Direct palladium-catalyzed alkenylation, benzylation and alkylation of ethyl oxazole-4-carboxylate with alkenyl-, benzyl- and alkyl halides

Article abstract of DOI:10.1039/b816374j

The ethyl oxazole-4-carboxylate was directly and regioselectively alkenylated, benzylated and alkylated with alkenyl-, benzyl-, allyl- and alkyl halides in the presence of catalytic amounts of palladium acetate with caesium carbonate using Buchwald's John

Full text of DOI:10.1039/b816374j

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COMMUNICATION
www.rsc.org/obc | Organic & Biomolecular Chemistry
Direct palladium-catalyzed alkenylation, benzylation and alkylation of ethyl
oxazole-4-carboxylate with alkenyl-, benzyl- and alkyl halides†
Ce´cile Verrier, Christophe Hoarau* and Francis Marsais
Received 18th September 2008, Accepted 19th December 2008
First published as an Advance Article on the web 9th January 2009
DOI: 10.1039/b816374j
Table 1 Ligand effect on the regioselective direct vinylation of 1 with 2aa
The ethyl oxazole-4-carboxylate was directly and regioselec-
tively alkenylated, benzylated and alkylated with alkenyl-,
benzyl-, allyl- and alkyl halides in the presence of catalytic
Yield (%)b
Run
Ligand
1, conversion (%)
3a
4a
amounts of palladium acetate with caesium carbonate using
Buchwald’s JohnPhos ligand.
1
2
3
4
5
6
7
8
9
none
PPh3
P(o-tol)3
PCy3
41
68
90
66
95
100
70
41
34
51
63
49
–
15
25
15
29
–
–
–
The direct functionalization of arenes proceeding through catalytic
transition metal-catalyzed C–H bond activation has raised a lot
of interest as an alternative to classical cross-coupling reactions
due to its atom-economy, high functional group tolerance, and
mild reaction conditions.1 The direct formation of C–Cazole bonds
has received particular attention as substituted azoles are archi-
tectural units in the design of natural products, pharmaceutics
and organic materials. Current developments in the direct viny-
lation and alkylation of heteroaromatics are mainly centered on
Fujiwara–Moritani oxidative Heck coupling and the transition
metal-catalyzed hydroheteroarylation of alkenes and alkynes.1d–j,2
The great feature of these processes based upon direct C–H
activation followed by addition to a double or a triple C–C bond
lies in the suppression of the pre-functionalization step. To date
the literature on direct transition metal-catalyzed alkenylation,
alkynylation and allylation of azoles with alkenyl-, alkynyl- and
allyl halides or triflates remains sparse although these coupling
partners could be more valuable than alkenes and alkynes for
controlling both the regio- and stereochemical outcomes of the
alkenylation and alkylation processes.3 In this communication
we report the direct C-2 regio- and stereocontrolled palladium-
catalyzed alkenylation, benzylation and alkylation with alkenyl-,
benzyl- and alkyl halides of the commercially available ethyl
oxazole-4-carboxylate 1. This approach provides novel access
to diverse 2-alkenylated and 2-alkylated oxazole-4-carboxylates4
which are common valuable precursors of increasing occurrence
in 2,4-disubstituted oxazole natural products.5
PtBu3·HBF4
P(biphen-2-yl)Cy2
IMes
63
92 (100)c
62
IPr
38
38
17
PEPPSI-IPre
HBPd,e
60
17
51
10
100f
a Reactions were performed using
1
(0.35 mmol), 1-bromo-2-
methylpropene (0.35 mmol), Pd(OAc)2 (5 mol%), Cs2CO3 (2 equiv.) and
ligand (10 mol%) in 1 ml of dioxane at 110 ◦C for 18 h. b Isolated
yield. c 1-Bromo-2-methylpropene (0.7 mmol). d HBP: Hermann-Beller’s
palladacycle. e Catalyst used without Pd(OAc)2 and ligand added. f The 2-
and 5-vinylated isomers were accompanied by the 2,5-divinylated isomer,
isolated in 23% yield.
Scheme 1 Pd(0)-catalyzed direct vinylation of 1 with 2a.
It should be noted that the direct vinylation of 1 occurring
without any ligand provided exclusively the 2-vinyl oxazole 3a in
poor 34% yield (run 1). By using a ligand, the conversion of 1 was
dramatically increased and 3a was obtained as the major product
along with the 5-vinyl oxazole isomer 4a whilst the divinylated ox-
azolecarboxylate was not produced (runs 1–8). Among the broad
range of trialkylphosphines and carbene ligands examined, excel-
lent conversions of 1 (90–100%) could be obtained using P(o-tol)3,
PtBu3 or P(biphenyl-2-yl)Cy2 but only Buchwald’s JohnPhos lig-
and provided exclusively 3a in 92% yield (run 6). Most remarkably,
3a was obtained in quantitative yield, without any trace of 2,5-
divinylated oxazole-4-carboxylate, when the direct vinylation was
carried out with a two-fold-excess of 1-bromo-2-methylpropene
(run 6). Finally, the use of N-heterocyclic carbene-based palladium
complex PEPPSI-IPr7 or the Hermann-Beller’s HBP palladacycle8
was examined but these two catalyst systems proved to be less effec-
tive than the Pd(OAc)2/JohnPhos ligand system (runs 9,10).9 The
scope and limitations of the optimized direct vinylation reaction
of 1 using two vinyl halide equivalents are summarized in Table 2.
