α-Diazo-β-oxosulfones as Partners in the Wolff 1,2,3-Triazole Synthesis and the Wolff Rearrangement in the Presence of Aromatic Amines

Article abstract of DOI:10.1002/ejoc.201900698

The readily available α-diazo-β-oxosulfones have been employed, for the first time, in the Wolff cyclocondensation with aromatic amines promoted by 1.5-fold excess of TiCl₄. The reaction was found to be general (as illustrated by 15 product examples) and resulted in moderate yields of medicinally relevant sulfonyl 1,2,3-triazoles. Excluding the Lewis acid promoter resulted in a clean and high-yielding formation of α-sulfonyl acetanilides resulting from the thermal Wolff rearrangement and trapping of the ketene intermediate with an aniline molecule.

Full text of DOI:10.1002/ejoc.201900698

A Journal of
Accepted Article
Title: Alfa-Diazo-beta-oxosulfones as Partners in the Wolff 1,2,3-
Triazole Synthesis and the Wolff Rearrangement in the Presence
of Aromatic Amines
Authors: Alexander Safrygin, Dmitry Dar'in, Grigory Kantin, and Mikhail
Krasavin
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10.1002/ejoc.201900698
European Journal of Organic Chemistry
-Diazo--oxosulfones as Partners in the Wolff 1,2,3-Triazole
Synthesis and the Wolff Rearrangement in the Presence of Aromatic
Amines
Alexander Safrygin[a], Dmitry Dar’in[a], Grigory Kantin[a], and Mikhail Krasavin*[a]
[a] Dr. A. Safrygin, Dr. D. Dar’in, Dr. G. Kantin, Prof. Dr. M. 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 readily available -diazo--oxosulfones have been employed, for the first time, in the Wolff
cyclocondensation with aromatic amines promoted by 1.5-fold excess of TiCl4. The reaction was
found to be general (as illustrated by 15 product examples) and resulted in moderate yields of
medicinally relevant sulfonyl 1,2,3-triazoles. Excluding the Lewis acid promoter resulted in a
clean and high-yielding formation of -sulfonyl acetanilides resulting from the thermal Wolff
rearrangement and trapping of the ketene intermediate with an aniline molecule.
Introduction
The Wolff 1,2,3-triazole synthesis from -diazo carbonyl compounds 1 and primary amines 2[1]
constitutes a valuable alternative to the currently much exploited Huisgen (‘click’) cycloaddition
of alkynes and azides.[2] Unlike the latter, the former method is regiochemically unambiguous
when delivering 1,4,5-trisubstituted 1H-1,2,3-triazoles 3, doesn’t rely on transition metal
catalysts (a favorable feature from the pharmaceutical process chemistry standpoint[3]) and is
rooted in two densely populated reagent areas: those of the primary amines and of -C-H
carbonyl compounds from which -diazo carbonyl compounds can be easily prepared[4]. The
innate deactivation of the carbonyl group in such compounds by the diazo group (due to the
contribution of resonance structure 1ʹ) reduces the electrophilicity of the former,[5] particularly
and requires that stoichiometric amounts of a Lewis acid promoter (most commonly, TiCl4[6]) are
employed, along with elevated reaction temperatures. It is unsurprising, therefore, that electron-
withdrawing groups R1 promote this process by increasing both the electrophilicity of the
carbonyl group in 1 toward reaction with amine 2 (to give imine 4). This is the likely reason why
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10.1002/ejoc.201900698
European Journal of Organic Chemistry
the variety of Wolff cyclization-derived 1,2,3-triazoles 3 is well represented by 4-carbonyl
derivatives such as 4-acyl-[7], 4-(alkoxycarbonyl)-[8] and, to a lesser extent[5,9], 4-
(aminocarbonyl)-1,2,3-triazoles. Surprisingly, 4-sulfonyl derivatives 1 (R1 = SO2R) have not
been reported as partners in the Wolff cyclization, possibly due to less efficient conjugation to
the carbonyl group in question (Figure 1). These compounds, however, are easily accessible
from the respective -keto sulfones by diazotransfer reaction[10] and have been reported to
undergo such transformations as the thermal Wolff rearrangement with the trapping of the
respective ketene intermediate with nitrogen nucleophiles (giving rise to amides 5)[11] and imines
(producing -lactams).[12]
Figure 1. The Wolff 1,2,3-triazole synthesis and electron-withdrawing R1 substituent variations
reported to-date and investigated in this work.
