Palladium-catalysed direct alkenylation of sydnones

Article abstract of DOI:10.1016/j.tetlet.2009.04.075

Sydnones have been directly functionalised with alkenyl halides and an alkynyl bromide under palladium catalysis.

Full text of DOI:10.1016/j.tetlet.2009.04.075

Tetrahedron Letters 50 (2009) 3942–3944
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Tetrahedron Letters
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Palladium-catalysed direct alkenylation of sydnones
*
Arantxa Rodriguez, Rebecca V. Fennessy, Wesley J. Moran
Department of Chemical and Biological Sciences, University of Huddersfield, Queensgate, Huddersfield HD1 3DH, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Sydnones have been directly functionalised with alkenyl halides and an alkynyl bromide under palladium
Received 13 March 2009
Revised 3 April 2009
Accepted 21 April 2009
Available online 24 April 2009
catalysis.
Ó 2009 Elsevier Ltd. All rights reserved.
The palladium-catalysed direct cross-coupling reaction of elec-
tron-rich heteroaromatics with aryl halides and pseudohalides has
emerged as an incredibly useful and general synthetic technique to
access biaryl structures.1 These processes are superior to tradi-
tional cross-coupling techniques because a stoichiometric amount
of an organometallic reagent is not required. This results in lower
costs, less waste and, if the organometallic would need to be pre-
pared, shorter syntheses. This concept has been applied success-
fully to the direct coupling of a range of heterocycles including
furans,2 oxazoles,3 imidazoles,4 triazoles,5 purines,6 indoles7 and
pyrroles.8 Examples of intramolecular direct couplings have also
been reported.9
Our research group recently reported the direct cross-coupling
of aryl iodides and bromides with sydnones under palladium catal-
ysis (e.g., in Scheme 1).10 N-Phenyl and N-methyl sydnones were
found to react efficiently with aryl iodides and bromides in the
presence of palladium acetate (5 mol %), triphenylphosphine
(10 mol %) and potassium carbonate (2 equiv) in wet N,N-dimeth-
ylformamide at reflux open to air. Sydnones are five-membered
heterocycles which are part of an intriguing family of molecules
termed mesoionic.11 Sydnones have been investigated for their po-
tential uses as therapeutic agents,12 as liquid crystals13 and as elec-
trolytic solvents.14 In synthesis, the principal reactions of sydnones
are metallation,15 electrophilic aromatic substitutions and 1,3-
dipolar cycloadditions,16 however little new reactivity has been re-
vealed over the last few decades.17 Kalinin and Min have shown
that sydnones can be deprotonated at C-4 with butyllithium to
form unstable species in solution. Subsequent addition of copper(I)
bromide leads to the formation of relatively stable complexes that
can take part in palladium-catalysed coupling reactions with iodo-
arenes and b-bromostyrene in excellent overall yields.15a A recent
report by Harrity and co-workers has shown the application of the
Suzuki cross-coupling reaction to functionalising 4-bromosydnon-
es with a range of aryl boronic acids and with styrylboronic acid
under palladium catalysis.18
We set out to increase the scope of the direct cross-coupling
reaction with sydnones and investigated the reactivity of alkenyl
halides under our optimised conditions.19 We were pleased to find
that
a-bromostyrene coupled efficiently with N-phenyl sydnone
providing the product in 78% yield (Table 1, entry 1).20 Both (E)-
and (Z)-b-bromostyrene coupled successfully with the sydnone
(entries 2 and 3), however the latter product underwent slow (Z)
to (E) alkene isomerisation at room temperature. After eight
months at ambient conditions a 1:7 (E)/(Z) mixture had formed.
The para-methyl-substituted (E)-b-bromostyrene derivative
underwent clean conversion providing 62% of product (entry 4)
and (E)-2-(2-bromovinyl)naphthalene furnished 65% of the cou-
pled sydnone (entry 5). The trisubstituted vinyl bromide (entry
6) was coupled successfully albeit in somewhat lower yield of
42%. Surprisingly, 1-bromohex-1-ene and (3-bromoallyl)benzene
failed to react under the reaction conditions returning starting
materials (entries 7 and 8). However, the trisubstituted alkenyl io-
dide synthesised from cyclohexanone was coupled successfully in
moderate yield (entry 9). N-Methyl sydnone also coupled with a-
bromostyrene and (Z)-b-bromostyrene in moderate yields at the
lower temperature of 80 °C (entries 10 and 11). In the latter case,
very slow interconversion of the alkene from (Z) to (E) occurred
with an 11:1 (E)/(Z) mixture being present after eight months. As
with the arylation reaction, the N-methyl sydnone decomposes un-
der the reaction conditions at 120 °C, so the reactions have to be
run at 80 °C.
With these results in hand, the direct coupling of other electro-
philes was investigated. Accordingly, under our standard conditions,
* Corresponding author. Tel.: +44 0 1484 473741.
E-mail address: w.j.moran@hud.ac.uk (W.J. Moran).
Scheme 1. An example of the direct arylation of N-phenyl sydnone with
iodobenzene.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.075

A. Rodriguez et al. / Tetrahedron Letters 50 (2009) 3942–3944
3943
Table 1
Direct alkenylation of sydnones
Entry
1
R
R0X
Yielda (%)
78
Ph
2
3
4
5
Ph
Ph
Ph
Ph
76
Figure 1. Postulated mechanism for the direct coupling reaction.
74
62
65
The mechanism of the coupling reaction is proposed to be oxi-
dative addition of Pd(0) to the alkenyl halide, then electrophilic
addition to the sydnone, followed by rearomatisation and reduc-
tive elimination to furnish the product and to regenerate the
Pd(0) catalyst (Fig. 1).10
In conclusion, the palladium-catalysed direct alkenylation of
sydnones with alkenyl halides has been achieved. The reaction
was found to be successful with di- and tri-substituted alkenyl ha-
lides. In addition, the first reported example of a palladium-cata-
lysed direct alkynylation of a heterocycle has been described.
6
7
Ph
Ph
Ph
Ph
Me
Me
42
0
Acknowledgements
We thank the Nuffield Foundation for the award of an Under-
graduate Summer Bursary (R.V.F.) and the University of Hudders-
field for funding.
8
0
Supplementary data
9
57
51b
46b
Supplementary data (full characterisation data of novel com-
pounds are provided) associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.075.
10
References and notes
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Scheme 2. Direct alkynylation of N-phenyl sydnone.

3944
A. Rodriguez et al. / Tetrahedron Letters 50 (2009) 3942–3944
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wet DMF (1 mL) and was heated at reflux for 12 h open to air. Upon cooling,
water (30 mL) was added to the reaction mixture that was extracted with
EtOAc (3 ꢀ 15 mL). The organic layers were combined, dried with MgSO4 and
filtered. The volatiles were removed in vacuo and the mixture was purified by
flash chromatography (5:1 PE/EtOAc on silica gel) to give 3-phenyl-4-(1-
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