Regioselective synthesis of pyrimidine annelated heterocycles from 6-(cyclohex-2-enyl)-1,3-dimethyl-5-hydroxyuracil

Article abstract of DOI:10.1016/S0040-4020(01)00656-1

6-(Cyclohex-2-enyl)-1,3-dimethyl-5-hydroxyuracil when treated with bromine in chloroform at 0-5°C for 6 h furnishes 6-bromo-1,3-dimethylhexahydrobenzofuro[3,2-d]pyrimidine-2,4-dione in 80% yield. The same heterocycle is also obtained in 90% yield on treat

Full text of DOI:10.1016/S0040-4020(01)00656-1

TETRAHEDRON
Pergamon
Tetrahedron 57 '2001) 7003±7007
Regioselective synthesis of pyrimidine annelated heterocycles
from 6-ꢀcyclohex-2-enyl)-1,3-dimethyl-5-hydroxyuracilq
K. C. Majumdar,p U. Das, U. K. Kundu and A. Bandyopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741 235, W.B., India
Received 10 November 2000;revised 22 May 2001;accepted 14 June 2001
AbstractÐ6-'Cyclohex-2-enyl)-1,3-dimethyl-5-hydroxyuracil when treated with bromine in chloroform at 0±58C for 6 h furnishes
6-bromo-1,3-dimethylhexahydrobenzofuro[3,2-d]pyrimidine-2,4-dione in 80% yield. The same heterocycle is also obtained in 90% yield
on treatment of the same substrate with pyridine hydrobromide perbromide for 30 min or with hexamethylenetetramine hydrotribromide for
15 min in methylene chloride at 0±58C. Cyclization of the same substrate with bis-benzonitrile palladium'II) chloride in benzene in the
presence of sodium methoxide afforded 1,3-dimethyl-6,7,8,9-tetrahydrobenzofuro[3,2-d]pyrimidine-2,4-dione in 82% yield. The same
substrate on treatment with cold conc. sulfuric acid at 0±58C for 2 h gave 1,3-dimethyl-5-oxabicyclo[3.3.1]nonano[3,2-d]pyrimidine-2,4-
dione in 94% yield. q 2001 Elsevier Science Ltd. All rights reserved.
5-Substituted uracils and their nucleosides are of immense
biological signi®cance because of their use in the
chemotherapy of cancer2 [e.g. FU '5-¯uorouracil), FUDR
'5-¯uoro-20-deoxy-uridine)] and viral diseases [F3TdR
cyclohexene in re¯uxing acetone in the presence of
anhydrous potassium carbonate.
Three approaches were considered for the cyclization of
substrate 1. Our ®rst approach for the cyclization of
compound 1 was to try brominating agents such as pyridine
hydrobromide perbromide, hexamine hydrobromide per-
bromide and elemental bromine. Accordingly compound 1
was treated with pyridine hydrotribromide in chloroform at
0±58C for 30 min to give the linearly fused bromo
compound 6-bromo-1,3-dimethylhexahydrobenzofuro[3,2-
d]pyrimidine-2,4-dione '2) in 90% yield. The same product
2 was also obtained in 92% yield when compound 1 was
treated with hexamethylenetetramine hydrotribromide in
methylene chloride at 0±58C for 15 min. Substrate 1 on
treatment with elemental bromine in chloroform at 0±58C
for 6 h also furnished the same product 2 in 80% yield
'Scheme 1). It may be noted that similar cyclization of
o-cyclohexenyl phenols with pyridine hydrobromide21 or
hexamethylene hydrotribromide22 generated bicyclic
heterocycles by a 6-endo cyclization.
'tri¯uorothymidine),
BVDU
{E-5-'2-bromovinyl-20-
deoxy-uridine)}, AZT '30azido-30-deoxythymidine)]3±6
and CEDU {5-'2-chloroethyl)-20-deoxyuridine}.7 Both
BVDU and CEDU compounds effectively inhibit herpes
simplex type 1 virus 'HSV-1) and varicella zoster virus
'VZU) replication in vitro3,7±10 and AZT11 is anti-AIDS.
