A practical approach for spiro- and 5-monoalkylated barbituric acids

Article abstract of DOI:10.1002/jhet.5570430313

The single step reactions of N,N′- substituted/-unsubstituted barbituric acids with various alkyl dihalides under phase transfer catalytic conditions using DMF-K₂CO₃ (base), TBAHSO₄ (catalyst) provide spirobarbituric acids

Full text of DOI:10.1002/jhet.5570430313

May-Jun 2006
607
A Practical Approach for Spiro- and
-Monoalkylated Barbituric Acids
5
Palwinder Singh and Kamaldeep Paul
Department of Chemistry, Guru Nanak Dev University,
Amritsar 143005, India.
e-mail: palwinder_singh_2000@yahoo.com
Received August 20, 2005
O
( )
n
R
O
Br
N
O
( )
n
O
n = 1
Nu
R
O
Br
R
O
Nu
N
R
O
N
N
n = 1,3,4
N
R
O
N
R
O
O
Br
R= H, CH
3
R
O
N
Br
N
R
O
The single step reactions of N,N'- substituted/-unsubstituted barbituric acids with various alkyl dihalides
under phase transfer catalytic conditions using DMF–K CO (base), TBAHSO4 (catalyst) provide
2
3
spirobarbituric acids in moderate to high yields. Irrespective of the existence of C -monoalkylated
5
compounds in the enolic form (confirmed by the isolation of some of its analogues), the second alkylation
predominantly takes place at C . The underlying mechanism for the reaction is discussed. The 5,7-
5
dimethyl-5,7-diaza-spiro[2.5]octane-4,6,8-trione undergoes ring opening with NaCN, PhSH, HS(CH ) OH
2
2
and Br to provide 5-monoalkylated barbiturates which are otherwise difficult to prepare by the usual
2
alkylation of barbituric acids.
J. Heterocyclic Chem., 43, 607 (2006).
Barbituric acid owes its significance due to similar type
of H-bonding as thymine in the biological systems and its
presence in many pharmaceutically important molecules
We report herein the synthesis of spiro[2.5], spiro[4.5],
spiro[5.5]barbituric acids in a single step by the reaction
of N,N'-unsubstituted/-substituted barbituric acids with
respective dihalo-alkanes/ arenes under phase transfer
catalytic conditions. The reaction mechanism for dialkyl-
[
1]. The spirobarbiturates, exhibiting the characteristic
feature of conformation locking [2] (common in spiro
compounds), are biologically important molecules used as
anticonvulsant [3], narcotic and analgesic agents [4], as
dihydroorotate dehydrogenase inhibitors [5] and in the
construction of modified oligonucleotides [6].
ation at C has been explained on the basis of tautomeric
5
forms of first alkylated intermediate. Further, C5-
monoalkylated barbituric acids are synthesized by the ring
opening of spiro[2.5]barbituric acid with NaCN, PhSH,
HS(CH ) OH and Br .
2
2
2
The widespread applications of barbituric acid based
spiro compounds in biology and their use as synthons for
Barbituric acid
1 (R=H) on reaction with 1.2
equivalents of dibromoethane in DMF using K CO as
2
3
C -monosubstituted barbituric acids prompted us to
5
base (2 equiv) and TBAHSO4 (Tetrabutylammonium
hydrogen sulphate) as catalyst (0.01 equiv) gave a solid
compound (63%, 50% of the consumed barbituric acid)
while 20% barbituric acid was recovered unchanged. The
develop a simple synthetic methodology for spirocyclo-
alkylbarbituric acids. A few reports for the synthesis of
spirocycloalkylbarbituric acids are available which
involve the condensation of 1,1-cycloalkanedicarboxylate
diester and urea in the presence of a base [3,5,7].
However, these reactions mainly suffer from low yields,
especially in the case of spirocyclopropanobarbiturate
+
solid compound [M +1 m/z 155, m.p. 320° (dec), lit. [7]
m.p. 320-25°] has been assigned structure 2. Earlier this
compound [7] has been synthesized only in 10% yield
where
1,1-cyclopropanedicarboxylic
diester
was
(
10%). The available routes for procuring 5-mono-
condensed with urea in the presence of a base. In these
reported reactions base promoted cyclopropane ring
opening before condensation with urea might be the cause
of low yield for spiro compound. Similarly, 1 (R=H) on
reaction with 1,4-dibromobutane and 1,5-dibromopentane
alkylated barbituric acids are by the reaction of monoalkyl
malonic esters with urea [8], reaction of barbituric acid
with aldehydes [9,10] /ꢀ,ꢁ-unsaturated ketones [11] or by
using 5-acylbarbituric acids as synthons [12].