Puzzled by the lack of reports in the literature on the involvement of -sulfonyl -diazocarbonyl
compounds 1 (R1 = SO2R) in the Wolff 1,2,3-triazoles synthesis, we decided to investigate this
possibility. Filling this methodology void, we reasoned, would provide a streamlined entry in the
1,5-disubstituted 4-sulfonyl 1,2,3-triazole core which is featured in a range of biologically active
compounds such as bromodomain inhibitor 6,[13] antifungal compound 7,[14] pregnane X receptor
antagonist 8 for attenuation of drug metabolism[15] and anti-inflammatory GPR43 receptor
agonist 9[16] (Figure 2). Notably, such an approach would complement the earlier reported
synthesis of similarly substituted 1,2,3-triazoles by the Dimroth cyclocondensation of -keto
sulfones with aryl azides.[17]
Figure 2. Examples of biologically active compounds bearing a 1,5-disubstituted 4-sulfonyl
1,2,3-triazole moiety.
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10.1002/ejoc.201900698
European Journal of Organic Chemistry
Results and Discussion
Table 1. Conditions screening for the reaction of 1a and 2a.
Entry
Solvent
T (°C)
Time
(h)
16
Catalyst
(equiv.)
TiCl4 (1.0)
Yield of
3a (%)
35
Yield of
5a (%)
13
1
2
PhMe
DMF
PhCl
80
80
80
80
80
80
80
80
80
80
80
80
110
110
80
80
80
110
80
80
16
16
16
16
16
16
16
16
16
16
16
16
3
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
TiCl4 (1.0)
Zn(OTf)4 (0.1)
BF3∙Et2O (0.2)
ZnCl2 (0.2)
AlCl3 (0.2)
Ti(OiPr)4 (1.0)
SnCl4 (1.0)
FeCl2 (1.0)
–
13
38
35
22
0
2
3
3
4
DCE
3
5
1,4-dioxane
PhCl
10
42
43
50
38
35
37
27
52
77
0
6
7
PhCl
0
8
PhCl
0
9
PhCl
5
10
11
12
13
14
15
16
17
18
19
20
PhCl
3
PhCl
1
PhCl
1
PhCl
0
PhCl
–
0
PhCl
16
8
TiCl4 (1.5)
TiCl4 (1.5)
TiCl4 (1.0)
TiCl4 (1.5)
TiCl4 (1.5)
TiCl4 (1.5)
51
22
38
40
36
48
PhCl
0
PhCl
40
16
40
16
4
PhCl
0
PhCl
0
PhCF3
0
In order to find suitable conditions for the efficient cyclocondensation of -keto--diazo
sulfones with primary amines, we investigated the reaction of diazo compound 1a[18] with p-
toluidine (2a) (Table 1). The initial reaction conducted in toluene at 80 ºC for 16 h in the
presence of equimolar amount of titanium(IV) chloride gave 35% yield of the desired triazole 3a
along with a substantial quantity (13%) of amide 5a resulting from the Wolff rearrangement and
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10.1002/ejoc.201900698
European Journal of Organic Chemistry
trapping of the ketene intermediate with the amine (Table 1, entry 1). While lowering the
temperature led to no conversion at all (not shown), our goal became to screen for solvents and
Lewis acid catalysts/promoters which would direct the reaction toward the formation of the
desired product (3a). As it follows from the data presented in Table 1, TiCl4 turned out to be the
most efficient promoter to cause the formation of 3a (the best yield of 51% was achieved with
1.5 equiv. of TiCl4, entry 15) while in other cases, 5a dominated in the product mixture.
Interestingly, excluding Lewis acid altogether, raising the temperature to 110 ºC and shortening
reaction time to 3 h resulted in 77% isolated yield of 5a (Table 1, entry 14).