Also, many 5-substituted uracils have been developed as
enzyme inhibitors12 and have been used in the synthesis of
modi®ed nucleotides.13 Recently, a 6-substituted uracil
derivative 1-['2-hydroxyethoxy)methyl]-6-phenylthiothymine
'HEPT)14±16 has attained considerable signi®cance as a
speci®c inhibitor of HIV-1, a causative agent of AIDS.17 Func-
tionalisation of uracils at C-5 and C-6 leads to biologically
interesting molecules but is not a simple task, requiring rather
sophisticated and tedious reaction conditions.18±20 Here we
report simple and regioselective synthesis of a number of
hitherto unreported pyrimidine annelated heterocycles.
The starting material for this study 6-'cyclohex-2-enyl)-1,3-
dimethyl-5-hydroxyuracil '1) was obtained in 90% yield by
the reaction of 1,3-dimethyl-5-hydroxyuracil with 3-bromo-
Compound 2 on treatment with alcoholic potassium
hydroxide at room temperature for 5 min furnished the
dehydrobrominated product 1,3-dimethyl-7,8,9,9a-tetra-
hydrobenzofuro[3,2-d]pyrimidine-2,4-dione '5) in 85%
yield. Compound 5 was further dehydrogenated by re¯uxing
with palladised charcoal in diphenyl ether for 30 min to
give the aromatised product 1,3-dimethylbenzofuro[3,2-
d]pyrimidine-2,4-dione '6) in 40% yield 'Scheme 2). Final
con®rmation for structure 2 came from its COSY-,
HETCOR- and 13C NMR spectral data. COSY spectrum
of compound 2 shows that proton H-1 at d 4.72 correlates
with proton H-9 at d 3.30±3.38 and proton H-2 at d 4.78.
q See Ref. 1.
Keywords: pyrimidine annelated heterocycles;heterocyclization;palladium
chloride bis-benzonitrile;pyridine hydrotribromide;6-cyclohex-2-enyl-
1,3-dimethyl-5-hydroxy pyrimidine-2,4-dione.
p
Corresponding author. Tel.: 191-33-582-7521;fax: 191-33-582-8282;
e-mail: kcm@klyuniv.ernet.in
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020'01)00656-1

7004
K. C. Majumdar et al. / Tetrahedron 57 &2001) 7003±7007
Scheme 1. Reagents: 'i) Br2, CHCl3, 6 h '80%) or PyHBr3, CH2Cl2, 0.5 h '90%) or C6H12N4HBr3, CH2Cl2, 15 min '92%).
Scheme 2. Reagents: 'i) KOH/EtOH, 5 min, rt '85%);'ii) Pd/C, Ph 2O, 30 min '40%).
Proton H-2 at d 4.78 correlates with proton H-3 at d
2.1±2.18, H-4 at d 2.08 and H-1 at d 4.72. Proton H-9 at
d 3.30±3.38 correlates with proton H-1 at d 4.72, H-7 at d
1.30 and H-8 at d 2.1±2.18. Proton H-5 at d 1.8±1.9 corre-
lates with H-7 at d 1.30, H-4 at d 2.08 and H-3 and H-8 at d
2.1±2.18. Proton H-6 at d 1.65 correlates with H-7 at d 1.30,
H-4 at d 2.08 and H-3 and H-8 at d 2.1±2.18. Proton H-6 at
d 1.65 correlates with H-7 at d 1.30, H-4 at d 2.08 and H-3
and H-8 at d 2.1±2.8. The 13C chemical shifts of compound
2 are assigned by DEPT and HETCOR experiments. Multi-
plicity was established by DEPT experiment. DEPT shows
eight protonated carbons, two ±CH3, three sCH±, and three
±CH2±. Protonated carbon resonances are established by
direct correlation with proton resonances by HETCOR
experiment 'normal one bond C±H coupling). Methyl
proton resonance at d 3.40 is related with protonated carbon
resonance at d 29.26 and another methyl proton at d 3.42 is
related with protonated carbon resonance at d 33.88.
