Carbon-carbon bond construction at the 2-position of polysubstituted pyrimidinones

Article abstract of DOI:10.1016/S0040-4039(02)02197-4

A novel synthetic method to introduce a carbon-carbon bond at the 2-position of pyrimidinones via nucleophilic addition of Grignard reagents to 2-cyano pyrimidinones at ambient conditions is disclosed. This unique approach leads to the preparation of such

Full text of DOI:10.1016/S0040-4039(02)02197-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8901–8903
Carbonꢀcarbon bond construction at the 2-position of
polysubstituted pyrimidinones
Dawei Zhang,* Kelvin Sham, Guo-Qiang Cao, Randall Hungate and Celia Dominguez
Department of Small Molecule Drug Discovery, AMGEN Inc., One AMGEN Center Drive, Thousand Oaks, CA 91320, USA
Received 29 August 2002; revised 27 September 2002; accepted 1 October 2002
Abstract—A novel synthetic method to introduce a carbonꢀcarbon bond at the 2-position of pyrimidinones via nucleophilic
addition of Grignard reagents to 2-cyano pyrimidinones at ambient conditions is disclosed. This unique approach leads to the
preparation of such biologically important molecules as polysubstituted pyrimidinones in good to excellent yields. © 2002 Elsevier
Science Ltd. All rights reserved.
During the course of a recent investigation, we became
interested in the introduction of a carbonꢀcarbon bond
at the 2-position of substituted pyrimidinones. It has
been previously reported in the literature that the car-
bonꢀcarbon bond can be built into 2-pyrimidines, a
similar heteroaromatic system to our targeted pyrimidi-
nones, by palladium catalyzed Stille,1 Suzuki2–4 or
Heck5,6 reaction derived from 2-chloropyrimidines.
Therefore, we first examined the cross-coupling reaction
of 2-chloropyrimidinones under these reported coupling
conditions for pyrimidines. As a readily available start-
ing material, 2-chloropyrimidinones have been prepared
in our lab7 in good overall yield and sub-kilogram scale
outlined in Scheme 1.
chloropyrimidinone 3a with an alkyne to afford com-
pound 7 in moderate yield (Scheme 3). The triple bond
was cleanly reduced under normal hydrogenation
conditions.
The limitation of the transition metal catalyzed reaction
discussed above is the difficulty of directly displacing
the chloride of the 2-chloropyrimidinones with an alkyl
group. Efforts to introduce the alkyl group under rela-
tively mild conditions were explored. Initially, nucle-
ophiles such as methyl magnesium bromide, phenethyl
magnesium chloride, phenyl magnesium bromide,
methyl lithium, and phenyl lithium at or below room
temperature failed to react with compound 2 or 3 to
generate the desired corresponding carbon analogs. As
in the case of chloropyrimidines, compounds 2 and 3
react readily with ‘soft’ nucleophiles such as amines,7
but their reactivity towards organo lithium reagents or
Grignard reagents is somewhat sluggish. The chloride
of starting material 3 was gradually hydrolyzed to
hydroxyl group under elevated temperature and pro-
longed reaction time. However, once the chloropyrim-
idinones 3 were converted to the cyanopyrimidinones 8
(Scheme 4), as reported for the synthesis of 2-cyano-
pyrimidine,10 compounds 9–13 were prepared cleanly in
2-Chloropyrimidinone 3b was cross-coupled success-
fully with piperidine triflate8 4 to give compound 5 in
moderate to good yields under the reported coupling
conditions for 2-chloropyrimidines (Scheme 2).9 The
double bond in the piperidine ring was reduced fol-
lowed by removal of the Boc group to give compound
6.
Alternatively, a carbonꢀcarbon bond was introduced
via palladium and CuI co-catalyzed reaction of 2-
Scheme 1. Preparation of 2-chloropyrimidinones.
* Corresponding author. Tel: (805) 447-4743; fax: (805) 480-1337; e-mail: daweiz@amgen.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02197-4

