Regioselective synthesis of the 3,4-dihydrofuro[3,2-d]pyrimidin-2(1H)-one skeleton: a new class of compound

Article abstract of DOI:10.1016/j.tet.2009.05.090

We hereby report the first preparation of the 3,4-dihydrofuro[3,2-d]pyrimidin-2(1H)-one skeleton formed by two controlled Curtius rearrangements of the corresponding acyl azides, prepared from 2-(2-methoxy-2-oxoethyl)furan-3-carboxylate via the hydrazide.

Full text of DOI:10.1016/j.tet.2009.05.090

Tetrahedron 65 (2009) 5973–5976
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Regioselective synthesis of the 3,4-dihydrofuro[3,2-d]pyrimidin-2(1H)-one
skeleton: a new class of compound
a
a
,
,
*
Gani Koza , Sevil Ozcan b, Ertan S¸ahin c, Metin Balci a
¨
a Department of Chemistry, Middle East Technical University, 06531 Ankara, Turkey
b
_
Department of Chemistry, Abant Izzet Baysal, 14280 Bolu, Turkey
c Department of Chemistry, Atatu¨rk University, 25240 Erzurum, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
We hereby report the first preparation of the 3,4-dihydrofuro[3,2-d]pyrimidin-2(1H)-one skeleton
formed by two controlled Curtius rearrangements of the corresponding acyl azides, prepared from 2-(2-
methoxy-2-oxoethyl)furan-3-carboxylate via the hydrazide. Rearrangement of the acyl azides followed
by trapping by nucleophiles and intramolecular trapping provided the target compounds.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 12 March 2009
Received in revised form 11 May 2009
Accepted 28 May 2009
Available online 6 June 2009
Keywords:
Pyrimidinone
Furopyrimidinone
Acyl azide
Acyl hydrazide
Curtius rearrangement
1. Introduction
antihypertensive compounds such as 2 and its derivatives.8 Fur-
thermore, it has been established that the absolute stereochemistry
The Italian chemist Biginelli reported for the first time in 1893
the synthesis of 3,4-dihydropyrimidin-2(1H)-ones (DHPM) of type
1 by a multiple-component chemical reaction starting from ethyl-
acetoacetate, aryl aldehyde and urea.1–4 Over the last two decades,
interest in dihydropyrimidones has increased dramatically.5
at the C4 carbon atom is very important. For example, the desired
antihypertensive effect was observed only with the (R)-enantiomer
of 2.6–8 Nitrofuryl-substituted DHPM derivative, nitractin 39 dis-
played activity against viruses of the trachoma group and modest
antibacterial activity.10,11 Besides the monocyclic DHMP derivatives,
some fused analogs, which incorporate hetero- or carbocyclic rings
attached to either C2/N3 or the C5/C6 positions of dihydropyrimidine
such as 412 and 513 also possess calcium channel blocking activity.
Recently, several isolated marine alkaloids with interesting bi-
ological activities were found to contain the dihydropyrimidinone-
5-carboxylate skeleton.14,15
O2N
O2N
O
CO2Me
O
CONH2
O
ROOC
H3C
iPrO2C
H3C
N
NH
N
N
H
N
H
O
N
H
O2N
NO2
1
2
3, nitractin
SMe
O
O
iPrO2C
H3C
NH
N
N
N
O
DHPMs and their derivatives show a wide scope of important
pharmacological properties, such as calcium channel modulation,
antihypertensive activity, and a1a-antagonists.6,7 However, most did
not show significant antihypertensive activity. Modification of the
substituent at N3 led to the development of orally long-lasting
N
H
O
N
H
SMe
N
H
NH2
O
6
5
4
The Biginelli reaction is not applicable to the synthesis of a C5/
C6 fused system, therefore, an efficient method for the preparation
of the fused analogs at the C5/C6 position of DHPMs is highly de-
sirable. In this paper we describe a new method for the synthesis of
* Corresponding author. Tel.: þ90 312 2105140; fax: þ90 312 2103200.
