Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2016.02.102

A regioselective cycloaddition reaction of arenediazonium salts with trimethylsilyldiazomethane is reported. A series of 2-aryltetrazoles were obtained in good to moderate yields with wide functional group compatibility. Furthermore, this cycloaddition reaction opens the way to build up the versatile intermediate 2-aryl-5-bromotetrazole.

Full text of DOI:10.1016/j.tetlet.2016.02.102

Accepted Manuscript
Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reac-
tion
Remi Patouret, Theodore M. Kamenecka
PII:
S0040-4039(16)30211-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.02.102
TETL 47377
Reference:
Tetrahedron Letters
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26 February 2016
Please cite this article as: Patouret, R., Kamenecka, T.M., Synthesis of 2-aryl-2H-tetrazoles via a regioselective
[3+2] cycloaddition reaction, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.02.102
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Tetrahedron Letters
Synthesis of 2-aryl-2H-tetrazoles via a regioselective [3+2] cycloaddition reaction
Remi Patouret* and Theodore M. Kamenecka
The Scripps Research Institute, Scripps Florida, Department of Molecular Therapeutics, 130 Scripps Way #A2A, Jupiter, FL 33458, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A regioselective cycloaddition reaction of arenediazonium salts with trimethylsilyldiazomethane
is reported. A series of 2-aryltetrazoles were obtained in good to moderate yields with wide
functional group compatibility. Furthermore, this cycloaddition reaction opens the way to build
up the versatile intermediate 2-aryl-5-bromotetrazole.
Available online
2016 Elsevier Ltd. All rights reserved.
Keywords:
[3+2] Cycloaddition
Silver catalysis
Trimethylsilyldiazomethane
2H-Tetrazole
Introduction
et al. also reported a regioselective 2-arylation of 5-
substituted tetrazoles catalyzed by [Cu(OH)(TMEDA)]2Cl2.
Tetrazoles are an important class of five-membered ring
heterocycles broadly used in pharmaceuticals,
12
We recently had the need for the synthesis of substituted N-
linked tetrazoles with versatility for substitution at the 5-
position (H or aryl) wherein none of the current published
methods proved useful. Therefore we embarked upon a
search for a facile and robust method to generate these
molecules. Chen et al. recently reported a cycloaddition
agrochemicals and material science. Surprisingly, the
synthesis of simple unsubstituted 2-aryltetrazoles is almost
non-existent in the literature. Lippmann et al. has developed
a regioselective method for the construction of 2-aryl
tetrazoles employing 2-(2-arylhydrazono)acetic acid and 1-
azido-2,4,6-tribromobenzene1. Ito’s synthesis employs
arylsulfonylhydrazones and arene diazonium salts but both
of these strategies afford 2-aryl-5-carboxylatetetrazole and
must be decarboxylated at 160 oC2. Genin et al. and Kitazaki
et al. reported a nucleophilic aromatic substitution between
4-nitrofluorobenzene or 3,4-difluoronitrobenzene and
tetrazole but these non-regioselective transformations gave
poor yields and require the nitro group for activation (10%
to 25%)3,4. Very recently, Ramanathan et al. reported a
cyclisation between an aryldiazonium salt and formamidine
in the presence of iodide5.
between
an
arene-diazonium
salt
and
2,2,2-
trifluorodiazoethane with a catalytic amount of silver salt13.
This method was attractive, however the tetrazole products
There are more examples of 2-aryl-5-substituted
tetrazoles in the primary literature. This scaffold has
recently acquired increasing attention from the medicinal
chemistry community. For example, this substitution pattern
has recently appeared in Breast Cancer Resistance Protein
inhibitors6, DNA methyltransferases 1 inhibitors7, 425
nicotinic acetylcholine receptors modulators8, FAAH
inhibitors9 and MDR1 inhibitors10. In addition to
Lippmann’s and Ito’s synthetic methods, Han and co-
workers reported the synthesis of 2-aryl-5-substituted
tetrazoles through the coupling of 5-substituted tetrazoles
with arylboronic acids in the presence of copper(II)11. Onaka
Figure 1. Tetrazole Formation
formed were CF3-substituted at the 5-position wherein we
needed a hydrogen atom or aryl ring. We envisioned that a
silver salt might also be utilized to promote the cyclization
of an arenediazonium salt with trimethylsilyldiazomethane.
