Palladium(0)-catalysed cross-coupling of 2-trimethylsilylpyridine with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2011.06.015

A general method for the Hiyama coupling reaction between aryl halides and 2-trimethylsilylpyridine has been developed. These conditions have been successfully applied to the synthesis of bis-heteroaryl systems, a key disconnection for the pharmaceutical industry in the synthesis of drug-like molecules.

Full text of DOI:10.1016/j.tetlet.2011.06.015

Tetrahedron Letters 52 (2011) 4192–4195
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium(0)-catalysed cross-coupling of 2-trimethylsilylpyridine
with aryl halides
⇑
David C. Blakemore, Louise A. Marples
Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method for the Hiyama coupling reaction between aryl halides and 2-trimethylsilylpyridine has
been developed. These conditions have been successfully applied to the synthesis of bis-heteroaryl sys-
tems, a key disconnection for the pharmaceutical industry in the synthesis of drug-like molecules.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 18 March 2011
Revised 24 May 2011
Accepted 3 June 2011
Available online 13 June 2011
Keywords:
2
-Trimethylsilylpyrdine
Hiyama
Copper(I)
Fluoride
The cross-coupling of 2-pyridyl metallated species with aryl
Negishi couplings of 2-pyridylzinc bromides6 are precedented
with a range of both aryl and heteroaryl halides. The zincates can
and heteroaryl halides is a powerful and highly desirable transfor-
mation in the synthesis of pharmaceutical compounds. However,
current methodology in this area has some limitations. Suzuki
cross-coupling of 2-pyridyl boronic acids or esters is low yielding
due to ready protodeborylation.1 Stille reactions using 2-pyridyl
7
be formed by the Reike method and are stable as THF solutions
6
a
under nitrogen for up to 12 months. However, these species are
typically made in situ and cannot be isolated as solids making
6d
them a less attractive option.
2
trialkylstannanes can be high yielding, but the difficulty in purifi-
2-Trimethylsilylpyridine is a stable and readily available liquid
and its use in a palladium-mediated coupling, where it might be
less prone to protodemetallation than the corresponding boronate,
is an attractive option. The Hiyama coupling reaction uses non-
toxic, stable, aryl silanes in palladium-mediated cross-coupling
reactions with aryl halides. There are limited examples in the
cation of the coupled products and the toxic tin waste streams gen-
erated make identification of an alternative highly desirable.
A number of methods have been developed to address proto-
3
–5
deborylation in Suzuki couplings with 2-pyridyl boronates.
For
example, lithium triisopropyl boronates of 2-pyridyl systems have
been coupled with both aryl bromides and aryl chlorides;4 how-
ever, very few examples of reactions with heteroaryl halides were
included. Recently, N-methyliminodiacetic acid (MIDA) boro-
e,f
8,9
literature of 2-trimethylsilylpyridines being used in the Hiyama
8
coupling. Gros et al. have reported palladium(0)-mediated cou-
pling of 2-pyridyl silanes possessing electron-withdrawing groups
in the presence of tetrabutylammonium fluoride (TBAF) and stoi-
4
d,i,h,k
nates
have shown promise in this area; these systems are
9
a
9b
postulated to work via a slow release mechanism in which the
weak base in the reaction mixture frees up boronic acids over
the course of the reaction minimising protodeborylation; again,
there are very few examples of cross-couplings with heteroaryl ha-
lides and there are challenges in synthesising and purifying MIDA
chiometric copper(I). The groups of both Napier and Gros have
published a palladium(0)-mediated coupling of the parent 2-trim-
ethylsilylpyridine in the presence of TBAF and silver(I) oxide.
However, the silver-mediated procedures require excess aryl silane
to obtain good yields. To our knowledge, there is no procedure
using sub-stoichiometric copper(I) to couple unsubstituted 2-trim-
ethylsilylpyridine with aryl and heteroaryl halides.
5
b
boronates. A large number of the Suzuki methods developed uti-
lise stoichiometric copper(I) salts and it has been suggested that
transmetallation to the 2-pyridyl copper species may be key part
of the catalytic cycle.4c
We decided to use the coupling of readily available 2-trimethyl-
silylpyridine (1) and 4-bromoacetophenone (2) as a model system
to evaluate the palladium-catalysed Hiyama reaction (Scheme 1).
We wanted to optimise the reaction conditions for aryl bromides
as a wide range are readily available and this system gave reason-
⇑
Corresponding author. Tel.: +44 1304 644411; fax: +44 1304 651987.
E-mail address: louise.marples@pfizer.com (L.A. Marples).
9
a
able yields in the conditions reported by Napier.
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.015

