Photoredox-Mediated Synthesis of Functionalized Sulfoxides from Terminal Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c02055

A photoredox-mediated protocol for the synthesis of α-alkoxy-β-ketosulfoxides and α,β-dialkoxysulfoxides using alkynes, thiol, and alcohols is reported. This work presents a rare single-step synthesis of α-substituted sulfoxides, involving tandem introduction of a thiol and alcohol as a key enabling advancement. Furthermore, the method can be easily employed to access vinyl sulfoxides and β-ketosulfoxides.

Full text of DOI:10.1021/acs.orglett.0c02055

pubs.acs.org/OrgLett
Letter
Photoredox-Mediated Synthesis of Functionalized Sulfoxides from
Terminal Alkynes
Jaswant Kumar,∥ Ajaz Ahmad,∥ Masood Ahmad Rizvi, Majid Ahmed Ganie, Chhavi Khajuria,
and Bhahwal Ali Shah*
Cite This: https://dx.doi.org/10.1021/acs.orglett.0c02055
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ABSTRACT: A photoredox-mediated protocol for the synthesis
of α-alkoxy-β-ketosulfoxides and α,β-dialkoxysulfoxides using
alkynes, thiol, and alcohols is reported. This work presents a rare
single-step synthesis of α-substituted sulfoxides, involving tandem
introduction of a thiol and alcohol as a key enabling advancement.
Furthermore, the method can be easily employed to access vinyl
sulfoxides and β-ketosulfoxides.
ulfoxides are valuable synthetic intermediates and a key
structural building block of a large number of naturally
S
occurring and pharmacologically active molecules such as
sulindac, mesoridazine, and sulfinpyrazone.1 Notably, sulfur is
the third most found heteroatom in FDA-approved drugs and
comprises one-fifth of the 200 most prescribed pharmaceutical
products.2 Conventionally, the synthesis of sulfoxides relies on
the oxidation of sulfides using strong/toxic oxidizing agents in
stoichiometric or excess amounts with associated side products
resulting from over or under oxidation.3 Furthermore, this
becomes even more challenging in cases where we may wish to
synthesize α-substituted sulfoxides, as their direct synthesis has
remained elusive so far. The only approach to access α-
substituted sulfoxides besides oxidation of sulfides involves
generation of an α-sulfinyl carbanion using a strong base for
attack on electrophilic centers, limiting them to α-alkyl
substitution.4 Despite these advances, and possibly due to
low bond dissociation energies of the C−S bond,5 the
synthesis of α-alkoxysulfoxides is hitherto unreported. Besides,
most of the work in the past has been around Pummerer
rearrangement, which is limited to the synthesis of α-
substituted sulfides (Figure 1).6 Moreover, the Pummerer
rearrangement requires multiple steps as alkyl sulfoxide is
typically its substrate, which requires further dehydration to
create a thionium ion for the addition of nucleophiles. In this
regard, previous reports7 including that from our group8 have
shown vinyl radicals emanating from radical additions where
thiyl radicals on alkynes can be utilized for diverse
functionalizations. Herein, we report a direct approach toward
the synthesis of α-alkoxy-β-ketosulfoxides and α,β-dialkoxysulf-
oxides via photoredox catalysis involving tandem diastereose-
lective introduction of two nucleophile, viz., alcohol and thiol.
The work is also significant from the perspective that geminal
difunctionalization of ketones is itself a challenging task, as
introduction of a second group requires a sequential
deprotonation for further enolization.9
Figure 1. Synthesis of substituted sulfoxides.
Furthermore, the reaction could be easily extended for the
synthesis of β-ketosulfoxides and vinyl sulfoxides in the
absence of a nucleophile, which as it turns out are substrates
for Pummerer reaction and in principle can be applied to
access a plethora of functionalized scaffolds.14b
Received: June 22, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02055
© XXXX American Chemical Society
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A

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Our efforts commenced with the reaction of phenylacetylene
(1) and 1-octanethiol (2) in the presence of Ru(bpy)3Cl2 as a
photocatalyst and DIPEA as a base (Table 1, entry 1). The
nucleophiles to afford products 21−25 in good yields.
