Tert-Butyl Sulfoxides: Key Precursors for Palladium-Catalyzed Arylation of Sulfenate Salts

Article abstract of DOI:10.1002/adsc.201500368

The present report describes an efficient and clean generation of sulfenate salts (R¹SO^-) by pyrolysis of readily available tert-butyl sulfoxides to give sulfenic acids (R¹SOH) and traceless isobutene, followed by hydrogen abstraction with a weak inorganic base (K₃PO₄). The relevance of this process was exemplified through an in situ palladium-catalyzed cross-coupling reaction with aryl halides/triflates leading to aryl sulfoxides. The operationally simple C-S bond-forming protocol developed uses Pd(dba)₂ as catalyst and Xantphos as ligand in toluene or a toluene/H₂O mixture. Further extensions include the use of di-tert-butyl sulfoxide as an equivalent for sulfur monoxide dianion (SO^2-) and the development of diastereoselective versions in the [2.2]paracyclophane and biaryl series.

Full text of DOI:10.1002/adsc.201500368

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DOI: 10.1002/adsc.201500368
tert-Butyl Sulfoxides: Key Precursors for Palladium-Catalyzed
Arylation of Sulfenate Salts
Fabien Gelat,a Jean-FranÅois Lohier,a Annie-Claude Gaumont,a
and StØphane Perrioa,*
a
Normandie UniversitØ, Laboratoire de Chimie MolØculaire et Thioorganique, UMR CNRS 6507, INC3M, FR 3038,
ENSICAEN & UniversitØ de Caen Basse-Normandie, 14050 Caen, France
Fax: (+33)-2-3145-2865; phone: (+33)-2-3145-2884; e-mail: stephane.perrio@ensicaen.fr
Received: April 14, 2015; Revised: May 21, 2015; Published online: June 10, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500368.
Abstract: The present report describes an efficient
and clean generation of sulfenate salts (R1SOÀ) by
pyrolysis of readily available tert-butyl sulfoxides to
give sulfenic acids (R1SOH) and traceless isobu-
tene, followed by hydrogen abstraction with a weak
inorganic base (K3PO4). The relevance of this pro-
cess was exemplified through an in situ palladium-
catalyzed cross-coupling reaction with aryl halides/
triflates leading to aryl sulfoxides. The operationally
the reaction of a sulfur nucleophile, i.e., a sulfenate
salt (R1SOÀ),[5] with an electrophilic carbon centre.
3
À
The construction of C(sp ) S bonds is quite classical
and takes advantage of the nucleophilic substitution
with alkyl halides.[6] C(sp ) S bonds can also be
2
À
formed through Pd-catalyzed cross-coupling reactions
with aryl halides but the examples remain scarce.[7–10]
This organometallic approach relies on an efficient
catalytic system,[11] but also on an appropriate method
for the generation of the highly reactive and transient
sulfenate derivatives, from a limited set of stable and
well-defined sulfoxides (Figure 1). Pioneering work of
Poli involved b-sulfinyl esters[7] and allyl sulfoxides,[8]
the sulfenates being released by a retro-Michael reac-
tion and a Mislow–Braverman–Evans rearrangement,
respectively. Nolan[9] and Walsh[10] reported later the
use of methyl and benzyl sulfoxides. With these inacti-
vated precursors, the sulfenate liberation is sophisti-
cated from a mechanistic point of view. It is promoted
by the Pd catalyst itself and also the sacrifice of one
equivalent of the electrophilic component. Even if
these reports are a real breakthrough for this chemis-
try, it is clear that arylation of sulfenates is still in its
À
simple C S bond-forming protocol developed uses
Pd(dba)2 as catalyst and Xantphos as ligand in tolu-
ene or a toluene/H2O mixture. Further extensions
include the use of di-tert-butyl sulfoxide as an
equivalent for sulfur monoxide dianion (SO2À) and
the development of diastereoselective versions in
the [2.2]paracyclophane and biaryl series.
