Synthesis of Pyrimidine Annelated Heterocycles [1]. Regioselective Heterocyclization of 6-Cyclopent-2-enyl-5-hydroxy-1,3-dimethylpyrimidine-2,4(1H, 3H)-dione and 5-Cyclopent-2-enyl-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)- dione

Article abstract of DOI:10.1007/s00706-003-0043-z

Two hitherto unreported pyrimidine annelated heterocycles were synthesized from 6-cyclopent-2-enyl-5-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione and 5-cyclopent-2-enyl-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione by reaction with pyridine hydrotr

Full text of DOI:10.1007/s00706-003-0043-z

Monatshefte f€ur Chemie 134, 1137–1143 (2003)
DOI 10.1007/s00706-003-0043-z
Synthesis of Pyrimidine Annelated
Heterocycles [1]. Regioselective
Heterocyclization of 6-Cyclopent-
2-enyl-5-hydroxy-1,3-dimethyl-
pyrimidine-2,4(1H,3H)-dione
and 5-Cyclopent-2-enyl-6-hydroxy-
1,3-dimethylpyrimidine-2,4(1H,3H)-dione
ꢀ
Krishna C. Majumdar , Uday K. Kundu, Swapan K. Samanta,
and Nirmal K. Jana
Department of Chemistry, University of Kalyani, Kalyani-741 235, W.B, India
Received October 28, 2002; accepted October 30, 2002
Published online June 2, 2003 # Springer-Verlag 2003
Summary. Two hitherto unreported pyrimidine annelated heterocycles were synthesized from 6-
cyclopent-2-enyl-5-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione and 5-cyclopent-2-enyl-6-
hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione by reaction with pyridine hydrotribromide or
hexamethylenetetramine hydrotribromide. The first one was also obtained by reaction with concen-
trated sulfuric acid.
Keywords. Pyridine hydrotribromide; Heterocycles; Cyclization; Hexamethylenetetramine hydro-
tribromide; 6-endo Cyclization.
Introduction
Pyrimidine derivatives are important due to their proven biological activity and
medicinal utility [2–9]. We have recently reported the synthesis of a number of
pyrimidine annelated heterocycles [10–12]. Here we report a simple and regiose-
lective synthesis of a number of hitherto unknown pyrimidine annelated hetero-
cycles.
ꢀ
Corresponding author. E-mail: kcm@klyuniv.ernet.in

1138
K. C. Majumdar et al.
Results and Discussion
The starting materials 4 and 5 for this study were easily obtained from the reaction
of 1,3-dimethyl-5-hydroxyuracil (1) and 1,3-dimethyl-6-hydroxyuracil (2) with 3-
chloro-cyclopentene (3) in refluxing acetone in the presence of anhydrous potas-
sium carbonate for 20 and 8 h (Scheme 1).
Recently, we have reported the use of pyridine hydrotribromide [13–19] and
hexamethylenetetramine hydrotribromide [20] for this type of heterocyclization.
Thus, 4 was treated with one equivalent of pyridine hydrotribromide or hexam-
ethylenetetramine hydrotribromide in chloroform at 0–5ꢁC for 30 min. to give the
bridged tricyclic bromo compound 6 (80%). The product was characterized by
its elemental analysis and spectral data. The IR spectrum of 6 showed ꢀꢀmax
¼
1700 cmÀ1 due to a carbonyl group. Two structures, 6 and 7, may be considered
for the product. The 1H NMR spectrum showed three nonequivalent protons, a one
proton triplet at ꢁ ¼ 3.91 ppm (J ¼ 8 Hz) assignable to Hc, a one proton broad
singlet at ꢁ ¼ 4.57 ppm assignable to Ha, and a one proton doublet at ꢁ ¼ 5.37 ppm
(J ¼ 8 Hz) assignable to Hb. From the splitting pattern and the coupling constant
values it is clear that Hb and Hc are vicinal protons. This clearly shows that the
product has the bridged tricyclic structure 6 instead of the linearly fused structure 7
where Hb and Hc are not at adjacent carbons.
Final confirmation for the structure of 6 came from its 13C NMR, DEPT, COSY,
and HETCOR experiments. The COSY spectrum of compound 6 shows that proton
Ha at ꢁ ¼ 4.57 ppm correlates with protons Hf and Hg at ꢁ ¼ 2.91–2.24 ppm, pro-
ton Hb at ꢁ ¼ 5.37 ppm correlates with proton Hc at ꢁ ¼ 3.91 ppm, and Hc corre-
lates with a proton resonance at ꢁ ¼ 2.48–2.59 ppm (Hd=He). Hd, He, Hf, and Hg are
correlated with each other. The 13C chemical shifts of compound 6 were assigned
by DEPT and HETCOR experiments. Multiplicity was established by DEPT
experiment. DEPT showed seven protonated carbons, two –CH3, three >CH–,
and two –CH2–. Protonated carbon resonances were established by direct correla-
tion with proton resonances by a HETCOR experiment (normal one bond C–H
Scheme 1

