A convenient synthesis of N1-substituted 3,4-dihydropyrimidin-2(1H)-ones by cyclocondensation of α-chlorobenzyl isocyanates with ethyl N-alkyl(aryl)-β-aminocrotonates

Article abstract of DOI:10.1055/s-2006-926241

A new convenient approach to the synthesis of N1-substituted 3,4-dihydropyrimidin-2(1H)-ones was developed using the regioselective cyclocondensation of α-chlorobenzyl isocyanates with ethyl N-alkyl(aryl)-β-aminocrotonates. A number of N1-aryl and N1-alky

Full text of DOI:10.1055/s-2006-926241

LETTER
375
A Convenient Synthesis of N1-Substituted 3,4-Dihydropyrimidin-2(1H)-ones
by Cyclocondensation of a-Chlorobenzyl Isocyanates with Ethyl N-alkyl(aryl)-
b-aminocrotonates
Synthesis of
N
1-Su
o
bstituted 3,4
l
-Dihyd
o
ropyrimidin
d
-2(1
H
)-ones ymyr A. Sukach, Andriy V. Bol’but, Anatoliy D. Sinitsa, Mykhaylo V. Vovk*
Institute of Organic Chemistry, National Academy of Science of Ukraine, Murmans’ka 5, 02094 Kiev, Ukraine
Fax +380(44)5732643; E-mail: mvovk@i.com.ua
Received 18 July 2005
three-component condensation to obtain a previously in-
Abstract: A new convenient approach to the synthesis of N1-sub-
stituted 3,4-dihydropyrimidin-2(1H)-ones was developed using the
regioselective cyclocondensation of a-chlorobenzyl isocyanates
with ethyl N-alkyl(aryl)-b-aminocrotonates. A number of N1-aryl
accessible condensed DHPM constituting the main struc-
tural moiety of saxitoxin.9 Thus, great progress has been
made in the chemistry of these partially unsaturated pyri-
and N1-alkyl substituted Biginelli compounds difficult to obtain by midine systems and a great manifold of their derivatives
other methods were prepared with high yields.
have been obtained. However, the simplest 1-aryl substi-
tuted DHPMs are represented in the literature very scant-
ily.10 This may be attributed to the fact that N-arylureas
involved in the Biginelli reaction lead to a complex
mixture of products containing a negligible amount of
the corresponding dihydropyrimidones.1a,11 N-Alkylureas
provide higher yields of the target compounds but they are
more conveniently obtained by an alternative method
based on selective alkylation of N1-unsubstituted ana-
logues.12
Key words: cyclocondensation, regioselectivity, a-chloroalkyl iso-
cyanates, dihydropyrimidones, b-aminocrotonic esters
Functionalized
3,4-dihydropyrimidin-2(1H)-ones
(DHPMs, Biginelli compounds) represent a heterocyclic
system that has aroused considerable interest of special-
ists on biologically active materials, drug design and re-
search, etc.1 A wide diversity of pharmacological
properties displayed by this class of compounds, along
with their relatively simple constitution, accessibility, and
modifiability of substituent structure, make them ex-
tremely advantageous objects for large-scale biological
screening (a recent vivid example is offered by the dis-
covery of monastrol).2
NHCO2Et
NHCO2Et
NCO
Cl
b
a
Ar
Ar CHO
Ar
1
Scheme 1 Reagents and conditions: (a) H2NCO2Et, H2SO4 (cat.),
150–160 °C, 15 min (94–98%); (b) PCl5, benzene, reflux, 4 h.
A conventional synthesis of DHPMs first performed by P.
