Synthesis of tri-or tetrasubstituted pyrimidine derivatives through the [5+1] annulation of enamidines with either N,N-dimethylformamide dialkyl acetals or orthoesters and their application in a ring transformation of pyrimidines to pyrido[2,3-d]pyrimidin

Article abstract of DOI:10.1002/chem.201100040

The [5+1] annulation of enamidines, which were prepared from functionalized silanes, organolithium compounds and two nitriles, with N,N-dimethylformamide dialkyl acetals as the C1 unit is described, leading to the synthesis of tri- and tetrasubstituted py

Full text of DOI:10.1002/chem.201100040

FULL PAPER
DOI: 10.1002/chem.201100040
Synthesis of Tri- or Tetrasubstituted Pyrimidine Derivatives through the
[5+1] Annulation of Enamidines with either N,N-Dimethylformamide
Dialkyl Acetals or Orthoesters and Their Application in a Ring
Transformation of Pyrimidines to PyridoACTHNUGRTNEUNG[2,3-d]pyrimidin-5-one Derivatives
Toshiaki Sasada, Youichi Aoki, Reiko Ikeda, Norio Sakai, and Takeo Konakahara*[a]
Abstract: The [5+1] annulation of en-
amidines, which were prepared from
functionalized silanes, organolithium
compounds and two nitriles, with N,N-
dimethylformamide dialkyl acetals as
the C1 unit is described, leading to the
synthesis of tri- and tetrasubstituted
pyrimidine derivatives under catalyst-
and solvent-free reaction conditions.
Furthermore, the [5+1] annulation of
enamidines by using orthoesters as the
C1 unit is described, in which catalytic
amounts of ZnBr2 catalyze the annula-
tion to produce polysubstituted pyrimi-
dines under toluene or xylene reflux
conditions. Moreover, the combination
of a reductive ring-opening reaction
with [Mo(CO)6] and a subsequent in-
tramolecular cyclization with tBuOK
effectively causes a skeletal transfor-
mation from the pyrimidines contain-
ing an isoxazolyl and an ethoxy sub-
Keywords: annulation
·
enami-
stituent to form pyrido
ACHTUNGTREN[NUGN 2,3-d]pyrimidin-
dines · multicomponent reactions ·
nitrogen heterocycles · pyrimidines
5-one frameworks in excellent yield.
Introduction
Tri- and tetrasubstituted pyrimidine derivatives constitute a
key structure[1,2] commonly found in natural products, such
as vitamin B1 (thiamine)[3] and heteromine F,[4] and in bio-
logically active substances, such as nimustine,[5] pyrimeth-
ACHTUNGTRENNUNG
amine,[6] and phosphatidylinsositol 3-kinase (PI3K) inhibi-
tors[7] (Scheme 1). A variety of approaches for the synthesis
of pyrimidine derivatives have been developed by a number
of organic and pharmaceutical chemists.[1,8–11] Most general
synthetic routes to the pyrimidine framework utilize one of
the following procedures (Scheme 2): i) [3+3] annulation be-
À À
À À
tween an N C N and a C C C fragment (known as the
Pinner-type synthesis;[12] path a),[13,14] or between a C C N
À À
[15]
À À
and a C N C fragment (path b); ii) [4+2] annulation of a
[16]
À À À
À
À
C C N C fragment with a C N fragment (path c), a C
[17]
À À
À
À
C C N fragment with a C N fragment (path d), or a C
N C N fragment with a C C fragment (path e);
[18]
À À
À
and
À À À À
iii) [5+1] annulation of a N C C C N fragment with a C1
unit (path f),[19] or of a C N C C C fragment with an N1
À À À À
unit (path g).[20] To our knowledge, the [5+1] annulation of
Scheme 1. Examples of pyrimidine derivatives.
À À À À
a C C N C N fragment with a C1 unit has not yet been
studied (path h). Moreover, the procedures shown in paths
a–g often require a greater than stoichiometric quantity of
additives, expensive transition-metal complexes, unavailable
reagents, multiple-step syntheses, and harsh reaction condi-
tions that lead to a decrease in the product yield. Hence, the
development of a novel synthetic route, such as pathway h,
for the simple and efficient preparation of polysubstituted
pyrimidine derivatives is in high demand.