Keywords: cross-coupling; diastereoselectivity; pal-
ladium; sulfenate salts; sulfoxides
Sulfoxides represent an important class of compounds infancy. For instance, no diastereoselective variant in-
that are widely employed as building blocks, chiral volving a chiral sulfenate has been described so far.[12]
auxiliaries or ligands in catalysis.[1] Furthermore, this We wish to present herein the results of our investiga-
sulfur functional group is present in some natural tions, which led to the development of a conceptually
products[2] or pharmaceuticals, the most notable ex- different approach to sulfenate salts from another
ample being the anti-ulcer agent esomeprazole.[3] type of inactivated sulfoxide, and suitable for a subse-
Conventional routes for the preparation of sulfoxides quent Pd-catalyzed arylation process.
fall in two categories,[4] namely (i) creation of the S
O bond by oxidation of the parent thioethers or (ii)
À
À
C S bond construction through the nucleophilic dis-
placement of a leaving group from an enantiopure
sulfinyl derivative by organometallic species (the An-
dersen approach).
An original and attractive alternative in C S bond
formation, based on the reversal of polarity of both
À
Figure 1. Precursors of sulfenates used in Pd-catalyzed aryla-
reaction partners, has emerged recently. It involves tion.
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Fabien Gelat et al.
Table 1. Optimization of cross-coupling conditions with
sulfenate precursor 1a.[a]
Figure 2. Sulfenates from tert-butyl sulfoxides and subse-
quent Pd-mediated arylation.
The basis for our work was the well-established
thermal fragmentation of sulfoxides possessing a hy-
drogen atom in the beta-position to furnish a sulfenic
acid and an alkene.[13] Among the plethora of sub-
stituents fulfilling this criterion, the tert-butyl group[14]
was identified as an appealing candidate (Figure 2).[15]
It offers a good compromise between the robustness
of the corresponding precursors 1 and the fragmenta-
tion temperature. Furthermore, the liberated olefin is
gaseous isobutene, which would be readily removed
from the reaction medium. A direct consequence
would be a limited number of side products and
hence an easier final purification. We believed then
that, in the presence of a base, hydrogen abstraction
of the sulfenic acid should occur.[16] The resulting
sulfenate could then enter in a classical catalytic
cycle, through a ligand substitution step, and furnish,
after reductive elimination, the anticipated aryl sulf-
oxide 2. Additional features would include (i)
a straightforward access to the precursors 1,[4] with re-
spect also to enantiopure substrates, from readily
available sulfur-based reagents such as the parent
thiols or tert-butyl tert-butanethiosulfinate (Ellmanꢁs
thiosulfinate), and (ii) compatibility with a weak inor-
ganic base (pKa value of about 6–7 for sulfenic
acid)[5b,17] and a stoichiometric amount of the electro-
phile. The overall sequence is however quite challeng-
Entry
[Pd]
Ligand
Base
Yield [%][b]
1
2
3
4
5
6
7
8
Pd2(dba)3
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
L1
L1
L1
L1
L1
L2
L3
L4
KOHaq
KOHaq
NaOH
K2CO3
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4aq
NaOHaq
52
82
32
90
95
9
0
19
<5
6
37
53
65
31
9
L5
10
11
12
13
14
L6
L7[c]
L8[c]
L8[c]
L8[c]
[a]
Reactions carried out on a 0.5 mmol scale. Conditions
(unless otherwise mentioned): sulfoxide 1a (1 equiv.), PhI
(1.2 equiv.), [Pd] (0.05 equiv.), ligand (0.1 equiv.), base
(2 equiv.), degassed PhMe (1 mL), 1008C, 15 h.
Isolated yield.
