Study of the products of reaction of 5-azauracil with malondiamide and aromatic c-nucleophiles

Full text of DOI:10.1023/A:1019686412555

Pharmaceutical Chemistry Journal
Vol. 36, No. 3, 2002
DRUG SYNTHESIS METHODS
AND MANUFACTURING TECHNOLOGY
STUDY OF THE PRODUCTS OF REACTION OF 5-AZAURACIL
WITH MALONDIAMIDE AND AROMATIC C-NUCLEOPHILES
Yu. A. Azev,1 S. V. Shorshnev,2 and D. Gabel3
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 36, No. 3, pp. 38 – 42, March, 2002.
Original article submitted October 4, 1991.
As is known, hexamethylmelamine has been used in the
USA for the treatment of lung carcinoma [1]. Another
1,3,5-triazine derivative, 5-azacytidine, was used for the
treatment of acute lymphoblastic leukemia [2]. Apparently,
the antitumor activity of some 1,3,5-triazine derivatives is re-
lated to the fact that these compounds, being antimetabolites
of pyrimidine bases, are capable of accumulating in tumor
cells and damaging these cells. At the same time, there are
well-known chemical transformations of 5-azauracils with
the formation of various pyrimidine derivatives. For exam-
ple, 1,3-dimethyl-5-azauracil interacting with fluoracetamide
in the presence of lithium diisopropylamide converts into the
well-known antitumor drug 5-fluorouracil [3]. 5-Carbox-
amido and 5-cyano substituted uracil derivatives were ob-
tained via interactions of 1,3-dimethyl-5-azauracil with
malonamide and cyanamide, respectively, in the presence of
sodium ethylate [4].
Previously, it was reported in a brief communication [5]
that 5-azauracil (I), interacting with 1-phenyl-3-methyl-5-py-
razolone (IIa) without charge activation of the reagents, con-
verted into a derivative of dipyrazolylmethane (IIIa) and
biuret (IV). The same paper reported on the formation of sta-
ble 6-indolyl adducts of 5-azauracil.
In continuation of the investigation of chemical transfor-
mations of 5-azauracil, we have studied the products of con-
version of this compound upon interaction with some
b-dicarbonyl compounds representing heterocyclic and aro-
matic C-nucleophiles.
well. In these reactions, 5-azauracil acts as the donor of a
one-carbon fragment; therefore, I can be used in preparative
chemistry for the synthesis of dipyrazolylmethane deriva-
tives III (see scheme and Table 1). The reaction of
5-azauracil with indoles (V) proceeds differently. This inter-
action (like that with pyrazolones) requires no charge activa-
tion of the reagents. The reaction products represent stable
s-adducts of 6-indolyl and 5-azauracil (VIa and VIb), the
1
structure of which was confirmed by the data of H and 13C
NMR spectroscopy and mass spectrometry [5].
In this study, we have synthesized for the first time a
s-adduct of 5-azauracil and b-dicarbonyl compound. Hea-
ting 5-azauracil in butanol with malonamide (VII) leads to
the formation of 1,2,3,4,5,6-hexahydro-6-(dicarbamino-
methyl)-1,3,5-triazine-2,4-dione (VIII). The character and
1
positions of proton signals in the H NMR spectrum of this
compound confirm the proposed structure. Indeed, the dou-
blet due to proton of the malonamide fragment is observed at
3.43 ppm; H-6 proton of triazine is manifested by a multiplet
at 4.8 ppm (the splitting is caused by spin–spin coupling with
the neighboring NH protons of the triazine ring and with pro-
ton of the malonamide fragment). The 1- and 5-NH signals
are observed in the region of 7.6 – 7.7 ppm. A broad singlet
due to 3-NH proton is observed at 9.28 ppm. The singlets
due to amino groups of the malonamide fragment are mani-
fested at 7.27 and 7.30 ppm.
It is interesting to note that adducts VI and VIII are
formed even when reagents are mixed in DMSO at room
temperature. The NMR spectrum measured upon keeping the
mixture at this temperature reveals an increase in the adduct
concentration.
