Synthesis of novel 2-phenyl-5-substituted dihydropyrimidines using 2-phenyl-1,3-diaza-1,3-butadienes and electron-deficient olefins

Article abstract of DOI:10.1016/j.tet.2012.02.064

A novel synthetic method for 2,5-disubstituted dihydropyrimidines was developed. The cyclization of 1,3-diaza-4-dimethylamino-1,3-butadienes having a N-protecting group (N-Boc, N-Cbz, N-n-C₄H₉, N-Bn or N-Ph) with electron-deficient olefins, such as α,β-unsaturated carbonyl compounds, phenyl vinyl sulfone, and acrylonitrile was studied in detail. The cyclization smoothly proceeded to afford 4-dimethylamino-1,4,5,6- tetrahydropyrimidines or 1,6-dihydropyrimidines in good yields. The isolated 4-dimethylamino-1,4,5,6-tetrahydropyrimidines were converted to 2,5-disubstituted-1,6-dihydropyrimidines through the β-elimination of the dimethylamino group. 2,5-Disubstituted-1,4(6)-dihydropyrimidines were obtained after removal of the N-Boc or N-Cbz group. Independent tautomers of the resulting dihydropyrimidines were observed.

Full text of DOI:10.1016/j.tet.2012.02.064

Tetrahedron 68 (2012) 3342e3350
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Synthesis of novel 2-phenyl-5-substituted dihydropyrimidines using
2-phenyl-1,3-diaza-1,3-butadienes and electron-deficient olefins
,
,d,
*
Yoshio Nishimura a, Yoshizumi Yasui b, Satoshi Kobayashi c, Masahiko Yamaguchi b c, Hidetsura Cho c
a Faculty of Pharmacy, Yasuda Women’s University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan
b WPI Advanced Institute for Materials Research, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
c Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
d Graduate School of Science, Tohoku University, 6-3 Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel synthetic method for 2,5-disubstituted dihydropyrimidines was developed. The cyclization of
Received 30 January 2012
Received in revised form 24 February 2012
Accepted 25 February 2012
Available online 3 March 2012
1,3-diaza-4-dimethylamino-1,3-butadienes having a N-protecting group (N-Boc, N-Cbz, N-n-C4H9, N-Bn
or N-Ph) with electron-deficient olefins, such as
a,b-unsaturated carbonyl compounds, phenyl vinyl
sulfone, and acrylonitrile was studied in detail. The cyclization smoothly proceeded to afford 4-
dimethylamino-1,4,5,6-tetrahydropyrimidines or 1,6-dihydropyrimidines in good yields. The isolated
4-dimethylamino-1,4,5,6-tetrahydropyrimidines
were
converted
to
2,5-disubstituted-1,6-
Keywords:
dihydropyrimidines through the -elimination of the dimethylamino group. 2,5-Disubstituted-1,4(6)-
b
2,5-Disubstituted dihydropyrimidine
1,3-Diaza-1,3-butadiene
Tetrahydropyrimidine
Tautomerism
dihydropyrimidines were obtained after removal of the N-Boc or N-Cbz group. Independent tautomers of
the resulting dihydropyrimidines were observed.
Ó 2012 Elsevier Ltd. All rights reserved.
Cyclization
1. Introduction
Dihydropyrimidines have received continuous interest owing to
their pharmaceutical activities, such as calcium antagonistic ac-
tivity,1 kinesin spindle protein (KSP) inhibitory activity,2 and anti-
mycobacterial activity.3 Additionally, a new application has re-
cently been reported in the field of materials sciences, that is,
a corrosion inhibitor for austenitic stainless steel in acidic media.4
Therefore, the development of useful synthetic methods for a vari-
ety of dihydropyrimidines may contribute to more pharmaceutical
studies and lead to the discovery of attractive applications.
The construction of dihydropyrimidines has generally been
performed by the condensation of amidine, guanidine or urea de-
rivatives with aldehydes and 1,3-dicarbonyl compounds (Scheme
1).5 To obtain a satisfactory yield by this method, it is preferred
that the substituents R1, R2, and R3 be aromatic or alkyl groups.6
Therefore, the obtained products are limited in terms of the sub-
stitution pattern. Much effort has been exerted to overcome this
limitation so far.7 We also reported the synthesis of 4-unsubstituted
2-aminodihydropyrimidines through nucleophilic substitution
at position-2,7c,d and the derivatization of position-6 with Suzu-
kieMiyaura coupling.8
Scheme 1. Typical construction of dihydropyrimidines by three-component
condensation.
The nearly unsolved problem in this research area concerns the
method of synthesizing less substituted dihydropyrimidines.5a,b,d,9 It
is hard to synthesize these compounds owing to polymerization of
formaldehyde by the condensation method described above, and
difficult to handle because of their instability toward oxidative at-
mosphere and acidic conditions.10aec The alternative methods are the
direct reduction of pyrimidine rings with complex metal hydrides11a
and Et3SiH/TFA,11b which however often give a mixture of dihy-
dropyrimidines and tetrahydropyrimidines owing to over-reduction.
To develop a novel synthetic method for less substituted dihy-
dropyrimidine rings, we designed the reactions of 1,3-diaza-1,3-
butadienes with various olefinic compounds (Scheme 2).12 The first
step is the cyclization of 1,3-diaza-4-dimethylamino-1,3-butadiene A
with electron-deficient olefin to give 1,4,5,6-tetrahydropyrimidine B.
A protecting group (R) is attached at position-1 of 1,3-diaza-1,3-
butadiene to stabilize itself as well as to control the reactivity
* Corresponding author. Tel.: þ81 22 795 5501; fax: þ81 22 795 5502; e-mail
address: hcho@mail.pharm.tohoku.ac.jp (H. Cho).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.02.064

Y. Nishimura et al. / Tetrahedron 68 (2012) 3342e3350
3343
during cyclization. The resulting tetrahydropyrimidineB isconverted
to dihydropyrimidine C by the elimination of a dimethylaminogroup.
Successive deprotection at position-1 of C affords the desired 2,5-
disubstituted dihydropyrimidines D.
Scheme 4. Preparation of 1-substituted 1,3-diaza-1,3-butadienes 3cee.
The cyclization was performed, in which 3a (1.0 equiv) was
treated with ethyl acrylate 5 (5.0 equiv) in DMA (N,N-dimethyla-
cetamide) at 100 ꢀC for 60 h. Although the reaction was very
sluggish, 1-tert-butyl 5-ethyl 2-phenyl-1,6-dihydropyrimidine-1,5-
dicarboxylate 7a was produced in a low yield of 5% (Table 1, entry
1). The cyclization was performed in a variety of organic solvents to
see what effect an organic solvent would have on the course of the
reaction. When polar solvents, such as diglyme and DMI (1,3-
dimethyl-2-imidazolidinone) were used, no cyclized products
were detected (entries 2 and 3). TLC observation suggested a rapid
decomposition of 3a prior to the desired cyclization. In contrast,
when less polar solvents, o-dichlorobenzene and toluene, were
used, dihydropyrimidine 7a was produced in 12% and 20% yields,
respectively (entries 4 and 5). Moreover, when the reaction was run
in mesitylene, the cyclization proceeded to give the desired 1-tert-
butyl 5-ethyl 4-dimethylamino-2-phenyl-1,4,5,6-tetrahydropyrimi
dine-1,5-dicarboxylate 6a in 21% yield, accompanied by a small
amount of 7a in 3% yield and with the recovery (39%) of 3a (entry
6). Again, it is worth noting that the addition of a tertiary amine is
crucial for the good yield isolation of 6a through silica gel column
chromatography. When excess amounts of ethyl acrylate (10 and
30 equiv) were used, the yield of 6a was increased to 41% and 78%,
respectively (entries 7 and 8). Although tetrahydropyrimidine 6a
should be the intermediate of 7a, prolonged reaction time did not
affect the yield of 7a (entry 9).
A
B
D
C
Scheme 2. Novel strategy for synthesis of 4,6-unsubstituted-2,5-disubstituted dihy-
dropyrimidines C and D.
1,3-Diaza-4-dimethylamino-1,3-butadienes A are useful for the
synthesis of pyrimidinone,13 heterocyclic fused pyrimidinone,14 or
pyrimidine,15 but have never been used for the synthesis of
dihydropyrimidines.
Herein, we report the details of novel synthetic method of 2-
phenyl-5-substituted dihydropyrimidines using 2-phenyl-1,3-
diaza-1,3-butadienes and electron-deficient olefins.
