Protecting group free synthesis of carboxyl-substituted dihydropyrimidines through Biginelli reaction

Article abstract of DOI:10.1002/jhet.1568

Chlorotrimethylsilane-promoted Biginelli-type reaction of benzaldehyde, acetoacetic acid derivatives, and various carboxyl-containing ureas was explored. It was found that the steric load of the urea substituents influenced strongly the reaction outcome; in particular, the method was efficient only in the case of unbranched mono-substituted ureas bearing either aliphatic or aromatic groups. The method allows performing a one-pot, protecting group free synthesis of dihydropyrimidines possessing carboxylic functionality.

Full text of DOI:10.1002/jhet.1568

Month 2013 Protecting Group Free Synthesis of Carboxyl-substituted Dihydropyrimidines
Through Biginelli Reaction
Eugeniy N. Ostapchuk,a,b Andrey S. Plaskon,a,b Oleksandr O. Grygorenko,a,b Andrey A. Tolmachev,a,b
and Sergey V. Ryabukhina,c
*
aEnamine Ltd., Oleksandra Matrosova Street, 23, Kyiv 01103, Ukraine
bKyiv National Taras Shevchenko University, Volodymyrska Street, 64, Kyiv 01033, Ukraine
cThe Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov Street
Kyiv 03187, Ukraine
*
E-mail: s.v.ryabukhin@gmail.com
Received June 14, 2011
DOI 10.1002/jhet.1568
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
O
R
N
H
O
O
Me3SiCl
DMF, rt
N
O
+
R
+
PhCHO
HN
NH2
COOH
R = OEt, N(CH2)4O, NHPh
O
COOH
Chlorotrimethylsilane-promoted Biginelli-type reaction of benzaldehyde, acetoacetic acid derivatives, and
various carboxyl-containing ureas was explored. It was found that the steric load of the urea substituents
influenced strongly the reaction outcome; in particular, the method was efficient only in the case of
unbranched mono-substituted ureas bearing either aliphatic or aromatic groups. The method allows performing
a one-pot, protecting group free synthesis of dihydropyrimidines possessing carboxylic functionality.
J. Hetercycl Chem., 00, 00 (2013).
In this contribution, we describe our results on
chlorotrimethylsilane-promoted Biginelli reaction involving
substituted ureas bearing the carboxyl functionality at their
substituents (2). It was shown in a few reports [15–21] that
the use of chlorotrimethylsilane as a mild condensation
promoter tolerating a wide range of functional groups
improved considerably the reaction yields. Therefore, the
chlorotrimethylsilane was used in this study. A set of
substituted ureas 2a–k was employed in present syntheses
to establish the scope and limitations of the method (Fig. 1).
To the best of our knowledge, only a limited number of
examples involving ureas of the type 2 in Biginelli reaction
was reported in the literature. In particular, reactions of urea
2e with ethyl/benzyl acetoacetate and a set of aldehydes
promoted by HCl were reported [22–24]. Several examples
of analogous transformations of urea 2c via multistep solid-
phase procedures were also reported [25].
The reactions of benzaldehyde with ureas 2a–k and
acetoacetic acid derivatives 3a–c were performed by keeping
the reagents in the presence of Me3SiCl (5 eq)—DMF
system at ambient temperature for 3–4 days (Scheme 1).
The results of the experiments are summarized in Table 1.
Steric hindrance in the starting urea 2 appeared to be a
predominant factor that determined the reaction outcome.
In particular, reactions of benzaldehyde, acetoacetic acid
INTRODUCTION
Multicomponent reactions represent a timely field of
organic chemistry for more than a century because they
allow huge diversity of rather complicated molecules to be
created using one synthetic procedure in an efficient and
timesaving manner [1–10]. The Biginelli reaction, one of
the most useful multicomponent reactions, offers an efficient
way to access multifunctionalized dihydropyrimidine deriva-
tives 1 (Fig. 1) and related heterocyclic compounds through
a condensation of an aldehyde, a b-dicarbonyl compound,
and urea derivatives [11,12]. Dihydropyrimidine structural
unit 1 is an important scaffold in the medical research. It is
found in calcium channel modulators, mitotic kinesine
inhibitors, adrenergic receptor antagonists, and antibacterial
and antiviral agents [13].
Biginelli reaction involving substituted ureas with addi-
tional functional groups at their substituents gives rise to
functionalized dihydropyrimidines. The latter are useful
building blocks for parallel synthesis of combinatorial
libraries for high-throughput screening. Notably, the Biginelli
reaction is not affected by many functional groups at the urea
substituent. This offers a nice opportunity to carry out one-
pot, protecting group free [14] syntheses of a number of
functionalized dihydropyrimidines.