[b]
[c]
Monodentate ligands (0.2 equiv.).
ing. A nice balance between each step is crucial to lideneacetone) combination with aqueous KOH in
avoid accumulation of the highly reactive entities, toluene led to the anticipated phenyl sulfoxide 2a in
which are produced, that is, the sulfenic acid[18] and its a 52% yield, thus validating our concept (entry 1). A
salt.
significant improvement with an 82% yield was ob-
The validity of the strategy was first examined with served by switching Pd2(dba)3 to Pd(dba)2 as the
the formation of p-tolyl phenyl sulfoxide 2a. Optimi- metal source (entry 2).[19] Replacing KOH by solid
zation was carried out on a 0.5 mmol scale with p- NaOH afforded a disappointing result (32% yield,
tolyl sulfoxide 1a and iodobenzene (1.2 equiv.) in tol- entry 3). Contrarily, both K2CO3 and K3PO4 were
uene solution. The temperature was fixed at 1008C shown to be appropriate inorganic bases under anhy-
according to preliminary tests, which indicated com- drous conditions, a nice 95% yield being observed
plete disappearance of 1a in a reasonable reaction with the phosphate salt (entries 4 and 5). A screening
time (<15 h). The influence of a range of reaction pa- of ligands with the related electron-rich phosphines
rameters was next examined, including the nature of L2 and L3 failed completely (entries 6 and 7). A simi-
the palladium source, the base and the phosphine lar outcome was obtained with BINAP, dppf and
ligand. Selected conditions are listed in Table 1. Use dppb (yields: <19%, entries 8–10). Finally, interesting
of the Pd2(dba)3/Xantphos (dba=trans,trans-dibenzy- but not optimal results were obtained with the Buch-
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tert-Butyl Sulfoxides: Key Precursors for Palladium-Catalyzed Arylation
Table 2. Scope of sulfenate precursors.[a]
pling was repeated at 1008C in a toluene/water mix-
ture (ratio 2:1). Pleasingly, a dramatic effect on the
overall process efficiency was observed (entries 8–10),
the aryl targets 2h–j being isolated in excellent yields
(79–91%). This result could be interpreted by a faster
deprotonation of the sulfenic acids in the presence of
water. In addition, the methodology also offered an
access to ferrocene 2k[22] via an unprecedented metal-
locenyl sulfenate species (entry 11). Although even
more challenging, the application of the methodology
to the aliphatic series afforded the expected arylation
products, but in lower yields (entries 12 and 13).
Indeed, the reaction was very slow and more than
3 days were required to observe disappearance of pre-
cursors 1l and 1m. Nevertheless, despite this extended
reaction time, benzyl sulfoxide 2l was produced in
a 40% yield (entry 12). A drop to 19% yield was ob-
served for methyl compound 2m (entry 13).
We then explored the scope of the reaction with
other electrophiles (Table 3). Bromobenzene was
found to be a suitable reaction partner (95% yield,
entry 1), whereas no coupling product[23] was pro-
duced when moving to the less reactive chloro ana-
logue (entry 2). Reaction with para-trifluoroiodoben-
zene took place in a nice 87% yield (entry 3).[24] 2-Io-
donaphthalene, 4-acetyl- and 4-methoxycarbonylbro-
mobenzenes, participate also efficiently to afford the
Entry R1
Temp. [8C] Time [h] 2
Yield [%][b]
1
2
3
4
5
6
7
8
4-Tol
Ph
2-naphthyl 90
100
90
15
36
36
15
15
15
15
15
15
15
24
72
144
2a 95
2b1 99
2c 99
2d 90
2e 93
2f 91
2-thienyl
110
4-F3CC6H4 90
4-MeOC6H4 110
3-MeOC6H4 110
2-MeOC6H4 110
2-MeC6H4
2-F3CC6H4 110
ferrocenyl
Bn
Me
2g 89
2h 47 (91)[c]
9
110
2i
50 (81)[c]
10
11
12
13
2j 21 (79)[c]
120
110
110
2k 65[d]
2l
40
2m 19
[a]
Reactions carried out on a 0.5 mmol scale. Conditions
(unless otherwise mentioned): sulfoxide 1 (1 equiv.), PhI
(1.2 equiv.), Pd(dba)2 (0.05 equiv.), Xantphos (0.1 equiv.),
K3PO4 (2 equiv.), degassed PhMe (1 mL).