Biginelli in 1893 involves a three-component condensa-
tion of 1,3-dicarbonyl compounds, aldehydes, and urea
under acidic conditions.3 In the last two decades, more ef-
ficient conditions have been found for the Biginelli reac-
tion using soft Lewis acids as catalysts.4 Microwave
exposure5 as well as solid-phase and fluoro-phase
techniques6 facilitating this synthesis have also become
increasingly widespread. Some modifications of the reac-
tion have been reported which depart from the initial mul-
ticomponent reaction scheme and provide notable
conveniences in the synthesis of biologically active 3-acyl
substituted DHPMs and their 4-alkyl substituted deriva-
tives.7 Overman et al. conducted the full synthesis of a
number of natural products, e.g., alkaloid batzelladine B
exhibiting anti-HIV activity, by the reaction between ace-
toacetic ester and the analogues of hydroxyalkyl urea; this
approach enabled convenient stereoselective construction
of the condensed 3,4-dihydropyrimidine nucleus.8 Alter-
natively, Kishi et al. reacted acetaldehyde, isocyanic acid,
and a cyclic derivative of the b-aminoacrylic ester in a
Table 1 Preparation of a-Chlorobenzyl Isocyanates 1
1
a
b
c
d
e
f
Ar
Bp (°C, torr)
125–128 (10)
119–123 (10)
141–145 (0.2)
161–164 (0.2)
126–130 (0.2)
140–143 (0.2)
152–156 (0.2)
148–152 (0.2)
Yield (%)a
Ph
68a
69
2-FC6H4
3-BrC6H4
3-(NO2)C6H4
4-ClC6H4
4-BrC6H4
4-(NO2)C6H4
3,4-Cl2C6H3
81
82
77
80a
75a
73
g
h
a For literature data see ref. 16.
We have recently demonstrated an efficient application of
a novel synthetic methodology for constructing a pyrimi-
dine ring via the synthon scheme [–C=C–N–]2–+ [–C=N–
C=O]2+. The bis-electrophilic synthon [–C=N–C=O]2+ is
furnished by a-chloroalkyl isocyanates.13 By systemati-
cally studying the heterocyclocondensation of 1-aryl-
SYNLETT 2006, No. 3, pp 0375–0378
1
5.
0
2.
2
0
0
6
Advanced online publication: 06.02.2006
DOI: 10.1055/s-2006-926241; Art ID: D20205ST
© Georg Thieme Verlag Stuttgart · New York

376
V. A. Sukach et al.
LETTER
2,2,2-trifluoro-1-chloroethyl isocyanates with various Table 2 3,4-Dihydropyrimidin-2(1H)-ones 3
C,N- and C,O-binucleophiles, we have found regioselec-
3
a
b
c
Ar
R
Mp (°C)
176–178b
148–150
145–147
151–153
157–159
165–167c
208–209
163–165
196–198
172–174
180–182
194–196
Yield (%)a
tive reactions yielding condensed dihydropyrimidine sys-
tems.14 In particular, 1-aryl-2,2,2-trifluoro-1-chloroethyl
isocyanates proved to produce 2,3-dihydropyrimidin-
4(1H)-ones by the reaction with ethyl N-methyl-b-amino-
crotonate in the presence of triethylamine.15 a-Chloro-
benzyl isocyanates 1, however, have hitherto been
unapplied in heterocyclic syntheses, though one of us
previously developed a facile synthetic access to them
starting from aromatic aldehydes, ethylurethane, and
phosphorus pentachloride.16 To gain a better insight into
the synthetic potential of a-chlorobenzyl isocyanates 1,
we synthesized a number of new compounds of this class
using the slightly modified procedure (see Scheme 1 and
Table 1).17 We studied their reaction with ethyl N-
alkyl(aryl)-b-aminocrotonates with the aim to develop a
general method for the preparation of N1-substituted
dihydropyrimidone derivatives.