E-mail address: mbalci@metu.edu.tr (M. Balci).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.05.090

5974
G. Koza et al. / Tetrahedron 65 (2009) 5973–5976
the 3,4-dihydrofuro[3,2-d]pyrimidin-2(1H)-one skeleton 6 and
some derivatives.
the initially formed isocyanate 14. COSY, HMQC, and HMBC experi-
ments allowed the assignment of the structure 16. Finally X-ray
diffraction analysis of 16 was carried out. The results of this study
confirmed unambiguously the proposed structure (Fig. 1).
2. Results and discussion
The synthesis of the key compound 11 used in the synthesis of
DHMPs began with the readily available chloroacetaldehyde 7 and
dimethyl acetonedicarboxylate 8 followed by the sequence of steps
outlined in Scheme 1.
O
Cl
OCH3
O
COOCH3
COOCH3
Pyridine, 50 °C
80%
+
O
O
OCH3
O
9
7
8
H2N-NH2.H2O
MeOH, 18 h
68%
CONHNH2
CONHNH2
CON3
CON3
NaNO2, HCl.H2O
0-5 °C, 72%
O
O
11
10
Scheme 1. Synthesis of the key compound, diazide 11.
Figure 1. Thermal ellipsoid drawing of compoud 16.
Treatment of dimethyl acetonedicarboxylate 8 with chloro-
acetaldehyde 7 in the presence of pyridine yielded the diester 9 in
80% yield.16 The diester was successfully converted to the desired
dihydrazide 10 by treatment of 9 with hydrazine in methanol. The
resulting compound was reacted at low temperature with NaNO2
and HCl to give the corresponding diazide 11 (Scheme 1).
In order to hinder the intermolecular addition reaction between
15 and 14, we decided to increase the nucleophilicity of the NH group
in 14 and force the system to undergo intramolecular cyclization. For
this reason, isocyanate 12 generated at 35–40 ꢀC in benzene, was
trapped with aniline to give 17 in 84% yield. Curtius rearrangement of
the acyl azide 17, carried out in dry tetrahydrofuran at reflux for 16 h
afforded the pyrimidinone derivative 18 in 71% yield (Scheme 3). The
structure of 18 has been fully characterized.
After successful synthesis of diacyl diazide 11 we turned our
attention to the Curtius rearrangement. Our plan for the con-
struction of the desired heterocyclic ring system involved an
intramolecular cyclization reaction of the diisocyanate, which can
be generated by the Curtius reaction.17–19 Compound 11 contains
two different acyl azide functionalities, with one of the carbonyl
groups conjugated with the furan ring while the other one is not.
We noticed that the stability of those acyl azides is different, with
the conjugated one more stable than the other one. Thus, diacyl
diazide 11 was allowed to heat in benzene at 35–40 ꢀC for 48 h to
effect the transformation of the alkyl acyl azide functionality to the
corresponding monoisocyanate 12 (Scheme 2). Treatment of the
formed isocyanate 12 in benzene with MeOH at 40 ꢀC for 1 h gave
the urethane 13 in 70% yield. The urethane 13 containing an acyl
azide functionality was again subjected to Curtius rearrangement by
heating at reflux for 30 h in benzene under nitrogen atmosphere to
effect its quantitative transformation. The expected intramolecular
cyclization product 15 was unfortunately only formed in 15%. The
major product 16 (46%) was formed by the addition of the NH in 15 to
1. Benzene
CON3
CON3
CON3
NH
35-40 °C, 48 h
C
O
NHPh
2. Aniline, rt,
5 min, 84%
O
O
11
17
THF
reflux, 16 h
71%
H
N
O
O
N
NHPh
O
18
Scheme 3. Curtius rearrangement of 17 and intramolecular cyclization.
CON3
CON3
N
CON3
NH
3. Conclusion
MeOH, 1h
40 °C
Benzene
C
O
OCH3
CON3 35-40 °C, 48 h
C O
O
O
O
In conclusion, 3,4-dihydrofuro[3,2-d]pyrimidin-2(1H)-one (6),
a new heterocyclic system has been prepared starting from methyl
2-(2-methoxy-2-oxoethyl)furan-3- carboxylate (9), by a 6 step
procedure, including two controlled Curtius rearrangements of the
corresponding acyl azides 11 and 17. Considering the multitude of
choices in nucleophile selection, we are confident that this ap-
proach can be extended to a variety of novel furo-condensed new
heterocyclic systems. Efforts to elucidate the versatility of 11
reported herein in expanded structures, and applications to gen-
erate furo-condensed seven-membered rings are currently un-
derway in our laboratories.
