Preparation of 5-formyl- and 5-acetylbarbituric acids, including the corresponding Schiff bases and phenylhydrazones

Article abstract of DOI:10.1016/S0040-4039(01)01830-5

Simple, effective, and high yield synthetic procedures for formylation and acetylation of barbituric acid derivatives is described. Generated 5-acylbarbituric acids are transformed into the corresponding Schiff bases in high yield condensation reactions with ω-aminoalkanoic acids and nitrophenylhydrazines.

Full text of DOI:10.1016/S0040-4039(01)01830-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8435–8439
Preparation of 5-formyl- and 5-acetylbarbituric acids, including
the corresponding Schiff bases and phenylhydrazones
Branko S. Jursic* and Donna M. Neumann
Department of Chemistry, University of New Orleans, New Orleans, LA 70148, USA
Received 23 August 2001; accepted 21 September 2001
Abstract—Simple, effective, and high yield synthetic procedures for formylation and acetylation of barbituric acid derivatives is
described. Generated 5-acylbarbituric acids are transformed into the corresponding Schiff bases in high yield condensation
reactions with v-aminoalkanoic acids and nitrophenylhydrazines. © 2001 Elsevier Science Ltd. All rights reserved.
Barbituric acid derivatives have proven their abilities to
attract attention for a long time as ‘holy grail’ pharma-
ceuticals with a wide variety of biological activity.1
Many new drugs are envisioned using the small 5-
acylbarbituric moiety as a primary building block in the
preparation. Synthetic procedures for the preparation
of 5-acylbarbiturates with acyl groups containing
phenyl as well as long alkyl groups are well docu-
mented in the literature.2 Direct pharmaceutical and
other industrial applications of 5-acylbarbiturates is
well documented.2,3 Unfortunately, there are no good
synthetic procedures for the preparation of simple
acylbarbiturates, such as formyl and acetylbarbiturates.
Here we present very efficient methods for the prepara-
tion of a wide variety of 5-formyl-, 5-acetylbarbiturates
and their corresponding phenylhydrazones and Schiff
bases with v-aminoalkanoic acids.
bonyl compounds.5 This reaction has a limited syn-
thetic scope because strong oxidants or SmI2 must be
used. Using a masked nucleophile (−C) is probably the
most important and widely developed method today.6
Classical examples of the formyl cation equivalents (+C)
are reactions of alkyl orthoformates with organometal-
lics.7 Direct formylation of organic compounds is also
well established in organic chemistry. The Vilsmeier or
the Vilsmeier–Haack reaction8 is the most common
method for the direct formylation of reactive aromatic
rings (anilines and phenols). Another direct formylation
that can be applied to phenols and certain heterocyclic
compounds such as pyrroles and indoles is the Reimer–
Tiemann reaction.9 The reaction is performed in basic
solution and the yields are generally low, seldom rising
>50%.10 This methodology was applied by Pantelei-
monov and Madrik in preparing 5-formylbarbituric
acid in 30% yield.11 With our modification of this
procedure (Scheme 1) we were able to simplify the
reaction procedure, obtain higher purity and very good
isolated yields of 5-formylbarbiturates. The lowest yield
(ꢀ45%) is for non-substituted barbituric acids. How-
ever, the apparent reactant conversion is more than
80%.12 We repeated the procedure with slight modifica-
There are several very efficient ways to introduce the
formyl group to organic molecules.4 General methods
for the introduction of a masked formyl group can be
divided into the three classes according to the nature of
−
+
the reactant (C, C, or C). The first group belong to
the Inanaga SmI2-induced masked-formylation of car-
O
O
O
O
O
O
R1
O
R1
O
(CH3CO)2O
N
CH3
R1
O
N
CHCl3/KOH
C2H5OH-H2O
N
H
∆
N
O
N
O
N
R2
R2
R2
1d-1f
R1=H, CH3, or C6H5; R2=H, CH3, or C6H5
1a-1c
Scheme 1. Paths for direct 5-formylation and 5-acetylation of barbituric acids.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01830-5

8436
B. S. Jursic, D. M. Neumann / Tetrahedron Letters 42 (2001) 8435–8439
temperature applied. It is commonly interpreted that
Schiff bases are compounds with a carbonꢀnitrogen
double bond,23 which can move throughout the
molecule producing a more thermally stable product
and/or this double bond can be moved throughout the
molecule via proton exchange with a solvent molecule
as well as with another Schiff base. Barbituric acid
based Schiff bases are perfect examples of this kind of
molecular equilibrium. The equilibrium is temperature
sensitive and two isomers, one with a carbonꢀnitrogen
and the other with a carbonꢀcarbon double bond have
substantially different NMR shifts, as demonstrated in
the example of Schiff base 2a (Fig. 1). The compound is
highly soluble in water and dimethyl sulfoxide
(DMSO), but only slightly soluble in methanol. At
room temperature more than 90% of compound 2a has
tions and the isolated yield of the product was 45%.