D. C. Blakemore, L. A. Marples / Tetrahedron Letters 52 (2011) 4192–4195
4193
O
The major by-product in all the above cases was due to
homo-coupling of 2 forming the symmetrical by-product 4.
Br
Pd (0) catalyst
10
+
CuI or Ag O
2
N
N
SiMe3
TBAF
+
Two pieces of work are relevant here to minimise this side-reac-
1
1
O
tion: DeShong has shown that fluoride can mediate the homo-
coupling of aryl halides; in this work, the yield of homo-coupled
product is highly dependent on the nature of the fluoride source.
1
DMF, 90 o
C
O
2
3
4
O
1
2
Scheme 1. Model reaction of 2-trimethylsilylpyridine (1) with 4-bromoacetophe-
none (2).
Additionally, Murata has shown that bidentate ligands prevent
homocoupling in the palladium(0)-mediated coupling of aryltrialk-
oxysilanes with aryl halides. Additional screening using these
results gave 36% yield of the target compound using 0.4 equiv of
CuI, 2.2 equiv of KF, 10 mol % of 1,1-bis(1,2-diphenylphos-
phino)ferrocene palladium(II) chloride complex with dichloro-
Pd(OAc)2
CataXCium A
CuI, KF
+
DMF
N
N
SiMe3
N
Br
methane (1:1) [Pd(dppf)Cl
2
ÁCH
2 2
Cl ], and DMF.
N
After screening 25 catalyst systems, the best six were chosen to
carry out additional optimisation studies using Design of Experi-
ments (DoE). Analysis indicated that the key process parameters
1
5
6
, 63%
Scheme 2. Example of cross-coupling of 1 with 2-chloro-5-methylpyridine (5).
2
were catalyst type and CuI loading. A mixture of Pd(OAc) and
di(1-adamantyl)n-butylphosphine (CataCXium A), gave the highest
yield. CuI (0.4 equiv) proved to be best, with reductions in yields
for higher or lower amounts. Additionally, a catalyst loading of
10 mol %, a temperature of 90 °C and a slight excess of 2-trimeth-
ylsilylpyridine were also found to improve yields.
When these reaction conditions were applied to the model sys-
tem, we were delighted to find that the desired product 3 was ob-
tained in 60% yield. Some homo-coupling of the aryl bromide was
still evident in the reaction.
The synthesis of bis-heteroaryl systems by cross-coupling
methodology is a key disconnection for the pharmaceutical indus-
try in the synthesis of drug-like moieties. We chose to look at the
challenging cross-coupling of 2-trimethylsilylpyridine (1) and 2-
bromo-5-methylpyridine (5) to validate our developed conditions.
Pleasingly, 63% isolated yield of the desired product was obtained
using 5 mol % of the palladium catalyst and our standard condi-
tions, Scheme 2. Reducing the catalyst loading to 1 mol % yielded
As expected, for the parent 2-trimethylsilylpyridine, the condi-
tions reported by Gros and co-workers8 gave none of the desired
product, even at elevated temperature and with prolonged reaction
times. In our hands, the conditions reported by Napier and co-
9
a
workers gave 30% yield of the desired product. We also tested
conditions optimised in-house for the analogous Stille reaction of
2
-tributylstannylpyridine with aryl halides; these conditions in-
t
volve the use of 10 mol % of palladium(II) tri butylphosphine
bromide [Pd(P Bu
t
3 2 2
) Br ] catalyst, 0.1 equiv of copper(I) iodide,
2
.2 equiv of caesium fluoride and 1,4-dioxane as solvent. These
8
,9
conditions gave the desired product in 6% yield. Previous work
indicated stoichiometric metal was required to ensure complete
transmetallation of the activated silicane; accordingly, increasing
the amount of CuI to 1 equiv improved the yield of the desired
species to 22%.
Table 1
Palladium-mediated cross-coupling of 2-trimethylsilylpyridine with various aryl and heteroaryl halidesa
Pd(OAc)2
CataXCium A
CuI, KF
DMF
+
R
N
R
N
SiMe3
C,N
X
C,N
Aryl halide
Yield%b
100
Aryl halide
Yield%b
Aryl halide
Yield%b
Aryl halide
Yield%b
82
O
Br
52
60
51
Cl
N
Br
67
69
60
MeO
F3C
N
Br
Br
Br
O
O
NC
I
72
72
60
N
N
Br
Cl
N
I
NC
N
N
94 (92)
Br
Br
Br
Cl
Br
N
9
6
8
3
8
4
68
92
84
57 (55)
47
65 (62)
I
N
Cl
N
O
MeO
N
5
Br
Boc N
N
N
Br
N
N
Cl
Br
2
MeO
N
81
66
Br
Boc N
Br
I
2
Br
OMe
a
2
The reaction was carried out with 1.2 mmol of 1, 1 mmol of aryl halide, 0.1 mmol of Pd(OAc) , 0.2 mmol of CataCXium A, 0.4 mmol of CuI and 2.2 mmol of KF with 1 ml of
degassed DMF as the solvent at 90 °C for 12 h.
b
Yield measured using calibrated LC–MS. Yields in brackets are isolated yields.