13
11
12
Benzene
reflux
O
H
N
HN
NH
OCH3
O
O
N
C
O
Benzene
reflux
+
O
N
O
N
NH
C
O
OCH3
OCH3
O
O
N
OCH3
O
14
O
O
15
(15%)
16
(46%)
Scheme 2. Curtius rearrangement of diazide 11.

G. Koza et al. / Tetrahedron 65 (2009) 5973–5976
5975
4. Experimental section
4.1. General
(2H, d, J 6.2 Hz, –CH2), 3.62 (3H, s, –OCH3); dC (100.6 MHz, CDCl3)
168.5, 159.4, 156.9, 141.9, 116.0, 110.5, 52.4, 37.6.
4.6. Thermolysis of 13
Melting points are uncorrected. Infrared spectra were obtained
from solution in 0.1 mm cells or KBr pellets on an FT-IR Bruker
Vertex 70 instrument. The 1H and 13C NMR spectra were recorded
on a Bruker-Biospin (DPX-400) instrument. Apparent splitting is
given in all cases. Column chromatography was performed on silica
gel (60-mesh, Merck), TLC was carried out on Merck 0.2 mm silica
gel 60 F254 analytical aluminum plates.
The acyl azide 13 (0.3 g, 3.35 mmol) was dissolved in dry ben-
zene (10 mL) and heated at reflux for 30 h. The solvent was evap-
orated and the crude product was purified and separated by
column chromatography eluting with ethyl acetate/dichloro-
methane (2:1) to give cyclic compound 15 and 16.
4.6.1. Methyl 2-oxo-1,4-dihydrofuro[3,2-d]pyrimidine-3(2H)-
carboxylate (15)
4.2. 2-(2-Hydrazino-2-oxoethyl)-3-furohydrazide (10)
White solid, 40 mg, 15%, mp 152–153 ꢀC. [Found: C, 49.11; H,
4.05; N, 14.43. C8H8N2O4 requires C, 48.98; H, 4.11; N, 14.28%.]
nmax(KBr) 3428, 1772, 1719, 1708, 1540, 1524, 1437, 1366, 1291, 1273,
Hydrazine monohydrate (9.8 mL, 202 mmol) was added to
a stirred solution of diester 9 (10 g, 50.5 mmol) in methanol
(150 mL) and heated at reflux for 18 h. The solvent was evaporated
and the crude product was purified by washing with a mixture of
methanol/ethyl acetate (2:1) to give dihydrazide 10 as a white solid
(6.8 g, 68%), mp 152–153 ꢀC. [Found: C, 42.22; H, 5.03; N, 28.10.
C7H10N4O3 requires C, 42.42; H, 5.09; N, 28.27%.] nmax(KBr) 3309,
1219, 1121 cmꢁ1
; dH (400 MHz, CDCl3) 7.40 (1H, br s, –NH), 7.24 (1H,
dt, J 2.0, 1.0 Hz,]CH), 6.20 (1H, d, J 2.0 Hz,]CH), 4.90 (2H, d, J
1.0 Hz, –CH2), 3.91 (3H, s, –OCH3); dC (100.6 MHz, CDCl3) 154.1,
149.7, 141.9, 130.1, 120.6, 101.5, 53.7, 44.1.
3009, 1687, 1626, 1515, 1418, 1350, 1238, 1016, 730 cmꢁ1
; dH
4.6.2. Methyl 1-[{2-[(methoxycarbonyl)amino]methyl-3-
furylamino}carbonyl]-2-oxo-1,4-dihydrofuro[3,2-d]pyrimidine-
3(2H)-carboxylate (16)
(400 MHz, DMSO-d6) 9.59 (1H, br s, NH), 9.24 (1H, br s, –NH), 7.56
(1H, d, J 1.9 Hz,]CH), 6.82 (1H, d, J 1.9 Hz,]CH), 4.33 (4H, br s,
–NH2) 3.82 (2H, s, –CH2); dC (100.6 MHz, DMSO-d6) 167.3, 162.4,
152.3, 141.6, 116.2, 109.0, 32.7.