Ph
Me
64
63
55
72
73
70
75
61
81
59
72
74
78
67
Ph
4-ClC6H4
Bn
2-FC6H4
2-FC6H4
3-BrC6H4
3-(NO2)C6H4
3-(NO2)C6H4
4-ClC6H4
4-ClC6H4
4-BrC6H4
4-BrC6H4
4-(NO2)C6H4
3,4-Cl2C6H3
3,4-Cl2C6H3
d
e
4-F2HCSC6H4
4-MeOC6H4
Ph
f
g
h
k
l
4-ClC6H4
Bn
4-(CN)C6H4
Me
m
n
o
p
4-MeOC6H4
Ph
As found, a-chlorobenzyl isocyanate 1a reacts with ethyl
N-methyl-b-aminocrotonate in a methylene chloride solu-
tion to smoothly furnish DHPM 3a in good yield. The
compound obtained is described in the literature18 and its
structure is unquestionable. To determine the synthetic
applicability limits for the conversion discovered, we
have synthesized and reacted various N-alkyl and N-aryl
substituted enamines of type 2.19 It has been shown that
N-aryl-b-aminocrotonic esters also enter readily into the
reaction with isocyanates 1 to give the corresponding
DHPMs of type 3 in 67–81% yields (see Scheme 2 and
Table 2).20 Structural determination of the compounds
4-Me-3-FC6H3 159–161
2-Naph 156–158
a Yields of pure isolated products.
b Lit.: mp 178–180 °C.18
c Lit.: mp 168 °C.10
obtain a variety of hitherto unknown N1-substituted Bigi-
nelli compounds 3a–e,g–p.
1
Among the limitations of the new synthetic approach is
the impossibility to produce a-chlorobenzyl isocyanates
(and hence the corresponding dihydropyrimidines)
containing electron-donor groups on the aromatic ring as
well as the groups sensitive to the action of phosphorus
pentachloride and phosphorus oxychloride. In addition,
synthesized was carried out reliably using IR, H NMR
and 13C NMR spectroscopy.21 The most plausible scheme
for the reaction between 1 and 2 involves initial isocyana-
toalkylation of the nucleophilic carbon atom in enamine 2
to generate intermediates A which rapidly cyclize into 3.
b-aminocrotonates
bearing
bulky
substituents
O
Ar
O
[R = PhCH(CH3), 2-MeC6H4] lead to the mixture of prod-
ucts and do not furnish the preparative yields of the target
derivatives 3. Nevertheless, the method makes easily
available a great diversity of N1-substituted DHPMs start-
ing from amines, acetoacetic ester, aromatic aldehydes,
ethyl carbamate, and phosphorus pentachloride. The new
strategy of constructing the dihydropyrimidine cycle al-
lows the synthesis of previously inaccessible hydrogenat-
ed condensed nuclei. For instance, ethyl (2H)-3,4-
dihydro-1,4-benzothiazin-3-ylidenacetate (5)22 was used
to obtain 2,3-dihydropyrimido[6,1-c][1,4]benzothiazin-
1(1H)-ones 6 (see Table 3).23,24
NCO
Cl
CH2Cl2
EtO
NCO
EtO
Ar
reflux, 2 h
– HCl
Me
NH
R
Me
NH
R
1
2
A
O
Ar
O
O
EtO
Me
NH
O
EtO
Me
NH
N
R
N
R
Ar
3
4
Scheme 2
In conclusion, we have elaborated a convenient synthetic
pathway to N1-substituted 3,4-dihydropyrimidin-2(1H)-
ones based on a novel regioselective cyclocondensation of
a-chlorobenzyl isocyanates with N-alkyl(aryl)-b-amino-
crotonates. The method provides evident advantages in
the synthesis of hardly obtainable N1-aryl-substituted
Biginelli compounds and hydrogenated pyrimidoben-
zothiazine derivatives.
