4-Bromomethyl-2-chlorooxazole - A versatile oxazole cross-coupling unit for the synthesis of 2,4-disubstituted oxazoles

Article abstract of DOI:10.1016/j.tetlet.2004.03.083

The synthesis of the novel oxazole building block, 4-bromomethyl-2- chlorooxazole, and its palladium-catalysed cross-coupling reactions to make a range of 2,4-disubstituted oxazoles, is described. Selectivity for the 4-bromomethyl position is observed, with Stille coupling effected in good to excellent yields, or Suzuki coupling in moderate yields, to provide a range of 4-substituted-2-chlorooxazoles. Subsequent coupling at the 2-chloro-position can be achieved through either Stille or Suzuki reactions in excellent yields.

Full text of DOI:10.1016/j.tetlet.2004.03.083

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3797–3801
4-Bromomethyl-2-chlorooxazole––a versatile oxazole
cross-coupling unit for the synthesis of 2,4-disubstituted oxazoles
Gail L. Young,a Stephen A. Smithb and Richard J. K. Taylora,*
aDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
bGlaxoSmithKline, Gunnels Wood Road, Stevenage, Herts SG1 2NY, UK
Received 25 February 2004; accepted 12 March 2004
Abstract—The synthesis of the novel oxazole building block, 4-bromomethyl-2-chlorooxazole, and its palladium-catalysed cross-
coupling reactions to make a range of 2,4-disubstituted oxazoles, is described. Selectivity for the 4-bromomethyl position is
observed, with Stille coupling effected in good to excellent yields, or Suzuki coupling in moderate yields, to provide a range of
4-substituted-2-chlorooxazoles. Subsequent coupling at the 2-chloro-position can be achieved through either Stille or Suzuki
reactions in excellent yields.
Ó 2004 Elsevier Ltd. All rights reserved.
The 2,4-disubstituted oxazole is a motif found in many
natural products, which display biological activity over
a wide range of therapeutic areas. Examples include
a reduction/bromination strategy (Scheme 1). Oxazole 2
can be synthesised on a 100 g scale in two steps from
ethyl bromopyruvate 1. Reduction of ethyl 2-chloro-
oxazole-4-carboxylate 2 to 4-hydroxymethyl-2-chloro-
oxazole 4 with DIBAL-H proceeds in excellent yield
following aqueous work-up and further purification is
not required. Triphenylphosphine–carbon tetrabromide
bromination then proceeds smoothly to provide 5,
which proved stable for periods in excess of 3 months
when kept under an inert atmosphere at )20 °C.
1
virginiamycin M2 (antibiotic), hennoxazole A2 (anti-
viral) and leucascandrolide A3 (cytotoxic and anti-
fungal) (Fig. 1).
The most commonly-used method for the installation of
oxazoles in synthesis is through cyclodehydration reac-
tions of peptide derivatives,4 but these can often prove
incompatible with sensitive functionality or require
extensive protecting group strategies. Palladium-cataly-
sed coupling for the preparation of substituted oxazoles
has also been used but this has been restricted to mono-
coupling with further derivatisation required for the
synthesis of di-substituted compounds.5;6
Alternative methods for the conversion of ester 2 into
alcohol 4 were also explored. Treatment of 2 with
sodium borohydride resulted in the formation of a
mixture of the desired product 4 together with the over-
reduced by-product 6 and competing polymerisation
products. Hydrolysis of 2 to the carboxylic acid 3 and
subsequent borane reduction to 4 was also investigated.
Interestingly, under basic saponification conditions the
desired compound 3 was obtained in good yield, whilst
under acidic hydrolysis the product isolated was 7,
where efficient displacement of the 2-chloro-moiety with
ethanol predominated. Disappointingly, borane reduc-
tion of acid 3 only gave a moderate yield of 4 and
therefore DIBAL-H reduction remains the preferred
method for the preparation of 4.
Due to the limitations of the present methodology,
we were keen to explore the possibility of developing a
pre-formed oxazole unit, which could be sequentially
elaborated under mild palladium-catalysed coupling
conditions to provide easy access to a range of 2,4-
disubstituted oxazoles. To this end, the novel oxazole,
4-bromomethyl-2-chlorooxazole 5, has been prepared in
good yield (84% over two steps) from the previously
reported ethyl 2-chlorooxazole-4-carboxylate 26 through
With 4-bromomethyl-2-chlorooxazole 5 in hand, we first
carried out a proof of principle study to determine the
success (and regioselectivity) of the proposed process.
Stille coupling7 of 4-bromomethyl-2-chlorooxazole 5
Keywords: Oxazole; Palladium; Cross-coupling; Stille; Suzuki.
* Corresponding author. Tel.: +44-0-1904-432606; fax: +44-0-1904-
434523; e-mail: rjkt1@york.ac.uk
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.03.083