© 2013 HeteroCorporation

E. N. Ostapchuk, A. S. Plaskon, O. O. Grygorenko, A. A. Tolmachev, and S. V. Ryabukhin
Vol 000
Ar
N
O
derivatives 3a–c, and ureas 2a–h resulted in target
dihydropyrimidines 4(a–h)(a–c) with 60–83% yields. In the
case of less reactive ureas 2i–k, we could not isolate the
corresponding dihydropyrimidines 4ia–4ka from the crude
product [18], although their formation (<10%) was detected
by NMR and HPLC–MS. It should be noted that lowering
the reactivity of b-dicarbonyl component 3 (from 3a to 3c)
did not affect considerably the outcome of the reaction.
The successful results obtained in the case of ureas
2a–h bearing small substituents can be explained by a
twofold role of the chlorotrimethylsilane. As illustrated in
Scheme 2, in our opinion, the chlorotrimethylsilane acts as
not only the condensation promoter but also as a dynamic
protecting group for the carboxyl moiety [18].
The one-pot, protecting group free chlorotrimethylsilane-
promoted Biginelli-type reaction with carboxyl-substituted
ureas is an efficient and practical method for the synthesis
of dihydropyrimidines from mono-substituted ureas with
aliphatic or aromatic groups. Prepared dihydropyrimidines
contain the carboxylic functionality valuable for further
modification of the molecule.
H
R3
O
N
O
N
R2
NH2
R4
COOH
H
R1
1
2
H
H
H2N
N
H2N
N
COOH
N
O
n
O
O
NH2
COOH
COOH
2f
2g
COOH
2a, n = 1
2b, n = 2
2c, n = 3
2d, n = 4
2e, n = 5
2h
NH
O
NH2
H2N
Ph
H
H
N
H
N
COOH
N
H2N
COOH
H2N
COOH
O
Ph
O
O
2k
2j
2i
Figure 1. Set of substituted ureas 2a-k.
Scheme 1
EXPERIMENTAL
O
Ph
NHR
O
1
O
O
Me3SiCl
DMF
CHO
Ph
+
+
The solvents were purified according to the standard procedures.
All the starting materials were purchased from Acros (Geel,
Belgium), Merck (Darmstadt, Germany), and Fluka (Dorset, United
Kindom). Analytical TLC was performed using Polychrom SI F254
plates. 1H NMR and 13C NMR spectra were recorded on a Bruker
170 Avance 500 spectrometer (at 499.9 MHz for protons and
124.9 MHz for carbon-13). Chemical shifts are reported in ppm
R2
HN
NH2
2a-i
R2
N
O
3a, R2 = OC2H5
R1
3b, R2 = N(CH2)4
3c, R2 = NHPh
4(a-i)(a-c)
Table 1
Biginelli reactions of benzaldehyde, ureas 2a–k, and acetoacetic acid derivatives 3a–c.
Entry No.
Urea
R1
Methylene component
R2
Product
Yield, %
1
2
3
4
5
6
7
8
2a
2a
2b
2c
2c
2d
2e
2e
2e
2f
CH2CO2H
CH2CO2H
(CH2)2CO2H
(CH2)3CO2H
(CH2)3CO2H
(CH2)4CO2H
(CH2)5CO2H
(CH2)5CO2H
(CH2)5CO2H
3a
3b
3a
3a
3b
3a
3a
3b
3c
3a
3b
3a
3b
3a
3b
3a
3b
3c
3a
3a
OC2H5
N(CH2)4O
OC2H5
OC2H5
N(CH2)4O
OC2H5
OC2H5
N(CH2)4O
NHPh
OC2H5
N(CH2)4O
OC2H5
N(CH2)4O
OC2H5
N(CH2)4O
OC2H5
N(CH2)4O
NHPh
OC2H5
4aa
4ab
4ba
4ca
4cb
4da
4ea
4eb
4ec
4fa
4fb
4ga
4gb
4ha
4hb
4ia
83
68
72
75
63
78
70
62
71
76
71
70
65
69
63
9a
9
10
11
12
13
14
15
16
17
18
19
20
p-C6H4CO2H
p-C6H4CO2H
2f
2g
2g
2h
2h
2i
2i
2i
2j
2k
m-C6H4CO2H
m-C6H4CO2H
CH2(p-C6H4CO2H)
CH2(p-C6H4CO2H)
CH(CH3)CO2H
CH(CH3)CO2H
CH(CH3)CO2H
CH(C6H5)CO2H
CH2CH(C6H5)CO2H
4ib
4ic
4ja
4ka
5a
5a
9a
OC2H5
5a
aYields detected by HPLC MS analysis.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Protecting Group Free Synthesis of Carboxyl-Substituted Dihydropyrimidines
Through Biginelli Reaction
3
Scheme 2
Me3SiCl
(m, 3H, 2,4,6-HPh), 7.35 (t, 2H, JH,H = 7.5Hz, 3,5-HPh), 7.67
(br. s, 1H, NH), 12.78 (br. s, 1H, CO2H). 13C NMR (125MHz,
DMSO-d6): d = 16.1, 41.9, 43.9, 46.6, 56.8, 65.8, 66.3, 106.7,
127.0, 128.2, 129.0, 131.7, 143.8, 153.0, 167.1, 172.1. Anal.