With 1-phenyl and 1,3-dimethylbarbituric acids13 the
isolated yields are substantially higher (Table 1).
To our surprise we were not able to find a reliable
procedure for the preparation of 5-acetylbarbiturates,
although the preparation of higher 5-acylbarbiturates is
well known.14 If 5-acetylbarbiturates are to be used as
precursors for the preparation of valuable pharmaceuti-
cals they should be inexpensive and available in large
quantities.15 To meet these requirements, a simple syn-
thetic procedure, preferably one-pot, starting with read-
ily available barbiturates must be developed. Here we
are reporting a synthetic procedure for a one-pot prepa-
ration of 5-acetylbarbiturates in high yields (Table 1).
The reaction involves refluxing the corresponding bar-
biturates in acetic anhydride for a few hours followed
by isolation of the corresponding 5-acetylbarbiturate.16
a
carbonꢀcarbon double bond.24 By refluxing
a
methanol and water solution for 5 min the ratio of the
isomers does not change to a degree that can be noticed
from NMR analysis. It seems obvious that due to the
low boiling point of these two solvents, the equilibrium
activation barrier cannot be reached thermally. On the
other hand, DMSO has a boiling point of 189°C and its
heat capacity is much higher than both methanol and
water, thus the higher equilibrium activation barrier
can be reached. By heating the DMSO solution, allow-
ing the solvent to reflux for 1 min the amount of the 2a
CꢀN isomer in solution increased from 18% (A, Fig. 1)
to 61% (B, Fig. 1). With prolonged solvent refluxing (3
min) (C, Fig. 1) the amount of the 2a CꢀN isomer
increased to 89%, and after 5 min the practically pure
DMSO solution of 2a CꢀN was observed. If the NMR
solution is left at room temperature for a long time the
carbonꢀcarbon double bond isomer 2a CꢀC reappears
(D, Fig. 1). Therefore carbonꢀcarbon double bond
isomers of type 2a CꢀC are more stable and separated
by a large activation barrier from the carbonꢀnitrogen
double bond isomer type 2a CꢀN. On the other hand,
the reaction barrier for transforming the less stable
carbonꢀnitrogen isomer into the more stable car-
bonꢀcarbon isomer is relatively low and when the
Schiff base product of barbituric acids is purified by
crystallization, only the carbonꢀcarbon double bond
isomer is isolated. This is the case with all of our
reported Schiff bases.
As mentioned previously, the Schiff bases of the 5-
acylbarbituric acids show some interesting biological
activity,17 therefore the need for the preparation of
these compounds in large quantity using a simple and
effective synthetic procedure is apparent. Especially
valuable are Schiff bases between v-aminoalkanoic
acids and 5-acylbarbituric acids.18 Our preliminary
results suggest that these compounds might be very
potent anticancer agents.19 We have developed a very
simple one-pot synthetic procedure to obtain these
compounds in multigram quantities. The procedure
involves the condensation between two of the reactants
in methanol.20 These compounds have physical proper-
ties that easily set them apart from both starting mate-
rials, as well as make them an easy subject of biological
evaluation. They have high water solubility, and are
similar to the zwitterionic character of amino acids.
