Construction of Difluoromethylated Tetrazoles via Silver-Catalyzed Regioselective [3 + 2] Cycloadditions of Aryl Diazonium Salts

Article abstract of DOI:10.1021/acs.orglett.9b01697

A silver-catalyzed regioselective [3 + 2] cycloaddition reaction of PhSO₂CF₂CHN₂ with aryl diazonium salts is described. This protocol enables the straightforward construction of a novel class of difluoromethylated tetrazoles under mild conditions, tolerates a broad spectrum of functionalities, and is applicable to one-pot operation from commercially available aniline derivatives. The synthetic merit of this method is further demonstrated by the facile preparation of versatile difluoromethylated azoles, including a valuable HCF₂-analogue of P2X3 receptor antagonist.

Full text of DOI:10.1021/acs.orglett.9b01697

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Construction of Difluoromethylated Tetrazoles via Silver-Catalyzed
Regioselective [3 + 2] Cycloadditions of Aryl Diazonium Salts
Xing Peng, Ming-Yang Xiao, Jun-Liang Zeng, Fa-Guang Zhang,* and Jun-An Ma*
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation
Center of Chemical Science & Engineering, Tianjin University, Tianjin 300072, P. R. of China
S
* Supporting Information
ABSTRACT: A silver-catalyzed regioselective [3 + 2]
cycloaddition reaction of PhSO2CF2CHN2 with aryl diazo-
nium salts is described. This protocol enables the straightfor-
ward construction of a novel class of difluoromethylated
tetrazoles under mild conditions, tolerates a broad spectrum
of functionalities, and is applicable to one-pot operation from
commercially available aniline derivatives. The synthetic merit
of this method is further demonstrated by the facile preparation of versatile difluoromethylated azoles, including a valuable
HCF2-analogue of P2X3 receptor antagonist.
he difluoromethylene (CF2) unit has emerged as a highly
useful moiety in the design and discovery of active
this chemistry cannot be easily applied to the synthesis of CF2-
tetrazoles, probably due to the difficult availability of the
corresponding CF2-containing precursors.7 Recently, our
group has first reported that the 1,3-disubstituted tetrazoles
could be constructed via a conceptually novel silver-catalyzed
regioselective cycloaddition reaction of aryl diazonium salts
with trifluorodiazoethane or diazoacetates (Scheme 1a).8
T
pharmaceuticals and agrochemicals.1 As a consequence, great
attention has been paid to the development of various
transition-metal-mediated difluoromethylation reactions in
the past decade.2 However, compared with the synthesis of
CF2-arenes, the construction of CF2-heterocycles often
encounters increased challenges.3 In particular, precedented
methods for the preparation of CF2-tetrazoles have remained
extremely rare until now,4 despite the fact that the tetrazoles
represent a remarkable class of commonly found core-azoles in
a vast plethora of molecules with medical or biochemical
relevance (Figure 1).5 While the conventional synthetic route
to aryl tetrazoles mainly relies on the cycloadditions of azide
reagents with nitriles or imidoyl derivatives,6 unfortunately,
Scheme 1. State of the Art for the Cycloadditions of Aryl
Diazonium Salts with Diazo Compounds
Subsequently, Kamenecka and co-workers demonstrated the
feasibility of employing trimethylsilyldiazomethane in such
cycloadditions to give the 2-aryl-2H-tertrazoles in a similar
fashion (Scheme 1a).9 Encouraged by these results, we
envisioned that the difluoromethylated tetrazoles might be
obtained by treating a CF2-diazo reagent with aryl diazonium
salts in the presence of an appropriate silver catalyst.10
Therefore, herein we report the realization of this design by
engaging our recently unveiled PhSO2CF2CHN2 in the
Figure 1. Aryl tetrazoles found applications in medical chemistry and
biochemistry.