Calcd for C18H21N3O5 C 60.16, H 5.89, N 11.69. Found C 59.94,
H 5.98, N 11.60. MS (APCI): m/z 360 (MH+).
H
H
N
O
N
O
OSiMe3
NH2
COOH
NH
Me3Si
2
O
3-[5-(Ethoxycarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-
dihydropyrimidin-1(2H)-yl]propanoic acid 4ba. Yield 72%.
3, PhCHO, Me3SiCl
(Biginelli reaction)
1
3
Mp 152ꢀC. H NMR (500 MHz, DMSO-d6): d =1.10 (t, 3H, JH,
H =7.1 Hz, CH2CH3), 2.44 (m, 1H, CHaHbCO2H), 2.52 (s, 3H,
CH3), 2.55 (m, 1H, CHaHbCO2H), 3.80 (m, 1H, NCHaHb), 3.93
O
R2
N
O
N
R2
N
3
(m, 1H, NCHaHb), 4.01 (q, 2H, JH,H =7.1Hz, CH2CH3), 5.14
Ph
Ph
H2O
3
3
(d, 1H, JH,H =3.0Hz, 4-HDHPM), 7.21 (d, 2H, JH,H =7.6Hz,
3
3
HN
2,6-HPh), 7.24 (t, 1H, JH,H =7.6Hz, 4-HPh), 7.31 (t, 2H, JH,
H = 7.6 Hz, 3,5-HPh), 7.95 (d, 1H, 3JH,H = 3.0 Hz, NH), 12.32 (br. s,
1H, CO2H). 13C NMR (125 MHz, DMSO-d6): d = 14.5, 16.1, 34.3,
38.7, 53.2, 60.1, 103.7, 126.7, 127.8, 128.9, 144.4, 149.9, 152.9,
166.1, 173.0. Anal. Calcd for C17H20N2O5 C 61.44, H 6.07, N
8.43. Found C 61.77, H 6.13, N 8.56. MS (APCI): m/z 333 (MH+).
4-[5-(Ethoxycarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-
dihydropyrimidin-1(2H)-yl]butanoic acid 4ca. Yield 75%. Mp
Me3Si
OSiMe3
O
and other silylated products,
see ref. 18
O
O
COOH
downfield from TMS (1H, 13C) as an internal standard. Elemental
analyses were performed at the Laboratory of Organic Analysis,
Department of Chemistry, Kiev National Taras Shevchenko
University. Mass spectra were recorded with Agilent 1100 LCMSD
SL instrument (chemical ionization). Flash chromatography was
performed on Teledyne ISCO CombiFlash Companion personal
flash chromatography system.
3
222ꢀC. 1H NMR (500 MHz, DMSO-d6): d =1.10 (t, 3H, JH,
H =7.0 Hz, CH2CH3), 1.58 (m, 1H, CH2CHaHbCH2), 1.70 (m, 1H,
3
CH2CHaHbCH2), 2.13 (t, 2H, JH,H =7.2Hz, CH2CO2H), 2.48
(s, 3H, CH3), 3.50 (m, 1H, NCHaHb), 3.83 (m, 1H, NCHaHb),
3
3
4.01 (q, 2H, JH,H =7.0Hz, CH2CH3), 5.14 (d, 1H, JH,H =3.5Hz,
3
3
4-HDHPM), 7.20 (d, 2H, JH,H = 7.6 Hz, 2,6-HPh), 7.23 (t, 1H, JH,
3
H =7.6 Hz, 4-HPh), 7.30 (t, 2H, JH,H = 7.6 Hz, 3,5-HPh), 7.93
General procedure for the reaction of ketones 1a–c and
(d, 1H, JH,H = 3.5 Hz, NH), 12.07 (br. s, 1H, CO2H). 13C NMR
3
aminoazoles 2a–c.
A mixture of compound 3 (2 mmol),
(125 MHz, DMSO-d6): d = 14.5, 16.1, 25.1, 31.1, 41.6, 53.0, 60.1,
103.8, 126.5, 127.8, 128.9, 144.5, 149.9, 153.2, 166.1, 174.4.
Anal. Calcd for C18H22N2O5 C 62.42, H 6.40, N 8.09. Found C
62.09, H 6.31, N 7.88. MS (APCI): m/z 347 (MH+)
benzaldehyde (2 mmol), urea 2 (2.0–2.2 mmol) in dry DMF
(2–3mL) was sonicated for 1h at RT to dissolve the starting
materials, and then, chlorotrimethylsilane (1.086 g, 10 mmol) was
added. The resulting mixture was allowed to stand for 3–4 days
and then poured into water (15 mL). The suspension formed was
sonicated for 1 h, and the precipitate was filtered and washed with
a small amount of diethyl ether (2 mL). If the solid product was not
formed, the mixture was extracted with CH2Cl2 (2 Â 10mL), the
combined extracts were evaporated, and the residue was triturated
with small amount of diethyl ether and filtered. The crude product
was recrystallized from 2-propanol or purified by flash
chromatography (Hexane/Ether 9:1 as an eluent) to yield the
dihydropyrimidines 4.