[a] T. Sasada, Y. Aoki, Dr. R. Ikeda, Prof. Dr. N. Sakai,
Prof. Dr. T. Konakahara
Department of Pure and Applied Chemistry
Tokyo University of Science (RIKADAI)
Noda, Chiba 278-8510 (Japan)
Fax : (+81)4-7123-9326
E-mail: konaka@rs.noda.tus.ac.jp
We have previously reported that intermolecular annula-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100040.
tion with an N-silyl-1-azaallylic anion,[21] which was generat-
Chem. Eur. J. 2011, 17, 9385 – 9394
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
9385

Results and Discussion
Synthesis of enamidine derivatives: Initially, a variety of en-
amidine derivatives were prepared by the one-pot, three-
component coupling reaction of functionalized silanes with
two nitriles,[27,29] or by the reaction of an organolithium com-
pound with a nitrile.[30] For example, when the reaction of 3-
methyl-5-(trimethylsilyl)methylisoxazole with benzonitrile
was carried out in THF in the presence of nBuLi at À708C
for 1 h, followed by addition of 2-cyanopyrazine, and the
mixture was stirred at room temperature for a further 2 h,
the desired enamidine derivative 1a was obtained in 90%
yield (Table 1, entry 1). The structure of enamidine 1a was
determined by use of spectral data and was unambiguously
confirmed by the X-ray crystallographic analysis of the simi-
lar compound 1b.
When the reaction of a benzonitrile with an electron-do-
nating or -withdrawing substituent as the first nitrile unit
was carried out with 2-cyanopyrazine as the second unit in
the presence of nBuLi, enamidines 1b–d were obtained in
moderate to good yield (Table 1, entries 2–4). Furthermore,
the employment of p-trifluoromethylbenzonitrile or 2-cya-
nopyrimidine as the second nitrile instead of 2-cyanopyra-
zine gave the corresponding enamidines 1e and f, although
the yield of 1e was low (Table 1, entries 5 and 6). On the
other hand, the preparation of enamidine 1g, which contains
an alkyl chain, that is, an nPr group, was achieved through
the reaction of an organolithium compound (nBuLi) with
two molecules of benzonitrile (Scheme 3).
Scheme 2. Typical methods for the synthesis of pyrimidines.
ed from a functionalized silane and an aromatic nitrile, and
its synthetic equivalent, an N-silylenamine,[22,23] efficiently
produce a variety of nitrogen-containing heterocyclic com-
pounds, such as pyridines,[24] pyrimidines,[25] and pyrroles.[26]
In our previous communication,[27] we showed that the [5+1]
annulation of an enamidine, which was prepared from the 1-
azaallylic anion and a nitrile, with an N,N-dimethylform-
ACHTUNGTRENNUNGamide dialkyl acetal or an orthoester produces polysub-
stitued pyrimidine derivatives (path h, Scheme 2). However,
this method still had some shortcomings: 1) a relatively high
reaction temperature (1408C) was required to cause the ex-
pected annulation of the enamidine with the acetal, 2) the
substituent on the substrates is limited to an isoxazolyl
group, and 3) only one reaction of the enamidine with an or-
thoester was described and it required a prolonged reaction
time (65 h). Thus, to overcome these synthetic problems and
to further extend the scope of this preparative route to mul-
tisubstituted pyrimidine derivatives, we decided to reinvesti-
gate the reaction conditions and attempt to increase the va-
riety of usable substrates. Herein, we report the full details
of the [5+1] annulation of an enamidine with an N,N-dime-
thylformamide dialkyl acetal, leading to the formation of
tri- or tetrasubstituted pyrimidine derivatives under catalyst-
and solvent-free reaction conditions. Moreover, we describe
a similar [5+1] annulation reaction of the enamidine with
an orthoester through ZnBr2 catalysis to form polysubstitut-
ed pyrimidines. Finally, we disclose a synthetic application
of this annulation reaction, in which a skeletal transforma-
tion of a pyrimidine framework containing an isoxazolyl
group on the C5 atom and an ethoxy group on the C4 atom
occurs with reductive ring-opening of the isoxazole ring, fol-
Catalyst-free annulation of enamidines with formamide ace-
tals leading to pyrimidine derivatives: On the basis of our
previous studies, the catalyst- and solvent-free annulation of
the prepared enamidines with N,N-dimethylformamide di-
ethyl acetal was then examined in the hope that trisubstitut-
ed pyrimidine derivatives would be synthesized. The results
of these reactions are summarized in Table 2. When the re-
action of enamidine 1a with an excess of N,N-di-
AHCTUNGTREGmNNUN ethylformamide diethyl acetal (2a) was carried out at
1208C for 2 h, the desired trisubstituted pyrimidine deriva-
tive 3a was obtained in nearly quantitative yield (Table 2,
entry 1). The structure of pyrimidine 3a was confirmed by
use of spectral data and by X-ray crystallographic analysis.