Received: May 15, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01697
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope of the Cycloaddition Reaction between PhSO2CF2CHN2 and Aryl Diazonium Salts 1
Scheme 3. One-Pot Diazotization/Cycloaddition Reaction of Various Aniline Derivatives
cycloaddition process with a broad range of aryl diazonium
salts (Scheme 1b).11 This highly regioselective transformation
represents a practical and modular method to access versatile
CF2-functionalized tetrazoles, including a valuable HCF2-
analogue of P2X3 receptor antagonist.12
On the basis of our previous study,13 a systemic screening of
various reaction parameters expeditiously identified the
optimized conditions as following: in the presence of silver
acetate (5 mol %) and cesium carbonate (2 equiv), a [3 + 2]
cycloaddition of PhSO2CF2CHN2 with phenyl diazonium salt
B
DOI: 10.1021/acs.orglett.9b01697
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
1a proceeded smoothly in a cosolvent of THF/DMF (20/1) at
0 °C, thus giving the desired tetrazole 2a in 94% yield with
exclusive regioselectivity. Subsequently, the remarkably wide
substrate scope of this reaction is demonstrated by the
evaluation of a large number of aryl diazonium salts (Scheme
2). In general, phenyl substrates bearing substituents with
varied electronic or steric properties at different positions on
the benzene ring could all participate in the desired
transformations uneventfully, thereby delivering the corre-
sponding CF2-functionalized tetrazoles 2b−2b′ in 63−95%
yields. In particular, phenyl diazonium salts substituted with a
basic amino group or polar nitro group also proved to be
feasible reaction partners (products 2k−2o). Notably, the
molecular structure of the obtained tetrazoles are assigned by
analogue via single-crystal X-ray diffraction analysis of
compound 2s. It should be mentioned that the halogens in
the afforded tetrazoles 2v−2a′ may offer new possibilities for
downstream cross-coupling-type manipulations. Furthermore,
diazonium salts possessing other aromatic motifs such as 1-
naphthyl, 3-thienyl, 3-quinolyl, and 3-pyridinyl are also well
compatible in this reaction and provided the corresponding
CF2-tetrazoles 2c′−2f′ in high yields. In all cases, excellent
regioselectivities were observed as confirmed by 19F NMR of
the crude reaction mixture.
Scheme 4. Gram-Scale Experiments and Further Synthetic
Transformations
Subsequently, a one-pot sequence directly from aniline
derivatives to produce CF2-tetrazoles was probed. As shown in
Scheme 3, by in situ generation of the diazonium salts in
almost quantitative yield from corresponding anilines, followed
by the successive addition of silver catalyst, base, and the diazo
reagent, the desired tetrazole derivatives could be produced in
good yields. Substrates with an unprotected hydroxyl or
carboxyl group proceeded much more smoothly to give the
corresponding cycloadducts 2h′−2j′ (72−80% yields) than
the preceding two-step protocol (lower than 10% yields).
Significantly, this silver-catalyzed one-pot diazotization/cyclo-
addition sequence is also amenable for the late-stage
modification of biologically interesting compounds, as
exemplified by the liberation of structurally complex molecular
2k′, which is derivatized from tocopherol accordingly.14
The practicality of this protocol is demonstrated by a gram-
scale preparation of 2a and 2s in isolated yields of 78% and
84%, respectively (Scheme 4a). Meanwhile, the difluoromethy-
lated tetrazole 2v could also be obtained in 75% yield through
the one-pot diazotization/cycloaddition sequence from 4-
chloroaniline directly on a 5.0 mmol scale (Scheme 4a). To
further demonstrate the synthetic utility of this method, we
also investigated the downstream diversifications of the
obtained cycloadducts. The phenyl sulfonyl moiety could be
owing to their enhanced metabolic stability and bioisosterism
to carboxylic acid and amide moieties,5 we also proceeded to
pursue the construction of the difluoromethylated analogue of
a P2X3 receptor antagonist.12 As outlined in Scheme 5, the
tetrazole 2l′ was obtained in 91% yield by a one-pot
diazotization/cycloaddition reaction from easily accessible
aniline 1l′. The target HF2C-functionalized aryltetrazole 7
was then provided in a total yield of 67% after hydrolysis,
Scheme 5. Synthesis of Difluoromethylated P2X3 Receptor
Antagonist Analogue
t
readily cleaved by being treated with LiAlH4 or BuOK at
ambient temperature, thus leading to the formation of the
corresponding HCF2-tetrazole 3a in 95% and 85% yield,
respectively (Scheme 4b).15 The two complementary protocols
proved to be applicable to a broad range of substrates and
provided HCF2-tetrazoles 3b−3g in 60−97% yields (Scheme
4b). The tetrazole core has been demonstrated to hold
excellent promise as a fluorophore-forming biorthogonal probe
in the past few years.16 As a proof of concept, both diethyl
malonate and dimethyl acetylenedicarboxylate (DMAD) were
employed as the dipolarophile to undergo the photoinduced
1,3-dipolar cycloaddition reaction with tetrazole 2j. Pleasingly,
CF2-functionalized pyrazoline 4 and pyrazole 5 were formed in
a yield of 67% and 90%, respectively (Scheme 4c). Finally, as
tetrazoles have been extensively explored in medical chemistry
C
DOI: 10.1021/acs.orglett.9b01697
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Pannecoucke, X. Chem. - Eur. J. 2015, 21, 12836. (e) Xu, P.; Guo,
S.; Wang, L.; Tang, P. Synlett 2014, 26, 36. (f) Ni, C.; Hu, M.; Hu, J.
