Synthetic Studies towards CH-Diazomethane Sulfonamides: a Novel Type of Diazo Reagents

Article abstract of DOI:10.1002/ejoc.202000446

Preparation of CH-diazomethane sulfonamides has been developed for the first time. Their utility as a new type of diazo reagents was showcased in cycloaddition reactions with electron-deficient alkynes and β-nitro styrenes which delivered medicinally important pyrazole-3-sulfonamides in good to excellent yields.

Full text of DOI:10.1002/ejoc.202000446

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthetic studies towards CH-diazomethane sulfonamides: a
novel type of diazo reagents
Authors: Andrey Bubyrev, Dmitry Dar'in, Grigory Kantin, and Mikhail
Krasavin
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1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000446
Synthetic studies towards CH-diazomethane sulfonamides: a novel type of
diazo reagents
Andrey Bubyrev, Dr. Dmitry Dar’in, Dr. Grigory Kantin 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
Preparation of CH-diazomethane sulfonamides has been developed for the first time. Their utility
as a new type of diazo reagents was showcased in cycloaddition reactions with electron-deficient
alkynes and -nitro styrenes which delivered medicinally important pyrazole-3-sulfonamides in
good to excellent yields.
Introduction
[
1]
In light of the prominence, on one hand, of sulfonamide functional groups in drug design and,
on the other hand, of the synthetic versatility of diazo compounds as building blocks with
multiple reactivity modes,[2] it is surprising that diazomethane sulfonamides remain a rather
unexplored type of diazo reagents. A few dozen examples of such diazo compounds listed in
®
[3]
SciFinder include -diazophosphonic acid 1 employed for photoaffinity labeling, stabilized
diazomethanesulfonamides 2 bearing an electron-withdrawing group which were involved in
Rh(II)-catalyzed intramolecular aromatic C-H insertion reactions,[4] diazomethane bis-
[
5]
sulfonamide 3 designed as pH-sensor for strong Brønsted acids and isolated examples 4 and 5
recently reported by us to illustrate the substrate scope of the ‘sulfonyl-azide-free’ (SAFE) diazo
transfer protocol in aqueous medium.[6] On top of the general rarity of C-substituted
diazomethanesulfonamides, their CH counterparts (6) have not been reported to date, with the
exception of N,N-diethyl diazomethanesulfonamide detected by IR spectroscopy as a postulated
[
3]
product of photochemical decomposition of -diazophosphonic acid 1. Considering the facility
and high yield with which compounds 4 and 5 were prepared from their active-methylene
precursors using the SAFE diazo transfer protocol[6] and facile alkaline deacetylation of -
[
7]
acetyl--diazocarbonyl compounds reported in the literature, we set off to investigate the ways
to synthesize CH-diazomethanesulfonamides (6) from C-acetyl precursors 7 and to employ them
as building blocks in heterocycle synthesis. Our interim goal was also to develop convenient
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European Journal of Organic Chemistry
10.1002/ejoc.202000446
protocol towards a wide range of diazomethanesulfonamides 7 from cheap stock reagents,
preferably without the need to isolate and purify intermediates 8, (Figure 1). Herein, we report
the results of our findings.
Figure 1. Current landscape of diazomethanesulfonamides in the literature vs. present work.
Results and discussion
First, we aimed to adapt the known protocol for the preparation of sulfonamides 8 from
[
8]
chloroacetone to make it compatible with the SAFE diazo transfer in aqueous medium so that
only one purification of deacylation precursors 7 would be required over the entire sequence of
steps. Reaction of chloroacetone with sodium sulfite conducted on multigram scale in refluxing
water yielded crude sodium sulfonate 9 (containing 27% sodium chloride by weight) in
quantitative yield. The latter is stable to storage and could be aliquoted as needed for the
preparation of 7. We reasoned that if acetonitrile was chosen as the solvent for the preparation of
8
from 9, the aqueous reagent solution for the diazo transfer (i. e. a solution of m-carboxyphenyl
sulfonyl chloride, sodium azide and potassium carbonate in water, dubbed the ‘SAFE
[
9]
cocktail’ ) would be miscible with the crude acetonitrile solution of 8 and the preparation of
diazo compounds 7 could be achieved in one-pot format from 9.
Much in line with our expectations, conversion of sodium sulfonate 9 to respective sulfonyl
chloride 10 proceeded smoothly in acetonitrile at room temperature. The solution of 10, once
filtered from inorganic salts, was reacted with primary and secondary amines in the presence of
pyridine and DMAP additive to give sulfonamide 8, still as a solution in acetonitrile. A slight
excess of the ‘SAFE cocktail’ was added directly to this solution and after some time sufficient
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European Journal of Organic Chemistry
10.1002/ejoc.202000446
for the completion of the diazo transfer, target diazo compounds 7 were isolated by simple
extraction and straightforward chromatography. The isolated yields of -acetyl--diazomethane
sulfonamides 7 were modest to high, as calculated over three steps (91087) (Scheme 1).
Scheme 1. Preparation of secondary and tertiary -acetyl--diazomethane sulfonamides 7a-u.
