Palladium-catalysed cross-coupling of 2-trimethylsilylpyridine with aryl halides

Article abstract of DOI:10.1016/j.tetlet.2008.08.068

Palladium-catalysed cross-coupling of 2-trimethylsilylpyridine with aryl halides in the presence of stoichiometric silver(I) oxide, and catalytic TBAF allows the rapid preparation of the corresponding pyridin-2-ylaryl compounds in moderate to good yields

Full text of DOI:10.1016/j.tetlet.2008.08.068

Tetrahedron Letters 49 (2008) 6314–6315
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Tetrahedron Letters
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Palladium-catalysed cross-coupling of 2-trimethylsilylpyridine with aryl halides
a
b
a
a,*
Spencer Napier , Sebastian M. Marcuccio , Heather Tye , Mark Whittaker
a
Evotec (UK) Ltd, 114 Milton Park, Abingdon, Oxfordshire, OX14 4SA, UK
Advanced Molecular Technologies Pty Ltd, Unit 1, 7-11 Rocco Drive, Scoresby, Victoria 3179, Australia
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Palladium-catalysed cross-coupling of 2-trimethylsilylpyridine with aryl halides in the presence of
stoichiometric silver(I) oxide, and catalytic TBAF allows the rapid preparation of the corresponding
pyridin-2-ylaryl compounds in moderate to good yields under mild thermal conditions.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 11 July 2008
Revised 12 August 2008
Accepted 19 August 2008
Available online 23 August 2008
Effective cross-coupling of 2-pyridyl compounds with aryl
derivatives is desirable for the synthesis of pharmacologically
Whilst we were encouraged by the successful formation of the
desired coupled compound, the conversion was not as good as we
had achieved for cross-couplings of arylsiloxanes and disiloxanes
with aryl iodides under similar conditions. Therefore, we screened
the effect of solvent and catalyst on reaction conversion. No con-
version was observed when tetrabutylammonium triphenyl-silyl-
difluorosilicate (TBAT) was used as the fluoride source or when
dibutyl ether or toluene were employed as solvents. NMP and
DMF were found to be solvents that gave the best conversion when
using palladium(0) tetrakis-triphenylphosphine as catalyst (entries
1
2
active molecules and functional materials. There is a need to find
alternative methods to the Stille cross-coupling using 2-trialkyl-
stannylpyridine and the Suzuki–Miyaura cross-coupling of 2-pyr-
idylboron reagents because of the difficulty of purifying the
coupled product from by-product tin salts, and since the boronates
are difficult to prepare and handle due to their susceptibility to
3
hydrolytic protodeboronation. Although N-phenyldiethanolamine
4
5
2
-pyridylboronate and its polymer supported-analogue have
been reported as stable 2-pyridyl boronates, they give rise to for-
mation of by-product 2-phenylpyridine in cross-coupling reactions
due to aryl-phenyl exchange when triphenylphosphine is used as
Table 1
4
Solvent and catalyst screen for cross-coupling of 2-trimethylsilylpyridine with
4-iodoacetophenone
the ligand. In an alternative approach to introducing the 2-pyridyl
a
6
group by a cross-coupling reaction, Gros and co-workers have
shown that substituted 2-trimethylsilylpyridines possessing elec-
tron-withdrawing substituents undergo palladium(0)-catalysed
Hiyama-type cross-coupling7 with aryl and heteroaryl halides in
the presence of stoichiometric copper(I) and excess tetra-n-butyl-
ammonium fluoride (TBAF). However, no cross-coupling was
I
Ag O, TBAF, 70 O
C
2
N
+
N
SiMe3
Pd(0) catalyst
O
1
2a
3a
O
observed for the parent unsubstituted 2-trimethylsilylpyridine
Entry
Solvent
Catalyst
Pd(PPh
Pd(PPh3)4
Fluoride source
Conv.b (%)
6
(
1). Herein, we report copper(I)-free conditions for the reaction
1
2
3
4
5
6
7
8
9
THF
THF
3
)
4
TBAF
TBAT
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
18
0
0
4
0
of 2-trimethylsilylpyridine (1) with aryl iodides and aryl bromides
to provide the cross-coupled products in moderate to good yields.
The starting point for our studies was the conditions that we
had found to be effective for the rapid preparation of biaryls in
palladium-catalysed Hiyama-type couplings of arylsiloxanes and
disiloxanes with aryl halides.8 These involve the use of palla-
dium(0) tetrakistriphenylphosphine catalyst, stoichiometric
silver(I) oxide, substoichiometric TBAF and heat. Under these
conditions, 2-trimethylsilylpyridine (1) was found to couple with
Bu
2
O
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
Pd(PPh
3
3
3
3
3
3
3
)
)
)
)
)
)
)
4
4
4
4
4
4
4
1,4-Dioxane
Toluene
DCM
7
4
MeCN
NMP
DMF
DMF
DMF
DMF
DMF
DMF
43
42
15
17
48
43
46
10
11
12
PdCl
PdSO
Allyl-PdCl(PPh
3 2
Pd(dba) (PPh )
2
(PPh
3 2
)
)
3 2
4
(PPh
3 2
)
4
2
-iodoacetophenone (2a) to provide the corresponding 4-pyridin-
-ylacetophenone (3a) in low conversion (Table 1, entry 1).
13
14
2
2 3 2
Pd(OAc) (PPh )
a
Reactions were carried out on 0.2 mmol scale with 5 mol % catalyst, 0.12 equiv
2
TBAF (1 M in THF) or 0.12 equiv TBAT, 1 equiv Ag O and 1.2 equiv 2-TMS-pyridine
for 30 min.
b
*
Corresponding author. Tel.: +44 (0)1238 441238; fax: +44 (0)1235 863139.
Conversion was calculated from the product peak versus the 4-iodoaceto-
phenone peak in the LCMS UV trace.
E-mail address: mark.whittaker@evotec.com (M. Whittaker).
0
040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.08.068

