A mild and efficient method for the deformylation of 5-formyl uracils and synthesis of 4,4￠-methylidenebis(1-phenyl-3-methyl-5-pyrazolone)

Article abstract of DOI:10.1055/s-0029-1217536

6-Substituted 5-formyl uracils undergo an interesting reaction with 1-phenyl-3-methyl-5-pyrazolone in the presence of base catalyst to afford deformylated uracils and 4,4￠-methylidenebis(1-phenyl-3-methyl-5- pyrazolone) in excellent yields. Georg Thieme V

Full text of DOI:10.1055/s-0029-1217536

1982
LETTER
A Mild and Efficient Method for the Deformylation of 5-Formyl Uracils and
Synthesis of 4,4¢-Methylidenebis(1-phenyl-3-methyl-5-pyrazolone)
S
ynthesis of 4,4
¢
-Meth
o
ylidenebis(1
h
phenyl-3-m
i
tpyrazolone) L. Deb, Swarup Majumder, Pulak J. Bhuyan*
Medicinal Chemistry Division, North East Institute of Science & Technology, Jorhat 785006, Assam, India
Fax +91(376)2370011; E-mail: pulak_jyoti@yahoo.com
Received 17 February 2009
1-Phenyl-3-methyl-5-pyrazolone (I) reacts with ketones
Abstract: 6-Substituted 5-formyl uracils undergo an interesting re-
action with 1-phenyl-3-methyl-5-pyrazolone in the presence of base
catalyst to afford deformylated uracils and 4,4¢-methylidenebis(1-
phenyl-3-methyl-5-pyrazolone) in excellent yields.
as well as aromatic and aliphatic aldehydes II to give 4-
substituted pyrazolone derivatives (Scheme 1).12 In most
instances bis-pyrazolones III are obtained as the major
product with minor amounts of Knoevenagel condensed
product IV. However, Betti et al. and Papine et al. ob-
served that, in the reaction of I and II (when R1 = H), an
occasional side reaction occurs to give trace amounts of
an orange colored compound.13 After characterization, it
was found that the compound was 4,4¢-methylidenebis(1-
phenyl-3-methyl-5-pyrazolone) (V), which is highly use-
ful as an antihalation dye in the photographic process.14
Key words: uracil, deformylation, pyrazolone, 4,4¢-methylidene-
bis(1-phenyl-3-methyl-5-pyrazolone)
The importance of uracil and its derivatives is well recog-
nized by synthetic as well as biological chemists.1 Com-
pounds with this ring system have diverse
pharmacological activity.2 Therefore, considerable effort
has been made towards the synthetic manipulation of the
uracil core.3
R2 R1
R1
R2
6-Hydroxy- and 6-aminouracils are two important classes
of functionalized uracils.4 6-Hydroxyuracils constitute the
basic moiety of clinically used hypnotic drugs of the bar-
biturates class, such as veronal, seconal, and phenobarbit-
al. 6-Aminouracils are the key intermediates in the
synthesis of purines, which constitute the basic moiety of
a number of drugs, including caffeine, penciclovir, theo-
bromine and theophylline. Moreover, 6-hydroxy- and 6-
aminouracils find wide application as precursors for the
synthesis of a large number of annelated uracils of biolog-
ical significance.5 The C5=C6 double bond of 6-hydroxy-
and 6-aminouracils is nucleophilic in nature and electro-
philes attack at the 5-position of these compounds. Thus,
Michael addition takes place at the 5-position of 6-amino-
or 6-hydroxyuracils.6 However, 5-substituted derivatives
of these compounds give aza- or oxa-Michael addition
products.7 Similarly, acylation of 6-aminouracils gives 5-
acylated compounds, whereas the 5-substituted analogues
afford N-acylated compounds.8 Moreover, many electro-
philic substitution reactions occurs at the 5-position in-
stead of the nitrogen atoms of uracils even under basic
conditions.9 Therefore, the protection and deprotection of
the 5-position of uracils is an important reaction from the
synthetic point of view.
R1COR2
+
N
N
N
or
N
O
N
N
N
Ph
[I]
O O
O
N
Ph
Ph
Ph
[IV]
[II] R1 = aryl, alkyl
[III] major
R
2 = H, alkyl
N
N
N
N
O
O
Ph
Ph
[V]
Scheme 1
Formylation at the 5-position of 6-amino- and 6-hydroxy-
uracils can be achieved by the action of Vilsmeier re-
agent.15 However, deformylation of these compounds has
not been reported so far. In a recent study, we showed that
6-substituted uracils are very good leaving groups.16 Tak-
ing all these observations in view, and in a continuation of
our work on uracils,17 we studied the reaction of various
5-formyl-6-substituted uracils 1 with 1-phenyl-3-methyl-
5-pyrazolone (2) and thus report herein a highly efficient
method for the deformylation of various 5-formyl-6-sub-
stituted uracils that affords the deformylated compound 3
(Scheme 2). Moreover, the reaction demonstrates a suit-
able method for the synthesis of 4,4¢-methylidenebis(1-
