A novel synthesis of 1,5-disubstituted fluorinated tetrazoles from 1,1-difluoroazides

Article abstract of DOI:10.1016/j.tetlet.2010.06.016

A new one-step reaction between 1,1-difluoroazides and primary amines is reported as an efficient synthetic approach for tetrazole formation. Examples include the syntheses of fluorine-containing 1,5-substituted tetrazoles from three fluorinated azide precursors and various amines. Greater substituent diversity in comparison with conventional methods is achieved.

Full text of DOI:10.1016/j.tetlet.2010.06.016

Tetrahedron Letters 51 (2010) 4205–4207
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel synthesis of 1,5-disubstituted fluorinated tetrazoles from
1,1-difluoroazides
Anna G. Polivanova a, Sergey V. Shkavrov b, Andrei V. Churakov c, Anatoly S. Lermontov c,
Sergey A. Lermontov d,
*
a D. Mendeleyev University of Chemical Technology of Russia, 125047 Moscow, Russia
b Chemical Diversity Research Institute, 141400 Khimki, Moscow Reg., Russia
c Institute of General and Inorganic Chemistry, RAS, 119991 Moscow, Russia
d Institute of Physiologically Active Compounds, RAS, 142432 Chernogolovka, Moscow Reg., Russia
a r t i c l e i n f o
a b s t r a c t
Article history:
A new one-step reaction between 1,1-difluoroazides and primary amines is reported as an efficient syn-
thetic approach for tetrazole formation. Examples include the syntheses of fluorine-containing 1,5-
substituted tetrazoles from three fluorinated azide precursors and various amines. Greater substituent
diversity in comparison with conventional methods is achieved.
Received 12 April 2010
Revised 19 May 2010
Accepted 4 June 2010
Available online 9 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Difluoroazides
1,5-Substituted fluorinated tetrazoles
Fluorine nucleophilic substitution
In pioneering studies in 19461 several alkyl-substituted 1,5-tet-
razoles were investigated for their anticonvulsant and analeptic
activities. Further studies revealed their similarity with the cis-
amide bond in peptides.2 A brief review of the pharmacological
activity of 1,5-substituted tetrazole compounds has been pub-
lished.3 They were shown to be potential P2X7-antagonists,4 TNF-
alpha inhibitors,5 and inhibitors of anandamide cellular uptake.6
1,5-Disubstituted tetrazoles are used as intermediates for the syn-
thesis of substituted dihydropyrimidinones,7 vinyl silanes,8 indo-
lizidinones,9 and other valuable compounds.10
Known methods for the synthesis of 1,5-disubstituted tetrazoles
are mostly based on reactions of azides with substituted nitriles,
suitable imidoyl derivatives, or on diazotization of amidrazones;10
these correspond to reaction types 1 and 2 in Scheme 1.
Recently reported approaches have led to an increase in selectiv-
ity and easier syntheses of the target compound, and these also
correspond to reaction types 1 and 2 in Scheme 1. These approaches
include ambient temperature reactions of imidoylbenzotriazoles
with NaN3,11 a catalyzed, one-pot, trimethylsilyl azide reaction with
a nitrile and an alkene,12 and a catalyzed Passerini-type reaction
involving an aldehyde, an isocyanide, and an HN3.13 The introduc-
tion of a substituent using an amine group was developed for the
preparation of 1H,5-substituted tetrazoles, for example, via reaction
of primary amines with NaN3 and triethyl orthoformate.14
Only a few examples of the synthesis of fluorinated 1,5-disub-
stituted tetrazoles exist, and all are based on general tetrazole ring
construction reactions: azide anion cycloaddition with fluorinated
nitriles15 and imidoyl halogenides.16 Difluoromethylenetetrazoles
are known as potent inhibitors of protein tyrosine phosphatases17
and estrone sulfate analogs,18 and their activity exceeds that of
non-fluorinated compounds. It should be mentioned that the intro-
duction of fluorine atoms often alters the biological activity of or-
ganic compounds significantly, sometimes resulting in the
discovery of important drugs.19
Here we report a novel method for the synthesis of fluorinated
1,5-disubstituted tetrazoles based on a reaction between 1,1-diflu-
oroazides (R1-CF2–N3) and primary aliphatic amines allowing the
direct introduction of a fluorine-containing 1C-substituent from
the 1,1-difluoroazide (reaction type 3 in Scheme 1, and Scheme 2).
This reaction proceeds under mild conditions and often at ambi-
ent temperature in dry EtOH or THF. It is sensitive to steric hin-
drance, but even adamantyl-containing and tert-alkyl amines can
be converted into the corresponding tetrazoles. The ratio of prod-
ucts 1:2 is not solvent dependent. In the case of azide A-2, an
N
1. C-N + N-N-N
2. N-N-C-N + N
3. C-N-N-N + N
N
* Corresponding author. Tel.: +7 (496) 524 95 08.
E-mail address: lermon@ipac.ac.ru (S.A. Lermontov).
N
N
Scheme 1. Different types of 1,5-disubstituted tetrazole ring construction methods.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.016