It was found that 5-azauracil (I) can smoothly react not
only with 1-phenyl-3-methyl-5-pyrazolone (IIa), but with
some other 1-phenyl-5-pyrazolone derivatives (IIb – IId) as
An original transformation was effected by interaction of
5-azauracil with o-phenylenediamine (IX): performed in the
presence of hydrochloric acid, this reaction yielded
1,2,3,4,5,6-hexahydro-6-(3¢,4¢-diaminophenyl)-1,3,5-triazine
1
Ural Research Institute of Medicinal Preparation Technology,
Yekaterinburg, Russia.
ChemBridge Corporation, Moscow, Russia.
University of Bremen, Bremen, Germany.
2
3
146
0091-150X/02/3603-0146$27.00 © 2002 Plenum Publishing Corporation

Study of the Products of Reaction of 5-Azauracil with Malondiamide and Aromatic C-Nucleophiles
147
O
O
R
R
O
O
H
O
H
H
H
O
H
H
N
N
O
O
N
N
H
H + N
N
N
H
N
H
N
H
NH2
NH2
N
N
N
H
NH2
N
H
O
O
H
R1
R1
NH2
NH2
IV
IIIà – IIId
VIII
X
NH2
CH2(CONH2)2
VII
R
IX
N
OH
O
O
N
R1
O
OH
H
H
H
II
H
O
N
N
OH
N
N
OH
XIII
OH
O
N
H
OH
N
H
I
OH
N
XIV
R
V
OH
N
O
XV
O
N
O
O
H
H
NHN
CHR
N
N
XIà – XIc
H
O
H
H
H
H
O
H
H
H
H
N
N
N
N
N
H
O
N
H
N
H
N
H
O
N
R
HO
OH
NHN
CHR
VIà, VIb
XIIà – XIIc
XVI
IIà – IId, IIIà – IIId: R' = Ph, R = CH3 (a);
R' = R = Ph (b);
VIà, VIb: R = H (a);
R = CH3 (b).
XIIà – XIIc: R = Ph—OCH3-para (a);
R = Ph—Cl-para (b);
R = Ph—NO2-para (c).
R' = Ph—NO2-para, R = CH3 (c);
R' = Ph, R = Ph—NO2-para (d).
1
-2,4-dione (X). The H NMR spectrum of this compound
contains a singlet at 5.2 ppm due to H-6 atom of the triazine
ring. The pattern of spin – spin splitting of the signal related
to aromatic protons of the o-phenylene fragment corresponds
to the 1,2,4,4-substituted phenyl (Fig. 1).
troscopy. The spectra of compounds XIV and XVI contain a
characteristic signal from the H-6 proton of the triazine cycle
(5.0 – 5.7 ppm), which is characteristic of all the obtained
s-adducts. The presence of two doublets from the aromatic
o-protons is indicative of the site of attachment of the
pyrogallol nucleus to 5-azauracil. The spectrum of resorcinol
derivative XVI exhibits two singlets of p-protons of the aro-
matic nucleus and the doubled number of protons in the
triazine cycle (Fig. 2).
The pattern of mass-spectrometric fragmentation of the
adducts (Fig. 3) reveals both common characteristic decay
pathways and certain special features for various derivatives.
The reactions of 5-azauracil with phenylhydrazones
(XIa – XIc) proceed under analogous conditions and
smoothly yields the corresponding 6-substituted 1,2,3,4,5,6-
hexahydro-1,3,5-triazine-2,4-diones (XIIa – XIIc). The 1H
NMR spectra of compounds XII also display the signals due
to H-6protons at sp3-hybridized carbon atom (5.4 – 5.5 ppm),
while the presence of two pairs of equivalent protons in the
aromatic ring is indicative of the p-addiction of the
phenylhydrazone fragment.