Considering the different physical properties in com-
parison to the starting materials, the isolated yields are
also very high (Table 2).
Positions of double bonds in the Schiff bases strongly
vary with the nature of the solvent, as well as the
Table 1. The isolated yields of 5-formyl- and 5-acetylbar-
bituric acid
O
O
Table 2. Some v-aminoalkanoic acid Schiff bases of 5-for-
myl-1,3-dimethylbarbituric and 5-acetylbarbituric acids21,22
R1
O
N
R2
1
O
R2
N
O
R1
O
N
N(CH2)nCOOH
R3
2
N
O
R1
R1
R2
R3
Method
Yield (%)
1a
1b
1c
1d
1e
1f
H
H
H
H
CH3
CH3
CH3
H
H
CH3
H
H
A
A
A
B
B
B
45
67
75
95
65
92
R1
R2
n
Yield (%)
C6H5
CH3
H
C6H5
CH3
2a
2b
2c
2d
2e
2f
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
2
3
5
2
3
5
93
91
95
89
85
87
CH3
A=Reimer–Tiemann formylation reaction; B=reaction in acetic
anhydride.

B. S. Jursic, D. M. Neumann / Tetrahedron Letters 42 (2001) 8435–8439
8437
Figure 1. Change of equilibrium for two structural isomers of 2a. (A) Isomers isolated from methanol reaction mixture. (B) Ratio
of isomers after heating DMSO-d6 NMR solution at 189°C for 1 min. (C) Same as B with heating for 3 min. (D) Solution was
heated for 5 min with the solvent refluxing and the left at room temperature for approximately 8 h.
It was recently demonstrated that simple nitrophenyl-
Table 3. Nitrophenylhydrazones of 5-formyl- and 5-acetyl-
hydrazones of 4-hydroxybenzophenone have strong
barbiturates
anticancer properties.25 In binding capabilities to
O
R3
H
N
R4
biomolecules, the barbituric acid moiety is superior to
phenols. Therefore, it was of interest to develop a
simple procedure for the preparation of phenylhydra-
zones with 5-formyl- and 5-acetylbarbiturates in rela-
tively large quantities for biological studies (various cell
assays an animal models for anticancer activity testing).
Several variations of the procedures for the preparation
of phenylhydrazones were tested to accomplish this
task. The simplest and most effective are the direct
condensation of the corresponding phenylhydrazine
with 5-acylbarbiturates in methanol at elevated temper-
atures. After the reaction is completed (after a few
hours of methanol refluxing) the isolation and purifica-
tion of the product depends on the physical proper-
ties.26 The optimized isolated yields for phenyl-
hydrazones of barbituric acid derivatives are presented
in Table 3.
R1
O
N
N
H
3
N
O
NO2
R2
R1
R2
R3
R4
H
NO2
H
NO2
H
NO2
H
NO2
H
NO2
H
Yield (%)
3a
3b
3d
3e
3f
3g
3h
3i
H
H
H
H
H
H
CH3
CH3
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
80
88
92
93
95
91
73
86
84
81
63
84
C6H5
C6H5
CH3
CH3
H
H
3j
3k
3l
C6H5
C6H5
CH3
CH3
H
CH3
CH3
In summary, a facile one-step synthetic procedure for
the preparation of both formyl and acetyl barbituric
3m
NO2

8438
B. S. Jursic, D. M. Neumann / Tetrahedron Letters 42 (2001) 8435–8439
acid in any desired quantity without protection–depro-
tection processes involved in the course of the prepara-
tion was developed. Very elegant high yield one-step
preparations of Schiff bases from these acylbarbi-
turates, v-aminoalkanoic acids and phenylhydrazines
were developed. All of these compounds have value in
medicinal chemistry and are now available as very
inexpensive materials in large quantities. It was also
demonstrated that barbituric acid-based Schiff bases in
the form of the carbonꢀnitrogen double bond are not
stable isomers, but rather the molecules exist in its
extended conjugated form as the carbonꢀcarbon double
bond isomer.
