Synthesis of pyrimidines via base-induced condensation of α-chloro oxime derivatives

Article abstract of DOI:10.1246/cl.2004.122

A facile synthesis of 2,4,6-trisubstituted pyrimidines from the reaction of α-chloro oxime ethers with Grignard reagents has been developed. Alkyl and aryl groups can be easily introduced at the 2-position of the pyrimidine core. In addition, a synthesis of unsymmetrical pyrimidines has been examined.

Full text of DOI:10.1246/cl.2004.122

122
Chemistry Letters Vol.33, No.2 (2004)
Synthesis of Pyrimidines via Base-induced Condensation of ꢀ-Chloro Oxime Derivatives
Takayuki Tsuritani, Hiroshi Shinokubo,ꢀy and Koichiro Oshimaꢀ
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510
yDepartment of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502
(Received October 30, 2003; CL-031038)
A facile synthesis of 2,4,6-trisubstituted pyrimidines from
Table 1. Reaction of carbenoid derived from 1a with butylmag-
nesium bromide
the reaction of ꢀ-chloro oxime ethers with Grignard reagents
has been developed. Alkyl and aryl groups can be easily intro-
duced at the 2-position of the pyrimidine core. In addition, a syn-
thesis of unsymmetrical pyrimidines has been examined.
nBu
OMe
OMe
Cl
N
lithium amide, nBuMgBr
N
N
N
+
Ph
THF, −78 °C to r. t.
Ph
Ph
Ph
Ph
1a
2a
3a
The pyrimidyl heterocyclic core is a common subunit in nu-
merous natural products.1 Classical condensation reactions of
1,3-dicarbonyl compounds with amidines or amidinium salts
can provide substituted pyrimidines. However, there have been
relatively few methods available to produce trisubstituted pyri-
midines.2 Recently, we have disclosed that treatment of ꢀ; ꢀ-
dibromo oxime ethers with Grignard reagents provides 2,4,6-
trisubstituted pyrimidines.3 Although the whole reaction mecha-
nism has not yet been clearly elucidated, it is clear that bromine–
magnesium exchange takes place to generate a magnesium car-
benoid in the initial stage. We anticipated that deprotonation at
the ꢀ-position of ꢀ-halo oxime ethers would also provide the
same type of carbenoid, and we set out to develop a pyrimidine
synthesis starting from ꢀ-halo oxime ethers. From a synthetic
point of view, widely available ꢀ-halo oxime ethers are undoubt-
edly superior substrates to ꢀ; ꢀ-dibromo oxime ethers. Herein
we wish to report a base-induced construction of 2,4,6-trisubsti-
tuted pyrimidines from ꢀ-chloro oxime ethers. Moreover, mod-
ification of this method allows for the synthesis of unsymmetri-
cal pyrimidines.
To a THF solution of ꢀ-chloroacetophenone O-methylox-
ime (1a) was added 1.2 equiv. of lithium diisopropylamide
(LDA) in THF dropwise at ꢁ78 ꢂC and the mixture was stirred
for 15 min. To the resulting mixture was added 1.5 equiv. of but-
ylmagnesium bromide in THF at ꢁ78 ꢂC, and gradual warming
to room temperature furnished 2-butyl-4,6-diphenylpyrimidine
(2a) in 38% yield along with 1,3-diphenylpropyn-1-one O-meth-
yloxime (3a) in 2% yield. After optimization of the reaction con-
ditions, we found that the addition of the Grignard reagent before
1a improved yield of 2a. The results obtained in this manner are
listed in Table 1. To attain a good conversion, more than 2.0
equiv. of lithium amide is necessary. Interestingly, the bulkiness
of lithium amide is crucial. The use of more sterically hindered
lithium amides affords higher selectivity (Runs 1–3).
Lithium
Amide
nBuMgBr
/equiv.
Yield /%
2a 3a
Run
/equiv.
1
2
3
4
5
LDA
LiNEt2
LTMP
LTMP
LTMP
LTMP
2.0
2.2
2.2
2.0
2.0
1.5
1.0
1.0
1.0
0.5
2.0
0.5
63
34
84
42
71
46
8
38
4
56
<1
3
6a
a
1a was recovered in 25%.
Table 2. Synthesis of pyrimidines
R2
OMe
LTMP (2.2 equiv.)
OMe
Cl
N
R2MgBr
N
N
N
+
R1
R1
THF, −78 °C to r. t.
R1
R1
R1
2
3
1
Yield /%
Run
R1
R2 /equiv.
nBu
2
3
1
2
3
4
5
6
7
8
9
Ph 1a
1a
1a
1a
1a
1.0 2a 84
3a 4
3a 3
3a 6
3-Octenyl 1.1 2b 79
cHexyl
Mea
Ph
vinyl
nBu
nBu
nBu
nBu
nBu
nBu
1.2 2c 76
1.1 2d 64 3a 13
2.0 2e 63
2.0 2f 64
1.5 2g 83 3b <1
1.1 2h 75 3c 8
1.0 2i 65 3d 12
1.0 2j 56
1.2 2k 42
1.2 2l 22
3a 9
-
1a
4-ClC6H4 1b
4-BrC6H4 1c
4-MeOC6H4 1d
cPen 1e
b
10
11
12c
a
-
-
-
b
b
nC8H17 1f
Me 1g
Methylmagnesium iodide was used. b The generation of al-
kynyl oxime ether was elusive due to the presence of other
unidentified products. To a THF solution of 1g was added
We then investigated the scope and limitations of this proce-
dure. Table 2 summarizes the results. Alkyl, aryl, and vinyl
groups can be introduced through the corresponding Grignard
reagent.4 Alkyl substituted ꢀ-chloro oxime ethers with ꢀ-pro-
tons on both sides afforded the pyrimidines in moderate yields
(Runs 10–12).
On the basis of these results, we propose a plausible mech-
anism, which has been modified from our previous proposal
(Scheme 1).3 Deprotonation of ꢀ-chloro oxime ether 1 generates
carbenoid 4, which then undergoes Neber-type cyclization5,6 to
c
LTMP and then added Grignard reagent.
provide highly reactive azirine 5.7 Nucleophilic addition of 4
to azirine 5 and subsequent intramolecular cyclization yields
2-chloro-1-azabicyclo[1.1.0]butane 7,8 which has been postulat-
ed as a common intermediate for both pyrimidines and alkynyl
oxime ethers. Halide displacement by the alkyl group at the
C2 position triggers ring opening to release strain giving imino
oxime ether 8. After an electrocyclization, 9 is converted to pyr-
Copyright Ó 2004 The Chemical Society of Japan

