General sulfone construction: Via sulfur dioxide surrogate control

Article abstract of DOI:10.1039/c9gc03841h

A highly efficient one-step synthesis of alkyl-alkyl and aryl-alkyl sulfones with a facile combination of halides, sulfur dioxide surrogates and phosphate esters is described. When thiourea dioxide was employed as a reductive sulfur dioxide surrogate, alkyl-alkyl sulfones were obtained under transition metal free conditions. Aryl-alkyl sulfones were obtained with an extremely low catalytic loading (0.2 mol%) via altering the mask of sulfur dioxide surrogates to sodium dithionite. A phosphate ester was employed as a stable and readily available alkyl source. Notably, this protocol has been applied to the late-stage modification of natural products and bioactive molecules.

Full text of DOI:10.1039/c9gc03841h

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General sulfone construction via sulfur dioxide
surrogate control†
Cite this: DOI: 10.1039/c9gc03841h
a,b
Shihao Chen,‡a Yaping Li,‡a Ming Wang *a and Xuefeng Jiang
*
Received 8th November 2019,
Accepted 5th December 2019
DOI: 10.1039/c9gc03841h
rsc.li/greenchem
A highly efficient one-step synthesis of alkyl–alkyl and aryl–alkyl
Conventionally, strategies for obtaining sulfones rely on the
sulfones with a facile combination of halides, sulfur dioxide surro- oxidation of sulfides,8 in which the application of strong oxi-
gates and phosphate esters is described. When thiourea dioxide dants resulting in low functional group compatibility was the
was employed as a reductive sulfur dioxide surrogate, alkyl–alkyl predicament. DABSO [DABCO (SO2)2], an air-stable and easy-
sulfones were obtained under transition metal free conditions. handling reagent first reported in 1988,9 was pioneered by
Aryl–alkyl sulfones were obtained with an extremely low catalytic Willis and Wu, applying it as a sulfur dioxide surrogate.10
loading (0.2 mol%) via altering the mask of sulfur dioxide surro- Subsequently, the direct insertion strategy of SO2 into two
gates to sodium dithionite. A phosphate ester was employed as a coupling partners has been intensively developed due to its
stable and readily available alkyl source. Notably, this protocol has step economy and oxidative economy for sulfone synthesis.11
been applied to the late-stage modification of natural products For example, two steps in one-pot processes were developed
and bioactive molecules.
via the use of aryl halides for the synthesis of aryl–alkyl sul-
fones.12 The one-step construction of sulfones from aryl-
boronic acid,13 aryllithium,14 aryl magnesium bromide,15 aryl
triethoxysilanes,16 and aryl halides17 has been explored
(Scheme 1B). Although the above coupling of aryl reagents
with alkyl halides affords aryl–alkyl sulfones effectively and
has been reported in considerable studies, the access to both
alkyl–alkyl and aryl–alkyl sulfones under green conditions con-
trollably is still unresolved.18 We envisioned that modification
of reducibility of sulfur dioxide surrogates via the masked
effect will tune the coupling rate between alkyl and aryl
halides (Scheme 1C). Based on the transformation from in-
organic sulfur to organic sulfides by our group,19 herein, we
employed two different types of sulfur dioxide surrogates to
adjust to diverse coupling partners for the divergent synthesis
of sulfones under transition metal free or low catalytic loading
(0.2 mol%) conditions. A phosphate ester was employed as a
stable and readily available alkyl source in the current one-step
strategy (Scheme 1D).
Sulfones1 are an indispensable motif in pharmaceuticals,2
agrochemicals,3 natural products4 and organic materials.5 For
example, apremilast, containing an alkyl–methyl sulfone struc-
ture, is a medication for the treatment of psoriasis and psoria-
tic arthritis.6 The alkyl–ethyl sulfone molecule Tinidazole is a
well-known anti-inflammatory drug. Vismodegib, possessing
an aryl–methyl sulfone fragment, has been used for the treat-
ment of basal-cell carcinoma.7 The aryl–methyl sulfone-con-
taining corn herbicide Topramezone is an inhibitor of the
4-hydroxyphenylpyruvate dioxygenase (4-HPPD) enzyme.3a The
heterocyclic-alkyl sulfone Fluensulfone is a new nematicide,
which is effective against a number of plant parasitic nema-
todes in a range of agricultural and horticultural crops.3d The
sulfone-containing natural product Craniformin, which was
isolated from Calvatia craniformis, shows an activity against
K562 leukemia cells4a (Scheme 1A).