8902
D. Zhang et al. / Tetrahedron Letters 43 (2002) 8901–8903
Scheme 2. Cross-coupling reaction employing 2-chloropyrimidinone.
Scheme 3. Construction of a carbonꢀcarbon bond between 2-chloropyrimidinone and an alkyne.
3.00 equiv.). Hexamethylditin (460 mg, 1.40 mmol, 1.00
good to excellent yields by reaction of Grignard
reagents with compounds 8 at 0°C for 30 min. (Scheme
4 and Table 1). No ketones were formed via direct
attack of Grignard reagents on the cyano group itself.
This result is in contrast to previously reported results
in the literature that Grignard reagents only add to the
cyano carbon of cyanopyridines11 or cyano-
pyrimidines.12
equiv.) was next added followed by anhydrous dioxane
(10 mL) and the mixture was heated to reflux for 18 h
under nitrogen. The cooled mixture was then poured
into saturated aqueous potassium fluoride solution and
vigorously stirred for 2 h. The two-phase mixture was
filtered and the organic layer was separated, washed
with brine, dried over MgSO4, and concentrated in
vacuum. Purification by flash column chromatography
(1–3% MeOH–CHCl3) afforded 5 (394 mg, 55%) as an
Yields of compounds 9–13 are reported in Table 1.
1
off-white foam: H NMR (CDCl3, 400 MHz) l 8.44 (d,
In summary, a novel synthetic method for the prepara-
tion of polysubstituted pyrimidinones has been
reported. In contrast to the low reactivity of 2-thiol-
methylpyrimidinones 2 or 2-chloropyrimidinones 3
toward Grignard reagents or organo lithium reagents,
2-cyanopyrimidinones 8 undergo facile reaction with
various Grignard reagents to directly afford 2-carbon
substituted pyrimidinones 9–13 in good isolated yields.
The biological evaluation of these compounds as well
as the application of this methodology to different
substrates is currently underway.
J=5.60 Hz, 2H), 7.43 (m, 2H), 7.32 (m, 2H), 7.08 (d,
J=5.69 Hz, 2H), 6.11 (brs, 1H), 4.11 (m, 2H), 3.68 (m,
2H), 3.58 (s, 3H), 2.54 (m, 2H), 1.45 (s, 9H). MS (ES+):
513.3 (M+H)+; (ES−): 511.5 (M−H)−.
Preparation of compound 13: To a solution of com-
pound 8b (149 mg, 0.42 mmol, 1.00 equiv.) in THF (15
Table 1.
Compound
X
R
Yield (isolated) (%)
Preparation of compound 5: To an oven-dried 50 mL
round bottom flask under nitrogen were added triflate 4
(466 mg, 1.40 mmol, 1.00 equiv.), chloride 3b (514 mg,
1.40 mmol, 1.00 equiv.), tetrakis(triphenylphos-
phine)palladium (0) (81 mg, 0.07 mmol, 0.05 equiv.),
and anhydrous lithium chloride (180 mg, 4.20 mmol,
9
4-F
4-F
4-F
3-CF3
3-CF3
-Me
94
72
46
58
78
10
11
12
13
-CH2CH2Ph
-CH2CN
-Ph
-CH2CH2Ph
Scheme 4. Reaction of Grignard reagents with 2-cyanopyrimidinones. Reagents and conditions: (i) NaCN (1.00 equiv.),
triethylenediamine (2.00 equiv.), NMP/water (20/1), rt, 1 h; (ii) RMgX, THF, 0°C, 30 min for compounds 9, 10, 12, and 13;
n-BuLi/CH3CN, THF, 0°C, 30 min for compound 11.

D. Zhang et al. / Tetrahedron Letters 43 (2002) 8901–8903
8903
mL) at 0°C was added phenethyl magnesium bromide
References
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30 min, the reaction was quenched with water (15 mL),
and extracted with EtOAc (3×50 mL). The organic
layer was washed again with water (3×15 mL), dried
over MgSO4, filtered and concentrated into yellow oil.
Purification by preparative TLC plate (1:1; hex-
ane:EtOAc) afforded compound 13 as a light yellow
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We would like to thank Gil Rishton, Jeff Chen and
Thomas Nixey for proof-reading this document.