Chemistry Letters Vol.33, No.2 (2004)
123
Table 3. Synthesis of unsymmetrical pyrimidines
OMe
Cl
OMe
Cl
N
nBu
N
N
base
LTMP (5.0 equiv.)
OMe
Cl
OX
Cl
R1
R1
R1
N
N
4
nBuMgBr (4.0 equiv.)
THF
N
N
5
+
1
Li
Cl
R1
R2
R1
R2
1
12 or 13
15
12b: X = Ts, R2 = 4-ClC6H4
13a: X = C(O)OEt, R2 = Ph 13b: X = C(O)OEt, R2 = 4-ClC6H4
OMe
N
OMe
12a: X = Ts, R2 = Ph
MeO
R1
N
N
N
N
N
base
R1
C2 Cl
R1
Cl
Cl
Run
T
/ꢂC
Yield / %
15
Hα
R1
R2
R1
7
10
R1
2
Cl
6
R1
1a
2a
4-ClC6H4 1b
1b
13a
13a
13a
13b
13b
12a
12b
13a
13b
13b
13a
ꢁ78
ꢁ98
ꢁ98
ꢁ98
ꢁ88
ꢁ98
ꢁ98
ꢁ78
ꢁ78
ꢁ78
ꢁ78
15a 11
15a 34
15a 56
15a 34
15a 57
15b 44
15c 44
15d 52
15e 56
15e 23
15f 60
2g 68
R2MgBr
R2
OMe
N
OMe
N
N
N
3b
1b
Ph 1a
MeO
R1
N
N
R1
4b
R1
Cl
R1
11
5b
1a
4-BrC6H4 1c
1c
nC8H17 1f
1f
2a 14
8
R1
OMe
R1
6c
7c
R2
R2
N
8a
MeO
R1
+
HCN
N
N
N
N
R1
9a
R1
MeOH
10b
11a
1f
R1
R1
R1
3
2
9
tBuCH2 1h
a
Scheme 1.
The reaction employed 13 (1.1 equiv.), and the yield is
b
imidine 2 upon elimination of methanol.3 On the other hand, re-
moval of an ꢀ-proton of 7 leads to alkynyl oxime ether 3 via cy-
cloreversion of highly unstable azacyclobutadiene intermediate
11.9,10 Although the present reaction pathway is still speculative,
it is in good agreement with the fact that a sterically hindered
lithium amide prefers the generation of pyrimidines to alkynyl
oxime ethers.
based on 1. The reaction employed 1 (2.0 equiv.), and the
yield is based on 13. c The reaction employed 1 (1.6 equiv.),
and the yield is based on 12.
References and Notes
1
2
K. Undheim and T. Benneche, ‘‘Comprehensive Heterocy-
clic Chemistry II,’’ ed. by A. R. Katritzky, C. W. Rees,
and E. F. V. Scriven, Pergamon, Oxford (1996), Vol. 6,
Chap. 6.02.
a) T. J. J. Muller, R. Braun, and M. Ansorge, Org. Lett., 2,
1967 (2000). b) J. M. Schomaker and T. J. Delia, J. Org.
Chem., 66, 7125 (2001).
In our recent study, we developed a cross-condensation re-
action to provide alkynyl oxime ether 14 (Eq 1). In this reaction,
selective generation of haloazirine from one of two different ox-
ime derivatives is a key issue.9 The difficulty was circumvented
by using a combination of oxime methyl ether 1 and oxime p-tol-
uenesulfonate 12 or ethoxycarbonate 13, where cyclization of
carbenoid derived from 12 or 13 proceeded much faster than that
of 1. We tested this methodology to see if it was also applicable
for the synthesis of unsymmetrical pyrimidines 15. After optimi-
zation of the reaction conditions, a variety of unsymmetrical pyr-
