Studies on pyrimidines: Synthesis of pyrimidine-annelated heterocycles from 5-amino-6-cyclohex-2-enyl-1,3-dimethyl-uracil

Article abstract of DOI:10.1007/s007060170100

Treatment of 5-amino-6-cyclohex-2-enyl-1,3-dimethyl-uracil with pyridinium hydrotribromide or hexamethylenetetrammonium hydrotribromide furnished the corresponding linear heterocyclic 6-bromo-1,3-dimethylhexahydroindolo[3,2-d]pyrimidine-2,4-diones in 90%

Full text of DOI:10.1007/s007060170100

Monatshefte fuÈr Chemie 132, 633±638 (2001)
Studies on Pyrimidines: Synthesis of
Pyrimidine-Annelated Heterocycles from
5-Amino-6-cyclohex-2-enyl-1,3-dimethyl-uracil
Ã
Krishna C. Majumdar and Nirmal K. Jana
Department of Chemistry, University of Kalyani, Kalyani-741235, India
Summary. Treatment of 5-amino-6-cyclohex-2-enyl-1,3-dimethyl-uracil with pyridinium hydrotri-
bromide or hexamethylenetetrammonium hydrotribromide furnished the corresponding linear
heterocyclic 6-bromo-1,3-dimethylhexahydroindolo[3,2-d]pyrimidine-2,4-diones in 90% yield. Reac-
tion of the same educt with molecular bromine in chloroform afforded the bicyclic 9-bromo-1,3-
dimethylhexahydrobicyclo[3.3.1]indolo[3,2-d]pyrimidine-2,4-diones in 85% yield. Upon treatment
of the above substrate with cold concentrated sulfuric acid, a mixture of 1,3-dimethylhexahydro-
indolo[3,2-d]pyrimidine-2,4-dione (28%) and 1,3-dimethylhexahydrobicyclo[3.3.1]indolo[3,2-d]pyr-
imidine-2,4-dione (60%) was obtained.
Keywords. Amino-Claisen rearrangement; Cyclization; Cyclohexene; Heterocycles; Pyridine
hydrotribromide.
Introduction
Recently there has been considerable activity in the synthesis of pyrimidine
derivatives due to their biological activity and medicinal utility [1]. We have
reported the synthesis of a number of pyrimidine-annelated heterocycles fused at
positions 5 and 6 of uracil [2]. In continuation of this work, we tackled the problem
of the regioselective synthesis of a number of hitherto unreported pyrimidine-
annelated heterocycles from 5-amino-6-cyclohex-2-enyl-1,3-dimethyluracil (4). The
results of this investigation is reported here.
Results and Discussion
The starting material for this study, 4, was obtained in 38% yield by the amino-
Claisen rearrangement of 5-(N-(cyclohex-2-enyl)-N-methyl)-1,3-dimethyluracil (3)
in re¯uxing EtOH/HCl for 10 h. In turn, 3 was prepared in 80% yield by the reaction
of 1,3-dimethyl-5-N-methylamino-uracil (1) with 3-bromocyclohexene (2) in
re¯uxing acetone in the presence of anhydrous potassium carbonate (Scheme 1).
The structures of 3 and 4 were assigned from their elemental analyses and
spectroscopic data. Thus, the IR spectrum of 3 showed the absence of an N±H
Ã
Corresponding author

