Synthesis of 4-unsubstituted dihydropyrimidines having acyl and alkoxycarbonyl groups at 5- and 6-positions by cyclization-elimination reactions using 1,3-diaza-1,3-butadienes

Article abstract of DOI:10.1016/j.tetlet.2013.11.038

A synthetic method for novel 4-unsubstituted 2-phenyldihydropyrimidines having acyl and alkoxycarbonyl groups at the 5- and 6-positions was developed. The cyclization of 4-dimethylamino-1,3-diaza-1,3-butadiene having N-protecting groups (Boc, Cbz) with 1,2-disubstituted ethylenes, such as diethyl maleate, diethyl fumarate, (Z)-hex-3-ene-2,5-dione, (E)-1,4-diphenylbut-2-ene-1,4-dione, and unsymmetrical (E)-ethyl 4-oxo-4-phenylbut-2-enoate, following the elimination of a dimethylamino group proceeded smoothly, producing the corresponding dihydropyrimidines in good overall yield. The N-protecting group (Boc) could be easily removed to obtain N-unsubstituted dihydropyrimidines as a mixture of tautomers, and their tautomeric behavior was analyzed by ¹H NMR spectroscopy.

Full text of DOI:10.1016/j.tetlet.2013.11.038

Tetrahedron Letters 55 (2014) 411–414
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Tetrahedron Letters
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Synthesis of 4-unsubstituted dihydropyrimidines having acyl
and alkoxycarbonyl groups at 5- and 6-positions
by cyclization–elimination reactions using 1,3-diaza-1,3-butadienes
b
Yoshio Nishimura a, , Hidetsura Cho
⇑
a Faculty of Pharmacy, Yasuda Women’s University, 6-13-1, Yasuhigashi, Asaminami-ku, Hiroshima 731-0153, Japan
b Graduate School of Pharmaceutical Sciences, 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 synthetic method for novel 4-unsubstituted 2-phenyldihydropyrimidines having acyl and alkoxycar-
bonyl groups at the 5- and 6-positions was developed. The cyclization of 4-dimethylamino-1,3-diaza-
1,3-butadiene having N-protecting groups (Boc, Cbz) with 1,2-disubstituted ethylenes, such as diethyl
maleate, diethyl fumarate, (Z)-hex-3-ene-2,5-dione, (E)-1,4-diphenylbut-2-ene-1,4-dione, and unsym-
metrical (E)-ethyl 4-oxo-4-phenylbut-2-enoate, following the elimination of a dimethylamino group
proceeded smoothly, producing the corresponding dihydropyrimidines in good overall yield. The
N-protecting group (Boc) could be easily removed to obtain N-unsubstituted dihydropyrimidines as a
mixture of tautomers, and their tautomeric behavior was analyzed by 1H NMR spectroscopy.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 8 October 2013
Revised 4 November 2013
Accepted 11 November 2013
Available online 19 November 2013
Keywords:
4-Unsubstituted dihydropyrimidine
1,3-Diaza-1,3-butadiene
1,2-Disubstituted ethylene
Cyclization
Elimination
Dihydropyrimidines have received much attention from syn-
thetic and medicinal chemists due to their biological activities
and unique physical and chemical characteristics.1 They exhibit a
wide range of activities for medicinal applications, such as antivi-
ral, antitumor, antibacterial, and anti-inflammatory activities. In
R1 = H) or b-oxoaldehyde (4; R2 = H) derivatives. To overcome this
problem, during the course of our continuous research on dihydro-
pyrimidines,7 we previously developed the stepwise synthesis of
4,6-unsubstituted 2-phenyldihydropyrimidines having 5-substitu-
ents by using our designed protocol.7d,e It was a versatile method
to obtain novel 2,5-disubstituted dihydropyrimidines.
addition, they are regarded as calcium channel antagonists,2
a
ROCK1 inhibitor for cardiovascular diseases,3 or a pharmaceutical
agent for anti-hepatitis B virus replication.4 Their anticancer po-
tential has also been explored recently.5 Therefore, the develop-
ment of versatile synthetic methods for dihydropyrimidines and
the expansion of the structural diversity of these compounds are
important, and will contribute to medicinal chemistry.