Similarly, when enamidines 1b–d, containing an electron-do-
nating or -withdrawing group on the benzene ring, were em-
ployed, the corresponding pyrimidine derivatives 3b–d were
obtained in good to excellent yield (Table 2, entries 2–4).
The introduction of a p-(trifluoromethyl)phenyl group or a
pyrimidine ring also allowed the formation of the desired
products 3e and f in excellent yield (Table 2, entries 5 and
6). In contrast, when enamidine 1g, containing an nPr
group, was used, the reaction proceeded cleanly, but pyrimi-
dine derivative 4 was unexpectedly formed along with the
expected pyrimidine 3g (Table 2, entry 7). The structure of
pyrimidine 4 was confirmed by use of spectral data.[31]
lowed by intramolecular cyclization to form pyridoACTHUNTGRNEUNG[2,3-
d]pyrimidin-5-one derivatives.[28]
To prepare tetrasubstituted pyrimidine derivatives 5, the
reaction of enamidines 1 with N,N-dimethylacetamide di-
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Synthesis of Tri- and Tetrasubstituted Pyrimidine Derivatives
FULL PAPER
Table 1. Synthesis of enamidine derivatives 1a–f.
Table 2. Catalyst- and solvent-free annulation of enamidines 1 with forma-
mide acetal 2a to give trisubstituted pyrimidine derivatives 3.
Enamidine
1
t
Pyrimidine
Yield
[%][a]
1
2
À
À
[h]
Ar CN Ar CN
t
Enamidine 1
Yield
[%][a]
[h]
1
2
3
4
5
1a
1b
1c
1d
1e
2
2
2
2
2
3a
3b
3c
3d
99
88
99
92
À
1
2
Ph CN
2
2
1a 90
1b 75
1c 50
1d 81
3
12
3e
3 f
90
97
4
2
6
7
1 f
1g
2
À
5
6
Ph CN
12
1e 30
24
+
3g+4 30+31
[a] Isolated yield.
À
Ph CN
6
1 f 63
methyl acetal (2b) was examined under our optimal reac-
tion conditions (Table 3). As a result, the desired 4-methyl-
pyrimidine derivative 5a was obtained in an 86% yield
(Table 3, entry 1). Regardless of the electronic effects of
substituents, such as a methoxy, an N,N-dimethylamino or a
halogen group, pyrimidine derivatives 5b–d were produced
in excellent yield (Table 3, entries 2–4). In addition, the re-
actions involving enamidines 1e and f, containing a p-tri-
fluoromethylated benzene and a pyrimidine ring, respective-
ly, provided the desired products 5e and f in good yield
(Table 3, entries 5 and 6). Moreover, when the annulation
was run with enamidine 1g, 4,5-dialkylated pyrimidine 5g
was obtained in nearly quantitative yield (Table 3, entry 7).
[a] Isolated yield.
Scheme 3. Synthesis of enamidine 1g.
