One-pot syntheses of 5-amino-1-aryltetrazole derivatives

Article abstract of DOI:10.1055/s-2006-926403

A novel facile route for the introduction of 5-amino and 5-alkylamino substituents into 1-aryltetrazoles has been developed. A range of 5-amino-1-aryltetrazoles was obtained directly from the corresponding 1-aryltetrazoles in one pot by consecutive ring-opening, azidation and intramolecular cyclization. 5-Alkylamino-1-aryltetrazoles were formed by a similar mechanism from 1,4-disubstituted tetrazolium salts. An influence of the nature of aryl substituents and reaction conditions on the regioselectivity of the intramolecular cyclization of intermediate guanyl azides is revealed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-926403

PAPER
1307
One-Pot Syntheses of 5-Amino-1-aryltetrazole Derivatives
S
ynthese
s
of 5-Am
n
ino-1-aryltet
d
razoles rey N. Vorobiov,*a Pavel N. Gaponik,b Petr T. Petrov,a Oleg A. Ivashkevichb
a
Scientific Pharmaceutical Center, RUE Belmedpreparaty, Fabritsiusa Str. 30, Minsk 220007, Belarus
Research Institute for Physico-Chemical Problems, Belarusian State University, Leningradskaya Str. 14, Minsk 220050, Belarus
Fax +375(17)2293926; E-mail: azole@bsu.by
b
Received 25 September 2005; revised 1 December 2005
which 1-aryltetrazoles were converted to 5-amino-1-
aryltetrazoles via cyanamide intermediates. The use of
large excess of sodium azide, low temperatures (–70 °C)
and organolithium reagents are the drawbacks of this
Abstract: A novel facile route for the introduction of 5-amino and
5-alkylamino substituents into 1-aryltetrazoles has been developed.
A range of 5-amino-1-aryltetrazoles was obtained directly from the
corresponding 1-aryltetrazoles in one pot by consecutive ring-open-
ing, azidation and intramolecular cyclization. 5-Alkylamino-1- method making it fairly complicated and potentially dan-
aryltetrazoles were formed by a similar mechanism from 1,4-disub-
gerous. Recently, we have described a sufficiently simple
stituted tetrazolium salts. An influence of the nature of aryl substit-
and convenient three-step synthesis of 5-amino-1-aryltet-
uents and reaction conditions on the regioselectivity of the
razoles from the corresponding arylamines (Scheme 1,
intramolecular cyclization of intermediate guanyl azides is re-
route A).5d In the first stage, aromatic amines 1 undergo
vealed.
heterocyclization with triethyl orthoformate and sodium
Key words: 5-aminotetrazoles, tetrazolium salts, heterocycles, tan-
azide in acetic acid to give 1-aryltetrazoles 2. The latter
dem reactions, regioselectivity
are smoothly decomposed by an inorganic alkali in di-
methyl sulfoxide yielding the corresponding N-arylcyan-
amides 3, which could be transformed to 5-amino-1-
aryltetrazoles 4 by the cycloaddition of an azide ion. De-
The area of use of various tetrazole derivatives expands
rapidly.1 In particular, a range of 5-aminotetrazoles has
spite rather versatile character of the described approach,
been reported as biologically active compounds or inter-
some disadvantages restrict its application. Thus, in cer-
mediates for their production,2 ingredients of gas-generat-
tain cases we encountered difficulties on the stage of cy-
ing and explosive compositions, and anticorrosive
anamide intermediates isolation and purification caused
additives.3 However, the utility of these compounds is
by their insufficient stability. Therefore, the overall yields
limited due to their insufficient synthetic availability.
of 5-amino-1-aryltetrazoles are frequently inadequate (see
Substituted 5-aminotetrazoles are conventionally synthe-
Table 1).
sized by diazotation of aminoguanidine derivatives4 or
azidation of cyanamides,5a–5d carbodiimides,5e thio-
N
ureas,5f,g,j aminoiminomethanesulfonic acids,5h benzotri-
H2N
N
N
azol-1-ylcarboximidamides5i and other suitable substrates
with subsequent intramolecular cyclization. 5-Amino
groups can also be introduced into the tetrazole cycle by
nucleophilic substitution of the tetrazoles containing leav-
ing groups in 5-position with the appropriate amines.6
Synthesis of 5-alkylaminotetrazoles by direct alkylation
of the exocyclic nitrogen atom in the corresponding 5-
aminotetrazoles is not applicable due to a concurrent for-
mation of ring-alkylated products. Only the use of specific
alkylating systems (e.g. alkyl iodide/hexamethyldisil-
azide) can be successful.5b It should be noted that most of
the above methods are laborious and often require unsta-
ble, toxic and poorly available starting materials and re-
agents. Consequently, there is a need for a simple method
for the synthesis of 5-aminotetrazole derivatives, which is
free of the said drawbacks.