White solid from ethyl acetate, 120 mg, 46%, mp 163–164 ꢀC.
[Found: C, 48.90; H, 4.11; N, 14.25. C16H16N4O8 requires C, 48.98; H,
4.11; N, 14.28%.] nmax(KBr) 3358, 3139, 2964, 1780, 1710, 1640, 1531,
1448, 1396, 1266, 1130, 1080, 765 cmꢁ1
; dH (400 MHz, CDCl3) 10.49
4.3. Synthesis of 2-(2-azido-2-oxoethyl)-3-furoyl azide (11)
(1H, br s, –NH), 7.31 (1H, d, J 2.0 Hz,]CH), 7.30 (1H, d, J
2.0 Hz,]CH), 6.92 (1H, d, J 2.0 Hz,]CH), 6.62 (1H, br s,]CH), 5.34
(1H, br s, –NH), 4.87 (2H, s, –CH2), 4.34 (2H, d, J 6.0 Hz, –CH2), 3.94
(3H, s, –OCH3), 3.68 (3H, s, –OCH3); dC (100.6 MHz, CDCl3) 157.4,
154.2, 152.3, 150.6, 142.3, 142.2, 141.6, 134.1, 121.6, 120.8, 108.9,
108.0, 55.1, 52.6, 44.5, 36.4.
Dihydrazide 10 (3 g, 15.15 mmol) was dissolved in aq solution of
HCl (70 mL, 1 M) and cooled to 0 ꢀC. To this, a solution of sodium ni-
trite (2.1 g, 30.3 mmol) in water (40 mL) was added dropwise at 0–
5 ꢀCandstirredatthistemperaturerangefor30 min. Themixturewas
extractedwithdiethylether(2ꢂ70 mL).Thecombinedorganicphases
were washed with satd aq Na2CO3 solution (50 mL) and then brine
(40 mL), dried over MgSO4 and the solvent was evaporated to give
diacyl azide 11 as a colorless oil (2.4 g, 72%); nmax(KBr) 2926, 2144,
4.7. 2-{[(Anilinocarbonyl)amino]methyl}-3-furoyl azide (17)
Aniline (0.94 mL, 10.4 mmol) was added to a stirred solution of
the half-isocyanate 12 (1.8 g, 8.7 mmol, synthesized as described
above) in dry benzene (80 mL) and stirred at room temperature for
5 min. The precipitate was filtered and washed with benzene
(50 mL) and purified by column chromatography eluting with ethyl
acetate/hexane (2:1) to give urethane 17 as a white solid from ethyl
acetate (2.1 g, 84%), mp 141–142 ꢀC. [Found: C, 54.30; H, 3.79; N,
24.33. C13H11N5O3 requires C, 54.74; H, 3.89; N, 24.55%.] nmax(KBr)
3326, 2153, 2128, 1689, 1638, 1596, 1570, 1444, 1306, 1263, 1184,
1687,1600,1517,1420,1300,1187,1071 cm .
ꢁ1 dH (400 MHz,CDCl3)7.30
(1H, d, J 2.0 Hz,]CH), 6.63 (1H, d, J 2.0 Hz,]CH), 4.05 (2H, s, –CH2); dC
(100.6 MHz, CDCl3) 174.9, 168.2, 154.2, 142.6, 117.5, 110.6, 35.9.
4.4. 2-(Isocyanatomethyl)-3-furoyl azide (12)
The diacyl azide 11 (2.8 g, 12.7 mmol) was dissolved in dry
benzene (100 mL) and stirred at 37–42 ꢀC for 48 h. The solvent was
evaporated to give a colorless oil of 12 was analyzed by NMR
spectroscopy indicating the formation of half-isocyanate in 85%
yield; nmax(KBr) 3162, 3134, 2257, 2137, 1688, 1599, 1516, 1404, 1341,
1052, 951 cmꢁ1
; dH (400 MHz, acetone-d6) 8.00 (1H, br s, –NH), 7.44
(1H, d, J5,4]2.0 Hz,]CH), 7.35 (2H, br d, J 7.6 Hz,]CH), 7.10 (2H, br
t, J 8.2 Hz,]CH), 6.79 (1H, tt, J 7.4, 1.0 Hz,]CH), 6.56 (1H, d, J
2.0 Hz,]CH), 6.19 (1H, br t, J 6.0 –NH), 4.62 (2H, d, J 6.0 Hz, –CH2); dC
(100 MHz, acetone-d6) 168.9, 161.9, 155.8, 143.2, 141.4, 129.5, 122.5,
119.0, 116.1, 111.2, 37.1.