10. For some variations of the method and improved yields,
see: (a) Cochran, J. C.; Melville, M. G. Synth. Commun.
1990, 20, 609; (b) Theor, A.; Denis, G.; Delmas, M.
Gaset, A. Synth. Commun. 1988, 18, 2095.
11. Panteleimonov, A. G.; Mandrik, V. S. Ukr. Khim. Zh.
1970, 36, 696.
12. From a set of small-scale (2 mg of barbituric acid) NMR
followed reactions, it is obvious that around 80% of
barbituric acid is converted into 5-formylbarbituric acid.
Unfortunately, the solubility of barbituric acid and 5-
formylbarbituric acid in water and methanol as purifica-
tion solvents are very similar, therefore to obtain pure
5-formylbarbiturates, a large quantity is lost during the
elimination of starting materials through crystallization
and washing with water and methanol. In the case of
substituted barbituric acids such as 1,3-dimethylbarbi-
turic acid, the conversion is higher than 85% and the lost
amount of product during purification is substantially
smaller.
13. Method A: Typical procedure for formylation of barbi-
turic acid with chloroform: The Reimer–Tiemann Reac-
tion. Preparation of 5-formyl-1,3-dimethylbarbituric acid
(1c). Into a 50% ethanol (400 mL) solution of potassium
hydroxide (84 g; 1.5 mol), the chloroform (50 mL) solu-
tion of 1,3-dimethylbarbituric acid (33.6 g; 0.2 mol) was
added. The reaction is exothermic and is controlled by an
ice-water bath. A yellow precipitate forms almost imme-
diately. The reaction suspension was stirred at room
temperature for an additional 3 h, then cooled in ice
water (ꢀ5°C). The solid was separated by filtration and
was slurred in water (ꢀ100 mL), and the pH was
adjusted to ꢀ3 by adding concentrated hydrochloric
acid. After cooling at ꢀ5°C for 1 h, the solid was
separated by filtration, washed with acetone (3×20 mL)
and dried at 110°C for 0.5 h, resulting in pure product. If
necessary, further purification can be performed by crys-
tallization from a small amount of water–ethanol mix-
ture. The yield of the white powdery product is 27.6 g
(75%) 1H NMR (DMSO-d6–D2O; 5:1) l 9.639 (1H, s)
and 3.049 ppm (6H, s); 13C NMR (DMSO-d6–D2O; 5:1)
l 188.220, 148.527, 147.222, 97.092, and 24.052 ppm;
MS-EI, m/z 184 (M+, 20%), 169 ((M−CH3)+, 28%), 156
((M−CO)+, 39%), anal. calcd for C7H8N2O4 (MW
184.15): C, 45.66; H, 4.38; N, 15.21. Found: C, 45.34; H,
4.65; N, 15.02.
References
1. (a) Goth, A. Medical Pharmacology, 4th Ed.; The C. V.
Mosby Company, Saint Louis, 1968; Burger’s Medicinal
Chemistry and Drug Discovery, Vols. 1–5; Wolff, M. E.,
Ed.; Wiley: New York, 1997; (b) Rastaldo, R.; Penna, C.;
Pagliaro, P. Life Sci. 2001, 69, 729; (c) Aiken, S. P.;
Brown, W. M. Front. Biosci. 2000, 5, 124; (d) Ghansah,
E.; Weiss, D. S. Neuropharmacology 2001, 40, 327; (e)
Levine, B. Princ. Forensic Toxicol. 1999, 185; (f) Oliva,
A.; Zimmermann, G.; Krell, Hans-Willi. Barbituric Acid
Derivatives with Antimetastatic and Antitumor Activity.
International Patent WO 98/58925; (g) Gulliya, K. S.