Isomeric 2,3-dihydropyrimidin-4(1H)-ones of type 4 are
not detected in the reaction mixture thus suggesting com-
plete heterocyclization regioselectivity, with the reaction
course depending on the structure of an initial a-chloro-
alkyl isocyanate. The method developed was employed to
Synlett 2006, No. 3, 375–378 © Thieme Stuttgart · New York

LETTER
Synthesis of N1-Substituted 3,4-Dihydropyrimidin-2(1H)-ones
(12) (a) George, T.; Tahilramani, R.; Metha, D. V. Synthesis
377
Table 3 Synthesis of 2,3-Dihydropyrimido[6,1-c][1,4]benzo-
thiazin-1(1H)-ones 6 by Cyclocondensation of a-Chlorobenzyl
Isocyanates 1 with Ethyl (2H)-3,4-Dihydro-1,4-benzothiazin-3-
ylidenacetate (5)
1975, 405. (b) Cho, H.; Takeuchi, Y.; Ueda, M.; Mizuno, A.
Tetrahedron Lett. 1988, 29, 5405.
(13) (a) Sinitsa, A. D.; Parkhomenko, N. A.; Markovskii, L. N. J.
Gen. Chem. USSR 1983, 53, 308. (b) Sinitsa, A. D.;
Parkhomenko, N. A.; Povolotskii, M. I.; Markovskii, L. N.
J. Gen. Chem. USSR 1984, 54, 633. (c) Sinitsa, A. D.;
Parkhomenko, N. A.; Markovskii, L. N. J. Gen. Chem. USSR
1980, 50, 683.
O
Ar
O
EtO
NH
EtO
CH2Cl2
NCO
Cl
N
O
Ar
NH
reflux, 2 h
(14) (a) Vovk, M. V.; Lebed’, P. S.; Sukach, V. A.; Kornilov, M.
Y. Russ. J. Org. Chem. 2003, 39, 1781. (b) Vovk, M. V.;
Lebed’, P. S.; Pyrozhenko, V. V.; Tsimbal, I. F. Russ. J. Org.
Chem. 2004, 40, 1669.
(15) Vovk, M. V.; Pyrozhenko, V. V. Chem. Heterocycl. Compd.
1994, 30, 85.
S
S
1
6
5
6
Ar
Ph
Mp (°C)
205–207
201–203
182–184
195–197
Yield (%)a
a
b
c
70
73
71
76
(16) Sinitsa, A. D.; Bonadyk, S. V.; Markovskii, L. N. J. Org.
Chem. USSR 1978, 14, 1030.
4-BrC6H4
3-BrC6H4
2-FC6H4
(17) Improved Protocol for Preparation of a-Chlorobenzyl
Isocyanates 1.
The mixture of aromatic aldehyde (1 mol, 1 equiv) and
ethylcarbamate (2.2 mol, 2.2 equiv) was heated to 140–160
°C and then few drops of concd H2SO4 was added. The
reaction mixture was heated at this temperature for 15 min
and then cooled. A solidified mass was quenched by H2O,
product(benzylidenebiscarbamate) was collected by
filtration, washed with H2O, dried and used without further
purification. The suspension of obtained benzylidenebis-
carbamate (0.5 mol, 0.5 equiv) and PCl5 (1.1 mol, 2.2 equiv)
in 500 mL of dry benzene was refluxed until no gas
evolution observed (usually 3–4 h). The homogeneous
solution was cooled, solvent and volatile substances were
distilled off and the residue fractioned at reduced pressure.
(18) Abdel-Fattah, A. A. A. Synthesis 2003, 2358.
(19) Gao, Y.; Zhang, Q.; Xu, J. Synth. Commun. 2004, 34, 909.
(20) General Procedure for Preparation of 3,4-Dihydro-
pyrimidin-2(1H)-ones 3.
d
a Yields of pure isolated products.
References and Notes
(1) For reviews see: (a) Kappe, C. O. Tetrahedron 1993, 49,
6937. (b) Kappe, C. O. Acc. Chem. Res. 2000, 33, 879.
(c) Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043.
(2) Mayer, T. U.; Kapoor, T. M.; Haggarty, S. J.; King, R. W.;
Schreiber, S. L. Science 1999, 286, 971.
(3) (a) Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
(b) Folkers, K.; Johnson, T. B. J. Am. Chem. Soc. 1933, 55,
3781.