6
08
P. Singh and K. Paul
Vol 43
gave compounds 3 (55%, lit. [7] 53%) and 4 (55%, lit.[4]
Scheme II
3
3 %) respectively (scheme-1).
Under similar reaction conditions N,N'-dimethylbar-
O
R
O
bituric acid (1, R=CH ) on reaction with 1.2 equivalents
3
N
Br
of dibromoethane gave a white solid (87%, 70% of
consumed barbituric acid), m.p. 265-67° and 20% starting
+
N
R
O
Br
1
barbituric acid is recovered unchanged. In H NMR
DMF-K
0-80 (4 hrs)
2
CO
3
, TBAHSO
4
,
(1)
spectrum, it shows a 4H singlet at ꢀ 2.23 and a 6H singlet
o
7
1
3
at ꢀ 3.22. In C/DEPT-135 NMR spectrum, it shows a –
ve signal at ꢀ 27.86 (CH ), a +ve signal at ꢀ 28.96 (CH ),
2
3
O
O
and quaternary carbon signals at ꢀ 48.76, 150.8 and
R
N
R
O
1
13
N
1
71.71 due to C , C and C /C respectively. H and
C
5
2
4
6
O
N
R
O
NMR spectra corroborate a symmetrical structure 5 for
this compound (scheme 1).
N
R
O
8
9
; R=H
; R=CH
10; R=CH3
Scheme I
3
and a 2H triplet at ꢀ 4.35. The downfield triplet at ꢀ 4.35
O
O
seems to be due to a methylene group linked to oxygen. In
R
R
O
Br
n
DMF-K
2
CO
3
-
N
( )
O
n
1
3
N
Br
(
)
C NMR spectrum, the C-5 quaternary carbon has been
shifted downfield in comparison to C-5 of compound 5.
+
2
: R = H, n = 1
TBAHSO
4
,
O
N
N
R
O
n = 1,3,4 70-80 (4 hrs)
o
3: R = H, n = 3
4: R = H, n = 4
5
6
7
1
3
R
From this spectral data along with C/DEPT-135 NMR
: R = CH
3
, n = 1
, n = 3
, n = 4
(
2-7)
(1)
spectra, the structure 11 has been assigned to this
: R = CH
3
: R = CH
3
compound and the expected compound 12 (R=CH ) was
3
not formed (Scheme III). The non-formation of compound
12 may be attributed to the preferred formation of six
membered ring in compound 11 over the four membered
ring in 12.
1
(R=CH ) on reaction with 1,4-dibromobutane and
3
1
,5-dibromopentane gave spiro[4.5] and spiro[5.5]-
barbituric acids 6 and 7. Therefore, the dialkylation with
alkyl dihalides at C-5 of barbituric acids provided a
straightforward method for synthesizing spirocycloalkyl-
barbituric acids in higher yields than the reported ones.
Keeping in mind the role of ꢀ-ꢀ interactions in the
various enzyme-inhibitor complexes, the above synthetic
methodology was extended to the reactions of barbituric
acids 1 with 1,2-bis[bromomethyl]benzene. 1 (R=H) on
reaction with 1,2-bis[bromomethyl]benzene in DMF
using K CO as base and TBAHSO as catalyst provided
compound 8 (60%, M +1 m/z 231). The reaction of 1
R=CH ) with 1,2-bis[bromomethyl]benzene gave two
compounds. The first one, 60%, M +1 m/z 259 in H
NMR spectrum shows a 6H singlet at ꢁ 3.33, a 4H singlet
at ꢁ 3.61 and 4H multiplet at ꢁ 7.20-7.26 has been
Scheme III
O
O
O
H
3
C
Br
CO
TBAHSO ,
4
0-80 (4 hrs)
3
H C
Br
3
H C
N
N
N
DMF-K
2
3
,
O
N
O
O
N
O
O
N
O
CH
3
o
CH
3
7
CH
3
1
11
12
2
3
4
+
1
As per the literature reports [13,14], the H NMR
(
spectrum of N,N'-dimethylbarbituric acid shows 2H
singlet at ꢁ 3.2 along with a 6H singlet corresponding to
3
+
1
two CH groups. The complete absence of olefinic proton
3
at C-5 in the region ꢁ 4-5 indicates the existence of this
barbituric acid in triketo- form 1 [15]. Due to the presence
of active methylene group at C-5, the first alkylation in
barbituric acids takes place at C-5 and not at NH (in case
of 1, R=H). The result of first alkylation is intermediate
13, which could exist in two tautomeric forms 13a and
13b (scheme V).