Chem. Eur. J. 2011, 17, 9385 – 9394
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9387

T. Konakahara et al.
Table 3. Catalyst- and solvent-free annulation of enamidines 1 with acet-
amide acetal 2b to give tetrasubstituted pyrimidine derivatives 5.
Table 4. Examination of the annulation of enamidine 1a with orthoester
6a.
Enamidine 1
t
Pyrimidine 5
Yield
[%][a]
6a
[equiv]
Additive
([equiv])
Solvent
T
t
Yield
[%][a]
[h]
G
G
[oC]
[h]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
20
2
2
2
2
2
2
2
2
2
2
2
2
1
5
2
none
TFA (0.1)
InCl3 (0.1)
none
160
140
140
140
140
140
140
140
140
140
140
110
100
110
110
110
40
48
24
30
40
40
40
24
24
24
24
72
72
60
60
65
18
8
10
trace
trace
trace
trace
6
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
o-Cl2C6H4
xylene
PhMe
dioxane
PhMe
PhMe
PhMe
1
2
3
4
5
1a
2
2
2
2
3
5a 86
Cu
N
BF3·OEt2 (0.1)
MgBr2·OEt2 (0.1)
AlCl3 (0.1)
ZnACTHNGUTREN(UNG OTf)2 (0.1)
1b
1c
1d
1e
5b 98
ZnCl2 (0.1)
ZnBr2 (0.1)
ZnBr2 (0.1)
ZnBr2 (0.1)
ZnBr2 (0.1)
ZnBr2 (0.1)
ZnBr2 (0.1)
ZnBr2 (1)
53
77
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
44
36
82
66
5c
99
[a] Yield determined by NMR spectroscopy (isolated yield).
AlCl3, was ineffective at improving the product yield
(Table 4, entries 2–7). The addition of Zn(OTf)2 also result-
5d 87
AHCTUNGTRENNUNG
ed in a low yield (Table 4, entry 8), but ZnCl2 and ZnBr2
showed catalytic effects. In particular, ZnBr2 drastically im-
proved the product yield (Table 4, entry 10). Next, the addi-
tion of common solvents, such as xylene and PhMe, pro-
duced the desired product in an even higher yield (Table 4,
entries 11 and 12). On the other hand, decreasing the
amount of orthoester 6a resulted in a reduction in yield to
36% (Table 4, entry 14); however, the employment of an
excess of orthoester 6a (5 equiv) gave the product in 82%
yield (Table 4, entry 15). On the other hand, an increase in
the quantity of ZnBr2 caused a slight decrease in the prod-
uct yield (Table 4, entry 16). Thus far, the best reaction con-
ditions for this type of annulation of an enamidine with an
orthoester were found to be those used in Table 4, entries 11
and 12.
5e 99
6
7
1 f
1g
2
5 f
70
12
5g 99
[a] Isolated yield.
With these conditions in hand, we then investigated the
generality of this annulation reaction by using a range of en-
amidines. The results are shown in Table 5. In most cases,
the desired 4-ethoxypyrimidine derivatives were obtained in
good yield. For instance, when the reactions of enamidines
1b and d with orthoester 6a were conducted under the
aforementioned conditions, the desired 4-ethoxypyrimidines
7b and d were obtained in good yield (Table 5, entries 3–6).
Interestingly, the conditions involving the use of PhMe at
1108C gave pyrimidine derivative 7e in an 80% yield
(Table 5, entry 7), whereas 7e was only obtained in a 40%
yield when using xylene at 1408C (Table 5, entry 8). On the
other hand, when the reaction of enamidine 1g, containing
an alkyl chain, was run in PhMe at 1108C, the desired prod-
uct 7g was produced in good yield (Table 5, entry 9).