The access to another series of derivatives was opened
by the transformations of 5-azauracil via reactions with
polyphenols. Even short-time heating of 5-azauracil with
pyrogallol (XIII) in the presence of hydrochloric acid leads
One common feature of the s-adducts is the decay of the
triazine nucleus. All the adducts studied yield ions with a
mass of [M–86]+ or [M–H–86]+, which correspond to the de-
tachment of two carbamide fragments. It is interesting to
note that no decays of this type take place in the initial
(unsibstituted) 5-azauracil.
to the formation of 1,2,3,4,5,6-hexahydro-6-(2¢,3¢,4¢-trihyd-
roxyphenyl)-1,3,5-triazine-2,4-dione (XIV). The interaction
of I with resorcinol (XV) proceeds differently and yields
2,4-bis(1¢,2¢,3¢,4¢,5¢,6¢-hexahydro-1¢,3¢,5¢-triazine-2¢,4¢-dion-
The mass spectra of compounds possessing less intense
peaks of molecular ions (indolyl, diaminophenyl, and
hydrazinophenyl derivatives) also display intense peaks of
[M–H]+. In the case of indolyl and diaminophenyl deriva-
tives, decay with the detachment of carbamide groups takes
place after proton detachment. In other cases, the carbamide
groups are probably detached from molecular ions.
6¢-yl)-1,5-dio(XVI).
Structures of the phenolic derivatives of 5-azauracil were
1
unambiguously established with the aid of H NMR spec-

148
Yu. A. Azev et al.
O
O
O
H
O
H
H
H
O
H
H
H
N
N
N
N
N
N
NH2
NH2
N
H
N
H
N
H
O
HO
OH
10
9
8
7
6
5
1
0 ppm
ppm
0
10
9
8
7
6
5
1
Fig. 1. 1H NMR spectrum of 1,2,3,4,5,6-hexahydro-6-(3,4-diami-
nophenyl)-1,3,5-triazine-2,4-dione (X).
Fig. 2. 1H NMR spectrum of 2,4-bis(1,2,3,4,5,6-hexahydro-
1,3,5-triazine-2,4-dion-6-yl)-1,5-dioxybenzene (XVI).
Although the mass spectra of pyrogallol (XIV) and
malonamide (VIII) derivatives exhibit no peaks of molecular
ions, there are signals (m/z = [M–86]+) confirming the decay
of s-adducts. At the same time, the spectra of these s-ad-
ducts display intense peaks of the ions with masses corre-
sponding to the initial components. This fact indicates that,
under the conditions of mass-spectroscopic measurements,
the adducts are subject to (impact or thermal) dissociation
into initial components.
azauracils bearing amino, hydrazino, or oxy groups in the ar-
omatic ring represent convenient substrates for saturation
with various biologically active fragments. For example,
TABLE 2. Yields and Physicochemical Characteristics of 5-Azau-
racil s
O
Thus, depending on the nature of nucleophiles,
5-azauracil can be used either as a donor of a one-carbon
fragment (e.g., for the synthesis of di(pyrazolylmethane) or
as a “trap” for b-dicarbonyl compounds, indoles, aromatic
amines, hydrazines, or phenols.
