Stereoselective heck reactions with vinyl sulfoxides, sulfides and sulfones

Article abstract of DOI:10.1002/adsc.201300678

We report the Heck cross-coupling of notoriously unreactive, but synthetically valuable olefins: vinyl sulfoxides, vinyl sulfones, and vinyl sulfides. Key findings include the importance of the sterically hindered (tri-tert-butyl)phosphine ligand and the unique effectiveness of triethylamine as the base. The method is general, E-selective, and can be used to synthesize disubstituted or trisubstituted olefins through simple adjustments of stoichiometry. Copyright

Full text of DOI:10.1002/adsc.201300678

UPDATES
DOI: 10.1002/adsc.201300678
Stereoselective Heck Reactions with Vinyl Sulfoxides, Sulfides
and Sulfones
Daniel G. Bachmann,a Christopher C. Wittwer,a and Dennis G. Gillinghama,*
a
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax : (+41)-61-267-0976; phone: (+41)-61-267-1148; e-mail: dennis.gillingham@unibas.ch
Received: July 30, 2013; Revised: October 7, 2013; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300678.
Abstract: We report the Heck cross-coupling of no-
toriously unreactive, but synthetically valuable ole-
fins: vinyl sulfoxides, vinyl sulfones, and vinyl sul-
fides. Key findings include the importance of the
sterically hindered (tri-tert-butyl)phosphine ligand
and the unique effectiveness of triethylamine as the
base. The method is general, E-selective, and can
be used to synthesize disubstituted or trisubstituted
olefins through simple adjustments of stoichiome-
try.
rendered electrophilic or nucleophilic at the a-posi-
tion,[5] they can be interchanged with halides,[6] or re-
ductively cleaved;[2a,4a,b] they can be transformed to
sulfur ylides[7] or exploited in the various flavors of
Pummerer-type chemistry.[8] Furthermore, the chirali-
ty of the sulfur atom in sulfoxides has been used as
a stereochemical control element in numerous pro-
cesses.[9] The current limiting factor in the synthetic
value of vinyl sulfoxides is not their synthetic poten-
tial, but rather the lack of efficient and general ways
to create them. A classic method is the E- or Z-selec-
tive reduction of alkynyl sulfoxides but only a few
simple examples have been described.[10] The more
recent Horner–Wittig approach leads to predominate-
ly E-configured products, but these are always conta-
minated with some Z-products (98:2 ratio in the best
cases).[11] The sole reports of vinyl sulfoxide cross-cou-
Keywords: cross-coupling; Heck reaction; palladi-
um; sulfoxides
Although the Heck reaction has become an essential plings are by Carretero and co-workers[2a] and
component of the organic chemistꢀs playbook,[1] Doucet, Santelli and co-workers.[2b] The Doucet/San-
strongly coordinating substrates are conspicuously telli procedure features an interesting tetradentate
absent from most methodology studies, likely because ligand concept, but the forcing conditions (1308C)
they interfere with the catalytic cycle. Olefins contain- and the complexity of the ligand have likely hindered
ing a sulfur substituent in any oxidation state (sulfide, the adoption of this approach by the synthetic com-
sulfoxide, or sulfone) are particularly problematic, munity. The Carretero work represents the most gen-
and only a handful of successful cross-coupling reac- eral approach to date, but there remain unmet chal-
tions are known.[2] Coordination of sulfoxides to lenges since their conditions employ excess aryl io-
Pd(II) is in fact well-established, and this interaction dides and silver salts. Herein we describe our findings
has even been employed to control the reactivity of on the chemistry of vinyl sulfoxide, vinyl sulfide, and
palladium(II) in a number of reactions.[3] We report vinyl sulfone cross-couplings.
here that the bulky phosphine complex Pd[P
G
We began our investigations by testing Carreteroꢀs
in combination with triethylamine as the base delivers conditions – optimized for aryl iodides – on our
an exceptionally active catalyst that can couple model system 1 (see header of Table 1);[2a] these con-
a broad-range of sulfur-bearing substrates.
ditions, however, failed to deliver any product
The poor behavior of sulfur-substituted olefins in (entry 1) and also did not lead to oxidative addition
À
Heck couplings is unfortunate since the products of into the Ar Br bond. While conditions with
these reactions are synthetically versatile. Our interest Pd
N
in this area stemmed from a need to create an optical- coupling, a first hint of success was achieved with the
ly enriched vinyl sulfoxide to employ in an enantiose- Pd[P
AHCTUNGTRENNUNG
lective synthesis of the kinamycin core. Vinyl sulfox- Buchwald and Fu have shown that the hindered
ides and sulfones are veritable chemical chameleons: amine base NCy2Me can have a dramatic accelerating
they are electrophilic at the b-position[4] and can be effect on Heck couplings.[13] As seen in entry 6,
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Table 1. Optimization of the catalyst system.
Table 2. Scope of the Heck reaction with phenyl vinyl sulf-
oxide.
