Synthesis of β-Hydroxysulfones from Sulfonyl Chlorides and Alkenes Utilizing Visible Light Photocatalytic Sequences

Article abstract of DOI:10.1021/acs.orglett.6b00734

The synthesis of β-hydroxysulfones from sulfonyl chlorides and styrenes in the presence of water by a visible light mediated atom transfer radical addition (ATRA)-like process utilizing fac[Ir(ppy)₃] as photoredox catalyst was developed in high

Full text of DOI:10.1021/acs.orglett.6b00734

Letter
pubs.acs.org/OrgLett
Synthesis of β‑Hydroxysulfones from Sulfonyl Chlorides and Alkenes
Utilizing Visible Light Photocatalytic Sequences
Santosh K. Pagire, Suva Paria, and Oliver Reiser*
Institut fur Organische Chemie, Universitat Regensburg, Universitatsstrasse 31, 93053 Regensburg, Germany
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* Supporting Information
ABSTRACT: The synthesis of β-hydroxysulfones from sulfonyl chlorides and styrenes in the presence of water by a visible light
mediated atom transfer radical addition (ATRA)-like process utilizing fac[Ir(ppy)3] as photoredox catalyst was developed in high
yields. This process could be combined with the visible light mediated synthesis of trifluoromethylated sulfonyl chlorides via an
ATRA reaction between alkenes and CF3SO2Cl utilizing [Cu(dap)2Cl] as photoredox catalyst, demonstrating the possibility of
sequential photoredox processes.
showcase the sequential utilization of two photoredox processes
he β-hydroxysulfone is a privileged scaffold that has been
Tutilized for several pharmaceutical drug candidates, fine for the synthesis of the target compounds, bringing together
two different photoreactions.
chemicals, and as a precursor in the synthesis of various
biologically active molecules.1 For example, the anticancer drug
bicalutamide and antifungal agents such as Sch42427 and
SSY726 feature a β-hydroxysulfone moiety.2
In the past few years, several advancements for synthesis of
β-hydroxysulfones have been reported, including the opening of
epoxides with sulfinate salts,3 chemical or bioreduction of β-
ketosulfones,4 and the addition of organometallic reagents to
carbonyl compounds.5 In particular, various approaches
utilizing the addition of sulfonic acid derivatives to styrenes
have been developed toward the target compounds.6
Given the wide availability of sulfonyl chlorides, some of
them like p-toluenesulfonyl chloride (TsCl) being industrially
produced on ton scale, this compound class appears to be
attractive for the direct synthesis of β-hydroxysulfones.
However, to the best of our knowledge, this has not been
achieved yet by photochemical methods.7 Recently, visible light
induced photoredox catalysis has attracted great interest in
organic synthesis, offering a nonpolluting, naturally abundant,
endlessly clean source of energy with unique applications in
synthetic chemistry.8
We report here the iridium-catalyzed, visible light mediated
atom transfer radical addition (ATRA)-like reaction of sulfonyl
chlorides and styrenes to β-hydroxysulfone, featuring mild and
economic reaction conditions, high yields, and excellent
regioselectivity. Moreover, since trifluoromethylated sulfonyl
chlorides can be synthesized by a copper-catalyzed, visible light
mediated ATRA reaction between CF3SO2Cl and alkenes,9 we
As a first step, we tested the feasibility of developing a
photochemical ATRA-like reaction of sulfonyl chlorides to β-
hydroxysulfones. Sulfinic acid salts10 and especially sulfonyl
chlorides11 have been utilized before in photoredox processes
suggesting that the generation of sulfonyl radicals by single
electron transfer (SET) should be feasible.
Using α-methylstyrene 1a and 4-nitrobenzenesulfonyl
chloride 2a as models, we tested various photoredox catalysts
under visible light irradiation in aqueous solvents, aiming for
the formation of hydroxysulfone 3a. Starting with [Ru-
(bpy)3Cl2] (bpy = bipyridine; E = −0.81 V versus SCE) as
catalyst under blue light irradiation (λmax = 455 nm), we quickly
realized that a combination of acetonitrile and water, ensuring
both solubility of reagents and catalyst as well as having a
source for introduction of the hydroxyl group, is required
(Table 1, entries 1−6).
The optimal ratio of acetonitrile/water was found to be 5:1
(Table 1, entry 5) giving rise to 3a in 90% yield. Replacing
[Ru(bpy)3Cl2] with [Cu(dap)2Cl]12 (dap =2,9-bis(p-anisyl)-
1,10-phenanthroline; E = −1.43 V versus SCE), as an even
stronger reductant in its excited state than [Ru(bpy)3Cl2], also
gave rise to 3a, however, in lower yields (Table 1, entry 7).