2. Result and discussion
We prepared five 1,3-diaza-4-dimethylamino-2-phenyl-1,3-
butadienes having different substituents at position-N(1) to test
their stability and reactivity.1-tert-Butoxycarbonyl-4-dimethylamino-
2-phenyl-1,3-diaza-1,3-butadiene 3a was prepared from phenyl-
amidine hydrochloride 1 according to the reported procedure (Scheme
3).15 The reaction of 1 and di-tert-butyl dicarbonate gave 1-tert-
butoxycarbonyl phenylamidine 2a, and the condensation of 2a with
dimethylformamide dimethyl acetal provided 3a. The diazabutadiene
3a was reported to be used for the following reaction without purifi-
cation.15 We also found out the purification of 3a was troublesome;
a mixture of decomposed material was obtained by distillation and
conventional silica gel column chromatography. Finally, it was found
out that the addition of a tertiary amine to the eluent of silica gel
column chromatography prevents the decomposition and enables the
purification of 3a without any loss of the product. In a similar manner,
Table 1
Reaction conditions for cyclization reaction of 3a and 5
Entry
Solvent
Ethyl acrylate (equiv)
Time (h)
Yield (%)
novel
1-benzyloxycarbonyl-4-dimethylamino-2-phenyl-1,3-diaza-
6a
7a
1,3-butadiene 3b was obtained as the sole product (Scheme 3).
1
2
3
4
5a
6
7
8
9
DMA
Diglyme
DMI
o-C6H4Cl2
Toluene
Mesitylene
Mesitylene
Mesitylene
Mesitylene
3
3
3
3
5
60
60
60
60
12
12
13
13
24
d
d
d
d
d
21
41
78
74
5
d
d
12
20
3
2
3
4
5
10
30
30
Scheme 3. Preparation of 1-alkoxycarbonyl-1,3-diaza-1,3-butadienes 3a and 3b.
a
At reflux.
Novel 1-dimethylamino-3-phenyl-2,4-diaza-1,3-octadiene 3c and
1-benzyl-1,3-diaza-4-dimethylamino-2-phenyl-1,3-butadienes 3d as
well as 1,3-diaza-4-dimethylamino-1,2-diphenyl-1,3-butadienes 3e
were preparedfromN-substitutedphenylamidines 2cee, whichwere
synthesized from benzonitrile 4 in the presence of AlCl3.16 Conden-
sation with dimethylformamide dimethyl acetal gave the desired 1,3-
diaza-1,3-butadienes (Scheme 4). However, such electron-rich 1,3-
diaza-1,3-butadienes were more unstable than 3a and 3b; 3cee
could not be purified with silica gel even in the presence of tertiary
amines. Therefore, 3c and 3e were purified through distillation and
recrystallization, respectively. The 1-benzyl derivative 3d was used in
the following reaction without purification because of its instability.
Under the optimized reaction conditions, a variety of substrates
were subjected to cyclization (Table 2). The 1-benzyloxycarbonyl
derivative 3b was tolerated in the reaction without incident, and
the corresponding tetrahydropyrimidine 6b was obtained in 81%
yield, accompanied by a small amount of 7b (entry 2). Similarly, the
1-alkyl derivatives 3c (R¼n-C4H9) and 3d (R¼Bn) reacted smoothly
with ethyl acrylate to afford the cyclized products 6c/7c and 6d/7d
in high yields, respectively (entries 3 and 4). The yields of 6c/7c and
6d/7d were determined by 1H NMR analysis because tetrahy-
dropyrimidines 6c/6d were partly converted to dihydropyrimidines
7c/7d during silica gel chromatographic separation. In contrast, the

3344
Y. Nishimura et al. / Tetrahedron 68 (2012) 3342e3350
Table 2
Table 3
Synthesis of tetrahydropyrimidine 6 and dihydropyrimidine 7
Elimination of NMe2 group with MeI
Entry
Diene
R
EWG
Time (h)
Yield (%)
Entry
Substrate
R
EWG
7: Yield (%)
1a
2
6a
6a
6b
6c
6d
6e
6f
Boc
Boc
Cbz
n-C4H9
Bn
Boc
Boc
Boc
CO2Et
CO2Et
CO2Et
CO2Et
CO2Et
CO2Me
SO2Ph
CN
7a: 9
6
7
7a: 79
7b: 84
7c: 20
7d: 32
7e: 88
7f: 81
7g: 21e
1
2
3a
3b
3c
3d
3e
3a
3a
3a
3a
3a
Boc
Cbz
n-C4H9
Bn
CO2Et
CO2Et
CO2Et
CO2Et
13
24
13
13
24
13
48
13
13
13
6a: 78
6b: 81
6c: 80a
6d: 60b
d
7a: 3
7b: 3
7c: 8a
7d: 9b
d
3
4b
5c
6
3
4a
5
Ph
CO2Et
7d
8
6c
7d
8c
9d
10d
Boc
Boc
Boc
Boc
Boc
CO2Me
SO2Ph
CN
COC6H5
COC6H4Cl-p
6e: 70
6f: 30
6g: 29a
6h: 0
7e: 0
7f: 30
7g: 0
7h: 92
7i: 91
6g
a
Triethylamine (15 equiv) and MeI (15 equiv) were used for 24 h.
b
A mixture of 6c and 7c (11.9:1 by 1H NMR analysis) was reacted. Compound 8c
6i: 0
was obtained in 34% yield.
c
A mixture of 6d and 7d (8.6:1 by 1H NMR analysis) was reacted. Compound 8d
a
Yields were determined by 1H NMR analysis.
was obtained in 48% yield.
Yields were determined by 1H NMR analysis from benzonitrile 4 (three steps).
Olefin (60.0 equiv) was used.
b
c
d
Olefin (5.0 equiv) was used.
1-phenyl derivative 3e gave no cyclized product (entry 5). In the
case of phenyl vinyl sulfone and acrylonitrile, the products 6f/7f
and 6g were obtained in modest yields (entries 7 and 8). The yield
of 6g was estimated by 1H NMR analysis because of difficulty to
separate 6g from by-product. Remarkably, the reaction of 3a with
phenyl vinyl ketone17 and p-chlorophenyl vinyl ketone17 provided
dihydropyrimidine 7h and 7i as the sole products without the
formation of 6h and 6i, in 92% and 91% yield, respectively (entries 9
d
MeI (40 equiv) was used for 15 h.
Yield from 3a.
e
(Table 4). Decreasing the amount of MeI (1.3 equiv) resulted in a low
yield of 7c (entry 1). The use of aluminum oxide (1000 wt %) also
resulted in a low yield of 7c (entry 2). However, when 6c was
treated with silica gel (1000 wt %) in CH2Cl2 for 7.5 h, 7c was
obtained in a modest yield (54%) accompanied by an unidentified
by-product (entry 3). The by-product might have been derived from
the hydrolysis of the product. Therefore, the addition of molecular
sieves to the reaction was tested. Finally, when 6c was treated with
and 10). These results were supposed to be due to the effective
elimination of the dimethylamino group from 6h and 6i supported
by the high acidity of the -hydrogen at C-5 enhanced by the car-
b-
a
bonyl group. All the reactions in Table 2 gave only a single isomer of
6/7, and the cyclization reaction proceeded regioselectively. The
cyclization of 3a with methyl vinyl ketone or diethyl vinyl-
phosphonate did not work out, but gave a complex mixture or
resulted in the recovery of 3a, respectively.
ꢀ
silica gel (1000 wt %) in the presence of MS 3 A (50 wt %), 7c was
obtained in 84% yield (entry 4). The other dihydropyrimidine 7d
was obtained in 71% yield under the same conditions (entry 5).
Subsequently, the b-elimination of the NMe2 group of the tet-
Table 4
rahydropyrimidine derivative 6 was undertaken under various re-
action conditions. The treatment of 6a with acids, such as
pyridinium p-toluenesulfonate, AcOH or TFA did not give any de-
sired dihydropyrimidine 7a, but resulted in a complex mixture.
Next, Hoffmann elimination was performed.18 When 6a was reac-
ted with MeI (15 equiv) and Et3N (15 equiv) in CH2Cl2 for 24 h,
dihydropyrimidine 7a was obtained in 9% yield (Table 3, entry 1). It
was found that the addition of Et3N was not necessary, and that the
Elimination of NMe2 group from tetrahydropyrimidine 6c and 6da
Entry
Substrate
Conditions
7: Yield (%)
b-elimination of the N,N-dimethylamino group of 6a proceeded
1b
2
6c
6c
Iodomethane (1.3 equiv), rt, 4 h
Aluminum oxide (1000 wt %), rt, 12 h
then reflux, 4 h
7c: 20
7c: 21
uneventfully to furnish dihydropyrimidine 7a in 79% yield only
with MeI (entry 2). Similarly, the reactions of 6b, 6e, 6f, and 6g with
MeI afforded 7b, 7e, 7f, and 7g in good yields, respectively (entries
3, 6e8). However, this method was ineffective in the case of 6c
(R¼n-C4H9): the linear amide 8c was obtained in 34% yield with 7c
(20%) (entry 4 and footnote). Compound 8c was possibly produced
by the reaction of 7c with excess MeI to give a quaternary ammo-
nium salt at N-3 followed by the hydrolytic ring opening between
positions C-2 and N-3. In the case of 7d (R¼Bn), a major product
was also formed corresponding to the amide 8d in 48% yield (entry
5). The electron-donating character at position-1 (alkyl groups) of
7c and 7d may cause the ring cleavage between positions 2 and 3,
although an electron-withdrawing group (Boc group) causes the
ring cleavage between positions 1 and 2 in another reaction, as
described in our previous report.7d
3
4
6c
6c
Silica gel (1000 wt %), rt, 7.5 h
Silica gel (1000 wt %), MS 3 A (50 wt %),
7c: 54
7c: 84
ꢀ
rt, 21 h
ꢀ
5
6d
Silica gel (1000 wt %), MS 3 A (50 wt %),
7d: 71
rt, 16 h
a
A mixture of 6c/7c (11.9:1 by 1H NMR analysis) or 6d/7d (8.6:1 by 1H NMR
analysis) was reacted.
b
Compound 8c was formed in 38% yield.