+
assigned structure 9. The second compound (20%, M +1
m/z 258) in H NMR spectrum shows two 3H singlets at ꢁ
.35 and 3.39, two 2H singlets at ꢁ 4.07 and 5.49 along
with 4H multiplet at ꢁ 7.33-7.38, has been assigned
structure 10 (scheme II).
1
3
The reactivity behaviour of 1 towards 1,3-dibromo-
propane is quite different where instead of the formation
of spiro compounds, pyranopyrimidines are formed. N,N'-
Dimethylbarbituric acid on reaction with 1,3-dibromo-
propane gave a solid product (60%), m.p. 122° which in
The enolic form of 13 has been confirmed by the
synthesis of its analogue 5-allyl-1,3-dimethylbarbituric
acid 18 (Scheme IV).
1
H NMR spectrum of 18 shows complete absence of
1
13
its H NMR spectrum shows a 2H quintet at ꢀ 1.98, 2H
C -H and its C NMR spectrum shows the presence of C5
5
triplet at ꢀ 2.48, 3H singlet at ꢀ 3.34, 3H singlet at ꢀ 3.35
as quaternary carbon at ꢁ 75.9.

May-Jun 2006
A Practical Approach for Spiro- and 5-Monoalkylated Barbituric Acids
609
Scheme IV
The cyclopropane ring present at C-5 of spirobar-
biturates (2 and 5) is important because of its reactivity
pattern equivalent to carbon-carbon double bond.
Compound 5 when taken in ethanol decolorize bromine
water and on usual work up gave a thick liquid that has
been identified as 19. The reaction of 5 with thiophenol,
O
O
R
N
Br
R
N
NH
2
NH
2
O
N
R
O
N
R
1
5; a, R = CH
b, R = CH
3
16; CH
17; CH
3
2
NaCN and 2-mercaptoethanol in ethanol gave C5-
Ph
Ph
monoalkylated products 20 (55%), 21 (52%) and 22
2
(
55%) respectively (Scheme VI).
Hydrolysis
O
O
Scheme VI
R
N
R
O
N
O
N
R
OH
N
R
O
O
O
X
H
3
C
H
3
C
Nu
N
N
18; R = CH
3
O
N
O
O
N
O
CH
3
CH
3
The presence of 13 in the enolic form is in favour of the
possibility of second alkylation to take place at OH
5
19-22
9; X = Br, Nu = Br
0; X = H, Nu = SPh
21; X = H, Nu = CN
2; X = H, Nu = S(CH ) OH
2 2
1
2
instead of C . Moreover, it is controlled by the ease of
5
-
electron transfer from C -O towards C-5 and the
6
2
stabilization of the annulated ring to be formed.
Intermediate 14 (Scheme V) formed by deprotonation
of OH, gets transformed to the product through three
All the new compounds have been characterized by
1
13
various spectral ( H NMR, C NMR and mass) tech-
niques and elemental analysis. The formation of
compounds 20 and 22 paves the way for these
compounds to act as thymidylate synthase inhibitors.
It is concluded that a synthetic methodology (in better
yields relative to literature reports) has been developed for
the spirobarbiturates except the formation of compound
routes: i) reaction of oxide ion at CH -Br via a forming
2
compound 11, ii) concerted cyclisation via c forming
compounds 2-7 and iii) formation of keto form 13b via b.
The stability of 6 membered ring in 11 favours route a
over b and c while in other cases for the formation of
compounds 2-7, either route b followed by cyclization is
adopted or route c is followed (Scheme V).
1
1 where the preferred formation of six membered ring
over four membered ring leads to the formation of
pyranopyrimidine. In spirocyclopropanobar-bituric acid 5
the reactivity of cyclopropane ring helps in the synthesis
of C-5 monoalkylated barbituric acids which otherwise
are not possible because the C-5 alkylation of barbituric
acids is always plagued by dialkylation.