Furthermore, acetic anhydride and propionic anhydride also
proved unproblematic under standardized reaction conditions
to give corresponding products 26 and 27 in good yields. The
above results reflect the broader applicability of this method in
terms of introducing different nucleophiles in the ketosulfoxide
framework. Next, we sought to examine the behavior of this
reaction with different aliphatic acetylenes. To our surprise, the
reaction of thiophenol with 1-octyne instead led to the
formation of α,β-dimethoxysulfoxide (28) in 64% yields. This
can possibly be explained based on the lower stability of the
vinyl radical in the case of aliphatic acetylenes rendering them
more reactive toward the thiol. The reaction was also feasible
with 1-heptyne and cyclopropyl acetylene to give correspond-
ing dimethoxy derivatives 29 and 30 in good yields. The
transformation was also expandable to various thiophenols like
4-tolyl, 4-F, 4-Cl, 4-Br, 4-ethyl, and 4-tert-butyl thiophenol to
yield corresponding sulfoxides 31−36 in 52−68% yields.
To gain mechanistic insights and further broaden the
substrate scope, we explored the reaction outcome in
acetonitrile. The reaction of phenylacetylene and thiophenol
pleasingly led to the synthesis of β-ketosulfoxide (37) in 67%
yields. To the best of our knowledge, this is first report for the
synthesis of β-ketosulfoxides from phenylacetylenes. Notably,
β-ketosulfoxides find extensive applications in the pharmaceut-
ical industry and synthetic organic chemistry as auxiliaries or
precursors for asymmetric synthesis.10,1a To establish the
generality and scope of this transformation, we carried out this
reaction with a range of alkynes and thiols. The reaction of
thiophenol proceeded smoothly with different halo-substituted
4-F, 3-Cl, and 3,5-difluoro phenylacetylenes to give corre-
sponding β-ketosulfoxides 38−40 in 65−68% yields. Likewise,
4-methyl, 4-propyl, 4-pentyl, 2,4,5-trimethyl, 4-tert-butyl, 4-
methoxy, and 4-CF3 phenylacetylene reacted efficiently with
thiophenol to generate corresponding sulfoxides 41−47 in
good yields. Furthermore, aliphatic acetylenes such as 1-
pentyne, 1-hexyne, 1-octyne, and 1-nonyne were also suitable
reactants, giving the desired products 48−51 in 54−61%
yields. Next, we screened different thiols for the synthesis of β-
ketosulfoxides. The phenylacetylene appeared as a suitable
reactant for the reaction with a variety of thiols such as 2-F, 2-
Br, 2,6-dichloro, 3-methyl, 4-methyl, 2,5-dimethyl, 4-ethyl, 3-
methoxy, and 4-tert-butyl thiophenol to yield the correspond-
ing products 52−60 in good yields. Aliphatic thiols like 1-
pentanethiol and 1-octanethiol also participated in the reaction
to produce the corresponding sulfoxides 61−62 in 56−58%
yields.
a
Table 1. Optimization of Reaction Conditions
a
entry
deviation from standard conditions
yield (%) of 3
1
2
3
4
5
6
7
8
9
none
70
31
53
39
traces
44
traces
38
pyridine instead of DIPEA
Et3N instead of DIPEA
NaOMe instead of DIPEA
Cs2CO3 instead of DIPEA
Mes-Acr+ClO4 as photocatalyst
eosin-Y as photocatalyst
−
Rose Bengal as photocatalyst
no photocatalyst, light, or base
n.d.
a
Reaction conditions: phenylacetylene (1, 1 mmol), 1-octanethiol (2,
1.5 mmol), photocatalyst (1 mol %), base (0.5 mmol), MeOH (1
mL), irradiation under air atmosphere, blue LEDs, room temperature:
25 °C, time: 4 h.
irradiation of the reaction mixture under blue LEDs in MeOH
as solvent led to the formation of α-methoxy-β-ketosulfoxide
(3) in 70% yield. To study the behavior of the reaction, various
bases as well as photocatalysts were also screened. The reaction
in the presence of pyridine, Et3N, NaOMe, and CS2CO3 did
not improve the yields (Table 1, entries 2−5). The use of Mes-
Acr+ClO4 gave the corresponding sulfoxide in 44% yield
−
(Table 1, entry 6), whereas trace amounts of product were
observed in the presence of eosin-Y and Rose Bengal (Table 1,
entries 7 and 8). Furthermore, control experiments established
the importance of photocatalyst, light source, and base, as
negligible or no product formation was observed in the
absence of these entities (Table 1, entry 9).