Finally, 2,5-disubstituted dihydropyrimidines were obtained by
removing the protecting groups. 1-Boc groups were cleaved
smoothly under acidic conditions (Table 5). Compound 7a was
treated with excess TFA in CH2Cl2 at room temperature for 3 h to
afford ethyl 2-phenyl-4,6-unsubstituted dihydropyrimidine-5-
carboxylate 9a in 97% yield (entry 1). The deprotection reactions
Subsequently, we investigated the reaction conditions for the
effective
b-elimination of the N,N-dimethylamino group of 6c

Y. Nishimura et al. / Tetrahedron 68 (2012) 3342e3350
3345
Table 5
difference depending on the solvent was probably the rapid
isomerization between the two tautomers of 9a that occurred in
CDCl3 or CD3OD compared with that in DMSO-d6 (Fig. 1). To de-
termine the effect of a solvent on the existence of dihydropyr-
imidines, we measured the 1H NMR spectra of 9f and 9i in CD3OD,
CDCl3, and DMSO-d6 (0.01 M, 25 ꢀC). Although both 9f and 9i were
observed as a single isomer in CD3OD, independent tautomers of 9f
(2.9:1.0 in CDCl3; 3.5:1.0 in DMSO-d6) and 9i (1.9:1.0 in CDCl3;
1.5:1.0 in DMSO-d6) were observed in CDCl3 and DMSO-d6, re-
spectively (Table 7, entries 2 and 3). Thus, it was found that all
dihydropyrimidines 9 existed as independent tautomers in DMSO-
d6 at a ratio of 1.5e3.5:1.0.
Cleavage of 1-Boc group from dihydropyrimidines 7a, eef, i
Entry
Substrate
EWG
9: Yield (%)
1
2
3
4
7a
7e
7f
7i
CO2Et
CO2Me
SO2Ph
COC6H4Cl-p
9a: 97
9e: 99
9f: 98
9i: 100
Table 7
1
Ratios of tautomers 9 in H NMR spectra (0.01 M, 25 ꢀC)
of 7eef, i with TFA uneventfully proceeded to afford the desired
dihydropyrimidines 9eef, i (entries 2e4).
Subsequently, the deprotection of other 1-substituents was
carried out (Table 6). The 1-benzyloxy derivative 7b was treated
with 10% Pd/C (20 wt %) under a hydrogen atmosphere (1 atm) in
EtOAc/MeOH at room temperature for 18 h to give 9a in 89% yield
(entry 1). On the other hand, the cleavage of 1-Bn group to give
dihydropyrimidines was not feasible: hydrogenolysis did not pro-
ceed with 10% Pd/C (entry 2). In the case of using 20% Pd(OH)2/C,
tetrahydropyrimidine 10 was isolated as a result of an undesired
reduction of the 2,3-double bond (entry 3).
Entry
Substrate
EWG
Solvent
CD3OD
CDCl3
DMSO-d6
1
2
3
9a
9f
9i
CO2Et
SO2Ph
COC6H4Cl-p
Single
Single
Single
Single
2.9:1.0
1.9:1.0
2.3:1.0
3.5:1.0
1.5:1.0
Table 6
3. Conclusion
Reductive removal of protecting groups from dihydropyrimidines 7b and 7d
A stepwise approach to synthesizing 2,5-disubstituted dihy-
dropyrimidines has been developed. A variety of 1,3-diaza-1,3-
butadienes having different substituents at position-1 were synthe-
sized and subjected to cyclization with electron-deficient olefins. The
cyclization proceeded smoothly to give 4-dimethylamino-1,4,5,6-
tetrahydropyrimidines and/or 1-protecting-2,5-disubstituted-1,6-
dihydropyrimidines. The ratio of both compounds was found to de-
pend on the type of electron-deficient olefin. The reactions of 1,3-
diaza-1,3-butadienes with acrylates mainly afforded tetrahydropyr-
imidines and the reactionwith vinyl sulfoneyieldeda 1:1 ratioof both
compounds. Remarkably, the reaction with aryl vinyl ketones pro-
vided dihydropyrimidines as the sole products without giving tetra-
hydropyrimidines. The isolated 4-dimethylamino-1,4,5,6-tetrahydro
pyrimidines were converted to 1,6-dihydropyrimidines through the
Entry
Substrate
R
Catalyst
9:Yield (%)
1
2
3
7b
7d
7d
Cbz
Bn
Bn
10% Pd/C (20 wt %)
10% Pd/C (20 wt %)
20% Pd(OH)2/C (40 wt %)
89
da
db
a
The starting material was recovered intact.
Tetrahydropyrimidine 10 was isolated in 33% yield.
b
A more effective procedure for synthesizing dihydropyrimidine
b
-elimination of the dimethylamino group under MeI or silica gel
9a from 3a was examined without isolating 6a and 7a after cycli-
zation, followed by the treatment of MeI and TFA. Consequently,
a three-step successive reaction was conveniently realized to afford
9a in 60% overall yield, as shown in Scheme 5.
treatment. The cleavage of the 1-Boc and 1-Cbz group afforded 2,5-
disubstituted-4(6)-dihydropyrimidines. In addition, a three-step
successive reaction from 1,3-diaza-1,3-butadiene without purifica-
tion of the intermediate was conveniently realized to afford 1,4(6)-
dihydropyrimidine in high overall yield.
Through this study, 2,5-disubstituted-1,6-dihydropyrimidines
have been made accessible in an efficient manner. This achieve-
ment may lead to further application of dihydropyrimidines in
many fields including heterocyclic chemistry and pharmaceutical
sciences.
Scheme 5. Three-step synthesis of 9a without isolating 6a and 7a.
4. Experimental section
4.1. General
The synthesized dihydropyrimidines 9 showed an interesting
behavior in their 1H NMR spectra (600 MHz).5c,e,7c,10d,12 For in-
stance, 9a was observed as a single isomer in CDCl3 and CD3OD, and
two independent isomers existed at a ratio of 2.3:1.0 in DMSO-d6
Melting points were determined on Yanaco micro melting point
apparatus and uncorrected. IR spectra were measured on SHI-
MADZU FTIR-8300 spectrometer. 1H NMR spectra were recorded on
a Varian Mercury (300, 400 MHz) or a Bruker AVANCE III 600
(600 MHz) with tetramethylsilane (0 ppm), CD3OD (3.30 ppm) or
DMSO-d6 (2.49 ppm) as an internal standard. The abbreviations of
signal patterns are follows: s, singlet; d, doublet; t, triplet; q,
(Fig. 1, Table 7, entry 1). The observed signals of NH protons [
d 9.48
(major), 8.43 (minor)] and methylene protons [ 4.32 (major), 4.21
d
(minor)] in DMSO-d6 indicated that the two isomers were 1,4- and
1,6-tautomers. The major isomer was assigned to the 1,4-isomer
because the vinyl proton (d 7.18) was observed as a doublet peak
(J 5.4 Hz) by coupling with an NH proton. The reason for the spectral

3346
Y. Nishimura et al. / Tetrahedron 68 (2012) 3342e3350
Fig. 1. 1H NMR spectra of 9a in CD3OD, CDCl3, and DMSO-d6 (600 MHz, 0.01 M, 25 ꢀC).
quartet; m, multiplet; br, broad. 13C NMR spectra were recorded on
a Varian Mercury (75, 100 MHz) or a Bruker AVANCE III 600
(150 MHz) with CDCl3 (77.0 ppm), CD3OD (49.0 ppm) or DMSO-d6
(39.7 ppm) as an internal standard. Mass spectra were recorded on
a JMS-DX303, JMS-700 or JMS-T100GC spectrometer. Flash column
a colorless oil; IR (neat) cmꢁ1: 2977, 1703, 1633, 1591, 1570, 1242,
1160; dH (600 MHz, CDCl3) 1.47 (9H, s, CMe3), 3.06 (3H, s, NMe), 3.09
(3H, s, NMe), 7.36 (2H, t, J 7.2 Hz, Arem-H), 7.41 (1H, tt, J 1.2, 7.2 Hz,
Arep-H), 7.41 (2H, dd, J 1.2, 7.2 Hz, Areo-H), 7.98 (1H, s, 4-CH); dC
(150 MHz, CDCl3) 27.9, 34.6, 40.6, 80.2, 127.9, 128.6, 130.5, 136.5,
155.6, 162.1, 165.7; m/z (EI) 275 (Mþ); HRMS (EI): Mþ, found
275.1621. C15H21N3O2 requires 275.1633.
chromatography was performed on silica gel 60
N (Kanto,
40e60 mm) using indicated solvent. Reactions and fractions of
chromatography were monitored by employing pre-coated silica
gel 60 F254 plates (Merck).
