Reactions of adamantyl-substituted keto esters with hydrazine and phenylhydrazine

Article abstract of DOI:10.1134/S1070428008120063

Reactions of adamantyl-substituted keto and diketo carboxylic acid esters with hydrazine and phenylhydrazine were studied. Ethyl 3-(1-adamantyl)-2-(1- adamantylcarbonyl)-3-oxopropanoate reacted with hydrazine to give ethyl 3,5-di(1-adamantyl)-1H-pyrazole-4-carboxylate. Reactions of ethyl 2-(1-adamantylcarbonyl)-3-oxobutanoate and ethyl 4-(1-adamantyl)-3-oxo-2-(1- oxoethyl)butanoate with hydrazine and phenylhydrazine followed a complicated pattern and led to the formation of mixtures of the corresponding hydrazides and pyrazolones.

Full text of DOI:10.1134/S1070428008120063

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 12, pp. 1760–1764. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © K.M. Bormasheva, O.N. Nechaeva, I.K. Moiseev, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 12,
pp. 1786–1790.
Reactions of Adamantyl-Substituted Keto Esters
with Hydrazine and Phenylhydrazine
K. M. Bormashevaa, O. N. Nechaevab, and I. K. Moiseeva
a Samara State Technical University, ul. Molodogvardeiskaya 244, Samara, 443100 Russia
e-mail: ikmoiseev@mail.ru
b Samara State University, Samara, Russia
Received June 5, 2007
Abstract—Reactions of adamantyl-substituted keto and diketo carboxylic acid esters with hydrazine and
phenylhydrazine were studied. Ethyl 3-(1-adamantyl)-2-(1-adamantylcarbonyl)-3-oxopropanoate reacted with
hydrazine to give ethyl 3,5-di(1-adamantyl)-1H-pyrazole-4-carboxylate. Reactions of ethyl 2-(1-adamantylcar-
bonyl)-3-oxobutanoate and ethyl 4-(1-adamantyl)-3-oxo-2-(1-oxoethyl)butanoate with hydrazine and phenyl-
hydrazine followed a complicated pattern and led to the formation of mixtures of the corresponding hydrazides
and pyrazolones.
DOI: 10.1134/S1070428008120063
Among numerous reactions of keto carboxylic acid
esters, reactions with hydrazine and its derivatives
were studied in most detail. The reaction of ethyl
3-oxo-2-(1-oxoethyl)butanoate with hydrazine gives
a mixture of ethyl 3,5-dimethyl-1H-pyrazole-4-carbox-
ylate, 3-methyl-1H-pyrazol-5-one (I), and 3,4-di-
methylpyrano[2,3-c]pyrazol-6(1H)-one (II) [1–3]
(Scheme 1). Adamantyl-substituted keto esters IIIa
and IIIb were converted into N-phenylpyrazolones
IVa and IVb by treatment with phenylhydrazine [4, 5]
(Scheme 2).
to Scheme 2, and the products were adamantyl-substi-
tuted pyrazolones Va and Vb whose structure was con-
firmed by spectral data.
In the reaction of ethyl 3-(1-adamantyl)-2-(1-ada-
mantylcarbonyl)-3-oxopropanoate (VI) with hydrazine
hydrate, the cyclization involved both carbonyl groups,
and the only product was ethyl 3,5-di(1-adamantyl)-
1H-pyrazole-4-carboxylate (VII) (Scheme 3); the
structure of ester VII was consistent with its spectral
parameters.
Unsymmetrical diketo esters, ethyl 2-(1-adamantyl-
carbonyl)-3-oxobutanoate (VIIIa) and ethyl 4-(1-ada-
mantyl)-3-oxo-2-(1-oxoethyl)butanoate (VIIIb) re-
acted with hydrazine and phenylhydrazine in a com-
plicated fashion, and these reactions gave mixtures of
products. In the reaction of compound VIIIa with
The goal of the present work was to examine the
behavior of previously synthesized adamantyl-substi-
tuted keto and diketo carboxylic acid esters [6] in
reactions with hydrazine and phenylhydrazine. Esters
IIIa and IIIb reacted with hydrazine hydrate according
Scheme 1.
O
O
O
Me
COOEt
O
O
O
NH2NH2
+
+
Me
OEt
N
Me
NHNH2
Me
OEt
Me
N
H
Me
Me
Me
Me
O
O
NH2NH2
MeC(O)CH2COOEt
N
N
O
Me
OEt
N
N
O
O
H
H
I
II
1760

