Reductive C-alkylation of barbituric acid derivatives with carbonyl compounds in the presence of platinum and palladium catalysts

Article abstract of DOI:10.1016/S0040-4039(01)00621-9

Effective synthetic procedures for the preparation of mono- and di-C-alkylated barbituric acid derivatives through palladium and platinum catalytic hydrogenation of solutions of barbituric acids (unsubstituted, N-mono, and N,N′-disubstituted barbituric acids) and carbonyl compounds (aliphatic and aromatic aldehydes and ketones).

Full text of DOI:10.1016/S0040-4039(01)00621-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4103–4107
Reductive C-alkylation of barbituric acid derivatives with
carbonyl compounds in the presence of platinum and
palladium catalysts†
Branko S. Jursic* and Donna M. Neumann
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Received 26 February 2001; revised 9 April 2001; accepted 10 April 2001
Abstract—Effective synthetic procedures for the preparation of mono- and di-C-alkylated barbituric acid derivatives through
palladium and platinum catalytic hydrogenation of solutions of barbituric acids (unsubstituted, N-mono, and N,N%-disubstituted
barbituric acids) and carbonyl compounds (aliphatic and aromatic aldehydes and ketones). © 2001 Elsevier Science Ltd. All rights
reserved.
The list of biologically active substituted barbituric
acids is very long;1 therefore, there is no surprise that
since the first synthesis research2 in this field, the syn-
thesis and applications of these compounds have only
increased with time. Pharmaceutical industries market
many of these compounds under various commercial
names. The majority of barbituric acids are single or
double C-alkylated barbituric acids. Barbituric acid by
itself (pyrimidine-2,4,6-trione) is an inexpensive com-
mercially available starting material, and the same is
true for 1-mono (N-substituted) and 1,3-substituted
(N,N%-disubstituted) barbituric acids. It is obvious that
these compounds should be ideal starting materials for
both laboratory and industrial preparation of C-alkyl-
ated barbituric acid derivatives. Surprisingly, however,
there is not a simple general synthetic procedure for the
preparation of mono- and C-alkylated barbituric acid
derivatives. The general route for their preparation is
through the condensation of urea and malonic ester
derivatives with sodium ethoxide in ethanol.3
phenobarbital is still used as a single agent, but in
adults, phenobarbital is considered a third- or fourth-
line anticonvulsant and is frequently administered in
combination with other agents. Generally, barbiturates
are somewhat effective in all seizure disorders, except in
absence (petit mal) seizures.5
Here, we would like to present several catalytic reduc-
tive alkylation procedures for the preparation of mono-
and di-C-alkylated barbituric acid derivatives.
Although our procedures are general and almost all
5-alkyl- or 5,5-dialkyl-derivatives can be prepared,
many of the reactions required different solvents, cata-
lysts and order of the reactants mixing. The best cata-
lysts for these reactions are palladium, 5 wt% (dry
basis) on active carbon with the water content normally
50%, and platinum, 5 wt% (dry basis) on active carbon
with the water content normally 50%. By combining
these catalysts together with a specific order of adding
the reactants into the reaction mixture, as well as the
solvent selection, the selective mono- and di-C-alkyla-
tions of three classes of barbituric acids were achieved,
using barbituric acid as the unsubstituted barbituric
acid, 1-phenylbarbituric acid as N-substituted acid, and
1,3-dimethylbarbituric acid as N,N%-disubstituted barbi-
turic acid.
Currently barbiturates have been used predominantly
for their anticonvulsant and sedative–hypnotic proper-
ties. Phenobarbital, the oldest of the commonly used
barbiturates, was first used as an anticonvulsant in
1911.4 It was regularly prescribed to prevent febrile
seizures in infants, but is now infrequently used for this
due to side effects and lack of efficiency. In pediatrics,
It is possible to selectively perform mono-C-alkylation
of barbituric acids with aliphatic aldehydes and ketones
under catalytic reductive alkylation conditions.6 The
first step in the reductive alkylation is the formation of
the Knoevenagel condensation product,7 followed by
catalytic reduction of the newly formed CꢀC double
* Corresponding author.
