Anomalous cyclization of ethyl acetoacetate (3,6-dimethyl-4-oxo-3,4- dihydropyrimidin-2-yl)hydrazone

Article abstract of DOI:10.1134/S1070363207010173

Structural modification of some (pyrimidin-2-yl)hydrazones derived from ethyl acetoacetate via methylation at the N³ atom promotes anomalous cyclization to give [1,2,4]triazolo[1,5-a]pyrimidine derivatives. The mechanism of this transformation includes specific cleavage of the aliphatic fragment in the substrate with subsequent rearrangement of carbene-like intermediate.

Full text of DOI:10.1134/S1070363207010173

ISSN 1070-3632, Russian Journal of General Chemistry, 2007, Vol. 77, No. 1, pp. 124 127.
Pleiades Publishing, Ltd., 2007.
Original Russian Text A.V. Erkin, V.I. Krutikov, 2007, published in Zhurnal Obshchei Khimii, 2007, Vol. 77, No. 1, pp. 133 136.
Anomalous Cyclization of Ethyl Acetoacetate
(3,6-Dimethyl-4-oxo-3,4-dihydropyrimidin-2-yl)hydrazone
A. V. Erkin and V. I. Krutikov
St. Petersburg State Institute of Technology,
Moskovskii pr. 26, St. Petersburg, 190013 Russia
Received September 21, 2006
Abstract Structural modification of some (pyrimidin-2-yl)hydrazones derived from ethyl acetoacetate via
methylation at the N3 atom promotes anomalous cyclization to give [1,2,4]triazolo[1,5-a]pyrimidine deriva-
tives. The mechanism of this transformation includes specific cleavage of the aliphatic fragment in the
substrate with subsequent rearrangement of carbene-like intermediate.
DOI: 10.1134/S1070363207010173
Cyclization of (pyrimidin-2-yl)hydrazones derived
from ethyl alkanoylacetates is known to produce 1-
(pyrimidin-2-yl)-3-alkylpyrazol-5(4H)-ones which are
used in the synthesis of physiologically active sub-
stances [1, 2] and dyes [3, 4]. The cyclizations of
ethyl 3-[(pyrimidin-2-yl)hydrazono]butanoates with
removal of ethanol by azeotropic distillation [5] and
via base-catalyzed ester cleavage [6] were studied
most thoroughly.
pyrimidin-4(3H)-one (III) thus formed with ethyl
acetoacetate in acetic acid. Intermediate hydrazine III
was identified as the corresponding benzylidene
derivative.
Unlike ethyl 3-[2-(6-methyl-4-oxo-3,4-dihydropy-
rimidin-2-yl)hydrazono]butanoate [5, 6], compound I
remained unchanged after heating for a long time in
toluene, while heating of I in ethanol in the presence
of potassium hydroxide lead to the formation of tarry
products. No pyrazole ring closure was observed even
when hydrazone I was heated at 170 190 C: under
these severe conditions, it underwent unusual cycliza-
tion to 4,7-dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-
5(4H)-one (IV). The formation and configuration of
bicyclic product IV are confirmed by the presence
In the present work we studied the cyclization of
ethyl acetoacetate (3,6-dimethyl-4-oxo-3,4-dihydro-
pyrimidin2-yl)hydrazone (I) under various conditions.
Initial compound I was prepared by treatment of 3,6-
dimethyl-2-methylsulfanylpyrimidin-4(3H)-one (II)
with excess hydrazine hydrate without solvent, fol-
lowed by condensation of 2-hydrazino-3,6-dimethyl-
1
of a signal at 9.35 ppm in the H NMR spectrum due
O
O
O
Me
N
Me
Me
(H2N)2
N
N
H2N
Me
N
N
N
MeS
Me
N
Me
N
H
N
II
III
V
AcCH2COOEt
MeI
O
O
O
Me
Me
N
HN
N
Me
N
N
H
S
Me
Me
N
N
Me
N
H
OEt
N
O
VI
I
IV
124