The synthesis of dihydropyrimidines 1 has generally been per-
formed by the reactions of (thio)urea 2 with aldehydes 3 and
1,3-dicarbonyl compounds 4, or the reactions of amidines, guani-
On the other hand, as for the acyl, alkoxycarbonyl, or amide
groups in dihydropyrimidines 1, they have conventionally been lo-
cated at the C-5 position. The groups could be introduced at the N-
1 or N-3 position; in the case of carbonylation with dihydropyrim-
idine tautomers, it occurs predominantly at the N-3 position.6f,7a,8
However, the introduction toward another position (especially the
C-4 and C-6 positions) of the groups has scarcely been reported due
to the lack of available synthetic methodologies.9 Herein, we report
a novel synthetic method using 1,3-diaza-1,3-butadienes 7 and
1,2-disubstituted ethylenes 8 to produce 4-unsubstituted dihydro-
pyrimidines 9 having acyl and alkoxycarbonyl groups at the 5- and
6-positions (Scheme 2). Because dihydropyrimidines 9 are difficult
to access by the conventional method described in Scheme 1, our
results are significant and novel. The general formulae of 9 and
deprotected N-unsubstituted dihydropyrimidines 10 shown in this
Letter have not been reported in the literature. It should also be
noted that we used a protocol simpler than the previous proce-
dure,7d,e which was improved as a one-pot cyclization–elimination
reaction sequence.
dines, and O(S)-alkyliso(thio)urea derivatives 5 with
a,b-unsatu-
rated carbonyl compounds 6 (Scheme 1).1a,6 Therefore, the R1
and R2 substituents at the C-4 and C-6 positions of 1 are typically
alkyl or aryl groups, and the COR3 substituent at the C-5 position is
an acyl, alkoxycarbonyl, or amide group. Multisubstituted dihydro-
pyrimidines 1 are comparatively easy to synthesize, whereas less
substituted dihydropyrimidines are difficult to prepare because
of the difficulty in controlling the reactivity of formaldehyde (3;
⇑
Our initial studies of the synthesis of dihydropyrimidines 9
Corresponding author. Tel.: +81 82 878 9498; fax: +81 82 878 9540.
E-mail address: nishimura-y@yasuda-u.ac.jp (Y. Nishimura).
started with the reaction between 1,3-diaza-1,3-butadiene 7a7e
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.11.038

412
Y. Nishimura, H. Cho / Tetrahedron Letters 55 (2014) 411–414
R1
subjected to sequential reactions to assemble dihydropyrimidines
9, and the results are summarized in Table 1. In entry 2, diethyl
fumarate 8b showed a similar reactivity to 8a, indicating that the
olefin geometry of 8 did not affect the reactivity. Indeed, almost
all of 8a were isomerized and recovered as trans isomer 8b at the
end of the reaction (entry 1). In addition to ethyl ester 8a, benzyl
ester 8c11 could be applied to the reaction (entry 3). Benzyloxycar-
bonyl diazadiene 7b also reacted with 8a, producing 9c in accept-
able yield (entry 4). In the case of the diketone (Z)-hex-3-ene-2,5-
dione 8d,12 it exhibited a higher reactivity than diesters 8a–c.
Therefore, the lower amount of 8d (5.0 equiv) and the reaction
temperature (80 °C) were sufficient to obtain 9d in good yield (en-
try 5). Similarly, (E)-1,4-diphenylbut-2-ene-1,4-dione 8e showed a
higher reactivity to give 9e in high yield (entry 6). The reaction of
7a with p-tolyl derivative 8f13 was slower than that with unsubsti-
tuted 8e, and provided 9f in moderate yield (entry 7). Even with
unsymmetrical (E)-ethyl 4-oxo-4-phenylbut-2-enoate 8g, the reac-
tion proceeded smoothly to give two dihydropyrimidines in 72%
yield (entry 8); 6-ethoxycarbonyl 5-benzoyl dihydropyrimidine
9g (62%) and 5-ethoxycarbonyl 6-benzoyl derivative 9h (10%) were
isolated. The structure of the major compound 9g was assigned by
NOE experiments: a significant NOE (1.3%) was observed between
the 4-H vinyl proton (d 7.38) and the aromatic protons (d 7.80) of
the 5-benzoyl group. Therefore, its structure was determined to be
9g. Thus, the N–C bond formation between 7a and 8g occurred
preferentially at the b-position of the benzoyl group of 8g due to
the stronger electron withdrawing property of the ketone than of
the ester. Unfortunately, our attempt to react 7a with other 1,2-
disubstituted ethylenes such as ethyl cinnamate, chalcone, 2-
cyclohexen-1-one, maleimide, and fumaric anhydride failed under
our reaction conditions; only the decomposition or recovery of the
starting materials occurred without the detection of cyclized
products.
