Transition-Metal-Free Arylations of In-Situ Generated Sulfenates with Diaryliodonium Salts

Article abstract of DOI:10.1021/acs.orglett.8b03046

A transition-metal-free arylation of sulfenate anions generated from β-sulfinyl esters with diaryliodonium salts was developed. In this process, a new C-S bond is formed under mild reaction conditions providing a wide range of S,S-diaryl and S-alkyl S-aryl sulfoxides.

Full text of DOI:10.1021/acs.orglett.8b03046

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Transition-Metal-Free Arylations of In-Situ Generated Sulfenates
with Diaryliodonium Salts
Hao Yu, Zhen Li, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University Landoltweg 1, 52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: A transition-metal-free arylation of sulfenate
anions generated from β-sulfinyl esters with diaryliodonium
salts was developed. In this process, a new C−S bond is
formed under mild reaction conditions providing a wide range
of S,S-diaryl and S-alkyl S-aryl sulfoxides.
ulfoxides are prevalent in natural products1 and have also
been applied as active ingredients in pharmaceuticals and
route e)11 and aryl 2-(trimethylsilyl)ethyl sulfoxides12 with
CsF (Scheme 1, route f)13 proved applicable, as demonstrated
by Perrio and Walsh, respectively. In both reactions the in-situ
formed sulfenates underwent palladium-catalyzed cross cou-
plings with aryl halides or triflates to give diaryl sulfoxides and
heteroaryl aryl sulfoxides. In light of this background and
noting the many advances in the development of transition-
metal-free C−C, C−N, C−O, and C−S bond-forming
processes,14 we wondered about a protocol for achieving
both sulfenate generation and consecutive aryl sulfoxide
formation without the presence of a transition metal catalyst.
The realization of this concept is reported here.
S
crop-protecting agents.2 Furthermore, sulfoxides serve as chiral
auxiliaries, ligands for metal complexes, and organocatalysts.3
Due to their importance, extensive research has been devoted
to the synthesis of sulfoxides, in particular those with S-aryl
groups.4 Along these lines, highly viable synthetic methods
based on palladium-catalyzed arylations of sulfenates (RSO−)
with aryl halides have emerged (Scheme 1).5 The pioneering
Scheme 1. Access to Diaryl Sulfoxides from Sulfenates
The key for establishing the new protocol was the use of
hypervalent iodine reagents,15,16 which have recently caught
significant attention as mild and environmentally benign agents
with high reactivity and wide tolerance of diverse functional
groups combined with good stability and low toxicity. Among
them, diaryliodonium salts are of particular interest, serving as
arylating agents in various transformations,17 including
transition-metal-free reactions. Here, we used them as an aryl
source at room-temperature couplings with in-situ generated
sulfenates to give aryl sulfoxides (Scheme 1, route g).
The initial reactivity search and subsequent optimization
study were carried out using β-sulfinyl ester 1a and
diphenyliodonium triflate (2a) as representative substrates.
To our disappointment, none of the expected product, p-tolyl
phenyl sulfoxide (3aa), was observed in toluene with Cs2CO3
as base (Table 1, entry 1). However, the reaction proceeded
well after replacing Cs2CO3 by KOH, providing 3aa in 84%
yield (Table 1, entry 2). This result could further be improved
by performing the coupling in a 1:1 solvent mixture of toluene
and water leading to 3aa in 98% yield (Table 1, entry 3).
Under these conditions, NaOH was less effective as base than
KOH, and the addition of tetra-n-butylammonium bromide
(TBAB) had no apparent impact on the reaction efficiency
(Table 1, entries 4 and 5).
work in this field stemmed from Poli, Madec, and co-workers,
who realized a smooth generation of the required anions by
base-mediated degradation of β-sulfinyl esters6 under biphasic
conditions (Scheme 1, route a).7 Alternatively, allyl sulfoxides
proved to be suitable sulfenate precursors (Scheme 1, route
b).8 In 2013, Nolan and co-workers used a well-defined Pd−
NHC complex for the formation of diaryl sulfoxides starting
from methyl aryl sulfoxides and aryl bromides or chlorides
(Scheme 1, route c).9 In the same year, Walsh and co-workers
applied aryl benzyl sulfoxides for palladium-catalyzed prepara-
tions of diaryl sulfoxides via the corresponding sulfenates
(Scheme 1, route d).10 Furthermore, tert-butyl sulfoxides in
combination with K3PO4 at elevated temperature (Scheme 1,
Received: September 24, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03046
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 3. Substrate Scope: Diaryliodonium Salts
entry
base
solvent
toluene
toluene
toluene/H2O
toluene/H2O
