Reaction of α,α-dibromo oxime ethers with Grignard reagents: Alkylative annulation providing a pyrimidine core

Article abstract of DOI:10.1021/ja0269284

A convergent synthesis of a pyrimidine core has been achieved. Treatment of α,α-dibromo oxime ethers, which are easily derived from the corresponding esters, with a variety of Grignard reagents provides trisubstituted pyrimidines in good yields. This new

Full text of DOI:10.1021/ja0269284

Published on Web 07/10/2002
Reaction of r,r-Dibromo Oxime Ethers with Grignard Reagents: Alkylative
Annulation Providing a Pyrimidine Core
Hirotada Kakiya, Kazunari Yagi, Hiroshi Shinokubo,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 606-8501, Japan
Received May 16, 2002
Scheme 1
Pyrimidines are an important class of heteroaromatic compounds
and have widespread applications from pharmaceuticals to materi-
als.1 A number of pyrimidines are known to have antimicrobial
and antitumor activities, and some of them are presently in use.
The electron-deficient nature of pyrimidines can provide highly
electron-accepting ability to conjugated polymers.2 In addition,
Scheme 2
conjugated molecules which have a pyrimidine core as the key unit
have received much attention recently, and they are prospective
candidates for light-emitting devices.3 Pyrimidine also has interest-
ing characteristics as a ligand for a variety of transition metals to
construct supramolecules.4
Table 1. Synthesis of Pyrimidines from Dibromo Oxime Ethersa
Due to these unique properties, development of synthetic methods
which enable rapid access to pyrimidines is desirable. In most cases,
synthesis of pyrimidine is based on classical condensation reactions
between C-C-C and N-C-N components5 or cross-coupling
reactions.6 Herein we wish to report a novel construction of a
pyrimidine core with incorporation of various alkyl and aryl groups
from the corresponding Grignard reagents. The reaction of R,R-
dibromo oxime ethers with a variety of Grignard reagents efficiently
provides 2,4,6-trisubstituted pyrimidines.
R,R-Dibromo oxime ethers are easily prepared from the corre-
sponding R,R-dibromo ketones upon treatment with O-methyl
hydroxylamine hydrochloride in methanol. R,R-Dibromo ketones
are readily available from the reaction of esters with dibromo-
methyllithium via Kowalski’s protocol7 or oxidation of dibromo-
methyl carbinols with PCC (Scheme 1).8
To a THF solution of R,R-dibromoacetophenone O-methyloxime
(1a, Z/E ) 84/16) was added 1.1 equiv of butylmagnesium bromide
in THF dropwise at 0 °C, and the color of the reaction mixture
turned deep purple. The mixture was stirred for 1 h. Aqueous
workup and purification afforded 2-butyl-4,6-diphenylpyrimidine
(2a) in 25% yield (Scheme 2). It then proved to be necessary to
employ more than 2.0 equiv of the Grignard reagent to improve
the yield. After optimization, treatment of 1a with 2.2 equiv of
n-BuMgBr at -42 °C and warming up the reaction mixture to room
temperature furnished 2a in 74% yield.
a Reaction conditions: Substrates (1.0 mmol), Grignard reagent (2.2
equiv), THF (5 mL), -42 °C then warming the reaction mixture up to room
temperature.
We examined various Grignard reagents to be incorporated in
the pyrimidine core. Not only alkyl groups but also aryl and vinyl
groups can be introduced. Table 1 summarizes the results. Several
characteristics of this reaction are noteworthy. p-Bromophenyl
derivative 1e provides the corresponding pyrimidine 2k without
reduction of bromide. Bromide 2k is a useful compound for the
synthesis of highly conjugated molecules via a Sonogashira-
coupling reaction (Scheme 3). Using p-bromophenylmagnesium
bromide, p-bromophenyl group can be introduced at the 2-position
of the pyrimidine core providing 2g. This protocol also enables
the synthesis of a heteroaromatic-substituted pyrimidine. Difu-
rylpyrimidine 2l can be prepared from 1f.
Interestingly, the use of allylic magnesium compounds instead
of alkyl or aryl Grignard reagents provided none of the correspond-
ing pyrimidines. Instead, the reaction afforded diallylated aziridines
3a or 3b in good yields (Scheme 4).
To obtain mechanistic insights, we carried out the reaction at
-98 °C (Scheme 5). Quenching the reaction at -98 °C provided
R-bromo oxime ether 4a exclusively. This result indicates that
bromine-magnesium exchange to furnish carbenoid 5 is the initial
* To whom correspondence should be addressed. E-mail: oshima@fm1.kuic.kyoto-
u.ac.jp; shino@fm1.kuic.kyoto-u.ac.jp.
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J. AM. CHEM. SOC. 2002, 124, 9032-9033
10.1021/ja0269284 CCC: $22.00 © 2002 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
In conclusion, we have achieved a facile synthesis of pyrimidines
from R,R-dibromo oxime ethers with a variety of Grignard reagents.
The alkyl or aryl group of a Grignard reagent is introduced at the
2-position of the pyrimidine core efficiently.
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research on Priority Area (No. 412: Exploitation of
Multi-Element Cyclic Molecules) from the Ministry of Education,
Culture, Sports, Science, and Technology, Japan. H.K. acknowl-
edges the Research Fellowships of the Japan Society for the
Promotion of Science for Young Scientists for financial support.
Scheme 4
Supporting Information Available: General procedures, spectral
data for compounds, and DFT calculations for electrocyclization of a
1,5-diaza-1,3,5-triene (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 5
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Scheme 6
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stage.9 Warming this reaction mixture yielded pyrimidine 2a. Even
at -78 °C, no other intermediary products than 4a were isolated.
We propose a plausible mechanism involving an azirine inter-
mediate as depicted in Scheme 6. Bromine-magnesium exchange
affords carbenoid 5, which is then alkylated at the R-position with
the Grignard reagent to furnish 6.10 R-Magnesiated oxime ether 6
undergoes Neber-type cyclization11 to provide highly reactive azirine
7.12 The reaction of azirine with 5 affords 8, which yields diimine
9 via ring opening. An electrocyclization of 9 provides a pyrimidine
skeleton 10,13 which is finally converted to pyrimidine 2 upon
elimination of methanol. Although the present reaction pathway is
speculative, the formation of allylated aziridine 3 from the reaction
of 1 with allylmagnesium chloride can support the presence of
azirine 7 as the intermediate.14
(14) The reaction of 11 with n-BuMgBr provided aziridine 12, which clearly
indicates the presence of the azirine intermediate 7 via 6. We thank a
reviewer for suggesting this experiment.
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