NH2OH-HCl-Mediated Umpolung α-Methylsulfonylation of α-Sulfonyl Ketones with Methylsulfoxides: Synthesis of α,β-Bis-sulfonyl Arylketones

Article abstract of DOI:10.1021/acs.orglett.9b00422

In this paper, a novel and efficient route for the synthesis of α,β-bis-sulfonyl arylketones via an NH₂OH-HCl-mediated intermolecular umpolung α-methylsulfonylation of α-sulfonyl ketones with methylsulfoxides is described. A plausible mechanism is proposed and discussed. Various reaction conditions for this efficient, one-pot, environmentally friendly transformation were investigated.

Full text of DOI:10.1021/acs.orglett.9b00422

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
NH2OH−HCl-Mediated Umpolung α‑Methylsulfonylation of
α‑Sulfonyl Ketones with Methylsulfoxides: Synthesis of α,β-Bis-
sulfonyl Arylketones
Meng-Yang Chang,*,†,‡ Han-Yu Chen,† and Yu-Lin Tsai†
†Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung 807, Taiwan
‡Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan
S
* Supporting Information
ABSTRACT: In this paper, a novel and efficient route for the synthesis of α,β-bis-
sulfonyl arylketones via an NH2OH−HCl-mediated intermolecular umpolung α-
methylsulfonylation of α-sulfonyl ketones with methylsulfoxides is described. A
plausible mechanism is proposed and discussed. Various reaction conditions for
this efficient, one-pot, environmentally friendly transformation were investigated.
mpolung functionalizations of carbonyl synthons are an
C−C and C−S bond, some groups have described one-pot
Uimportant tool for constructing carbon−carbon bonds syntheses of α-sulfenyl,6a,b β-sulfenyl,6c and β,β-disulfenyl
ketones.6d Other umpolung routes based on various classical
methods have been studied.7 Overall, the facile intermolecular
cross-couplings of different enolate, nitro, imine, and sulfenyl
derivatives with a variety of carbonyl synthons via acid-, base-,
or NHC-promoted reactions have attracted substantial interest.
To the best of our knowledge, no direct route for the
formation of one S−C bond (red) and one C−S bond (blue)
under mild conditions has been reported. Based on reported
umpolung reactions, herein, we report the development of a
novel, one-pot method for the synthesis of α,β-bis-sulfonyl
ketones via the NH2OH−HCl-mediated cross-coupling of α-
sulfonyl ketones with dimethyl sulfoxide (DMSO). Recently,
Alves et al. reported the pyrrolidine-catalyzed synthesis of the
core skeleton of sulfonyl 1,2,3-triazoles via the cycloaddition of
α-sulfonyl ketones and azides in the presence of DMSO
(Scheme 2).8 These results highlight the key role of DMSO in
these two similar sets of reaction conditions.
via polarity inversion modes.1 Various cross-coupling routes
(e.g., α-alkylations and 1,2- or 1,4-additions) based on
umpolung reactions have been reported for functionalized
building blocks and bioactive molecules.2 Among the synthetic
variations of different methods, one-pot carbon−carbon bond
(C−C, green marks) formations from carbonyl synthons are a
major route, as shown in Scheme 1.3−5
Scheme 1. Umpolung Cross-Coupling of Dicarbonyl
Synthons
Scheme 2. Reactions of α-Sulfonyl Ketones in DMSO
Using Koser’s reagent, Szpilman et al. demonstrated a BF3·
OEt2-mediated cross-coupling of two nucleophilic enolonium
species that provided asymmetric 1,4-diketones via the
formation of two C−C bonds (red and blue).3a Ioffe et al.