Isolated yield.
In brackets yields with the addition of degassed H2O
(0.5 mL) at 1008C.
In degassed xylenes (1 mL) in the presence of Pd(dba)2
(0.1 equiv.) and Xantphos (0.2 equiv.).
[b]
[c]
[d]
Table 3. Scope of the (pseudo)halides.[a]
wald-type monodentate ligands SPhos and XPhos (en-
tries 11–14). To summarize this preliminary investiga-
tion, optimal reaction conditions involve a combina-
tion of Pd(dba)2 and Xantphos (5 and 10 mol%, re-
spectively), K3PO4 as a base and toluene as solvent.
Sulfoxide 2a was thus obtained after an overnight re-
action in an excellent 95% yield.[20]
With optimal conditions in hands, the scope of the
methodology was examined using a variety of sulfen-
ate precursors 1.[21] The results are collected in
Table 2. Yields above 89% were obtained with various
phenyl substrates displaying substituents in meta or
para position, as well as naphthalene and thiophene
derivatives (entries 1–7).
In contrast, a significantly lower efficiency of the
process was observed with an ortho substitution
(yields <50%, entries 8–10). Careful examination of
the crude mixtures indicated total disappearance of
the precursors, along with significant amounts of
sulfur-containing side products. We reasoned that,
with these more hindered ortho-substituted precur-
sors, the initial liberation of the sulfenic acid should
be facilitated,[13a] whereas the ligand substitution step
with the sulfenate should be more difficult. A direct
consequence would be the accumulation of the insta-
ble intermediate sulfur species, which can in turn lead
to side reactions. To overcome this problem, the cou-
Entry
Ar1
R1X
2
Yield [%][b]
1
2
3
4
5
6
7
8
4-Tol
4-Tol
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PhBr
PhCl
2a
2a
2e
2c
2b2
2b3
2h
2a
2g
2a
2a
2c
95
0
87
4-F3CC6H4I
2-naphthylI
4-AcC6H4Br
4-(MeO2C)C6H4Br
2-MeOC6H4I
4-MeC6H4Br
3-MeOC6H4Br
PhOTf
84 (16)[c]
71 (16)[c]
90 (10)[c]
47 (20)[c]
40 (26)[c]
54 (25)[c]
<5
9
10
11
12
4-Tol
4-Tol
Ph
PhOTf
2-naphthylOTf
76[d]
53[d] (4)[c]
13
Ph
2b4
37[d] (13)[c]
[a]
Reactions carried out on a 0.5 mmol scale. Conditions
(unless otherwise mentioned): sulfoxide 1 (1 equiv.), R1X
(1.2 equiv.), Pd(dba)2 (0.05 equiv.), Xantphos (0.1 equiv.),
K3PO4 (2 equiv.), degassed PhMe (1 mL), 100–1108C,
15 h.
[b]
[c]
Isolated yield.
In brackets, yield for the scrambling product 2b1 (Ar2 =
Ph).
[d]
With addition of degassed H2O (0.5 mL).
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Fabien Gelat et al.
desired aryl sulfoxides in 70–91% isolated yields (en-
tries 4–6). In these three coupling reactions, diphenyl
sulfoxide 2b1 (Ar2 =Ph) was detected in yields lower
than 20%. The formation of this side product can be
interpreted by the transfer of a phenyl group of Xant-
phos ligand through the catalytic cycle, according to
the well-established scrambling phenomenon.[25,26]
Worthy of note is that the overall coupling yield is
almost quantitative, as both sulfoxides produced origi-
nate from the intermediate sulfenates. Finally, the cat-
alytic system proved to be slightly less efficient with
2-iodoanisole, 4-bromotoluene and 3-bromoanisole
(entries 7–9). Nevertheless, the expected sulfoxides
2h, 2a and 2g were isolated in reasonable 40–54%
yields, along with scrambling product 2b1 (20–26%
yields).