H
O
H
H
N
N
N
H
R
The obtained 5-azauracil derivatives offer a unique ex-
ample of stable crystalline s-adducts. These adducts can be
useful as model intermediate compounds for studying reac-
tions of the nucleophilic displacement of hydrogen or the
transformation (metabolism) of 5-azauracil derivatives into
other heterocyclic systems. At the same time, 6-aryl-5-
Com-
pound
Empirical
formula
Yield,
%
R
M.p., °C
VIII
X
CH(CONH2)2
C6H9N5O4
C9H11N5O2
30 – 35 220 – 221
30 – 35 > 300
NH2
NH2
XIIa
XIIb
XIIc
XIV
C17H17N5O3
50 – 55 275 – 277
55 – 60 273 – 275
40 – 45 284 – 286
50 – 55 215 – 217
OCH3
Cl
TABLE 1. Yields and Physicochemical Characteristics of
Dipyrazolylmethane Derivatives (IIIa – IIId)
C16H14ClN5
O2
R
R
C16H14N6O4
C9H9N3O5
N
N
NO2
N
N
O
H
O
R1
R1
OH
OH
OH
Com-
pound
Empirical
formula
Yield,
%
R¢
R
M.p., °C
IIIa
Ph
Ph
CH3
Ph
C21H18N4O2 70 – 75 168 – 170
C31H22N4O2 45 – 50 240 – 241
IIIb
IIIc
IIId
XVI
C12H12N6O6
30 – 35 260 – 262
C6H4NO2-p
Ph
CH3
C21H16N6O6 30 – 35
> 300
C6H4NO2-p C31H20N6O6 35 – 40 277 – 279
HO
OH

Study of the Products of Reaction of 5-Azauracil with Malondiamide and Aromatic C-Nucleophiles
149
O
+·
H
–CO
N
N
85(16)
–HCN
–CONH
O
N
H
43(44)
70(83)
I, [M]+· 113(100)
O
+·
H
H
H
–CONH
N
N
186(6)
–H
229(57)
–NHCONH
O
N
H
171(10)
N
–CONHCONH
–HCN
143(100)
116(38)
H
VIa, [M]+· 230(51)
O
+·
H
H
H
N
N
–H
NH2
NH2
–CONH
–CONH
–CN
O
N
H
108(100)
220(270)
177(3)
134(53)
X, [M]+· 221(60)
O
H
O
H
+·
N
N
H
–H
N
H
353(10)
N
–NHCONHCO
–HCN
268(76)
N
H
241(19)
XIIc, [M]+· 354(22)
NO2
+·
–H2
O
H
O
H
H
237(5)
N
N
OH
–OH–CONH
179(11)
OH
N
H
–NHCONHCO
153(43)
–C3H3N3O2
–C6H3(OH)3
OH
126(100)
XIV, [M]+· 239(4)
113(53)
O
+·
H
O
H
–NHCONHCO
–HCN
129(3)
113(2)
N
N
O
112(100)
102(31)
–CH2(CONH2)2
N
H
NH2
NH2
O
–C3H3N3O2
VIII, [M]+· 215(0)
Fig. 3. The main pathways for the decay of s-adducts.
these adducts can be used for the delivery of boron to tumor
cells [6] within the framework of boron neutron capture ther-
apy.
agree with the results of calculations using the empirical for-
mulas (Tables 1 and 2).
Dipyrazolylmethane derivatives IIIb – IIId were synthe-
sized similarly to compound IIIa as described in [5].
1,2,3,4,5,6-Hexahydro-6-(dicarbaminomethyl)-1,3,5-t
EXPERIMENTAL PART
riazine-2,4-dione (VIII).
A
mixture of 5-azauracil
1
The H NMR spectra were measured on a Bruker 80
(2.0 mmole) and malondiamide (2.0 mmole) in 10 ml of
butanol was boiled for 3 – 4 h and cooled to room tempera-
ture. The precipitate of compound VIII was separated by fil-
spectrometer (Germany). The chemical shifts were measured
relative to TMS as the internal standard. The mass spectra
were recorded on a Varian MAT-311A instrument operating
at an accelerating voltage of 3 kV, cathode emission current
of 300 mA, ionizing energy of 75 eV, and ion source tempera-
ture of 200°C. The data of elemental analyses (C, H, N)
1
tration and recrystallized (Table 2). H NMR spectrum in
DMSO-d6 (d, ppm): 3.43 (d, 1H, J 9.0 Hz, CH malonamide),
4.80 (m, 1H, H-6 triazine), 7.6 – 7.7 (m, 1H, NH triazine),
9.28 (bs, 1H, 3-NH triazine). A method for the synthesis of

150
Yu. A. Azev et al.
6-indolyl derivatives of 1,2,3,4,5,6-hexahydro-1,3,5-tria-
zine-2,4-dione (VIa, VIb) was described in [5],
J 8.3 Hz, CH arom.), 7.7 (d, 2H, J 8.3 Hz, CH arom.), 7.8 (s,
1H, CH=N), 8.0 (s, 2H, 1-NH, 3-NH), 9.3 (s, 1H, NH), 10.5
(s, 1H, NH).