investigated the synthesis of β-nitroesters via the TBSOTf-
catalyzed conjugation of silyl enol ethers with nitronates by the
formation of one C−C bond (red) and one C−N bond
(blue).4a The Reddy group explored LiHMDS-mediated cross-
additions of two different kinds of imines, which produced
vicinal diamines via the formation of one N−C bond (red) and
one C−N bond (blue).5a For the umpolung conjugation of a
Based on our long-standing interest in the synthetic
applications of α-sulfonyl ketones,9 NH2OH−HCl was chosen
as the initial promoter to study the synthesis of vicinal bis-
sulfonyl ketones in DMSO. Many studies on related syntheses
and applications of bis-sulfonyl-containing skeletons have been
reported.10 Our initial study commenced with treating model
substrate 1a (R1 = Ph; R = Tol, 1.0 mmol) with NH2OH−HCl
Received: January 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00422
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(1.0 equiv) in DMSO (2a, 2 mL). Compound 1a was easily
prepared by nucleophilic substitution of α-bromo-
acetophenone (3a) with TolSO2Na (4a) in a mixture of
dioxane and water in a nearly quantitative yield.9g First, when
NH2OH−HCl (1.1 equiv) was added and the reaction was
conducted in DMSO (2 mL) at 25 °C, no reaction was
observed after 10 or 20 h. Then, after elevating the
temperature from 25 °C to 50, 80, 100, and 150 °C for 10
h, 5a was isolated in yields of 0%, 35%, 87%, and 72%,
respectively (Table 1, entries 1−4). After adjusting the
mediated umpolung cross-coupling of α-sulfonyl ketones 1a in
DMSO. The structure of 5a (CCDC 1884133) was
determined by single-crystal X-ray crystallography. On the
basis of the dual roles of the reagent and solvent,11 a number of
DMSO-mediated one-carbon elongation reactions (thiome-
thylations,12a−c methylenations,12d,e methylsulfonylations,12f−g
and other routes12h) have been reported for the installation of
methylsulfenyl, methylenyl, or methylsufonyl substituents.
Based on our experimental results, a plausible mechanism for
the formation of 5a is proposed as illustrated in Scheme 3.
a
Table 1. Reaction Conditions
Scheme 3. Plausible Mechanism
b
entry
promoter
solvent
time (h) temp (°C) 5a (%)
c
1
2
3
4
5
6
7
8
NH2OH−HCl
NH2OH−HCl
NH2OH−HCl
NH2OH−HCl
NH2OH−HCl
NH2OH−HCl
NH2OH−HCl
NH2OH−HCl
NH2OH−HCl
C5H5N−HCl
Et3N−HCl
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10
10
10
10
20
10
10
10
10
10
10
10
10
10
50
80
−
35
87
72
68
74
35
62
25
100
150
100
100
100
100
100
100
100
100
100
100
d
e
f
g
h
9
c
c
i
Initially, condensation of 1a with NH2OH in the presence of
HCl yields oxime A and H2O. The oxime−enamine
tautomerization of A affords both enamines B1 (Z-form)
and B2 (E-form). The hydroxy(dimethyl)sulfonium chloride
(Me2SOHCl) salt could be formed after a reaction between
HCl and DMSO.12h,13 Me2SO2 and Me2S2 could not generate
the intermediate, which is why no reactions were observed
with these solvents. Following equilibration between B1 and
B2, an oxygen atom on the oxime attacks the in situ generated
sulfonium cation to form C. Then, the released chloride anion
traps the α-proton to yield enaminyl sulfur ylide D. In a six-
membered ring transition state, D is immediately converted to
iminyl sulfoxide E via a [3.3]-sigmatropic process (umpolung
bond formation).14 Subsequent hydrolysis of E then generates
β-ketosulfoxide F. Finally, 5a can spontaneously form after the
autoxidation of methyl sulfoxide.12f,15
To study the scope and limitations of this approach, 1a−1ak
were reacted with NH2OH−HCl in methylsulfoxides 2a−2d to
afford products 5a−5an, as shown in Table 2. With the
optimal conditions established (Table 1, entry 3) and a
plausible mechanism proposed, we found that this route
allowed direct, one-pot umpolung cross-couplings under mild
conditions in good to excellent yields (65%−95%). By
maintaining the sulfonyl site as a tosyl group (R = Tol, entries
1−12) in the reactions of 1a−1l with DMSO (2a, R2 = Me),
aryl groups with more electron-withdrawing substituents (R1 =
4-CF3C6H4 and 4-NO2C6H4) provided lower yields (65% and
72%, entries 7 and 8) than those obtained with substrates with
electron-donating and electron-neutral groups.