i
iii
ii
N
NH2
N
N
NH
Ar
N
N
N
Ar
Route A Ar
Ar
1a–g
3a–g
4a–g
2a–g
iv
Route B
Scheme 1 Reagents and conditions: i) NaN3 (1.1 equiv), triethyl or-
thoformate (3.0 equiv), AcOH (8.0 equiv), 80 °C, 3–4 h, 70–95%; ii)
aq NaOH (1.5 equiv), DMSO; iii) NaN3 (1.5 equiv), NH4Cl (2.0
equiv), DMF, 80 °C, 3 h; iv) NaN3 (1.5 equiv), NaOH (1.5 equiv),
Et3N (2.0 equiv), i-PrOH, DMSO, r.t., 0.5–2 h, then AcOH (3.0
equiv), 70–80 °C, 2 h.
Here, we report on an improved synthetic approach pro-
viding significantly higher yields of desired products in
shorter time, including the cases when the intermediate
cyanamides were not stable enough to be isolated. The
proposed method is shown as route B in Scheme 1.
1-Aryltetrazoles are known to decompose under the ac-
tion of strong bases yielding N-arylcyanamides.7a
Congreve5b has proposed a two-step reaction sequence in
Both stages of the synthesis proceed successively in one
pot, without isolation of intermediate cyanamides. The
mechanism of the decomposition of 1-aryltetrazoles oc-
curring under basic conditions on the first stage is similar
to that of the same process induced by n-butyllithium.8
The strong ionizing character of the NaOH/DMSO system
SYNTHESIS 2006, No. 8, pp 1307–1312
x
x
.
x
x
.2
0
0
6
Advanced online publication: 27.03.2006
DOI: 10.1055/s-2006-926403; Art ID: T13505SS
© Georg Thieme Verlag Stuttgart · New York

1308
A. N. Vorobiov et al.
PAPER
Table 1 5-Aminotetrazoles 4 Prepared
function in 5-position of the heterocycle. Such com-
pounds can be synthesized by azidation of N,N¢-disubsti-
tuted carbodiimides.5e Unfortunately, this approach is not
well developed due to poor availability and insufficient
stability of functionalized carbodiimides. Moreover, the
above mentioned synthesis requires the use of highly toxic
and explosive hydrazoic acid. We have elaborated a safe
and convenient one-pot procedure for the synthesis of 5-
alkylamino-1-aryltetrazoles from the corresponding 1-
alkyl-4-aryltetrazolium salts by treatment with triethy-
lammonium azide in the presence of dimethyl sulfoxide.
These tetrazolium salts are relatively stable and syntheti-
cally available compounds, which are known to decom-
pose in basic media to form carbodiimides.1d,7b
Product
Aryl
Yield (%)a
Route A
Route B
75
4a
4b
4c
4d
4e
4f
Ph
53
b
4-EtOC6H4
4-NO2C6H4
4-MeC6H4
2-MeC6H4
2-MeOC6H4
3-Cl,4-FC6H3
–
80
b
–
60
66
87
b
–
72
21
66
71
4g
86
The initial 1-alkyl-4-aryltetrazolium perchlorates 7 were
synthesized by quaternization of 1-aryltetrazoles with ei-
ther dimethyl sulfate or tert-butyl alcohol in perchloric ac-
id. In both cases the process was not completely
regioselective, therefore more or less significant amounts
(up to 26%, as estimated by NMR) of 1,3-isomers were
formed together with the desired 1,4-salts. Notably, the
influence of electronic properties of aryl substituents on
the regioselectivity of methylation was found to be negli-
gible, while it was rather strong in the case of tert-butyla-
tion. The amount of 1,3-isomer was low for the
compounds bearing electron-withdrawing groups in aryl
substituents (e.g., 7f, less than 1%) and high for the com-
pounds containing electron-donating groups (e.g., 7e,
26%). In the case of tert-butylation, the regioselectivity
may be improved. Elongation of the reaction time resulted
in rearrangement of initially formed 1,3-disubstituted tet-
razolium salts into the corresponding 1,4-isomers that
takes place in acidic media.1d,9 We did not observe any in-
fluence of 1,3-isomers on the course of the further synthe-
sis and used crude quaternization products without
purification.