4-[6-Methyl-5-(morpholin-4-ylcarbonyl)-2-oxo-4-phenyl-3,
4-dihydropyrimidin-1(2H)-yl]butanoic acid 4cb. Yield 63%.
Mp 214ꢀC. 1H NMR (500 MHz, DMSO-d6): d =1.71 (m, 2H,
CH2CH2CH2), 1.84 (s, 3H, CH3), 2.23 (m, 2H, CH2CO2H), 3.04
(m, 2H, NCH2), 3.21 (m, 2H, NCH2), 3.41 (m, 2H, OCH2), 3.54
3
(m, 2H, OCH2), 3.71 (m, 2H, NCH2), 5.03 (d, 1H, JH,H =3.5Hz,
3
3
4-HDHPM), 7.17 (d, 2H, JH,H = 7.5 Hz, 2,6-HPh), 7.29 (t, 1H, JH,
3
H =7.5 Hz, 4-HPh), 7.35 (t, 2H, JH,H = 7.5 Hz, 3,5-HPh), 7.52
(d, 1H, JH,H = 3.5 Hz, NH), 12.04 (br. s, 1H, CO2H). 13C NMR
3
(125 MHz, DMSO-d6): d = 16.0, 25.4, 31.3, 41.3, 41.9, 46.7, 56.6,
65.9, 66.4, 107.1, 126.6, 128.1, 129.1, 131.8, 143.8, 153.1, 167.4,
174.6. Anal. Calcd for C20H25N3O5 C 62.00, H 6.50, N 10.85.
Found C 62.37, H 6.40, N 10.99. MS (APCI): m/z 388 (MH+).
5-[5-(Ethoxycarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-
dihydropyrimidin-1(2H)-yl]pentanoic acid 4da. Yield 78%.
5-(Ethoxycarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-dihydro-
pyrimidin-1(2H)-yl]acetic acid 4aa. Yield 83%. Mp 183ꢀC. 1H
3
NMR (500 MHz, DMSO-d6): d = 1.09 (t, 3H, JH,H = 7.0 Hz,
CH2CH3), 2.38 (s, 3H, CH3), 4.00 (m, 2H, CH2CH3), 4.32 (d, 1H,
2
2JH,H = 18.3Hz, CHaHb), 4.47 (d, 1H, JH,H = 18.3 Hz, CHaHb),
5.17 (d, 1H, 3JH,H = 3.0 Hz, 4-HDHPM), 7.23 (t, 1H, 3JH,H = 7.2 Hz,
1
3
Mp 141ꢀC. H NMR (500 MHz, DMSO-d6): d =1.11 (t, 3H, JH,
3
4-HPh), 7.30 (m, 4H, 2,3,5,6-HPh), 8.03 (d, 1H, JH,H = 3.0 Hz,
NH), 12.84 (br. s, 1H, CO2H). 13C NMR (125MHz, DMSO-d6):
d = 14.5, 16.1, 44.5, 53.6, 60.1, 103.4, 127.0, 127.9, 128.8, 144.7,
149.5, 152.8, 166.0, 171.5. Anal. Calcd for C16H18N2O5 C 60.37,
H 5.70, N 8.80. Found C 60.62, H 5.97, N 9.13. MS (APCI):
m/z 319 (MH+).
H =7.1 Hz, CH2CH3), 1.40 (m, 3H, CHaHbCH2CH2CO2H), 1.50
3
(m, 1H, NCH2CHaHbCH2), 2.19 (t, 2H, JH,H =7.1Hz,
CH2CO2H), 2.48 (s, 3H, CH3), 3.49 (m, 1H, NCHaHb), 3.84
3
(m, 1H, NCHaHb), 4.03 (q, 2H, JH,H =7.1Hz, CH2CH3), 5.15
3
3
(d, 1H, JH,H =3.7Hz, 4-HDHPM), 7.21 (d, 2H, JH,H =7.6Hz,
3
3
2,6-HPh), 7.24 (t, 1H, JH,H =7.6Hz, 4-HPh), 7.31 (t, 2H, JH,
[6-Methyl-5-(morpholin-4-ylcarbonyl)-2-oxo-4-phenyl-3,4-
dihydropyrimidin-1(2H)-yl]acetic acid 4ab. Yield 68%. Mp
3
H = 7.6 Hz, 3,5-HPh), 7.92 (d, 1H, JH,H = 3.7Hz, NH), 12.00 (br.
s, 1H, CO2H). 13C NMR (125 MHz, DMSO-d6): d = 14.5, 16.1,
22.2, 29.3, 33.7, 41.8, 53.0, 60.1, 103.7, 126.5, 127.8, 128.9,
144.6, 149.9, 153.2, 166.1, 174.7. Anal. Calcd for C19H24N2O5 C
63.32, H 6.71, N 7.77. Found C 63.05, H 7.00, N 7.73. MS
(APCI): m/z 361 (MH+).
