A two-step synthesis of 1,5-disubstituted tetrazoles containing a siloxy or sulfonamide group

Article abstract of DOI:10.1016/j.tetlet.2011.08.114

A simple two-step route to the synthesis of 1,5-disubstituted tetrazoles containing a β-siloxy or β-sulfonamide group is presented. The synthesis takes place via an isocyanide-based multicomponent reaction and allows incorporation of a wide variety of substitution patterns starting from commercially available reagents. This is followed by cyclization of the ketenimines with trimethylsilyl azide without using any catalyst or activation.

Full text of DOI:10.1016/j.tetlet.2011.08.114

Tetrahedron Letters 52 (2011) 5930–5933
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Tetrahedron Letters
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A two-step synthesis of 1,5-disubstituted tetrazoles containing a siloxy or
sulfonamide group
Afshin Sarvary a, Shabnam Shaabani a, Ahmad Shaabani a, , SeikWeng Ng b
⇑
a Department of Chemistry, Shahid Beheshti University, G. C., PO Box 19396 4716, Tehran, Iran
b Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
A simple two-step route to the synthesis of 1,5-disubstituted tetrazoles containing a b-siloxy or b-sulfon-
amide group is presented. The synthesis takes place via an isocyanide-based multicomponent reaction
and allows incorporation of a wide variety of substitution patterns starting from commercially available
reagents. This is followed by cyclization of the ketenimines with trimethylsilyl azide without using any
catalyst or activation.
Received 16 May 2011
Revised 9 August 2011
Accepted 19 August 2011
Available online 7 September 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,5-Disubstituted tetrazole
Ketenimine
Isocyanide
Multicomponent
1,5-Disubstituted tetrazoles are useful heterocycles because of
their biological and pharmacological properties. They function as
Also, the Ugi four-component reaction (U-4CR) of isocyanides with
amines, aldehydes or ketones, and TMSN3 affords 1,5-disubstituted
tetrazoles.7 The corresponding tetrazoles were also obtained via
isocyanide-based reactions, according to a sequential one-pot pro-
cedure.8 Therefore, development of a new synthetic approach not
requiring any catalyst under mild reaction conditions that could
be used to prepare a variety of these templates remains an impor-
tant task.
It has been shown that addition of isocyanides to electron-defi-
cient alkynes, such as dimethyl acetylenedicarboxylate (DMAD)
generates zwitterionic species. These reactive intermediates can
be trapped by a third component, such as CH-acids,9 NH-acids like
amides,10 OH-acids like oximes11, and carboxylic acids.12
Due to the above-mentioned reasons and as part of our ongoing
research on isocyanide-based multicomponent reactions
(IMCRs),13 a simple two-step strategy for the preparation of 1,5-
disubstituted tetrazoles containing siloxy 6 or sulfonamide 8
groups via an IMCR, followed by intermolecular cycloaddition reac-
tion of the intermediate ketenimines 4 or 7 with trimethylsilyl
azide (without using any catalyst or activation), is reported
(Scheme 1). To the best of our knowledge, these ketenimines have
not been used previously in intermolecular cycloaddition
reactions.