634
K. C. Majumdar and N. K. Jana
Scheme 1
absorption band; its 1H NMR spectrum consisted of three N±CH3 singlets and a two
multiplets of ethylenic protons, together with the singlet of the C6±H of the uracil
moiety. The IR spectrum of 4 exhibited an N±H absorption band, and its 1H NMR
spectrum exhibited two N±CH3 singlets, two ethylenic multiplets and one multiplet
accounting for eight aliphatic protons. The molecular ion peak in the mass spectrum
‡
of 4 appeared at m/z ˆ 235 (M ).
Two approaches were considered for the cyclization of 4. The ®rst one involved
brominating agents like pyridinium hydrotribromide [3] ꢀPyHBr3†, hexa-methyle-
netetrammonium hydrotribromide [4] ꢀC6H12N4HBr3†, and bromine. When 4 was
treated with PyHBr3 in dichloromethane at 0±5ꢁC for 30 minutes, the novel linearly
fused bromocompound 6 was obtained in 90% yield. The same product in the same
yield resulted also from the reaction of C6H12N4HBr3 in dichloromethane at 0±5ꢁC
for 15 minutes. However, treatment of 4 with bromine in chloroform at 0±5ꢁC for
6 h afforded the novel bicyclic bromocompound 7 in 85% yield.
The formation of the cyclic products 6 and 7 from 4 may be easily explained via
an intermediate cyclic bromonium ion (5). This may be opened by the nucleophilic
attack of NH2 group to give products 6 and 7 instead of the dibromide. Compound 6
was dehydrogenated with 10% palladized charcoal in re¯uxing diphenyl ether for
30 minutes to give 8 in 91% yield. When compound 7 was treated similarly, only
unchanged starting material was recovered (Scheme 2).
The structures of compounds 6, 7, and 8 were established from their elemental
analyses and spectroscopic data. The IR spectra of all compounds showed broad
1
1
N±H absorption bands at 3320 cm , their H NMR spectra were in accordance
with the proposed structures. The mass spectra of both 6 and 7 gave the same
‡
molecular ion peak at m/z ˆ 315, 313 ꢀM †; the molecular ion peak of 8 was
‡
observed at m/z 229 ꢀM †.
The second approach proceeded via an acid catalyzed cyclization [5] of 4. Thus,
4 was treated with concentrated sulfuric acid at 0±5ꢁC for 2 h to furnish 10 and 11.
Re¯uxing compound 10 in diphenyl ether with 10% palladized charcoal gave 8 as
veri®ed by TLC and mixed melting point determinations with an authentic sample.
When 11 was treated similarly, only unchanged starting material was recovered
(Scheme 3).

Synthesis of Pyrimidine-Annelated Heterocycles
635
Scheme 2
Scheme 3

636
K. C. Majumdar and N. K. Jana
Compounds 10 and 11 were characterized by their elemental analyses and
1
spectroscopic data. The H NMR spectrum of 10 showed a multiplet for eight
cyclohehexenyl protons and two ring juncture protons. The 1H NMR spectrum of 11
exhibited similar but shifted peaks. The mass spectra of 10 and 11 gave the same
‡
molecular ion peak at m/z ˆ 235 ꢀM †.
In conclusion, 4 was regioselectively cyclized under simple and mild reaction
conditions to give different pyrimidine-annelated heterocycles in excellent yields,
the cyclization with molecular bromine being especially noteworthy.
Experimental
Melting points are uncorrected. UV/Vis spectra were recorded on a Hitachi 200-20 spectrophotometer
1
(absolute ethanol). IR spectra were run as KBr discs on a Perkin-Elmer 1330 apparatus. H NMR
spectra were recorded in CDCl3 with TMS as internal standard on a 300 MHz spectrometer (Bruker).
Elemental analyses (data in accordance with the calculated values) and mass spectra were obtained
from RSIC (CDRI), Lucknow. Silica gel (60±120) was purchased from Spectrochem. Extracts were
dried over anhydrous Na2SO4.
5-(N-(Cyclohex-2-enyl)-N-methyl)-1,3-dimethylamino-uracil (3; C13H19N3O2†
A mixture of 16.9 g 1 (0.1 mol), 16.1 g 2 (0.1 mol), and 3 g anhydrous K2CO3 was re¯uxed in
200 cm3 dry acetone on a water bath for 10 h. The reaction mixture was then cooled and ®ltered. The
solvent was removed, and the residue was extracted with 3 Â 50 cm3 CHCl3, washed with H2O, and
dried over Na2SO4. Removal of the solvent gave a crude mass which was chromatographed over
silica eluting with ethyl acetate-benzene (1:3) to give 3.
Yield: 80%; viscous liquid; 1H NMR ꢀCDCl3; ꢀ; 300 MHz†: 6.59 (s, 1H), 5.61±5.87 (m, 2H), 4.23
(m, 1H), 3.38 (s, 3H), 3.36 (s, 3H), 2.55 (s, 3H), 1.53±2.03 (m, 6H) ppm; IR (neat): ꢁ ˆ 2950, 1680,
‡
1630, 1450 cm 1; UV/Vis (EtOH): ꢂmaxꢀ"† ˆ 217 (10657), 309 (4058) nm; MS: m=z ˆ 249 ꢀM †.
5-Amino-6-(cyclohex-2-enyl)-1,3-dimethyluracil (4; C12H17N3O2)
A mixture of 10 g 3 (0.04 mol), 60 cm3 EtOH, and 3 cm3 concentrated HCl was re¯uxed on a water
bath for 10 h. The reaction mixture was evaporated to dryness, cooled, neutralized with NaHCO3
solution, and extracted with ether. The organic layer was washed with H2O and dried over Na2SO4.
Ether was distilled off, and the product was obtained by column chromatography over silica (ethyl
acetate:benzene ˆ 1:9).
1
Yield: 38%; m.p.: 170±172ꢁC; H NMR ꢀCDCl3, ꢀ, 300 MHz†: 5.59±5.89 (m, 2H), 4.07±4.10
(m, 1H), 3.42 (s, 3H), 3.38 (s, 3H), 1.65±2.10 (m, 8H) ppm; IR (KBr): ꢁ ˆ 3280, 2900, 1680,
‡
1605 cm 1; UV/Vis (EtOH): ꢂmaxꢀ"† ˆ 213 (4958), 289 (5663) nm; MS: m=z ˆ 235 ꢀM †.
Cyclization of 4 with brominating agents
Solid pyridinum hydrotribromide (0.9 g, 3 mmol) was added slowly to 20 cm3 of a well-stirred
solution of 0.705 g (3 mmol) 4 in CH2Cl2 at 0±5ꢁC, and stirring was continued for 30 min. The
reaction mixture was washed with H2O and dried over Na2SO4. After removal of the solvent, the
residue was subjected to column chromatography over silica (ethyl acetate:benzene ˆ 1:1). When 4
was treated similarly with hexamethylenetetrammonium hydrotribromide in a CH2Cl2 solution at
0±5ꢁC for 15 minutes, also 6 was formed. When, however, 3 cm3 Br2 in 30 cm3 CHCl3 were added to
0.705 g 4 (3 mmol) in 30 cm3 CHCl3 at 0±5ꢁC, 7 was obtained. Stirring was continued for 6 h, and