1
253ꢀC. H NMR (500 MHz, DMSO-d6): d = 1.75 (s, 3H, CH3),
1.99 (m, 1H, NCH), 2.86 (m, 1H, NCH), 2.92–3.12 (m, 3H,
NCH2 + OCH), 3.19 (m, 1H, OCH), 3.54 (m, 1H, OCH), 3.76
2
(m, 1H, OCH), 4.23 (d, 1H, JH,H = 18.1 Hz, CHaHb), 4.42
2
(d, 1H, JH,H = 18.1Hz, CHaHb), 5.05 (m, 1H, 4-HDHPM), 7.29
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

E. N. Ostapchuk, A. S. Plaskon, O. O. Grygorenko, A. A. Tolmachev, and S. V. Ryabukhin
Vol 000
6-[5-(Ethoxycarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-
(m, 1H, OCH), 5.17 (m, 1H, 4-HDHPM), 7.34 (m, 3H, 3,4,5-HPh),
7.42 (m, 4H, 3,5-HAr +2,6-HPh), 7.88 (br. s, 1H, NH), 7.99 (d, 2H,
3JH,H = 8.6 Hz, 2,6-HAr), 12.94 (br. s, 1H, CO2H). 13C NMR
(125 MHz, DMSO-d6): d = 17.7, 42.0, 46.8, 56.9, 66.3, 108.0,
126.9, 128.3, 129.2, 130.2, 130.4, 130.9, 142.6, 143.4, 145.4,
152.3, 166.8, 167.3. Anal. Calcd for C23H23N3O5 C 65.55, H 5.50,
N 9.97. Found C 65.27, H 5.49, N 10.14. MS (APCI): m/z 422
(MH+).
3-[5-(Ethoxycarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-
dihydropyrimidin-1(2H)-yl]benzoic acid 4ga. Yield 70%.
Mp 239ꢀC. 1H NMR (500 MHz, DMSO-d6): d = 1.13 (t, 3H,
3JH,H = 7.1 Hz, CH2CH3), 2.02 (s, 3H, CH3), 4.06 (q, 2H,
3JH,H = 7.1 Hz, CH2CH3), 5.31 (d, 1H, 3JH,H = 3.0 Hz, 4-HDHPM),
dihydropyrimidin-1(2H)-yl]hexanoic acid 4ea. Yield 70%.
1
3
Mp 152ꢀC. H NMR (500 MHz, DMSO-d6): d = 1.11 (t, 3H, JH,
H = 7.1Hz, CH2CH3), 1.14 (m, 2H, CH2), 1.36 (m, 1H, CH), 1.44
3
(m, 2H, CH2), 1.49 (m, 1H, CH), 2.13 (t, 2H, JH,H = 7.4Hz,
CH2CO2H), 2.48 (s, 3H, CH3), 3.47 (m, 1H, NCHaHb), 3.82
3
(m, 1H, NCHaHb), 4.03 (q, 2H, JH,H = 7.1 Hz, CH2CH3), 5.14
3
3
(d, 1H, JH,H = 3.0 Hz, 4-HDHPM), 7.21 (d, 2H, JH,H = 7.6 Hz,
3
3
2,6-HPh), 7.24 (t, 1H, JH,H = 7.6 Hz, 4-HPh), 7.32 (t, 2H, JH,
3
H = 7.6Hz, 3,5-HPh), 7.94 (d, 1H, JH,H = 3.0 Hz, NH), 11.99
(br. s, 1H, CO2H). 13C NMR (125MHz, DMSO-d6): d = 14.5,
16.1, 24.7, 26.2, 29.5, 34.1, 42.0, 52.9, 60.1, 103.7, 126.5, 127.8,
128.9, 144.5, 150.0, 153.2, 166.1, 174.8. Anal. Calcd for
C20H26N2O5 C 64.16, H 7.00, N 7.48. Found C 63.89, H 7.26,
N 7.41. MS (APCI): m/z 375 (MH+).
3
3
7.32 (t, 1H, JH,H = 7.5 Hz, 4-HPh), 7.39 (d, 2H, JH,H = 7.5 Hz,
3
2,6-HPh), 7.42 (t, 2H, JH,H = 7.5 Hz, 3,5-HPh), 7.69 (m, 2H,
3
4,5-HAr), 7.96 (d, 1H, JH,H = 7.2 Hz, 6-HAr), 8.16 (d, 1H,
6-[6-Methyl-5-(morpholin-4-ylcarbonyl)-2-oxo-4-phenyl-3,
4-dihydropyrimidin-1(2H)-yl]hexanoic acid 4eb. Yield 62%.