4.2.2. 1-Benzyloxycarbonyl-4-dimethylamino-2-phenyl-1,3-diaza-
1,3-butadiene (3b). Compound 3b was prepared in a similar manner
to 3a as described above. Pale yellow oil; IR (neat) cmꢁ1: 2929,1703,
1633, 1588, 1569, 1219, 1091; dH (600 MHz, CDCl3) 2.93 (3H, s, NMe),
3.01 (3H, s, NMe), 5.18 (2H, s, CH2Ph), 7.27e7.38 (7H, m, AreH), 7.41
(1H, t, J 7.8 Hz, Arep-H), 7.81 (2H, d, J 7.8 Hz, Areo-H), 7.88 (1H, s, 4-
CH); dC (150 MHz, CDCl3) 34.6, 40.6, 67.3, 127.8, 128.0, 128.2, 128.4,
128.6, 130.8, 136.3, 136.4, 155.9, 162.8, 166.8; m/z (EI) 309 (Mþ);
HRMS (EI): Mþ, found 309.1481. C18H19N3O2 requires 309.1477.
4.2. Preparation of 1,3-diaza-1,3-butadiene 3
4.2.1. 1-tert-Butoxycarbonyl-4-dimethylamino-2-phenyl-1,3-diaza-
1,3-butadiene (3a). To a suspension of phenylamidine hydrochlo-
ride 1 (3.12 g, 19.9 mmol) in THF (40 mL) was dropwise added
a solution of NaOH (2.00 g, 50.0 mmol) in H2O (40 mL) at 0 ꢀC. Di-
tert-butyl dicarbonate (4.40 g, 20.2 mmol) was added, and the re-
action mixture was stirred at 0 ꢀC for 1 h, and EtOAc (150 mL) was
added. The organic layer was separated, and washed with water,
brine, dried over anhyd Na2SO4, and concentrated under reduced
pressure to give N-tert-butoxycarbonyl phenylamidine 2a (3.81 g).
To a solution of crude 2a (3.81 g) in anhyd THF (35 mL) was added
dimethylformamide dimethyl acetal (3.00 mL, 22.6 mmol) under an
argon atmosphere. The reaction mixture was stirred at reflux for
5 h, and EtOAc (100 mL) was added. The organic layer was washed
with water, brine, dried over anhyd Na2SO4, and concentrated un-
der reduced pressure to give the residue, which was purified by
4.2.3. 1-Dimethylamino-3-phenyl-2,4-diaza-1,3-octadiene (3c). To
anhyd aluminum chloride (3.00 g, 22.5 mmol) was added benzo-
nitrile 4 (2.10 mL, 20.5 mmol) dropwise at room temperature under
an argon atmosphere. After cooled to room temperature, n-butyl-
amine (2.50 mL, 25.1 mmol) was added, and the reaction mixture
was heated at 100 ꢀC for 12 h. The mixture was poured slowly into
a stirred mixture of concentrated hydrochloric acid (0.6 mL) and
water (30 mL), and the suspension was stirred for 20 min and fil-
tered through a Celite. The filtrate was basified with 2 M NaOH
aqueous solution, and the aqueous layer was extracted with chlo-
roform three times. The combined organic layer was washed with
flash
column
chromatography
(toluene/EtOAc/Et3N¼85:
10:5) to afford 3a (4.51 g, 16.4 mmol, 82% for two steps) as

Y. Nishimura et al. / Tetrahedron 68 (2012) 3342e3350
3347
brine, dried over anhyd Na2SO4, and concentrated under reduced
pressure to give N-n-butyl phenylamidine 2c (3.15 g). To a solution
of crude 2c (1.32 g) in anhyd THF (15 mL) was added dime-
thylformamide dimethyl acetal (1.50 mL, 11.3 mmol) under an ar-
gon atmosphere. The reaction mixture was stirred at reflux for 12 h.
After concentrated under reduced pressure, the residue was dis-
tilled in vacuo to give 3c (881 mg, 3.81 mmol, 44% for two steps) as
a yellow oil; IR (neat) cmꢁ1: 2926, 1643, 1596, 1574, 1371, 1087, 705;
dH (600 MHz, CDCl3) 0.95 (3H, t, J 7.2 Hz, CH2CH2CH2CH3), 1.42 (2H,
tq, J 7.2, 7.2 Hz, CH2CH2CH2CH3), 1.65 (2H, tt, J 7.2, 7.2 Hz,
CH2CH2CH2CH3), 2.95 (3H, s, NMe), 3.05 (3H, s, NMe), 3.50 (2H, t, J
7.2 Hz, CH2CH2CH2CH3), 7.31 (1H, s, 4-CH), 7.32e7.35 (3H, m, AreH),
7.62e7.67 (2H, m, AreH); dC (150 MHz, CDCl3) 14.1, 20.9, 33.5, 34.0,
40.0, 49.0, 128.0, 128.2, 128.8, 139.3, 154.0, 163.0; m/z (EI) 231 (Mþ);
HRMS (EI): Mþ, found 231.1728. C14H21N3 requires 231.1735.
(6H, s, NMe2), 2.86 (1H, ddd, J 6.6, 9.6, 10.8 Hz, 5-CH), 3.91 (1H, dd, J
10.8, 12.0 Hz, 6-CH), 3.93 (1H, dd, J 6.6, 12.0 Hz, 6-CH), 4.17e4.28
(2H, m, OCH2CH3), 4.33 (1H, d, J 9.6 Hz, 4-CH), 4.97 (2H, s, CH2Ph),
6.87 (2H, d, J 7.8 Hz, Areo-H), 7.21 (2H, t, J 7.8 Hz, Arem-H),
7.23e7.28 (1H, m, Arep-H), 7.32 (2H, t, J 7.8 Hz, Arem-H), 7.38 (1H, t,
J 7.8 Hz, Arep-H), 7.52 (2H, d, J 7.8 Hz, Areo-H); dC (150 MHz, CDCl3)
14.1, 40.2, 44.7, 45.5, 61.1, 68.3, 77.7, 127.0, 128.0, 128.10, 128.14,
128.3, 129.7, 134.8, 137.2, 153.7, 153.9, 171.3; m/z (EI) 409 (Mþ);
HRMS (EI): Mþ, found 409.2002. C23H27N3O4 requires 409.2001.
4.3.3. Ethyl 1-butyl-4-dimethylamino-2-phenyl-1,4,5,6-
tetrahydropyrimidine-5-carboxylate (6c). Pale yellow oil contain-
ing small amounts of 7c (6c/7c¼11.9:1); IR (neat) cmꢁ1: 2960, 1731,
1608, 1599, 1577, 1375, 1178; dH (600 MHz, CDCl3) 0.78 (3H, t, J
7.2 Hz, CH2CH2CH2CH3), 1.12 (2H, tq, J 7.2, 7.2 Hz, CH2CH2CH2CH3),
1.29 (3H, t, J 7.2 Hz, OCH2CH3), 1.45 (2H, tt, J 7.2, 7.2 Hz,
CH2CH2CH2CH3), 2.38 (6H, s, NMe2), 2.77 (1H, ddd, J 4.2, 9.6,10.8 Hz,
5-CH), 2.95 (1H, dt, J 7.2, 14.4 Hz, CHCH2CH2CH3), 3.04 (1H, dt, J 7.2,
14.4 Hz, CHCH2CH2CH3), 3.29 (1H, dd, J 4.2, 12.0 Hz, 6-CH), 3.57 (1H,
dd, J 10.8, 12.0 Hz, 6-CH), 4.17e4.27 (2H, m, OCH2CH3), 4.35 (1H, d, J
9.6 Hz, 4-CH), 7.32e7.43 (5H, m, AreH); dC (150 MHz, DMSO-d6)
13.6, 14.2, 19.2, 29.8, 39.7, 41.1, 47.2, 51.0, 60.2, 76.6, 128.0, 128.1,
128.7, 137.7, 157.6, 172.4; m/z (EI) 331 (Mþ); HRMS (EI): Mþ, found
331.2249. C19H29N3O2 requires 331.2260.
4.2.4. N-Benzyl phenylamidine (2d). Compound 2d was prepared in
a similar manner to 2c as described above. Pale yellow crystals; mp
54e56 ꢀC (n-hexane/chloroform); IR (neat) cmꢁ1: 3303, 1604, 1568,
1552, 696; dH (600 MHz, DMSO-d6) 4.33 (2H, s, CH2Ph), 6.20e6.60
(2H, br s, NH2), 7.19 (1H, t, J 7.2 Hz, Arep-H), 7.31 (2H, t, J 7.2 Hz,
Arem-H), 7.35e7.50 (5H, m, AreH), 7.70e7.95 (2H, br s, AreH); dC
(150 MHz, DMSO-d6) 49.5 (br), 126.2, 126.7, 127.6, 128.1, 128.2,
129.5, 137.4, 142.1, 156.8 (br); m/z (EI) 210 (Mþ); HRMS (EI): Mþ,
found 210.1137. C14H14N2 requires 210.1157.