This would provide for TMS-substituted tetrazoles, which
could either be desilylated to produce the unsubstituted
tetrazole or converted to the bromo-tetrazole for further

2
Tetrahedron
functionalization (Figure 1). Herein, we report a [3+2]
The use of 2 equivalents of CF3CO2Ag did not
improve the yield (entries 15 and 16). In sharp
contrast, the reaction did not proceed without the silver
catalyst or with only 10 mol% of CF3CO2Ag (entries
17 and 21). The control of the temperature is a critical
parameter : a mixture of uncharacterized by-products
is obtained when the reaction is conducted at 4oC and
poor yield was obtained at -20oC (entries 18 and 19).
Note that 1-aryl-1H-Tetrazole has never been detected.
Next, we turned our attention to testing a range of
mineral and organic bases. Triethylamine was found to
be the base of choice for this cycloaddition reaction
(entries 8-12). The yield substantially decreased with
only 1 equivalent of trimethylamine (entry 20) and no
reaction was observed without any base (entry 21), but
2.0 equivalents of Et3N did not improve the yield when
compared to that obtained with 1.5 equivalent of Et3N
(entries 1 and 13). A solvent screen was conducted in
order to explore this parameter further (entries 23-27).
THF was identified as the optimal solvent from those
screened.
cycloaddition between an arenediazonium salt and
trimethylsilyldiazomethane with a silver salt catalyst. This
cycloaddition affords 2-aryl-5-trimethylsilyltetrazoles, a key
intermediate which can be easily cleaved in one pot with
CsF to provide 2-aryltetrazoles.
Results and discussion
Table 1. Optimization of reaction conditionsa
Entry Catalyst
Base (equiv)
Solvent
Yieldb (%)
1
CF3CO2Ag Et3N (1.5)
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
DCM
DMF
82 (75)
70 (61)
69
2
AgBF4
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
Et3N (1.5)
3
AgNO3
AgOTf
AgOAc
Ag2CO3
Cu(OAc)2
4
70 (62)
42
5
6
<10
<10
36
7
8
CF3CO2Ag Cs2CO3 (1.5)
CF3CO2Ag Na2CO3 (1.5)
CF3CO2Ag Lutidine (1.5)
CF3CO2Ag DBU (1.5)
CF3CO2Ag DABCO (2.0)
CF3CO2Ag Et3N (2.0)
CF3CO2Ag Et3N (2.5)
CF3CO2Ag Et3N (3.0)
CF3CO2Ag Et3N (3.0)
CF3CO2Ag Et3N (1.5)
CF3CO2Ag Et3N (1.5)
CF3CO2Ag Et3N (1.5)
CF3CO2Ag Et3N (1.0)
9
<10
<10
71
10
11
12
13
14
15b
16c
17d
18e
19f
20
21
22
23
24
25
26g
27
49
79
74
77
79
<10
<10
23
54
—
Et3N (1.5)
<10
<10
<10
<10
<10
CF3CO2Ag
—
CF3CO2Ag Et3N (1.5)
CF3CO2Ag Et3N (1.5)
CF3CO2Ag Et3N (1.5)
CF3CO2Ag Et3N (1.5)
CF3CO2Ag Et3N (1.5)
THF/DMF 23
Toluene 77 (69)
aGeneral reaction conditions: 1a (0.2 mmol), Me3SiCHN2
(1.1eq), catalyst (1.2 eq), base (x equiv) in 2 mL of solvent under
Ar at -78°C for 1 h. Yields were determined by HPLC with 3,5-
Dimethoxybromobenzene as an internal standard. The values in
parentheses represent the yields of isolated products.b2 eq
Scheme 1. Substrate scope of cycloaddition
reaction of TMSCHN2 with aryl diazonium salts
Having established optimal conditions, we set out
to explore the scope of this silver-mediated
cycloaddition reaction, and the results are summarized
in Scheme 1. In the case of phenyl diazonium salts, the
cycloaddition reaction tolerates various substitution
patterns and a range of different substituents on the
phenyl ring. Alkyl-, alkoxy-, amino-, cyano-, nitro-,
acid-, halo- and phenyl-substituted phenyldiazonium
salts all undergo the desired reaction to give the
cycloadducts 2a-l in moderate to good yields. It is
worth noting that anilines bearing a free phenol group
c
d
CF3CO2Ag; 2 eq CF3CO2Ag and 1.5 eq Me3SiCHN2; 10 mol%
f
of CF3CO2Ag was used; ereaction at 4oC; reaction at -20oC;
gTHF/DMF = 10/1.