1302, 1262, 1184, 1129, 1049, 913 cmꢁ1
; dH (400 MHz, CDCl3) 7.40
(1H, d, J 2.0 Hz,]CH), 6.70 (1H, d, J 2.0 Hz,]CH), 4.78 (2H, s, –CH2);
dC (100.6 MHz, CDCl3) 167.5, 156.0, 142.3, 124.9, 115.9, 111.4, 38.4.
4.5. Methyl (3-(azidocarbonyl)furan-2-yl)methyl-
carbamate (13)
4.8. 2-Oxo-N-phenyl-1,4-dihydrofuro[3,2-d]pyrimidine-
3(2H)-carboxamide (18)
Excess methanol (5 mL) was added to a stirred solution of the
half-isocyanate 12 (2.1 g, 10.9 mmol) in dry benzene (50 mL) and
stirred at 40 ꢀC for 1 h. The solvent was evaporated to give the
crude product, which was then purified and separated by column
chromatography eluting with dichloromethane/hexane/ethyl ace-
tate (1:1:1) to give urethane 13 as a white solid (1.72 g, 70%), mp
95–96 ꢀC. [Found: C, 43.07; H, 3.65; N, 24.95. C8H8N4O4 requires C,
42.86; H, 3.60; N, 24.99%.] nmax(KBr) 3334, 3129, 2944, 2159, 1715,
The acyl azide 17 (0.8 g, 2.81 mmol) was dissolved in dry THF
(60 mL) and heated at reflux for 16 h. The solvent was evaporated
and the crude product was purified by column chromatography
using silica gel (50 g) eluting with ethyl acetate/dichloromethane
(1:1) to give cyclic compound 18 as a white solid from ethyl acetate
(0.51 g, 71%), mp 203–205 ꢀC. [Found: C, 61.11; H, 4.60; N, 16.12.
C13H11N3O3 requires C, 60.70; H, 4.31; N, 16.33%.] nmax(KBr) 3413,
3202, 3142,1719,1655,1595,1558,1438,1205,1161,1025, 747 cmꢁ1
;
1671, 1518, 1446, 1256, 1070 cmꢁ1
J 2.0 Hz,]CH), 6.58 (1H, d, J 2.0 Hz,]CH), 5.40 (1H, br s, –NH), 4.61
;
dH (400 MHz, CDCl3) 7.25 (1H, d,
dH (400 MHz, CDCl3) 11.42 (1H, br s, –NH), 7.46 (2H, br d, J
7.6 Hz,]CH), 7.26 (2H, br t, J 7.4 Hz,]CH), 7.22 (1H, dt, J 2.0,

5976
G. Koza et al. / Tetrahedron 65 (2009) 5973–5976
1.0 Hz,]CH), 7.04 (1H, tt, J 7.4, 1.0 Hz,]CH), 6.51 (1H, br s, –NH),
6.10 (1H, d, J 2.0 Hz,]CH), 4.99 (2H, br s, –CH2); dC (100.6 MHz,
CDCl3) 153.9, 152.3, 142.7, 137.8, 130.9, 129.0, 124.1, 120.4, 120.1,
101.4, 43.6.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication num-
bers CCDC 719646. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
UK [fax: þ44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk].
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2009.05.090.
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Acknowledgements
The authors are indebted to TUBITAK (Scientific and Techno-
logical Research Council of Turkey, Grant 108-M168), the De-
partment of Chemistry at Middle East Technical University, and
TUBA (Turkish Academy of Sciences) for their financial support of
this work. E.S thanks Atatu¨rk University for the use of X-ray dif-
fractometer purchased under grant number 2003/219 of University
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Supplementary data
1H and 13C NMR spectra for all new compounds and crystallo-
graphic information file (CIF) for compound 16 are provided. Sup-