The synthesis of substituted pyridylpyrimidine fungicides using palladium-catalysed cross-coupling reactions

Article abstract of DOI:10.1016/S0040-4039(00)00007-1

Various substituted phenyl, pyridyl and benzyl zinc chlorides have been generated from the corresponding lithium or magnesium organometallic reagents. These have been cross-coupled with 2-(6-bromo-2- pyridyl)pyrimidines in the presence of tetrakis(triphenylphosphine)palladium(0) to produce a series of substituted pyridylpyrimidine fungicides in 32-99% yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00007-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1653–1656
The synthesis of substituted pyridylpyrimidine fungicides using
palladium-catalysed cross-coupling reactions
Stephanie L. Hargreaves, Brian L. Pilkington, Sally E. Russell and Paul A. Worthington ∗
Department of Chemistry, Zeneca Agrochemicals, Jealott’s Hill Research Station, Bracknell, Berkshire RG42 6ET, UK
Received 5 November 1999; accepted 21 December 1999
Abstract
Various substituted phenyl, pyridyl and benzyl zinc chlorides have been generated from the corresponding
lithium or magnesium organometallic reagents. These have been cross-coupled with 2-(6-bromo-2-
pyridyl)pyrimidines in the presence of tetrakis(triphenylphosphine)palladium(0) to produce a series of substituted
pyridylpyrimidine fungicides in 32–99% yields. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: coupling reactions; palladium catalysts; pyridines, pyrimidines; fungicides.
As part of a research programme designed to identify new agrochemical fungicides with novel modes
of action, we have been involved in the synthesis of pyridylpyrimidines (1) (Fig. 1).1 These compounds
are broad spectrum fungicides, acting by cycling copper through cell membranes, where it accumulates
internally to toxic levels.2
Fig. 1.
These pyridylpyrimidines (1) are generally prepared by a pyrimidine ring synthesis1a,3 involving the
condensation of a substituted picolinamidine with a β-dicarbonyl compound or a suitably protected form
such as the formylacetone dimethylacetal.3 This route also requires the initial synthesis of the substituted
picolinamidine4 from a 2-cyanopyridine.5 The route is not very convenient for preparing a range of
compounds (1) in which the R1 group is varied widely.
An alternative approach involving the palladium-catalysed cross-coupling reaction of an organome-
tallic derivative of R1 with a bromopyridylpyrimidine (2) is much more attractive and versatile. In this
∗
Corresponding author. Tel: +0044 1344 414843; fax: +0044 1344 455629; e-mail: paul.worthington@aguk.zeneca.com
(P. A. Worthington)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00007-1
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case, the R1 group being varied is introduced in the last step of the sequence. The key intermediates (2)
(R2=H or CH3) are available in multi-gram quantities by a palladium-catalysed cross-coupling reaction
of the organozinc species derived from 2,6-dibromopyridine with a 2-bromopyrimidine (3) (Scheme 1).
Lithiation of 2,6-dibromopyridine at −60°C with t-butyllithium (t-BuLi) is reported to give 2-bromo-
6-lithiopyrimidine selectively.6 Bromination of the corresponding 2-chloropyrimidines with phosphorus
tribromide7 generates the 2-bromopyrimidines in 80% yield. The 2-chloropyrimidines are prepared in
70% yield by chlorination (using phosphorus oxychloride) of the available 2-hydroxypyrimidines.
Scheme 1.
Several cross-coupling reactions of this type are known to be induced by organozinc reagents8
generally prepared from lithio derivatives using an excess of zinc chloride9 or zinc bromide. In this
procedure, the organometallic derivatives of R1 are prepared by reaction of substituted bromobenzenes
and bromopyridines with n-butyllithium (n-BuLi) or by the treatment of substituted benzyl chlorides with
magnesium to form the corresponding Grignard reagents (Scheme 2). These organometallic derivatives
(1.5–2.0 equivalents) are transmetallated using 3.0 equivalents of anhydrous zinc chloride. The resulting
organozinc reagents are coupled with the bromopyridines (2) (1.0 equivalents) in the presence of a
catalytic amount of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, under refluxing conditions, to
afford the required pyridylpyrimidines (1) in moderate to very high yields (32–99%) (Table 1).
Scheme 2.
Table 1

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This one-pot synthesis involving sequential metallation, transmetallation and cross-coupling reactions
provides an extremely effective and versatile route to pyridylpyrimidines (1). A related protocol10 was
being employed, around the same time this research programme was being carried out, to make the
2,20-bipyridyl sub-unit of the caerulomycin antibiotics.
Benzyllithium, prepared by the direct lithiation of toluene with n-BuLi in the presence of N,N,N0,N0-
tetramethylethylenediamine (TMEDA),11 can also be used successfully in these reactions as an alterna-
tive to benzylmagnesium chloride (Table 1, Entry 6). The subsequent transmetallation and cross-coupling
reactions gave 2-(6-benzylpyrid-2-yl)-4-methylpyrimidine (4) (Scheme 3) in 59% yield after purification.
Scheme 3.
In a further extension of this methodology, the bromopyridylpyrimidine (2) (R2=CH3) can also be
cross-coupled with phenylacetylene and bis(triphenylphosphine)palladium chloride–cuprous chloride
((Ph3P)2PdCl2–CuCl) in diethylamine12 to give the disubstituted acetylene (5) (Scheme 4) in 54%
yield.13
Scheme 4.
The experimental details of this cross-coupling procedure are illustrated by the preparation of 2-(6-m-
chlorobenzylpyrid-2-yl)-4-methylpyrimidine) (Table 1, Entry 10).
Anhydrous zinc chloride (24 ml, 24 mmol of a 1.0 M solution in diethyl ether) was added drop-
wise to a stirred solution of m-chlorobenzylmagnesium chloride (8 mmol) in anhydrous diethyl ether
(40 ml) at 20°C under a nitrogen atmosphere. To this mixture was added 2-(6-bromopyrid-2-yl)-4-
methylpyrimidine (1.0 g, 4 mmol) and tetrakis(triphenylphosphine)palladium(0) (100 mg, 0.087 mmol)
in dry THF (25 ml). The mixture was refluxed for 2 hours, cooled to room temperature and poured into
10% ethylenediaminetetraacetic acid disodium salt solution (150 ml) at pH 8. The aqueous layer was
extracted with ethyl acetate and the combined organic solutions dried and concentrated in vacuo to give
a bright orange oil. This was purified by HPLC1 (silica gel eluted with 2% MeOH in EtOAc) to give (1)
(Table 1, Entry 10) as an orange gum (58%).
1H NMR (270 MHz, CDCl3); δ=2.66 (s, 3H), 4.37 (s, 2H), 7.09 (d, J=7.1 Hz, 1H), 7.15–7.30 (m, 4H),
7.18 (d, J=5.0 Hz, 1H), 7.75 (t, J=7.1 Hz, 1H), 8.34 (d, J=7.1 Hz, 1H), 8.81 (d, J=5.0 Hz, 1H) ppm.
M+-294 and 296.
1
Substantial losses of material were noted during chromatography as the compounds were presumably bound to trace metals
on silica gel. This could be overcome by eluting a pyridylpyrimidine down the column and removing the metal chelate with
20% MeOH in CH2Cl2. The same column could then be used for subsequent chromatography after this conditioning.

1656
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