Studies on the palladium-catalysed direct alkenylation of 1,2-azoles

Article abstract of DOI:10.1016/j.tetlet.2011.04.051

Electron-rich isoxazoles, isothiazoles and pyrazoles undergo palladium-catalysed direct alkenylation in moderate yields.

Full text of DOI:10.1016/j.tetlet.2011.04.051

Tetrahedron Letters 52 (2011) 3223–3225
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Studies on the palladium-catalysed direct alkenylation of 1,2-azoles
⇑
Ben Chappell, Nathan Dedman, Simon Wheeler
Worldwide Medicinal Chemistry, Pfizer, Ramsgate Road, Sandwich, Kent CT13 9ND, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Electron-rich isoxazoles, isothiazoles and pyrazoles undergo palladium-catalysed direct alkenylation in
Received 8 February 2011
Revised 15 March 2011
Accepted 12 April 2011
Available online 18 April 2011
moderate yields.
Ó 2011 Elsevier Ltd. All rights reserved.
Despite many recent advances C–H activation chemistry fre-
quently requires a directing group. However, it is possible instead
to exploit the intrinsic reactivity of aromatic heterocycles and this
tactic enables the synthetic chemist to join substructures to a pre-
viously unfunctionalised heteroaromatic ring. Most commonly
these substructures are other aromatic rings,1 but other moieties
have also been successfully appended. Reports of such methods
include the rhodium-catalysed chemistry of Bergman and co-
workers,2 and nickel-mediated alkenylations (starting from al-
kynes) published by Nakao et al.3 Alkynes have also been attached
to aromatic heterocycles.4 Alkylations catalysed by either nickel or
palladium have been reported.5 Very recently, acylations and re-
lated reactions have been developed.6 However, perhaps the most
attractive approach is what has become known as the Fujiwara–
Moritani reaction where C–H activation is combined with a Heck
reaction. Thus, under the influence of a Pd(II) salt a heterocycle
and an alkene are coupled with the formation of a new C–C bond.
Whilst the original report7 was mostly restricted to furan and thi-
ophene, and required stoichiometric amounts of palladium, a cata-
lytic version, using Cu(OAc)2 as the stoichiometric oxidant, was
then developed and also applied to benzofuran and benzothio-
phene.8 Subsequently the reaction has been applied to indoles9
(including a version allowing regioselective vinylation at C-2 or
C-3),10 pyrroles,11 pyridones,12 enaminones,13 indolizines14 and
1,2,3-triazoles.15 Miura has disclosed conditions [catalytic
Pd(OAc)2 and stoichiometric AgOAc in propionic acid as solvent]
which allow for the alkenylation of oxazoles and thiazoles.16 The
mechanism is traditionally assumed to involve an electrophilic pal-
ladation.17 The het-Pd(II)-X species thereby generated can react
with alkenes according to the usual Heck reaction mechanism to
give the organic product and Pd(0). Oxidation of the palladium to
Pd(II) by a stoichiometric oxidant completes the catalytic cycle.
This mechanism, exemplified for thiophene, is shown in Scheme
1. It should be noted that neither the heterocycle nor the alkene
requires prior functionalisation.
We successfully applied Miura’s conditions16 to the alkenyla-
tion of isoxazoles. Moreover, we were able to demonstrate that
air could be used as the stoichiometric oxidant without significant
loss of yield (Scheme 2).
However, under these conditions, yields were often low and the
reaction times long so we attempted to refine the reaction param-
eters. A brief survey of solvents and oxidants demonstrated that
bubbling air through the reaction gave a messy profile and the
S
Pd(OAc)2
[O]
PdOAc
Pd(0)
S
H
R
S
-H+
R
PdOAc
PdOAc
S
S
R
Scheme 1. The Fujiwara–Moritani reaction exemplified for thiophene.
R'
cat. Pd(OAc) 2,
air atmosphere
R'
N
R
N
O
EtCO2H, 120 oC,
24-48 h
R
O
6 examples, average yield 35%
⇑
Corresponding author. Tel.: +44 1304 649173; fax: +44 1304 651817.
E-mail address: simon.wheeler@pfizer.com (S. Wheeler).
Scheme 2. Direct alkenylation of isoxazoles with air as the stoichiometric oxidant.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.051