Finally, fac[Ir(ppy)3]13 (ppy = 2-phenylpyridine; E = −1.73 V
versus SCE) having the strongest reducing power after
Received: March 14, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00734
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Letter
a
a
Table 1. Optimization Reactions
Scheme 1. Scope for Sulfonyl Chlorides
a
Reaction conditions: α-methylstyrene 1a (1.0 mmol), sulfonyl
chloride 2 (1.5 mmol), fac[Ir(ppy)3] (1 mol %), MeCN (1.67 mL),
water (0.33 mL), LED455 at room temperature.
mesityl, or o-bromophenyl efficiently reacted with styrenes to
afford the corresponding tertiary hydroxysulfones 3j−m in 78−
92% yield. Sulfonyl chlorides bearing a strong electron-deficient
substitutent such as trifluoromethyl are not compatible with the
hydroxysulfone protocol reported here due to their fast
hydrolysis under aqueous conditions. In addition to fully
consistent spectroscopic data, the identity of the β-hydroxy-
sulfones 3 was further proven by the X-ray crystal structure of
o-bromo hydroxysulfone derivative 3m (Scheme 1).
a
Reaction conditions: 1a (1.0 mmol), sulfonyl chloride 2 (1.5 mmol),
b
photocatalyst (1 mol %), solvent(s) (2 mL), LED455. Isolated yields.
c
d
Detected by TLC analysis, starting materials remain unchanged. 24 h
e
irradiation time. 10 h irradiation time.
Furthermore, when tosyl chloride was used as a reaction
partner (Scheme 2), a variety of styrene-type alkenes also gave
the desired β-hydroxysulfones in high yields, tolerating 1,1- and
excitation of all catalysts tested allowed the isolation of 3a in
95% yield (Table 1, entry 8). Control experiments further
demonstrated that both light and a photoredox catalyst are
necessary for the reaction to proceed (Table 1, entries 9 and
10).
a
Scheme 2. Scope for Alkenes
Switching from the aromatic 4-nitrosulfonyl chloride (E =
−0.44 V versus SCE) to the aliphatic mesyl chloride 2b, having
more negative reduction potential (E = −1.39 V versus SCE),
only catalyst fac[Ir(ppy)3] gave the hydroxysulfone 3b in
preparatively useful yields (Table 1, entries 11−13). Con-
sequently, the scope and limitations for the synthesis of β-
hydroxysulfones 3 were subsequently explored using the latter
photocatalyst.
Various sulfonyl chlorides could be coupled with α-
methylstyrene 1a (Scheme 1), demonstrating the broad
functional group tolerance for the photochemical process. A
series of aryl sulfonyl chlorides bearing strong or weak electron-
donating groups (−OMe, −Me) and electron-withdrawing
groups (−NO2, acetyl,−F, −Cl, −Br) afforded the desired
hydroxysulfones in up to 97% yield. Notably, a nitro
substituent, which is usually a limitation for photochemical14
or radical processes,15 was fully compatible under these
conditions. Moreover, sterically demanding groups at the
sulfonyl chloride such as 2-naphthyl, pentafluorophenyl,
a
Reaction conditions: alkene 1 (1.0 mmol), tosyl chloride 2f (1.5
mmol), fac[Ir(ppy)3] (1 mol %), MeCN (1.67 mL), distilled water
(0.33 mL), LED455 at room temperature.
B
DOI: 10.1021/acs.orglett.6b00734
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Organic Letters
Letter
a
1,2-disubstitution as well as various functional groups in the
aromatic moiety.
Scheme 4. Sequential Photocatalysis (One-Flask Synthesis)
In agreement with other reported sulfonyl radical additions
to alkenes,10 the limitation of the process was found with
aliphatic alkenes, which did not react at all. When cis-oleic acid
methyl ester was employed, no isomerization of the alkene
double bond was observed, indicating that the initial sulfonyl
radical addition to such alkenes might already be inefficient.
However, we recently reported the [Cu(dap)2Cl]-catalyzed,
visible light mediated ATRA reactions16 between alkenes and
CF3SO2Cl (E = −0.18 V versus SCE) under anhydrous
conditions,17 which surprisingly led to the formation of sulfonyl
chlorides,9 in contrast to the Ru(bpy)3Cl2-catalyzed processes
that resulted in chlorinated products.18 Along with the process
toward β-hydroxysulfones developed here, we explored the
possibility of coupling two photocatalytic sequences together.