imidines 15 were obtained. Several comments are worth noting.
1) Aryl substituted oxime methyl ethers undergo dimerization to
provide 2 even at ꢁ88 ꢂC (Run 5). At ꢁ98 ꢂC the dimerization of
1 is suppressed. On the other hand, carbenoids derived from al-
kyl substituted oxime methyl ethers are stable at ꢁ78 ꢂC under
the reaction conditions. 2) The use of an excess of aryl substitut-
ed oxime methyl ethers (2.0 equiv.) improved the yield of 15
(Runs 2 and 3). However, this was not the case for alkyl substi-
tuted oxime methyl ethers (Runs 9 and 10).
3
4
H. Kakiya, K. Yagi, H. Shinokubo, and K. Oshima, J. Am.
Chem. Soc., 124, 9032 (2002).
To a solution of LTMP (2.2 mmol) in THF (4 mL) was added
a solution of n-BuMgBr (1.0 mL, 1.0 M solution in THF,
1.0 mmol) dropwise at ꢁ78 ꢂC. To the resulting mixture
was added 1a (183.6 mg, 1.0 mmol) in THF (2 mL) at ꢁ78
ꢂC, and the mixture was warmed up to room temperature
gradually. After aqueous workup, purification by chromatog-
raphy afforded 2a (121.1 mg, 0.42 mmol). Spectral data for
2a were identical with those reported in the literature.
Recent examples, see: a) F. Palacios, A. M. O. de Retana,
and J. I. Gil, Tetrahedron Lett., 41, 5363 (2000). b) T. Ooi,
M. Takahashi, K. Doda, and K. Maruoka, J. Am. Chem.
Soc., 124, 7640 (2002).
The recent SN2-type substitution reactions at sp2 nitrogen,
see: H. Yanagisawa, K. Miura, M. Kitamura, K. Narasaka,
and K. Ando, Bull. Chem. Soc. Jpn., 76, 2009 (2003).
W. H. Pearson, B. W. Lian, and S. C. Bergmeier, ‘‘Compre-
hensive Heterocyclic Chemistry II,’’ ed. by A. R. Katritzky,
C. W. Rees, and E. F. V. Scriven, Pergamon, Oxford (1996),
Vol. 1A, Chap. 1.01.
5
6
7
OMe
OMe
Cl
OX
N
N
N
LDA
+
Cl
R1
R1
R2
R2
1
14
12 X = Ts
13 C(O)OEt
(1)
This work was supported by a Grant-in-Aid for Scientific
Research on Priority Areas (No. 412: Exploitation of Multi-Ele-
ment Cyclic Molecules) and the Grant of the 21st Century COE
program from the Ministry of Education, Culture, Sports, Sci-
ence and Technology, Japan. H. S. thanks Tokuyama Science
Foundation for financial support.
8
9
a) R. Mauze, Tetrahedron Lett., 25, 843 (1984). b) S. Calet
and H. Alper, Tetrahedron Lett., 27, 2739 (1986).
T. Tsuritani, K. Yagi, H. Shinokubo, and K. Oshima, Angew.
Chem., Int. Ed., 42, 5613 (2003).
10 The generation of HCN was confirmed. see Ref. 9.
Published on the web (Advance View) January 8, 2004; DOI 10.1246/cl.2004.122