To optimize reaction conditions, phenyl diazonium
tetrafluoroborate 1a was employed as a substrate using
trimethylsilyldiazomethane with various silver salts
and one copper salt (widely used in click chemistry) in
THF at -78 oC (entries 1-7, Table 1). To our delight,
CF3CO2Ag was found to be optimal, and the
cycloaddition proceeded smoothly to furnish the
desired cycloadduct 2a in 75% yield (entry 1).

(2h) or carboxylic acid (2g) are tolerated as are
cycloaddition
reaction
of
electron poor (2c 2e 2m) or electron rich (2d 2h
,
-
f
,
,
-
i
,
k
)
trimethylsilyldiazomethane with various aryl and
heteroaryl diazonium salts. A broad range of 2-
substituted tetrazoles were obtained in moderate
to good yields. The practicality of this
methodology was further demonstrated by the
facile synthesis of a gram scale sequence. We
believe this motif has the potential for use in drug
aromatics. Note that in these reactions, only the 2-aryl
tetrazole was formed and the 1-aryltetrazole was not
observed.
To be synthetically useful, this new method also
needed to scale well. Hence we conducted this reaction
sequence on a 1g scale. As shown in Scheme 2, the
diazotation step from the commercial aniline afforded
1k in 91% yield which does not require purification.
Intermediate 1k reacted with TMSCHN2 to give the
corresponding 2-substituted tetrazole 2k with a 67%
yield in two steps.
discovery programs as
a
valuable synthetic
building block, which is now readily available via
this methodology.
Acknowledgments
The authors thank Dr. Xiaohai Li for performing HRMS (Grant
1S10OD010603-01A1). T.M.K. received funding from the
National Institutes of Health, National Institute on Drug Abuse
Grant P01DA033622.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at.
Scheme 2. Gram scale reaction
Finally, we turned our attention to the key
Corresponding Author
intermediate 2-aryl-5-trimethylsilyl tetrazole
(3k,
* E-mail : rpatoure@scripps.edu
Scheme 3). This reaction could be carried out without
the addition of CsF and, under these conditions, we
were able to isolate the trimethylsilyl derivate 3k in
good yield. With this compound in hand, we
demonstrated the versatile properties by substitution of
the trimethylsilyl group with a bromine on the 5-
References and notes
1. Lippmann, E.; Konnecke, A.; Beyer, G.; Monatsh. Chem. 1975, 106, 437-
442.
2. Ito, S.; Tanaka, Y.; Kakehi, A.; Kondo, K.; Bull. Chem. Soc. Jpn. 1976, 49,
1920-1923
position to afford 4k
.
From this compound,
3. Genin, M.-J.; Allwine, D.-A.; Anderson, D.-J.; Barbachyn, M.-R.; Emmert,
D.-E.; Garmon, S.-A.; Graber, D.-R.; Grega, K.-C.; Hester, J.-B.; Hutchinson,
D.-K.; Morris, J.; Reischer, R.-J.; Ford, C.-W.; Zurenko, G.-E.;Hamel, J.-C.;
Schaadt, R.-D.; Stapert, D.; Yagi, B.-H.,J. Med. Chem. 2000, 43, 953-970.