Finally, the N-protecting (Boc) group was removed and N-
unsubstituted dihydropyrimidines 10 were synthesized (Table 2).
Compound 9a was treated with excess trifluoroacetic acid (TFA)
in CH2Cl2 at room temperature to afford 10a in 95% yield (entry
1).14 The deprotection reaction of 9g with TFA proceeded to give
10g in high yield (entry 2). Subsequently, the tautomeric behavior
of 10a and 10g was analyzed by 1H NMR spectroscopy. The spectra
were measured in CD3OD, CDCl3, and DMSO-d6 at 25 °C (0.01 M,
600 MHz). Prior to the analysis, CDCl3 was filtered through acti-
vated aluminum oxide in order to eliminate the effect of trace
amounts of acid on tautomerization. Diester 10a was observed as
two independent isomers at ratios of 1.6:1.0 (CDCl3) and 4.9:1.0
(DMSO-d6) (entry 1). The observed signals of NH protons [d 9.94
(major), d 9.22 (minor)] and 4-protons [d 5.16 (major), d 5.01 (min-
or)] in DMSO-d6 indicated that the two isomers were 1,4- and 1,6-
tautomers. The major tautomer of 10a in DMSO-d6 was assigned to
the 1,4-isomer because the 6-H vinyl proton (d 7.31) was observed
as a doublet peak by its coupling (J = 5.4 Hz) with the 1-NH proton
(d 9.94). In CD3OD, 10a was observed as a single isomer (average
spectrum of tautomers). As for 10g, two tautomers were observed
only in CDCl3 (entry 2). The major tautomer of 10g in CDCl3 was
assigned to the 1,6-isomer because the 6-H proton (d 5.60) was ob-
served as a doublet peak by its coupling (J = 2.4 Hz) with the 1-NH
proton. In our previous report, 2-phenyldihydropyrimidine 5-car-
boxylic acid ethyl ester showed a similar behavior to 10a; the
1,4-isomer was observed as a major tautomer in DMSO-d6.7e These
analytical results showed that the position and property of acyl
and alkoxycarbonyl groups in dihydropyrimidines significantly af-
fected the rate of hydrogen transfer in tautomerism.
R1
O
O
R1 R3
4
O
O
H
R3
3
N
O
3
R3
5
NH
NH2
NH2
2
R2
6
R4
R2
N
NH2
1
R5
6
O
R2
X
H
2
4
1
5
X = O, S
R
5 = alkyl, aryl, OR', SR', NR'2
R1, R2 = alkyl, aryl, R3 = alkyl, aryl, OR, NR2
R4 = O, S, alkyl, aryl, OR', SR', NR'2
Scheme 1. Synthesis of dihydropyrimidines by condensation reactions.
R
O
O
R
N
O
R
O
8
O
O
6
R'
X
1) cyclization
X
R'
HN
R'
+
5
4
N
2) elimination
Ph
N
Ph
N
Ph
N
NMe2
9
10
7
Scheme 2. Synthetic strategy for dihydropyrimidines 9 and 10.
and diethyl maleate 8a. After the optimization of the reaction con-
ditions, namely, the reaction temperature, the solvent used, and
the molar ratio of the reactants, we found that the reaction pro-
ceeded smoothly with an excess amount of 8a under solvent-free
condition. Namely, 7a reacted with 8a (30 equiv) at 100 °C for
40 h to give three cyclized products; two stereoisomers of
1,4,5,6-tetrahydropyrimidine 11a (1.1:1.0) and 1,6-dihydropyrimi-
dine 9a were obtained in 31% and 30% yields, respectively
(Scheme 3). Successive elimination reaction of the 4-dimethyl-
amino group of 11a was attempted; when a mixture of two stereo-
isomers 11a (1.1:1.0) was treated with MeI (40 equiv) in CH2Cl2 at
room temperature for 7 h, 11a underwent an elimination reaction
to give 9a in 78% yield (Scheme 3). For a more effective and oper-
ationally simple procedure, the one-pot synthesis of 9a from 7a
was tested; the crude mixture after the cyclization of 7a and 8a
was subjected to an elimination reaction [MeI (51 equiv) in CH2Cl2
for 4 h] to provide 9a in 52% overall yield from 7a (Scheme 3). The
result indicates that the reaction of 11a with MeI proceeded
uneventfully without the isolation of 11a from the crude mixture.
Hence, we established the one-pot cyclization–elimination reac-
tion sequence as the standard procedure in this study.