Scheme 1. Arylations from di-tert-butyl sulfoxide 1n.
Our methodology was next applied to triflate deriv-
atives (Table 3). As far as we are aware, cross-cou-
pling of sulfenates with pseudohalides is unprecedent-
ed.[7–10] Only traces of the desired arylation product
were found with phenyl triflate (entry 10). To our de-
light, a significant improvement was again observed
when carrying out the reaction in the presence of
water.[27] Sulfoxide 2a was this time produced in
a nice 76% yield (entry 11). 2-Naphthyl triflate was
Scheme 2. Arylation in the [2.2]PCP series.
also a suitable coupling partner and 2c was isolated in 1H NMR data, which was further confirmed by an X-
a 53% yield (entry 10). Diphenyl sulfoxide 2b1 result- ray diffraction analysis.[30]
ing from a scrambling side reaction was also detected,
The case of axial chirality was next considered with
but in a small amount (4%, entry 12). Vinyl triflates the racemic[31] biaryl structure 1q. Following our cou-
can also participate effectively as exemplified in pling protocol, treatment of 1q with iodobenzene at
entry 13.
908C in a PhMe/H2O mixture afforded 2q quantita-
We next examined the possibility to perform tively (Scheme 3). Two diastereoisomeric species in
a double arylation reaction from di-tert-butyl sulfox- an 88:12 ratio were detected. All attempts for separa-
ide 1n.[28] This compound can be viewed as a sulfur tion by column chromatography on silica gel failed.
monoxide dianion SO2Àequivalent. Indeed, use of our However, recrystallization in
a
CH2Cl2/pentane
classical coupling conditions in the presence of iodo- system furnished a pure sample of the major com-
benzene in excess (2.4 equiv.) led to 2b1 in an excel- pound. Monocrystals suitable for X-ray analysis were
lent 91% yield (Scheme 1A). An unsymmetrical ver- grown, enabling us to assign an (aR,SS)* configuration
sion was then investigated with the introduction of (see the Supporting Information).
two different aryl iodides in stoichiometric amounts.
To conclude, we have shown that tert-butyl sulfox-
Iodobenzene and the more reactive 1-trifluoromethyl- ides constitute a novel, clean and readily available
4-iodobenzene were subjected to our conditions, thus source of sulfenate salts by heating (<1208C) under
providing 4-trifluorophenyl phenyl sulfoxide 2e in mild basic conditions (16 examples). This operational-
a 59% yield (Scheme 1B). The selectivity is however ly simple approach is perfectly adapted to an in situ
not total as symmetrical sulfoxides 2o and 2b1 were Pd-catalyzed arylation to provide aryl sulfoxides. The
also detected (8 and 18% yields, respectively).
Finally, we focused our attention on the diastereo-
selective version of the reaction. An asymmetric in-
duction involving a planar chiral sulfenate was first
examined in the [2.2]paracyclophane ([2.2]PCP)
series. Submitting racemic[29] [2.2]PCP derivative 1p
to the coupling conditions in the presence of iodoben-
zene afforded [2.2]paracyclophane-4-yl phenyl sulfox-
ide 2p, in an excellent 91% yield, as a separable mix-
ture of two diastereoisomers in
a 75:25 ratio
(Scheme 2). An (SP,SS)* configuration was unambigu-
ously assigned to the major product according to Scheme 3. Arylation in the biaryl series.
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tert-Butyl Sulfoxides: Key Precursors for Palladium-Catalyzed Arylation
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and biaryl derivatives. Future studies in our laborato-
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asymmetric synthesis.
