Some regioselective cross-coupling reactions of halopyridines and halopyrimidines

Article abstract of DOI:10.1039/b205027g

A high yielding approach for the synthesis of bipyridines, pyridylpyrimidines and pyridylquinolines was described. The approach employed regioselective cross-coupling reactions using palladium catalysts. The synthesis involved lithiation of a heterocycle at low temperatures, and eliminated the need to prepare and handle active zinc. The bipyridine group in the compounds exhibits antibiotic and cytotoxic properties and some have potential to be used as fungicides.

Full text of DOI:10.1039/b205027g

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Some regioselective cross-coupling reactions of halopyridines and
halopyrimidines
a
a
a
b
Nadja M. Simkovsky,* Monika Ermann, Stanley M. Roberts, David M. Parry and
Andy D. Baxter
b
1
a
Department of Chemistry, University of Liverpool, PO Box 147, Liverpool, UK L69 3BX
Celltech R&D Ltd, Granta Park, Cambridge, UK CB1 6GS
b
Received (in Cambridge, UK) 23rd May 2002, Accepted 19th July 2002
First published as an Advance Article on the web 29th July 2002
An efficient procedure for cross-coupling of 3-bromo-
pyridine and 4-bromoanisole to various mono- and
dichloro heteroaryl compounds—giving the corresponding
biaryls in 74–96% yield—is described.
Lithiation and metal–metal exchange were better carried out in
ether at Ϫ78 ЊC, with solvent exchange such that the cross-
coupling was performed in THF. Pleasingly an excellent yield
was achieved on using an excess of bromopyridine, butyl-
lithium and zinc bromide to give 4-pyridyl-2-chloropyrimidine
(
Table 1, entry 1). Care was taken not to use too large an
Introduction
excess of reagents as over-reaction could occur, involving the
second chlorine atom, giving rise to substantial amounts of
dipyridylpyrimidine. The method was then extended to other
dichloro heterocycles, namely 2,3- and 2,5-dichloropyridines
and 4,7-dichloroquinoline as well as 2-chloropyridine and
The bipyridine group is a key feature in some important natural
products, such as the caerulomycins and collismycins which
show antibiotic and cytotoxic activities. Similarly selected
pyridylpyrimidines display biological activity; some have poten-
tial use as fungicides, acting by cycling copper through the cell
membrane where it accumulates internally to toxic levels.
Furthermore, pyridylpyrimidine scaffolds have been identified
as tyrosine kinase inhibitors.
Nowadays bipyridines are frequently synthesised by transi-
tion metal catalysed cross-coupling reactions,
1,2
2
-chloropyrimidine (Table 1, entries 2–6). In all cases highly
satisfactory yields of a single product were obtained; in cases
–4 regioselective coupling was observed.
To show the scope of the reaction we have extended the
methodology to bromoanisole, which (in contrast to 3-bromo-
pyridine) can be lithiated in THF at Ϫ78 ЊC (Table 2). Once
again clean, high-yielding reactions were observed.
3
1
4–6
1,7–9
while in con-
trast substituted pyrimidines such as pyridylpyrimidines are
often prepared via the classical route by construction of a
4
,10–12
pyrimidine ring from the appropriate guanidine derivative.
Conclusions
Herein we report a high yielding protocol for the preparation
of bipyridines, pyridylpyrimidines, and pyridylquinolines with
excellent regio-control employing palladium-catalysed cross-
coupling reactions.
By judicious choice of experimental conditions excellent
coupling reactions involving two heterocyclic species can be
achieved extending the range of products previously reported
3
by other groups.
Results and discussion
Experimental
As an approach to heteroaryl pyridines cross-coupling under
Negishi conditions was studied, which involves the reaction of
a pyridylzinc halide with a suitable coupling partner (Scheme 1).
2
-(3Ј-Pyridyl)-5-chloropyridine
3
-Bromopyridine (1.42 eq., 3.06 mmol) was dissolved in
Ϫ1
anhydrous diethyl ether (2 mL mmol ) under a nitrogen
atmosphere and cooled to Ϫ78 ЊC. n-BuLi (1.49 eq., 1.6 M
solution in hexanes, 3.22 mmol) was then introduced dropwise
and the resulting bright yellow mixture stirred for a further
2
5 minutes. ZnBr (1.49 eq., 3.22 mmol) was dried under vac-
2
uum for at least 1 hour and then stirred with anhydrous diethyl
ether (3.5 mL mmol ) until fully dissolved. The zinc bromide
Scheme 1 Representation of the Negishi reaction for the cross-
coupling of 3-pyridylzinc bromide with a heteroaryl species (Ar–H).
Ϫ1
Reagents and conditions: a) BuLi, diethyl ether, Ϫ78 ЊC b) ZnBr , diethyl
solution was added quickly to the lithiated species and stirred
for 50 minutes at Ϫ78 ЊC; the cooling bath was removed and the
mixture allowed to warm to rt under vacuum. The residue was
2
ether, Ϫ78 ЊC to rt, c) Ar–Cl, THF, Pd(PPh ) , reflux.
3
4
Ϫ1
Pyridylzinc halides have been previously prepared by the
dissolved in anhydrous THF (5 mL mmol 3-bromopyridine),
13,14
oxidative addition of active zinc to pyridyl halides.
Alternatively, they can be prepared via metal–metal exchange
2,5-dichloropyridine (1 eq., 2.16 mmol) was added followed by
tetrakis(triphenylphosphine)palladium (0.047 eq., 0.10 mmol)
and the light yellow solution heated to reflux for 18 hours. Ethyl
acetate was added (10 mL) and the basic components dissolved
into the aqueous layer with 2 M HCl solution (4 × 10 mL). The
pH was re-adjusted to about 10 with solid NaOH and the mix-
ture extracted with ethyl acetate (4 × 15–20 mL). The organic
layer was washed with water (2 × 30 mL), dried over MgSO4,
filtered and evaporated. The crude product was further purified
by flash column chromatography (petroleum ether (PE) :
15
of lithiopyridines.
Our studies focused on the latter method thus avoiding the
need to prepare and handle active zinc.
The initial lithiation of a heterocycle is the key step in this
cross-coupling process. Such a lithiation requires low tempera-
ture; the reaction of bromopyridines has to be performed at
Ϫ100 ЊC in THF or around Ϫ40 ЊC in diethyl ether, in order to
avoid side-reactions such as deprotonation, elimination to give
16–18
pyridynes, bromine migration, or ring opening reactions.
EtOAC 1 : 2) to obtain the title compound (348 mg, 87%).
Ϫ1
Attempts to lithiate 3-bromopyridine with n-BuLi in THF at
Ϫ100 ЊC did not give satisfactory results. After addition of zinc
bromide to 3-lithiopyridine a gummy residue was obtained.
Mp 68–69 ЊC; R (PE : EtOAc 1 : 2) 0.22; νmax/cm 3034,
f
1582, 1470, 1416, 1367, 1118, 1009, 868, 749, 703, 620; δ (300
H
MHz, CDCl ) 7.40 (1H, ddd, J 8.1 Hz, J5,6 4.8 Hz, J5,2 0.9 Hz,
3
5,4
DOI: 10.1039/b205027g
J. Chem. Soc., Perkin Trans. 1, 2002, 1847–1849
This journal is © The Royal Society of Chemistry 2002
1847