Synthesis of Pyrimidine-Annelated Heterocycles
637
after usual workup the residue was subjected to column chromatography (silica, ethyl acetate:
benzene ˆ 1:3). The product was recrystallised from ethanol.
6-Bromo-1,3-dimethylhexahydroindolo[3,2-d]pyrimidine-2,4-dione (6; C12H16BrN3O2;
mixture of diastereomers)
Yield: 90%; gummy mass; 1H NMR ꢀCDCl3; ꢀ; 300 MHz†: 4.86 (m, 1H), 3.59 (s, 3H), 3.41 (s, 3H),
2.79±2.89 (m, 1H), 2.63±2.73 (m, 1H), 2.09±2.10 (m, 1H), 1.39±2.06 (m, 6H) ppm; IR (neat):
ꢁ ˆ 2940, 1700, 1650, 1440 cm 1; UV/Vis (EtOH): ꢂmaxꢀ"† ˆ 218 (2215), 300 (1874) nm; MS:
‡
m=z ˆ 315, 313 (M ).
9-Bromo-1,3-dimethylhexahydrobicyclo[3.3.1]indolo[3,2-d]pyrimidine-2,4-dione
(7; C12H16BrN3O2; mixture of diastereomers)
1
Yield: 85%; m.p.: 150ꢁC; H NMR ꢀCDCl3; ꢀ; 300 MHz†: 4.71±4.75 (m, 2H), 3.38 (s, 3H), 3.36
(s, 3H), 3.28±3.32 (m, 1H), 2.06±2.15 (m, 3H), 1.68±1.83 (m, 1H), 1.55±1.67 (m, 2H), 1.21±1.32
(m, 1H) ppm; IR (KBr): ꢁ ˆ 2940, 1700, 1650, 1440 cm 1; UV/Vis (EtOH): ꢂmaxꢀ"† ˆ 218 (2235),
‡
300 (1954) nm; MS: m=z ˆ 315, 313 ꢀM †.
Attempted dehydrogenation of 6 and 7
Compound 6 (0.314 g, 1 mmol) was re¯uxed with 0.1 g 10% Pd/C in 2 cm3 diphenyl ether for 30 min.
It was then subjected to column chromatography over silica. Diphenyl ether was eluted with petrol
ether, and 8 was obtained when the column was eluted with ethyl acetate: benzene ˆ 1:9. The product
was recrystallized from EtOH. Similarly, 7 was re¯uxed with 10% Pd/C in diphenyl ether for 1 h.
However, only unchanged starting material was recovered in this case.
1,3-Dimethyl-indolo[3,2-d]pyrimidine-2,4-dione (8; C12H11N3O2)
1
Yield: 91%; m.p.: 225ꢁC; H NMR ꢀCDCl3; ꢀ; 300 MHz†: 7.94±7.96 (m, 1H), 7.60±7.68 (m, 2H),
1
7.39±7.44 (m, 1H), 3.92 (s, 3H), 3.51 (s, 3H) ppm; IR (KBr): ꢁ ˆ 2940, 1700, 1640, 1440 cm
;
‡
UV/Vis (EtOH): ꢂmaxꢀ"† ˆ 220 (19007), 294 (12252) nm; MS: m=z ˆ 229 ꢀM †:
Cyclization of 4 in concentrated sulfuric acid
Compound 4 (0.705, 3 mmol) was added to 4 cm3 of well-stirred concentrated sulfuric acid at 0±5ꢁC,
and stirring was continued for 2 h at this temperature. The reaction mixture was poured onto crushed
ice and extracted with 3 Â 20 cm3 CHCl3. The CHCl3 extract was washed with 2 Â 25 cm3 5%
NaHCO3 solution, 2 Â 25 cm3 H2O, and dried over Na2SO4. Removal of the solvent gave a crude
mass which was subjected to column chromatography over silica. 10 and 11 were obtained as white
solids using ethyl acetate:benzene ˆ 1:3 as the eluent.
1,3-Dimethylhexahydroindolo[3,2-d]pyrimidine-2,4-dione (10; C12H17N3O2;
mixture of diastereomers)
1
Yield: 28%; m.p.: 124ꢁC; H NMR ꢀCDCl3; ꢀ; 500 MHz†: 4.57±4.56 (m, 1H), 3.41 (s, 3H), 3.38
(s, 3H), 2.98±3.00 (m, 1H), 2.35±2.38 (m, 1H), 1.55±2.05 (m, 6H), 1.24±1.32 (m, 2H) ppm; IR (KBr):
ꢁ ˆ 2940, 1700, 1650, 1440 cm 1; UV/Vis (EtOH): ꢂmaxꢀ"† ˆ 217 (5617), 300 (5006) nm; MS:
‡
m=z ˆ 235 ꢀM †.