Having conditions optimized, we then proceeded for the
evaluation of substrate scope of the reaction with a range of
alkynes, thiols, and alcohols (Scheme 1). A wide range of
phenylacetylenes served as suitable coupling partners with 1-
octanethiol. The reaction with various halo-substituted phenyl-
acetylenes like 4-fluoro, 3-chloro, 4-bromo, and 3,5-difluoro
gave corresponding α-methoxy-β-ketosulfoxides 4−7 in 53−
62% yields. The electron-deficient 4-trifluoromethyl-substi-
tuted phenylacetylene also reacted to produce compound 8 in
51% yield. The electron-rich phenylacetylenes bearing 4-ethyl,
4-propyl, 4-pentyl, 4-tert-butyl, and 4-methoxy substituents
participated efficiently in this three-component reaction to
generate the corresponding sulfoxides 9−13 in 54−61% yields.
In addition, various aliphatic thiols like 1-hexanethiol, 1-
pentanethiol, and 1-butanethiol showed good reactivity to
yield products 14−16 in 66−70% yields. A range of
thiophenols bearing functional groups like 4-methoxy, 2,5-
dimethyl, and 3-Br thiophenol generated the corresponding
products 17−19 in good yields.
Next, we sought to study the fate of reaction in water. We
were pleased to see that the reaction of phenylacetylene and
thiophenol in water led to the formation of vinyl sulfoxide 63
in 52% yield (Scheme 2). 1-Hexyne and cyclopropyl acetylene
were also used for the synthesis of vinyl sulfoxides 64−65 in 51
and 55% yields, respectively. Moreover, phenylacetylene as
well as various substituted phenylacetylenes such as 4-pentyl,
4-tert-butyl, 4-propyl, and 4-methoxy phenylacetylene reacted
efficiently with 1-octanethiol to give a range of vinyl sulfoxides
66−70 in good yields.
In order to gain further insights into the mechanism,
additional experiments were carried out. As depicted when
TEMPO was used as a radical scavenger under standard
reaction conditions, the reaction was completely inhibited. The
use of benzoquinone as a scavenger of superoxide radical also
resulted in almost complete inhibition of the reaction.11
Encouraged by these transformations, we became intrigued
to explore the feasibility of the reaction with other alcohols. To
our delight, replacement of methanol as a solvent by ethanol
resulted in the formation of the ethoxy-substituted product 20
in 58% yield. Even isopropanol, trifluoroethanol, methanol-d4,
phenol, and benzyl alcohol proved to be competent
B
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a
Scheme 1. Substrate Scope for the Synthesis of α-Alkoxy-β-ketosulfoxides and α,β-Dimethoxysulfoxides
a
Note: (i) alkyne (1 mmol), thiol (1.5 mmol), alcohol: as a solvent. (ii) Reaction of phenol was carried out in water.
Furthermore, we could observe product in trace amounts only
under an argon (degassed) atmosphere or in the absence of
light or without catalyst. The 18O-labeling experiment with
isotope-labeled water (H218O) was performed to determine the
source of oxygen in sulfoxide (see Supporting Information).
The results show that the oxygen is sourced from air in the
reaction.8a,17a The photoluminescence quenching studies of
the [Ru(bpy)3]Cl2 photocatalyst with all the reaction
ingredients were analyzed using the Stern−Volmer model.
Among the various possible quenchers in the reaction system,
the photoluminescence of [Ru(bpy)3]Cl2 was efficiently
quenched by thiophenol in methanol solvent, supporting the
proposed thiyl radical path as a probable SET mechanism (see
Supporting Information). Based on control experiments and
literature precedence, a plausible reaction mechanism is
depicted in Scheme 3.
The photoexcited [Ru]2+* generated from [Ru]2+ under
blue LEDs irradiation undergoes reductive quenching with
thiophenol to give a thiyl radical cation that deprotonates in
the presence of a peroxy radical anion to give thiyl radical I.12
The [Ru]2+ is regenerated by molecular oxygen.13 This is
followed by the addition of a thiyl radical to the alkyne 1 to
give vinyl radical adduct II,14 which can possibly follow two
different paths. For the formation of α-methoxy-β-ketosulf-
oxides, the vinyl radical on hydroperoxide insertion gives
peroxy intermediate III, which on subsequent peroxide
cleavage15 produces β-ketosulfide V. An electron transfer
between the photoexcited [Ru]2+* generates radical cation VI,
C
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Scheme 2. Substrate Scope for the Synthesis of β-
Scheme 3. Plausible Mechanism
Ketosulfoxides and Vinylsulfoxides
which a lone pair is antiperiplanar to the heteroatom is
preferred because of the stabilizing interaction (hyper-
conjugation) between the unshared electron pair and the σ*-
orbital of the C−O bond. Notably, in the case of α,β-
dimethoxysulfoxides the predominant isomer is possibly anti,
as there is a sufficient upfield shift of the β-carbon. This can be
because of the γ-gauche effect, according to which the upfield
shift is only observed for that γ-gauche position, in which the
respective β-carbon is anti to the sulfoxides-sulfur lone pair,
while the carbons which are synclinal to sulfoxide lone pair are
not affected.20b
In summary, a new photocatalytic strategy to introduce
diverse alkoxide functionalities into the α- and β-position of
sulfoxides using Ru(bpy)3Cl2 as a photocatalyst has been
developed. The protocol presents a remarkable tandem
introduction of two nucleophiles, viz., alcohol and thiol, as a
key to enabling advancement. Moreover, it uses atmospheric
oxygen for the oxidation of sulfides to sulfoxides, thereby
circumventing the requirement of any external oxidizing
agents. Further development of related radical reactions,
including catalytic versions mediated by photocatalysts, is
currently under investigation in our laboratory.