4
194
D. C. Blakemore, L. A. Marples / Tetrahedron Letters 52 (2011) 4192–4195
Pd dba
F3C
+
cross-coupling methodology to synthesise the key trimethylsilyl-
containing intermediates is highly desirable.
2
3
Johnphos
F3C
F3C
KF, H
DMF
2
O
N
SiMe3
N
Me Si
It is interesting to note that the synthesis of triethoxysilylaryl
compounds by cross-coupling of aryl bromide and triethoxysilane
+
3
N
SiMe3
N
Br
CF3
1
5
8
9
(12) is precedented using bis(acetonitrile)(1,5-cyclooctadiene)
rhodium(I) tetrafluoroborate as catalyst. When these conditions
were applied to the synthesis of pyridyl derivative 13 the product
was obtained in 80% isolated yield. However, applying these condi-
tions to the synthesis of 2-triethylsilylpyridine (15) using 2-bro-
mopyridine and triethylsilane failed to give any reaction (Scheme
7
10
Scheme 3. Attempted synthesis of 2-trimethylsilyl-5-trifluoromethylpyridine.
Rh(cod)(MeCN)2
TBAI, Et N
DMF
3
4).
+
HSi(OEt)3
Cross-coupling of aryltriethoxysilanes with aryl halides is
N
Br
N
Si(OEt)
3
16
known in the literature. Although 2-pyridine triethoxysilane
13) is a known compound, there are no examples of it being used
1
1
12
13, 80%
(
1
6
in coupling reactions. Initial attempts at using Zhang’s base-cat-
alysed conditions for this coupling gave no reaction, however, the
Murata conditions gave the desired cross-coupled product in 11%
Rh(cod)(MeCN)2
TBAI, Et N
DMF
3
12
+
HSiEt3
N
SiEt3
N
Br
yield (Scheme 5). Further optimisation of this reaction is ongoing
to identify if workable yields can be obtained.
11
14
15, 0%
Good to excellent yields have been obtained for the Hiyama
coupling of 2-trimethylsilylpyridine with a range of aryl and het-
eroaryl halides. The major limitation for this reaction is currently
the synthesis of heteroarylsilane. The cross-coupling of 2-trieth-
oxysilylpyridine may also be a viable alternative as synthesis of
the required silane intermediates appears to be reliable.
Scheme 4. Rhodium-mediated synthesis of 2-triethoxysilyl-pyridine.
Pd(dppf)Cl .CH Cl
2
TBAF.H O
Toluene
2
2
O
2
N
+
N
Si(OEt)3
Br
Supplementary data
O
13
2
3, 11%
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.06.015.
Scheme 5. Attempted cross-coupling of 13 with 2.
References and notes
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1

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