NADPH oxidase inhibitors,1a glucokinase activators,1b
a-methy-
lene tetrazole based peptidomimetic HIV protease inhibitors,1c
calcitonin gene-related peptide receptor antagonists, and antim-
igraine agents.1d Furthermore, 1,5-disubstituted tetrazoles are
useful synthetic intermediates2a for the synthesis of energetic
salts,2b 3,4-dihydropyrimidin-2(1H)-ones,2c piericidins,2d (+)-
trans-5-allylhexahydroindolizidin-3-ones,2e acacetin,2f (+)-stricti-
folione,2g vinylsilanes,2h and leucascandrolide A.2i Moreover, in
the design of peptidomimetics, it is often possible to enhance
the pharmacological properties of
a molecule by replacing
amides with amide isosteres. Common replacements which mi-
mic cis amides are 1,5-disubstituted tetrazoles.3
The synthesis of 1,5-disubstituted tetrazoles has generated sig-
nificant interest.4–8 The most direct synthetic routes to 1,5-disub-
stituted tetrazoles are via intermolecular cycloaddition reactions
and conversion of substituted tetrazoles into 1,5-disubstituted tet-
razoles.4 Moreover, isocyanide-based reactions have been used for
the preparation of 1,5-disubstituted tetrazoles. The first synthesis
of these compounds via isocyanide-based reactions was under-
taken by Ugi and Meyr, in which they reported the synthesis of
1,5-disubstituted tetrazoles using a Passerini three-component
reaction (P-3CR) of isocyanides, highly reactive carbonyl com-
pounds, and hydrazoic acid (HN3).5 Nixey and Hulme developed
a TMSN3-modified P-3CR for the synthesis of these compounds.6
As indicated in Scheme 2, isocyanides 1, dialkylacetylenedicarb-
oxylates 2, and triphenylsilanol 3 undergo a smooth 1:1:1 addition
reaction to produce, selectively, stable ketenimines 4a–i contain-
ing a siloxy group in high yields in CH2Cl2 (Table 1). All of the prod-
ucts are new compounds and their structures were deduced from
their IR, mass, 1H NMR, and 13C NMR spectra. It is important to
⇑
Corresponding author. Tel.: +98 2129902800; fax: +98 2122431663.
E-mail address: a-shaabani@cc.sbu.ac.ir (A. Shaabani).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.114

A. Sarvary et al. / Tetrahedron Letters 52 (2011) 5930–5933
R2
5931
SiPh3
R2
R1
O
N
N
Ph3SiOH
SiPh3
N
C
N
O
R2
R2
3
4
N
R2
R2
R1
6
TMSN3(5)
C
rt, 8 h
H2Cl2
R1
N
C
+
O
R2
t-BuOH
rt, 12 h
O
O
O
O
S
O
S
R2
R1
N
NH R3
N
N
R3
S
R3
NH2
N
N
H
C
1
2
N
R1
R2
9
7
R2
8
Scheme 1. Synthesis of 1,5-disubstitutedtetrazoles.
R2
SiPh3
R2
R1
O
CH2Cl2
rt, 8 h
R1
Ph3SiOH
C
N
+
N C
+
R2
R2
2
4a-i
1
3
Scheme 2.
Table 1
Synthesis of ketenimine derivatives 4a–i
Entry
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
t-Bu
t-Bu
t-Bu
Cyclohexyl
Cyclohexyl
Cyclohexyl
CO2Me
CO2Et
CO2t-Bu
CO2Me
CO2Et
CO2t-Bu
CO2Me
CO2Et
4a
4b
4c
4d
4e
4f
4g
4h
4i
92
91
84
94
90
85
96
93
84
CO2t-Bu
N
N
N
R2
R2
OSiPh3
Figure 1. ORTEP representation of 6f (CCDC 817391).
t-BuOH
C
N
+
TMSN3
N
rt, 8 h
Ph3SiO
4a-i
R1
R1
R2
R2
6a-i
N
N
N
N
N
N
N
N
CO2t-Bu
Hb
OSiPh3
CO2t-Bu
Hb
OSiPh3
Scheme 3.
aH
t-BuO2C
Ha
t-BuO2C
Table 2
(2R,3R)-, or (2S,3S)-6f'
(2R,3S)- or (2S,3R)-6f
Figure 2. NOE studies of compounds 6f and 6f0.