View Online
Table 1 Cross-coupling of 3-bromopyridine with various mono- and dichloroheteroaryls
Entry
1
Substrate
Product
Yield (%)
88
Ref.
19
2
74
7
3
4
87
75
20
21
5
6
90
89
22
22
Table 2 Cross-coupling of 4-bromoanisole with various mono- and dichloroheteroaryls
Entry
1
Substrate
Product
Yield (%)
90
Ref.
23
2
3
88
78
24
25
4
5
82
96
26
27
5
-H), 7.71 (1H, dd, J3Ј,4Ј 8.4 Hz, J3Ј,6Ј 0.9 Hz, 3Ј-H), 7.78 (1H, dd,
1.52 M solution in hexanes, 2.82 mmol) was added
J4Ј,3Ј 8.4 Hz, J4Ј,6Ј 2.4 Hz, 4Ј-H), 8.30 (1H, ddd, J4,5 8.1 Hz, J4,2
quickly and the resulting mixture stirred for a further
50 minutes. ZnBr2 (1.3 eq., 3.06 mmol, pre-dried under
vacuum for at least 1 hour,) dissolved in anhydrous THF,
2
2
2
.1 Hz, J4,6 2.0 Hz, 4-H), 8.66–8.68 (2H, m, J6,5 4.8 Hz, J6Ј,4Ј
.4 Hz, J6,4 1.8 Hz, J6Ј,3Ј 0.9 Hz, 6-H and 6Ј-H), 9.18 (1H, dd, J2,4
Ϫ1
.1 Hz, J2,5 0.9 Hz, 2-H); δ (75 MHz) 121.1 (d), 123.6 (d), 131.5
(2 mL mmol ) was added quickly and stirring was continued
C
(
1
(
s), 133.8 (s), 134.2 (d), 136.7 (d), 148.1 (d), 149.0 (d), 150.3 (d),
53.0 (d); MS (EI) 192 (33), 191 (33), 190 (100), 189 (79), 164
25), 155 (13), 76 (13), 74 (10), 51 (16), 50 (26); required C 63.01,
H 3.70, N 14.70%; found C 62.94, H 3.73, N 14.78%.
for a further 45 minutes whereupon the cooling bath was
removed and the mixture allowed to warm to rt. 2,4-
Dichloropyrimidine (1 eq., 2.34 mmol) and tetrakis(triphenyl-
phosphine)palladium (0.047 eq., 0.12 mmol) were added under
a flow of nitrogen and the resulting light yellow solution heated
to reflux overnight. The mixture was cooled to rt, ethyl acetate
was added (20 mL) and the organic layer washed with water
(2 × 20 mL), dried over magnesium sulfate, filtered and the
solvent evaporated. Purification by column chromatography
(PE : EtOAc 2 : 1) gave the title compound (458 mg, 90%)
4
-(4-Methoxyphenyl)-2-chloropyrimidine
4
-Bromoanisole (1.1 eq., 2.59 mmol) was dissolved in
Ϫ1
anhydrous THF (2 mL mmol ) under a nitrogen atmosphere
and cooled to Ϫ78 ЊC. A solution of BuLi in hexanes (1.2 eq.,
1
848
J. Chem. Soc., Perkin Trans. 1, 2002, 1847–1849