Notably, the direct vinylation of 1 with 1-chloro-2-methylpropene
was successfully accomplished, providing 3a in excellent 91% yield
without any trace of 5-vinyl- or 2,5-divinylisomers. However, the
Initially, the direct palladium-catalyzed vinylation of 1 was
investigated using the combination of Pd(OAc)2 pre-catalyst,
Cs2CO3 as the base and dioxane as the solvent, which proved
effective in the analogous direct (hetero)arylation of 1 with aryl
halides6 (Scheme 1 and Table 1). The performance of the ligand in
the direct vinylation of 1 with 1-bromo-2-methylpropene carried
out in dioxane in a sealed tube at 110 ◦C for 18 h is summarized
in Table 1 (runs 1–10).
Institut de Chimie Organique Fine (IRCOF) associe´ au CNRS (UMR
6014), INSA et Universite´ de Rouen, BP08 76131, Mont Saint Aignan,
France. E-mail: christophe.hoarau@insa-rouen.fr; Fax: +(33) 0235522462;
Tel: +(33) 0235522401
† Electronic supplementary information (ESI) available: General & exper-
imental procedures with all spectral data. See DOI: 10.1039/b816374j
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Table 2 Pd-catalyzed direct alkenylation of 1 with various vinyl halides
be an ineffective coupling partner since the direct allylation of 1
using indifferently one or two equivalents of allyl bromide failed.
As previously observed in vinylating and benzylating experiments,
the chlorinated coupling partner showed excellent reactivity with
1 (runs 8–10) but only the 2-vinylated oxazole-4-carboxylates
3i and 3a arising from subsequent palladium-catalyzed side-
isomerization of the 2-allyloxazole-4-carboxylate were obtained
in almost quantitative yields using 2 equivalents of allyl chloride
(runs 9,10).
2a
Run 2, R-X
X
Product
3
Yield (%)
91
1
2b
Cl
3a
2
3
4
2c
Br
Br
Br
3b
55b
97
In the final part of this study we turned to the challenging direct
alkylation of 1 using alkyl halides (runs 11–14). Interestingly,
a first assay of direct alkylation of 1 using 1 equivalent of
butyl bromide was successfully achieved providing exclusively
the 2-butyloxazole-4-carboxylate 3j in modest 32% yield (run
11). However, the yield could be dramatically improved (60%)
using 2 equivalents of electrophile (run 12) and notably occurs
without any trace of 5-mono- or 2,5-dialkylated oxazole. It should
be noted that the butyl chloride proved an ineffective coupling
partner even when other ligands were used such as Buchwald’s
SPhos and XPhos ligands, IMes, IPr as well as PtBu3 which were
originally designed for the crucial oxidative step of C–Cl bonds.
Moreover, the reaction with the highly sterically hindered tert-
butyl bromide failed (runs 13). However, interestingly the direct
C-2 methylation of 1 with methyl iodide was successfully achieved
(run 14) affording a mixture of 2-methyloxazole-4-carboxylate 3l
and starting material 1 which could be separated only by using
preparative HPLC on silica gel (Li-chrosorb 10 mm). To our
knowledge there is no literature precedent of the direct Pd(0)-
catalyzed C–H alkylation of heteroaromatics using alkyl halides
and here we have reported the first two examples. It should be
noted that the direct C–H benzylation and alkylation of 1 with
benzyl- and alkyl bromides and iodides could not be regarded as
being a simple nucleophilic displacement of the halogen by a C-2
carbanionic intermediate arising from a deprotonative pathway at
the 2-position of 1 since direct alkylations of 1 carried out without
the Pd(OAc)2 precatalyst failed. Moreover, when acetone-d6 was
used as a cosolvent as a source of deuterium, the H/D exchange
occurred predominantly at the C-5 position (Scheme 2).
2d
2ec
(E)-3c
(Z)-3d 60d
a 1 (0.35 mmol) was reacted with 2 equiv. of vinyl halide 2 with
Pd(OAc)2/P(biphenyl-2-yl)Cy2 (5:10 mol%), Cs2CO3 (2 equiv.) in dioxane
at 110 ◦C. b The 2,5-divinylated product was isolated in 28% yield. c 5:1
mixture of Z- and E- isomers. d The E-isomer was isolated in 13% yield.