Synthesis of 1,5-disubstituted tetrazoles 6a–i containing a siloxy group
Entry R1 R2 Product Yield (%) (anti:syn)a
1
2
3
4
5
6
7
8
9
1,1,3,3-Tetramethylbutyl CO2Me
1,1,3,3-Tetramethylbutyl CO2Et
1,1,3,3-Tetramethylbutyl CO2t-Bu 6c
6a
6b
83 (84:16)
86 (100:Trace)
81 (100:Trace)
85 (100:Trace)
85 (77:23)
79 (66:34)
80 (26:74)
N
N
N
R2
R2
HNO2SR3
t-Bu
t-Bu
CO2Me
CO2Et
6d
6e
t-BuOH
C
N
+
TMSN3
N
rt, 12 h
R3SO2NH
7a-h
R1
R1
R2
R2
t-Bu
CO2t-Bu 6f
Cyclohexyl
Cyclohexyl
Cyclohexyl
CO2Me
CO2Et
CO2t-Bu 6i
6g
6h
8a-h
82 (23:77)
78 (12:88)
Scheme 4.
A
Anti:syn ratio determined from the 1H NMR spectra of the crude mixtures.
As indicated in Scheme 3, the reactions proceeded very efficiently,
and led to the formation of the corresponding siloxy 1,5-disubsti-
tuted tetrazoles 6b–i in good yields (Table 2). Because of the diver-
sity of substitution patterns possible, this reaction can be used to
create combinatorial libraries.
The structures of products 6a–i were deduced from their IR,
mass, 1H NMR, and 13C NMR spectra. The mass spectra of these
compounds displayed molecular ion peaks at the appropriate m/z
values. The structure of compound 6f was confirmed unambigu-
ously by single-crystal X-ray analysis (Fig. 1).
note that trapping of the initially formed 1:1 intermediate with tri-
phenylsilanol has not been reported until now.
Next, the intermolecular cycloaddition reaction of siloxy keteni-
mines with trimethylsilyl azide was investigated. In a pilot exper-
iment, a mixture of ketenimine 4a and trimethylsilyl azide (5) was
stirred in tert-butanol at room temperature for 8 h to give product
6a in 83% yield.
To explore the scope and limitations of this reaction, the proce-
dure was extended to various siloxy ketenimine derivatives 4b–i.

5932
A. Sarvary et al. / Tetrahedron Letters 52 (2011) 5930–5933
Table 3
Synthesis of 1,5-disubstituted tetrazoles 8a–h containing a sulfonamide group
Entry
R1
R2
R3
Product
Yield (%) (anti:syn)a
1
2
3
4
5
6
7
8
Cyclohexyl
Cyclohexyl
Cyclohexyl
Cyclohexyl
CO2Me
CO2Me
CO2Et
CO2t-Bu
CO2t-Bu
CO2Me
CO2Et
Ph
8a
8b
8c
8d
8e
8f
71 (83:17)
68 (77:23)
70 (85:15)
73 (66:34)
67 (75:25)
78 (67:33)
74 (74:26)
73 (70:30)
4-MeC6H4
4-MeC6H4
Ph
4-MeC6H4
Ph
Cyclohexyl
1,1,3,3-Tetramethylbutyl
1,1,3,3-Tetramethylbutyl
t-Bu
Ph
Ph
8g
8h
CO2Et
A
Anti:syn ratio determined from the 1H NMR spectra of the crude mixtures.
Compounds 6 have two stereogenic centers, and as indicated in
Figure 2, two pairs of diastereoisomers are expected. The 1H NMR
and 13C NMR spectra of the crude reaction mixtures obtained for
the products (except 6b–d) were consistent with two diastereoiso-
mers. On the basis of 1H homonuclear J couplings (3JHH) and NOE
measurements, the R,S or S,R diastereoisomer (anti arrangement)
31.8, 51.4, 51.9, 54.7, 65.3, 66.2, 69.4, 127.9, 130.2, 135.1, 135.7,
164.7, 169.0, 171.8 ppm. Anal. Calcd for C33H39NO5Si: C, 71.06; H,
7.05; N, 2.51. Found: C, 72.32; H, 6.80; N, 2.66.