(4) (a) Kappe, C. O.; Falsone, S. F. Synlett 1998, 718. (b) Hu,
E. H.; Sidler, D. R.; Dolling, U.-H. J. Org. Chem. 1998, 63,
3454. (c) Lu, J.; Ma, H. Synlett 2000, 63. (d) Ma, Y.; Qian,
C.; Wang, L.; Yang, M. J. Org. Chem. 2000, 65, 3864.
(e) Ranu, B. C.; Hayra, A.; Jana, U. J. Org. Chem. 2000, 65,
6270. (f) Zavyalov, S. J.; Kulikova, L. B. Khim.-Farm. Zh.
1992, 1655.
(5) (a) Stadler, A.; Kappe, C. O. J. Chem. Soc., Perkin Trans. 1
2000, 1363. (b) Stefani, H. A.; Gatti, P. M. Synth. Commun.
2000, 30, 2165. (c) Kappe, C. O.; Kumar, D.; Varma, R. S.
Synthesis 1999, 1799.
To the solution of appropriate ethyl b-aminocrotonate 2 (5
mmol, 1 equiv) in 20 mL of CH2Cl2 the solution of
isocyanate 1 (5.5 mmol, 1.1 equiv) in 10 mL of CH2Cl2 was
added dropwise. The reaction mixture was refluxed for 2 h,
cooled and the solvent was evaporated. The crude product
was treated with hot 70–80% aq EtOH, allowed to stand
overnight at 9 °C and then collected by filtration, washed
with small amount of EtOH and dried in air.
(21) Selected Data.
1-(4¢-Chlorophenyl)-5-ethoxycarbonyl-6-methyl-4-
phenyl-3,4-dihydropyrimidin-2(1H)-one (3b).
IR (KBr pellets): 3250, 3130, 1710, 1700, 1650 cm–1. 1H
NMR [300 MHz, (CD3)2SO–CCl4, 2:1]: d = 1.14 (t, J = 6.5
Hz, 3 H), 2.04 (s, 3 H), 4.06 (q, J = 6.5 Hz, 2 H), 5.27 (d,
J = 1.0 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.35 (m, 5 H),
7.45 (d, J = 8.0 Hz, 2 H), 8.14 (d, J = 1.0 Hz, 1 H). 13C NMR
[75.5 MHz, (CD3)2SO]: d = 14.50, 18.54, 53.65, 60.28,
104.48, 126.78, 128.03, 129.13, 129.37, 132.23, 133.13,
137.10, 144.35, 148.91, 152.36, 165.86.
1-Benzyl-4-(4¢-chlorophenyl)-5-ethoxycarbonyl-6-
methyl-3,4-dihydropyrimidin-2(1H)-one (3h).
IR (KBr pellets): 3260, 3120, 1730, 1700, 1640 cm–1. 1H
NMR [300 MHz, (CD3)2SO–CCl4, 2:1]: d = 1.14 (t, J = 6.6
Hz, 3 H), 2.40 (s, 3 H), 4.03 (q, J = Hz, 2 H), 4.85 (d,
J = 18.9 Hz, 1 H), 5.09 (d, J = 18.9 Hz, 1 H), 5.22 (d, J = 3.3
Hz, 1 H), 7.07 (d, J = 6.3 Hz, 2 H), 7.26 (m, 7 H), 8.15 (d,
J = 3.3 Hz, 1 H). 13C NMR [75.5 MHz, (CD3)2SO]:
d = 14.47, 16.50, 45.43, 52.44, 60.22, 103.65, 126.62,
127.35, 128.62, 128.85, 128.95, 132.47, 139.06, 143.38,
150.30, 153.34, 165.91.
(6) (a) Lewandowski, K.; Murer, P.; Svec, F.; Frechet, J. M. J.
Chem. Commun. 1998, 2237. (b) Lewandowski, K.; Murer,
P.; Svec, F.; Frechet, J. M. J. J. Comb. Chem. 1999, 1, 105.