†
All reactions presented in this paper are part of a pending US
Patent.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00621-9

4104
B. S. Jursic, D. M. Neumann / Tetrahedron Letters 42 (2001) 4103–4107
bond (Table 1). The condensation reaction is catalyzed
by acid. Barbituric acid by itself is an acid and if one or
both R1 and R2 are hydrogens then the condensation
reaction can be carried in solvents such as methanol or
ethanol. With aliphatic aldehydes and ketones, the
reduction can be carried out immediately upon conden-
sation, making the reaction a one-pot synthesis. In
some instances when the carbonyl compound is also the
solvent (acetone), the reaction can be carried out in
large molar excesses of the carbonyl compound. Even
in these cases, only the mono-C-alkylation product of
the barbituric acid was isolated. Both aliphatic ketones
and aldehydes are good alkylating agents and there is
no restriction on the structure of the carbonyl com-
pounds, with the exception of compounds with reduc-
tive hydrogenation-sensitive functionalities. If both R1
and R2 are not hydrogens, then acidic conditions are
required for the reaction to proceed. Acetic acid, with a
few drops of sulfuric acid, seems to be sufficient to
catalyze the condensation reactions.
methanol is completed in several seconds. Therefore,
the catalytic reduction can be carried out in the same
reaction mixture without isolation of the condensation
product. Conjugated double bonds of the condensation
product (Table 2) hydrogenate first, but both platinum
and palladium catalysts are capable of reducing the
aromatic ring with electron-donating groups such as
methoxy and dimethylamino. Reduction of the double
conjugated double bond is practically over in 1–2 h. If
the reaction is stopped at this point the reaction mix-
ture will also contain the product of the aromatic
reduction. Adding into the reductive solution a small
amount of 4-methoxybenzyl alcohol can solve this
problem. It was demonstrated that arylidenebarbituric
acid derivatives, under mild conditions, might be
reduced to the corresponding benzylbarbituric acid with
allylic and benzylic alcohols.8 Through further experi-
ments, we have demonstrated that benzene as solvent
reduces or totally eliminates the aromatic ring reduc-
tion. Therefore, when benzene is used as a co-solvent
the only product isolated is the pure, mono-C-benzyl-
ated barbituric acid derivative.9
Mono-C-benzylation of barbituric acid with aromatic
aldehydes seems to be a particularly straightforward
procedure that affords C-benzylated barbituric acids in
high yields (Table 2). If the monoalkylated product is
to be synthesized the reaction has to be carried out in
two steps: the first being to produce the product of the
Knoevenagel condensation and the second being the
reduction of this product into the substituted benzyl-
barbituric acid. Extended conjugation on the aromatic
aldehyde, or electron-donating groups such as methoxy
and dimethylamino, substantially decrease the reaction
time. For instance, the condensation between barbituric
acid and 4-dimethylaminobenzaldehyde in hot
With reactive aromatic or conjugated aldehydes the
double benzylation of barbituric acid is possible. In this
case, it seems that a 50% excess of the aromatic alde-
hyde also serves as an inhibitor to stop further reduc-
tion, as seen with the previous examples using benzene.
Isolation of the product is simple and the yields of
double benzylation are very high (Table 3). If the
reaction is performed with a barbituric acid that is
sufficiently acidic enough to catalyze the condensation
reaction, the addition of sulfuric acid is not necessary.
In other cases, such as reactions with 1,3-dimethylbar-
Table 1. Reductive alkylation of barbituric acid derivatives with aliphatic ketones and aldehydes
R1
N
O
R1
N
O
R1
N
O
O
R3
R4
R3
R4
R3
R4
H2/5%Pt-C
solvent
O
+
O
O
O
N
R2
N
R2
N
R2
O
O
Entry
R1
R2
R3
R4
Solvent
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
H
H
H
H
Methanola
Methanola
Methanola
Methanola
Methanola
Methanola
Acetic acid
Acetic acid
Acetic acid
Acetic acid
Acetic acidb
Acetic acidb
Acetic acidb
Acetic acidb
Acetic acidb
83
97
95
95
98
93
92
92
95
96
93
93
97
91
91
n-C6H7
n-C11H23
-(CH2)5-
CH3
CH3
H
n-C6H13
-(CH2)5-
CH3
H
n-C6H7
CH3
CH3
n-C6H5
H
H
9
H
H
10
11
12
13
14
15
CH3
H
H
CH3
n-C6H13
CH3
CH3
CH3
CH3
CH3
CH3
-(CH2)5-
a The product was isolated by separation of catalyst by filtration, concentrating the filtrate to 1/10 volume and precipitation of product by dilution
with water.
b A few drops of concentrated sulfuric acid were added into the reaction suspension prior to hydrogenation.