direct vinylation reaction using 2-bromopropene led to a mixture
of 2- and 5-vinyl isomers which were isolated in 55% and 28% yields
respectively (runs 2,3). We then focused on the stereochemical
behaviour of the direct palladium-catalyzed vinylation process
of 1. In the first experiment, the commercially available (E)-2-
bromobut-2-ene was reacted with 1 leading exclusively to the single
stereoisomer (E)-3c in an excellent 97% yield (run 3). A direct
vinylation reaction using the bromostyrene 2e as a 5:1 mixture of
Z- and E-isomers was then carried out with 1, providing a 4.8:1
mixture of styrenyloxazole conformers (Z)-3d and (E)-3d isolated
in 60% and 13% yields (run 4). The applicability of the optimized
catalyst system (5 mol% Pd(OAc)2, 10 mol% JohnPhos ligand and
Cs2CO3) in the direct vinylation with vinyl halides encouraged us
to further explore novel functionalizations of 1 at the C-2 position,
such as direct allylation, benzylation and alkylation using allyl-,
benzyl- and alkyl halides (Table 3). The palladium-catalyzed direct
benzylation of 1 with benzyl halides 2f,g was first carried out
(runs 1–4). Although the direct benzylations of 1 using one
or two equivalents of benzyl bromide were fully regioselective
for the 2-position, surprisingly both reactions proceeded very
smoothly affording the 2-benzyloxazole-4-carboxylate 3e in 15%
and 39% yields respectively. In fact the benzyl chloride proved
a much more efficient coupling partner than benzyl bromide in
the direct benzylation leading to the expected 2-benzyloxazole-
4-carboxylate in 86% yield when two equivalents of electrophile
were used. Substrates bearing an electron-withdrawing group such
as 4-fluorobenzyl chloride 2h as well as those with electron-
releasing groups such as 4-methoxybenzyl chlorides 2i or 2-
(chloromethyl)naphthalene 2j were also successfully engaged in
direct benzylation of 1 affording the corresponding 2-substituted
oxazole-4-carboxylates in good 82%, 91% and 80% yields (runs
5–7). It should be noted that two equivalents of electrophiles were
used to complete the conversion of 1 and 5-arylmethyl isomers
appeared to be the exclusive side-compounds, which were ready
isolated from the 2-arylmethyl isomers 3f–h. Thus, contrary to
the direct vinylation of 1 , no trace of dibenzylated oxazole-4-
carboxylate was observed. At this stage direct allylation of 1 with
allyl halides was evaluated. Allyl bromide immediately proved to
Scheme 2 C-2 vs C-5 H/D exchange experiments.a Percentage of 1, 1a–b
b
was determined by 1H NMR analysis.10 Isolated yield of the mixture of
1, 1a and 1b based on the amount of 1 used.
In conclusion we succeeded in carrying out the C-2 re-
gioselective palladium-catalyzed direct alkenylation, benzylation
and alkylation of the commercially available ethyl oxazole-4-
carboxylate with alkenyl-, benzyl- and alkyl halides. The method-
ology provides new routes towards highly valuable oxazole-4-
carboxylate precursors and can be directly used for an innovative
synthetic approach towards 2,4-disubstituted oxazole natural
product synthesis. Furthermore, in the recent context of research
into novel coupling partners for the direct palladium-catalyzed
coupling of heteroaromatics via C–H bond activation, the first
examples of palladium-catalyzed direct C–H benzylation and
alkylation of heteroaromatics with benzyl- and alkyl halides are
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Table 3 Pd-catalyzed direct alkylation of 1 with benzyl-, allyl- and alkyl halides 2a
Run
2, R-X
X
Equiv.
Product
3
Yield (%)
1
2
3
4
2f
2f
2g
2g
Br
Br
Cl
Cl
1
2
1
2
3e
15
39
51
86b
5
2h
Cl
2
3f
82c
6
2i
Cl
2
3g
91
7
2j
Cl
2
3h
80d
8
9
2k
2k
Cl
Cl
1
2
3i
41
97
10
2l
Cl
2
3a
98
11
12
2m
2m
Br
Br
1
2
3j
32
60
13
2n
Br
2
3k
3l
n.r.
14
2o
I
2
41
a 1 (0.35 mmol) was reacted with 1 or 2 equiv. of alkyl halide with Pd(OAc)2/P(biphenyl-2-yl)Cy2 (5:10 mol%), Cs2CO3 (2 equiv.) in dioxane at 110 ◦C.
b The 5-benzylated product was also isolated in 14% yield. c The 5-benzylated product was also isolated in 11% yield. d The 5-benzylated product was also
isolated in 17%.
described here. Further investigations to highlight in detail the
mechanism of the direct regioselective C-2 functionalizations of
1 including the previously reported direct C-2 (hetero)arylation6
are being undertaken. The anionic cross-coupling mechanism
involving deprotonation at the C-2 position of 1 is ruled
out on the basis of the H/D exchange study (Scheme 2).1,10
The other palladium-catalyzed pathways, concerted metallation-
deprotonation (CMD), oxidative C–H insertion, electrophilic
substitution (SEAr), and Heck–like are now considered.11
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3 For examples of direct alkynylation, alkenylation and allylation of
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650 | Org. Biomol. Chem., 2009, 7, 647–650
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