Next, the effect of an additive on the reaction was investigated
to increase the yield of 9a. Although none of the additives showed
a crucial effect, the yield was slightly increased from 52% to 61%
when the reaction was conducted in the presence of Li2CO3
(1.0 equiv) (Table 1, entry 1).10 Other additives used such as Na2-
CO3, K2CO3, and BF3 etherate did not show a superior effect. Under
the optimized reaction conditions, various substrates were
MeI (40 eq)
CO2Et
78%
CO2Et
CH2Cl2, rt, 7 h
CO2Et
CO2Et
6
1
N
1
N
6
Boc
Ph
CO2Et
CO2Et
Boc
Ph
Boc
Ph
8a (30 eq)
N
5
+
neat
N
NMe2
4
N
N
NMe2
100 oC, 40 h
11a
31% (1.1:1.0)
9a
7a
30%
1) 8a (30 eq), 100 ºC, 40 h
In summary, it was demonstrated that 4-unsubstituted 2-phen-
yldihydropyrimidines having acyl and alkoxycarbonyl groups at
the 5- and 6-positions were synthesized by the cyclization-elimi-
nation reaction sequence. The reactions using 1,2-disubstituted
52%
2) MeI (51 eq), CH2Cl2, rt, 4 h
Scheme 3. Stepwise and one-pot synthesis of dihydropyrimidine 9a.

Y. Nishimura, H. Cho / Tetrahedron Letters 55 (2014) 411–414
413
Table 1
Synthesis of dihydropyrimidines 9
R
N
O
O
X
6
O
R
1) Li2CO3 (1.0 eq), heating
X
N
R'
R'
5
+
Ph
N
NMe2
O
2) MeI (51 eq), CH2Cl2, rt, 4 h
Ph
N
4
7a (X = Boc) 7b (X = Cbz)
8
9
3.0-30 eq
0.3 mmol
Entry Diene
Substrate 8
Reaction
conditions
Product 9
9a (R = Et)
Yielda
(%)
7
CO2R
CO2R
1
7a
8a (R = Et, cis isomer, 30 equiv)
8b (R = Et, trans isomer, 30 equiv)
100 °C, 40 h
61
CO2R
Boc
CO2R
9a (R = Et)
N
2
3
7a
7a
100 °C, 40 h
100 °C, 18 h
61
52
Ph
N
8c (R = Bn, cis:trans = 5.0:1.0, 30
9b (R = Bn)
equiv)
CO2Et
Cbz
CO2Et
N
9c
4
7b
7a
8a (R = Et, cis isomer, 30 equiv)
8d (R = CH3, cis isomer, 5.0 equiv)
100 °C, 60 h
80 °C, 12 h
50
64
9c
Ph
N
5b
9d (R = CH3)
O
R
N
O
O
R
R
Boc
6b
7c
7a
7a
8e (R = Ph, trans isomer, 3.0 equiv)
80 °C, 15 h
80 °C, 40 h
77
56
9e (R = Ph)
R
O
Ph
N
8f (R = C6H4p-Me, trans isomer, 5.0
9f (R = C6H4p-Me)
equiv)
O
Ph
O
EtO2C
N
O
Boc
Boc
Ph
CO2Et
9h
Ph
8b
7a
8g (5.0 equiv)
80 °C, 48 h
72
N
+
EtO2C
Ph
N
9g
Ph
N
9h
(9g:9h = 6.2:1.0)
a
b
c
Overall yield of 9 from 7 (two steps).
Mesitylene (0.5 mL) was used as solvent.
Mesitylene (1.0 mL) was used as solvent.
based heterocyclic chemistry and pharmaceutical sciences for drug
development.
Table 2
Synthesis and 1H NMR analysis of N-unsubstituted dihydropyrimidines 10a and 10g
Supplementary data
R
N
O
R
N
O
R
O
O
O
O
TFA
1
4
6
Boc
Ph
Supplementary data (synthesis and characterization of com-
pounds, spectroscopic data of IR, NMR, MS) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.11.038.