Uses for Barbituric Acid Analogs. US patent US 943,385,
1997.
2. (a) Sakai, K.; Satoh, Y. Barbituric Acid Derivative and
Preventive and Therapeutic Agent for None and Carti-
lage Containing the Same. International Patent WO 99/
50252; (b) Grosscurt, A. C.; Terpstra, J. W. Preparation
of 5-Acylbarbituric Acid Derivatives as Insecticides.
European Patent EP 455300, 1991.
3. Hirono, Y.; Ishikawa, H.; Iwataki, I.; Sawaki, M.;
Nomura, O. Herbicidal Barbituric Acid Derivatives. Ger-
man Patent DE 2524578, 1975.
4. (a) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th Ed.; John Wiley & Sons: New York, 2001;
p. 715; (b) Corey, E. J.; Chang, X.-M. The Logic of
Chemical Synthesis; John Wiley & Sons: New York,
1989.
5. Matsukawa, M.; Inanaga, J.; Yamaguch, M. Tetrahedron
Lett. 1987, 28, 5877.
14. See Ref. 2 and for some examples (a) Kende, A. S.;
Koch, K.; Smith, C. A. J. Am. Chem. Soc. 1988, 110,
2210; (b) Strekowski, L.; Ismail, M. A.; Zoorob, H. H.
Heterocycl. Commun. 1999, 5, 107.
15. For instance, 5-acetylbarbituric acid can be purchased
from Aldrich Co. as a product in the Rare Chemical
Library for the price of $50 for 50 mg.
16. Method B: Typical procedure for the preparation of
5-acetylbarbiturates. Preparation 5-acetylbarbituric acid
(1d). A mixture of barbituric acid (12.8 g; 0.1 mol) and
acetic anhydride (300 mL) with a few drops of concen-
trated sulfuric acid was refluxed for 1 h. The reaction in
the beginning is a suspension but after ꢀ10 min of
refluxing it changes color (orange) and becomes a solu-
tion. The reaction mixture was concentrated to 1/2 of its
original volume and cooled at ꢀ10°C (ice-water bath).
The formed solid was separated by filtration, washed with
hot water (3×25 mL), then acetone (3×25 mL), and dried
6. (a) For instance, see: Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis; John Wiley &
Sons: New York, 1991; (b) Corey, E. J.; Seebach, D. J. J.
Org. Chem. 1966, 31, 4097; (c) Ogura, K.; Tsushihashi,
G. Tetrahedron Lett. 1971, 3151; (d) Kocienski, P. J.
Tetrahedron Lett. 1980, 21, 1559.
7. (a) Deno, N. C. J. Chem. Soc. 1947, 2233; (b) Sond-
heimer, F. J. Chem. Soc. 1952, 4040; (c) Wibaut, J. P.;
Huls, R. Rec. Trav. Chim. 1952, 71, 1021.
8. (a) Vilsmeier, A.; Haack, A. Ber. 1927, 60, 119; (b)
Blaser, D.; Calmes, M.; Daunis, J.; Natt, F.; Tardy-
Delussus, A.; Jacquier, R. Org. Prep. Proc. Int. 1993, 25,
338; (c) Jutz, C. Adv. Org. Chem. 1976, 9, 255.
9. (a) Reimer, K.; Tiemann, F. Ber. 1876, 9, 824; (b) Wyn-
berg, H. Chem. Rev. 1960, 60, 169; (c) Wynberg, H.;
Meijer, E. W. Org. React. 1982, 28, 1.