Synthesis of Pyrimidine Annelated Heterocycles
1139
Scheme 2
coupling). Methyl protons (NMe) resonance at ꢁ ¼ 3.34 ppm is related to a carbon
resonance at ꢁ ¼ 28.68 ppm and the other methyl protons signal at ꢁ ¼ 3.38 ppm
(NMe) is related to a carbon resonance at ꢁ ¼ 32.87 ppm. Methine proton reso-
nance at ꢁ ¼ 4.57 ppm (Ha) is related to a carbon resonance at ꢁ ¼ 53.37 ppm (C8)
and two methine protons resonances at ꢁ ¼ 5.37 (Hb) and 3.91 ppm (Hc) are related
to carbon resonances at ꢁ ¼ 93.51 (C12) and 45.63 ppm (C11). Methylene protons
resonance at ꢁ ¼ 2.48–2.59 ppm (Hf, Hg) is related to the carbon resonance at
ꢁ ¼ 33.47 ppm (C9), another two methylene protons resonances at ꢁ ¼ 2.19–2.24
and 1.87–1.97 ppm (Hd, He) are related with a carbon resonance at ꢁ ¼ 29.51 ppm
(C10).
The mass spectrum of 6 showed molecular ion peaks at m=z ¼ 300, 302. Final
confirmation for the structure 6 was gained from the observation that 6 remained
unchanged upon treatment with alcoholic KOH at reflux for 2 h or on heating with
palladised charcoal in diphenyl ether at 260ꢁC for 2 h (Scheme 2). Therefore, the
alternating structure 7 was ruled out on the basis of chemical and spectroscopic
evidence.
Cold conc. H2SO4 has been widely used for the cyclization of ortho-allyl
phenols [21–23] and other related substrates [24, 25]. Thus, 4 was treated with
conc. H2SO4 at 0–5ꢁC to give a white solid. This was characterized as the bridged
tricyclic product 9 by its elemental analysis and spectral data. The IR spectrum of 9
showed ꢀꢀmax ¼ 1700 cmÀ1 due to the carbonyl group. The 1H NMR spectrum of 9
revealed a one proton broad singlet at ꢁ ¼ 3.29 ppm due to the proton Hc and a one
proton broad singlet at ꢁ ¼ 4.91 ppm due to the proton Ha. The mass spectrum of 9
showed a molecular ion peak at m=z ¼ 222. 13C NMR showed eleven carbon atoms
and DEPT experiment showed seven protonated carbon atoms, two –CH3, three
>CH2, and two >CH–. Confirmation for structure 9 came from the observation
that the product 9 remained unchanged when heated with palladised charcoal in
diphenyl ether at 260ꢁC for 2 h. (Scheme 2).

1140
K. C. Majumdar et al.
Scheme 3
The substrate 5 was similarly treated with one equivalent of pyridine hydro-
tribromide or hexamethylenetetramine hydrotribromide to afford a gummy mass.
This was characterized as the bridged tricyclic bromo compound 10 by its elemen-
tal analysis and spectral data. The IR spectrum of 10 showed ꢀꢀmax ¼ 1690 cmÀ1
due to a carbonyl group. Two structures 10 and 11 may be considered for the
1
product. The H NMR spectrum showed three lone protons, one a triplet at
ꢁ ¼ 3.99 ppm (J ¼ 8 Hz) assignable to Hc, a broad singlet at ꢁ ¼ 4.47 ppm assign-
able to Ha, and a doublet at ꢁ ¼ 5.49 ppm (J ¼ 8 Hz) assignable to Hb. 13C NMR
showed eleven carbon atoms and DEPT experiment showed seven protonated
carbon atoms, two –CH3, two >CH2, and three >CH–. Arguments presented
for assignment of structure 6 were extended to this product and bridged tricyclic
structure 10 was assigned to it instead of the linearly fused structure 11 (Scheme
3). As proton Ha appears as a broad singlet in compounds 6 and 10 it is not easily
possible to specify the particular diastereoisomer for the product. However, the
chemical shift of proton Hb (a doublet) being at relatively down field (ꢁ ¼ 5.37 (6)
and 5.49 ppm (10)) indicate that the proton is in the deshielding cone of the
>C¼O. Thus, the products may be assigned as diastereoisomers with exo-Br (6
and 10). The mass spectrum of 10 showed molecular ion peaks at m=z ¼ 300, 302.
Final confirmation for structure 10 could be reached when it was found that 10
remained unchanged on treatment with alcoholic KOH at reflux for 2 h and on
heating with palladised charcoal in diphenyl ether at 260ꢁC for 2 h.
The formation of products 6, 9, and 10 from 4 and 5 may be explained via the
formation of the ionic intermediates 8a, 8b, and 12, which may then undergo a ‘‘6-
endo’’ cyclization to give the products 6, 9, and 10 [26].
In conclusion the heterocyclization of 4 and 5 was found to be regioselective
with pyridine hydrotribromide, hexamethylenetetramine hydrotribromide, and cold
conc. H2SO4 to give the bridged tricyclic heterocycles 6, 9, and 10.