Synthesis of dimethyl 2-[1-(2,4,4-trimethylpentan-2-yl)-1H-
tetrazol-5-yl]-3-(triphenylsilyloxy)succinate (6a)
3
was the major diastereoisomer. For example, the JHH values of
the vicinal methine protons (Ha and Hb) in diastereoisomers 6f
and 6f0 were 10.0 and 7.6 Hz, respectively. Also NOE studies on dia-
stereoisomer 6f0, showed that Ha exhibited an NOE (3.7%) after the
irradiation of Hb. The same trend was not observed for diastereo-
isomer 6f. These results indicate that the major diastereoisomer
has an anti arrangement (R,S or S,R) and that the minor diastereo-
isomer has a syn arrangement (R,R or S,S) (Fig. 2).
N-Arylsulfonamides constitute an important class of therapeu-
tic agents in medicinal chemistry and more than 30 drugs contain-
ing this moiety are known.14 In this respect, the synthesis of
tetrazoles containing a sulfonamide group is relevant. Therefore,
the versatility of this intermolecular cycloaddition reaction with
respect to ketenimines 7a–h was studied.10a As shown in Scheme
4, reaction of ketenimine derivatives 7a–h containing a sulfon-
amide group with trimethylsilyl azide (5) in tert-butanol led to
the formation of a new class of 1,5-disubstituted tetrazole deriva-
tives 8a–h in high yields after 12 h at room temperature. Represen-
tative products of this reaction are shown in Table 3. The 1H NMR
and 13C NMR spectra of the crude reaction mixtures showed the
presence of two pairs of diastereoisomers.
Typical procedure: To a magnetically stirred solution of keteni-
mine 4a (0.56 g, 1 mmol) in t-BuOH (5 mL) was added trimethyl-
silyl azide (0.12 g, 1 mmol) and the reaction mixture was stirred
for 12 h at room temperature. After completion of the reaction as
indicated by TLC, the mixture was purified by silica gel column
chromatography using n-hexane: AcOEt (3:1) to afford the product
as a yellow oil, yield 0.5 g (83%); IR (KBr) mmax = 2936, 2863, 1734,
1593, 1436 cmꢀ1; MS, m/z (%): 685 (M+ꢀ77, 5), 457 (2), 429 (2),
411 (100), 351 (25), 277 (25), 213 (50), 97 (20), 57 (70); 1H NMR
(300 MHz, CDCl3): d = 0.77–2.19 [34H, m, (CH3)3, (CH3)2 and
CH2(R,S and R,R)], 3.22 [3H, s, OCH3(R,R)], 3.32 [3H, s, OCH3(R,S)],
3.48 [3H, s, OCH3(R,R)], 3.65 [3H, s, OCH3(R,S)], 4.90 [1H, d,
3
3JHH = 9.2 Hz, CH(R,R)], 5.12 [1H, d, JHH = 11.4 Hz, CH(R,S)], 5.18
3
3
[1H, d, JHH = 11.4 Hz, CH(R,S)], 5.49 [1H, d, JHH = 9.2 Hz, CH(R,R)],
7.25–7.67 [30H, m, H–AR(R,S and R,R)] ppm; 13C NMR (75 MHz,
CDCl3) R,S: d = 29.7, 30.9, 31.6, 46.2, 52.8, 54.5, 61.1, 65.9, 73.2,
127.8, 130.3, 132.3, 135.5, 150.4, 167.2, 170.7 ppm. Anal. Calcd
for C33H40N4O5Si: C, 65.97; H, 6.71; N, 9.33. Found: C, 66.29; H,
6.35; N, 9.74.
In summary, we have demonstrated an efficient and simple
route for the preparation of 1,5-disubstituted tetrazole derivatives
containing siloxy and sulfonamide groups from readily available
substrates in fairly good yields. The advantages of the present pro-
cedure are as follows: the reaction is performed by simple mixing
of the starting materials, requires neutral reaction conditions, and
displays good functional group tolerance. To the best of our knowl-
edge, this reaction is the first example of the conversion of siloxy-
or sulfonamide-ketenimines into the corresponding 1,5-disubsti-
tuted tetrazoles.
Acknowledgment
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University.
Supplementary data
Supplementary data (experimental procedure and spectral
data) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.08.114.
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