Indeed, sulfonyl chlorides could be synthesized by the
[Cu(dap)2Cl]-catalyzed ATRA process followed by their
fac[Ir(ppy)3]-catalyzed addition to styrenes to yield 7a−d
(Scheme 3).
a
Reaction conditions: 1-hexene 5a (1.0 mmol), CF3SO2Cl (2.0
mmol), [Cu(dap)2Cl] (1 mol %), MeCN (1.67 mL), LED455 at room
temperature for 24 h then α-methylstyrene 1a (1.0 mmol, 1.0 equiv,
fac[Ir(ppy)3] (1 mol %), distilled water (0.33 mL), LED455 at room
temperature for 24 h.
a
Scheme 5. Synthesis of Vinyl Sulfones
a
Scheme 3. Sequential Photocatalysis (Two-Flask Synthesis)
a
Reaction conditions: 7b (0.5 mmol), Ac2O (1.0 mmol), DMAP (1.0
mmol, 2.0 equiv), DCM (7 mL), at room temperature for 60 h.
As a plausible reaction mechanism for the hydroxysulfony-
lation reaction, we propose the initial excitement of the Ir(III)
photoredox catalyst by irradiation with blue light to generate
excited *Ir(III). Single electron transfer to sulfonyl chloride 2
generates the corresponding sulfonyl radical I concurrent with
oxidation to Ir(IV). Regioselective sulfonyl radical I addition to
styrene 1 takes place to give the carbon-centered radical
intermediate II, which subsequently undergoes oxidation to
carbocation III by back-electron-transfer processes regenerating
the Ir(III). The resulting carbocation III is trapped by water
(Scheme 6). In agreement with this proposal, isotope labeling
showed that the oxygen of the hydroxyl group in compound 3fa
only originated from H2O18 (see the SI).
To summarize, we have developed a visible light mediated,
iridium(III)-catalyzed ATRA-like reaction for synthesis of β-
hydroxysulfone derivatives from readily available alkenes and
sulfonyl chlorides. In combination with the visible light
mediated copper(I)-catalyzed synthesis of trifluoromethyl-
substituted sulfonyl chlorides, two photochemical processes
a
Reaction conditions: (1) alkene 5 (1.0 mmol), CF3SO2Cl (2.0
mmol), K2HPO4 (2.0 mmol), [Cu(dap)2Cl] (1 mol %), MeCN (2
mL), LED455 at room temperature for 24 h; (2) α-methylstyrene 1a
(1.0 mmol), sulfonyl chloride 6 (1.5 mmol), fac[Ir(ppy)3] (1 mol %),
MeCN (1.67 mL), distilled water (0.33 mL), LED455 at room
temperature for 24 h.
Notably, each specific photocatalyst is required for the
individual steps of the sequence: When fac[Ir(ppy)3] is used in
an attempt to synthesize the sulfonyl chlorides 6a−d, net
addition of trifluoromethyl and chloride instead of sulfonyl
chloride is observed, while [Cu(dap)2Cl] was not sufficient for
the activation of 6a−d to engage in the coupling with styrenes
to give rise to the corresponding hydroxysulfones 7a−d
(Scheme 3).
Scheme 6. Proposed Reaction Mechanism
This sequence can also be run in a single flask without the
requirement of isolating the sulfonyl chlorides; for example, 7d
could be directly synthesized by first irradiating 5a and
CF3SO2Cl in the presence of [Cu(dap)2Cl] (1 mol %)
followed by the addition of water, α-methylstyrene (1a), and
fac[Ir(ppy)3] (1 mol %) (Scheme 4).
The resulting sulfones of this two-step sequence are obtained
as an equimolar mixture of diastereomers, reflecting the nature
of the two sequential radical addition processes. To arrive at
diastereomerically pure compounds, the hydroxysulfones can
be converted to vinylsulfones by a known procedure,19 as
demonstrated by the conversion of 7b to 8a (Scheme 5).
C
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Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00734.
(8) For leading reviews on photocatalysis, see: (a) Teply, F. Collect.
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Experimental procedures and spectral data (PDF)
Crystallographic data for 3m (CIF)
AUTHOR INFORMATION
Corresponding Author
■
(9) Bagal, D. B.; Kachkovskyi, G.; Knorn, M.; Rawner, T.; Bhanage,
*E-mail: oliver.reiser@chemie.uni-regensburg.de.
B. M.; Reiser, O. Angew. Chem., Int. Ed. 2015, 54, 6999−7002.
(10) Meyer, A. U.; Jager, S.; Prasad Hari, D.; Konig, B. Adv. Synth.
̈
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Notes
Catal. 2015, 357, 2050−2054.
The authors declare no competing financial interest.
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C. R. J. J. Am. Chem. Soc. 2012, 134, 8875−8884. (b) Jiang, H.; Chen,
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ACKNOWLEDGMENTS
This work was supported by DFG (Graduiertenkolleg 1626)
and the DAAD (fellowship for S.K.P.). We are also thankful to
■
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Reiser, O. Adv. Synth. Catal. 2014, 356, 2853−2858.
Dr. Michael Bodensteiner, Universitat Regensburg, for carrying
out the X-ray crystal structure analysis.
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