Synthesis of Pyrimidine Annelated Heterocycles
1141
Experimental
Melting points were measured in a sulfuric acid bath and are uncorrected. UV absorption spectra were
recorded in EtOH on a Hitachi 200–20 spectrophotometer. IR spectra were run on KBr disks on a
Perkin-Elmer 1330 apparatus. 1H NMR Spectra were determined for solutions in CDCl3 with TMS as
internal standard on a 200 MHz spectrometer (Bruker). 13C NMR Spectra were measured of 75 MHz.
Elemental analyses results agreed favorably with the calculated values and recording of mass spectra
was carried out by RSIC (CDRI) Lucknow on a JEOL D-300 (El) instrument. Silica gel (60–
120 mesh), Spectrochem, India, was used for chromatographic separations. Petroleum ether refers to
the fraction boiling between 60 and 80ꢁC.
6-Cyclopent-2-enyl-5-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4, C11H14N2O3)
A mixture of 1.56 g of 1 (10 mmol), 1.02 g of 3 (10 mmol), and 3 g of anhydrous K2CO3 in 100 cm3 of
dry acetone was refluxed on a water bath for 20h. The reaction mixture was cooled, filtered, and
the solvent was removed. The residue was extracted with 3 Â 25cm3 of CHCl3, the organic layer
was separated, washed with 2 Â 25cm3 of H2O, dried (Na2SO4), and the solvent was evaporated.
Purification of the crude product by column chromatography (ethylacetate:benzene¼ 1:9) over
silica gel gave 4. Yield: 65%; white solid; mp 144ꢁC; 1H NMR: ꢁ ¼ 1.7–2.7 (m, 4H), 3.42
(s, N–CH3), 3.43 (s, N–CH3), 4.40–4.47 (m, 1H), 5.71–5.79 (m, 1H), 5.91–5.97 (m, 1H) ppm; IR
(KBr): ꢀꢀ ¼ 1070, 1600, 1690, 2900, 3300 cmÀ1; UV-Vis (EtOH): ꢂmax ¼ 215, 291 nm; MS: m=z ¼ 222
(Mþ ).
5-Cyclopent-2-enyl-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (5, C11H14N2O3)
A mixture of 1.56 g of 1,3-dimethylbarbituric acid (10 mmol), 1.02 g of 3-chlorocyclopentene
(10 mmol), and 3 g of anhydrous K2CO3 in 100cm3 of dry acetone was refluxed for 8 h. The reaction
mixture was cooled, filtered, and the solvent was removed. The residue was extracted with 3Â 25cm3 of
CHCl3, the organic layer was separated, washed with 2 Â 25cm3 of water, dried (Na2SO4), and the
solventwasevaporated.Purificationofthecrudeproductbycolumnchromatography(benzene:petroleum-
1
ether ¼ 3:1) over silica gel gave 5. Yield: 55%; gummy mass; H NMR: ꢁ ¼ 1.97–2.36 (m, 4H),
3.26 (s, N–CH3), 3.30 (s, N–CH3), 3.48–3.54 (m, 1H), 5.56–5.59 (m, 1H), 5.89–5.92 (m, 1H)ppm;
IR (neat): ꢀꢀ ¼ 1120; 1700; 2980; 3420 cmÀ1; UV-Vis (EtOH): ꢂmax ¼ 214, 260 nm; MS: m=z ¼ 222
(Mþ ).
(10-anti)-10-Bromo-6,7,8,9-tetrahydro-1,3-dimethyl-6,9-methanooxepano[2,3-e]-
pyrimidine-2,4(1H,3H)-dione (6, C11H13BrN2O3)
A solution of 0.33g of 4 (1.5mmol) in 100 cm3 of CHCl3 was stirred with 0.45 g of pyridine
hydrotribromide (1.5mmol) or 0.58 g hexamethylenetetramine hydrotribromide (1.5 mmol) at 0–5ꢁC
for 1 h. The CHCl3 solution was washed with 2 Â 25cm3 of 5% Na2CO3 solution, then with 2 Â 25cm3
of H2O, and dried (Na2SO4). Evaporation of CHCl3 left a gummy residue. This was purified by column
chromatography over silica gel. Compound 6 was obtained when the column was eluted with
1
ethylacetate:benzene¼ 1:3. Yield: 80%; white solid; mp 168ꢁC; H NMR: ꢁ ¼ 1.89–1.97 (m, 1H),
2.19–2.24 (m, 2H), 2.48–2.59 (m, 1H), 3.34 (s, N–CH3), 3.38 (s, N–CH3), 3.91 (t, J ¼ 8 Hz, Hc), 4.57
(brs, Ha), 5.37 (d, J ¼ 8 Hz, Hb) ppm; 13C NMR: ꢁ ¼ 28.68, 29.51, 32.87, 33.47, 45.63, 53.37, 93.51,
132.15, 136.37, 151.72 (>C¼O), 155.12 (>C¼O); IR (KBr): ꢀꢀ ¼ 1110; 1700; 2970 cmÀ1; UV-Vis
(EtOH): ꢂmax ¼ 218, 299 nm; MS: m=z ¼ 300, 302 (Mþ ).

