Tert-butyl phenyl sulfoxide: A traceless sulfenate anion precatalyst

Article abstract of DOI:10.1021/acs.orglett.5b00117

tert-Butyl phenyl sulfoxide is employed as a traceless precatalyst for the generation of sulfenate anions under basic conditions and has been used to catalyze the coupling of benzyl halides to trans-stilbenes. The advantage of this precatalyst over previous precatalysts is that the byproduct generated on catalyst formation is a gas, facilitating product isolation in high purity. Using this second generation catalyst, a variety of trans-stilbenes were generated in 39-98% isolated yield.

Full text of DOI:10.1021/acs.orglett.5b00117

Letter
pubs.acs.org/OrgLett
tert-Butyl Phenyl Sulfoxide: A Traceless Sulfenate Anion Precatalyst
Mengnan Zhang,† Tiezheng Jia,† Irina K. Sagamanova,‡ Miquel A. Pericas,‡,§ and Patrick J. Walsh*,†
́
†Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
‡Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
§Departament de Química Organica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
S
* Supporting Information
ABSTRACT: tert-Butyl phenyl sulfoxide is employed as a
traceless precatalyst for the generation of sulfenate anions
under basic conditions and has been used to catalyze the
coupling of benzyl halides to trans-stilbenes. The advantage of
this precatalyst over previous precatalysts is that the byproduct
generated on catalyst formation is a gas, facilitating product
isolation in high purity. Using this second generation catalyst, a
variety of trans-stilbenes were generated in 39−98% isolated yield.
ulfenate anions and their conjugate acids, sulfenic acids
(Figure 1), are highly reactive intermediates in
As proof of concept, benzyl phenyl sulfoxide was applied as
a precatalyst in coupling of benzyl halides to form
symmetrical trans-stilbenes under basic conditions (Scheme
2).5 In this process, a variety of trans-stilbenes could be
prepared in good to excellent yields with catalyst loadings as
low as 2 mol %.
The proposed mechanism for the sulfenate anion-catalyzed
coupling of benzyl halides is illustrated in Scheme 2.
Beginning with benzyl phenyl sulfoxide (A), deprotonation
by KOtBu generates the anion (B), which was demonstrated
to be the catalyst resting state. The anion B undergoes
nucleophilic substitution with benzyl halide (C) to form
S
biochemistry1 and organic synthesis.2 In organic chemistry,
sulfenate anions can be trapped with alkyl halides to afford
sulfoxides. We,3 and others,4 have recently developed methods
to arylate sulfenate anions with aryl halides under palladium
catalysis to afford aryl sulfoxides. Our approach (Scheme 1)
begins with aryl benzyl sulfoxides, which undergo an initial α-
arylation under basic conditions to generate diarylmethyl aryl
sulfoxides. The palladium catalyst next promotes the cleavage
of the C−S bond to liberate the sulfenate anion, which is
arylated in the third catalytic cycle. In this process the
sulfenate anion behaves as a leaving group in the second cycle
and as a nucleophile in the third cycle.3 Inspired by the ability
of sulfenate anions to behave as both leaving groups and
nucleophiles in the tricatalytic cycle in Scheme 1, we
recognized their potential to act as organocatalysts. No
examples of sulfenate anion catalysts were previously known.
Scheme 2. Proposed Mechanism for Sulfenate Anion
Catalyzed trans-Stilbene Formation from Benzyl Halides
Figure 1. Sulfenic acid and its conjugate base, sulfenate anion.
Scheme 1. Palladium Promotes the Tricatalytic Cycle with
Sulfenate Anion as the Leaving Group in the Second Cycle
and Nucleophile in the Third Cycle
Received: January 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
sulfoxide D. Deprotonation of the β-position of D is followed
by elimination to generate the double bond in E with very
high trans selectivity and the sulfenate anion F. A rather
serious limitation to use of benzyl phenyl sulfoxide (A) as
precatalyst is that the first turnover installs a phenyl group on
the trans-stilbene. In cases where the benzylic halide (C) is
other than benzyl chloride or bromide, the first cycle forms an
unsymmetrical stilbene (PhCHCHAr, E′) that is usually
difficult to separate from the desired symmetric trans-stilbene,
ArCHCHAr (E). To make the sulfenate anion catalyzed
synthesis of trans-stilbenes more attractive, we envisioned
entry into the catalytic cycle at the sulfenate anion, F.
Herein, we report a second-generation sulfenate anion
catalyst that avoids contamination of the first cycle. The
precatalyst, tert-butyl phenyl sulfoxide, undergoes base
promoted elimination to generate phenyl sulfenate anion
and isobutylene as a gaseous byproduct (Scheme 2).
conditions yielded 69% trans-stilbene (entry 4). Lowering
the coupling temperature to 50 °C resulted in formation of
the product with 94% assay yield (entry 5). Finally, we found
that lowering the base loading to 2.0 equiv provided a slightly
higher yield (96%) of trans-stillbene under more economical
conditions (entry 6). Unfortunately, attempts to increase the
reaction concentration from 0.1 to 0.2 M led to increased tert-
butyl phenyl ether (entry 7). The assay yield remained at 96%
when the coupling time was cut to 6 h (entry 8 vs 6). Further
decreasing the coupling time to 4 h caused a drop in the assay
yield to 88% (entry 9). Therefore, the optimized reaction
conditions for tert-butyl phenyl sulfoxide catalyzed trans-
stilbene formation from benzyl halides is 2.5 mol %