ZnBr2-catalyzed annulation of enamidines with orthoesters
leading to pyrimidine derivatives: To further explore the
scope of this reaction, we attempted the synthesis of poly-
substituted pyrimidine derivatives by employing an orthoest-
er instead of the formamide acetal. Unfortunately, when the
reaction of enamidine 1a with tetraethoxymethane (6a) was
carried out under our previously optimized conditions, the
desired pyrimidine derivative 7a was obtained in only 18%
yield (Table 4, entry 1). We therefore re-examined the reac-
tion conditions, first trying various additives. For example,
the addition of typical acid catalysts, such as trifluoroacetic
acid (TFA), InCl3, CuACHTNUGTREN(NUG OTf)2, BF3·OEt, MgBr2·OEt2, and
9388
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Synthesis of Tri- and Tetrasubstituted Pyrimidine Derivatives
FULL PAPER
Table 5. ZnBr2-catalyzed annulation of enamidines with orthoester 6a to
give 4-ethoxypyrimidine derivatives 7.
Table 6. ZnBr2-catalyzed annulation of enamidines 1 with orthoesters 6
to give polysubstituted pyrimidine derivatives.
1
Solvent
T
t
Pyrimidine 7
Yield
[%][a]
[8C] [h]
Enamidine 1 Orthoester 6 Solvent
T
t
Pyrimidine Yield
[%][a]
[8C] [h]
1
2
3
4
5
6
7
8
9
1a
1b
1d
1e
1 f
1g
1a
1a
1b
6b
6b
6b
6b
6b
6b
6c
6c
6c
6c
6c
6c
6c
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
110 18 3a
110 16 3b
110 16 3d
110 15 3e
110 15 3 f
110 24 3g
110 36 5a
99
92
98
99
84
65
92
87
99
90
99
56
99
1
2
3
4
5
6
7
1a PhMe
110 72
7a 80
1a xylene 140 24
7a 80
7b 80
7b 82
7d 64
7d 70
7e 80
xylene 140 16 5a
PhMe
PhMe
PhMe
PhMe
PhMe
110 36 5b
110 42 5d
110 14 5e
110 96 5 f
110 24 5g
1b PhMe
110 72
10 1d
11 1e
12 1 f
13 1g
1b xylene 140 18
[a] Isolated yield.
1d PhMe
110 72
enamidine 1 f was employed, the desired product 5 f was ob-
tained in only a 56% yield and the starting enamidine 1 f
was recovered in a 40% yield (determined by NMR spec-
troscopy; Table 6, entry 12). On the other hand, when the
annulation of enamidine 1g with 6c was carried out, the de-
sired reaction proceeded to produce dialkylated pyrimidine
5g in nearly quantitative yield (Table 6, entry 13).
1d xylene 140 18
1e PhMe
110 72
The formation of enamidine derivatives 1, shown in
Table 1, consists of a two-step reaction. The first step is the
formation of an N-silylenamine (or an enamine) from the
functionalized silane and the first nitrile. The second step is
the nucleophilic addition of the enamine to the second ni-
trile compound to form enamidines 1. In previous work, we
have reported that a variety of functionalized silanes react
with nitriles to form the corresponding enamines in good
yield. In these reactions 2-pyridyl,[32–36] 4-pyridyl,[33] tert-but-
8
9
1e xylene 140 36
7e 40
7g 67
1g PhMe
110 72
[a] Isolated yield.