phenyl-3-methyl-5-pyrazolone) (4), which is a compound
of considerable industrial importance.
The formyl group has been widely used as an activating/
protecting group during the synthesis of secondary amines
from primary amines;10 however, it has been limited from
wide use due to the harsh conditions required for its re-
moval.11
In our reaction strategy, utilizing one equivalent of N,N-
dimethyl-5-formyl-6-hydroxyuracil (1a)15a with two
equivalents of 1-phenyl-3-methyl-5-pyrazolone (2), in the
presence of a catalytic amount of piperidine at room tem-
perature, afforded, after work up, 80% of N,N-dimethyl-6-
SYNLETT 2009, No. 12, pp 1982–1984
x
x
.x
x
.2
0
0
9
Advanced online publication: 03.07.2009
DOI: 10.1055/s-0029-1217536; Art ID: D05609ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 4,4′-Methylidenebis(1-phenyl-3-methyl-5-pyrazolone)
1983
hydroxyuracil 3a (Scheme 2).18 The structure of the com- With suitable conditions established, the deformylation
pound was ascertained from the spectroscopic data and by reaction was studied by utilizing other cyclic active meth-
comparison with an authentic sample.19 Compound 4 was ylene compounds e.g. N,N-dimethylbarbituric acid, Mel-
obtained as a dark orange solid in the reaction mixture, drum’s acid, dimedone etc. in place of pyrazolone 2.
which could be isolated simply by filtration.
However, no satisfactory results were obtained except
with dimedone, which was found to react with 1 to afford
the deformylated compound 3 in comparatively low yield
and only under reflux after a long period of time (4–5
hours). Therefore, 1-phenyl-3-methyl-5-pyrazolone is
considered to be the most suitable reagent for the de-
formylation reaction. We also studied the deformylation
process with other bulky heterocyclic aldehydes e.g. vari-
ous 2-substituted-3-formyl-quinolines, which only gave
the Knoevenagel condensed product.
O
R1
O
CHO
X
N
N
+
N
O
N
R2
Ph
1a–h
2
piperidine
O
R1
O
N
+
N
NPh
N
N
N
N
O
N
O
X
O
O
O
R2
Ph
Ph
Me
O
Me
O
CHO
OH
base
N
N
3a–h
4
+
N
N
O
N
OH
[VI]
N
Scheme 2
Table 1 Deformylation Reaction of 6-Substituted 5-Formyluracils 1
Ph
Me
Me
1a
2
Ph
O
N
N
H
Entry X
R1
R2
Product Time Yield
(min) (%)
NPh
O
N
O
O
Ph
1
2
3
4
5
6
OH
Me
Me
Me
Me
Me
Me
Me
Me
Me
3a
3b
3c
3d
3e
3f
30
30
80
2
Me
O
N
N
base
N
Cl
75
N
OH
NH2
60
60
Me
N(Me)(CH2CH=CH2) Me
150
40
80a
75
O
O
Me
Me
N
N(Ph)(CH2CH=CH2) Me
N
+
N
N
80a
N
O
N
O
N
Me
150
O
O
N
OH
O
Ph
Me
Ph
Me
N
4
3
7
8
OH
Cl
H
H
Me
Me
3g
3h
40
40
70
70
Scheme 3
a Performed under reflux in the presence of DIPEA.
A suitable mechanism for the reaction is outlined in the
Scheme 3. First the Knoevenagel condensation of 1 and 2
occurs to give intermediate VI and then a second mole-
cule of pyrazolone 2 adds in a Michael addition to the
newly formed double bond of the intermediate VI. The
substituted uracil moiety, being a good leaving group, is
eliminated to give the deformylated compound 3 and
4,4¢-methylidenebis(1-phenyl-3-methyl-5-pyrazolone) (4).
The mechanism and the formation of the product 3 are
supported by the isolation and characterization of the
compound 4, which is obtained in each deformylation
reaction.
The structure of compound 4 was determined from the
spectroscopic data and elemental analysis. The H NMR
1
spectrum showed a resonance at d = 2.36 ppm for the two
equivalent methyl groups and the aromatic protons ap-
peared in the range d = 7.18–7.91 ppm. The single hydro-
gen at the 4-position appeared much further downfield
because of resonance participation with the amide carbo-
nyl groups. The mass spectrum showed the molecular ion
peak (m/z 357.5 [M – H]+) that is quite close to the calcu-
lated value.
In conclusion, we have reported a very mild and highly ef-
ficient method for the deformylation of various 5-formyl-
6-substituted uracils. Moreover, the reaction offers a
method for the synthesis of 4,4¢-methylidenebis(1-phe-
nyl-3-methyl-5-pyrazolone) (4), which is an industrially
important compound. A suitable mechanism is put for-
warded for the reaction. This reaction, which demon-
In order to establish the generality of the reaction, a num-
ber of 5-formyl-6-substituted uracils 115 were reacted with
1-phenyl-3-methyl-5-pyrazolone (2) and, in all the cases,
deformylated compounds 3 were obtained in excellent
yields. In each case we isolated the bis-pyrazolone prod-
uct 4 in 60–80% yield. Our observations are recorded in
Table 1.
Synlett 2009, No. 12, 1982–1984 © Thieme Stuttgart · New York