10
11
12
13
14
−
−
−
−
−
N2H4−2HCl
NH2OH−HCl
NH2OH−HCl
c
c
Me2SO2
Me2S2
a
Reactions were run on a 1.0 mmol scale with 1a, base (1.1 equiv),
b
and solvent (2 mL); the reactions were monitored by TLC. Isolated
yields. No reaction. 2.2 equiv. 0.5 equiv. DMSO (5 mL) was
c
d
e
f
g
h
added. DMF (2 mL) was added. 1a (60%) was recovered.
i
Complex mixture of unknown compounds (43%) and 1a (20%) was
recovered.
temperature to 100 °C, an extended reaction time (20 h)
did not enhance the isolated yield of 5a (68%, entry 5). With
these results in mind, we used 10 h as the reaction time and
100 °C as the reaction temperature to evaluate the effects of
the loading of the protomer and the reaction concentrations on
the umpolung cross-coupling process. However, lower yields
(74% and 35%) of 5a were observed with both 0.5 and 2.2
equiv of NH2OH−HCl (entries 6 and 7), and 5 mL of DMSO
resulted in a lower yield (62%, entry 8). When DMF (2 mL)
was added, only a 25% yield of 5a was obtained, and 60% of 1a
was recovered (entry 9). To increase the yield, three
promoters, C5H5N−HCl, Et3N−HCl, and N2H4−2HCl, were
investigated. However, no 5s was observed when using
C5H5N−HCl or Et3N−HCl as the promoter (entries 10 and
11), and N2H4−2HCl provided a complex mixture of
unidentified compounds in 43% yield, with 20% of 1a being
recovered (entry 12).
From these results, we found that only NH2OH−HCl could
provide desired 5a. Furthermore, when the solvent was
changed from dimethyl sulfoxide (Me2SO) to dimethylsulfone
(Me2SO2) and dimethyl disulfide (Me2S2), the umpolung
reactions were not successful (entries 13 and 14). From these
observations, we concluded that entry 3 corresponded to the
optimal conditions for the formation of α,β-bis-sulfonyl
ketones 5a (87%) via the thermally driven, NH2OH−HCl-
For substrates with heterocyclic rings, 2-furyl derivative
provided a lower yield than the 2-thienyl derivative due to its
lower aromaticity (entries 11 and 12). Changing the R group
from Tol to Ph and Me (entries 13−19) showed that R1
substituents with electron-neutral, electron-donating, and
electron-withdrawing groups were tolerated, and 5m−5s
were obtained in yields of 72%−83%. Furthermore, by
changing the R group to other aromatic rings with electron-
B
DOI: 10.1021/acs.orglett.9b00422
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
−
raphy. Entries 34−37 show that 5ah−5ak were produced in
80%−84% yields. Then, methylsulfoxides 2b−2c (R2 = Ph,
tBu) were studied. After changing 2a to methyl phenyl
sulfoxide (2b), no desired 5al was observed, and 1a was
recovered (entry 38). tert-Butyl methyl sulfoxide (2c) provided
the same result, and 5am was not produced (entry 39). This
could be because the phenyl and tert-butyl groups provided
more electron density and steric hindrance, decreasing the
reactivity of the sulfonium ion, hindering the one-pot reaction.
Finally, when R1 was changed to a methyl group (for 1al),
desired 5an was not obtained, and only a complex product was
detected (entry 40). Compared to the aryl groups, the methyl
group may have more easily triggered a Beckmann rearrange-
ment of oxime A, resulting in the observed complex product.
All products 5a−5ak were obtained as racemates.