While the yield of the target product (3a) was rather moderate, we attributed it to the limited
ability of substrates like 1a to enter the Wolff cyclocondensation (thereby justifying the absence
of any examples of such reaction in the literature to-date, vide supra). This was confirmed by the
preliminary scope investigation of the newly developed 4-sulfonyl 1,2,3-triazole synthesis
undertaken with the use of substrates 1a,[18] 1b[19] and 1c[19-20] as well as a set of substituted
anilines 2 (Scheme 1).
Scheme 1. Synthesis of triazoles 3a-o.
a Reaction was conducted over 40 h.
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10.1002/ejoc.201900698
European Journal of Organic Chemistry
It was apparent that the moderate yields of these cyclocondensations were virtually independent
of substrates employed and are, again, likely a corollary of a difficult reactivity. Interestingly,
neither the nature of the ketone nor that of the sulfone portion (aromatic vs. aliphatic) in
substrates 1a-c appeared to affect the yield of the reaction. However, methyl sulfone 1c required
substantially longer reaction time to achieve full conversion and the isolated yields of the
respective products (3l-o). It should be noted that aliphatic amines have been tried in this
reaction and led to no appreciable 1,2,3-triazole formation.
Compounds 3a-o indeed represent the first examples of compounds bearing a sulfonyl 1,2,3-
triazole core of high medicinal relevance assembled in one step via the Wolff cyclocondensation.
At the same time, the Wolff rearrangement product 5a obtained in respectable 77% yield (vide
supra) is also a representative of a useful class of compounds. This notion is attested to by such
examples as glucagon receptor antagonist 10,[21] cholesterol O-acyl transferase inhibitor 11,[22]
antiviral compound 12[23] as well as compound 13, an inhibitor of enzymes containing redox-
sensitive cysteines[24] (Figure 3). Considering that examples of the Wolff rearrangement of -
diazo--oxo sulfones reported in the literature are limited to those of trifluoromethyl sulfones
(triflones),[11-12] establishing the generality of transformation 15 appeared a worthy
undertaking.
Figure 3. Examples of biologically active compounds bearing the -sulfonyl acetanilide moiety.
As it follows from the data presented in Scheme 2, the thermal Wolff rearrangement of diazo
compounds 1a-c with subsequent nucleophilic trapping of the ketene intermediate proceeded
with markedly higher isolated yields of compounds 5a-f compared to the respective TiCl4-
promoted cyclocondensation into 1,2,3-triazoles 3a-o (vide supra). In this case, however, methyl
sulfones appeared to give somewhat lower product yields compared to their aryl sulfone
counterparts. At the same time, with the latter, migration of methyl (1a) and phenyl (1b) groups
proceeded with similar efficiency as reflected, for instance, in comparable yields of 5a and 5e.
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10.1002/ejoc.201900698
European Journal of Organic Chemistry
Scheme 2. Synthesis of -sulfonyl acetanilides 5a-f.
Conclusion
We have described the first example of involving -diazo--oxo sulfones in the Wolff
cyclocondensation with aromatic amines. The reaction is promoted by 1.5-fold excess of
titanium(IV) chloride and, while rather clean, gives moderate yields of the target medicinally
relevant sulfonyl 1,2,3-triazoles. Exclusion of TiCl4 from the reaction leads to thermal Wolff
rearrangement of the same substrates providing, at higher temperature and over shorter period of
time, products of trapping of the ketene intermediates with anilines.
ASSOCIATED CONTENT
Supporting Information
Synthetic procedures, analytical data, copies of the 1H and 13C 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.
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10.1002/ejoc.201900698
European Journal of Organic Chemistry
ACKNOWLEDGEMENTS
This research was supported by the Russian Science Foundation (project grant 19-75-30008).
Alexander Safrygin is grateful to Saint Petersburg State University for the provision of his
postdoctoral fellowship. 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: -diazo--oxosulfones; 1,2,3-triazoles, -sulfonyl acetanilides; Wolff
cyclocondensation; Wolff rearrangement
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Graphical abstract
TOC text:
-Diazo--oxosulfones have been shown to undergo a TiCl4-promoted Wolff cyclocondensation
with anilines to give moderate yields of medicinally relevant sulfonyl 1,2,3-triazoles. If TiCl4 is
omitted, a thermal Wolff rearrangement occurs, leading to -sulfonyl acetanilides formed via
trapping of the respective ketene intermediate.
Key topic:
Diazo compounds
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