Scheme V
O
O
O
c
R
O
Br
R
O
Br
R
O
Br
a
N
N
n
N
n
Br
n
b
O-
N
R
O
N
R
(
OH
N
R
13a)
14
EXPERIMENTAL
1
; R = H, CH
3
a
c
b
Melting points were determined in open capillaries and are
O
O
O
1
13
uncorrected. H and C NMR spectra in CDCl /DMSO-d were
H
3
6
R
Br
R
O
R
O
(
)n
( )n
O
run on JEOL JNM-AL FT NMR 300 MHz and 75 MHz
spectrometer, respectively using TMS as an internal standard
chemical shifts in ꢀ, ppm). Column chromatography was
performed using silica gel (60-120 mesh) using ethyl acetate-
hexane as eluents. Mass spectra were recorded at Electrospray
Ionization Interface in the +ve mode. C, H, N analysis were
recorded at RSIC, Lucknow.
N
N
N
n
O
N
R
O
N
R
O
N
R
(
(13b)
2-7
11
n = 2
n = 1,3,4
Therefore, the existence of C -monalkylated barbituric
5
General Method for Synthesis of Compounds 2-11.
acids in enolic forms creates a competition between C-/
O-alkylation and reaction going through the participation
of intermediate 14 is predominantly controlled by the
stability of the product.
A mixture of barbituric acid (1.56 g / 1.86 g, 10 mmol),
dibromoalkane (2.22 g, 12 mmol), K CO (2.76 g, 20 mmol) and
2
3
TBAHSO (catalyst, 0.1 mmol) in DMF was stirred at 70-80°
4
for 4 hrs. On completion of reaction (TLC), it was filtered. After

6
10
P. Singh and K. Paul
Vol 43
removing the solvent under reduced pressure, the residue was
purified by column chromatography using ethyl acetate and
hexane as eluents. Recrystallization from ethanol obtained
analytically pure product. The yields are reported with respect to
consumed barbituric acid.
[2.3]Benzo-7,9-diaza-spiro[4.5]decane-6,8,10-trione (8):
This compound was obtained as whitish solid (ethanol); 60%;
-1
1
mp 280°; ir (KBr): CO 1684, 1701 cm ; H nmr (CDCl +
3
13
DMSO-d ): ꢀ 3.73 (s, 4H, 2xCH ), 7.25-7.36 (m, 4H, Ph);
C
6
2
nmr (normal/DEPT-135): ꢀ 44.2 (-ve, CH ), 55.9 (C-5), 124.0
2
5
,7-Diaza-spiro[2.5]octane-4,6,8-trione (2).
(+ve, ArCH), 127.8 (+ve, ArCH), 128 (ArC), 150.9 (C-2), 175.3
+
(
C-4 C-6); ms: m/z 231 (M +1).
,
This compound was obtained as whitish solid (ethanol); 63%,
Anal. Calcd. for C H N O : C, 62.60; H, 4.38; N, 12.17.
-
1
1
12 10
2
3
mp 320° (dec.); ir (KBr): CO 1670, 1693 cm ; H nmr
1
3
Found: C, 62.40; H, 4.62; N, 11.92.
(CDCl +DMSO-d ):
ꢀ
2.26 (s, 4H, 2xCH );
C
nmr
3
6
2
(
1
normal/DEPT-135): ꢀ 28.2 (-ve, CH ), 47.8 (C-5), 151.9 (C-2),
71.7 (C-4,C-6); ms: m/z 155 (M +1).
[2.3]Benzo-7,9-dimethyl-7,9-diaza-spiro[4.5]decane-6,8,10-
trione (9).
2
+
Anal. Calcd. for C H N O : C, 46.76; H, 3.92; N, 18.18.
Found: C, 47.03; H, 4.02; N, 17.92.
6
6
2
3
This compound was obtained as whitish solid (ethanol); 60%;
-1
1
mp 120°; ir (KBr): CO 1678 cm ; H nmr (CDCl ): ꢀ 3.33 (s,
3
1
3
7
,9-Diaza-spiro[4.5]decane-6,8,10-trione (3).
6H, N-CH ), 3.61 (s, 4H, 2xCH ), 7.20-7.26 (m, 4H, Ph);
C
3
2
nmr (normal/DEPT-135): ꢀ 29.0 (+ve, N-CH ), 44.2 (-ve, CH ),
3
2
This compound was obtained as whitish solid (ethanol); 55%;
-1
1
56.1 (C-5), 124.0 (+ve, ArCH), 127.3 (+ve, ArCH), 127.9
mp 259°; ir (KBr): CO 1645, 1660 cm ;
H
nmr
+
(
ArC), 151.4 (C-2), 172 (C-4 C-6); ms: m/z 259 (M +1).
