From Rare Reagents to Rare Products: Regiospecific Silver-Catalyzed [3+2] Cycloaddition of Aryl-, Alkyl- and Aminosulfonyl Diazomethanes with Arenediazonium Tosylates

Article abstract of DOI:10.1002/ejoc.202000619

The scope of silver nitrate-catalyzed cycloaddition of arenediazonium salts has been expanded to include aryl- and alkylsulfonyl diazomethanes as well as the recently introduced diazomethyl sulfonamides. The reliance on these two classes of diazo compounds led to a new synthetic approach to the rare 2-aryltetrazol-5-yl sulfones as well as to the synthesis of hitherto not described 2-aryltetrazol-5-yl sulfonamides.

Full text of DOI:10.1002/ejoc.202000619

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: From rare reagents to rare products: regiospecific silver-
catalyzed [3+2] cycloaddition of aryl-, alkyl- and aminosulfonyl
diazomethanes with arenediazonium tosylates
Authors: Ekaterina Levashova, Olga Bakulina, Dmitry Dar'in, Andrey
Bubyrev, and Mikhail Krasavin
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000619
Link to VoR: https://doi.org/10.1002/ejoc.202000619
01/2020

10.1002/ejoc.202000619
European Journal of Organic Chemistry
From rare reagents to rare products: regiospecific silver-catalyzed [3+2]
cycloaddition of aryl-, alkyl- and aminosulfonyl diazomethanes with
arenediazonium tosylates
Ekaterina Levashova, Dr. Olga Bakulina, Prof. Dr. Dmitry Dar’in, Andrey Bubyrev and Prof. Dr.
Mikhail Krasavin*
Saint Petersburg State University, Saint Petersburg, 199034 Russian Federation
E-mail: m.krasavin@spbu.ru
http://www.krasavin-group.org/
Supporting information and ORCID(s) from the author(s) for this article are available on the
WWW under http://dx.doi.org/10.1002/ejoc.xxxxxxxxx.
ABSTRACT
The scope of silver nitrate-catalyzed cycloaddition of arenediazonium salts has been expanded to
include aryl- and alkylsulfonyl diazomethanes as well as the recently introduced diazomethyl
sulfonamides. The reliance on these two classes of diazo compounds led to a new synthetic
approach to the rare 2-aryltetrazol-5-yl sulfones as well as to the synthesis of hitherto not
described 2-aryltetrazol-5-yl sulfonamides.
Introduction
Diazo compounds are distinctly versatile reagents with multiple reactivity modes.[1] However,
some types of diazo reagents are either scarce (owing perhaps to the difficulties associated with
their synthesis) or have not been investigated in preparative chemistry context.[2] The scarcity or
absence of every such type of diazo reagent in the current arsenal of diazo reagents essentially
deprives us from access to entire domains of the druglike chemical space.[3] Thus, developing
new types of diazo reagents or alleviating synthetic hurdles to rare ones through new
methodology findings is a worthy goal on its own which may immediately impact the outlook of
synthetically accessible compounds for biotarget interrogation.[4]
Recently, we discovered a convenient, one-pot synthetic route to various α-diazo-β-ketosulfones
1[5] which had been accessed via more cumbersome approaches. It occurred to us that acetyl
variants of these compounds (1, R2 = Me) could be deacetylated,[6] which would give rise to
sulfonyl diazomethanes 2. The latter represent a scarcely populated class of ‘terminal’ diazo
compounds[7] which have been accessed predominantly by entirely different strategies.[8]
Another class of diazo compounds which had been completely absent from the synthetic
chemistry toolbox were the recently reported [9] CH-diazomethanesulfonamides 3. Both 2 and 3
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10.1002/ejoc.202000619
European Journal of Organic Chemistry
appeared suitable partners for a [3+2] cycloaddition reaction with arenediazonium salts. As
reported recently by us[10] and others[11] such a reaction, catalyzed by silver(I) salts, provides a
facile and regiospecific entry into medicinally important[12] 2,5-disubstituted tetrazoles. We
reasoned that this cycloaddition, if successfully applied towards 2 and 3, would deliver 2-aryl
tetrazol-5-yl sulfones 4 and sulfonamides 5 (Figure 1). Considering the significance of tetrazoles
in general as amide bond replacements[13] as well as scaffolds with favorable physicochemical
characteristics for drug design,[14] we noted that tetrazol-5-yl sulfones analogous to 4[15] had been
constructed in such a convenient and atom-economical manner. Moreover, preparation of 2-
substituted tetrazol-5-yl sulfonamides in general (and of 5 in particular) have not been reported
in the literature, which is a significant void to fill considering the importance of sulfonamides in
drug design.[16] Thus, we set off to investigate this approach and would like to report our findings
herein.
Figure 1. New approach to 2-aryl tetrazol-5-yl sulfones 4 and sulfonamides 5 investigated in this
work.
Results and discussion
There are reports in the literature on the use of α-diazo-β-ketosulfones 1 (R2 = Me) in the
cycloaddition reactions with nitroolefins leading to pyrazoles.[17] In these reactions, substrates 1
were deacetylated in situ with sodium alkoxide in the respective alcohol as the reaction medium
to give diazomethyl sulfones 2. Unfortunately, such an in situ protocol was not found applicable
to subsequent silver(I)-catalyzed cycloaddition with arenediazonium salts and we resorted to the
