NMR spectra were obtained on a Varian EM-
360A Spectrometer using CF3COOH as an external stan-
dard, positive for down®eld shift. EI±MS were obtained on a
HP5989A Mass Spectrometer. Elemental analysis was per-
formed in our institute.
Scheme 1.
N-substituted tri¯uoroacetimidoyl chlorides were pre-
pared by literature methods [17]. Sodium azide was pur-
chased from Shanghai Chemical. Acetonitrile was dried by
re¯uxing with P2O5, then distilled prior to use. DMF was
dried by re¯uxing with CaH2, then distilled.
¯uoroacetimidoyl chlorides followed by azide substitution
and subsequent cyclization and discuss the effect of the
substituents on the yields of the title compounds. This
synthesis is convenient since the building block tri¯uoro-
acetimidoyl chlorides can be easily prepared by re¯uxing a
mixture of tri¯uoroacetic acid and primary amine in carbon
tetrachloride in the presence of triethylamine and triphe-
nylphosphine [17]. The chemical reaction and the structural
effect on the 19F NMR chemical shift of these tetrazoles are
being carried on in our laboratory. The biological investiga-
tion data will be published elsewhere.
3.1. 1-(p-methoxyphenyl)-5-trifluoromethyltetrazole (3i):
typical procedure
To an oven-dried two-necked 25 ml round-bottom ¯ask
®tted with a magnetic stirring bar and charged with dry N2
was added N-(p-methoxyphenyl)-tri¯uoroacetimidoyl
chloride (590 mg, 2.5 mmol) and acetonitrile (4 ml) and
sodium azide (177 mg, 2.5 mmol). The resulting mixture
was stirred at room temperature for 10 h. Completion of
reaction was monitored by TLC. The mixture was ®ltered
and concentrated to give a crude product, which was sub-
jected to column chromatography on silica gel (eluent: 10%
3. Experimental
Melting points are uncorrected. IR spectra were taken on
a Shimadzu-440 Spectrophotometer. 1H NMR spectra were
Table 1
Trifluoromethyltetrazoles prepared
Table 2
Spectral characteristics of compounds 3
1
)
Compounds
Melting
Yield
(%)
Molecular formula
IR ꢁ (cm
19F NMR
MS
point (8C)
ꢀ (ppm)
(m/z)
‡
‡
3a
3b
3c
3d
3e
3f
Oil
Oil
80
91
68
53
50
55
70
53
94
91
61
70
C8H5F3N4 (214.1)
C9H7F3N4 (228.2)
3190, 1160, 1500, 1535
3050, 2920, 1165, 1510
2960, 1160, 1510, 1530
3090, 1170, 1490, 1530
3090, 1155, 1485, 1525
3100, 1160, 1495, 1530
3080, 1150, 1495, 1525
3040, 1165, 1490, 1540
3100, 2900, 1165, 1610
2900, 1160, 1535
18.7
17.6
18.0
18.0
18.0
18.4
19.3
17.0
17.5
17.0
16.5
17.4
214 (M )
228 (M )
‡
43±45
Oil
C
10H9F3N4 (242.2)
242 (M )
‡
C8H4ClF3N4 (248.6)
C8H3Cl2F3N4 (283.0)
C8H4BrF3N4 (293.0)
C8H4F3N5O2 (259.1)
C8H4F3N5O2 (259.1)
C9H7F3N4O (244.2)
248 (M )
‡
Oil
283 (M )
293 (M )
‡
51±53
70±72
82±84
Oil
‡
3g
3h
3i
260 (M ‡1)
‡
259 (M )
244 (M )
‡
‡
3j
39±41
38±40
102±104
C
C
C
10H9F3N4 (242.2)
10H9F3N4 (242.2)
12H7F3N4 (264.2)
242 (M )
‡
3k
3l
3000, 1160, 1500, 1530
3150, 1165, 1510, 1525
242 (M )
‡
264 (M )

J. Xiao et al. / Journal of Fluorine Chemistry 99 (1999) 83±85
85
Table 3
1H NMR (CCl4) ꢀ (ppm), J (Hz) spectra of compounds 3
Compounds
1H NMR (CCl4), ꢀ (ppm), J (Hz)
3a
3b
3c
3d
3e
3f
7.60±7.93 (m, 5H, Ph)
7.37±7.50 (m, 4H, Ph); 2.58 (s, 3H, CH3)
7.56 (s, 3H, Ph); 2.60 (s, 3H, p-CH3); 2.30 (s, 3H, m-CH3)
7.63 (d, 2H, J ˆ 8.1 Hz, Ph); 7.48 (d, 2H, J ˆ 8.1 Hz, Ph)
7.26±7.82 (m, 3H, Ph)
7.83 (d, 2H, J ˆ 9.0 Hz, Ph); 7.47 (d, 2H, J ˆ 9.0 Hz, Ph)
8.59 (d, 2H, J ˆ 11.7 Hz, Ph); 7.87 (d, 2H, J ˆ 11.7 Hz, Ph)
7.55±8.46 (m, 4H, Ph)
3g
3h
3i
7.45 (d, 2H, J ˆ 9.0 Hz, Ph); 7.10 (d, 2H, J ˆ 9.0 Hz, Ph); 3.98 (s, 3H, CH3)
7.31±7.40 (m, 5H, Ph); 5.70±5.93 (m, 1H, CH); 2.15 (d, 3H, J ˆ 7.2 Hz, CH3)
7.25±7.51 (m, 5H, Ph); 4.89 (t, 2H, J ˆ 8.1 Hz, N±CH2); 3.60 (t, 2H, J ˆ 8.1 Hz, CH2±Ph)
7.16±8.32 (m, 7H, naphthalene±H)
3j
3k
3l
Table 4
Acknowledgements
Microanalysis data for compounds 3
The authors thank the National Science Foundation of
China (No. 29832052) for ®nancial support.
Products
Calculated (%)
Found (%)
C
C
H
N
H
N
3a
3b
3c
3d
3e
3f
44.87
47.38
49.54
38.65
33.95
32.79
37.08
37.08
44.27
49.59
49.59
54.55
2.36
3.09
3.74
1.62
1.07
1.38
1.56
1.56
2.89
3.75
3.75
2.67
26.16
24.55
23.21
22.54
19.80
19.12
27.03
27.03
22.95
23.13
23.13
21.21
44.28
47.07
49.61
38.15
34.14
32.63
37.19
36.71
44.49
49.59
49.32
54.50
2.16
2.75
3.55
1.50
1.05
1.21
1.38
1.33
2.89
3.58
3.63
2.49
26.42
25.07
23.29
22.44
20.14
19.33
27.50
27.38
23.15
23.35
23.24
21.35
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