,
(
CDCl +DMSO-d ): ꢀ 1.95 (m, 4H, 2xCH ), 2.24 (t, 4H, 2xCH ,
3
6
2
2
13
Anal. Calcd. for C14H N O : C, 65.11; H, 5.46; N, 10.85.
14 2 3
J=6.6 Hz); C nmr (normal/DEPT-135): ꢀ 28.0 (-ve, CH ), 39.6
2
Found: C, 65.08; H, 5.78; N, 10.83.
(
(
-ve, CH ), 57.0 (C-5), 160 (C-2), 174.1 (C-4, C-6); ms: m/z 183
2
+
M +1).
1
,3-Dimethyl-5,10-dihydro-1H-11-oxa-1,3-diaza-dibenzo[a,b]-
cycloheptene-2,4-dione (10).
2
,4-Diaza-spiro[5.5]undecane-1,3,5-trione (4):
This compound was obtained as whitish solid (ethanol); 20%;
mp 105°; ir (KBr): CO 1681 cm ; H nmr (CDCl ): ꢀ 3.35 (s,
3
This compound was obtained as whitish solid (ethanol); 55%;
-1
1
-
1
1
mp 279°; ir (KBr): CO 1675, 1692 cm ;
H
nmr
3
H, N-CH ), 3.39 (s, 3H, N-CH ), 4.07 (s, 2H, CH ), 5.49 (s, 2H,
3 3 2
(
4
(
CDCl +DMSO-d ): ꢀ 1.56-1.65 (m, 2H, CH ), 1.72-1.83 (m,
3
6
2
13
1
3
O-CH ), 7.33-7.38 (m, 4H, Ph); C nmr (normal/DEPT-135): ꢀ
2
H, 2xCH2), 1.98 (t, 4H, 2xCH2, J=6.4 Hz);
C nmr
2
7.4 (-ve, CH ), 29.0 (+ve, N-CH ), 29.5 (+ve, N-CH ), 72.5 (-
2 3 3
normal/DEPT-135): ꢀ 21.7 (-ve, CH ), 25.0 (-ve, CH ), 33.8 (-
2
2
ve, CH ), 89.7 (C-5), 127.4 (+ve, ArCH), 128.6 (+ve, ArCH),
2
ve, CH ), 52.1 (C-5), 162.4 (C-2), 172.8 (C-4, C-6); ms: m/z 197
2
+
128.7 (+ve, ArCH), 130.3 (ArC), 150.6 (C-2) 158.3 (C-4), 164.5
,
(
M +1).
+
(
C-6); ms: m/z 258 (M +1).
5
,7-Dimethyl-5,7-diaza-spiro[2.5]octane-4,6,8-trione (5):
Anal. Calcd. for C H N O : C, 65.11; H, 5.46; N, 10.85.
1
4
14
2
3
Found: C, 65.38; H, 5.78; N, 11.10.
This compound was obtained as whitish solid (ethanol); 87%;
-
1
1
mp 265-67°; ir (KBr): CO 1666, 1697 cm ; H nmr (CDCl ): ꢀ
3
1,3-Dimethyl-1H,5H-6,7-dihydro-pyrano[2,3-d]pyrimidine-2,4-
dione (11).
1
3
2
(
(
.23 (s, 4H, 2xCH2), 3.22 (s, 6H, N-CH );
C
nmr
3
normal/DEPT-135): ꢀ 27.8 (-ve, CH ), 28.9 (+ve, N-CH ), 48.8
2
3
+
This compound was obtained as whitish solid (ethanol); 60%;
mp 122°; ir (KBr): CO 1610, 1631 cm ; H nmr (CDCl ): ꢀ
C-5), 150.8 (C-2), 171.7 (C-4, C-6); ms: m/z 183 (M +1).
-1
1
Anal. Calcd.. for C H N O : C, 52.74; H, 5.53; N, 15.38.
3
8
10
2
3
1
3
.92-2.04 (m, 2H, CH ), 2.48 (t, 2H, CH , J=6.4 Hz), 3.34 (s,
2 2
Found: C, 52.44; H, 5.16; N, 15.22.