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G. L. Young et al. / Tetrahedron Letters 45 (2004) 3797–3801
O
OH
N
O
N
OMe
O
O
N
O
O
H
OMe H
N
N
O
HO
O
(-)-Hennoxazole A
(-)-Virginiamycin M2
O
O
O
OMe O
O
O
N
O
O
N
H
MeO
Leucascandrolide A
Figure 1. Representative oxazole natural products.
O
O
O
Br
1
a.
b. 89%
e. 87%
d.
O
f. 54%
O
O
O
O
O
Cl
Cl
Cl
Cl
+
N
N
N
N
N
O
HO
HO
HO
6
2
3
HO
4
4
O
O
O
c. 94%
g. 71%
O
Cl
O
N
N
Br
HO
5
7
Scheme 1. Synthesis of 4-bromomethyl-2-chlorooxazole 5. Reagents and conditions: (a) two steps;6 (b) DIBAL-H, CH2Cl2, )78 °C to rt, 89%; (c)
CBr4, PPh3, 2,6-lutidine, MeCN, 0 °C, 94%; (d) NaBH4, EtOH, rt, 38% of 4; (e) NaOH (aq), THF, rt, 87%; (f) BH3, THF, )10 °C–rt, 54%; (g) HCl
(aq), 1,4-dioxane, 110 °C, 71%.
with ethyl (E)-3-(tributylstannyl)propenoate 8 showed
selectivity for the 4-bromomethyl position and sub-
sequent coupling of the isolated product 9 at the
2-chloro-position with tributyl(vinyl)tin also proceeded
in reasonable yield to give the novel 2,4-disubstituted
oxazole 10 (Scheme 2).
PdCl2(PPh3)2 showed little or no coupling, even after
extended periods at reflux. Studies on Suzuki coupling9
with trans-phenylvinyl boronic acid also identified the
Pd2(dba)3/TFP combination to be optimum using DME
as the solvent and Na2CO3 as the base (entry v).
Stille and Suzuki reactions were then employed to pre-
pare a variety of 4-substituted-2-chlorooxazoles (Table
1). Stille reactions were generally achieved in good yields
using the optimised conditions (entries i and ii) but due
to the substrate sensitivity of the reaction, an alternative
catalyst can sometimes offer augmented yields (entries iii
and iv). Intriguingly, it was observed that when coupling
was carried out with (E)-8 (entry ii), the desired coupled
product 9 was isolated in good yield, whereas when
the cis-stannane (Z)-8 (entry iii) was used, coupling
proceeded with migration of the double bond into
Optimisation of the Stille cross-coupling of 5 was carried
out with tributylphenyltin to form 4-benzyl-2-chloro-
oxazole 11 (Table 1, entry i). Efforts to minimise
observed homocoupling of the organostannane8
provided optimum conditions of Pd2(dba)3 with added
tri-2-furylphosphine (TFP) ligands in dry degassed
NMP. With this system, complete selectivity for the
4-bromomethyl position was obtained. Pd(PPh3)4 and
PdBnCl(PPh3)2 produced mixtures of mono-coupling at
the bromide site and the double coupled product whilst

G. L. Young et al. / Tetrahedron Letters 45 (2004) 3797–3801
O
3799
O
O
O
i. 85%
Cl
+
Cl
N
Br
O
SnBu3
(E)-8
O
N
9
5
ii. 48%
O
O
N
O
10
Scheme 2. Selective Stille coupling of 5. Reagents and conditions: (i) Pd2(dba)3, tri-2-furylphosphine (TFP), NMP, 80 °C, 3 h, 85%; (ii) tributyl-
(vinyl)tin, PdCl2(PPh3)2, 1,4-dioxane, 100 °C, 3 h, 48%.
Table 1. Stillea and Suzukib cross-coupling of 4-bromomethyl-2-chlorooxazole 5 to form 4-substituted-2-chlorooxazoles
Entry
Organometallic
Product
Isolated yield (%)
58c
O
i
11
9
Cl
SnBu3
O
N
O
O
O
ii
85
Cl
O
SnBu3
N
O
O
(E)-8
(Z)-8
O
O
SnBu3
39 (78)d
O
iii
12
13
O
Cl
N
O
O
Cl
iv
76 (84)e
SnBu3
N
O
v
14
11
67
34
Cl
B(OH)2
N
O
vi
Cl
B(OH)2
N
F
F
O
vii
15
16
35
44
Cl
B(OH)2
N
MeO
MeO
O
viii
Cl
B(OH)2
N
a Stille reaction conditions. 5 (1 equiv), organostannane (1.2 equiv), Pd2dba3 (2.5 mol %), TFP (20 mol %), NMP (0.1 M), 80 °C, 1–3 h.
b Suzuki reaction conditions. 5 (1 equiv), boronic acid (1.2 equiv), Pd2dba3 (2.5 mol %), TFP (20 mol %), Na2CO3 (2 M aq, 4 equiv), toluene/EtOH 1:1
(0.1 M), 80 °C, 18 h.
c Reaction was carried out at 100 °C.
d {Pd[C(CO2Me)]4(Succ)}2(NBu4Þ (5 mol %), THF (0.1 M), 80 °C, 1 h.
2
e PdBnCl(PPh3)2 (5 mol %), THF (0.1 M), 50 °C, 1 h.
conjugation with the oxazole with retention of the cis-
geometry to form 12. The somewhat lower yields ob-
tained in the Suzuki couplings (entries v–viii) are due to
reduced selectivity for the 4-bromomethyl position over
the 2-chloro-position, resulting in mixtures of mono and
di-substituted oxazoles, and competing polymerisation
reactions.
tion of coupling at the chloride site was primarily carried
out on the Suzuki coupling of 11 with phenylboronic
acid to form 17 (Table 2, entry i). These studies identi-
fied the preferred system as catalytic PdCl2(PPh3)2 with
DME as the solvent and Na2CO3 as the base.
PdBnCl(PPh3)2 also gave reasonable yields with DME
and Na2CO3 (58%) and Pd(PPh3)4 provided the coupled
product 17 in a moderate yield (32%). PdCl2(PPh3)2 also
proved to be optimum for Stille coupling at the
2-chloro-moiety using DMF or 1,4-dioxane as the sol-
vent. It must be noted that all couplings at the 2-chloro
Due to the increased reactivity of the chloride moiety in
the Suzuki reaction, seen by a much higher proportion
of double-coupled product in reactions of 5, optimisa-