4.3.4. Ethyl 1-benzyl-4-dimethylamino-2-phenyl-1,4,5,6-
tetrahydropyrimidine-5-carboxylate (6d). Yellow oil containing
small amounts of 7d (6d/7d¼8.6:1); IR (neat) cmꢁ1: 2977, 1729,
1609,1599,1265,1184, 701; dH (600 MHz, CDCl3) 1.24 (3H, t, J 7.2 Hz,
OCH2CH3), 2.39 (6H, s, NMe2), 2.72 (1H, ddd, J 4.2, 9.6, 10.8 Hz, 5-
CH), 3.22 (1H, dd, J 4.2, 12.0 Hz, 6-CH), 3.50 (1H, dd, J 10.8,
12.0 Hz, 6-CH), 4.10e4.20 (2H, m, OCH2CH3), 4.22 (1H, d, J 15.6 Hz,
PhCH), 4.32 (1H, d, J 15.6 Hz, PhCH), 4.40 (1H, d, J 9.6 Hz, 4-CH), 7.19
(2H, d, J 7.2 Hz, Areo-H), 7.25e7.55 (8H, m, AreH); dC (150 MHz,
CDCl3) 14.0, 39.8, 40.9, 47.4, 55.6, 60.6, 76.6, 127.0, 127.4, 128.1,
128.3, 128.7, 129.1, 137.0, 137.2, 158.5, 172.6; m/z (EI) 365 (Mþ);
HRMS (EI): Mþ, found 365.2088. C22H27N3O2 requires 365.2103.
4.2.5. 4-Dimethylamino-1,2-diphenyl-1,3-diaza-1,3-butadiene
(3e). Compound 3e was prepared in a similar manner to 3c as de-
scribed above, and purified by recrystallization from n-hexane/EtOAc
as a mixture of isomers (2.3:1.0). Pale yellow crystals; mp 101 ꢀC (n-
hexane/EtOAc); IR (neat) cmꢁ1: 1638,1602,1588,1572,1373,1051, 706;
dH (600 MHz, CDCl3) 2.80 (3H, s, NMe), 2.91 (3H, s, NMe), 3.11* (s, NMe),
3.12* (s, NMe), 6.71* (d, J7.2 Hz, Areo-H), 6.88* (t, J7.2 Hz, Arep-H), 6.96
(1H, t, J 7.2 Hz, Arep-H), 7.02 (2H, d, J 7.2 Hz, Areo-H), 7.11* (t, J 7.2 Hz,
Arep-H), 7.15e7.29* (2H, m, AreH), 7.30* (d, J6.6 Hz, Areo-H), 7.34 (1H,
s, 4-CH), 7.37e7.50 (3H, m, AreH), 7.93 (2H, d, J 6.6 Hz, Areo-H), 8.29*
(s, 4-CH)(*Peaksof minor isomer); dC (150 MHz, CDCl3) 34.0, 34.9, 39.9,
40.8,121.8,122.0, 122.6, 127.6, 128.0,128.2,128.4, 128.50, 128.54,129.5,
129.8, 136.2, 138.4, 150.6, 151.1, 155.0, 156.0, 162.3, 164.8; m/z (EI) 251
(Mþ); HRMS (EI): Mþ, found 251.1415. C16H17N3 requires 251.1423.
4.3.5. 1-tert-Butyl 5-methyl 4-dimethylamino-2-phenyl-1,4,5,6-
tetrahydropyrimidine-1,5-dicarboxylate (6e). Colorless crystals; mp
119 ꢀC (n-hexane/Et2O); IR (KBr) cmꢁ1: 2976, 2875, 1739, 1624,
1350; dH (400 MHz, CDCl3) 1.12 (9H, s, CMe3), 2.42 (6H, s, NMe2),
2.87 (1H, ddd, J 6.0, 9.6, 10.8 Hz, 5-CH), 3.77 (3H, s, OCH3), 3.78 (1H,
dd, J 10.8, 12.0 Hz, 6-CH), 3.97 (1H, dd, J 6.0, 12.0 Hz, 6-CH), 4.37 (1H,
d, J 9.6 Hz, 4-CH), 7.32e7.41 (3H, m, AreH), 7.52 (2H, d, J 7.2 Hz,
Areo-H); dC (100 MHz, CDCl3) 27.5, 40.2, 44.5, 45.0, 52.3, 77.6, 82.3,
127.0, 127.9, 129.5, 138.2, 152.7, 154.4, 172.0; m/z (EI) 361 (Mþ);
HRMS (EI): Mþ, found 361.2009. C19H27N3O4 requires 361.2002.
4.3. General procedure for cyclization reaction of 1,3-diaza-
1,3-butadiene 3 with olefins for synthesis of 6aef
4.3.1. 1-tert-Butyl 5-ethyl 4-dimethylamino-2-phenyl-1,4,5,6-
tetrahydropyrimidine-1,5-dicarboxylate (6a). A solution of 3a
(208 mg, 0.757 mmol) and ethyl acrylate 5 (2.50 mL, 23.0 mmol) in
mesitylene (6 mL) was heated at 100 ꢀC for 13 h under an argon at-
mosphere. The reaction mixture was concentrated under reduced
pressure to give the residue, which was purified by flash column
chromatography (n-hexane/EtOAc/i-Pr2NEt¼30:5:1 to 30:30:1) to
afford 6a (222 mg, 0.591 mmol, 78%) and 7a (7.4 mg, 0.022 mmol,
3%). Compound 6a: Colorless crystals; mp 103 ꢀC (n-hexane/Et2O); IR
(KBr) cmꢁ1: 2984, 1735, 1712, 1614, 1348; dH (600 MHz, CDCl3) 1.12
(9H, s, CMe3), 1.29 (3H, t, J 7.2 Hz, OCH2CH3), 2.42 (6H, s, NMe2), 2.84
(1H, ddd, J 6.6, 9.6,10.8 Hz, 5-CH), 3.78 (1H, dd, J 10.8,12.0 Hz, 6-CH),
3.97 (1H, dd, J 6.6, 12.0 Hz, 6-CH), 4.18e4.27 (2H, m, OCH2CH3), 4.35
(1H, d, J 9.6 Hz, 4-CH), 7.32e7.40 (3H, m, AreH), 7.51 (2H, d, J 7.2 Hz,
Areo-H); dC (150 MHz, CDCl3) 14.1, 27.5, 40.2, 44.6, 45.1, 61.0, 77.6,
82.2, 127.0, 127.9, 129.4, 138.3, 152.7, 154.3, 171.5; m/z (EI) 375 (Mþ);
HRMS (EI): Mþ, found 375.2163. C20H29N3O4 requires 375.2158.
4.3.6. tert-Butyl
4-dimethylamino-2-phenyl-5-phenylsulfonyl-
1,4,5,6-tetrahydropyrimidine-1-carboxylate (6f). Yellow amorphous;
IR (KBr) cmꢁ1: 2977,1719,1628,1146; dH (600 MHz, CDCl3) 1.14 (9H, s,
CMe3), 2.23 (6H, s, NMe2), 3.54 (1H, ddd, J 6.0, 7.2, 7.8 Hz, 5-CH), 3.83
(1H, dd, J 6.0, 13.8 Hz, 6-CH), 4.15 (1H, dd, J 7.8, 13.8 Hz, 6-CH), 4.67
(1H, d, J 7.2 Hz, 4-CH), 7.35 (2H, d, J 7.2 Hz, Areo-H), 7.40(1H, t, J 7.2 Hz,
Arep-H), 7.53 (2H, d, J 7.2 Hz, Areo-H), 7.58 (2H, d, J 7.8 Hz, Areo-H),
7.67 (1H, t, J 7.8 Hz, Arep-H), 8.01 (2H, d, J 7.8 Hz, Areo-H); dC
(150 MHz, CDCl3) 27.4, 39.6, 40.8, 62.2, 73.6, 82.6, 127.2, 127.9, 128.9,
129.2,129.9,133.8,137.4,138.2,152.3,155.1; m/z (EI) 443 (Mþ); HRMS
(EI): Mþ, found 443.1883. C23H29N3O4S requires 443.1879.