View Online
15 A. S. Bell, D. A. Roberts and K. S. Ruddock, Synthesis, 1987, 843.
without any impurities of triphenylphosphine or triphenyl-
1
1
1
6 F. Trécourt, G. Breton, V. Bonnet, F. Mongin, F. Marsais and
G. Quéguiner, Tetrahedron, 2000, 56, 1349.
7 F. Trécourt, G. Breton, V. Bonnet, F. Mongin, F. Marsais and
G. Quéguiner, Tetrahedron Lett., 1999, 40, 4339.
8 M. Mallet, G. Branger, F. Marsais and G. Quéguiner, J. Organomet.
phosphine oxide.
Mp 140–141 ЊC; R (PE : EtOAc 2 : 1) 0.25; νmax/cm 3064,
Ϫ1
f
2
978, 2937, 1610, 1574, 1347, 1258, 1184, 826; δH (300 MHz,
CDCl ) 3.89 (3H, s, OCH ), 7.01 (2H, apparent dt, J and
3
3
2,3
J6,5 9.0 Hz, J2,5 and J6,3 2.2 Hz, 2-H and 6-H), 7.56 (1H, d, J5Ј,6Ј
.4 Hz, 5Ј-H), 8.08 (2H, apparent dt, J3,2 and J5,6 9.0 Hz, J3,6
and J5,2 2.2 Hz, 3-H and 5-H), 8.56 (1H, d, J6Ј,5Ј 5.4 Hz, 6Ј-H); δC
75 MHz) 55.4 (q), 114.5 (d), 114.5 (d), 127.5 (s), 129.2 (d),
59.5 (d), 161.8 (s), 162.9 (s), 166.7 (s); MS (EI) 222 (30), 221
Chem., 1990, 382, 319.
5
Ϫ1
19 Mp 142–143 ЊC; R (PE : EtOAc 1 : 2) 0.23; ν
max/cm 3053, 2923,
f
1595, 1569, 1532, 1408, 1198, 1183, 771, 699, 648; δH (300 MHz,
CDCl ) 7.48 (1H, ddd, J 8 Hz, J4,5 4.8 Hz, J4,2 0.8 Hz, 4-H),
(
3
4,3
1
7.71 (1H, d, J5Ј,6Ј 5 Hz, 5Ј-H), 8.45 (1H, ddd, J3,4 8 Hz, J3,2 2.3 Hz,
J3,5 1.7 Hz, 3-H), 8.72 (1H, d, J6Ј,5Ј 5 Hz, 6Ј-H), 8.78 (1H, dd, J5,4
(
(
13), 220 (100), 205 (18), 177 (23), 116 (16), 89 (23), 63 (16), 62
11); required C 59.88, H 4.11, N 12.69, Cl 16.07%; found C
4
.8 Hz, J5,3 1.7 Hz, 5-H), 9.26 (1H, dd, J2,4 2.3 Hz, J2,3 0.8 Hz, 2-H);
δC (75 MHz, CDCl ) 115.3 (d), 123.9 (d), 131.0 (s), 135.0 (d), 148.7
3
5
9.68, H 4.08, N 12.59, Cl 16.21%.
(
d), 152.6 (d), 160.4 (d), 162.2 (s), 164.9 (s); accurate mass calculated
1
1
91.02502, found 191.02483; MS (EI) 193 (31), 192 (19), 191 (100),
90 (31), 156 (16), 129 (23), 103 (16), 76 (17), 75 (16), 51 (18), 50 (24).
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Ϫ1
25 Mp 96–98 ЊC; R (PE : EtOAc 2 : 1) 0.38; νmax/cm 3007, 2925, 1610,
f
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(1H, d, J3Ј,2Ј 4.4 Hz, 3Ј-H), 7.39 (2H, apparent d, J3,2 and J5,6 9.6 Hz,
3-H and 5-H), 7.39–7.43 (1H, m, 6Ј-H, overlapping with anisole d at
7.39 ppm), 7.88 (1H, d, J5Ј,6Ј 9.0 Hz, 5Ј-H), 8.14 (1H, d, J8Ј,6Ј 2.1 Hz,
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J. Chem. Soc., Perkin Trans. 1, 2002, 1847–1849
1849