B. S. Jursic, D. M. Neumann / Tetrahedron Letters 42 (2001) 4103–4107
Table 2. Monoreductive benzylation with aromatic aldehydes
4105
R1
N
O
R1
N
O
R1
N
O
O
R3
H
R3
H
H2/5%Pd-C(50%H2O)
Benzene+methanol
+
O
O
O
O
CH2R3
N
R2
N
R2
N
R2
O
O
Entry
R1
R2
R3
Yield (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
2-Naphthyl
85
90
93
95
92
94
95
97
92
89
92
94
91
93
96
97
88
93
91
97
91
94
95
m-CH3OC6H4
p-CH3C6H4
o-CH3OC6H4
m-CH3OC6H4
p-CH3OC6H4
p-(CH3)2NC6H4
C6H5CHꢀCHa
p-(CH3)2NC6H4CHꢀCHa
3-Indoyl
9
H
H
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
C6H5
C6H5
C6H5
C6H5
C6H5
CH3
CH3
CH3
CH3
CH3
CH3
CH3
C6H5
p-CH3C6H4
p-CH3OC6H4
p-(CH3)2NC6H4
3-Indoyl
C6H5
p-CH3C6H4
p-CH3OC6H4
p-(CH3)2NC6H4
C6H5CHꢀCHa
p-(CH3)2NC6H4CHꢀCHa
3-Indoyl
a In the product, the conjugated double bond is hydrogenated (CHꢀCH is replaced with CH2CH2).
Table 3. Symmetric, double benzylation with aromatic and conjugated aldehydes
R1
N
O
O
R1
N
O
O
R3
H
CH2R3
CH2R3
H2/5%Pd-C(50%H2O)
O
+
O
O
methanol + a drop of H2SO4
N
R2
N
R2
(~3 eq)
Entry
R1
R2
R3
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
CH3
CH3
C6H5
86
91
95
95
94
95
91
94
93
92
p-CH3C6H4
p-CH3OC6H4
p-(CH3)2NC6H4
C6H5CHꢀCHa
p-(CH3)2NC6H4CHꢀCHa
p-CH3OC6H4
p-(CH3)2NC6H4
p-CH3OC6H4
p-(CH3)2NC6H4
CH3
CH3
10
a The conjugated double bond is reduced in the product.
bituric acid, a few drops of sulfuric acid substantially
facilitates the reaction.10
with activated, unsaturated aldehydes, such as 4-
dimethylaminocinnamaldehyde (Table 4).
C-Benzylation can also be performed on C-monoalkyl-
ated barbituric acids through reductive alkylation with
activated aromatic aldehydes.11 Unfortunately, the sec-
ond alkylation with aliphatic aldehydes and ketones
was not successful unless the alkylation was performed
It was demonstrated that through catalytic reductive
alkylation, various derivatives of barbituric acids can
be prepared in almost quantitative yields from simple,
readily available barbituric acids and aldehydes and
ketones. If carbonyl compounds are aliphatic then only

4106
B. S. Jursic, D. M. Neumann / Tetrahedron Letters 42 (2001) 4103–4107
Table 4. Second reductive alkylation with activated unsaturated and aromatic aldehydes
R1
N
O
O
R1
N
O
O
R4
H
R3
R3
H2/5%Pt-C(67%H2O)
methanol
O
+ O
O
CH2R4
N
R2
N
R2
(~1.5 eq)
Entry
R1
R2
R3
R4
C6H5
p-CH3C6H4
p-CH3OC6H4
p-(CH3)2NC6H4
p-(CH3)2NC6H4
p-(CH3)2NC6H4CHꢀCHa
p-CH3OC6H4
Yield (%)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
CH(CH3)2
CH(CH3)2
CH(CH3)2
CH(CH3)2
C6H5(CH2)3
C6H5(CH2)3
CH(CH3)2
CH(CH3)2
CH(CH3)2
75
83
87
85
79
89
85
87
92
p-(CH3)2NC6H4
p-(CH3)2NC6H4CHꢀCHa
a The conjugated double bond is reduced in the product.
the single C-alkylation is possible, while with activated
aromatic or conjugated aldehydes, both single and dou-
ble alkylation can also be achieved. If asymmetric
double alkylation is to be achieved, first the simple
alkylation with aliphatic aldehydes should be per-
formed, followed by the reductive alkylation with con-
jugated or aromatic aldehydes. All of these reactions
can be achieved without isolation of intermediates (one-
pot synthesis).