1984
M. L. Deb et al.
LETTER
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Acknowledgment
We thank the DST, New Delhi, for financial support. M.L.D. and
S.M. thank the CSIR (India) for the award of Research Fellowships.
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(18) In a simple experimental procedure, N,N-dimethyl-5-
formyl-6-hydroxyuracil (1a; 184 mg, 1 mmol) and 1-phenyl-
3-methyl-5-pyrazolone (2; 348 mg, 2 mmol) were stirred in
ethanol (8 mL) at r.t. in the presence of two drops of
piperidine for 30 min. The dark-orange solid compound 4
that appeared was filtered, washed with cold ethanol and
dried in air. Yield: 286 mg (80%); mp 182–184 °C (Lit.13
183–184 °C); 1H NMR (300 MHz, CDCl3): d = 2.36 (s, 6 H),
7.18–7.31 (m, 3 H), 7.45 (t, J = 7.52 Hz, 4 H), 7.91 (d,
J = 7.72 Hz, 4 H); 13C NMR (75 MHz, CDCl3): d = 13.46,
110.03, 121.60, 127.08, 129.44, 138.18, 138.82, 153.27,
161.78; MS: m/z = 357.5 [M – H]+. The solvent was
evaporated and the residue was purified by column
chromatography using CH2Cl2 as eluent. The yield of
product 3a = 80% (125 mg); mp 120–122 °C (Lit.19 121–
122 °C); 1H NMR (300 MHz, CDCl3): d = 3.31 (s, 6 H), 3.69
(s, 2 H); IR: 3364, 1706, 1651 cm–1; MS (EI): m/z = 157
[M + H]+, 155 [M – H]+.
(19) Devi, I.; Bhuyan, P. J. Tetrahedron Lett. 2005, 46, 5727.
Synlett 2009, No. 12, 1982–1984 © Thieme Stuttgart · New York

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