S. Napier et al. / Tetrahedron Letters 49 (2008) 6314–6315
6315
Table 2
with electron-withdrawing groups in the 4-position of the aryl ha-
lide (Table 2, entries 4 and 13). Silver(I) oxide is reported to accel-
a
Cross-coupling of 2-trimethylsilylpyridine with aryl iodides and aryl bromides
1
0
erate certain Suzuki–Miyaura cross-couplings, and was found
here to be a crucial additive with no reaction occurring in its ab-
sence (data not shown) but increasing the number of equivalents
from 1 to 3 conferred no additional benefit (Table 2, entry 1). We
have not investigated the mechanistic role of the combination of
TBAF and silver(I) oxide but we speculate that the reaction involves
formation of a silicate (by reaction of 2-trimethylsilylpyridine with
TBAF) in a catalytic amount, followed by formation of a pyridylsil-
ver intermediate and subsequent transmetallation with palladium
leading to cross-coupling with the aryl halide.
In conclusion, the cross-coupling between 2-trimethylsilyl-
pyridine (1) and aryl halides reported herein overcomes the
reported lack of reactivity of unsubstituted 2-trimethylsilylpyri-
dine (1), and is an attractive alternative to the use of 2-
pyridylboronates.
X
Pd(PPh ) , Ag O
3 4 2
+
R
+
N
N
TBAF, DMF, 90 O
C
N
SiMe3
R
1
2
3
4
Entry
R
X
3 Yieldb (%)
4 Conv.c (%)
1
2
3
4
5
6
7
8
9
4-COMe
4-OMe
4-CF
4-NO
4-CO
3-COMe
3-CN
2-COMe
2-Me
I
I
I
I
I
I
I
I
47 (36)d
45
<1
<1
<1
<1
<1
<1
<1
<1
<1
<1
3
3
50
75
47
61
65
48
21
2
2
Me
I
10
11
12
13
4-COMe
4-OMe
4-Me
Br
Br
Br
Br
40
e
6
e
9
3
4-NO
2
67
<1
References and notes
a
Reactions were carried out on 1 mmol scale with 5 mol % catalyst, 0.1 equiv
1.
(a) Wang, B.; Vernier, J.-M.; Rao, S.; Chung, J.; Anderson, J. J.; Brodkin, J. D.;
Jiang, X.; Gardner, M. F.; Yang, X.; Munoz, B. Bioorg. Med. Chem. 2004, 12, 17–
TBAF (1 M in THF), 1 equiv Ag
2
O and 3 equvi 2-TMS-pyridine.
b
Isolated yield.
21; (b) Xu, J.; Wei, L.; Mathvink, R.; He, J.; Park, Y.-J.; He, H.; Leiting, B.; Lyons, K.
c
Estimated by LCMS prior to isolation of the desired product.
A.; Marsilio, F.; Patel, R. A.; Wu, J. K.; Thornberry, N. A.; Weber, A. E. Bioorg. Med.
Chem. Lett. 2005, 15, 2533–2536; (c) Quesnelle, C. A.; Gill, P.; Roy, S.; Dodier,
M.; Marinier, A.; Martel, A.; Snyder, L. B.; D’Andrea, S. V.; Bronson, J. J.; Frosco,
M.; Beaulieu, D.; Warr, G. A.; DenBleyker, K. L.; Stickle, T. M.; Yang, H.;
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d
e
1
.2 equiv was of 2-TMS-pyridine was used. In brackets; yield with 3 equiv Ag
2
O.
Product was not isolated; conversion (%) was estimated by LCMS.
8
and 9). DMF was selected as the preferred solvent and different
1
5, 2728–2733; (d) Shinozuka, T.; Shimada, K.; Matsui, S.; Yamane, T.; Ama, M.;
palladium(0) catalysts were screened, and it was found that a
modest improvement in conversion was obtained with allyl-
Fukuda, T.; Taki, M.; Takeda, Y.; Otsuka, E.; Yamato, M.; Naito, S. Bioorg. Med.
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PdCl(PPh
3
)
2
(entry 12) and Pd(OAc)
2
(PPh
3
)
2
(entry 14).
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M. Y. J. Am. Chem. Soc. 1996, 118, 5783–5790; (b) Sindkhedkar, M. D.; Mulla, H.
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Khlobystov, A. N.; Brett, M. T.; Blake, A. J.; Champness, N. R.; Gill, P. M. W.;
O’Neill, D. P.; Teat, S. J.; Wilson, C.; Schröder, M. J. Am. Chem. Soc. 2003, 125,