4.4. General procedure for elimination of NMe2 group of 6aeg
using MeI for synthesis of 7aeg
4.3.2. 1-Benzyl 5-ethyl 4-dimethylamino-2-phenyl-1,4,5,6-
tetrahydropyrimidine-1,5-dicarboxylate (6b). Colorless crystals; mp
73e74 ꢀC (n-hexane/chloroform); IR (KBr) cmꢁ1: 2866, 1736, 1620,
1276, 1195; dH (600 MHz, CDCl3) 1.28 (3H, t, J 7.2 Hz, OCH2CH3), 2.40
4.4.1. 1-tert-Butyl 5-ethyl 2-phenyl-1,6-dihydropyrimidine-1,5-
dicarboxylate (7a). To a solution of 6a (75.0 mg, 0.200 mmol) in

3348
Y. Nishimura et al. / Tetrahedron 68 (2012) 3342e3350
CH2Cl2 (2 mL) was added MeI (0.130 mL, 2.09 mmol) dropwise at
room temperature under an argon atmosphere. The reaction mix-
ture was stirred at room temperature for 4 h, and triethylamine
(0.5 mL), EtOAc (20 mL), water (10 mL) were added. The organic
layer was separated, and the aqueous layer was extracted with
EtOAc (10 mLꢂ2). The combined organic layer was washed with
water, brine, dried over anhyd Na2SO4, and concentrated under
reduced pressure to give the residue, which was purified by flash
column chromatography (n-hexane/EtOAc/i-Pr2NEt¼100:10:1) to
afford 7a (52.2 mg, 0.158 mmol, 79%) as yellow crystals; mp 107 ꢀC
(n-hexane); IR (KBr) cmꢁ1: 2986, 1721, 1699, 1529, 1284, 1153; dH
(600 MHz, CDCl3) 1.12 (9H, s, CMe3), 1.34 (3H, t, J 7.2 Hz, OCH2CH3),
4.28 (2H, q, J 7.2 Hz, OCH2CH3), 4.52 (2H, d, J 1.2 Hz, 6-CH2), 7.41 (2H,
t, J 7.2 Hz, Arem-H), 7.48 (1H, t, J 7.2 Hz, Arep-H), 7.65 (2H, d, J
7.2 Hz, Areo-H), 7.70 (1H, d, J 1.2 Hz, 4-CH); dC (150 MHz, CDCl3)
14.3, 27.4, 40.2, 60.8, 83.1, 115.6, 128.2, 128.5, 131.0, 136.8, 143.1,
152.0, 158.2, 164.8; m/z (EI) 330 (Mþ); HRMS (EI): Mþ, found
330.1570. C18H22N2O4 requires 330.1580.
130.0,134.8,135.3,145.8, 163.4,166.1; m/z (EI) 320 (Mþ); HRMS (EI):
Mþ, found 320.1502. C20H20N2O2 requires 320.1525.
4.4.6. N-Benzyl-N-[(2-ethoxycarbonyl-3-methylamino)-prop-2-en-
1-yl]benzamide (8d). Colorless oil; IR (neat) cmꢁ1: 2933,1673,1644,
1631, 1100; dH (600 MHz, CDCl3) 1.16 (3H, t, J 7.2 Hz, OCH2CH3), 3.02
(3H, d, J 4.8 Hz, NHCH3), 4.08 (2H, q, J 7.2 Hz, OCH2CH3), 4.40 (2H, s,
CH2Ph or 6-CH2), 4.57 (2H, s, CH2Ph or 6-CH2), 7.18 (2H, d, J 7.2 Hz,
Areo-H), 7.29e7.41 (8H, m, AreH), 7.57 (1H, d, J 13.8 Hz, CH3NHCH);
dC (150 MHz, CDCl3) 14.5, 35.2, 39.8, 52.3, 59.2, 92.7, 126.5, 126.9,
127.3, 128.47, 128.52, 129.6, 136.0, 137.1, 153.3, 169.7, 173.2; m/z (EI)
352 (Mþ); HRMS (EI): Mþ, found 352.1769. C21H24N2O3 requires
352.1787.
4.4.7. 1-tert-Butyl 5-methyl 2-phenyl-1,6-dihydropyrimidine-1,5-
dicarboxylate (7e). Yellow crystals; mp 115 ꢀC (n-hexane); IR
(KBr) cmꢁ1: 2994,1722,1533, 1369,1288,1149; dH (400 MHz, CDCl3)
1.12 (9H, s, CMe3), 3.82 (3H, s, OCH3), 4.52 (2H, d, J 1.2 Hz, 6-CH2),
7.41 (2H, t, J 7.2 Hz, Arem-H), 7.48 (1H, t, J 7.2 Hz, Arep-H), 7.65 (2H,
d, J 7.2 Hz, Areo-H), 7.71 (1H, J 1.2 Hz, 4-CH); dC (100 MHz, CDCl3)
27.4, 40.1, 51.9, 83.1, 115.3, 128.2, 128.5, 131.1, 136.7, 143.3, 151.9,
158.3, 165.2; m/z (EI) 316 (Mþ); HRMS (EI): Mþ, found 316.1410.
C17H20N2O4 requires 316.1423.
4.4.2. 1-Benzyl 5-ethyl 2-phenyl-1,6-dihydropyrimidine-1,5-
dicarboxylate (7b). Yellow oil; IR (neat) cmꢁ1: 2982, 1725, 1537,
1281, 1230, 1184; dH (600 MHz, CDCl3) 1.34 (3H, t, J 7.2 Hz,
OCH2CH3), 4.28 (2H, q, J 7.2 Hz, OCH2CH3), 4.59 (2H, d, J 1.2 Hz, 6-
CH2), 4.99 (2H, s, CH2Ph), 6.83 (2H, d, J 7.2 Hz, Areo-H), 7.19 (2H,
t, J 7.2 Hz, Arem-H), 7.24 (1H, t, J 7.8 Hz, Arep-H), 7.37 (2H, t, J 7.8 Hz,
Arem-H), 7.46 (1H, t, J 7.2 Hz, Arep-H), 7.65 (2H, d, J 7.8 Hz, Areo-
H), 7.70 (1H, d, J 1.2 Hz, 4-CH); dC (150 MHz, CDCl3) 14.2, 40.7, 60.8,
68.7, 115.9, 127.9, 128.2, 128.3, 128.4, 128.5, 131.3, 134.4, 135.7, 143.0,
153.4, 157.2, 164.6; m/z (EI) 364 (Mþ); HRMS (EI): Mþ, found
364.1433. C21H20N2O4 requires 364.1423.
4.4.8. tert-Butyl 2-phenyl-5-phenylsulfonyl-1,6-dihydropyrimidine-
1-carboxylate (7f). Colorless crystals; mp 154e156 ꢀC (n-hexane/
chloroform); IR (KBr) cmꢁ1: 2973, 1727, 1601, 1524, 1313, 1146; dH
(600 MHz, CDCl3) 1.07 (9H, s, CMe3), 4.40 (2H, d, J 1.2 Hz, 6-CH2),
7.40 (2H, t, J 7.5 Hz, Arem-H), 7.49 (1H, t, J 7.5 Hz, Arep-H), 7.56 (2H,
t, J 7.5 Hz, Arem-H), 7.60e7.67 (3H, m, AreH), 7.71 (1H, s, 4-CH),
7.94 (2H, d, J 7.5 Hz, Areo-H). dC (150 MHz, CDCl3) 27.2, 39.5, 83.7,
123.7, 127.7, 128.3, 128.6, 129.4, 131.6, 133.6, 135.9, 139.8, 141.7, 151.3,
158.4; m/z (EI) 398 (Mþ); HRMS (EI): Mþ, found 398.1307.
C21H22N2O4S requires 398.1300.
4.4.3. Ethyl 1-butyl-2-phenyl-1,6-dihydropyrimidine-5-carboxylate
(7c). Compound 7c was obtained in 20% yield, accompanied by
amide 8c (34%) (Table 3, entry 4). Compound 7c: Yellow oil; IR (neat)
cmꢁ1: 2960, 2933, 1693, 1622, 1514, 1444, 1262, 1101; dH (600 MHz,
CDCl3) 0.81 (3H, t, J 7.2 Hz, CH2CH2CH2CH3),1.18 (2H, tq, J 7.2, 7.2 Hz,
CH2CH2CH2CH3), 1.31 (3H, t, J 7.2 Hz, OCH2CH3), 1.57 (2H, tt, J 7.2,
7.8 Hz, CH2CH2CH2CH3), 3.16 (2H, t, J 7.8 Hz, CH2CH2CH2CH3), 4.23
(2H, q, J 7.2 Hz, OCH2CH3), 4.33 (2H, s, 6-CH2), 7.38e7.45 (5H, m,
AreH), 7.50 (1H, s, 4-CH); dC (150 MHz, CDCl3) 13.5, 14.4, 19.6, 29.0,
45.6, 52.4, 60.0, 104.2, 127.8, 128.5, 129.9, 135.4, 146.2, 163.5, 166.3;
m/z (EI) 286 (Mþ); HRMS (EI): Mþ, found 286.1686. C17H22N2O2
requires 286.1681.
4.4.9. tert-Butyl 5-cyano-4-dimethylamino-2-phenyl-1,4,5,6-
dihydropyrimidine-1-dicarboxylate (7g). A solution of 3a (100 mg,
0.365 mmol) and acrylonitrile (1.40 mL, 21.4 mmol) in mesitylene
(0.7 mL) was heated at 100 ꢀC for 13 h under an argon atmosphere.