Table 2. Synthesis of 5a−5ak
c
entry
1, R1 = , R =
1a, Ph, Tol
2, R2 =
5 (%)
1
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2a, Me
2b, Ph
2c, tBu
2a, Me
5a, 87
5b, 86
5c, 80
5d, 78
5e, 76
5f, 75
5g, 65
5h, 72
5i, 76
5j, 86
5k, 73
5l, 67
2
3
4
5
6
7
8
9
1b, 4-FC6H4, Tol
1c, 4-MeC6H4, Tol
1d, 4-MeOC6H4, Tol
1e, 2-naphthyl, Tol
1f, 4-PhC6H4, Tol
1g, 4-CF3C6H4, Tol
1h, 4-NO2C6H4, Tol
1i, 4-ClC6H4, Tol
1j, 3,4-CH2O2C6H3, Tol
1k, 2-thienyl, Tol
1l, 2-furyl, Tol
Encouraged by the above results (Table 2, entries 1−40),
after replacing the NH2OH−HCl(s) with 50% NH2OH(aq), 6
was synthesized, as shown in Scheme 4, eq 1. However, none
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
1m, Ph, Ph
5m, 80
5n, 80
5o, 83
5p, 72
5q, 74
5r, 83
Scheme 4. Synthesis of 6−7, 9a−9c, and 9a-1
1n, 4-FC6H4, Ph
1o, 4-PhC6H4, Ph
1p, Ph, Me
1q, 4-MeOC6H4, Me
1r, 4-FC6H4, Me
1s, 4-PhC6H4, Me
1t, Ph, 4-FC6H4
1u, Ph, 4-MeOC6H4
1v, Ph, 4-EtC6H4
1w, Ph, 4-iPrC6H4
1x, Ph, 4-nBuC6H4
1y, Ph, 4-tBuC6H4
5s, 80
5t, 84
5u, 80
5v, 73
5w, 70
5x, 76
5y, 79
5z, 95
5aa, 84
5ab, 84
5ac, 84
5ad, 86
5ae, 85
5af, 90
5ag, 84
5ah, 84
5ai, 80
5aj, 83
5ak, 83
1z, 3,4,5-(MeO)3C6H2, Ph
1aa, 3-MeOC6H4, Tol
1ab, 3,4-(MeO)2C6H3, Ph
1ac, 3,4-(MeO)2C6H3, Me
1ad, 3,4-(MeO)2C6H3, nBu
1ae, 3,4-(MeO)2C6H3, 4-FC6H4
1af, 3,4-(MeO)2C6H3, 4-MeOC6H4
1ag, 3,4-(MeO)2C6H3, 3-MeC6H4
1ah, 4-MeC6H4, Me
1ai, 4-MeC6H4, Ph
1aj, Ph, nBu
1ak, Ph, 3-MeC6H4
1a, Ph, Tol
1a, Ph, Tol
1al, Me, Ph
c
5al, −
of desired compound 5g was observed, and only 6 was formed
(93% yield). These results indicate that HCl is a key factor in
triggering the one-pot reaction. After changing DMSO (2a) to
DMSO-d6 (2d, eq 2), 7 was isolated in 82% yield. This
important result confirms the proposed reaction mechanism.
In the following reactions, three 1,3-dicarbonyl synthons were
examined (eqs 3 and 4). Unlike α-sulfonyl ketones 1a−1ak,
the treatment of symmetrical β-diketone 8a with NH2OH−
HCl did not afford the desired β-sulfonyl group, and isoxazole
9a16 was formed in a 47% yield along with 12% of 9a-1.17 For
the generation of 9a-1, the Cui group also reported similar
results when using DMSO as a carbon source.17a However,
when using asymmetric β-diketone 8b, only 9b was produced
in 68% yield, and other regioisomers, 9b-1, were not
observed.18 With the above one-pot reaction conditions,
interestingly, β-ketoester 8c could be converted to 9c, which
possesses an isoxazolone skeleton, in 70% yield.19 The
structures of 6 (CCDC 1884138), 7, and 9a-1 (CCDC
1888352) were determined by single-crystal X-ray crystallog-
raphy, but the reactions of 8d or 8e, which possess α-methyl
c
5am, −
5an, −
d
a
Reactions were run on a 1.0 mmol scale with 1a−1al, 2a−2c (2 mL),
b
and NH2OH−HCl (76 mg, 1.1 equiv) for 10 h at 100 °C. Isolated
c
d
yields. No reaction. Complex products.