Methine protons resonance at d 4.70±4.80 'H-1 and H-2)
are related with carbon resonances at d 83.93 'C-5a) and
47.74 'C-6) and at d 3.30±3.38 'H-9) is related with carbon
resonance at d 39.27 'C-9a). Methylene protons resonances
at d 1.65 'H-6) and 1.8±1.9 'H-5) are related with carbon
resonance at d 17.71 'C-8), d 2.08 'H-4) is related with
carbon resonance at d 30.03 'C-7), d 2.10±2.18 'H-3 and
H-8) are related with carbon resonance at d 30.03 'C-7) and
28.49 'C-9), respectively and at d 1.3 'H-7) is related with
carbon resonance at d 28.49 'C-9). Therefore, the alterna-
tive structure 4 for the product was ruled out on the basis of
chemical and spectroscopic evidences.
hydrobenzofuro-[3,2-d]pyrimidine-2,4-dione '7) was obtained
in 82% yield. It was characterised from its elemental
analysis and spectral data. This was subjected to dehydro-
genation by re¯uxing with palladised charcoal in diphenyl
ether for 1 h to give the aromatised product 6 'Scheme 3).
Acid catalysed cyclization of the substrate 1 was also
attempted. The substrate 1 was treated with cold conc.
sulfuric acid at 0±58C for 2 h to give a single product,1,3-
dimethyl-5-oxabicyclo[3.3.1]nonano[3,2-d]pyrimi-dine-2,4-
dione '8) in 94% yield. Compound 8 resisted dehydrogena-
tion when re¯uxed with 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone in xylene or with palladised charcoal in
diphenyl ether 'Scheme 4). This was characterised from
its elemental analysis and spectral data. The alternative
structure 9 for this cyclization product was ruled out from
COSY-, HETCOR- and 13C NMR spectral data. COSY
spectrum of compound 8 shows that proton H-1 at d
4.60±4.70 correlates with proton H-9 at d 2.08±2.20, H-2
and H-3 at d 1.88±1.96 and H-10 at d 1.48±1.55. Proton
H-4 at d 3.00±3.06 correlates with proton H-2 and H-3 at d
1.88±1.96 and H-5 and H-6 at d 1.76±1.83. Protons H-2 and
H-3 correlate with H-1 at d 4.60±4.70 and H-4 at d 3.00±
3.06. The 13C chemical shifts of compound 8 are assigned by
DEPT and HETCOR experiments. Multiplicity was estab-
lished by DEPT experiment. DEPT shows eight protonated
Our second approach for the cyclization of substrate 1 was
to try the palladium mediated reaction. Therefore, substrate
1 was re¯uxed with bis-benzonitrile palladium'II) chloride
in benzene in the presence of sodium methoxide for 3 h and
a linearly cyclized new product 1,3-dimethyl-6,7,8,9-tetra-
Scheme 3. Reagents: 'i) PdCl2'PhCN)2, C6H6, heat '82%);'ii) Pd/C, Ph 2O,
heat '40%).

K. C. Majumdar et al. / Tetrahedron 57 &2001) 7003±7007
7005
Scheme 4. Reagents: 'i) Conc. H2SO4, 2 h '94%).
carbons, two ±CH3, two sCH± and four ±CH2±. Protonated
carbon resonances are established by direct correlation with
proton resonances by HETCOR experiment 'normal one
bond C±H coupling). Methyl proton resonance at d 3.32
is related with protonated carbon resonance at d 28.49 and
another methyl proton at d 3.34 is related with protonated
carbon resonance at d 30.03. Methine proton resonance at d
3.00±3.06 'H-4) is related with carbon resonance at d 27.72
'C-8a) and d 4.60±4.70 'H-1) is related with carbon reso-
nance at d 70.02 'C-5a). Methylene protons resonance at d
1.38±1.47 'H-7) is related with carbon resonance at d 17.71
'C-7), d 1.48±1.55 'H-10) is related with carbon resonance
at d 32.34 'C-6), d 1.58±1.63 'H-8) is related with carbon
resonance at d 17.71 'C-7), d 1.76±1.83 'H-5 and H-6) are
related with carbon resonance at d 29.26 'C-8), d 1.88±1.96
'H-2 and H-3) are related with carbon resonance at d 29.27
'C-9), d 2.08±2.20 'H-9) is related with carbon resonance at
d 32.34 'C-6). Its resistance to dehydrogenation has also
indicated its bicyclic nature.