The reaction mixture was concentrated under reduced pressure to
give cyclized products 6g (29% NMR yield). The residue was dis-
solved in CH2Cl2 (3.7 mL) and MeI (0.230 mL, 3.69 mmol) was
added to the solution dropwise at room temperature under an ar-
gon atmosphere. The reaction mixture was stirred at room tem-
perature for 5 h, and triethylamine (1.8 mL), EtOAc (37 mL), water
(37 mL) were added. The organic layer was separated, and the
aqueous layer was extracted with EtOAc. The combined organic
layer was washed with water, brine, dried over anhyd Na2SO4, and
concentrated under reduced pressure to give the residue, which
was purified by flash column chromatography (n-hexane/EtOAc/i-
Pr2NEt¼60:30:1) to afford 7g (21.6 mg, 0.0762 mmol, 21% for two
steps) as pale yellow crystals; mp 156e157 ꢀC (n-hexane/chloro-
form); IR (KBr) cmꢁ1: 2976, 2208, 1728, 1533, 1325, 1144; dH
(400 MHz, CDCl3) 1.14 (9H, s, CMe3), 4.43 (2H, d, J 1.6 Hz, 6-CH2),
7.41e7.45 (3H, m, Arem-H and 4-CH), 7.52 (1H, t, J 7.6 Hz, Arep-H),
7.64 (2H, d, J 8.0 Hz, Areo-H); dC (100 MHz, CDCl3) 27.3, 40.5, 84.0,
95.9, 116.2, 128.4, 128.6, 131.7, 136.0, 147.5, 151.5, 158.4; m/z (EI) 283
(Mþ); HRMS (EI): Mþ, found 283.1296. C16H17N3O2 requires
283.1321.
4.4.4. N-Butyl-N-[(2-ethoxycarbonyl-3-methylamino)-prop-2-en-1-
yl]benzamide (8c). Colorless crystals; mp 63e63 ꢀC (n-hexane); IR
(neat) cmꢁ1: 2953, 1687, 1629, 1434, 1266, 1134, 1098; dH (600 MHz,
CDCl3) 0.77 (3H, t, J 7.2 Hz, CH2CH2CH2CH3), 1.12 (2H, tq, J 7.2, 7.2 Hz,
CH2CH2CH2CH3), 1.28 (3H, t, J 7.2 Hz, OCH2CH3), 1.60 (2H, tt, J 7.2,
7.2 Hz, CH2CH2CH2CH3), 3.00 (3H, d, J 4.8 Hz, NHCH3), 3.19 (2H, t, J
7.2 Hz, CH2CH2CH2CH3), 4.16 (2H, q, J 7.2 Hz, OCH2CH3), 4.43 (2H, s,
NCH2), 7.28e7.43 (6H, m, AreH, NH), 7.56 (1H, d, J 13.8 Hz,
CH3NHCH); dC (150 MHz, CDCl3) 13.5, 14.6, 19.7, 30.2, 35.0, 38.8,
48.1, 59.1, 92.5, 126.1, 128.3, 129.1, 136.5, 152.9, 169.5, 172.6; m/z (EI)
318 (Mþ); HRMS (EI): Mþ, found 318.1927. C18H26N2O3 requires
318.1943.
4.4.5. 5-Ethyl 1-benzyl-2-phenyl-1,6-dihydropyrimidine-5-
carboxylate (7d). Compound 7d was obtained in 32% yield, ac-
companied by amide 8d (48%) (Table 3, entry 5). Compound 7d:
Yellow oil; IR (neat) cmꢁ1: 2979, 1689, 1624, 1512, 1263, 1106; dH
(600 MHz, CDCl3) 1.26 (3H, t, J 7.2 Hz, OCH2CH3), 4.17 (2H, q, J 7.2 Hz,
OCH2CH3), 4.24 (2H, s, CH2Ph or 6-CH2), 4.42 (2H, s, CH2Ph or 6-
CH2), 7.22 (2H, d, J 8.4 Hz, Areo-H), 7.28e7.44 (6H, m, AreH), 7.49
(2H, dd, J 7.4, 1.5 Hz, Areo-H), 7.52 (1H, s, 4-CH); dC (150 MHz,
CDCl3) 14.3, 45.9, 56.3, 60.0, 105.2, 127.1, 127.7, 128.0, 128.7, 129.0,
4.5. General procedure for elimination of NMe2 group of 6c
and 6d using silica gel for synthesis of 7c and 7d
4.5.1. Ethyl 1-butyl-2-phenyl-1,6-dihydropyrimidine-5-carboxylate
ꢀ
(7c). Silica gel (510 mg, 1000 wt %) and molecular sieves 3 A
(25.5 mg, 50 wt %) was dried at heating in vacuo. To a mixture of the

Y. Nishimura et al. / Tetrahedron 68 (2012) 3342e3350
3349
ꢀ
silica gel and molecular sieves 3 A was added a mixture of 6c and 7c
(KBr) cmꢁ1: 2947, 2850, 1695, 1508, 1263, 1107; dH (400 MHz,
CD3OD) 3.72 (3H, s, OCH3), 4.36 (2H, s, NCH2), 7.33 (1H, s, NCH), 7.45
(2H, t, J 7.2 Hz, Arem-H), 7.52 (1H, t, J 7.2 Hz, Arep-H), 7.67 (2H, d, J
7.2 Hz, Areo-H); dC (100 MHz, CD3OD) 43.5, 51.8, 101.9, 128.0, 129.7,
132.4, 135.0, 141.5, 158.0, 168.2; m/z (EI) 216 (Mþ); HRMS (EI): Mþ,
found 216.0902. C12H12N2O2 requires 216.0899.
(11.9:1.0, 51.0 mg, 0.155 mmol) in CH2Cl2 (2 mL) under an argon
atmosphere. Stirring was continued at room temperature for 21 h.
The reaction mixture was quenched with triethylamine (2 mL),
filtered, and concentrated under reduced pressure to give the res-
idue, which was purified by flash column chromatography (n-
hexane/Et3N¼5:1) to afford 7c (37.5 mg, 0.131 mmol, 84%) (See
Experimental section 4.4.3).
4.7.3. 2-Phenyl-5-phenylsulfonyl-1,4(6)-dihydropyrimidine
(9f). Colorless crystals; mp 200e202 ꢀC (n-hexane/chloroform); IR
(KBr) cmꢁ1: 2921, 1683, 1526, 1281, 1146; dH (600 MHz, CD3OD) 4.24
(2H, s, 6-CH2), 7.32 (1H, s, 4-CH), 7.43 (2H, t, J 7.5 Hz, Arem-H), 7.51
(1H, t, J 7.5 Hz, Arep-H), 7.62 (2H, t, J 7.5 Hz, Arem-H), 7.66 (2H, d, J
7.5 Hz, Areo-H), 7.69 (1H, t, J 7.5 Hz, Arep-H), 7.89 (2H, d, J 7.5 Hz,
Areo-H); dC (150 MHz, CD3OD) 43.4, 110.6 (br), 128.0, 128.4, 129.7,
130.5, 132.4, 134.5, 134.7, 139.4 (br), 141.5, 156.5 (br); m/z (EI) 298
(Mþ); HRMS (EI): Mþ, found 298.0786. C16H14N2O2S requires
298.0776.
4.5.2. 5-Ethyl 1-benzyl-2-phenyl-1,6-dihydropyrimidine-5-
carboxylate (7d). Similarly, compound 7d was obtained from 6d
in 71% yield (See Experimental section 4.4.5).
4.6. General procedure for cyclization reaction of 1,3-diaza-
1,3-butadiene 3a with olefins for synthesis of 7h and 7i
4.6.1. tert-Butyl 5-benzoyl-2-phenyl-1,6-dihydropyrimidine-1-
carboxylate (7h). A solution of 3a (161 mg, 0.585 mmol) and phe-
nyl vinyl ketone (390 mg, 2.95 mmol) in mesitylene (2 mL) was
heated at 100 ꢀC for 13 h under an argon atmosphere. The reaction
mixture was concentrated under reduced pressure to give the
residue, which was purified by flash column chromatography (n-
hexane/EtOAc/i-Pr2NEt¼60:4:1) to afford 7h (196 mg, 0.541 mmol,
92%) as yellow crystals; mp 154e155 ꢀC (n-hexane/chloroform); IR
(KBr) cmꢁ1: 2966, 1714, 1626, 1523, 1373, 1097; dH (300 MHz, CDCl3)
1.17 (9H, s, CMe3), 4.71 (2H, d, J 1.2 Hz, 2-CH2), 7.41e7.61 (7H, m,
AreH and 6-CH), 7.66e7.75 (4H, m, AreH); dC (75 MHz, CDCl3) 27.3,
40.3, 83.2, 123.5, 128.2, 128.3, 128.5, 128.9, 131.2, 131.9, 136.5, 138.0,
146.6, 151.7, 158.4, 193.4; m/z (EI) 362 (Mþ); HRMS (EI): Mþ, found
362.1629. C22H22N2O3 requires 362.1630.
4.7.4. p-Chlorophenyl 4-phenyl-2,3(5)-dihydropyrimidinyl ketone
(9i). Pale yellow crystals; mp 210e211 ꢀC (n-hexane/chloroform); IR
(KBr) cmꢁ1: 3336, 1673, 1584, 1554, 1476; dH (600 MHz, CD3OD) 4.52
(2H, s, 6-CH2), 7.10e7.26 (1H, br s, 4-CH), 7.48 (2H, t, J 7.2 Hz, Arem-H),
7.49 (2H, d, J 8.4 Hz, AreH), 7.55 (1H, t, J 7.2 Hz, Arep-H), 7.58 (2H, d, J
8.4 Hz, AreH), 7.74 (2H, d, J 7.2 Hz, Areo-H); m/z (EI) 296 (Mþ); HRMS
(EI): Mþ, found 296.0682. C17H13ClN2O requires 296.0717.