which on loss of a proton in the presence of base gives radical
intermediate VII. The radical intermediate VII is available for
another electron transfer with [Ru]2+* to give thionium
intermediate VIII, which on nucleophilic attack at the α-
position produces α-methoxy-β-ketosulfide intermediate IX.
The intermediate IX in the presence of [Ru]2+* gives radical
cation X,16 which reacts with the oxygen radical anion to
produce persulfoxide intermediate XI. The intermediate XI
consequently delivers the α-methoxy-β-ketosulfoxide with
another sulfide IX.17 The base-H (DIPEA) in the reaction is
possibly regenerated while donating its proton to persulfoxide
intermediate XI. The intermediate VI in the absence of
nucleophiles undergoes sensitized photooxidation with dioxy-
gen, producing β-ketosulfoxide. In the case of aliphatic alkynes,
we believe due to less stability of the vinyl radical that a
hydrogen atom transfer (HAT) between the vinyl radical and
thiol is more favored to produce vinyl sulfide and a thiyl
radical.18 The vinyl sulfide IV on photooxidation with
dioxygen leads to the formation of alkenylsulfoxides. The
alkenyl sulfoxides can undergo Pummerer reaction19 in the
presence of a nucleophile at α and β positions to give α,β-
dimethoxy sulfide XIV which on photooxidation with dioxygen
gives α,β-dimethoxysulfoxides. The diastereoselective forma-
tion of α-methoxy-β-ketosulfoxide may be attributed to
Gauche effects.20a Out of various possible conformations of
the α-methoxy-β-ketosulfide radical cation (X), the one in
ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02055.
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1
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AUTHOR INFORMATION
Corresponding Author
■
Bhahwal Ali Shah − AcSIR and Natural Product Microbes,
CSIR-Indian Institute of Integrative Medicine, Jammu 180001,
Jammu and Kashmir; orcid.org/0000-0001-6629-0002;
Email: bashah@iiim.ac.in
Authors
Jaswant Kumar − AcSIR and Natural Product Microbes, CSIR-
Indian Institute of Integrative Medicine, Jammu 180001,
Jammu and Kashmir
Ajaz Ahmad − AcSIR and Natural Product Microbes, CSIR-
Indian Institute of Integrative Medicine, Jammu 180001,
Jammu and Kashmir
Masood Ahmad Rizvi − Department of Chemistry, University of
Kashmir, Srinagar 190006, Jammu and Kashmir
Majid Ahmed Ganie − AcSIR and Natural Product Microbes,
CSIR-Indian Institute of Integrative Medicine, Jammu 180001,
Jammu and Kashmir
Chhavi Khajuria − AcSIR and Natural Product Microbes,
CSIR-Indian Institute of Integrative Medicine, Jammu 180001,
Jammu and Kashmir; Department of Chemistry, Guru Nanak
Dev University, Amritsar, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02055
Author Contributions
∥J.K. and A.A. contributed equally to this work.
(11) (a) Bonesi, S. M.; Manet, I.; Freccero, M.; Fagnoni, M.; Albini,
A. Chem. - Eur. J. 2006, 12, 4844. (b) Hayyan, M.; Hashim, M. A.;
AlNashef, I. M. Chem. Rev. 2016, 116, 3029.
Notes
(12) Tyson, E. L.; Ament, M. S.; Yoon, T. P. J. Org. Chem. 2013, 78,
2046.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
B.A.S. thanks CSIR for a Young Scientist Award Grant (P-81-
113) and DBT (1151/2016), New Delhi, for financial
assistance. J.K. and M.A.G. thank CSIR for fellowship.
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