H, N-CH ), 3.36 (s, 3H, N-CH ), 4.35 (t, 2H, O-CH , J=5.2
3
3
2
1
3
7
,9-Dimethyl-7,9-diaza-spiro[4.5]decane-6,8,10-trione (6):
Hz); C nmr (normal/DEPT-135): ꢀ 17.5 (-ve, CH ), 21.1 (-ve,
2
CH ), 27.8 (+ve, N-CH ), 28.3 (+ve,
N-CH ), 69.4 (-ve, O-
3
This compound was obtained as whitish solid (ethanol); 52%;
2
3
-1
1
CH ), 86.9 (C-5), 151 (C-2), 155.9 (C-4), 163.2 (C-6); ms: m/z
2
mp 87°; ir (KBr): CO 1624 cm ; H nmr (CDCl ): ꢀ 1.93 (t, 4H,
3
+
1
97 (M +1).
2
xCH , J=6.6 Hz), 2.22 (t, 4H, 2xCH , J=6.6 Hz), 3.31 (s, 6H,
2
2
13
Anal. Calcd. for C H N O : C, 55.09; H, 6.16; N, 14.28.
N-CH ); C nmr (normal/DEPT-135): ꢀ 27.4 (-ve, CH ), 28.9
9
12
2
3
3
2
Found: C, 55.29; H, 5.82; N, 14.10.
(
(
+ve, N-CH ), 39.2 (-ve, CH ), 56.6 (C-5), 151.5 (C-2), 173.4
2 2
+
C-4, C-6); ms: m/z 212 (M +1).
Synthesis of Compounds 16 and 17.
Anal. Calcd. for C H N O : C, 57.13; H, 6.71; N, 13.33.
10
14
2
3
Equimolar amounts of 1,3-dialkyl-6-aminouracil (1.55g, 10
mmol) and allyl bromide (1.20 g, 10 mmol) were stirred at 70-
Found: C, 56.77; H, 6.85; N, 13.19.
2
,4-Dimethyl-2,4-diaza-spiro[5.5]undecane-1,3,5-trione (7):
8
0° in DMF (10 ml) using K CO (2.76 g, 20 mmol) as base and
2 3
TBAHSO as catalyst (0.1 mmol) for 3 hrs. After filtration,
This compound was obtained as whitish solid (ethanol); 31%;
4
-1 1
solvent was removed under reduced pressure. The impure
residue was purified by column chromatography using ethyl
acetate hexane as eluents and recrystallized from ethanol.
mp 60°; ir (KBr): CO 1678, 1685 cm ; H nmr (CDCl ): ꢀ 1.51-
3
1
2
1
3
.60 (m, 2H, CH ), 1.67-1.84 (m, 4H, 2xCH ), 1.96 (t, 4H,
2
2
13
xCH , J=6.4 Hz) 3.30 (s, 6H, N-CH ); C nmr (normal/DEPT-
2
3
35): ꢀ 21.2 (-ve, CH ), 24.5 (-ve, CH ), 28.8 (+ve, N-CH ),
2
2
3
5
-Allyl-6-amino-1,3-dimethyl-1H-pyrimidine-2,4-dione (16).
2.7 (-ve, CH ), 50.7 (C-5), 161 (C-2), 172.4 (C-4, C-6); ms:
2
+
m/z 225 (M +1).
This compound was obtained as whitish solid (ethanol); 53%;
1
Anal. Calcd. for C H N O : C, 58.91; H, 7.19; N, 12.49.
mp 165°; H nmr (CDCl
3
): ꢀ 3.28 (dd, 2H, CH
), 3.49 (s, 3H, N-CH
3
2
, J=8.0 Hz,
), 4.49 (bs,
11
16
2
3
Found: C, 58.61; H, 7.37; N, 12.39.
J=10.0 Hz), 3.38 (s, 3H, N-CH
3

May-Jun 2006
A Practical Approach for Spiro- and 5-Monoalkylated Barbituric Acids
611
2
H, NH ), 5.16 (dd, 2H, CH , J=6.0 Hz, J=8.0 Hz), 5.65 (m, 1H,
1,3-Dimethyl-5-(2-phenylsulfanyl-ethyl)-1H-pyrimidine-2,4,6-
trione (20).
2
2
13
CH); C nmr (normal/DEPT-135): ꢀ 28.1 (-ve, CH ), 28.2 (+ve,
2
CH ), 29.3 (+ve, CH ), 85.0 (C-5), 115.3 (-ve, CH ), 135.4 (+ve,
CH), 151.2 (C-2), 151.4 (C-4), 162.4 (C-6); ms: m/z 196 (M ).