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B. Chappell et al. / Tetrahedron Letters 52 (2011) 3223–3225
Table 1
Alkenylation reactions of 1,2-azoles. General reaction conditions: 100 mg of azole, 2 equiv of alkene, 10 mol % Pd(OAc)2, 2 equiv of Cu(OAc)2 in 2 ml of DMA
Entry
Heterocycle
Alkene
CO2nBu
Temperature (°C)
Time (h)
Product
Isolated yield (%)
CO2nBu
N
O
1
120
1
63
N
O
CO2tBu
Ph
t
CO2 Bu
N
O
2
3
120
120
1
1
50
68
N
O
Ph
N
O
N
O
O
NMe2
O
NMe2
N
O
4
5
6
120
120
120
1
8
8
56
55
58
N
O
CO2nBu
CO2nBu
N
Ph
O
N
O
Ph
O
NMe2
O
NMe2
N
Ph
O
N
O
Ph
CO2nBu
CO2nBu
7a
120
150
18
3
15b
24
N
Ph
S
N
S
Ph
t
CO2 Bu
t
CO2 Bu
N
N
8
N
N
t
CO2 Bu
N
N
CO2tBu
9
150
4
22c
N
N
a
b
c
The preparation of the starting isothiazole has been described in Ref. 20.
Starting isothiazole (52%) was also recovered.
Approximately 30% yield of a 4:1 mixture of 4,5- and 3,4-dialkenylated products was also recovered.
acts rapidly (entries 1–4), its 5-phenyl analogue requires a much
longer time to react completely (entries 5 and 6). Moreover the iso-
thiazole example (entry 7) is less reactive still; presumably the
poorer overlap of the sulfur orbitals renders the molecule less
nucleophilic. It is also noteworthy that the compounds shown in
Figure 1 are almost entirely unreactive under the conditions dis-
closed, whereas their more electron-rich counterparts (entries 5,
6 and 9) are productive.
Further support is lent to the SEAr hypothesis by the observa-
tion that 1-methylpyrazole reacts principally at the 4-position (en-
try 9), the preferred site for electrophilic reactions of this
heterocycle. It should also be noted that in our screen of reaction
conditions, no improvement was found when PivOH/K2CO3 was
added to the reaction mixture. This reagent combination is known
to promote the arylation of heterocycles that proceeds via a con-
certed metallation deprotonation mechanism.1c
N
N
Ph
N
CO2Et
O
Figure 1. Unreactive 1,2-azoles under the conditions described in Table 1.
reaction could not be driven to completion. Running the reaction
under neutral conditions was more effective than using acid sol-
vents, and indeed, the addition of 0.3 equiv of pivalic acid was of
no benefit in any of the cases examined. Thus, from the conditions
examined, dimethylacetamide (DMA) appeared to be the optimum
solvent and Cu(OAc)2 an efficient oxidant. We were able to apply
our preferred conditions to a small set of commercially available
1,2-azoles and our results are shown in Table 1. The E-isomer
was formed in all cases.
We believe that the SEAr mechanism shown in Scheme 1 is a
reasonable working hypothesis to explain most of the reactivity
differences apparent in Table 1. Thus while dimethylisoxazole re-
However, the much lower reactivity of pyrazoles (compare en-
tries 2 and 8) is less easy to explain by appealing to an electrophilic
palladation. Preliminary spectroscopic and computational investi-