phenylbarbituric acid. A suspension of 1-phenylbarbituric
acid (2.04 g, 10 mmol) and 5% Pt–C with 50% water (0.2
g) in acetone (30 mL) and acetic acid (100 mL) was
hydrogenated under a hydrogen pressure of 50 psi for
ꢀ20 h. The catalyst was separated by filtration, the
filtrate was evaporated to an oily residue and benzene
(3×50 mL) was added successively and evaporated to
eliminate residue of acetic acid to give racemic 5-isopro-
pyl-1-phenylbarbituric acid (2.35 g, 96%). 1H NMR
(DMSO-d6): l 11.583 (1H, s, NH), 7.435 (3H, m), 7.220
(2H, d, J=8.1), 3.410 (1H, d, J=3.9), 2.480 (1H, m),
1.080 (6H, 2d, J=5.7); 13C NMR (DMSO-d6): l 165.662,
165.473, 147.374, 131.278, 1.25.292, 125.262, 125.160,
124.774, 124.636, 51.302, 28.848, 16.008, 15.957; MS (EI):
m/z 69 (40%, CH3CHꢀCHCO+), 77 (5%, C6H5+), 83
(40%, (CH3)2CꢀCHCO+), 91, 119 (80%, PhNꢀCꢀO+), 176
(25%, PhNHCOCH2CONH2+), 204 (100%, M−
C(CH3)2+), 231 (20%, M−CH3+), 246 (20%, M+), 247 (2%,
M++1). Anal. calcd for C13H14N2O3 (FW 246.26): C,
63.40; H, 5.73; N, 11.38. Found: C, 63.21; H, 5.92; N,
11.14.
References
1. For instance, see: Smith, C. M.; Reynard, A. M. Essen-
tials of Pharmacology; W. B. Sanders: Philadelphia, 1995.
2. For an historical account of barbituric acids, see: (a)
Carter, M. K. J. Chem. Ed. 1951, 28, 524. For the
preparation of barbital by the condensation of the diethyl
ester of diethylmalonic acid with urea in sodium ethoxide
solution, see: (b) Fischer, Dilthey, Ann. 1904, 335, 334;
German Patent No. 146,497, 1903. For early therapeutic
work, see: (c) Fischer, V. M. Therapeutische Monatsh.
1903, 17, 208.
3. For instance, see: (a) A Textbook of Practical Organic
Chemistry (Vogel), 3rd ed.; Wiley: New York, 1966; p.
1001; (b) Weygand/Hilgetag Preparative Organic Chem-
istry; Wiley: New York, 1972; p. 493; (c) Dickey, J. B.;
Gray, A. R. Org. Syn. Coll. Vol. II 1943, 60; (d) Beres, J.
A.; Pearson, D. E.; Bush, M. T. J. Med. Chem. 1967, 10,
1078.
4. For preparation, see: (a) German Patent No. 247,952,
1911 (Bayer Pharmaceutical Co.). Also see: (b) Pinhey, J.
T.; Rowe, B. A. Tetrahedron Lett. 1980, 21, 965. For
toxicity, see: (c) Goldenthal, Toxicol. Appl. Pharmacol.
1971, 18, 185.
5. For a general review of barbituric acids, see: (a) Burger’s
Medical Chemistry and Drug Discovery: Therapeutical
Agents, 5th ed.; Wolff, M. E., Ed.; Wiley: New York,
1997; Vol. II–V; (b) Goth, A. Medical Pharmacology, 4th
ed.; The Mosby Company: St. Louis, MN, 1968.
6. Typical procedure for mono-C-alkylation with aliphatic
aldehydes and ketones: Preparation of 5-isopropyl-1-
7. Recently, we have published preparation of the Knoeven-
agel condensation products for aromatic aldehydes: Jur-
sic, B. S. J. Heterocyclic Chem., in press.
8. Tanaka, K.; Chen, X.; Kimura, T.; Yoneda, F. Chem.
Pharm. Bull. 1988, 36, 60.
9. Typical procedure for reductive benzylation with aromatic
aldehydes: Preparation of 5-naphthalen-2-ylmethylbarbi-
turic acid. Barbituric acid (1.28 g, 10 mmol) and 2-naph-
thaldehyde (1.56 g, 10 mmol) was refluxed in methanol
(100 mL) for 30 min. The reaction suspension was cooled
to room temperature and 5% Pd–C with 50% water (0.1
g) was added, together with benzene (50 mL) and hydro-
genated at 30 psi for 4 h. The catalyst was separated by
filtration and the solvent was evaporated to a solid
residue. The solid residue was dissolved in methanol
(ꢀ10 mL) and diluted with water (300 mL). The white
precipitate was separated by filtration and dried in air to
give 5-naphthalen-2-ylmethylbarbituric acid (2.4 g, 90%).