638
K. C. Majumdar and N. K. Jana: Synthesis of Pyrimidine-Annelated Heterocycles
1,3-Dimethylhexahydrobicyclo[3.3.1]indolo[3,2-d]pyrimidine-2,4-dione (11; C12H17N3O2;
mixture of diastereomers)
Yield: 60%; m.p.: 84ꢁC; 1H NMR ꢀCDCl3; ꢀ; 500 MHz†: 4.60 (s, 1H), 3.40 (s, 3H), 3.36 (s, 3H), 3.06
(s, 1H), 2.17±2.20 (m, 1H), 1.82±1.96 (m, 4H), 1.48±1.68 (m, 4H) ppm; IR (KBr): ꢁ ˆ 2940, 1690,
‡
1630, 1430 cm 1; UV/Vis (EtOH): ꢂmaxꢀ"† ˆ 216 (9235), 293 (8201) nm; MS: m=z ˆ 235 ꢀM †.
Attempted dehydrogenation of 10 and 11
Compound 10 (0.05 g, 0.2 mmol) was re¯uxed with 0.01 g Pd/C (10%) in 2 cm3 diphenyl ether for 2 h.
The formation of 8 was monitored by TLC and con®rmed by a mixed melting point with an authentic
sample. Compound 11 was treated similarly, but no change was observed and the starting material
was recovered.
Acknowledgements
We are grateful to CSIR (New Delhi) for ®nancial assistance. N. K. Jana is grateful to CSIR (New
Delhi) for a fellowship.
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Received August 4, 2000. Accepted (revised) November 15, 2000