4206
A. G. Polivanova et al. / Tetrahedron Letters 51 (2010) 4205–4207
R2
N
1,1-Difluoroazides are stable and safe compounds which are
O
easily prepared from fluoroolefins and possess a wide range of R1
groups;20 these include alkyl, aryl, keto, ester, or hydroxy. They
have been reported as precursors for fluoroazirines and fluoro-
monomers,21 oxidative fluorinating reagents,20f and fluorinated tri-
azole precursors.22
R1
r.t. or reflux
EtOH or THF
R2
R1-CF2-N3
R2 -NH2
N
R1
N
H
+
+
N
N
1
2
O
R1
=
CHFCF3 (A1), CF2COOCH3 (A2),
(A3)
CF2
N
Compounds 1 and 2 are probably the products of competitive
nucleophilic substitution of the fluorine atoms, or of an azide
group, by the primary amine (Scheme 3).
CH3
CH3
CH3
R2
=
,
,
,
,
,
CH3
The amide structure was attributed to by-product 2 according
to LC–MS data and by isolation of compound 3 during the prepara-
tion of azide A-3 (Scheme 4).
Scheme 2. Reaction of 1,1-difluoroazides with various amines.
It is necessary to mention that the reaction of a CF2–N3 moiety
with primary amines could not be predicted a priori from literature
data. 1,1-Difluoroazides are quite stable in alcohols and a standard
procedure for their preparation implies the presence of a very basic
and nucleophilic alkoxide anion which does not react with the
excess of amine reacts with the ester group to afford the corre-
sponding amides (the sterically hindered tert-butyl amine provides
both the ester and amide forms of 1 together with the amide and
ester forms of 2). The results are summarized in Table 1.
Table 1
Reaction conditions and yields of fluorinated tetrazoles
Product
R2
Azide
Reaction conditions
Isolated yield (%) of 1
Molar ratio 1:2 (LC–MS)
F
CF3
N
rt, 8 h, EtOH
rt, 12 h, THF
60
45
3:2
3:2
1aa
c-C6H11
A-1
N
N
N
rt, 2.5 h, EtOH
rt, 4 h, THF
85
70
6:1
6:1
1ba
1ca
1da
c-C6H11
c-C5H9
PhCH2
A-2
A-2
A-2
N
CF2
N
HN
N
N
O
rt, 2.5 h, EtOH
rt, 4 h, THF
83
75
6:1
6:1
N
CF2
N
HN
N
N
O
rt, 2.5 h, EtOH
rt, 4 h, THF
70
60
5:2
5:2
N
CF2
N
HN
N
N
O
rt, 10 h, EtOH
rt, 16 h, THF
70
60
7:3
7:3
1e
PhCH2
A-3
N
CF2
N
N
N
N
N
O
1faa,b
t-Bu
t-Bu
A-2
A-2
Reflux, 15 h, THF
Reflux, 15 h, THF
10
50
1:3
5:1
N
CF2
HN
N
N
O
1fbb
N
CF2
N
CH3O
N
N
O
H3C
CF2
N
1g
1-AdCHCH3
A-3
A-2
Reflux, 15 h, THF
40
2:3
N
N
N
N
O
rt, 2.5 h, EtOH
rt, 4 h, THF
80
70
6:1
6:1
1ha
c-C3H5
N
CF2
N
N
H
N
N
O
a
Structure confirmed by X-ray analysis.
Compounds 1fa (amide) and 1fb (ester) were isolated from the reaction mixture together with compounds 2.
b

A. G. Polivanova et al. / Tetrahedron Letters 51 (2010) 4205–4207
4207
R2
R
N
HN
N3
N
R1
R2
N
R1
N3
-HF
H2O
R1
F
N
N
R1-CF2-N3
R2 -NH2
+
R2
1
R1-CF2-NH-R2
R1
HN
O
2
Scheme 3. Probable reaction pathways leading to the formation of 1 and 2.
O
plementary data for compounds 1a, 1e, 1b, 1c, 1h, and 1fa, respec-
tively. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif. Supplementary data associated with this article
can be found, in the online version, at doi:10.1016/j.tetlet.2010.
06.016.
r.t.
+
CF2CF2N3
HN
THF
CH3O
A-2
O
O
O
N
CF2CF2N3
CH3O
CF2
N
+
3
A-3
References and notes
Scheme 4. Products of the reaction of azepane with A-2 (A-2 to azepane ratio = 1:3,
ratio of A-3:3 = 3:1).
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Supplementary data
Characterization data for all new compounds as well as X-ray
studies results are available. CCDC 762986–762991 contain the sup-