preparation and isolation of reagents 2 prior to their subsequent use. A selection of eight α-diazo-
β-ketosulfones 1a-h prepared as described previously[5] was treated with excess alumina in
dichloromethane at r. t. The deacetylation proceeded smoothly over 3-5 h and produced
diazomethyl sulfones 2a-h in good to excellent yields (Scheme 1).
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10.1002/ejoc.202000619
European Journal of Organic Chemistry
Scheme 1. Preparation of diazomethyl sulfones 2a-h (Ad = 1-adamantyl).
Sulfonyl diazomethanes 2a-h, along with three sulfamoyl diazomethanes 3a-c prepared as
described recently,[9] were employed in the cycloaddition reactions with a series of
arenediazonium tosylates 6a-k (Figure 2) which had been earlier found[18] to be stable and easy
to handle non-hygroscopic solid reagents and, importantly, proven efficient partners in similar
cycloaddition reactions with acyl diazomethanes.[10]
Figure 2. Selection of reagents for the tetrazole synthesis scope exploration.
Reaction conditions identified earlier for the cycloaddition of arenediazonium tosylates 6a-k
with acyl diazomethanes (1.1 equiv. 6, 10 mol% AgNO3, DABCO, 10% DMF in THF, 0 °C to r.
t., 18 h)[10] were found to give high yields of the desired cycloaddition products and, therefore,
were not optimized further. These conditions were employed throughout the scope investigation
the results of which are presented in Scheme 2.
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10.1002/ejoc.202000619
European Journal of Organic Chemistry
Scheme 2. Synthesis of 2,5-disubstituted tetrazoles 4 and 5. The reactions were conducted on a
0.3 mmol scale, in the mixture of dry DMF (0.2 mL) and dry THF (1.8 mL).
The yields of products 4a-n and 5a-e are generally good throughout. However, the yields were
noticeably lower for the diazonium partners with electron-donating groups (4d, 5e) or o-
substituents (4e, 4g, 4j). The structures of the tetrazoles thus obtained were consistent with the
13
1H and C NMR data, high-resolution mass-spectrometry. For a representative compound (4b),
single-crystal X-ray crystallography confirmed the anticipated regiochemistry.
The high regiospecificity of the reaction is thought to be due to the silver(I) catalyst
employed.[10] A plausible mechanism may include deprotonation of the starting diazomethyl
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10.1002/ejoc.202000619
European Journal of Organic Chemistry
sulfone or sulfonamide and coordination of the reacting substrates with the silver cation. The
latter event likely activates the partners towards the cycloaddition (which liberates the catalyst)
and ensures the observed regiochemical outcome (Scheme 3).
Scheme 3. Plausible mechanism of the tetrazole formation involving a silver(I) catalyst.
Much in line with this mechanistic consideration, the reaction between 2g and 6a conducted
under identical conditions in the absence of the silver(I) catalyst proved not only less efficient
but also turned out to be completely non-regiospecific and afforded a 1:1 mixture of tetrazoles 4a
and 4a′ in combined 40% yield (both regioisomers were isolated by preparative HPLC in 12%
yield each). The structure of 4a′ was unequivocally confirmed by single-crystal X-ray analysis
(Scheme 4).
Scheme 4. Non-catalyzed cycloaddition reaction.
Conclusion
Based on two rare classes of diazo compounds – diazomethyl sulfones and sulfonamides – we
developed a [3+2] cycloaddition approach to the respective 2,5-disubstituted tetrazoles via
AgNO3-catalyzed reaction with arenediazonium tosylates. While only four tetrazol-5-yl sulfones
with the same substitution pattern have been reported so far in the literature as prepared in
entirely different manner, preparation of tetrazol-5-yl sulfonamides has not been described to-
date. These findings expand the methodologically enabled toolbox of synthetic diazo chemistry.
ASSOCIATED CONTENT
Supporting Information
Experimental procedures, analytical and crystallographic data, copies of the NMR spectra.
CCDC 1994531 (4b) and 1994532 (4a') contain the supplementary crystallographic data for this
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10.1002/ejoc.202000619
European Journal of Organic Chemistry
paper. These data can be obtained free of charge from The Cambridge Crystallographic Data
Centre via http://www.ccdc.cam.ac.uk.
AUTHOR INFORMATION
Corresponding Author
* E-mail: m.krasavin@spbu.ru.
ORCID
Olga Bakulina: 0000-0002-4930-0739
Dmitry Dar’in: 0000-0002-0413-7413
Mikhail Krasavin: 0000-0002-0200-4772.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This research was supported by the Russian Foundation for Basic Research (project grant 18-33-
20194). We thank the Research Centre for Magnetic Resonance and the Center for Chemical
Analysis and Materials Research of Saint Petersburg State University Research Park for
obtaining the analytical data.
KEYWORDS: sulfonyl diazomethanes; sulfamoyl diazomethanes; deacetylation; cycloaddition;
arenediazonium tosylate; regiospecificity; silver(I) catalysis.
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European Journal of Organic Chemistry
Graphical abstract
TOC text
Ag(I)-catalyzed [3+2] cycloaddition between diazomethyl sulfones and sulfonamides with
arenediazonium tosylates provides regiospecific access to novel tetrazoles.
Key topic
Diazo compounds
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