neutral, electron-donating, and electron-withdrawing groups,
5t−5y were isolated in similar yields (70%−84%, entries 20−
25). When maintaining the arylketone site as the oxygenated
R1 group (entries 26−33) for the formation of 5z−5ag, both
aliphatic and aromatic substituents (R) were well tolerated.
These results showed that when R1 was an oxygenated group,
better yields were obtained relative to what was achieved with
other substituents. This could be caused by the fact that,
compared to other aromatic systems, the oxygenated group
was better able to facilitate the conversion of oxime A to
enamines B1/B2. The structures of 5b (CCDC 1884134), 5e
(CCDC 1884135), 5k (CCDC 1884136), and 5t (CCDC
1884137) were determined by single-crystal X-ray crystallog-
C
DOI: 10.1021/acs.orglett.9b00422
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Organic Letters
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and phenyl substituents, did not afford α,β-bis-sulfonyl
arylketones 9d or 9e since the increased steric hindrance at
the α-carbon interfered with the one-pot reaction (eq 5).
As an extension of the NH2OH−HCl-mediated umpolung
α-methylsulfonylation of α-sulfonyl ketones with DMSO, we
were able to synthesize quinoxaline, as shown in Scheme 5.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mychang@kmu.edu.tw.
ORCID
Meng-Yang Chang: 0000-0002-1983-8570
Notes
Scheme 5. Synthesis of 10a−10c
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the Ministry of Science and Technology of
the Republic of China for financial support (MOST 106-2628-
M-037-001-MY3).
REFERENCES
■
(1) For reviews on umpolung reactions, see: (a) Miyata, O.;
Miyoshi, T.; Ueda, M. ARKIVOC 2013, ii, 60−81. (b) Izquierdo, J.;
Hutson, G. E.; Cohen, D. T.; Scheidt, K. A. A. Angew. Chem., Int. Ed.
2012, 51, 11686−11698.
(2) For recent examples on umpolung reactions, for α-alkylation,
see: (a) Shneider, O. S.; Pisarevsky, E.; Fristrup, P.; Szpilman, A. M.
Org. Lett. 2015, 17, 282−285. For 1,2-addition, see: (b) Xu, X.; Min,
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(c) Hu, L.; Wu, Y.; Li, Z.; Deng, L. J. Am. Chem. Soc. 2016, 138,
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(3) For umpolung conjugation of C−C and C−C bond, for 1,4-
diketones, see: (a) Parida, K. N.; Pathe, G. K.; Maksymenko, S. M.;
Szpilman, A. M. Beilstein J. Org. Chem. 2018, 14, 992−997. For 1,4-
ketoamides, see: (b) Kaiser, D.; Teskey, C. J.; Adler, P.; Maulide, N. J.
Am. Chem. Soc. 2017, 139, 16040−16043.
(4) For umpolung conjugation of C−C and C−N or N−N bond, for
β-nitroketones, see: (a) Smirnov, V. O.; Khomutova, Y. A.;
Tartakovsky, V. A.; Ioffe, S. L. Eur. J. Org. Chem. 2012, 2012,
3377−3384. For α-cyanoketones, see: (b) Shen, H.; Li, J.; Liu, Q.;
Pan, J.; Huang, R.; Xiong, Y. J. Org. Chem. 2015, 80, 7212−7218. For
α-azidoketones, see: (c) More, A. A.; Pathe, G. K.; Parida, K. N.;
Maksymenko, S.; Lipisa, Y. B.; Szpilman, A. M. J. Org. Chem. 2018,
83, 2442−2447.