B. S. Jursic, D. M. Neumann / Tetrahedron Letters 42 (2001) 8435–8439
8439
at 80°C for 30 min. The yield of yellow powder was 16.1
g (95%). 1H NMR (DMSO-d6) l 11.768 (1H, s, NH),
11.035 (1H, s, NH), and 2.563 ppm (3H, s, CH3); 13H
NMR (DMSO-d6) l 191.343, 168.146, 158.736, and
145.502 four different carbonyls, 91.913 (C-5 from barbi-
turic acid), and 20.385 ppm (C from acetyl). MS (electro-
spray, ES+, in methanol with 0.1% CH3COOH) 215.2
(M+2Na) and 251.1 (M+Na+HOAc).
are recorded in DMSO-d6 then the hydrogen–hydrogen
splitting signals for the zwitterionic form of the Schiff
base 2 are observed. For instance, in the 1H NMR
spectra of 2f at 10.30 ppm there is a double splitting of
the triplet for CHꢁNH-CH2-, at 8.2 ppm a doublet for
-CHꢁNH-, and a double triplet for NH-CH2-CH2-. Due
to the hydrogen–deuterium exchange in DMSO-d6–D2O
(3:1) as an NMR solvent (NH is now mostly ND) the
spectra is changed. There is no NH signal and therefore
CHꢁ becomes a singlet and N-CH2- is a simple triplet.
22. Schiff bases made from 5-acetylbarbituric acids have
substantially lower solubility in methanol than ones made
from 5-formyl-1,3-dimethybarbituric acid. All three com-
pounds of this series (2a, 2b, and 2c) are not soluble at 5
mmol concentration per 200 mL of refluxing methanol.
These compounds are isolated as crystalline products by
filtration of the hot reaction suspension. They are ꢀ98%
pure. If necessary, these compounds can be further
purified by crystallization from acetic acid.
17. For instance, see: Toth, I.; Dekany, G.; Kellam, B.
Preparation of Cyclic Compounds as Protecting and
Linking Groups for Organic Synthesis. International
Patent WO 9915510, 1999. Sasaki, I.; Gaudemer, A.;
Chiaroni, A.; Riche, C. Inorg. Chim. Acta 1986, 112, 119.
Hasegawa, S.; Imamura, S.; Muto, M.; Okamoto, Y.
Japanese Patent Jpo1163129, 1989; Mohsen, M. K. Phar-
mazie 1982, 37, 147.
18. Based on the structural–activity relationship with already
known histone deacetylase inhibitors as anticancer com-
pounds, we have designed barbituric acid derivatives that
can structurally resemble these inhibitors. For more
information, see: (a) Finnin, M. S.; Donigian, J. R.;
Cohen, A.; Richon, V. M.; Rifkind, R. A.; Marks, P. A.;
Breslow, R.; Pavletich, N. P. Nature 1999, 401, 188; (b)
Coffey, C. D.; Kutko, M. C.; Glick, R. D.; Butler, L. M.;
Heller, G.; Rifkind, R. A.; Marks, P. A.; Richon, V. M.;
La Quaglia, M. P. Cancer Res. 2001, 61, 3591; (c)
Richon, V. M.; Emiliani, S.; Verdin, E.; Webb, Y.;
Breslow, R.; Rifkind, R. A.; Marks, P. A. Proc. Natl.
Acad. Sci. USA 1988, 95, 3003.
23. Cordes, E. H.; Jencks, W. P. J. Am. Chem. Soc. 1963, 85,
2843 and references cited therein.
24. The structural assignment was based on the chemical
shifts for b-alanine in DMSO-d6 as the NMR solvent.
Reference for the chemical shift is the middle signal of
the five signals for DMSO as the solvent at 2.49 ppm.
b-Alanine is slightly soluble in DMSO. All hydrogens on
the nitrogens are exchanged with deuterium from the
solvent, therefore besides the two huge signals for the
solvent and water, two additional triplets, one at 2.798
ppm (J=4.5 Hz) for -NCH2- and the other at 2.060 ppm
(J=4.5 Hz) for -CH2CO- are observed. With the assump-
tion that the chemical shifts for -NCH2- of 2a in its
carbonꢀcarbon double bond isomer 2a CꢀC is similar to
b-alanine, the chemical shift at 2.973 ppm is assigned to
-NCH2- in the 2a CꢀC isomer and the chemical shifts at
3.632 and 3.616 ppm to -NHCH2- in the 2a CꢀN isomer.