Chem. Rev. 2015, 115, 765. (g) Rong, J.; Ni, C.; Hu, J. Asian J. Org.
Chem. 2017, 6, 139. (h) Yerien, D. E.; Barata-Vallejo, S.; Postigo, A.
Chem. - Eur. J. 2017, 23, 14676. (i) Feng, Z.; Xiao, Y.-L.; Zhang, X.
Acc. Chem. Res. 2018, 51, 2264. (j) Lemos, A.; Lemaire, C.; Luxen, A.
Adv. Synth. Catal. 2019, 361, 1500.
(3) For selected examples, see: (a) Fujiwara, Y.; Dixon, J. A.;
Rodriguez, R. A.; Baxter, R. D.; Dixon, D. D.; Collins, M. R.;
Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc. 2012, 134, 1494.
(b) Mykhailiuk, P. K. Angew. Chem., Int. Ed. 2015, 54, 6558.
(c) Okusu, S.; Tokunaga, E.; Shibata, N. Org. Lett. 2015, 17, 3802.
(d) Zhu, S.-Q.; Liu, Y.-L.; Li, H.; Xu, X.-H.; Qing, F.-L. J. Am. Chem.
Soc. 2018, 140, 11613. (e) Xu, C.; Guo, W.-H.; He, X.; Guo, Y.-L.;
Zhang, X.-Y.; Zhang, X. Nat. Commun. 2018, 9, 1170.
(4) Fore relevant reviews, see: (a) Petrov, V. A. Fluorinated
Heterocyclic Compounds: Synthesis, Chemistry, and Applications; John
Wiley & Sons: Hoboken, NJ, 2009. (b) Ostrovskii, V. A.; Trifonov, R.
E. Fluorinated Triazoles and Tetrazoles. In Fluorine in Heterocyclic
Chemistry Vol. 1:5-Membered Heterocycles and Macrocycles;
Nenajdenko, V., Ed.; Springer International Publishing: Switzerland,
2014. (c) Zhang, F.-G.; Peng, X.; Ma, J.-A. Youji Huaxue 2019, 39,
109. For the only reported example to prepare ArF2C-tetrazoles, see:
(d) Kotoris, C. C.; Chen, M.-J.; Taylor, S. D. Bioorg. Med. Chem. Lett.
1998, 8, 3275.
(5) (a) Herr, R. Bioorg. Med. Chem. 2002, 10, 3379. (b) Gaponik, P.
N.; Voitekhovich, S. V.; Ivashkevich, O. A. Russ. Chem. Rev. 2006, 75,
507. (c) Myznikov, L. V.; Hrabalek, A.; Koldobskii, G. I. Chem.
Heterocycl. Compd. 2007, 43, 1. (d) Ostrovskii, V. A.; Trifonov, R. E.;
Popova, E. A. Russ. Chem. Bull. 2012, 61, 768. (e) Neochoritis, C. G.;
amidation, and simultaneous desulfonation under operationally
simple conditions.17
In conclusion, we have successfully developed a silver-
catalyzed regioselective [3 + 2] cycloaddition reaction of
PhSO2CF2CHN2 with aryl diazonium salts to give the novel
difluoromethylated tetrazoles. This protocol exhibits high
functional group compatibility, mild reaction conditions,
good scalability, and feasible one-pot operation from
commercially available aniline derivatives. A variety of
structurally diverse CF2-functionalized tetrazoles, pyrazoline,
pyrazole, and a valuable HCF2 analogue of P2X3 receptor
antagonist, were constructed via further synthetic trans-
formations. Future investigations including mechanistic
elucidation and other relevant applications are underway in
our laboratory and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01697.
Experimental details and spectral data of all the new
compounds (PDF)
Accession Codes
CCDC 1915044 and 1915069 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
̈
Zhao, T.; Domling, A. Chem. Rev. 2019, 119, 1970.
́
́
́
(6) Roh, J.; Vavrova, K.; Hrabalek, A. Eur. J. Org. Chem. 2012, 2012,
6101.