ANOMALOUS CYCLIZATION OF ETHYL ACETOACETATE
125
to proton in the fused triazole ring and of a character-
istic [7] absorption band with its maximum at 267 nm
(log 4.04) in the UV spectrum.
the mechanism of the observed transformation of
compound I involves specific cleavage of the aliphatic
fragment therein with liberation of ethanol (M 46) and
generation of unstable ketene A; elimination of
methylketene (M 56) from the latter gives bicyclic
product IV through carbene intermediate B.
Taking into account the data reported in [8] on the
thermolysis of methyl acetoacetate, we presumed that
O
O
Me
N
Me
N
IV.
N
N
Me
I
Me
Me
N<
H
N
:C
N
H
N
EtOH
MeCH=C=O
O
A
B
In fact, thermogravimetric analysis of hydrazone I
showed that irreversible process at 170 190 C (see
figure, curve 1) is accompanied by weight loss by
39% (curve 2), which is equivalent to elimination
from molecule I of a fragment with an overall weight
of 102 a.m.u. (see figure).
duct of 3,6-dimethyl-2-(2-formylhydrazino)pyrimidin-
4(3H)-one formed initially from hydrazine III and
formic acid [10] is structurally similar to carbene B,
we tried to synthesize compound IV by reaction of
the above reagents in an inert solvent (toluene) with
simultaneous removal of the liberated water by azeo-
tropic distillation. Unlike method b, this procedure
ensured increased concentration of isomer IV in the
reaction mixture (by a factor of 15), but the conver-
sion of initial hydrazine III was low (no more than
25%). Furthermore, we failed to separate the resulting
mixture of triazolopyrimidines IV and V by fractional
Elimination of methylketene from intermediate
butenone A gives electron-deficient carbene B which
is capable of being stabilized via cyclization to 5,8-
dimethyl[1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-one
(V) or bicyclic compound IV with preliminary elec-
tron density redistribution and cleavage of the N N
bond. The first path can be ruled out, for no com-
pound V was detected among the thermolysis pro-
ducts of hydrazone I (thermal isomerization of V into
IV does not occur). When compound V was heated
for 6 h at 170 190 C, its spectral parameters (the
chemical shift of the 3-H proton at 8.8 ppm in the
1H NMR spectrum and the position of the absorption
maximum at 249 nm in the UV spectrum [7]) did
not change.
500
T
DTG
400
1
300
200
100
0
Triazolopyrimidine V was synthesized by condensa-
tion of hydrazine III with triethyl orthoformate (me-
thod a) under the conditions similar to those reported
in [9]. This reaction gives mainly compound V rather
1
10
20
than isomeric products IV; according to the H NMR
2
data, the fraction of the latter in the reaction mixture
does not exceed 10%. An analogous regioselectivity
is inherent to reactions of hydrazine III with other
synthetic equivalents of onecarbon fragments, such as
formic acid (method b) and ethyl formate (method c).
10
20
30
40
50
60
, min
Derivatogram of ethyl 3-[2-(3,6-dimethyl-4-oxo-3,4-di-
hydropyrimidin-2-yl)hydrazono]butanoate (I); the T and
DTG curves show, respectively, change of the sample
temperature with time and temperature difference be-
tween the sample and reference.
Stabilization of carbene B via cyclization to the tri-
azolo[1.5-a]pyrimidine system (compound IV) is
likely to be favored by the absence of the reversible
solvation effect. Assuming that the dehydration pro-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 77 No. 1 2007