25. Morgan, L. R.; Rodgers, A. H.; LeBlanc, B. W.; Boue, S.
M. Biorg. Med. Chem. Lett. 2001, 11, 2193 and references
cited therein.
26. Table 3: Usually preparation of nitrophenylhydrazones of
barbituric acids involve refluxing the corresponding
hydrazine and 5-acylbarbituric acid in methanol, fol-
lowed by the isolation and purification of the product.
Physical properties of the product determine what proce-
dure will be used for the hydrazone isolation and purifi-
cation. Preparation of 5-[(4-nitrophenyl)hydrazonomethyl]-
pyrimidine-2,4,6-trione (3a). A methanol (200 mL) sus-
pension of 5-formylbarbituric acid (1.56 g; 10 mmol) and
4-nitrophenylhydrazine (1.53 g; 10 mmol) was refluxed
overnight. After cooling to room temperature, the solid
was separated by filtration, slurred in hot water, washed
with methanol and crystallized from acetic acid (500 mL)
to give 2.3 g (80%) of pure compound. 1H NMR
(DMSO-d6) l 11.22 (1H, broad singlet), 10.847 (1H, s),
10.749 (1H, s), 9.859 (1H, s), 8.123 (2H, d, J=9.0 Hz),
7.985 (1H, s), and 6.819 (2H, d, J=9 Hz) ppm; 13C NMR
19. Some of the barbituric acid derivatives show encouraging
differentiation activity on the human leukemia cancer cell
lines. Results will be published elsewhere.
20. Typical procedure for the preparation of Schiff bases
with v-aminoalkanoic acids and 5-acyl barbituric acids.
Preparation of 6-[(1,3-dimethyl-2,4,6-trioxo-hexahydro-
pyrimidin-5-ylmethylene)-amino]-hexanoic acid (2f).
A
mixture of 5-formyl-1,3-dimethylbarbituric acid (0.92 g; 5
mmol) and 5-aminohexanoic acid (0.655 g; 5 mol) in
methanol (200 mL) was refluxed for 5 h. Methanol was
evaporated to a solid residue and the solid residue was
re-dissolved in a small amount of hot methanol (ꢀ50
mL). This solution was left at room temperature to
slowly evaporate to 1/5 of the volume. The formed white
needles of product were separated by filtration, washed
with cold methanol (3×5 mL) and dried at 60°C for 30
min to afford the pure product. The yield is 1.3 g (87%).
1H NMR (DMSO-d6:D2O=3:1)19 l 8.084 (1H, s), 3.414
(2H, d, J=6.7 Hz, NCH2), 3.080 (6H, d, J=0.6 Hz, two
NCH3), 2.180 (2H, t, J=7.2 Hz), 1.489 (m, 4H), and
1.215 ppm (m, 2H); 13C NMR (DMSO-d6:D2O=3:1) d
173 (-COO), 161.380, 160.484, and 156.653 (three car-
bonyls carbons from the barbituric acid ring), 149.465
(-CHꢁN-), 86.793 (C-5 from barbituric acid ring), 47.165
(NCH2), 30.967, 26.714, 22.599, and 21.346 (four carbons
of five methylene carbons of hexanoic acid moiety) and
25.068 and 24.412 ppm (two carbons of N-CH3). MS
(electrospray, ES+, in methanol with 0.1% CH3COOH),
320.1 and 320.3 (M+Na), 617.0 and 618.1 (2M+Na).
21. The 1H NMR spectra of the Schiff base 2 strongly
depend on the pH and the capability of the H–D
(DMSO-d6)
l
155.488, 150.018, 147.163, 136.005,
122.196, 108.227, 108.227, and 87.062 ppm; anal. calcd
for C11H9N5O5 (MW 291.2): C, 45.37; H, 3.11; N, 24.05.
Found: C, 45.04; H, 3.38; N, 23.88%.
1
exchange between 2 and the solvent. If H NMR spectra