Next, the cross-coupling of 2-trimethylsilylpyridine (1) was
explored with a range of substituted aryl halides 2, using DMF as
solvent and palladium(0) tetrakistriphenylphosphine as catalyst.
The reaction temperature was increased from 70 °C as used in the
initial investigations reported in Table 1 to 90 °C on the basis of a
6753–6761; (d) Mudadu, M. M.; Singh, A.; Thummel, R. P. J. Org. Chem. 2006, 71,
7611–7617; (e) Wong, W.-Y.; Ho, C.-L.; Gao, Z.-Q.; Mi, B.-X.; Chen, C.-H.; Cheah,
K.-W.; Lin, Z. Angew. Chem., Int. Ed. 2006, 45, 7800–7803.
separate Design of Experiments (DoE) study. The coupled products
3. (a) Tyrrell, E.; Brookes, P. Synthesis 2003, 469–483; (b) Ishiyama, T.; Ishida, K.;
Miyaura, N. Tetrahedron 2001, 57, 9813–9816; (c) Fuller, A. A.; Hester, H. R.;
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9
3
were obtained in moderate to good yields (Table 2). The aryl
iodides gave higher yields in comparison to the corresponding aryl
bromides. We had anticipated that the aryl bromides might be less
reactive and chose to increase the number of equivalents of 2-trim-
ethylsilylpyridine (1) from 1.2 equiv to 3 equiv to drive the reac-
tions to high conversion. However, for the more reactive aryl
iodides, the use of 3 equiv of 2-trimethylsilylpyridine (1) may not
confer a significant benefit (Table 2, entry 1) since, although not
seen by LCMS analysis of the crude reaction mixtures, varying
4.
Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685–687.
5. Gros, P.; Doudouh, A.; Fort, Y. Tetrahedron Lett. 2004, 45, 6239–6241.
6
7
.
.
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8.
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3939–3942.
0
amounts of 2,2 -bipyridine were observed during purification by
9. Representative procedure: To 1 mmol of aryl iodide and 1 mmol of silver(I) oxide
in 7.5 ml of DMF was added 3 mmol of 2-trimethylsilylpyridine (1),11
column chromatography of the products of reactions performed
with 3 equivalents of silane 1. A potential side reaction is desilyla-
tion to give pyridine but this, if formed, would be lost in the reac-
tion work-up procedure. Whilst no by-product formation due to
aryl-phenyl exchange with the triphenylphosphine could be de-
tected for the reaction with aryl iodides, minor amounts of the
by-product 2-phenylpyridine (4) were obtained with certain aryl
bromides (Table 2, entries 11 and 12) but other minor side prod-
ucts were not isolated and characterised from these low yielding
reactions. The best yields of the coupled product 3 were obtained
0
.05 mmol of tetrakis(triphenylphosphine)palladium(0) and 0.1 mmol of
tetrabutylammonium fluoride (1 M in THF). The resulting suspension was
stirred in a pressure tube at 90 °C for 18 h. The reaction was then filtered, the
retained residue was washed with EtOAc and the combined filtrates were
diluted with heptane, washed with water and the organics were dried over
anhydrous Na SO , filtered and added to 1.5 g of silica, and concentrated to
2 4
give the adsorbed crude product which was then purified by column
chromatography heptane + 0–30% EtOAc). All compounds 3 reported in Table
2
are known in the literature and were characterised by LCMS and 1H NMR.
1
0. Chen, J.; Cammers-Goodwin, A. Tetrahedron Lett. 2003, 44, 1503–1506.
11. Commercial suppliers include: Advanced Molecular Technologies Pty Ltd,
Sigma–Aldrich and Wako.