1H NMR (DMSO-d6): l 11.151 (1H, s, NH), 8.138 (1H,
d, J=6.6), 7.899 (1H, d, J=6.6), 7.71 (1H, d, J=8.7),
7.517 (2H, m), 7.412 (1H, t, J=7.5), 7.254 (1H, d,

B. S. Jursic, D. M. Neumann / Tetrahedron Letters 42 (2001) 4103–4107
4107
J=6.6), 3.959 (1H, t, J=6.6), 3.668 (2H, d, J=6.6); 13C
NMR (DMSO-d6): l 166.017, 146.607, 130.271, 129.251,
127.416, 124.437, 122.922, 122.558, 44.862, 25.933; MS
(CI): m/z 91 (C7H7+), 115 (12%, C8H9+), 128 (17%,
barbituric acid), 129 (16%, C10H9+), 141 (100%, C11H10+),
169 (7%, C11H10CO+), 268 (45%, M+), 269 (10%, M++1).
Anal. calcd for C16H12N2O3 (FW 268.27): C, 67.16; H,
4.51; N, 10.44. Found: C, 67.01; H, 4.82; N, 10.08.
10. Typical procedure for symmetric double reductive benzyla-
tion of barbituric acid: Preparation of 5,5-di(4-dimethyl-
aminobenzyl)barbituric acid. A mixture of barbituric
acid (0.64 g, 0.005 mol) and 4-dimethylaminobenzalde-
hyde (2.44 g, 15 mmol) in methanol (100 mL) was
refluxed for ꢀ15 min. The reaction mixture changed
from a suspension (low solubility of barbituric acid) to a
clear solution followed by a new suspension. Into this
suspension 5% Pd–C with 50% water (0.150 g) was added
and the suspension was hydrogenated at 30 psi at room
temperature overnight (ꢀ14 h). The catalyst was sepa-
rated by filtration and methanol was evaporated to a
reduced volume (10 mL). Water was added (ꢀ100 mL)
and the resulting solid was separated by filtration and
washed with CCl4 (3×50 mL), and dried in air to give
5,5-di(4-dimethylaminobenzyl)barbituric acid (1.87 g,
95%). The product decomposed at temperatures above
230°C. 1H NMR (DMSO-d6): l 11.092 (2H, s, NH),
6.840 (4H, d, J=8.7, Ar), 6.572 (4H, d, J=8.7, Ar), 3.103
(4H, s, CH2), 2.816 (12H, s, CH3); 13C NMR (DMSO-d6):
l 169, 145, 145, 126, 118, 108, 56, 39, 36; MS (EI): m/z
134 (100%, N(CH3)2C6H4CH2+), 261 (12%, M−
CH2C6H5N(CH3)2+1+), 394 (48%, M+). Anal. calcd for
C22H26N4O3: C, 66.99; H, 6.64; N, 14.20. Found: C,
66.55; H, 6.85; N, 13.97.
11. Typical procedure for reductive benzylation of C-substi-
tuted barbituric acid: Preparation of 5-(4-dimethyl-
aminobenzyl)-5-(3-phenylpropyl)barbituric acid. A sus-
pension of barbituric acid (0.64 g, 5 mmol) and cin-
namaldehyde (0.66 g, 5 mmol) in methanol (50 mL) was
heated at 80°C for 2 h. The reaction suspension was
cooled to room temperature and 4-dimethylaminoben-
zaldehyde (0.750 g, 5 mmol) and 5% Pt–C (0.5 g) with
67% water was added. The suspension was hydrogenated
at 70 psi hydrogen pressure for 4 h at room temperature.
The catalyst was separated by filtration, and the filtrate
concentrated to a volume of 10 mL and diluted to a
volume of 200 mL with water. The resulting white precip-
itate was separated by filtration and dried at room tem-
perature to give 5-(4-dimethylaminobenzyl)-5-(3-phenyl-
1
propyl)barbituric acid (1.55 g, 79%). H NMR (DMSO-
d6): l 7.247 (2H, t, J=5.7), (1H, t, J=5.4), 7.116 (2H, d,
J=5.7), 6.775 (2H, d, J=5.7), 6.540 (2H, d, J=5.7),
2.928 (2H, s, benzyl), 2.797 (6H, s, N(CH3)2), 2.514 (2H,
t, J=0.018), 1.912 (2H, m), 1.359 (2H, m); 13C NMR
(DMSO-d6):
l 169.693, 146.289, 146.228, 137.937,
126.550, 125.161, 125.017, 122.719, 118.819, 108.836,
54.040, 40.423, 34.316, 31.570, 23.285. Anal. calcd for
C22H25N3O3: C, 66.64; H, 6.64; N, 11.07. Found: C,
66.32; H, 6.88; N, 10.83.
.