a Isolated overall yield of 4 from 2.
b N-Arylureas and other by-products were mostly formed.
favors stabilization of the intermediate carbanion 5 and,
therefore, results in dramatic acceleration of the reaction,
compared to other solvents. Decomposition proceeds at
room temperature and finishes within 0.5–2 hours, de-
pending on the nature of an aryl substituent and reagents
ratio. On the completion of the first stage, the second one
is initiated by partial acidification of the reaction mixture.
The resulting aminotetrazole derivatives were not ob-
tained when no acid had been added. The importance of
the acidification can be explained by the formation of tri-
ethylammonium azide, which is required for the comple-
tion of the heterocyclization process. Therefore, the
amount of acid should be enough to neutralize an inorgan-
ic alkali and to form the amine salt, but should not exceed
the total molar amount of bases in the reaction mixture to
avoid the evolution of explosive and toxic hydrazoic acid.
A possible reaction mechanism is shown in Scheme 2.
N
The synthesis of 5-alkylamino-1-aryltetrazoles from the
corresponding 1-alkyl-4-aryltetrazolium salts includes
two successive stages (Scheme 3). First, tetrazolium salts
7 undergo ring-opening under action of the bases con-
tained in the reaction medium (dimethyl sulfoxide, sodi-
um azide). Apparently, the strength of these bases is
enough for the cleavage of the labile proton attached to the
carbon atom of a heterocycle leading to unstable tetra-
zolidene intermediates. The latter decompose rapidly with
the elimination of N2 and formation of N-alkyl-N¢-arylcar-
bodiimides 8. In the second stage, carbodiimides 8 are at-
tacked by an azide ion furnishing 5-alkylamino-1-
aryltetrazoles 9 through the intermediate open-chain iso-
mers 11. The reaction normally completes within 1.5–2
H
N
N
N
N
H+
NaOH
DMSO
N
N
N
N
– N2
N
Ar
H
Ar
Ar
2
5
3
Et3N⋅HN3
NEt3
NEt3
N
H
NH
C
H2N
H
NH
N–
N
–N
N
+N
N+
– Et3N
N
N
N
N
Ar
N
Ar
Ar
4
6
Scheme 2
The stability of cyanamide intermediates did not affect the hours being performed at 70–90 °C.
yields of aminotetrazoles 4. We succeeded in performing
N-Arylcyanamides and N-alkyl-N¢-arylcarbodiimides
the reaction even with the substrates which give no de-
sired product by the route A. In other cases, yields were
significantly improved (Table 1).
were previously reported to react with hydrazoic acid giv-
ing solely 5-alkylamino-1-aryltetrazoles.5a–5e In the
course of our work, we have observed that the regioselec-
Next, we attempted to broaden the applicability of the tivity of cycloaddition of an azide ion to the heterocumu-
above-described approach in order to expand it for the lene moiety of carbodiimides is strongly affected by the
synthesis of tetrazoles containing a substituted amino nature of aryl substituents and reaction conditions. The
Synthesis 2006, No. 8, 1307–1312 © Thieme Stuttgart · New York

PAPER
Syntheses of 5-Amino-1-aryltetrazoles
1309
NHY
NR
C
Ar
R
Ar
N+
ClO4
N
i or ii
iii
N
N
N
X
–
N
N
N
N
N
NAr
8a–f
N
N
7a–f
2a–c
9a–f: X = Ar; Y = R
10a–f: X = R; Y = Ar
–
Scheme 3 Reagents and conditions: i) 1. (MeO)2SO2; 2. ClO4 ; ii) t-BuOH, HClO4; iii) NaN3 (2.0 equiv), Et3N⋅HCl (2.0 equiv), MeCN,
DMSO, 70 °C, 2 h.
aforesaid tendency has been reproduced for the substrates aminotetrazole derivative 9. The cyclization process is
with aryl substituents bearing electron-donating groups. practically irreversible for the compounds 9a, 9b and
In such cases only the corresponding 5-alkylamino-1- alike. The functional groups with strong electron-with-
aryltetrazoles 9 were obtained. On the other hand, when drawing effect in aryl substituents of compounds 9c and
the aryl substituent had contained electron-withdrawing 9f at the reaction temperature (80 °C and higher) favor the
groups, significant or even prevalent amounts of isomeric increase of the azido form 11 in the equilibrium with tet-
1-alkyl-5-arylaminotetrazoles 10 were detected in the re- razole 9. Consequently, isomeric 5-arylaminotetrazoles
action products.