4. Kitazaki, T.; Ichikawa, T.; Tasaka, A.; Hosono, H.; Matsushita, Y.;
Hayashi, R.; Okonogi, K.; Itoh, K., Chem. Pharm. Bull. 2000, 48(12), 1935-
1946.
5. Ramanathan, M.; Wang, Y-H.; Liu, S-T., Org. Lett. 2015, 5886-5889.
6. Kohler, S.-C.; Wiese, M., J. Med. Chem. 2015, 58, 3910-3921.
7. Zhu, B.; Ge, J.; Yao, S.-Q.; Bioorg. Med. Chem. 2015, 23, 2917-2927.
8. Jin, Z.; Khan, P.,Shin, Y.; Wang, J.; Lin, L.; Cameron, M.-D; Lindstrom,
J.-M.; Kenny, P.-J.; Kamenecka, T.-M., Bioorg. Med. Chem. Let. 2014, 24,
674-678.
introduction of many other groups and functionalities
are possible via metal-mediated coupling reactions.
This route offers an approach for rapid structure-
activity relationship studies (SAR) of the 5-position of
the tetrazole ring. This strategy complements that of
Ramanathan et al. and offers a new synthetic method
for the synthesis of functionalized tetrazoles.
9. Garfunkle, J.; Ezzili, C.; Rayl, T.-J; Hochstatter, D.-G.; Hwang, I.; Boger,
D.-L., J. Med. Chem. 2008, 51, 4392-4403.
10. Sprachman, M.-M.; Laughney, A.-M.; Kohler, R.-H.; Weissleder, R.,
Bioconjugate Chem. 2014, 25, 1137-1142.
11. (a) Li, Y.; Gao, L.-X.; Han, F.-S.; Chem. Commun. 2012, 48, 2719-2721.
(b) Liu, C.-Y.; Li, Y.; Ding, J.-Y.; Dong, D.-W.; Han, F.-S., Chem.-Eur. J.
2014, 20, 2373-2381.
12. Onaka, T.; Umemoto, H.; Miki, Y.; Nakamura, A.; Maegawa, T.; J. Org.
Chem. 2014, 79, 6703-6707.
13. Chen, Z.; Fan, S.-Q.; Zheng, Y.; Ma, J.-A.; Chem. Commun. 2015, 51,
16545-16548.
Scheme 3. Access to the 2-aryl-5-bromo-tetrazole
14. Zhang, K.; Xu, X.-H.; Qing, F.-L.; J. Org. Chem. 2015, 80, 7658-7665.
15. Huisgen, R.; Fliege, W.; Kolbeck, W.; Chem. Ber. 1983, 116(9), 3027-
3038.
Conclusions
16. Nishiyama, K.; Oba, M.; Watanabe, A.; Tetrahedron 1987, 43(4), 693-
700.
In summary, we have successfully disclosed a
quick and general method to synthesize 2-
aryltetrazoles
by
a
[3+2]
regioselective

4
Tetrahedron
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Synthesis of 2-aryl-2H-tetrazoles via a
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regioselective [3+2] cycloaddition reaction
Remi Patouret and Theodore M. Kamenecka
A regioselective cycloaddition reaction of arenediazonium salts with trimethylsilyldiazomethane is reported. A series of 2-aryltetrazoles were obtained
in good to moderate yields with wide functional group compatibility. Furthermore, this cycloaddition reaction opens the way to build up the versatile
intermediate 2-aryl-5-bromotetrazole.
Research highlights
► Regioselective cycloaddition reaction of arenediazonium salts with trimethylsilyldiazomethane.
►Best catalyst to perform this reaction was silver trifluoroacetate.
►A large set of diazonium salt was used under optimized conditions.
►Gram scale have been successfully accomplished