To explore the assumption, our initial investigations were
performed via three component coupling of (2-bromoethyl)
benzene 1a, thiourea dioxide and phosphate esters (Table 1).
First, the influence of a base was investigated (entries 1–9). No
product was observed in the absence of a base even with the
addition of KI and TBAB (entry 1). After screening of the
different organic (entries 2–5) and inorganic bases (entries
6–9), caesium carbonate was found to be the best base provid-
ing the desired sulfone 2a in 67% yield (entry 8). When
aShanghai Key Laboratory of Green Chemistry and Chemical Process,
School of Chemistry and Molecular Engineering, East China Normal University,
3663 North Zhongshan Road, Shanghai 200062, P. R. China
bState Key Laboratory of Elemento-organic Chemistry, Nankai University,
Tianjin 300071, P. R. China. E-mail: xfjiang@chem.ecnu.edu.cn,
wangming@chem.ecnu.edu.cn
†Electronic supplementary information (ESI) available. CCDC 1921692 and
1921697. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c9gc03841h
‡These authors contributed equally to this work.
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Table 1 Condition optimizationa
Equivalent
of additive
Yield
(%)
Entry
Base
Additive
1
2
3
4
5
6
7
8
—
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAB
TBAC
TBAI
—
TBAI
TBAI
TBAI
TBAI
TBAI
2
2
2
2
2
2
2
2
2
2
2
—
0.2
0.5
1.5
0.5
0.5
ND
ND
25
42
60
ND
52
67
ND
66
79
DABCO
DIPEA
Et3N
DBU
KHCO3
KOAc
Cs2CO3
KOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16b
17c
71
70
77
79
66
76(71)d
a Reaction conditions: 1a (0.2 mmol), thiourea dioxide (0.6 mmol, 3
equiv.), PO(OMe)3 (0.6 mmol, 3 equiv.), base (0.4 mmol, 2 equiv.), KI
(0.4 mmol, 2 equiv.), additive (0.1 mmol, 0.5 equiv.), DMSO (2.0 mL),
80 °C, N2, 15 h. NMR yields. b KI was absent. c KI (0.3 mmol,
1.5 equiv.). d Isolated yields.
-deficient (2d–2h), and -rich (2i–2k) groups, including hetero-
cycles (2i, 2l, 2m, and 2p), were well tolerated in this sulfony-
lated reaction. The structure of 2i was further confirmed via
X-ray diffraction analysis.20 Notably, the substrates containing
sensitive but transformable functional groups, such as
bromine (2f), alkyne (2n) and olefin (2o), generated the corres-
ponding products in acceptable yields. The cyclobutyl bromide
with a tension ring worked well under standard conditions,
and the desired product 2q was obtained in 76% yield.
Compound 2r was afforded in 63% yield when cyclopentane
bromide was employed in this transformation. Besides cyclic
substrates, secondary bromide with an open chain could also
be converted into the desired sulfone smoothly (2s). The
triethyl phosphate was proved to be applicable in this trans-
Scheme 1 The synthesis and application of sulfones.
stronger base KOtBu was used, the desired product was not formation as well, affording the ethyl sulfone 2t in a moderate
detected (entry 9). Further examination of phase transfer cata- yield.
lysts of different species (entries 10 and 11) indicated that
Encouraged by the above results, this protocol was further
TBAI was the best choice. The efficiency of the reaction was applied in the preparation of (hetero)aryl alkyl sulfones. We
lower without TBAI (entry 12), and only a half equivalent of commenced the study with the coupling of aryl iodides,
TBAI was enough to keep the reaction working efficiently sodium dithionite and phosphate esters. Excitingly, the reac-
(entry 14). It was found that the yield of the reaction was dra- tions provide the corresponding products efficiently with an
matically lower in the absence of KI since it was necessary to extremely low catalytic loading (0.2 mol% PdCl2dppf). A wide
activate alkyl bromides via a bromine–iodide exchange process range of aryl iodides with electron-withdrawing or electron-
(entry 16). However, no apparent decline was observed when donating groups at the para-position were well tolerated under
KI was decreased to 1.5 equivalents (entry 17).