Mp 112ꢀC. 1H NMR (500 MHz, DMSO-d6): d =1.24 (m, 2H,
4JH,H = 1.4 Hz, 2-HAr), 8.22 (d, 1H, JH,H = 3.0 Hz, NH), 13.01
3
(br. s, 1H, CO2H). 13C NMR (125 MHz, DMSO-d6): d = 14.5,
18.6, 53.6, 60.3, 104.6, 126.7, 128.1, 129.2, 129.4, 129.5, 129.8,
131.8, 132.2, 133.3, 138.4, 144.3, 152.5, 165.9, 167.7. Anal.
Calcd for C21H20N2O5 C 66.31, H 5.30, N 7.36. Found C 66.27,
H 4.98, N 7.71. MS (APCI): m/z 381 (MH+).
3
CH2), 1.51 (m, 4H, 2CH2), 1.83 (s, 3H, CH3), 2.19 (t, 2H, JH,
H =7.2Hz, CH2CO2H), 2.77 (m, 1H, NCH), 3.05 (m, 1H, 2NCH),
3.12 (m, 1H, NCH), 3.23 (m, 1H, OCH), 3.40 (m, 1H, NCHaHb),
3.54 (m, 2H, 2OCH), 3.70 (m, 1H, OCH), 3.76 (m, 1H, NCHaHb),
5.02 (m, 1H, 4-HDHPM), 7.17 (d, 2H, 3JH,H = 7.5 Hz, 2,6-HPh), 7.28
(t, 1H, 3JH,H =7.5Hz, 4-HPh), 7.36 (t, 2H, 3JH,H = 7.5 Hz, 3,5-HPh),
7.49 (br. s, 1H, NH), 11.96 (br. s, 1H, CO2H). 13C NMR
(125 MHz, DMSO-d6): d = 16.0, 24.8, 26.3, 29.8, 34.2, 41.7,
41.9, 46.8, 56.5, 65.8, 66.2, 104.1, 126.6, 128.1, 129.0, 131.1,
143.8, 153.1, 167.4, 174.8. Anal. Calcd for C22H29N3O5 C 63.60,
H 7.04, N 10.11. Found C 63.27, H 6.74, N 10.40. MS (APCI):
m/z 416 (MH+).
3-[6-Methyl-5-(morpholin-4-ylcarbonyl)-2-oxo-4-phenyl-3,
4-dihydropyrimidin-1(2H)-yl]benzoic acid 4gb. Yield 65%.
Mp > 300ꢀC. 1H NMR (500 MHz, DMSO-d6): d =1.41 (s, 3H,
CH3), 2.11 (m, 1H, NCH), 2.91–3.15 (m, 3H, 3NCH), 3.24
(m, 1H, OCH), 3.54 (m, 2H, 2OCH), 3.77 (m, 1H, OCH), 5.17
(m, 1H, 4-HDHPM), 7.34 (d + t, 3H, 3JH,H = 7.5 Hz, 2,4,6-HPh), 7.42
(t, 2H, 3JH,H = 7.5 Hz, 3,5-HPh), 7.56 (m, 2H, 4,5-HAr), 7.81 (s, 1H,
3
2-HAr), 7.87 (br. s, 1H, NH), 7.94 (d, 1H, JH,H =7.2Hz, 6-HAr),
13.15 (br. s, 1H, CO2H). 13C NMR (125 MHz, DMSO-d6):
d = 17.8, 41.9, 46.7, 57.0, 66.3, 107.4, 126.9, 128.3, 129.1, 129.2,
129.5, 131.3, 131.4, 132.0, 135.1, 138.8, 143.5, 152.5, 166.9,
167.3. Anal. Calcd for C23H23N3O5 C 65.55, H 5.50, N 9.97.
Found C 65.37, H 5.29, N 10.10. MS (APCI): m/z 422 (MH+).
4-{[5-(Ethoxycarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-
dihydropyrimidin-1(2H)-yl]methyl}benzoic acid 4ha. Yield
69%. Mp 224ꢀC. 1H NMR (500 MHz, DMSO-d6): d = 1.10
6-[5-(Anilinocarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-
dihydropyrimidin-1(2H)-yl]hexanoic acid 4ec. Yield 71%. Mp
1
244ꢀC. H NMR (500 MHz, DMSO-d6): d =1.21 (m, 2H, CH2),
1.43 (m, 1H, CH), 1.50 (m, 3H, CH), 2.15 (s, 3H, CH3), 2.18
3
(t, 2H, JH,H = 7.2 Hz, CH2CO2H), 3.39 (m, 1H, NCHaHb), 3.81
3
(m, 1H, NCHaHb), 5.25 (s, 1H, 4-HDHP), 7.02 (t, 1H, JH,
H = 7.4 Hz, 4-HPh’), 7.21–7.29 (m, 5H, 3,4,5-HPh + 2,6-HPh’), 7.32
3
3
(t, 2H, JH,H = 7.4Hz, 3,5-HPh’), 7.56 (d, 2H, JH,H = 8.1Hz, 2,6-
HPh), 7.66 (br. s, 1H, NH), 9.82 (s, 1H, CONHPh), 12.00 (br. s,
1H, CO2H). 13C NMR (125MHz, DMSO-d6): d = 16.7, 24.8,
26.3, 29.8, 34.1, 41.7, 54.6, 110.7, 120.1, 123.8, 126.7, 127.8,
128.9, 129.1, 138.5, 139.6, 144.2, 153.6, 166.5, 174.9. Anal.