1142
K. C. Majumdar et al.
6,7,8,9-Tetrahydro-1,3-dimethyl-6,9-methanooxepano[2,3-e]-pyrimidine-2,4(1H,3H)-dione
(9, C11H14N2O3)
To 2 cm3 of concentrated H2SO4 0.22 g of 4 (1mmol) were added in portions at 0–5ꢁC and the mixture
was stirred for 2 h at this temperature. The solution was then poured into crushed ice and extracted with
3 Â 25cm3 of CHCl3. The CHCl3 layer was washed with 3Â 10cm3 of 5% Na2CO3 solution, then with
3 Â 20cm3 of H2O, and dried (Na2SO4). Evaporation of CHCl3 gave a gummy mass. This was purified
by column chromatography over silica gel. Elution of the column with benzene:ethylacetate¼ 3:1 gave
1
9. Yield: 75%; white solid; mp 128ꢁC; H NMR: ꢁ ¼ 1.56–2.3 (m, 6H), 3.29 (brs, Hc), 3.42 (s,
N–CH3), 3.48 (s, N–CH3), 4.91 (brs, Ha) ppm; 13C NMR: ꢁ ¼ 27.89, 30.11, 31.93, 31.95, 32.16,
33.64, 33.69, 126.79, 135.90, 150.12 (>C¼O), 158.18 (>C¼O); IR (KBr): ꢀꢀ ¼ 1140;
1700; 2970 cmÀ1; UV-Vis (EtOH): ꢂmax ¼ 216, 296 nm; MS: m=z ¼ 222 (Mþ ).
(10-anti)-10-Bromo-5,6,7,8-tetrahydro-1,3-dimethyl-5,8-methanooxepano[3,2-e]-
pyrimidine-2,4(1H,3H)-dione (10, C11H13BrN2O3)
A solution of 0.33 g of 5 (1.5mmol) in 100cm3 of CHCl3 was stirred with 0.45g of pyridine hydro-
tribromide (1.5mmol) or 0.58 g of hexamethylenetetramine hydrotribromide (1.5mmol) at 0–5ꢁC for
1 h. The CHCl3 solution was washed with 2 Â 25 cm3 of 5% Na2CO3 solution, then with 2 Â 25 cm3 of
H2O, and dried (Na2SO4). Evaporation of CHCl3 left a gummy residue. This was purified by column
chromatography over silica gel. Compound 10 was obtained when the column was eluted with
1
benzene:petroleum ether¼ 1:1. Yield: 70%; gummy mass; H NMR: ꢁ ¼ 2.04–2.57 (m, 4H), 3.30
(s, 6H, N–CH3), 3.99, (t, J ¼ 8 Hz, Hc), 4.47 (brs, Ha), 5.49 (d, J ¼ 8 Hz, Hb) ppm; 13C NMR:
ꢁ ¼ 28.90, 29.73, 33.09, 33.68, 45.83, 53.57, 93.71, 131.32, 135.59, 151.97 (>C¼O), 156.32
(>C¼O); IR (neat): ꢀꢀ ¼ 1110; 1690; 2970 cmÀ1; UV-Vis (EtOH): ꢂmax ¼ 216, 299 nm; MS:
m=z ¼ 300, 302 (Mþ ).
Acknowledgement
We thank the CSIR (New Delhi) for financial assistance. One of us (S. K. Samanta) is grateful to CSIR
(New Delhi) for a fellowship. We also thank Professor D. K. Bates of the Department of Chemistry and
Chemical Eng., Michigan Technological University, Houghton, Michigan, USA, for recording of 13C,
DEPT, and 2D NMR spectra.
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Synthesis of Pyrimidine Annelated Heterocycles
1143
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