10 are gradually accumulated in the reaction mixture due
to practically irreversible character of their formation
from azides 11¢.
The reasons for the observed variations of regioselectivity
are clarified by the following experimental facts. We
found that the regioselectivity of the cyclization was re-
stored and the principal products isolated from the reac-
tion were 5-alkylamino-1-aryltetrazoles 9 when the
reaction had been carried out at lower temperature (45–50
°C). Longer reaction periods were required in these cases
to obtain satisfactory yields (Table 2). The pure N-meth-
yl-1-(4-nitrophenyl)-1H-tetrazol-5-amine (9c) obtained
this way gives a mixture of 9c and 10c at 1:7 ratio on heat-
ing at 80 °C for 1.5 hours in a mixture of DMSO and ace-
tonitrile. Therefore, the most probable reason of
accumulation of regioisomers 10 in the reaction mixture is
a Dimroth-type rearrangement that occurs with the initial-
ly formed aminotetrazoles 9 (a possible mechanism is
shown in Scheme 4). The nucleophilic attack of an azide
ion onto the carbon atom of carbodiimide occurs in the
first stage. The intermediate guanyl azide 11 undergoes
intramolecular cyclization yielding almost exclusively the
N+Et3
H
N–
Ar
RHN
Ar
R
[Et3NH]+N3
–
N
N
Ar
N
C
N
R
N
N
–N
8
+N
N
N
9
11
R = H
HN
C N
Ar
N+Et3
3
H
Ar N–
R
N
ArHN
R
N
–N
N
N
+N
11'
N
N
10
Scheme 4
Table 2 5-Aminotetrazoles 4c and 9a–f Prepared
Product
Ar
R
H
Reaction conditions
90–100 °C, 2.5 h
90–100 °C, 1.5 h
60 °C, 2.5 h
70 °C, 2 h
Total yield (%)
Ratio of regioisomers 9:10a
4c
4-NO2C6H4
78
72
37
60
92
82
52
62
65
76
46
31:69b
57:43
100:0
100:0
100:0
2:98
9a
9b
9c
Ph
Me
Me
Me
4-EtOC6H4
4-NO2C6H4
70 °C, 2 h
85 °C, 4 h
45–50 °C, 4 h
70 °C, 2 h
87:13
100:0
100:0
9:91
9d
9e
9f
Ph
t-Bu
t-Bu
t-Bu
4-EtOC6H4
4-NO2C6H4
70 °C, 2 h
85 °C, 4 h
45–50 °C, 4 h
95:5
a Determined by NMR spectra of crude products.
b Ratio of 4c:10g.
Synthesis 2006, No. 8, 1307–1312 © Thieme Stuttgart · New York

1310
A. N. Vorobiov et al.
PAPER
1H NMR (DMSO-d6): d = 3.80 (s, 3 H, CH3), 6.62 (s, 2 H, NH2),
7.12 (t, J = 7.6 Hz, 1 H, Ar), 7.28 (d, J = 8.4 Hz, 1 H, Ar), 7.40 (d,
J = 7.7 Hz, 1 H, Ar), 7.57 (t, J = 7.3 Hz, 1 H, Ar).
13C NMR (DMSO-d6): d = 55.6, 112.7, 120.5, 121.1, 128.1, 131.6,
153.9, 155.6.
Such rearrangements of 5-aminotetrazole derivatives
were previously reported and discussed.1a,5c Usually, they
were performed under harsh conditions (very high tem-
peratures, acid catalysis). In the present work, we have
demonstrated that the rearrangement products can be se-
lectively obtained in relatively mild conditions as a result
of the conventional azidation–cyclization process.