toluene/H2O
additive
yield (%)
1
2
3
4
5
Cs2CO3
KOH
KOH
NaOH
KOH
-
-
-
-
---
84
98
83
98
b
b
b
c
TBAB
a
Reaction conditions: 1a (0.20 mmol), 2a (0.22 mmol, 1.1 equiv); for
entry 1: Cs2CO3 (0.8 mmol, 4.0 equiv), for entries 2, 3, and 5: KOH
(50% aq. 20.0 equiv), and for entry 4: NaOH (30% aq, 20.0 equiv).
b
c
Ratio of 1:1. Use of 1.0 equiv.
a
Reaction conditions: 1a (0.20 mmol), 2 (0.22 mmol, 1.1 equiv),
Scheme 2 describes the scope of the arylation reaction with
respect to β-sulfinyl esters 1. For S-aryl derivatives, the
KOH (50% aq, 20.0 equiv), 1:1 toluene/H2O, at rt under argon for 24
h.
a
Scheme 2. Substrate Scope: β-Sulfinyl Esters
results for p-tert-butyl-containing derivative 3ac, which was
isolated in 97% yield. Applying halo-substituted iodine
reagents led to slightly lower yields, and thus, sulfoxides 3ae,
3af, and 3ag with p-fluoro, p-chloro, and p-bromo aryl groups
were obtained in only 86%, 72%, and 66% yield, respectively.
Product 3ah with two methyl substituents in the ortho and
para position was isolated in 80% yields. In general, however,
the presence of ortho substituents seemed to hamper the
reaction as indicated by the moderate yields for 3ai (50%) and
3aj (40%). The aryl transfer from di(2-thienyl) iodonium salt
2k was sluggish providing sulfoxide 3ak in only 19% yield.
A mechanistic proposal for the aforereported transition-
metal-free sulfoxide synthesis is presented in Scheme 4. Key
Scheme 4. Proposed Mechanism
a
Reaction conditions: 1 (0.20 mmol), 2a (0.22 mmol, 1.1 equiv),
KOH (50% aq, 20.0 equiv), 1:1 toluene/H2O, at rt under argon for 24
b
h. In parentheses: use of 1.0 mmol of 1a.
substitution pattern of the arene had no apparent influence on
the yield of the corresponding sulfoxides. In general, the yields
were high to excellent reaching up to 98%, with the exceptions
of products 3da, 3ha, and 3la, which were isolated in 82%,
80%, and 82% yield, respectively. Probably, the steric demand
of the aryl substituents (o-ethyl, p-tert-butyl, and o-aryl)
affected the reaction outcome, although this assumption can be
questioned considering the excellent results obtained in the
formation of ortho-substituted products 3ca and 3ja (98% yield
each). Also, sulfoxides with heteroatom-containing S-aryl
groups could be prepared as exemplified by the formation of
3ma and 3na, which were isolated in 98% and 95% yield,
respectively. β-Sulfinyl esters with aliphatic S substituents led
to sulfoxides in lower yields as observed in the synthesis of S-
isopropyl-bearing 3oa (42%) and S-benzyl-substituted 3pa
(70%).
steps, which proceed in sequence, are: First, a base-mediated
sulfenate formation by retro-Michael reaction of deprotonated
β-sulfinyl esters 1. Second, a ligand exchange at the
diaryliodonium salt with loss of triflate.18 Third, an aryl−
sulfenyl coupling with concomitant elimination of aryl iodide
to give the observed product. While every individual step in
this reaction path is supported by literature evidence,6−13,18 the
structural details of the newly formed iodine(III) intermediate
A remain unknown and shall be determined in future work.
To conclude, we developed a transition-metal-free sulfoxide
synthesis via in-situ generated sulfenates and their coupling
with diaryliodonium salts. The reaction conditions are mild,
and the functional group tolerance is broad. Considering the
accessibility of both reagents, we foresee applications in
agricultural and medicinal chemistry.
The scope of this reaction was further examined by testing a
range of diaryliodonium salts (Scheme 3). The coupling
partner was β-sulfinyl ester 1a. In this series, the yields of the
resulting sulfoxides varied significantly (19−97%). Para-
substituted diaryliodonium salts reacted well with the best
B
DOI: 10.1021/acs.orglett.8b03046
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03046.
■
S
General methods and analytical data including NMR
spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: carsten.bolm@oc.rwth-aachen.
ORCID
Carsten Bolm: 0000-0001-9415-9917
Notes
(9) Izquierdo, F.; Chartoire, A.; Nolan, S. P. ACS Catal. 2013, 3,
2190.
(10) (a) Jia, T.; Bellomo, A.; Montel, S.; Zhang, M.; El Baina, K.;
Zheng, B.; Walsh, P. J. Angew. Chem., Int. Ed. 2014, 53, 260. (b) Jia,
T.; Zhang, M.; Sagamanova, I. K.; Wang, C. Y.; Walsh, P. J. Org. Lett.
2015, 17, 1168.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
H.Y. thanks the China Scholarship Council for a predoctoral
stipend.
■
(11) Gelat, F.; Lohier, J.-F.; Gaumont, A.-C.; Perrio, S. Adv. Synth.
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V. P.; Punji, B. RSC Adv. 2013, 3, 11957. (c) Zhu, C.; Falck, J. R. Adv.
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DOI: 10.1021/acs.orglett.8b03046
Org. Lett. XXXX, XXX, XXX−XXX