cooled, ®ltered and the solvent was removed. The residue
was extracted with chloroform '3£20 mL), the organic layer
was separated, washed with water '2£20 mL), dried
'Na2SO4) and the solvent evaporated. Puri®cation of crude
product by column chromatography 'benzene±ethyl
acetate, 5:1) over silica gel gave the title compound 1
'2.12 g, 90%) as a white solid, mp 1768C;[Found: C
61.25, H 6.99, N 11.58. C12H16N203 requires C 61.02, H
6.78, N 11.86%]; nmax'KBr) 3300, 2960, 1700, 1620,
1300, 1100, 720 cm21; lmax 'log e) 212 '3.03), 290
'3.04) nm; dH '500 MHz, CDCl3) 1.60±1.70 '2H,
m),1.78±1.88 '2H, m), 1.95±2.05 '2H, m), 3.32 '3H, s),
3.38 '3H, s), 3.90±4.00 '1H, m), 5.48±5.55 '2H, m),
5.74±5.82 '1H, m); m/z 236 'M1).
1.1.2. 6-Bromo-1,3-dimethylhexahydrobenzofuro[3,2-
d]pyrimidine-2,4-dione ꢀ2). Pyridine hydrotribromide
'0.45 g, 1.5 mmol) was added to a stirred solution of
compound
1 '0.35 g, 1.5 mmol) in dichloromethane
'25 mL) at 0±58C. Stirring was continued for 30 min. It
was then extracted with water and dried 'Na2SO4). The
solvent was removed and the crude mass was puri®ed by
column chromatography over silica gel. Elution of the
column with benzene±ethyl acetate '3:1) furnished the
title compound 2 '0.42 g, 90%) as white solid, mp 1468C;
[Found C 45.91, H 4.99, N 8.59. C12H15BrN2O3 requires C
45.71, H 4.76, N 8.89%]; nmax'KBr) 3040, 1680, 1640,
1480, 1100, 750 cm21; lmax 'log e) 213 '3.17), 296
'3.03) nm; dH '500 MHz, CDCl3) 1.30 '8 lines, H-7,
Jˆ4.23, 13.6 Hz), 1.65 'dt, H-6, Jˆ3.7, 13.7 Hz), 1.8±1.9
'm, H-5), 2.08 'dt, H-4, Jˆ3.4, 15.12 Hz), 2.1±2.18 '2H, m,
H-3 and H-8), 3.30±3.38 'm, H-9) 3.40 '3H, s), 3.42 '3H, s),
4.70±4.80 '2H, m, H-1 and H-2); dC '67.8 MHz, CDCl3)
17.71 'C-8), 28.49 'C-9), 29.26 'N±CH3), 30.03 'C-7),
33.88 'N±CH3), 39.27 'C-9a), 47.74 'C-6), 83.93 'C-5a),
132.34 'C-9b), 143.12 'C-4a), 152.36 'C-4), 156.98 'C-2);
m/z 314, 316 'M1).
In conclusion, 6-'cyclohex-2-enyl)-1,3-dimethyl-5-hydroxy-
uracil '1) has been successfully and regioselectively
cyclized under simple and mild reaction conditions to give
different pyrimidine-annelated heterocycles in excellent
yields. The cyclization with elemental bromine is note-
worthy. These heterocylic derivatives have the potential to
be useful as drugs.