Entry Catalyst
Base[a]
Solvent Yield
[%]
1
2
3
4
5
6
7
Pd
Pd
N
Ag2CO3
Cs2CO3
Cs2CO3
Ag2CO3
Cs2CO3
DMF
DMF
DMF
DMF
0
0
11
0
Pd[P
Pd[P
Pd[P
Pd[P
Pd[P
G
ACHTUNGTRENNUNG
R
E
dioxane 0
NCy2Me dioxane 60[b]
R
N
N
dioxane 20[b]
dioxane 0[b]
Pr)2Et
DBU
8
9
Pd[P
Pd[P
ACHTUNGTRENNUNG
A
pyridine dioxane 15[b]
10
Pd[P
G
NEt3
dioxane 93
11
NEt3
dioxane 0[b]
[a]
[b]
The main observable product with inorganic bases was
dehalogenation.
Represents % conversion according to H NMR; an iso-
1
lated yield was not determined in these cases.
NCy2Me was also superior to inorganic bases in sulf-
oxide cross-coupling but still did not deliver complete
conversion. A screen of other common amine bases
led to even lower conversions (entries 7–9). Triethyl-
ACHTUNGTRENNUNGamine was the sole exception, proving uniquely effec-
tive for efficient coupling (entry 10: >98% conver-
sion, 93% isolated yield). Curiously the palladium(I)
dimer complex that has proven so active as a precata-
lyst in other forms of cross-coupling,[14] was complete-
ly unreactive with vinyl sulfoxides (entry 11).
With an effective catalyst system identified we ex-
plored the scope of the reaction with electronically
and sterically diverse aryl bromides (Table 2). Phenyl
bromide underwent complete vinylation in 30 min,
delivering an 82% isolated yield. Electron-rich sys-
tems such as p-methoxybromobenzene or o-bromoto-
luene were successfully converted in good yield (73%,
80% respectively). It is noteworthy that unfunctional-
ized aryl bromides (entry 1) or those with only ali-
phatic functionalization (entry 3) can be run with
5 mol% catalyst, but heteroatom-substituted systems
required 10 mol% catalyst loading to reach full con-
version in a reasonable time.
[a]
5 mol% Pd[P
4 equiv NEt3.
ACHTUNGRTEN(NUNG t-Bu)3]2.
[b]
Electron-poor substrates (entries 4–8) furnished the
desired products in good yields as well: p-cyano-, p-
methanoato- and p-acetamidobromobenzene under- of nitro-substituted aryl bromide was sluggish, reach-
went the transformation with full conversions and ing only 90% conversion under the standard condi-
yields of 80% and above (see entries 5–7). Reaction tions (entry 4). p-Bromobenzoic acid underwent full
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Stereoselective Heck Reactions with Vinyl Sulfoxides, Sulfides and Sulfones
conversion, although four equivalents of triethylamine
were needed to cope with the additional acidic pro-
tons.
More challenging heterocyclic aryl bromides as well
as sterically encumbered substrates were also tolerat-
ed. 3-Bromopyridine (entry 9) was converted into the
desired product with 88% yield, although forty hours
were required for complete conversion. 3-Bromofuran
was the most poorly accepted bromide substrate, de-
Scheme 2. Sulfoxide stereocenters are unaffected in the
Heck coupling.
livering only 40% conversion and 37% yield after a 50% yield of 7 as the expected E-adduct exclusively
24 h. Entry 11 represents a challenging substrate in – a result that not only demonstrates the catalysts po-
terms of steric and electronic factors, and yet full con- tency, but also establishes alkyl-substituted vinyl sulf-
version and 69% yield were attained.
oxides as substrates.
Entry 12 indicates that triflates are also viable
The cross-coupling conditions are compatible with
cross-coupling partners. In this case the vinyl triflate sulfoxide stereocenters since enantiopure R-tolyl vinyl
was fully consumed but unreacted sulfoxide was still sulfoxide 8(R) leads to enantiopure product 9(R) (see
present. Although this suggests that some of the tri- Scheme 2). This result bodes well for using the cou-
flate decomposed during the reaction, 23% yield was pling method to introduce sulfoxide-based chiral aux-
still achieved. To our surprise phenyl chloride failed iliaries.
to react, although examples with aryl chlorides and
different Heck acceptors are known with Pd[P
Although vinyl sulfoxides were our primary inter-
AHCTUNGTREG(NNNU t- est, we were aware that sulfones and sulfides are also
Bu)3]2.[13a] We therefore compared the known Heck poorly tolerated in Heck coupling. For example, vinyl
coupling of 4-chloroacetophenone with styrene[13a] sulfides in particular have only been employed in two
and found that the presence of phenyl vinyl sulfoxide cases that we could find.[2c,16] Nevertheless employing
inhibits the normal Heck coupling. This result sug- the conditions we identified led to complete conver-
gests that one of the steps in the catalytic cycle with sion of phenyl vinyl sulfide 10 in two cases and 90%
aryl chlorides is perturbed in the presence of sulfox- conversion in the case of nitrobromobenzene
ides.