3
3
2
This compound was obtained as white solid (ethanol); 55%;
+
-1
1
mp 175°; ir (KBr): CO 1645 cm ; H nmr (CDCl ): ꢀ 3.24 (s,
3
5
-Allyl-6-amino-1,3-dibenzyl-1H-pyrimidine-2,4-dione (17).
3H, N-CH
3
), 3.29 (s, 3H, N-CH
), 3.30 (t, 2H, CH , J=6.3 Hz),
3 2
4
5
.16 (t, 2H, S-CH , J=5.8 Hz), 5.01 (s, 1H, C-5H), 7.27-7.39 (m,
1
2
This compound was obtained as yellowish oil; 42%; H nmr
13
H, Ph); C nmr (normal/DEPT-135): ꢀ 27.8 (+ve, N-CH ), 28.9
3
(
2
CDCl ): ꢀ 2.41 (dd, 2H, CH , J=6.0 Hz, J=8.0 Hz), 2.72 (dd,
H, CH , J=6.0 Hz, J=8.0 Hz), 4.94 (dd, 2H, CH , J=4.0 Hz,
2 2
J=10.0 Hz), 5.01 (s, 2H, CH ), 5.18 (s, 2H, CH ), 5.34 (m, 1H,
CH); 7.28 (m, 10H, 2xPh); C nmr (normal/DEPT-135): ꢀ 44.1
-ve, CH ), 45.0 (-ve, CH ), 46.0 (-ve, CH ), 54.3 (C-5), 120.7 (-
3
2
(+ve, N-CH ), 32.6 (-ve, CH ), 68.6 (-ve, S-CH ), 78.3 (+ve, C-
3
2
2
5
H), 127.4 (+ve, ArCH), 129.3 (+ve, ArCH), 130.9 (+ve,
2
3
2
ArCH), 134.0 (ArC), 160.0 (C-2), 163.1 (C-4,C-6); ms: m/z 293
1
+
(M +1).
(
2
2
2
Anal. Calcd. for C H N O S: C, 57.52; H, 5.52; N, 9.58; S,
1
4
16
2
3
ve, CH ), 125.9 (+ve, ArCH), 127.3 (+ve, ArCH), 127.5 (+ve,
ArCH), 128.3 (+ve, ArCH), 128.6 (+ve, ArCH), 128.8 (ArC),
2
1
0.97. Found: C, 57.29; H, 5.32; N, 9.28; S, 10.82.
1
1
28.9 (+ve, ArCH), 130.3 (+ve, CH), 136.6 (ArC), 150.5 (C-2),
61.5 (C-4), 170.2 (C-6).
3-(1,3-Dimethyl-2,4,6-trioxo-hexahydro-pyrimidin-5-yl)-
propionitrile (21).
Syntheses of 18.
This compound was obtained as yellowish oil; 52%; ir (KBr):
-
1
1
CO 1660, CN 2250 cm ; H nmr (CDCl ): ꢀ 2.28 (t, 2H, CH ,
3
2
Method A: 5-Allyl-6-amino-1,3-dimethyluracil (1.95 g, 10
mmol) and m-chloroperbenzoic acid (1.725 g, 10 mmol) were
taken in CHCl3 (10 ml) and stirred for 12 hrs at room
temperature. The reaction was monitored by TLC. After the
starting material is consumed, the reaction mixture was treated
with saturated solution of NaHCO and extracted with CHCl .
The combined organic extractions were dried over anhydrous
sodium sulphate. On removing the solvent, the crude residue
was purified by column chromatography using ethyl acetate and
hexane as eluents.
J=6.0 Hz), 3.33 (s, 3H, N-CH ), 3.37 (s, 3H, N-CH ), 3.42 (t,
3
3
1
3
2
(
(
1
H, CH2, J=6.4 Hz,), 5.11 (s, 1H, C-5H),
C nmr
normal/DEPT-135): ꢀ 24.0 (-ve, CH ), 27.8 (+ve, N-CH ), 28.7
2
3
+ve, N-CH ), 32.2 (-ve, CH ), 78.1 (+ve, C-5), 160.4 (C-2 ),
3
2
,
+
63.4 (C-4,C-6); ms: m/z 210 (M +1).
Anal. Calcd. for C H N O : C, 51.67; H, 5.30; N, 20.09.
3
3
9
11
3
3
Found: C, 51.82; H, 5.39; N, 19.95.
5-[2-(2-Hydroxy-ethylsulfanyl)-ethyl]-1,3-dimethyl-pyrimidine-
2,4,6-trione (22).