1. Experimental
1.1. General
Melting points are uncorrected. UV absorption spectra were
recorded in EtOH. IR spectra were run on KBr discs. H
1
NMR spectra were determined for solution in CDCl3 with
TMS as an internal standard on Jeol FX-100 spectrometer at
IICB, Calcutta and DRX-500 '500 MHz) at Nottingham,
England. Elemental analysis and recording of mass
spectra were carried out at RSIC 'CDRI), Lucknow. Silica
gel '60±120 mesh) was used for chromatographic separa-
tion. Petroleum ether refers to the fraction boiling between
60 and 808C.
Similarly hexamethylenetetramine hydrotribromide '0.57 g,
1.5 mmol) was added to a solution of compound 1 '0.35 g,
1.5 mmol) in CH2Cl2 at 0±58C and stirring was continued
for 15 min. It was extracted with water and worked up as
above. Yield 0.43 g, 92%, mp 1468C.
Similarly bromine '0.25 g, 1.5 mmol) in 20 mL chloroform
was added slowly to a stirred solution of compound 1
'0.35 g, 1.5 mmol) in 5 mL chloroform at 0±58C. Stirring
was continued for 6 h. It was then extracted with water and
worked up as above. Yield 0.38 g, 80%, mp 1468C.
1.1.1. 6-ꢀCyclohex-2-enyl)-5-hydroxy-1,3-dimethyluracil
ꢀ1). A mixture of 1,3-dimethyl-5-hydroxyuracil '1.56 g,
10.0 mmol), 3-bromocyclohexene '1.6 g, 10.0 mmol) and
anhydrous potassium carbonate '3 g) in dry acetone
'100 mL) was re¯uxed for 8 h. The reaction mixture was

7006
K. C. Majumdar et al. / Tetrahedron 57 &2001) 7003±7007
1.1.3. 1,3-Dimethyl-7,8,9,9a-tetrahydrobenzofuro[3,2-
d]pyrimidine-2,4-dione ꢀ5). A mixture of compound 2
'0.315 g, 1.0 mmol) and potassium hydroxide '0.056 g,
1.0 mmol) in recti®ed spirit '5 mL) was stirred for 5 min.
Solvent was removed and the residue was extracted with
chloroform. The chloroform extract was washed repeatedly
with water and dried 'Na2SO4). Removal of solvent gave the
title compound 5, which was recrystallised from chloro-
form±petroleum ether '60±808C), '0.26 g, 85%) as a
white solid, mp 1388C;[Found: C 61.34, H 6.25;N 11.77.
C12H14N2O3 requires C 61.54, H 5.98, N 11.97%];
'2£50 mL), washed with water and dried with sodium
sulphate. The solvent was removed and the residual mass
was chromatographed over a silica gel column. Elution of
the column with benzene±ethyl acetate '3:1) gave the title
compound 8 '0.22 g, 94%) as a white solid, mp 908C;
[Found;C 61.18, H 6.88, N 11.56. C 12H16N2O3 requires C
61.02, H 6.78, N 11.86%]; nmax'KBr) 2960, 1680, 1640,
1100, 750 cm21; lmax 'log e) 211 '3.24), 292 '3.20) nm;
dH '500 MHz, CDCl3) 1.38±1.47 '1H, m, H-7), 1.48±1.55
'1H, m, H-10), 1.58±1.63 '1H, m, H-8), 1.76±1.83 '2H, m,
H-5 and H-6), 1.88±1.96 '2H, m, H-2 and H-3), 2.08±2.20
'1H, m, H-9), 3.00±3.06 '1H, m, H-4), 3.32 '3H, s), 3.34
'3H, s), 4.60 '1H, brs, H-1); dC '67.8 MHz, CDCl3) 17.71
'C-7), 27.72 'C-8a), 28.49 'N±CH3), 29.26 'C-8), 29.27
'C-9), 30.03 'N±CH3), 32.34 'C-6), 70.02 'C-5a), 130.80
'C-8b), 131.57 'C-4a), 150.77 'C-4), 158.47 'C-2); m/z 236
'M1).
n
max'KBr) 2960, 1680, 1650, 1100, 750 cm21; lmax
'log e) 213 '3.06), 307 '2.84) nm; dH '500 MHz, CDCl3)
1.12±1.20 '2H, m H-8), 1.80±1.84 '1H, m H-9), 2.01±
2.08 '2H, m H-9 and H-7), 2.21±2.50 '1H, m H-7), 2.36±
2.40 '1H, m H-9a), 3.35 '3H, s), 3.60 '3H, s), 4.56 '1H, brs
H-6); m/z 234 'M1).