We also examined the annulation by using orthoesters 6b
and c, instead of 6a, to produce tri- or tetrasubstituted pyri-
midine derivatives 3 and 5, respectively, under our opti-
mized reaction conditions (Table 6). When the reaction of
enamidine 1a with orthoester 6b was carried out in PhMe
at 1108C in the presence of a catalytic amount of ZnBr2, the
desired trisubstituted pyrimidine derivative 3a was obtained
in nearly quantitative yield (Table 6, entry 1). Furthermore,
the reaction with enamidines 1b and d–f, containing an iso-
xazole group, as well as with enamidine 1g, containing an
nPr group, successfully proceeded to produce the corre-
sponding pyrimidine derivatives 3b and d–g in good to ex-
cellent yield (Table 6, entries 2–6). Moreover, the employ-
ment of orthoester 6c succeeded in introducing an alkyl
group to form desired pyrimidine derivatives 5a–g in good
yield (Table 6, entries 7–13). Enamidines 1a, b, d, and e
gave the corresponding products 5a, b, d, and e, respective-
ly, in excellent yield (Table 6, entries 7–11). However, when
AHCTUNGTRENNUNG
oxycarbonyl,[33,34] 2-(3-methyl)pyridyl,[37] 2-thiazolinyl,[36] and
N,N-dimethylcarbamoyl[36] groups were used instead of the
3-methyl-5-isoxazlyl group.[32–37] Furthermore, the addition
of an alkyl lithium to alkylcyanides in the presence of trime-
thylsilyl chloride gave the corresponding N-silylimines in
high yield.[38] These imines were lithiated with lithium di-
AHCTUNGTREGiNNNU sopropylamide (LDA), leading to the formation of N-silyl-
1-azaallyl anions, which are precursors to enamines. Sym-
metrically substituted dialkylimines gave the corresponding
cis/trans N-silyl-1-azaallyl anion in high yield as the only
product.[38] Most of these enamines are able to react with ni-
triles to generate the corresponding enamidines. Therefore,
the enamidine substitution pattern is not limited to the 3-
methylisoxazolyl group. However, the unsymmetrically sub-
stituted imines gave a mixture of the different substituted
N-silyl-1-azaallyl anions because of abstraction of an a-hy-
drogen from each a-methylene group. This is the limitation
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T. Konakahara et al.
on applications of this method to aliphatic nitriles. If aryl-
cyanides were used as the first nitrile compounds, this limi-
tation will be avoided in the synthesis of compounds like 1g.
As an initial step, the reductive ring opening of the isoxa-
zole ring with [Mo(CO)6][39] (0.5 equiv) was examined
(Table 7). As expected, the reaction proceeded successfully
to produce the corresponding pyrimidine derivatives 8, con-
taining an amino group, in nearly quantitative yield
(Table 7, entries 1–4). As the second step, when pyrimidines
8 were treated with tBuOK in THF at 608C, intramolecular
Skeletal transformation to form pyridoACTHNUTRGNEUNG[2,3-d]pyrimidin-5-
one derivatives: Finally, to illustrate the versatility of an iso-
xazole ring, we examined an intramolecular skeletal trans-
formation between the pyrimidine ring and the tethered
amino group, which was formed through reductive ring
cyclization proceeded cleanly to produce pyridoACTHNUTRGNE[UNG 2,3-d]pyri-
midin-5-one derivatives 9 in excellent yield (Table 8).
opening of the isoxazole ring, to produce a pyrido
imidin-5-one derivative (Scheme 4).
ACHTUNGTRENUN[NG 2,3-d]pyr-
Mechanism: A plausible mechanism for the synthesis of a
pyrimidine skeleton from an enamidine derivative and an
N,N-dimethylformamide dialkyl acetal under catalyst-free
conditions is shown in Scheme 5. First, the enamidine reacts
with the N,N-dimethylformamide dialkyl acetal to form in-
termediate 10 with liberation of two molecules of alcohol.
Intramolecular cyclization of intermediate 10 then occurs to
produce intermediate 11. Finally, aromatization of the inter-
mediate by elimination of dimethylamine would be the driv-
ing force leading to the preparation of the corresponding
pyrimidine derivative.
Table 8. Synthesis of pyridoACTHNUGRTENUNG[2,3-d]pyrimidin-5-one derivatives 9.
Scheme 4. Transformation of pyrimidines into pyrido
one derivatives.
ACHTUNGTREN[NUNG 2,3-d]pyrimidin-5-
Table 7. Reductive ring-opening reaction of the isoxazolyl group.
Pyrimidine 8
Product 9
Yield
[%][a]
1
2
8a
9a
99
Pyrimidine 7
Product 8
Yield
[%][a]
1
2
3
4
7a
8a
8b
8d
8e
96
99
99
99
8b
9b
92
7b
7d
7e
3
4
8d
9d
96
99
8e
9e
[a] Isolated yield.
[a] Isolated yield.