Experimental Section
General Cross-Coupling Procedure from tert-Butyl
Sulfoxides 1
To a Schlenk tube, under nitrogen, were introduced succes-
sively tert-butylsulfinyl derivative 1 (0.5 mmol, 1 equiv.),
Pd(dba)2 [bis(dibenzyldieneacetone)palladium, 14.4 mg,
0.025 mmol, 0.05 equiv.], Xantphos [9,9-dimethyl-4,5-bis(di-
phenylphosphino)xanthene, 29 mg, 0.05 mmol, 0.1 equiv.],
K3PO4 (212 mg, 1.0 mmol, 2 equiv.), degassed solvent system
and aryl halide (0.6 mmol, 1.2 equiv.). The reaction mixture
was heated and monitored until consumption of starting ma-
terials by TLC. After completion, the mixture was purified
by column chromatography to afford the anticipated sulfox-
ides 2.
[8] E. Bernoud, G. Le Duc, X. Bantreil, G. Prestat, D.
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phos-based palladacycle as catalytic systems. See
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[12] A single diastereoselective version for arylation of
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Acknowledgements
We acknowledge financial support from the “Minist›re de la
Recherche”, CNRS (Centre National de la Recherche Scienti-
fique) and the “RØgion Basse-Normandie”. ERDF funding
(ISCE-Chem & INTERREG IVa program) and Synorg
Labex are gratefully thanked for financial support.
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[15] During the manuscript preparation, Walsh reported the
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Adv. Synth. Catal. 2015, 357, 2011 – 2016
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[17] Previously employed bases for arylation reactions of
sulfenates were KOH, t-BuOK, t-BuONa and t-
AmOK. See refs.[7–10]
[18] For a review, see: M. C. Aversa, P. Bonaccorsi, D.
Madec, G. Poli, The Fabulous Destiny of Sulfenic
Acids, in: Innovative Catalysis in Organic Synthesis,
(Ed.: P. G. Andersson), Wiley-VCH, Weinheim, 2012,
pp 47–76.
[19] M. Cong, Y. Fan, J.-M. Raimundo, J. Tang, L. Peng,
Org. Lett. 2014, 16, 4074–4077.
[20] Formation of the transient arenesulfenic acid was evi-
denced by a trapping experiment with methyl propio-
late, as described in the Supporting Information. See:
M. C. Aversa, A. Barattucci, P. Bonaccorsi, A. Contini,
J. Phys. Org. Chem. 2009, 22, 1048–1057.
[21] See the Supporting Information for syntheses of 1. It
was achieved mainly by treatment of the required thiol
with tert-butyl alcohol under acidic conditions to give
sulfide 3, followed by oxidation of the sulfur centre. In-
terestingly, it was possible to merge these two steps
into a one-pot sequence, without isolation of the inter-
mediate thioether 3.
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[26] 2b3 was isolated in a moderate 56% yield, but as the
sole sulfoxide product, when using Pd2(dba)2/XPhos in
a PhMe/H2O mixture.
[27] Polar solvents are generally preferred with triflates, due
to the intermediacy of a cationic (s-aryl)palladium
complex: A. Jutand, A. Mosleh, Organometallics 1995,
14, 1810–1817.
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[29] The reaction could be easily extended to the enantio-
pure series: a) G. J. Rowlands, R. J. Seacome, Beilstein
J. Org. Chem. 2009, 5, DOI: 10.3762/bjoc.5.9; b) L.
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[30] An induction model is provided in the Supporting In-
formation.
[31] The reaction could be easily extended to the corre-
sponding enantiopure substrate: F. Colobert, V. Valdi-
via, S. Choppin, F. R. Leroux, I. Fernµndez, E. lvarez,
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[22] See the Supporting Information for crystallographic
data of 2k.
[23] PhCl is a suitable reaction partner with Pd2(dba)2/
XPhos in PhMe/H2O and in the presence of a catalytic
amount of NBu4I. 2b1 was thus produced in an 85%
yield. See the Supporting Information.
[24] An improved 94% yield was observed by heating only
at 708C.
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ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2015, 357, 2011 – 2016