Anal. Calcd for C8H9N5O (191.2): C, 50.26; H, 4.74; N, 36.63.
Found: C, 50.14; H, 4.77; N, 36.51.
In conclusion, we have developed a facile and efficient
method of introduction of 5-amino and 5-alkylamino
groups into 1-aryltetrazoles. The proposed scheme in-
volves readily available and chemically stable starting
materials and reagents. The reactions have temperature-
dependent regioselectivity and proceed in high yields un-
der mild conditions.
1-(3-Chloro-4-fluorophenyl)-1H-tetrazol-5-amine (4g)
Yield: 86%; mp 187–188 °C (Lit.5d mp 188–189 °C).
1H NMR (DMSO-d6): d = 7.00 (s, 2 H, NH2), 7.60–7.68 (m, 2 H,
Ar), 7.89–7.91 (m, 1 H, Ar).
13C NMR (DMSO-d6): d = 117.6 (d, J = 22.6 Hz), 120.2 (d, J = 19.2
Hz), 125.5 (d, J = 8.1 Hz), 126.9, 129.9 (d, J = 2.4 Hz), 154.7, 157.0
(d, J = 249.0 Hz).
Anal. Calcd for C7H5ClFN5 (213.6): C, 39.36; H, 2.36; N, 32.79.
Found: C, 39.30; H, 2.23; N, 32.90.
Melting points were determined in open capillary tubes using Elec-
trothermal IA9200 apparatus and are uncorrected. Analytical TLC
1
was performed using Merck 60 F254 silica gel plates. H and 13C
N-(4-Nitrophenyl)-1H-tetrazol-5-amine (10g)
1-(4-Nitrophenyl)-1H-tetrazole was treated according to the above-
described general procedure except that the temperature was kept at
100 °C for 2.5 h. The compound 4c was filtered off. The filtrate was
acidified with several drops of conc. HCl. The precipitate was sep-
arated by filtration, washed with H2O and dried at reduced pressure
at 50 °C to give the title compound which was chromatographically
pure; yield: 53%; mp 221–223 °C (dec.) [Lit.10 mp 221–223 °C
(dec.)].
NMR spectra were recorded on Bruker Avance 500 spectrometer at
operating frequencies of 500 MHz and 125 MHz, respectively, us-
ing DMSO-d6 or CD3CN as a solvent. The data are reported in parts
per million relative to TMS and referenced to the solvent in which
they were run.
Commercially available reagents and solvents were used in synthe-
ses. 1-Aryltetrazoles 2a–g were synthesized by heterocyclization of
substituted anilines with triethyl orthoformate and NaN3 in AcOH
according to the previously reported method.5d
1-Aryl-4-methyltetrazolium Perchlorates 7a–c; General
Procedure
Melting points and NMR spectra of previously reported compounds
were in agreement with those of the authentic samples and/or avail-
able literature data.
A solution of 1-aryltetrazole 2 (2.0 mmol) in dimethyl sulfate (0.57
mL, 6.0 mmol) was kept at 80 °C for 3 h or at 45 °C for 16 h. The
mixture was extracted several times with Et2O to remove unreacted
starting materials. The insoluble residue was mixed with 12.5% aq
solution of Mg(ClO4)2 (4 mL). The precipitate was filtered, washed
with H2O and dried at reduced pressure to furnish the tetrazolium
salts 7a–c that were used in the next stage without further purifica-
tion.
5-Amino-1-aryltetrazoles 4a–g; General Procedure
A stirred mixture of 1-aryltetrazole 2 (5.0 mmol), NaN3 (7.5 mmol,
488 mg), NaOH (7.5 mmol, 300 mg) and Et3N (10.0 mmol, 1.01 g)
in i-PrOH (1.5 mL) was treated dropwise with DMSO (3.5 mL). The
mixture was stirred at r.t. until the gas evolution ceased (0.5–2 h)
and then was treated with glacial AcOH (15 mmol, 900 mg). The re-
sulting suspension was stirred at 70–80 °C for 2 h, cooled and dilut-
ed with brine (70 mL). The precipitate was separated by filtration,
washed with H2O and dried in vacuo at 50 °C to give 5-amino-1-
aryltetrazoles 4a–g. Analytical samples were obtained after recrys-
tallization from i-PrOH.
4-Methyl-1-phenyl-1H-tetrazolium Perchlorate (7a)
Yield: 68% (contains ca. 11% of 1,3-isomer).