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Chem. Eur. J. 2011, 17, 9385 – 9394

Synthesis of Tri- and Tetrasubstituted Pyrimidine Derivatives
FULL PAPER
opening of the isoxazole ring with [Mo(CO)6], followed by
intramolecular cyclization with tBuOK.
Experimental Section
General procedure for the reaction of enamidines 1 with acetals 2: En-
amidine 1 (0.200 mmol) and acetal
2 (4.00 mmol) were sequentially
added to a screw-capped vial, and the vial was sealed with a cap contain-
ing a PTFE septum. The mixture was heated at 1208C. After 2 h, volatile
compounds were evaporated under reduced pressure, and the crude
product was purified by silica gel column chromatography (AcOEt/
hexane) to give the pyrimidines in the yields given in Tables 2 and 3.
Scheme 5. A plausible mechanism for the solvent- and catalyst-free annu-
lation reaction.
2,4-Diphenyl-5-propylpyrimidine (3g): Compound 3g was formed as a
colorless crystalline solid (AcOEt/hexane). M.p. 55.1–55.98C; 1H NMR
3
(500 MHz, CDCl3, 258C, TMS): d=8.70 (s, 1H; ArH), 8.49 (d, J
N
8.0 Hz, 2H; ArH), 7.65 (d, 3J
6H; ArH), 2.72 (t, 3J(H,H)=7.5 Hz, 2H; CH2), 1.58 (sex, 3J
7.5 Hz, 2H; CH2), 0.90 ppm (t, 3J(H,H)=7.5 Hz, 3H; CH3); 13C NMR
ACHTUNGTRENNUNG
Likewise, Scheme 6 shows a plausible mechanism for the
ZnBr2-catalyzed annulation of an enamidine with an or-
thoester, which produces the polysubstituted pyrimidine de-
rivatives. First, ZnBr2 coordinates with an oxygen atom of
the orthoester to facilitate the intermolecular attack of the
enamidine. The intermediate formed (12) then undertakes
the intramolecular cyclization to produce intermediate 13.
Finally, aromatization of the intermediate proceeds to pro-
duce the corresponding pyrimidine by liberating ethanol.
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
(125 MHz, CDCl3, 258C, TMS): d=165.3, 162.2, 158.6, 138.6, 137.7,
130.3, 130.1, 129.0, 128.8, 128.4, 128.3, 128.0, 31.7, 23.7, 13.8 ppm; MS
(FAB): m/z (%): 275 (100) [M+H]; elemental analysis calcd (%) for
C19H18N2: C 83.18, H 6.61, N 10.21; found: C 83.17, H 6.91, N 10.21.
6-Methyl-5-(3’-methylisoxazol-5’-yl)-4-phenyl-2-(pyrazin-2-yl)pyrimidine
(5a): Compound 5a was formed as pale yellow needles (AcOEt/hexane).
M.p. 138.1–139.08C; 1H NMR (500 MHz, CDCl3, 258C, TMS): d=9.85
(d, 4J
1.5 Hz, 1H; ArH), 8.73 (d, 3J
(H,H)=7.5 Hz, 2H; ArH), 7.44 (t, 3J
3J
(H,H)=7.5 Hz, 2H; ArH), 5.94 (s, 1H; ArH), 2.67 (s, 3H; CH3),
A
N
ACHTUNGTRENNUNG(H,H)=
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
2.31 ppm (s, 3H; CH3); 13C NMR (125 MHz, CDCl3, 258C, TMS): d=
169.0, 165.9, 165.8, 161.9, 160.1, 149.8, 145.9, 145.8, 144.5, 136.9, 130.2,
129.0, 128.4, 119.6, 106.4, 23.5, 11.4 ppm; MS (FAB): m/z (%): 330 (100)
[M+H]; elemental analysis calcd (%) for C19H15N5O: C 69.29, H 4.59, N
21.26, found: C 69.02, H 4.27, N 21.27%.