126
ERKIN, KRUTIKOV
crystallization or thin-layer chromatography (both
isomers have similar Rf values in suitable eluent
systems).
2-Hydrazino-3,6-dimethylpyrimidin-4(3H)-one
(III). A mixture of 3.06 g of compound II and 2.03 g
of 85% hydrazine hydrate was heated for 1 h at 100 C.
The mixture solidified and was twice recrystallized
from ethanol; the product was dried under reduced
pressure over phosphoric anhydride. Yield 1.04 g
(38%), mp 198 C; published data: mp 198 C [9],
201 203 C [13]; Rf 0.32 (B).
EXPERIMENTAL
1
The H NMR spectra were recorded on a Bruker
WM-400 spectrometer at 400.13 MHz using DMSO-
d6 as solvent; the chemical shifts were measured re-
lative to the residual proton signal of the solvent. The
UV spectrum was obtained on an SF-26 spectropho-
tometer from solutions in dilute hydrochloric acid
2-(2-Benzylidenehydrazino)-3,6-dimethylpyri-
midin-4(3H)-one was synthesized from 0.50 g of
hydrazine III and 0.34 g of benzaldehyde. Yield
0.38 g (48%), mp 204 C (from ethanol); published
5
(pH 1, c = 2.5 10 M); molar absorption coefficient
1
data [14]: mp 202 203 C ; Rf 0.33 (A). H NMR
of 5,8-dimethyl[1,2,4]triazolo[4,3-a]pyrimidin-7(8H)-
one (V) is not given because of its limited stability.
The purity of the products was checked by TLC on
Silufol UV-254 plates using the following solvent
systems as eluent: acetone hexane, 2:1 (A); butan-1-
ol acetic acid water, 1:1:1 (B), acetone hexane,
2:1, plus 2 drops of pyridine (C); propan-2-ol 3%
aqueous ammonium chloride, 5:1 (D). Spots were
visualized under UV light. The elemental composi-
tions were determined on Hewlett Packard B-185 and
Leco CHNS-932 analyzers. Thermogravimetric
analysis was performed on a Paulik Paulik Erdey
derivatograph (temperature range 25 to 500 C, heating
spectrum, , ppm: 2.22 s (3H, Me), 3.24 s (3H, MeN),
5.27 s (1H, CH), 7.84 m (6H, C6H5, NH), 10.02 s (1H,
CH=N).
4,7-Dimethyl[1,2,4]triazolo[1,5-a]pyrimidin-
5(4H)-one (IV). Hydrazone I, 1.00 g, was heated at
170 190 C until gaseous products no longer evolved.
The residue solidified and was recrystallized from
DMF, washed with diethyl ether, and dried under
reduced pressure. Yield 0.25 g (41%), mp >300 C
(decomp.), Rf 0.59 (B), 0.33 (C), 0.48 (D). 1H
NMR spectrum, , ppm: 2.14 s (3H, Me), 3.23 s (3H,
MeN), 5.18 s (1H, CH), 9.35 s (1H, CH). Found, %:
C 51.27; H 5.34; N 30.29. C7H8N4O. Calculated, %:
C 51.21; H 4.91; N 34.13.
1
rate 5 degmin , sample weight 20.2 mg). The sol-
vents used were purified and dehydrated by standard
procedures [11].
5,8-Dimethyl[1,2,4]triazolo[4,3-a]pyrimidin-
7(8H)-one (V). a. A mixture of 0.50 g of hydrazine
III and 3 ml of triethyl orthoformate was heated for
3 h at 140 C. The precipitate was filtered off, recrys-
tallized twice from DMF, washed with diethyl ether,
and dried under reduced pressure. Yield 0.36 g (64%),
mp >295 C (decomp.), Rf 0.59 (B), 0.33 (C), 0.48 (D).
1H NMR spectrum, , ppm: 2.49 s (3H, Me), 3.48 s
(3H, MeN), 6.05 s (1H, CH), 8.82 s (1H, CH). UV
Ethyl 3-[2-(3,6-Dimethyl-4-oxo-3,4-dihydro-
pyrimidin-2-yl)hydrazono]butanoate (I). A mixture
of 0.50 g of hydrazine III and 0.46 g of ethyl aceto-
acetate in 10 ml of acetic acid was heated for 1 h at
100 C. The mixture was cooled and filtered, and the
filtrate was evaporated under reduced pressure. The
residue was treated with 10 ml of boiling benzene,
the mixture was cooled, the undissolved material was
filtered off, and the filtrate was evaporated to dryness.
The residue was ground with diethyl ether to make it
crystalline, and the precipitate was filtered off, washed
with diethyl ether, and dried under reduced pressure.
spectrum:
249 nm. Found, %: C 51.36; H 5.10;
N 34.07. C7mHa8xN4O. Calculated, %: C 51.21; H 4.91;
N 34.13.
1
Yield 0.43 g (50%), mp 107 C, Rf 0.62 (A). H NMR
b. A mixture of 0.50 g of hydrazine III and 5 ml
of 85% formic acid was heated for 8 h under reflux.
Excess formic acid was distilled off under reduced
pressure (to dryness), and the residue was recrystal-
lized twice from DMF, washed with diethyl ether, and
dried under reduced pressure. Yield 0.28 g (52%).
spectrum, , ppm: 1.22 m (3H, OCH2Me), 2.08 m (6H,
Me), 3.12 d and 3.18 d (3H, MeN), 3.37 d and 3.46 d
(2H, CH2), 4.09 m (2H, OCH2Me), 5.20 s (1H, CH),
9.83 d and 9.90 d (1H, NH). Found, %: C 53.23; H
6.58; N 20.99. C12H18N4O3. Calculated, %: C 54.12;
H 6.81; N 21.04.
c. A mixture of 0.25 g of hydrazine III and 15 ml
of ethyl formate was heated for 10 h under reflux. The
precipitate was filtered off, recrystallized twice from
DMF, washed with diethyl ether, and dried under
reduced pressure. Yield 0.14 g (52%).
3,6-Dimethyl-2-methylsulfanylpyrimidin-4-(3H)-
one (II) was synthesized by exhaustive methylation
of 6-methyl-2-thiouracil (VI) with methyl iodide ac-
cording to the procedure described in [12].
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ANOMALOUS CYCLIZATION OF ETHYL ACETOACETATE
127
ACKNOWLEDGMENTS
p. 3834; Beckett, A.H., Spickett, R.G.W., and
Wright, S.H.B., Tetrahedron, 1968, vol. 24, no. 7,
p. 2839.
The authors are grateful to NOVBYTKhIM Ltd.
(St. Petersburg) for comprehensive support of this
study.
8. Den Tonkelaar, W.A.M., Louw, R., and Kooy-
man, E.C., Recl. Trav. Chim. Pays Bas, 1968, vol. 87,
no. 11, p. 1281.
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