4.8. Procedure for cleavage of N-Cbz and N-Bn groups
(hydrogenation) from 7b and 7d
4.8.1. Ethyl 2-phenyl-1,4(6)-dihydropyrimidine-5-carboxylate
(9a). To a solution of 7b (55.6 mg, 0.153 mmol) in EtOAc/MeOH
(2:1, 3.0 mL) was added 10% Pd/C (11.0 mg, 20 wt %), and the re-
action mixture was stirred at room temperature for 18 h under
a hydrogen atmosphere (1 atm). The mixture was filtered through
a Celite and concentrated under reduced pressure to give the res-
idue, which was purified by flash column chromatography (n-
hexane/EtOAc/i-Pr2NEt¼60:30:1 to 50:50:1) to afford 9a (31.1 mg,
0.135 mmol, 89%).
4 . 6 . 2 . t e r t - B u t yl 5 - ( 4 - ch l o ro b e n z o yl ) - 2 - p h e nyl - 1, 6 -
dihydropyrimidine-1-carboxylate
(7i). Yellow
crystals;
mp
122e123 ꢀC (n-hexane/Et2O); IR (KBr) cmꢁ1: 1705, 1631, 1524, 1369,
1331, 1147; dH (600 MHz, CDCl3) 1.16 (9H, s, CMe3), 4.69 (2H, s, 2-
CH2), 7.41e7.48 (5H, m, AreH and 6-CH), 7.51 (1H, t, J 7.2 Hz,
Arep-H), 7.65e7.72 (4H, m, AreH); dC (150 MHz, CDCl3) 27.4, 40.3,
83.4, 123.4, 128.3, 128.6, 128.7, 130.4, 131.4, 136.3, 136.5, 138.3, 146.6,
151.8, 158.7, 192.1; m/z (EI) 396 (Mþ); HRMS (EI): Mþ, found
396.1247. C22H21ClN2O3 requires 396.1240.
4.8.2. Ethyl 3-benzyl-2-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (10). To a solution of 7d (27.0 mg, 0.0843 mmol) in
EtOAc/MeOH (2:1, 3 mL) was added 20% Pd(OH)2/C (10.8 mg,
40 wt %), and the reaction mixture was stirred at room temperature
for 4 h under a hydrogen atmosphere (1 atm). The mixture was
filtered through a Celite and concentrated under reduced pressure
to give the residue, which was purified by flash column chroma-
tography (n-hexane/EtOAc/i-Pr2NEt¼60:20:1 to 0:80:1) to afford
4.7. General procedure for cleavage of N-Boc group from 7a,
eef, i for synthesis of 9a, eef, i
4.7.1. Ethyl 2-phenyl-1,4(6)-dihydropyrimidine-5-carboxylate
(9a). To a solution of 7a (51.6 mg, 0.156 mmol) in CH2Cl2 (2 mL)
was added trifluoroacetic acid (0.500 mL, 6.73 mmol) dropwise at
0 ꢀC. The reaction mixture was stirred at room temperature for 3 h,
and 2 M NaOH aqueous solution (10 mL) and EtOAc (20 mL) were
added. The organic layer was separated, and the aqueous layer was
extracted with EtOAc (10 mLꢂ2). The combined organic layer was
washed with water, brine, dried over anhyd Na2SO4, and concen-
trated under reduced pressure to give the residue, which was pu-
rified by flash column chromatography (n-hexane/EtOAc/i-
Pr2NEt¼50:25:1 to 25:25:1) to afford 9a (34.9 mg, 0.152 mmol,
97%) as yellow crystals; mp 111e112 ꢀC (n-hexane/chloroform); IR
(KBr) cmꢁ1: 3165, 1702, 1682, 1668, 1504, 1262, 1100; dH (600 MHz,
CD3OD) 1.29 (3H, t, J 7.2 Hz, OCH2CH3), 4.19 (2H, q, J 7.2 Hz,
OCH2CH3), 4.36 (2H, s, NCH2), 7.33 (1H, s, NCH), 7.45 (2H, t, J 7.2 Hz,
Arem-H), 7.52 (1H, t, J 7.2 Hz, Arep-H), 7.69 (2H, d, J 7.2 Hz, Areo-
H); dC (150 MHz, CD3OD) 14.7, 43.6, 61.2, 102.1, 128.0, 129.7, 132.4,
135.0, 141.4, 158.0, 167.8; m/z (EI) 230 (Mþ); HRMS (EI): Mþ, found
230.1069. C13H14N2O2 requires 230.1085.
10 (8.90 mg, 0.0276 mmol, 33%) as a colorless oil; IR (neat) cmꢁ1
:
3150e3480 (br), 1672, 1651, 1620, 1301, 1208, 1108; dH (600 MHz,
DMSO-d6) 1.12 (3H, t, J 7.2 Hz, OCH2CH3), 2.92 (1H, d, J 15.9 Hz,
PhCH), 3.12 (1H, d, J 15.9 Hz, PhCH), 3.57 (1H, d, J 13.5 Hz, 6-CH),
3.66 (1H, d, J 13.5 Hz, 6-CH), 3.95 (2H, q, J 7.2 Hz, OCH2CH3), 4.94
(1H, d, J 3.0 Hz, 2-CH), 7.23e7.41 (10H, m, AreH), 7.59 (1H, dd, J 5.4,
3.0 Hz, 3-NH), 7.66 (1H, d, J 5.4 Hz, 4-CH); dC (150 MHz, CDCl3) 14.5,
43.6, 57.0, 59.1, 70.3, 94.8, 126.8, 127.2, 128.0, 128.4, 128.5, 129.0,
138.9, 140.2, 140.9, 167.7; m/z (EI) 322 (Mþ); HRMS (EI): Mþ, found
322.1660. C20H22N2O2 requires 322.1681.
4.9. Three-step successive reactions from 3a for the synthesis
of 9a
A solution of 3a (208 mg, 0.757 mmol) and ethyl acrylate 5
(2.50 mL, 23.0 mmol) in mesitylene (6.0 mL) was heated at 100 ꢀC
for 13 h under an argon atmosphere. The reaction mixture was
concentrated under reduced pressure to give cyclized products 6a/
7a. The residue was dissolved in CH2Cl2 (5.0 mL), and MeI
4.7.2. Methyl 2-phenyl-1,4(6)-dihydropyrimidine-5-carboxylate
(9e). Yellow crystals; mp 143e144 ꢀC (n-hexane/chloroform); IR

3350
Y. Nishimura et al. / Tetrahedron 68 (2012) 3342e3350
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(0.470 mL, 7.55 mmol) was added to the solution dropwise at room
temperature under an argon atmosphere. The reaction mixture was
stirred at room temperature for 4 h, and quenched with triethyl-
amine (2.0 mL), EtOAc (20 mL), water (10 mL). The organic layer
was separated, and the aqueous layer was extracted with EtOAc
(10 mLꢂ2). The combined organic layer was washed with water,
brine, dried over anhyd Na2SO4, and concentrated under reduced
pressure. To a solution of the residue in CH2Cl2 (8.0 mL) was added
trifluoroacetic acid (2.00 mL, 26.9 mmol) dropwise at 0 ꢀC. The
reaction mixture was stirred at room temperature for 5 h, and 2 M
NaOH aqueous solution (20 mL) and EtOAc (20 mL) were added.
The organic layer was separated, and the aqueous layer was
extracted with EtOAc (20 mLꢂ2). The combined organic layer was
washed with water, brine, dried over anhyd Na2SO4, and concen-
trated under reduced pressure to give the residue, which was pu-
rified by flash column chromatography (n-hexane/EtOAc/i-
Pr2NEt¼80:40:1) to afford 9a (105 mg, 0.456 mmol, 60%).
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Acknowledgements
We appreciate the financial support of the Tohoku University G-
COE program ‘IREMC’. This work was also carried out with the fi-
nancial support of Japan Tobacco Inc. to H.C.
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Supplementary data
1H and 13C NMR spectra of all compounds. Supplementary data
related to this article can be found online at doi:10.1016/
j.tet.2012.02.064.
References and notes
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