Calcd for C24H27N3O4 C 68.39, H 6.46, N 9.97. Found C 68.08,
H 6.22, N 10.13. MS (APCI): m/z 422 (MH+).
3
(t, 3H, JH,H = 7.1 Hz, CH2CH3), 2.35 (s, 3H, CH3), 4.03 (q, 2H,
2
3JH,H = 7.1 Hz, CH2CH3), 4.94 (d, 1H, JH,H = 17.3Hz, CHaHb),
5.14 (d, 1H, 2JH,H = 17.3Hz, CHaHb), 5.27 (d, 1H, 3JH,H = 3.0 Hz,
3
4-HDHPM), 7.17 (d, 2H, JH,H = 7.6 Hz, 3,5-HAr), 7.27 (d, 2H,
3
3JH,H = 7.7 Hz, 2,6-HPh), 7.28 (t, 1H, JH,H = 7.7 Hz, 4-HPh), 7.35
3
3
(t, 2H, JH,H = 7.7 Hz, 3,5-HPh), 7.86 (d, 2H, JH,H = 7.6 Hz,
3
2,6-HAr), 8.21 (d, 1H, JH,H = 3.0 Hz, NH), 12.91 (br. s, 1H,
4-[5-(Ethoxycarbonyl)-6-methyl-2-oxo-4-phenyl-3,4-
dihydropyrimidin-1(2H)-yl]benzoic acid 4fa. Yield 76%.
Mp 234ꢀC. 1H NMR (500 MHz, DMSO-d6): d =1.12 (t, 3H,
CO2H). 13C NMR (125 MHz, DMSO-d6): d = 14.5, 16.5, 45.5,
52.9, 60.2, 104.3, 126.7, 127.4, 127.9, 128.9, 129.8, 129.9, 130.0,
144.3, 149.7, 153.5, 166.0, 167.5. Anal. Calcd for C22H22N2O5 C
66.99, H 5.62, N 7.10. Found C 67.22, H 5.60, N 7.43. MS
(APCI): m/z 395 (MH+).
3
3JH,H =7.1Hz, CH2CH3), 2.03 (s, 3H, CH3), 4.05 (q, 2H, JH,
3
H =7.1Hz, CH2CH3), 5.29 (d, 1H, JH,H =3.0Hz, 4-HDHPM), 7.30
3
(t, 1H, JH,H =7.6 Hz, 4-HPh), 7.34–7.42 (m, 6H, 2,3,5,6-HPh +3,
3
5-HAr), 8.00 (d, 2H, JH,H = 8.5 Hz, 2,6-HAr), 8.23 (d, 1H,
4-{[6-Methyl-5-(morpholin-4-ylcarbonyl)-2-oxo-4-phenyl-3,
4-dihydropyrimidin-1(2H)-yl]methyl}benzoic acid 4hb. Yield
63%. Mp 244ꢀC. 1H NMR (500 MHz, DMSO-d6): d =1.72 (s, 3H,
CH3), 2.08 (m, 1H, NCH), 2.77 (m, 1H, NCH), 3.00 (m, 3H,
NCH2 + OCH), 3.18 (m, 1H, OCH), 3.52 (m, 1H, OCH), 3.74
(m, 1H, OCH), 4.90 (d, 1H, 2JH,H = 17.3 Hz, CHaHb), 5.01 (d, 1H,
3JH,H = 3.0 Hz, NH), 13.07 (br. s, 1H, CO2H). 13C NMR
(125 MHz, DMSO-d6): d = 14.5, 18.6, 53.7, 60.3, 104.8, 126.8,
128.1, 129.2, 130.4, 130.7, 130.9, 142.2, 144.3, 148.7, 152.2,
165.8, 167.2. Anal. Calcd for C21H20N2O5 C 66.31, H 5.30, N
7.36. Found C 66.05, H 5.51, N 7.62. MS (APCI): m/z 381 (MH+).
4-[6-Methyl-5-(morpholin-4-ylcarbonyl)-2-oxo-4-phenyl-3,
4-dihydropyrimidin-1(2H)-yl]benzoic acid 4fb. Yield 71%.