(Table 3, entry 3), delivering the products 11a–c in
The cross-coupling system is exceptionally active 68–73% yield (see Table 3). It is noteworthy, that
with aryl bromides and allows the formation of sym- product 11c was the first and only example where not
metrical and unsymmetrical trisubstituted olefins (see only E- but also small amounts of the Z-isomer were
Scheme 1). For symmetrical olefins simply employing observed.
2 equivalents of the aryl bromide at elevated temper-
Interestingly, the system developed by Yoshida[2c]
ature affords the desired product in good yield (see for pyrimidine-directed Heck coupling of vinyl sul-
top line in Scheme 1). The ability to select between fides is almost identical to the system we describe
the single or double Heck products by simply adjust- here and yet they required aryl iodides to achieve
ing the stoichiometry should prove of considerable cross-coupling. It is not clear why in Yoshidaꢀs case
synthetic value.
To obtain an unsymmetrically trisubstituted olefin
sulfoxide 6[15] was employed. After 21 h under the
Table 3. Vinyl sulfides are viable substrates.
standard conditions with 5 mol% catalyst, the reac-
tion proceeded to 80% conversion and delivered
Scheme 1. Synthesis of symmetrical (top) and unsymmetrical
(bottom) trisubstituted olefins.
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Daniel G. Bachmann et al.
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Table 4. Additions to vinyl sulfones are also efficient.
Scheme 3. Additions to ethyl vinyl sulfide, sulfoxide and sul-
fone.
the hope that it will support efforts to reduce the cat-
alyst loading. Even with low turn-over numbers, how-
ever, the present catalyst system fills a void in Heck
cross-coupling chemistry and should find broad ap-
plicability in the synthetic community.
the ostensibly more reactive iodides also require a di-
recting group to activate the olefin substrate, whereas
we see that less reactive aryl bromides can be effi- Experimental Section
ciently cross-coupled to vinyl sulfides lacking a direct-
ing group. It could be that although aryl iodides are General Procedure for the Heck Vinylation
superior in oxidative addition, the iodide anion gener-
ated in the process is deleterious to other steps of the
flask was charged with 5 mL of dioxane. The bromide
An oven-dried, nitrogen-flushed, two-necked, round-bottom
catalytic cycle. Solvent effects may also be a factor as
they used toluene and we used dioxane; but Fu has
shown that with aryl chlorides there is a marginal dif-
ference between these two solvents in Heck reac-
tions.[12]
(0.63 mmol, 1.00 equiv.), the sulfoxide/sulfone/sulfide
(0.63 mmol, 1.00 equiv.), NEt3 (1.27 mmol, 2.00 equiv.) and
Pd[PACTHNURTGNE(NUG t-Bu)3]2 (5–10 mol%, see the Supporting Information)
were added and the mixture was immersed into a pre-
heated oil bath at 708C. The pale yellow to dark brown so-
lution was stirred under a nitrogen atmosphere and the reac-
tion was followed by NMR. As soon as conversion stopped
the solution was cooled to room temperature before remov-
ing the solvent under reduced pressure. The residue was dis-
solved in DCM and silica was added. After subsequent re-
moval of the solvent, the product-laden silica was dry-
loaded on a column for flash chromatography.
If phenyl vinyl sulfone were accepted as a cross-
coupling partner, then olefins bearing the whole set
of sulfur oxidation states would be accessible through
one unified protocol. Indeed phenyl vinyl sulfone 12
was efficiently coupled under the optimized condi-
tions to deliver the sulfones 13a–c in 74–92% yield
(Table 4). In order to broaden the scope of the de-
scribed methodology even further, we employed the
catalyst system to ethyl vinyl sulfide/sulfoxide/sulfone
(14–16); these substrates bear acidic alpha protons
that could interfere with the catalytic reaction. In all
three cases the desired product was furnished in good
yield (Scheme 3) with 5 mol% catalyst.
Acknowledgements
The Swiss National Science Foundation (Grant # 200021-
134770), and the University of Basel are gratefully acknowl-
edged for support of this work.
Vinyl sulfur compounds in their various oxidation
states are challenging substrates for Heck cross-cou-
plings. The generality of the Pd[PACHTNUTRGNEUNG(t-Bu)3]2/NEt3
system opens up this class of molecules for further
synthetic exploitation. Some practical points merit
mention: the catalyst is commercially available, the
procedure is operationally simple, and reaction times
are shorter than with other catalyst systems (typically
2 h vs. 24 h with other catalysts). A disadvantage is
the relatively high catalyst loading required (5–10%)
for complete conversion. We are currently working to
understand the catalyst decomposition pathways in
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6 Stereoselective Heck Reactions with Vinyl Sulfoxides,
Sulfides and Sulfones
Adv. Synth. Catal. 2013, 355, 1 – 6
Daniel G. Bachmann, Christopher C. Wittwer,
Dennis G. Gillingham*
6
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