General procedure for the reaction of enamidines 1 with orthoesters 6:
ZnBr2 (4.5 mg, 0.020 mmol) was added to a solution of enamidine 1
(0.200 mmol) and orthoester 6 (0.400 mmol) in PhMe (0.4 mL) in a
screw-capped vial, and the vial was sealed with a cap containing a PTFE
septum. The mixture was heated at 1108C for 72 h. To quench the reac-
tion, a saturated aqueous solution of NaHCO3 (5 mL) was added to the
mixture. The mixture was extracted several times with CHCl3, and the
combined organic extracts were dried over Na2CO3, filtered, and then
concentrated under reduced pressure. The crude product was purified by
silica gel column chromatography (AcOEt/hexane) to produce the pyri-
midines in the yields given in Tables 6 and 7.
Scheme 6. A plausible mechanism for the ZnBr2-catalyzed annulation re-
action.
Conclusion
4-Ethoxy-5-(3’-methylisoxazol-5’-yl)-6-(4-methoxyphenyl)-2-(pyrazin-2-
yl)pyrimidine (7b): Compound 7b was formed as a yellow solid (AcOEt/
hexane); M.p. 132.1–133.28C; 1H NMR (500 MHz, CDCl3, 258C, TMS):
We have developed procedures for the synthesis of tri- and
tetrasubstituted pyrimidine derivatives by an unprecedented
[5+1] annulation using enamidines that were prepared from
a silane or organolithium compound and two types of nitrile.
The first method involves the [5+1] annulation of the enam-
d=9.76 (d, 4J
(H,H)=1.5 Hz, 1H; ArH), 8.71 (d, 3J
3J(H,H)=8.5 Hz, 2H; ArH), 6.88 (d, 3J
(s, 1H; ArH), 4.70 (q, 3J
(H,H)=7.0 Hz, 2H; CH2), 3.83 (s, 3H; CH3),
2.35 (s, 3H; CH3), 1.47 ppm (t, 3J(H,H)=7.0 Hz, 3H; CH3); 13C NMR
(H,H)=1.5 Hz, 1H; ArH), 8.81 (dd, 3J
ACHUTGTNRENNUG CAHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
AHCTUNGTRENNUNG
(125 MHz, CDCl3, 258C, TMS): d=167.9, 165.9, 163.6, 161.3, 161.1,
159.8, 149.9, 145.9, 145.6, 144.4, 130.8, 129.7, 113.7, 106.9, 106.2, 63.9,
55.3, 14.3, 11.6 ppm; MS (FAB): m/z (%): 390 (100) [M+H]; elemental
analysis calcd (%) for C21H19N5O3: C 64.77, H 4.92, N 17.98; found: C
64.77, H 4.94, N 18.38.
idine with an N,N-dimethylformamide or N,N-dimethyl
ACHTUNGTRENNUNG
ACHTUNGTNERaNUNG cet-
vent-free reaction conditions, which led to the synthesis of a
variety of polysubstituted pyrimidine derivatives in good
yield. The second synthetic method for the formation of
multisubstituted pyrimidines was accomplished by the
ZnBr2-catalyzed annulation of the enamidine with an or-
thoester as the C1 unit. Moreover, we have demonstrated
the skeletal transformation of the pyrimidine skeletons con-
Acknowledgements
taining an isoxazolyl group on the C5 atom into pyrido
d]pyrimidin-5-one frameworks through the reductive ring
ACHTUNGTNER[NUNG 2,3-
This work was partially supported by a grant from the Japan Private
School Promotion Foundation, 2008 and 2009, a Grant-in-Aid for Scien-
Chem. Eur. J. 2011, 17, 9385 – 9394
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
9391

T. Konakahara et al.
tific Research from MEXT (16550148), 2004–2005, a Grant-in-Aid for
Scientific Research from MEXT (21590025), 2009–2011, and a grant
from the “High-Tech Research Center” Project for Private Universities,
which is a matching fund subsidy from MEXT, 2000–2004 and 2005–2007.
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Chem. Eur. J. 2011, 17, 9385 – 9394

Synthesis of Tri- and Tetrasubstituted Pyrimidine Derivatives
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Received: January 5, 2011
Published online: July 20, 2011
9394
www.chemeurj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 9385 – 9394