1H NMR (CD3CN): d = 4.43 (s, 3 H, CH3), 7.71–7.89 (m, 5 H,
C6H5), 10.61 (s, 1 H, CH).
13C NMR (CD3CN): d = 39.0, 118.3, 123.4, 131.6, 133.5, 142.0.
1-Phenyl-1H-tetrazol-5-amine (4a)
Anal. Calcd for C8H9ClN4O4 (260.6): C, 36.87; H, 3.48; N, 21.50.
Found: C, 36.99; H, 3.37; N, 21.38.
Yield: 75%; mp 162–163 °C (Lit.5a mp 163–163.5 °C).
1-(4-Ethoxyphenyl)-1H-tetrazol-5-amine (4b)
1-(4-Ethoxyphenyl)-4-methyl-1H-tetrazolium Perchlorate (7b)
Yield: 74% (contains ca. 8% of 1,3-isomer).
Yield: 80%; mp 199–201 °C (Lit.5g mp 197 °C).
1H NMR (CD3CN): d = 1.41 (t, J = 7.0 Hz, 3 H, CH3), 4.16 (q,
J = 7.0 Hz, 2 H, CH2), 4.41 (s, 3 H, CH3), 7.19 (d, J = 9.1 Hz, 2 H,
Ar), 7.74 (d, J = 9.1 Hz, 2 H, Ar), 10.49 (s, 1 H, CH).
13C NMR (CD3CN): d = 14.7, 38.8, 65.3, 116.8, 118.2, 125.0, 125.1,
141.4.
1-(4-Nitrophenyl)-1H-tetrazol-5-amine (4c)
Yield: 60%; mp 176, 222–224 °C (dec.) [Lit.5a mp 176, 221–223 °C
(dec.)].
1-(4-Methylphenyl)-1H-tetrazol-5-amine (4d)
Yield: 87%; mp 174–175 °C (Lit.5c mp 175.5–177 °C).
Anal. Calcd for C10H13ClN4O5 (304.7): C, 39.42; H, 4.30; N, 18.39.
Found: C, 39.28; H, 4.21; N, 18.22.
1-(2-Methylphenyl)-1H-tetrazol-5-amine (4e)
Yield: 72%; mp 189–190 °C (Lit.5c mp 191–192 °C).
4-Methyl-1-(4-nitrophenyl)-1H-tetrazolium Perchlorate (7c)
Yield: 70% (contains ca. 9% of 1,3-isomer).
1H NMR (CD3CN): d = 4.47 (s, 3 H, CH3), 8.11 (d, J = 9.2 Hz, 2 H,
Ar), 8.54 (d, J = 9.2 Hz, 2 H, Ar), 10.74 (s, 1 H, CH).
1-(2-Methoxyphenyl)-1H-tetrazol-5-amine (4f)
Yield: 71%; mp 164–166 °C (Lit.5c mp 172–174 °C).
13C NMR (CD3CN): d = 39.1, 118.0, 124.7, 126.7, 142.4.
Synthesis 2006, No. 8, 1307–1312 © Thieme Stuttgart · New York

PAPER
Syntheses of 5-Amino-1-aryltetrazoles
1311
Anal. Calcd for C8H8ClN5O6 (305.6): C, 31.44; H, 2.64; N, 22.91.
Found: C, 31.52; H, 2.69; N, 22.79.
Anal. Calcd for C10H13N5O (219.2): C, 54.78; H, 5.98; N, 31.94.
Found: C, 54.61; H, 5.95; N, 31.99.
1-Aryl-4-tert-butyltetrazolium Perchlorates 7d–f; General
Procedure
N-Methyl-1-(4-nitrophenyl)-1H-tetrazol-5-amine (9c)
Yield: 67%; mp 284–286 °C (dec.).
A solution of 1-aryltetrazole 2 (2.0 mmol) and 1,1-dimethylethanol
(450 mg, 6.1 mmol) in HClO4 (70%, 2 mL) was kept at r.t. for 5 d.
The mixture was diluted with H2O (10 mL) and cooled to 10 °C. The
precipitate was filtered, washed with H2O and Et2O and dried at re-
duced pressure to furnish the tetrazolium salts 7d–f that were used
in the next stage without further purification.