Mp 298ꢀC. 1H NMR (500 MHz, DMSO-d6): d =1.42 (s, 3H,
CH3), 2.11 (m, 1H, NCH), 2.90–3.15 (m, 3H, 3NCH), 3.24
(m, 1H, OCH), 3.44 (m, 1H, OCH), 3.55 (m, 1H, OCH), 3.77
3
2JH,H = 17.3 Hz, CHaHb), 5.18 (d, 1H, JH,H =3.0Hz, 4-HDHPM),
7.25 (d, 2H, 3JH,H = 7.5 Hz, 3,5-HAr), 7.31 (m, 3H, 2,4,6-HPh), 7.38
3
3
(t, 2H, JH,H = 7.5 Hz, 3,5-HPh), 7.77 (d, 1H, JH,H =3.0Hz, NH),
3
7.94 (d, 2H, JH,H = 7.6 Hz, 2,6-HAr), 12.91 (br. s, 1H, CO2H).
13C NMR (125 MHz, DMSO-d6): d = 16.2, 41.9, 45.1, 46.6, 56.7,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013
Protecting Group Free Synthesis of Carboxyl-Substituted Dihydropyrimidines
Through Biginelli Reaction
[11] Biginelli, P. Gazz Chim Ital 1893, 23, 360.
[12] Kappe, C. O. Acc Chem Res 2000, 33, 879.
[13] Kappe, C. O. Eur J Med Chem 2000, 35, 1043.
[14] Young, I. S.; Baran, P. S. Nature Chem 2009, 1, 193.
[15] Volochnyuk, D. M.; Ryabukhin, S. V.; Plaskon, A. S.; Grygorenko,
O. O. Synthesis 2009, 3719.
65.8, 66.2, 107.2, 126.5, 126.8, 127.4, 128.2, 129.1, 129.9, 130.2,
143.5, 145.2, 153.4, 167.1, 167.6. Anal. Calcd for C24H25N3O5 C
66.19, H 5.79, N 9.65. Found C 66.02, H 5.84, N 9.60. MS
(APCI): m/z 436 (MH+).
[16] Ryabukhin, S. V.; Plaskon, A. S.; Ostapchuk, E. N.; Volochnyuk,
D. M.; Shishkin, O. V.; Shivanyuk, A. N.; Tolmachev, A. A. Org Lett 2007,
9, 4215.
[17] Ryabukhin, S. V.; Plaskon, A. S.; Ostapchuk, E. N.; Volochnyuk,
D. M.; Shishkin, O. V.; Tolmachev, A. A. J Fluorine Chem 2008, 129, 625.
[18] Ryabukhin, S. V.; Plaskon, A. S.; Ostapchuk, E. N.; Volochnyuk,
D. M.; Tolmachev, A. A. Synthesis 2007, 417.
[19] Zhu, Y.-L.; Pan, Y.-J.; Huang, S.-L. Synth Commun 2004,
34, 3167.
[20] Zhu, Y.-L.; Huang, S.-L.; Pan, Y.-J. Eur J Org Chem 2005,
2354.
Acknowledgments. The authors thank Mr. Vitaliy V. Polovinko
for NMR measurements and Mrs. Olga V. Manoylenko for
chromatographic separations.
REFERENCES AND NOTES
[1] Zhu, J.; Bienaymé, H. Multicomponent Reactions. Wiley-
VCH: Weinheim, Germany, 2005.
[2] Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown,
S. D.; Keating, T. Acc Chem Res 1996, 29, 123.
[3] Tietze, L. F.; Lieb, M. E. Curr Opin Chem Biol 1998, 2, 363.
[4] Domling, A. Comb Chem High Throughput Screen 1998, 1, 1.
[5] Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr Med Chem
1999, 6, 255.
[6] Tietze, L. F.; Modi, A. Med Res Rev 2000, 20, 304.
[7] Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem Eur J
2000, 6, 3321.
[21] Zhu, Y.-L.; Pan, Y.-J.; Huang, S.-L. Heterocycles 2005,
65, 133.
[22] Werner, S.; Turner, D. M.; Lyon, M. A.; Huryn, D. M.;
Wipf, P. Synlett 2006, 2334.
[23] Wright, C. M.; Chovatiya, R. J.; Jameson, N. E.; Turner, D.
M.; Zhu, G.; Werner, S.; Huryn, D. M.; Pipas, J. M.; Day, B. W.; Wipf,
P.; Brodsky, J. L. Bioorg Med Chem 2008, 16, 3291.
[24] Chiang, A. N.; Valderramos, J.-C.; Balachandran, R.; Chovatiya,
R. J.; Mead, B. P.; Schneider, C.; Bell, C. L.; Klein, M. G.; Huryn, D. M.;
Chen, X. S.; Day, B. W.; Fidock, D. A.; Wipf, P.; Brodsky, J. L. Bioorg
Med Chem 2009, 17, 1527.
[8] Ugi, I.; Heck, S. Comb Chem High Throughput Screen 2001, 4, 1.
[9] Weber, L. Drug Discov Today 2002, 7, 143.
[10] Domling, A. Curr Opin Chem Biol 2002, 6, 306.
[25] Wipf, P.; Cunningham, A. Tetrahedron Lett 1995, 36, 7819.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet