Diaminomethyleneaminocarbonyldinitromethane, formed during the preparation of 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone by nitration of 2-amino-6-chloro-4(3H)-pyrimidinone

Article abstract of DOI:10.1016/S0040-4039(00)02360-1

Difficulties in the nitration of 2-amino-6-chloro-4(3H)-pyrimidinone to give the widely used heterocyclic precursor 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone are shown to be due to formation of an unusual open-chain gem-dinitro compound, identified as diaminomethyleneaminocarbonyldinitromethane. The latter is also formed by the nitration of 2-amino-4,6(3H,5H)-pyrimidinedione. It decomposes with loss of carbon dioxide in dimethyl sulfoxide, or in aqueous potassium hydroxide, to give guanidine and dinitromethane.

Full text of DOI:10.1016/S0040-4039(00)02360-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1793–1795
Diaminomethyleneaminocarbonyldinitromethane, formed during
the preparation of 2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone
by nitration of 2-amino-6-chloro-4(3H)-pyrimidinone
Peter H. Boyle,* Karen M. Daly, Fabien Leurquin, J. Kenneth Robinson and Damien T. Scully
University Chemical Laboratory, Trinity College, Dublin 2, Ireland
Received 22 September 2000; revised 29 November 2000; accepted 21 December 2000
Abstract—Difficulties in the nitration of 2-amino-6-chloro-4(3H)-pyrimidinone to give the widely used heterocyclic precursor
2-amino-6-chloro-5-nitro-4(3H)-pyrimidinone are shown to be due to formation of an unusual open-chain gem-dinitro compound,
identified as diaminomethyleneaminocarbonyldinitromethane. The latter is also formed by the nitration of 2-amino-4,6(3H,5H)-
pyrimidinedione. It decomposes with loss of carbon dioxide in dimethyl sulfoxide, or in aqueous potassium hydroxide, to give
guanidine and dinitromethane. © 2001 Elsevier Science Ltd. All rights reserved.
2
-Amino-6-chloro-5-nitro-4(3H)-pyrimidinone 2 is an
4(3H)-pyrimidinone 2. These conditions are milder and
less hazardous than the usual concentrated/fuming
important intermediate in heterocyclic synthesis and is
the key starting material for the regiospecific Boon and
Leigh synthesis of pteridines that has been used in the
preparation of a wide variety of biologically important
and drug related compounds. It was first prepared by
Davoll and Evans by the nitration of 2-amino-6-chloro-
4–8
nitric and sulfuric acid mixtures, but here as well, the
product obtained depends upon the exact reaction con-
ditions. For example, after 3 hours, the major product
is 2, whereas after 72 hours all chlorine is lost from the
molecule and the only product obtained is 2-amino-5-
nitro-4,6(3H,5H)-pyrimidinedione 5. Small amounts of
this compound 5 have been reported previously as a
by-product in the nitration of 1 with concentrated
1
–3
4
(3H)-pyrimidinone 1 with concentrated nitric and sul-
4
furic acids, but the reaction is a difficult one, and
several variations of the original experimental proce-
4,6–8
5
dure have been published.
We wish to report that
nitric/sulfuric acids. Further nitration of it leads to the
depending upon the reaction conditions used, the
desired product 2 is frequently contaminated by sub-
stantial amounts of a second product, which we show
to be the unusual gem-dinitro compound 3. For exam-
ple, when 1 is nitrated with fuming nitric acid in
concentrated sulfuric acid at 0–10°C for 3 hours, the
product obtained is 2 containing a small amount of 3.
On the other hand, if the same reaction mixture is left
for 72 hours at 20°C, the only product obtained is the
new compound. This new compound 3 is also formed
by extended nitration of 2, showing that under more
vigorous nitrating conditions hydrolysis of the 6-chlo-
rine atom occurs, together with cleavage of the pyrim-
idine ring and loss of carbon dioxide. Nitration of 1
open chain gem-dinitro compound 3, presumably via
the dinitro intermediate 6. None of the latter dinitro
compound could be isolated, but small amounts of it
were present in a sample of 3 prepared by nitration of
the mononitro compound 5, as shown by the negative
ion electrospray mass spectrum, which contained a
+
peak at m/z 216 (M−H ). The easiest route to the new
open-chain gem-dinitro product 3 is by the nitration of
2-amino-4,6(3H,5H)-pyrimidinedione
4 with excess
KNO in sulfuric acid. This reaction proceeds via the
3
mono and dinitro pyrimidines 5 and 6, since use of a 1
M ratio of KNO allowed isolation of the mononitro
3
intermediate 5. Further details of the above reactions
are summarised in Table 1. The new compound 3 is an
insoluble bright yellow solid, and may easily pass unde-
tected and cause trouble if 2 is being prepared for use
as a reagent. It may be distinguished readily from 2,
with a 1 M ratio of KNO in sulfuric acid at room
3
temperature can also give 2-amino-6-chloro-5-nitro-
however, by HPLC (cyano column, MeOH/H O), and
Keywords: pyrimidines; nitration; gem-dinitro; dinitromethane; ring
2
cleavage.
by its high wavelength UV absorption band, l
nm in 0.1 M NaOH; (m 16,130).
max.
370
*
Corresponding author. Tel.: +353 1 6081423; e-mail: pboyle@tcd.ie
0
040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)02360-1

1
794
P. H. Boyle et al. / Tetrahedron Letters 42 (2001) 1793–1795
The structure of 3 is established by the following experi-
exploding in a mp tube at 360°C. On heating at 100°C
for 1 hour in 1 M aqueous KOH it is hydrolysed with
loss of carbon dioxide, and the potassium salt of dini-
tromethane 9 can be isolated from the reaction mixture
1
mental data. Its H NMR spectrum shows three signals,
corresponding to five protons [l 400 MHz, DMSO-d ,
h
6
8
.06 (s, 2H), 8.77 (s, 2H) and 11.41 (s, 1H)], while its
C NMR spectrum shows three signals, consistent with
1
3
9
10
(mp 215°C (explosive), lit. 220°C (expl.), lit. 208°C
the presence of three carbon atoms (lc 100 MHz,
(expl.), lh 400 MHz, DMSO-d6 8.16; l 100 MHz,
c
DMSO-d , 134.54, 154.98 and 156.69). None of the
DMSO-d 122.02). Compound 3 decomposes within 3
6
6
carbon atoms in 3 carries any attached hydrogen
atoms, as shown by the fully coupled spectrum. The
carbon atom giving rise to the signal at l 134.54 carries
two nitro groups, since it appears as a triplet if 3 is
days at room temperature in DMSO solution, and in 1
hour at 70°C in the same solvent. This decomposition
in DMSO also involves loss of carbon dioxide, and may
1
be followed by NMR, when the original three
H
15
prepared from 4 by nitration with labelled K NO and
signals at l 8.06, 8.77 and 11.41 become replaced by
two signals at l 8.17 and 6.93, and the original three
3
as a doublet if prepared from unlabelled 5 with
1
5
13
K NO . Presence of the extended chromophore in 3 is
C signals at l 134.54, 154.98 and 156.69 become
3
shown by its UV absorption maximum at 370 nm (0.1
M NaOH) and 320 nm (MeOH). An IR absorption
band occurs at 1690 cm (nujol). Finally, the high-res-
replaced by two signals at l 122.10 and 157.89. The
signal at l 157.89 is due to the guanidinium carbon
atom. The signal at l 122.10 is due to the anion of
dinitromethane 9, and appears as a doublet in a fully
coupled spectrum, and as a triplet in a C–H decoupled
spectrum if both nitro groups in the starting material 3
−
1
olution electrospray positive ion mass spectrum of 3
+
shows a main peak at m/z 192.0372 (M+H ), (calcd. for
C H N O 192.0369). This molecular formula was
3
6
5
5
15
confirmed by microanalysis (found: C, 18.91; H, 2.64;
N, 35.99, calcd. for C H N O : C, 18.86; H, 2.64; N,
are N labelled. Product 9 may be separated as a single
peak on HPLC, and its high resolution electrospray
negative ion mass spectrum, shows a peak at m/z
3
5
5
5
3
6.65). Negative ion electrospray mass spectrum shows
+
+
+
a peak at m/z 190 (M−H ). Of the various tautomeric
forms possible for this compound, both the zwitterionic
form 3 and the enolic form 7 fit the above data. Other
tautomers are ruled out by the observation that none of
the carbon atoms carries a hydrogen atom.
232.9774 (2M−2H +Na ), (calcd. for C H N NaO
2 2 4 8
232.9770). A possible intermediate in the decomposition
of 3 might be the ketene 11, which on reaction with
water would give dinitroacetic acid, which in turn
would decarboxylate to give 9. However, warming 3 in
DMSO (dried over 4 A
,
molecular sieve) containing
molecular sieve) afforded no
The new guanidinium gem-dinitro compound 3 is a
stable solid at room temperature, and shows no sign of
ethanol (dried over 3 A
,
trace of the ethyl ester 10, so that it is more likely that

P. H. Boyle et al. / Tetrahedron Letters 42 (2001) 1793–1795
Table 1. Nitration of pyrimidines with KNO in sulfuric acid
1795
3
Reaction
Starting pyrimidine mg (mmol)
H SO (ml)
KNO3 mg (mmol) Time (h)
Product mg (mmol)
Yield (%)
2
4
(1)“(2)
(1)“(5)
(2)“(3)
(4)“(3)
(4)“(5)
(5)“(3)
291 (2.00)
291 (2.00)
40 (0.21)
254 (2.00)
510 (4.01)
90 (0.52)
2.0
2.0
0.5
4.0
20.0
2.0
202 (2.00)
202 (2.00)
65 (0.64)
607 (6.00)
405 (4.01)
210 (2.08)
1.5
72
10
2.5
2
275 (1.44)
266 (1.55)
35 (0.18)
325 (1.70)
554 (3.22)
80 (0.42)
72
77
87
85
80
81
8
The KNO3 (anhydrous) was added in small portions to a stirred solution of the starting pyrimidine in concentrated sulfuric acid. The resulting
solution was stirred at room temperature and then poured on to ice. The solid product was filtered off, washed with water, ethanol, diethyl ether,
and dried in vacuo.
3
is hydrolysed by direct attack of nucleophile on the
Taylor, E. C., Ed. Fused pyrimidines, pteridines. Wiley:
New York, 1988; Vol. 24, Part 3, p. 120.
2. Pfleiderer, W. In Comprehensive Heterocyclic Chemistry
II; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.
Bicyclic 6–6 systems: pteridines. Elsevier: Oxford, 1996;
p. 716.
. Pfleiderer, W. In Comprehensive Heterocyclic Chemistry;
Katritzky, A. R.; Rees, C. W., Eds. Pteridines. Perga-
mon: Oxford, 1984; Vol. 3, p. 315.
carbonyl carbon atom. These reactions are similar to
those reported recently by Bergman, Latypov and co-
1
1
workers in the nitration of barbituric acid, although
in this case it was possible to isolate 5,5-dinitrobarbi-
turic acid as a stable solid.
3
Acknowledgements
4
5
. Davoll, J.; Evans, D. D. J. Chem. Soc. 1960, 5041.
. Bailey, S. W.; Ayling, J. E. Biochemistry 1983, 22, 1790.
We would like to express our thanks to Enterprise
Ireland and to the European Commission for support
of this work, and to Professor Colin Suckling, Dr.
Colin Gibson and Dr. Martin Rice for interesting dis-
cussions. We are most grateful to Dr. John O’Brien for
the NMR spectra.
6. Browne, D. T.; Eisinger, J.; Leonard, N. J. J. Am. Chem.
Soc. 1968, 90, 7302.
7. Stuart, A.; West, D. W.; Wood, H. C. S. J. Chem. Soc.
1964, 4769.
8. Stuart, A.; Wood, H. C. S. J. Chem. Soc. 1963, 4186.
9. Grakauskas, V.; Guest, A. M. J. Org. Chem. 1978, 43,
3485.
1
1
0. Feuer, H.; Bachman, G. B.; Kispersky, J. P. J. Am.
Chem. Soc. 1951, 73, 1360.
1. Langlet, A.; Latypov, N. V.; Wellmar, U.; Goede, P.;
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