standard conditions, delivering the desired products 3a–3i
With the optimal conditions in hand, the reaction with fluoro, chloro, trifluoromethyl, cyano, amide and methyl-
scope was then explored for this catalyst-free reaction, which thio groups. Substitutions from the para position to either
afforded a divergent functionalized sulfone library. A broad meta-(3j–3m) or even ortho-(3n–3p) showed that steric and elec-
range of alkyl bromides with electron-neutral (2a–2c), tronic effects were successfully compatible. It is worth men-
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Table 2 General synthesis of alkyl–alkyl and aryl–alkyl sulfones.a
a Reaction conditions: 1 (0.5 mmol), PO(OR2)3 (1.5 mmol, 3 equiv.), isolated yields. R1 = alkyl: thiourea dioxide (1.5 mmol, 3 equiv.), Cs2CO3
(1.0 mmol, 2 equiv.), KI (0.75 mmol, 1.5 equiv.), TBAI (0.25 mmol, 0.5 equiv.), DMSO (2 mL), 80 °C, 15 h; R1 = aryl: PdCl2(dppf)2 (0.001 mmol,
0.2 mol%), Na2S2O4 (1.5 mmol, 3 equiv.), TBAB (0.75 mmol, 1.5 equiv.), DMSO (5 mL), 120 °C, 15 h. b T = 120 °C. c 1 (0.2 mmol), PO(OR2)3
(0.6 mmol, 3 equiv.), Na2S2O5 (0.4 mmol, 2 equiv.), PdCl2(dppf)2 (0.01 mmol, 5 mol%), Mn (0.6 mmol, 3 equiv.), TBAB (0.3 mmol, 1.5 equiv.),
DMSO (2 mL).
tioning that the heterocycles were also tolerated in this trans- in the current transformation, which provided the evidence of
formation affording the desired products (3r–3t) in good an alkyl radical intermediate involved in this transformation
yields. Furthermore, a range of different types of phosphate (Scheme 3a). A postulated reaction pathway is displayed in
esters, such as triethyl, tributyl, trihexyl and tris(2-butoxyethyl) Scheme 3b; the sulfur dioxide radical anion was formed from
phosphates, provided the desired products in satisfactory thiourea dioxide in the presence of caesium carbonate.12c The
yields (3v–3y) (Table 2).
alkyl radical was initiated to generate alkyl radical II, which
To reveal the versatility and applicability of the three-com- was trapped by the sulfur dioxide radical anion providing alkyl
ponent coupling protocol, late-stage modification of estrone and sulfinate salt III. Then, alkylation of the intermediate III
cholesterol was further conducted (Scheme 2). The introduction afforded the alkyl–alkyl sulfone product. On the other hand,
of the –SO2R motif into hormone drug Estrone was achieved to oxidation addition of the Pd0 catalyst to aryl iodides generated
provide the product 4a in a good yield. The late-stage modifi- palladium species IV. A sulfur dioxide radical anion was gener-
cation of steroid compound cholesterol was also tolerant via the ated from sodium dithionite with sulfur dioxide release, fol-
present approach to afford the sulfone product 4b.
lowed by intermediate V formation. Ligand exchange between
In order to gain more insight into the reaction mechanism, intermediates V and IV gave intermediate VI. The reductive
the control experiment was performed. Compound 5a was elimination and alkylation of intermediate VI formed the
afforded in 26% yield when cyclopropyl bromide was employed desired products, as well as regenerated the Pd(II) catalyst.
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors are grateful for financial support provided by the
National Key Research and Development Program of China
(2017YFD0200500), the NSFC (21971065, 21722202, 21672069;
and 21871089 for M.W.), S&TCSM of Shanghai (Grant
18JC1415600), Professor of Special Appointment (Eastern
Scholar) at Shanghai Institutions of Higher Learning, and the
National Program for Support of Top-notch Young Professionals.
Scheme 2 Late-stage modification of estrone and cholesterol.
Notes and references
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In summary, a novel pathway to access both alkyl–alkyl and
aryl–alkyl sulfones was established via a three-component
cross-coupling protocol of halides, masked sulfur dioxides and
phosphate esters. Through exploring different masked sulfur
dioxide surrogates, alkyl–alkyl sulfones were constructed
under one-pot, transition metal free conditions via thiourea
dioxide as the SO2 surrogate. Aryl–alkyl sulfones were achieved
under low catalyst loading conditions through employing
sodium dithionite as both the SO2 surrogate and reductant. A
phosphate ester was employed as a stable and readily available
alkyl source. Furthermore, late-stage modification of pharma-
ceuticals and bioactive molecules was achieved efficiently
through the current transformation. Further sulfone-contain-
ing molecule syntheses and corresponding drug discovery are
in progress in our laboratory.
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