precatalyst and 2.0 equiv of KOtBu in CPME preheated at
110 °C for 30 min, followed by addition of benzyl chloride
and heating at 50 °C for 6 h.
The most surprising finding during the optimization process
is that the sulfenate anion, generated at 110 °C, seems to be
stable under these conditions in the absence of trapping
reagents, at least for short periods of time.7
To explore the use of tert-butyl phenyl sulfoxide as
precatalyst, we initially employed conditions for our catalytic
coupling of benzyl chlorides using KOtBu and benzyl phenyl
sulfoxide precatalyst at 80 °C for 12 h. Under these
conditions, tert-butyl phenyl sulfoxide (2.5 mol %) afforded
only 33% assay yield of trans-stilbene (Table 1, entry 1). The
With the optimized conditions in hand, we set out to
explore the substrate scope. In general, benzyl chloride
derivatives are better substrates than benzyl bromides because
the latter undergo more rapid SN2 reactions with the base to
generate benzyl tert-butyl ethers. To compensate for the
increased reactivity of benzyl bromide derivatives, 5 mol %
precatalyst loading was employed with these substrates. Benzyl
chloride and bromide gave trans-stilbene (2a) in 94% and
76% yield, respectively. Benzyl chlorides with substituents at
para position (2b, 2d, 2e, and 2f) were found to give higher
yields at 80 °C and in some cases with 3.0 equiv of base (1b
and 1d) (Scheme 3). Electron-donating groups increased the
pKa of the benzylic protons of intermediates A and D
(Scheme 2) making them more difficult substrates. For
example, only 71% of 2b was obtained. Substrates bearing
electron withdrawing groups were better coupling partners.
For example, 4,4′-difluorostilbene (2d), 4,4′-dichlorostilbene
(2e), and 4,4′-dibromostilbene (2f) were produced in 60−
97% yield. Compounds 2e and 2f could be easily elaborated
by standard cross-coupling methods. More sterically hindered
substrates, such as 2-methyl benzyl chloride (1h) and 1-
(chloromethyl)naphthalene (1i), afforded 2h and 2i in 86%
and 85% yields, respectively. Diortho-substituted 2,6-dichlor-
obenzyl chloride was an excellent substrate, leading to trans-
stilbene 2j in 98% yield. Benzyl halides substituted at the
meta position with Me, F, or CF3 group were good substrates,
giving 2k, 2l, and 2m in 89%, 89% and 84% yield,
respectively. Heterocycle-containing stilbenes usually exhibit
interesting photochemistry properties, but are more challeng-
ing to synthesize.8 Heterocyclic 2-(chloromethyl)pyridine did
not couple under our optimized conditions. Using non-
nucleophilic KH, however, generated the product 2n, but only
in 39% yield.
Table 1. Optimization of Sulfenate Anion Catalyzed trans-
a
Stilbene (2a) Formation from Benzyl Chloride (1a)
b
KOtBu
(equiv)
catalyst
(mol %)
temperature
time
(h)
yield
(%)
entry
(°C)
1
2
3.0
3.0
3.0
3.0
3.0
2.0
2.0
2.0
2.0
2.5
2.5
2.5
1.0
2.5
2.5
2.5
2.5
2.5
80
12
12
12
12
12
12
12
6
33
c
80
43
97
69
94
96
90
d
3
110 → 80
110 → 80
110 → 50
110 → 50
110 → 50
110 → 50
110 → 50
d
4
d
5
d
6
d
d
d
,e
7
8
9
f
96 (94 )
88
4
a
Reactions performed using 1.0 equiv of 1a on a 0.2 mmol scale in
b
1
CPME. Crude yield determined by H NMR using 0.1 mmol of
CH2Br2 as internal standard. Before benzyl chloride was added, base
and precatalyst were preheated at 80 °C for 30 min. Before benzyl
c
d
chloride was added, base and precatalyst were preheated at 110 °C for
e
f
30 min. 0.4 mmol of 1a. Isolated yield.
low yield was due to the reaction of benzyl chloride with
KOtBu via a SN2 process to generate benzyl tert-butyl ether.6
We hypothesized that the low conversion to the desired
stilbene was due to the slower E2 elimination of tert-butyl
phenyl sulfoxide. To address this issue, we conducted the
reaction in two stages. First, the precatalyst tert-butyl phenyl
sulfoxide was heated with 3 equiv of KOtBu in CPME at 80
°C for 30 min before addition of benzyl chloride for the
coupling. The assay yield of trans-stilbene (2a) increased to
43% (entry 2). Elevating the preheating temperature to 110
°C followed by cooling the reaction mixture, addition of
benzyl chloride and heating to 80 °C for the coupling led to
97% assay yield of trans-stilbene (entry 3). Decreasing the
catalyst loading to 1 mol % under otherwise identical
To demonstrate the potential utility of this approach, we
performed the coupling of 1-(chloromethyl)naphthalene (1i,
8.4 mmol, 1.48 g) to the trans-stilbene (2i) in 88% yield
(Scheme 4), suggesting the reaction is scalable.
In summary, trans-stilbenes are widely used as industrial
dyes, laser-dyes, and optoelectronic materials,9 and significant
effort has been devoted to their synthesis.10−14 We have
developed an organocatalytic method for their preparation
that addresses a deficiency in our prior precatalyst, wherein a
catalytic amount of an inseparable impurity was generated in
B
DOI: 10.1021/acs.orglett.5b00117
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Substrate Scope of Stilbene Formation from
Benzyl Halides Catalyzed by Sulfenate Anions
ASSOCIATED CONTENT
■
S
* Supporting Information
Procedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pwalsh@sas.upenn.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation [CHE-1152488]
and National Institutes of Health (NIGMS 104349). I.K.S.
and M.A.P. thank the Spanish MINECO (grant CTQ2012-
38594-C02-01) and the Institute of Chemical Research of
Catalonia (ICIQ) Foundation for financial support.
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