(c) Wipf, P.; Cunningham, A. A. Tetrahedron Lett. 1995, 36,
7819. (d) Kappe, C. O. Bioorg. Med. Chem. Lett. 2000, 10,
49. (e) Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org.
Chem. 1997, 62, 2917.
(7) (a) O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26,
1185. (b) Atwal, K. S.; Rovnyak, G. C.; O’Reilly, B. C.;
Schwartz, J. J. Org. Chem. 1989, 54, 5898. (c) Shutalev, A.
D.; Kishko, E. A.; Sivova, N. V.; Kuznetsov, A. Y.
Molecules 1998, 3, 100.
(8) McDonald, A. I.; Overman, L. E. J. Org. Chem. 1999, 64,
1520.
(9) (a) Hong, C. Y.; Kishi, Y. J. Am. Chem. Soc. 1992, 114,
7001. (b) Taguchi, H.; Yazawa, H.; Arnett, J. F.; Kishi, Y.
Tetrahedron Lett. 1977, 627.
(10) Namazi, H.; Mirzaei, Y. R.; Azamat, H. J. Heterocycl.
Chem. 2001, 38, 1051.
(11) See: Dallinger, D.; Kappe, C. O. Synlett 2002, 1901; and
references cited therein.
Synlett 2006, No. 3, 375–378 © Thieme Stuttgart · New York

378
V. A. Sukach et al.
LETTER
MHz, (CD3)2SO]: d = 14.46, 30.59, 53.06, 53.07, 60.97,
(22) Puebla, P. H. Z.; Medarde, M. M. L.; Caballero, E. F. A.
Tetrahedron 1999, 55, 7915.
(23) For examples of this heterocyclic system see: Chorvat, R.;
Radak, S. E.; Desai, B. N. J. Org. Chem. 1987, 52, 1366.
(24) Prepared from 5 according to the general procedure for
preparation of 3.
103.73, 126.03, 126.53, 126.70, 128.00, 128.20, 129.13,
129.25, 130.63, 135.20, 143.15, 149.59, 152.08, 165.36.
3-(3¢-Bromophenyl)-4-ethoxycarbonyl-2,3-dihydro-
pyrimido[6,1-c][1,4]benzothiazin-1(1H)-one (6c).
IR (KBr pellets): 3250, 3130, 1710, 1650 cm–1. 1H NMR
[300 MHz, (CD3)2SO–CCl4, 2:1]: d = 1.21 (t, J = 6.8 Hz, 3
H), 3.52 (d, J = 16.5 Hz, 1 H), 4.15 (m, 2 H), 5.19 (d,
J = 16.5 Hz, 1 H), 5.35 (d, J = 5.1 Hz, 1 H), 7.33 (m, 8 H),
8.61 (d, J = 5.1 Hz, 1 H). 13C NMR [75.5 MHz, (CD3)2SO]:
d = 14.45, 30.46, 52.62, 61.05, 102.91, 122.35, 125.51,
126.14, 126.73, 127.92, 129.17, 129.63, 130.68, 131.11,
131.60, 135.04, 145.78, 150.24, 151.86, 165.17.
Selected Data.
4-Ethoxycarbonyl-3-phenyl-2,3-dihydropyrimido[6,1-
c][1,4]benzothiazin-1(1H)-one (6a).
IR (KBr pellets): 3240, 3140, 1710, 1650 cm–1. 1H NMR
[300 MHz, (CD3)2SO–CCl4, 2:1]: d = 1.17 (t, J = 6.8 Hz, 3
H), 3.54 (d, J = 16.5 Hz, 1 H), 4.11 (q, J = 6.8 Hz, 2 H), 5.17
(d, J = 16.5 Hz, 1 H), 5.37 (d, J = 4.2 Hz, 1 H), 7.29 (m, 2
H), 7.36 (m, 7 H), 8.62 (d, J = 4.2 Hz, 1 H). 13C NMR [75.5
Synlett 2006, No. 3, 375–378 © Thieme Stuttgart · New York