R'
R'
HN
Ph
10
R'
CH2Cl2
rt, 4 h
N
Ph
10
N
N
1
H
9
(1,4-isomer)
(1,6-isomer)
DMSO-d6
Entry Product 10
CO2Et
CO2Et
Yield (%) CD3OD CDCl3
References and notes
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HN
1
95
95
Single
Single
1.6:1.0 4.9:1.0
10a
10g
Ph
N
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1.0:1.6 Single
Ph
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ene-2,5-dione, (E)-1,4-diphenylbut-2-ene-1,4-dione, and unsym-
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(E)-ethyl
4-oxo-4-phenylbut-2-enoate,
proceeded
smoothly to give the corresponding dihydropyrimidines. Because
all the dihydropyrimidines presented in this Letter have hitherto
been unavailable compounds, this unprecedented achievement
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414
Y. Nishimura, H. Cho / Tetrahedron Letters 55 (2014) 411–414
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saturated NaHCO3 aqueous solution (5 mL), and the organic layer was
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flash column chromatography [hexane–EtOAc–(i-Pr)2NEt (40:5:1)] to give 9a
(73.2 mg, 0.182 mmol, 61%) as colorless crystals. mp 97–98 °C (hexane). IR
(KBr) cmÀ1: 2980, 1745, 1726, 1534, 1369, 1285, 1223, 1151. 1H NMR (CDCl3) d
1.13 (9H, s), 1.23 (3H, t, J = 7.2 Hz), 1.36 (3H, t, J = 7.2 Hz), 4.14 (1H, dq, J = 10.8,
7.2 Hz), 4.20 (1H, dq, J = 10.8, 7.2 Hz), 4.29 (1H, dq, J = 10.8, 7.2 Hz), 4.37 (1H,
dq, J = 10.8, 7.2 Hz), 5.99 (1H, s), 7.43 (2H, t, J = 7.8 Hz), 7.49 (1H, t, J = 7.8 Hz),
7.73 (1H, s), 7.84 (2H, d, J = 7.8 Hz). 13C NMR (CDCl3) d 13.9, 14.3, 27.3, 51.2,
60.9, 62.0, 83.8, 114.9, 128.1, 128.6, 131.0, 136.7, 142.3, 151.5, 156.9, 164.6,
169.0. HRMS-FAB m/z: 403.1863 (Calcd for C21H27N2O6: 403.1869). MS (FAB)
m/z: 403 [(M+H)+].
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10. Under an atmosphere of argon, a mixture of 7a (82.5 mg, 0.300 mmol), 8a
(1.45 mL, 9.00 mmol), and Li2CO3 (22.0 mg, 0.300 mmol) was heated at 100 °C
for 40 h. After cooled to room temperature, the reaction mixture was filtrated
and concentrated under reduced pressure. To the crude mixture was added
CH2Cl2 (2.0 mL) and MeI (0.950 mL, 15.3 mmol) at 0 °C and the mixture was
stirred at room temperature for 4 h. After removal of excess MeI under reduced
pressure, to the reaction mixture was added EtOAc (15 mL) followed by
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12. (Z)-Hex-3-ene-2,5-dione 8d was prepared by the reaction of 2,5-dimethylfuran
and 3-chloroperbenzoic acid (1.1 equiv) in CH2Cl2 at rt for 1 h. The structural
identification was made according to the literature; Matturro, M. G.; Reynolds,
R. P.; Kastrup, R. V.; Pictroski, C. F. J. Am. Chem. Soc. 1986, 108, 2775–2776.
13. p-Tolyl derivatives 8f were prepared according to the reported procedure;
Conant, J. B.; Lutz, R. B. J. Am. Chem. Soc. 1923, 45, 1303–1307.
14. To
a solution of 9a (111 mg, 0.276 mmol) in CH2Cl2 (4 mL) was added
trifluoroacetic acid (0.800 mL, 10.8 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 at 0 °C. The organic layer was
separated, and the aqueous layer was extracted with EtOAc (10 mL Â 2). The
combined organic layers were washed with water (5 mL), brine (5 mL), dried
over anhydrous Na2SO4, and concentrated under reduced pressure. The residue
was purified by flash column chromatography [hexane-EtOAc-Et3N (30:20:1)]
to give 10a (79.5 mg, 0.263 mmol, 95%) as a yellow oil. IR (neat) cmÀ1: 2982,
1739, 1698, 1478, 1254, 1196. 1H NMR (CD3OD) d 1.27 (3H, t, J = 7.2 Hz), 1.29
(3H, t, J = 7.2 Hz), 4.15–4.27 (4H, m), 5.24 (1H, s), 7.38–7.60 (4H, m), 7.65–7.85
(2H, m). 13C NMR (CD3OD) d 14.5, 14.6, 57.2, 61.5, 62.5, 101.8, 128.3, 129.7,
132.6, 134.7, 139.7, 156.5, 167.5, 172.9. HRMS-FAB m/z: 303.1334 (Calcd for
C
16H19N2O6: 303.1345). MS (FAB) m/z: 303 [(M+H)+].