Method B: 5-Allyl-6-amino-1,3-dimethyluracil (1.95 g, 10
mmol) and oxone (12.30 g, 20 mmol) were stirred at 0° in
Acetone-Water mixture (7:3) for 2 hrs. The reaction was
monitored by TLC and after the completion of the reaction, it
This compound was obtained as yellowish oil; 55%; ir (KBr):
-
1
1
CO 1680 cm ; H nmr (CDCl ): ꢀ 2.87 (t, 2H, CH , J=4.8 Hz),
3
2
3
.31 (s, 3H, N-CH ), 3.40 (s, 3H, N-CH ), 3.68 (t, 2H, CH ,
3 3 2
J=4.8 Hz), 3.91 (t, 2H, S-CH , J=5.4 Hz), 4.34 (t, 2H, CH ,
2
2
was extracted with CHCl . The impure residue obtained after the
3
13
J=5.4 Hz), 5.11 (s, 1H, C-5H); C nmr (normal/DEPT-135): ꢀ
4.6 (-ve, CH ), 27.3 (+ve, N-CH ), 28.9 (+ve, N-CH ), 41.5 (-
removal of solvent was purified by column chromatography
with ethyl acetate-hexane mixture.
2
2
3
3
ve, S-CH ), 60.2 (-ve, S-CH ), 69.3 (-ve, O-CH ), 78.3 (+ve, C-
2
2
2
+
5
-Allyl-6-hydroxy-1,3-dimethyl-1H-pyrimidine-2,4-dione (18):
5H), 169.8 (C-2), 163.2 (C-4,C-6); ms: m/z 261 (M +1).
Anal. Calcd. for C10 S: C, 46.14; H, 6.20; N, 10.76, S,
2.32. Found: C, 46.20; H, 6.35; N, 10.58, S, 12.20.
1
H N O
16 2 4
This compound was obtained as yellowish oil; 45%; H nmr
1
(
(
(
(
CDCl ): ꢀ 2.70 (d, 2H, CH , J=6 Hz), 3.31 (s, 6H, N-CH ), 5.21
3
2
3
1
3
dd, 2H, CH , J=6.0 Hz, J=8.0 Hz), 5.61 (m, 1H, CH); C nmr
2
Acknowledgement
normal/DEPT-135): ꢀ 28.8 (+ve, CH ), 46.9 (-ve, CH ), 75.9
3
2
Thanks are due to CSIR and DST, New Delhi for the financial
assistance [project no. 01(1735)/02/EMR-II and SR/FTP/CS-
0/2001]. Authors are also thankful to Prof. Subodh Kumar of
C-5), 122.0 (-ve, CH ), 128.4 (+ve, CH), 150.5 (C-2), 169.8 (C-
2
+
4
, C-6); ms: m/z 197 (M ).
2
General Method for Synthesis of Compounds 19-22.
our department for fruitful discussions on this topic.
A mixture of 5 (1.82 g, 10 mmol) and the appropriate reagent
viz. Br2, PhSH, NaCN, HS(CH ) OH (10 mmol) was taken in
2
2
REFERENCES
ethanol and stirred at 50-60° for 8-10 hrs. After removing the
solvent, the impure residue was purified by column
chromatography using ethyl acetate-hexane as eluents.
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1a] A. R. Katritzky, C. W. Rees, Comprehensive Heterocyclic
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5
-Bromo-5-(2-bromoethyl)-1,3-dimethyl-pyrimidine-2,4,6-
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-1
1
CO 1666, 1697 cm ; H nmr (CDCl ): ꢀ 3.20 (t, 2H, CH , J=8.0
3
2
1
3
Hz), 3.40 (s, 6H, N-CH ), 3.45 (t, 2H, CH , J=8.0 Hz); C nmr
3
2
[
(
normal/DEPT-135): ꢀ 26.7 (-ve, CH ), 29.5 (+ve, N-CH ), 30.1
2
3
3
(
4
+ve, N-CH ), 37.6 (-ve, CH ), 79.0 (C-5), 149 (C-2) 165.5 (C-
3
2
,
[
+
), 168.7 (C-6); ms: m/z 343 (M +1).
Anal. Calcd. for C H Br N O : C, 28.10; H, 2.95; N, 8.19.
8
10
2
2
3
[6]
A. Renard, J. Lhomme, M. Kotera, J. Org. Chem., 67, 1302-
Found: C, 28.25; H, 3.01; N, 8.11.
1307 (2002).

6
12
P. Singh and K. Paul
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[
(