Quinoxaline is a versatile skeleton common in useful synthetic
intermediates20 and bioactive molecules.21 Among these
synthetic routes, no examples using α,β-bis-sulfonyl arylke-
tones for the formation of quinoxaline have been reported.
Furthermore, the condensation of 5a with substituted 1,2-
diaminobenzenes (X = H, Me, Cl) in dioxane at 100 °C for 10
h provided quinoxalines 10a−c (74%−82%)20f,g via a tandem
process involving the dehydration of 5a and 1,2-diaminoben-
zene, the sequential intramolecular detosylation of I, the
demesylation of II (by removal of TolSO2H and MeSO2H),
and the aromatization of III.
In summary, we have developed a facile one-pot route for
synthesizing α,β-bis-sulfonyl arylketones via the NH2OH−
HCl-mediated, intermolecular umpolung α-methylsulfonyla-
tion of α-sulfonyl ketones with methylsulfoxides. Related
plausible mechanisms have been proposed. The structures of
the key products were confirmed by X-ray crystallography. The
effects of various reaction conditions were investigated to
optimize the transformation. Further investigations regarding
synthetic applications of α-sulfonyl ketones will be conducted
and published in due course.
(5) For umpolung conjugation of N-C and C-N bond, for 1,4-
diamines, see: (a) Reddy, L. R.; Kotturi, S.; Shenoy, R.; Nalivela, K.
S.; Patel, C.; Raval, P.; Zalavadiya, V. Org. Lett. 2018, 20, 5423−5426.
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2118−2121. (c) Zhan, M.; Pu, X.; He, B.; Niu, D.; Zhang, X. Org.
Lett. 2018, 20, 5857−5860.
ASSOCIATED CONTENT
■
S
* Supporting Information
(6) For umpolung conjugation of C−S bond, for α-sulfenyl ketones,
see: (a) Hatcher, J. M.; Kohler, M. C.; Coltart, D. M. Org. Lett. 2011,
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00422.
́
13, 3810−3813. (b) Gabillet, S.; Lecercle, D.; Loreau, O.; Carboni,
́
M.; Dezard, S.; Gomis, J. M.; Taran, F. Org. Lett. 2007, 9, 3925−3927.
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Tsujimoto, Y.; Shimizu, M. Org. Lett. 2018, 20, 2291−2296. For β,β-
disulfenyl ketones, see: (d) Lai, J.; Tian, L.; Huo, X.; Zhang, Y.; Xie,
X.; Tang, S. J. Org. Chem. 2015, 80, 5894−5899.
Detailed experimental procedures and spectroscopic
data for all new compounds and X-ray analysis data
for 5a, 5b, 5e, 5k, 5t, 6, and 9a-1 (PDF)
(7) For other umpolung routes, see: (a) Liu, J.; Das, D. K.; Zhang,
G.; Yang, S.; Zhang, H.; Fang, X. Org. Lett. 2018, 20, 64−67.
(b) Chen, N.; Dai, X.-J.; Wang, H.; Li, C.-J. Angew. Chem., Int. Ed.
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Glorius, F. Org. Lett. 2014, 16, 3134−3137. (d) Garapati, V. K. R.;
Gravel, M. Org. Lett. 2018, 20, 6372−6375.
Accession Codes
CCDC 1884133−1884138 and 1888352 contain the supple-
mentary 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.
(8) Saraiva, M. T.; Costa, G. P.; Seus, N.; Schumacher, R. F.; Perin,
G.; Paixao
6209.
̃
, M. W.; Luque, R.; Alves, D. Org. Lett. 2015, 17, 6206−
D
DOI: 10.1021/acs.orglett.9b00422
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Organic Letters
Letter
(9) For recent examples on synthetic applications of α-sulfonyl
ketones by the authors, see: (a) Chang, M.-Y.; Cheng, Y.-C.; Lu, Y.-J.
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DOI: 10.1021/acs.orglett.9b00422
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