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G. L. Young et al. / Tetrahedron Letters 45 (2004) 3797–3801
Table 2. Suzukia and Stilleb cross-coupling of 4-substituted-2-chlorooxazoles to form 2,4-disubstituted oxazoles
Entry
i
Oxazole chloride
Organometallic
Product
Isolated yield
(%)
O
N
O
11
17
97
Cl
N
B(OH)2
B(OH)2
O
O
ii
14
11
14
11
11
9
18
19
20
17
21
22
10
81
Cl
Cl
N
N
O
N
O
S
iii
iv
v
60 (82)c
67
Cl
B(OH)2
N
S
O
O
S
B(OH)2
N
N
S
O
O
96
Cl
N
SnBu3
SnBu3
N
O
O
vi
vii
viii
94
Cl
N
N
O
O
O
O
31
SnBu3
SnBu3
Cl
N
N
O
O
O
O
O
O
O
O
9
47d
Cl
Cl
N
N
O
O
O
O
ix
13
23
34d;e
SnBu3
N
N
a Suzuki reaction conditions: oxazole chloride (1 equiv), boronic acid (1.2 equiv), PdCl2(PPh3)2 (5 mol %), Na2CO3 (2 M aq, 4 equiv), DME (0.1 M)
80 °C, 48–64 h.
b Stille reaction conditions: oxazole chloride (1 equiv), organostannane (1.2 equiv), PdCl2(PPh3)2 (5 mol %), DMF (0.1 M), 100 °C, 48 h.
c Yield in parentheses based on recovered starting material.
d 1,4-Dioxane replaced DMF as the solvent, 100 °C, 3–6 h.
e The isomer of 13 with the alkene in conjugation with the oxazole was isolated in 42% yield.
position proceed relatively slowly with the need for
portion-wise addition of the catalyst and organometallic
reagent to push the reaction to completion.
Suzuki and Stille reactions can provide excellent yields
of 2,4-disubstituted oxazoles (entries i and v).
We have described the synthesis of 4-bromomethyl-2-
chlorooxazole 5 and shown its synthetic utility in the
formation of a variety of 2,4-disubstituted oxazoles. For
the initial reaction, Stille cross-coupling proves opti-
mum, due to the pronounced selectivity for the 4-bro-
momethyl position. Both Suzuki and Stille reactions are
effective for subsequent coupling at the 2-chloro position
in excellent yields. We are currently investigating other
palladium-catalysed coupling reactions, including one-
pot variants, and applying this methodology to natural
product synthesis.
Using these conditions, we have synthesised a range of
2,4-disubstituted oxazoles using both Stille and Suzuki
coupling reactions (Table 2). The Suzuki conditions re-
sulted in good to excellent yields of the coupled products
(entries i–iv). Unfortunately, coupling with 3-thiophene
boronic acid (entries iii and iv) proceeded particularly
slowly leading to only a moderate yield of 19, previously
reported as being of biological interest.10 However, in all
cases the only materials, other than the desired product,
isolated from the reaction mixture were the homocou-
pled compounds and starting material, and hence longer
reaction times should give higher yields. Stille coupling
proceeds well with PdCl2(PPh3)2 as the catalyst, but at a
much slower rate relative to the corresponding Suzuki
coupling. With DMF as the solvent, reactions proceeded
at an acceptable rate (entries v–vii), although with sys-
tems containing double bonds prone to migration into
conjugation with the oxazole, such as 9, DMF results in
the formation of the migrated product 22 (entry vii).
Acceptable yields of the nonmigrated product 10 can be
obtained using 1,4-dioxane as the solvent system, still
with some loss of yield due to the migration of the
double bond (entry viii). In appropriate systems both
Acknowledgements
We wish to thank GlaxoSmithKline and the BBSRC for
a CASE studentship.
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