1H NMR (DMSO-d6): d = 2.92 (d, J = 4.6 Hz, 3 H, CH3), 7.21 (q,
J = 4.5 Hz, 1 H, NH), 7.90 (d, J = 8.9 Hz, 2 H, Ar), 8.44 (d, J = 9.0
Hz, 2 H, Ar).
13C NMR (DMSO-d6): d = 30.1, 124.6, 125.0, 138.1, 146.8, 155.2.
Anal. Calcd for C8H8N6O2 (220.2): C, 43.64; H, 3.66; N, 38.17.
Found: C, 43.62; H, 3.70; N, 38.04.
4-tert-Butyl-1-phenyl-1H-tetrazolium Perchlorate (7d)
Yield: 97% (contains ca. 16% of 1,3-isomer).
1H NMR (CD3CN): d = 1.86 (s, 9 H, t-C4H9), 7.74–7.94 (m, 5 H,
Ar), 10.61 (s, 1 H, CH).
13C NMR (CD3CN): d = 29.1, 31.3, 118.4, 123.4, 131.7, 133.5,
140.2.
N-tert-Butyl-1-phenyl-1H-tetrazol-5-amine (9d)
Yield: 62%; mp 114–115 °C (Lit.5e mp 113–114 °C).
N-tert-Butyl-1-(4-ethoxyphenyl)-1H-tetrazol-5-amine (9e)
Yield: 65%; mp 141–143 °C.
1H NMR (DMSO-d6): d = 1.36 (t, J = 6.9 Hz, 3 H, CH3), 1.37 (s, 9
H, t-C4H9), 4.10 (q, J = 6.8 Hz, 2 H, CH2), 6.14 (s, 1 H, NH), 7.11
(d, J = 8.4 Hz, 2 H, Ar), 7.43 (d, J = 8.3 Hz, 2 H, Ar).
Anal. Calcd for C11H15ClN4O4 (302.7): C, 43.64; H, 4.99; N, 18.51.
Found: C, 43.53; H, 5.08; N, 18.47.
13C NMR (DMSO-d6): d = 14.3, 28.1, 51.8, 63.3, 115.1, 125.8,
126.2, 153.6, 158.8.
4-tert-Butyl-1-(4-ethoxyphenyl)-1H-tetrazolium Perchlorate
(7e)
Yield: 99% (contains ca. 26% of 1,3-isomer).
Anal. Calcd for C13H19N5O (261.3): C, 59.75; H, 7.33; N, 26.80.
Found: C, 59.62; H, 7.26; N, 26.67.
1H NMR (CD3CN): d = 1.42 (t, J = 7.0 Hz, 3 H, CH3), 1.84 (s, 9 H,
t-C4H9), 4.17 (q, J = 7.0 Hz, 2 H, CH2), 7.21 (d, J = 9.1 Hz, 2 H,
Ar), 7.81 (d, J = 9.2 Hz, 2 H, Ar), 10.48 (s, 1 H, CH).
13C NMR (CD3CN): d = 14.8, 28.9, 32.4, 65.3, 116.9, 118.2, 125.0,
125.1, 146.7.
N-tert-Butyl-1-(4-nitrophenyl)-1H-tetrazol-5-amine (9f)
Yield: 61%; mp 183–185 °C (darkens), 205–207 °C (melts with
dec.).
1H NMR (DMSO-d6): d = 1.40 (s, 9 H, t-C4H9), 6.75 (s, 1 H, NH),
7.90 (d, J = 8.8 Hz, 2 H, Ar), 8.44 (d, J = 8.8 Hz, 2 H, Ar).
13C NMR (DMSO-d6): d =28.5, 52.7, 125.4, 125.5, 139.1, 147.3,
159.9.
Anal. Calcd for C13H19ClN4O5 (346.8): C, 45.03; H, 5.52; N, 16.16.
Found: C, 45.17; H, 5.54; N, 16.11.
4-tert-Butyl-1-(4-nitrophenyl)-1H-tetrazolium Perchlorate (7f)
Yield: 95% (contains <1% of 1,3-isomer).
1H NMR (CD3CN): d = 1.87 (s, 9 H, t-C4H9), 8.17 (d, J = 9.3 Hz, 2
H, Ar), 8.57 (d, J = 9.3 Hz, 2 H, Ar), 10.76 (s, 1 H, CH).