It should be noted that the use of pyridine/DMAP combination in the preparation of 8 was
critical not only from the standpoint of achieving rapid conversion: with other bases (TEA,
DIPEA), aliphatic amines gave only a trace yield of the respective active-methylene sulfonamide
8
7
. Even with pyridine/DMAP, the yields of aliphatic -acetyl--diazomethane sulfonamides (7e,
l, 7n-p, 7r-t) were markedly lower compared to their aromatic counterparts. This may have to
do with the higher basicity of aliphatic amines which could deprotonate 8 at the active methylene
group and thus trigger unwanted side reactions.
However, the major difference we discovered in our subsequent effort to achieve the desired
deacylation under basic conditions was between secondary and tertiary sulfonamides 7.
Secondary -acetyl--diazomethane sulfonamides 7 resisted all our attempts to remove the
acetyl group under basic conditions by either remaining intact (e. g., on treatment with TEA,
pyrrolidine or DABCO in CH
products. The latter outcome was observed at room temperature on treating compounds 7a or 7e
with Al in CH Cl , K CO in either aqueous THF or methanol, Na PO or MeONa in
2
Cl
2
, r. t. to reflux) or decomposing to give a complex mixture of
2
O
3
2
2
2
3
3
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000446
methanol. At the same time, tertiary -acetyl--diazomethane sulfonamides 7 underwent a clean
and smooth deacylation on treatment with excess (70 equiv.) aluminum oxide in CH Cl to give
2
2
CH-diazomethane sulfonamides 6a-h in good yields with no need for chromatographic
purification (Scheme 2).
Scheme 2. Deacylation of tertiary -acetyl--diazomethane sulfonamides 7.
The purity of ‘terminal’ diazomethane sulfonamides 6 was sufficient to use them as reagents in
subsequent synthetic transformations. These compounds were successfully involved in [3+2]
cycloaddition reactions[10] with acetylene mono- and bis-carboxylic esters. The resulting
pyrazole adducts 11a-k were obtained in good to excellent yields and, in the case of monoesters,
with complete regiospecificity (Scheme 3).
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European Journal of Organic Chemistry
10.1002/ejoc.202000446
Scheme 3. Syntheses of pyrazoles 11 via cycloaddition of ‘terminal’ diazomethane sulfonamides
and acetylene mono- and dicarboxylic esters.
7
It should be noted that while the tertiary 1H-pyrazole-3-sulfonamide moiety can be rather
commonly encountered in compounds endowed with various biological activities (such as anti-
inflammatory,[11] glucocorticoid receptor (GR) antagonistic[12] and antidiabetic[13]), this is the
first time they have been accessed via cycloaddition of diazo compounds.
Encouraged by the facile cycloaddition reactions with electron-deficient alkynes shown in
Scheme 3, we were curious to see if more substituent diversity can be achieved by involving -
nitro styrenes as cycloaddition partners under basic conditions.[14] To our delight, the reaction of
an exemplary ‘terminal’ diazomethane sulfonamide 6a with -nitro styrene 12 in the presence of
cesium carbonate afforded a satisfactory yield of the respective 4-arylpyrazole-3-sulfonamide 13
(Scheme 4).
Scheme 4. Pyrazole synthesis from 6a and -nitro styrene 12.
Conclusion
We developed a practical synthesis of a new type of diazo reagents – CH-diazomethane
sulfonamides. The synthesis was achieved by preparing their -acetyl--diazomethane
sulfonamide precursors from chloroacetone in a four-step sequence involving only one
chromatographic purification. Deacetylation envisioned as the final step towards the target CH-
diazomethane sulfonamides worked well only for tertiary sulfonamides while their secondary
counterparts proved either non-reactive or prone to decomposition under multiple conditions
tried. Successfully obtained tertiary CH-diazomethane sulfonamides were involved in
cycloaddition reactions with acetylene mono- and dicarboxylic esters as well as -nitro styrenes
to give medicinally important pyrazole adducts in good to excellent yields. Further applications
of the new type of diazo reagents described herein are being investigated in our laboratories; the
results of these studies will be reported in due course.
ASSOCIATED CONTENT
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European Journal of Organic Chemistry
10.1002/ejoc.202000446
Supporting Information
1
19
13
Experimental procedures, analytical data and copies of the H, F and C NMR spectra.
AUTHOR INFORMATION
Corresponding Author
*
E-mail: m.krasavin@spbu.ru.
ORCID
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 Science Foundation (project grant 19-75-30008). We
thank 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: SAFE diazo transfer; deacetylation; diazomethane sulfonamides; cycloaddition;
alkynes; -nitro styrene.
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[
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[
Graphical abstract
TOC text
Hitherto not described CH-diazomethane sulfonamides have been synthesized from
chloroacetone in 5 steps with one chromatographic purification and gave pyrazoles in
cycloaddition reaction with acetylenes.
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European Journal of Organic Chemistry
10.1002/ejoc.202000446
Key topic
Diazo compounds
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