1.1.8. Attempted dehydrogenation of compound 8.
Compound 8 '0.236 g, 1 mmol) was re¯uxed with DDQ
'0.2 g) in dry xylene '5 mL) for 2 h. No change was
observed as evidenced from TLC of the reaction mixture.
Co-TLC with the starting material 8, superimposable IR
spectra and mmp also indicated the recovery of the starting
material.
1.1.4. 1,3-Dimethylbenzofuro[3,2-d]pyrimidine-2,4-dione
ꢀ6). Compound 5 '0.06 g, 0.25 mmol) was re¯uxed with
10% palladium on charcoal '0.02 g) in diphenyl ether
'2 mL) for 30 min. The mixture was chromatographed
over silica gel. The column was eluted with petroleum
ether '60±808C) to remove diphenyl ether and the title
compound 7 was obtained as a yellow solid by using
benzene±ethyl acetate '3:1) as eluant '0.02 g, 40%), mp
2648C;[Found: C 62.81, H 4.45, N 12.07. C 12H10N2O3
requires C 62.61, H 4.35, N 12.17%]; nmax'KBr) 3040,
1680, 1640, 1460, 1200, 750 cm21; lmax 'log e) 243
'3.26), 295 '2.81), 346 '2.72) nm; dH '100 MHz, CDCl3)
3.52 '3H, s), 4.04 '3H, s), 7.08±7.40 '3H, m), 8.46 '1H,
brs); m/z 230 'M1).
Similarly compound 8 '0.118 g, 0.05 mmol) was re¯uxed
with 10% palladium on charcoal '0.02 g) in diphenyl ether
'4 mL) for 2 h. No change was observed as evidenced from
the TLC of the reaction mixture, co-TLC with the starting
material 8 and also from superimposable IR spectra.
1.1.5.
1,3-Dimethyl-6,7,8,9-tetrahydrobenzofuro-[3,2-
Acknowledgements
d]pyrimidine-2,4-dione ꢀ7). Into the suspension of sodium
salt prepared from compound 1 '0.118 g, 0.5 mmol) and
sodium methoxide '0.027 g, 0.5 mmol) in benzene '5 mL)
was added PdCl2'PhCN)2 '0.019 g, 0.5 mmol) at rt. After
re¯uxing the solution for 3 h, the resulted palladium black
was ®ltered off and ®ltrate was concentrated and the mixture
was puri®ed by column chromatography over silica gel.
Elution of the column with benzene±ethyl acetate '3:1)
gave the title compound 7 '0.10 g, 82%) as white solid,
mp 1408C;[Found: C 61.75, H 6.23, N 11.74. C 12H14N2O3
requires C 61.54, H 5.98, N 11.97%]; nmax'KBr) 3040,
1680, 1640, 1478, 1100, 750 cm21; lmax 'log e) 224 '2.8),
284 '2.9) nm; dH '100 MHz, CDCl3)) 1.76±1.96 '4H, m),
2.56±2.92 '4H, m), 3.22 '3H, s), 3.60 '3H, s); m/z 234 'M1).
We thank the CSIR 'New Delhi) for the ®nancial assistance.
We also thank Dr S. K. Chattopadhyay for providing us
500 MHz PMR, COSY, 13C NMR, DEPT, and HETCOR
spectra of compounds 2 and 8 reported in this paper. One
of us 'U. D.) is grateful to UGC 'New Delhi) for a Junior
Research Fellowship.
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