13C NMR (CD3CN): d = 28.7, 68.3, 118.0, 124.3, 126.8, 140.5.
Anal. Calcd for C11H14N6O2 (262.3): C, 50.38; H, 5.38; N, 32.04.
Found: C, 50.34; H, 5.36; N, 31.91.
1-Methyl-N-(4-nitrophenyl)-1H-tetrazol-5-amine (10c)
Yield: 78%; mp 284–286 °C (dec.).
Anal. Calcd for C11H14ClN5O6 (347.7): C, 38.00; H, 4.06; N, 20.14.
Found: C, 37.89; H, 4.10; N, 20.02.
1H NMR (DMSO-d6): d = 3.99 (s, 3 H, CH3), 7.86 (d, J = 9.2 Hz, 2
H, Ar), 8.27 (d, J = 9.2 Hz, 2 H, Ar), 10.17 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 32.1, 116.0, 124.6, 140.2, 145.5, 151.1.
5-Aminotetrazoles 9a–f, 10c, 10f; General Procedure
A stirred mixture of tetrazolium salt 7a–f (1.5 mmol), NaN3 (3.0
mmol, 195 mg) and triethylammonium chloride (3.0 mmol, 414
mg) in MeCN (2 mL) was treated dropwise with DMSO (2 mL). On
the completion of vigorous gas evolution, the mixture was heated to
70 °C and stirred at this temperature for 2 h. In the syntheses of the
compounds 10c and 10f, the temperature was kept at 85 °C for 4 h.
The mixture was allowed to cool and diluted with brine (40 mL).
The precipitate was filtered, washed with H2O and dried at reduced
pressure to give 5-aminotetrazole. Analytical samples were ob-
tained after recrystallization from i-PrOH.
Anal. Calcd for C8H8N6O2 (220.2): C, 43.64; H, 3.66; N, 38.17.
Found: C, 43.73; H, 3.62; N, 38.22.
1-tert-Butyl-N-(4-nitrophenyl)-1H-tetrazol-5-amine (10f)
Yield: 69%; mp 205–207 °C (dec.).
1H NMR (DMSO-d6): d = 1.70 (s, 9 H, t-C4H9), 7.46 (d, J = 9.2 Hz,
2 H, Ar), 8.19 (d, J = 9.2 Hz, 2 H, Ar), 9.26 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 28.0, 60.3, 116.0, 125.0, 140.2, 147.7,
150.3.
Anal. Calcd for C11H14N6O2 (262.3): C, 50.38; H, 5.38; N, 32.04.
Found: C, 50.44; H, 5.29; N, 32.00.
N-Methyl-1-phenyl-1H-tetrazol-5-amine (9a)
Yield: 60%; mp 133–134 °C (Lit.5e mp 133–134 °C).
1-(4-Ethoxyphenyl)-N-methyl-1H-tetrazol-5-amine (9b)
Yield: 92%; mp 155–157 °C.
References
(1) For reviews of tetrazole chemistry, see: (a) Butler, R. N. In
Comprehensive Heterocyclic Chem. II, Vol. 4; Katritzky, A.
R.; Rees, C. W.; Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996, 621. (b) Wittenberger, S. J. Org. Prep. Proced. Int.
1994, 26, 499. (c) Herr, R. J. Bioorg. Med. Chem. 2002, 10,
3379. (d) Voitekhovich, S. V.; Gaponik, P. N.; Ivashkevich,
O. A. Russ. Chem. Rev. 2002, 71, 721.
1H NMR (DMSO-d6): d = 1.35 (t, J = 6.9 Hz, 3 H, CH3), 2.85 (d,
J = 4.6 Hz, 3 H, CH3), 4.10 (q, J = 6.9 Hz, 2 H, CH2), 6.70 (q,
J = 4.4 Hz, 1 H, NH), 7.11 (d, J = 8.8 Hz, 2 H, Ar), 7.43 (d, J = 8.7
Hz, 2 H, Ar).
13C NMR (DMSO-d6): d = 14.4, 30.1, 63.5, 115.3, 125.6, 126.3,
155.7, 159.1.
Synthesis 2006, No. 8, 1307–1312 © Thieme Stuttgart · New York

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A. N. Vorobiov et al.
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Synthesis 2006, No. 8, 1307–1312 © Thieme Stuttgart · New York