(7) (a) Norris, W. P. J. Org. Chem. 1962, 27, 3248. (b) Uneyama, K.
J. Fluorine Chem. 1999, 97, 11. (c) Xiao, J.; Zhang, X.; Wang, D.;
Yuan, C. J. Fluorine Chem. 1999, 99, 83. (d) Armour, D. R.; Chung, K.
M. L.; Congreve, M.; Evans, B.; Guntrip, S.; Hubbard, T.; Kay, C.;
Middlemiss, D.; Mordaunt, J. E.; Pegg, N. A.; Vinader, M. V.; Ward,
P.; Watson, S. P. Bioorg. Med. Chem. Lett. 1996, 6, 1015.
(8) Chen, Z.; Fan, S.-Q.; Zheng, Y.; Ma, J.-A. Chem. Commun. 2015,
51, 16545.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: majun_an68@tju.edu.cn.
*E-mail: zhangfg1987@tju.edu.cn.
ORCID
(9) Patouret, R.; Kamenecka, T. M. Tetrahedron Lett. 2016, 57,
1597.
Jun-Liang Zeng: 0000-0003-2442-8653
Fa-Guang Zhang: 0000-0002-0251-0456
Jun-An Ma: 0000-0002-3902-6799
Notes
(10) For a recent review on HF2CCHN2, see: Mykhailiuk, P. K.;
Koenigs, R. M. Chem. - Eur. J. 2019, 25, 6053. HF2CCHN2 was also
employed to react with phenyl diazonium salt 1a under otherwise
identical reaction conditions, but no desired product 3a was observed.
(11) (a) Zeng, J.-L.; Chen, Z.; Zhang, F.-G.; Ma, J.-A. Org. Lett.
2018, 20, 4562. (b) Ma, J.-A.; Zeng, J.-L.; Zhang, F.-G. China Patent
CN 108383761A, 2018.
(12) (a) Ford, A. P. Purinergic Signalling 2012, 8, S3. (b) Dillon, M.
P.; Hawley, R. C.; Chen, L.; Feng, L.; Yang, M. U.S. Pat. Appl. Publ.
US 20150191487 A1, 2015.
(13) See the Supporting Information for detailed screening results.
(14) Tolstyakov, V. V.; Tolstobrova, E. S.; Zarubina, O. S.; Popova,
E. A.; Protas, A. V.; Chuprun, S. S.; Trifonov, R. E. Russ. J. Org. Chem.
2016, 52, 1681.
(15) (a) Alonso, D. A.; Ajera, C. Org. React. 2009, 72, 367.
(b) Akgun, E.; Mahmood, K.; Mathis, C. A. J. Chem. Soc., Chem.
Commun. 1994, 761.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21472137, 21532008, and
21772142) and the National Basic Research Program of
China (973 Program, 2014CB745100).
REFERENCES
■
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (b) Kirk, K. L. Org. Process Res. Dev. 2008, 12,
305. (c) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;
Meanwell, N. A. J. Med. Chem. 2015, 58, 8315. (d) Zafrani, Y.; Yeffet,
D.; Sod-Moriah, G.; Berliner, A.; Amir, D.; Marciano, D.; Gershonov,
E.; Saphier, S. J. Med. Chem. 2017, 60, 797. (e) Sessler, C. D.; Rahm,
M.; Becker, S.; Goldberg, J. M.; Wang, F.; Lippard, S. J. J. Am. Chem.
Soc. 2017, 139, 9325.
(16) Lim, R. K. V.; Lin, Q. Acc. Chem. Res. 2011, 44, 828. (b) Tian,
Y.; Lin, Q. Chimia 2018, 72, 758.
(17) As shown in Scheme 4b, an appropriate base can facilitate the
cleavage of PhSO2-group. We assumed that the observed simulta-
neous desulfonation in this particular case is attributed to the basic
property of the amidating reagents or corresponding intermediates.
(2) For selected reviews, see: (a) Hu, J.; Zhang, W.; Wang, F. Chem.
Commun. 2009, 7465. (b) Chen, B.; Vicic, D. Top. Organomet. Chem.
2014, 52, 113. (c) Lu, Y.; Liu, C.; Chen, Q.-Y. Curr. Org. Chem. 2015,
19, 1638. (d) Belhomme, M.-C.; Besset, T.; Poisson, T.;
D
DOI: 10.1021/acs.orglett.9b01697
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