Compound XIIc: 5.5 (s, 1H, H-6), 7.2 (s, 2H, J 8.3 Hz,
CH arom.), 7.3 (d, 2H, J 8.3 Hz, CH arom.), 7.9 (d, 2H,
J 8.5 Hz, CH arom.), 8.0 (s, 1H, CH=N), 8.1 (s, 2H, 1-NH,
5-NH), 8.2 (d, 2H, J 8.5 Hz, CH arom.), 9.3 (s, 1H, NH), 11.0
(s, 1H, NH).
Compound XIV: 5.6 (s, 1H, H-6), 6.3 (d, 2H, J 7.8 Hz,
CH arom.), 6.5 (d, 1H, J 7.8 Hz, CH arom.), 7.6 (s, 2H,
1-NH, 3-NH), 8.4 (bs, 1H, OH), 8.6 (s, 1H, OH), 9.2 (bs, 2H,
NH, OH).
Compound XVI: 5.6 (s, 1H, H-6, H-6¢), 6.4 (s, 1H, CH
arom.), 7.1 (s, 1H, CH arom.), 7.6 (s, 4H, 1-NH, 5-NH,
1¢-NH, 5¢-NH), 9.2 (s, 2H, 3-NH, 3¢-NH), 9.8 (s, 2H, 2 OH).
Reaction of 5-azauracil with aromatic C-nucleophiles.
A mixture of 5-azauracil (1.0 mmole) and the corresponding
C-nucleophile (1.0 mmole) in 5 ml of ethanol with 0.2 ml of
concentrated HCl was boiled for 1 h and cooled to room tem-
perature. The precipitate of compound X × HCl was dis-
solved on heating in a minimum amount of water and treated
with a saturated aqueous solution of sodium acetate until
reaching neutral pH. This solution was cooled for 1.5 – 2 h
on an ice bath. The precipitate was separated by filtration and
recrystallized from water (Table 2). The products
XIIa – XIIc and XIV were purified by reprecipitation from
DMF with water. The resorcinol derivative XIV was
reprecipitated from DMSO with water.
The 1H NMR spectrum in DMSO-d6 (d, ppm):
Compound X: 4.5 (s, 4H, 2 NH2), 5.2 (s, 1H, H-6), 6.4
(d, 1H, J 7.8 Hz, CH arom.), 6.5 (d, 1H, J 7.8 Hz, CH arom.),
6.6 (s, 1H, CH arom.), 7.8 (s, 2H, 2 NH), 9.2 (s, 1H, NH).
Compound XIIa: 3.8 (s, 3H, OCH3), 5.4 (s, 1H, H-6), 6.9
(s, 2H, J 8.3 Hz, CH arom.), 7.1 (d, 2H, J 8.7 Hz, CH arom.),
7.2 (d, 2H, J 8.3 Hz, CH arom.), 7.6 (d, 2H, J 8.7 Hz, CH
arom.), 7.8 (s, 1H, CH=N), 7.9 (s, 2H, 1-NH, 5-NH), 9.3 (s,
1H, NH), 10.2 (s, 1H, NH).
REFERENCES
1. A. A. Borkovec and A. B. Demilo, J. Med. Chem., 10, 461 – 465
(1967).
2. J. Vesely and F. Sorm, Neoplazma (Bratisl.), 12, 3 – 9 (1965).
3. W. K. Chung, J. H. Chung, and K. A. Watanabe, J. Heterocycl.
Chem., 20, 457(1983).
4. W. K. Chung, Ch. K. Chu, K. A. Watanabe, and J. J. Fox., J. Org.
Chem., 44(22), 3982 – 3983 (1979).
Compound XIIb: 5.4 (s, 1H, H-6), 7.1 (s, 2H, J 7.9 Hz,
CH arom.), 7.2 (d, 2H, J 7.9 Hz, CH arom.), 7.4 (d, 2H,
5. Yu. A. Azev, Mendeleev Commun., pp. 164 – 165 (1997).
6. D. Gabel, Chemie in unserer Zeit., No. 5, 235 – 240 (1997).