B. Chappell et al. / Tetrahedron Letters 52 (2011) 3223–3225
3225
Chem., Int. Ed. 2010, 49, 4451–4454; (c) Yao, T.; Hirano, K.; Satoh, T.; Miura, M.
Chem. Eur. J. 2010, 16, 12307–12311.
gations have so far not succeeded in elucidating the underlying
reasons for this surprising lack of reactivity. Our findings in this re-
spect are in line with previous work suggesting that these hetero-
cycles are difficult substrates for C–H activation chemistry.18
In conclusion we have demonstrated a method for the direct
alkenylation of 1,2-azoles.19 Regrettably, it has not so far been pos-
sible to extend the reaction scope beyond ring systems bearing
simple substituents. Furthermore, extension to less usual Heck
substrates (alkenes bearing sulfonyl, phosphonyl or phthalimido
substituents) has likewise been unsuccessful. While the electro-
philic palladation mechanism can be seen as a useful tool to under-
stand the reaction, further investigations are warranted to discover
if this pathway is genuinely operative in this case, and in the Fujiw-
ara–Moritani reaction more generally. It is to be hoped that such
mechanistic understanding will lead to better catalyst systems that
operate under milder conditions and across a broader range of
substrates.
6. Leading references for each metal are: For copper: (a) Boogaerts, I. I. F.;
Fortman, G. C.; Furst, M. R. L.; Cazin, C. S. J.; Nolan, S. P. Angew. Chem., Int. Ed.
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Soc. 2010, 132, 8858–8859; For palladium: (c) Wu, X.-F.; Anbarasan, P.;
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45, 663–664; (b) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633–
639; Included in the review article: (c) Rossi, R.; Bellina, F.; Lessi, M. Synthesis
2010, 4131–4153.
8. (a) Fujiwara, Y.; Maruyama, O.; Yoshidomi, M.; Taniguchi, H. J. Org. Chem. 1981,
46, 851–855; For more recent catalytic work on thiophenes, see: (b) Maehara,
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12. (a) Itahara, T.; Ouesto, F. Synthesis 1984, 488–490; (b) Cheng, D.; Gallagher, T. C.
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Acknowledgements
14. Yang, Y.; Cheng, K.; Zhang, Y. Org. Lett. 2009, 11, 5606–5609.
15. Jiang, H.; Feng, Z.; Wang, A.; Liu, X.; Chen, Z. Eur. J. Org. Chem. 2010, 1227–1230.
16. Miyasaka, M.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2010, 75, 5421–
5424.
We thank Alexander Alex, Mark Andrews, David Blakemore,
Manuel Perez and Guy Lloyd-Jones (University of Bristol) for useful
discussions.
17. See especially Refs. 10,11.
18. Arylation of 1,3,5-trimethylpyrazole has been reported by (a) Fall, Y.; Doucet,
H.; Santelli, M. Synthesis 2010, 127–135; But it is noteworthy that the reaction
requires more forcing conditions than those reported by the same group for the
arylation of 3,5-dimethylisoxazole, for which see: (b) Fall, Y.; Reynaud, C.;
Doucet, H.; Santelli, M. Eur. J. Org. Chem. 2009, 4041–4050; Pyrazoles have
successfully been arylated by exploiting the SEM group to enhance reactivity:
(c) Goikhman, R.; Jacques, T. L.; Sames, D. J. Am. Chem. Soc. 2009, 131, 3042–
3048; To our knowledge the only other report of arylation of C-H pyrazoles is
intramolecular: (d) Blaszykowski, C.; Aktoudianakis, E.; Alberico, D.; Bressy, C.;
Hulcoop, D. G.; Jafarpour, F.; Joushaghani, A.; Laleu, B.; Lautens, M. J. Org. Chem.
2008, 73, 1888–1897.
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n-butyl acrylate (180 lL, 161 mg, 1.26 mmol) and DMA (2 ml). The mixture
was stirred at 120 °C for 8 h. The cooled reaction mixture was then partitioned
between dil. NH3(aq)/Et2O. The aqueous layer was re-extracted with Et2O. The
combined organic layers were washed with brine, dried over MgSO4 and
evaporated. The resulting brown oil was columned over silica (15 g) eluting
with PhMe. Relevant fractions were combined and evaporated to give the
product as a clear oil (99 mg, 0.35 mmol, 55%). 1H NMR (400 MHz, CDCl3) 0.90
(3H, t, J = 7.4 Hz), 1.36 (2H, m), 1.61 (2H, m), 2.43 (3H, s), 4.14 (2H, t, J = 6.8 Hz),
6.23 (1H, d, J = 16.3 Hz), 7.44–7.48 (3H, m), 7.60–7.63 (2H, m), 7.64 (1H, d,
J = 16.3 Hz). 13C NMR (100 MHz, CDCl3) 12.6, 14.0, 19.4, 31.0, 64.9, 111.3, 120.2,
125.6, 127.4, 128.3, 129.3, 131.0, 133.4, 159.1, 167.0, 169.5. MS (ESI): m/z 286
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