REACTIONS OF ADAMANTYL-SUBSTITUTED KETO ESTERS
1761
Scheme 2.
O
O
N
O
O
NH2NHR
N
R
R
( )n
IIIa, IIIb
OEt
( )n
( )n
N
N
H
IVa, IVb, Va, Vb
n = 0 (a), 1 (b); IV, R = Ph; V, R = H.
Scheme 3.
O
OEt
O
O
OEt
O
N2H4 ·H2O
N
N
R
VI
VII
hydrazine at ratios of 1:1.5, 1:6, and 1:9, the products
were 3-methyl-1H-pyrazol-5-one (I), 3-(1-adamantyl)-
1H-pyrazol-5-one (Va), and adamantane-1-carbohy-
drazide (IX). The reaction of VIIIa with phenylhydra-
zine gave N′-phenyladamantane-1-carbohydrazide (X)
as the major product and a small amount of ethyl 3-(1-
adamantyl)-5-methyl-1-phenyl-1H-pyrazole-4-carbox-
ylate. Ester VIIIb reacted with hydrazine and phenyl-
hydrazine to give, respectively, 3-(1-adamantylmeth-
yl)-1H-pyrazol-5-one (Vb) and 3-(1-adamantylmeth-
yl)-1-phenyl-1H-pyrazol-5-one (IVb) together with
acetohydrazide. Taking into account published data
[7], the formation of the above products in the reac-
tions of esters VIIIa and VIIIb with hydrazine and
phenylhydrazine may be illustrated by Scheme 4.
carbon atoms in molecules VIIIa and VIIIb. The
charges on the carbonyl carbon atoms in VIIIa are
similar (0.26); therefore, the probability for attack
by hydrazine molecule on the acetyl carbonyl group
(path b) is the same as that for attack at the adamantyl-
carbonyl fragment (path a). In contrast, the positive
charge on the acetyl carbonyl carbon atom in molecule
VIIIb (0.27) is larger than that on the carbonyl carbon
atom neighboring to the adamantyl fragment (0.22), so
that attack by hydrazine molecule on the former seems
to be more probable, and the products are acetohydra-
zide and ethyl 4-(1-adamantyl)-3-oxobutanoate (IIIb).
It is known that 3-substituted pyrazolone deriva-
tives can exist as three tautomers A–C (Scheme 5);
however, tautomer A is commonly preferred [8]. The
1H NMR spectra of compounds IVa, IVb, Va, and Vb
(DMSO-d6) contained a one-proton singlet in the
region δ 5.15–5.34 ppm, which was assigned to 4-H,
and a broadened singlet in the region δ 10.2–11.48 ppm
Paths a and b are equally probable for compound
VIIIa, whereas path b predominates in the reaction
with VIIIb. This is consistent with the results of quan-
tum-chemical calculations of charges on the carbonyl
Scheme 4.
Me
Me
O
O
NH2NHR'
NH2NHR'
N
HN
–R(CH2)nC(O)NHNHR'
O
O
Me
OEt
N
N
O
O
O
IX, X
a
b
R'
R'
R
( )n
Me
OEt
I
( )n
N
( )n
R
R
O
O
VIIIa, VIIIb
NH2NHR'
NH2NHR'
HN
R
–MeC(O)NHNHR'
O
O
( )n
OEt
N
N
R'
R'
IIIa, IIIb
IVa, IVb, Va, Vb
n = 0 (a), 1 (b); IV, X, R = 1-adamantyl, R′ = Ph; V, IX, R = 1-adamantyl, R′ = H.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

BORMASHEVA et al.
1762
Scheme 5.
R
R
R
HN
N
O
N
N
O
OH
N
N
Ph
A
Ph
Ph
B
C
(1H, NH in IVa and IVb; 2H, NH in Va and Vb). In
the spectra of IVa and IVb, recorded from solutions in
CDCl3, we observed a two-proton singlet at δ 3.35–
3.40 ppm due to protons in position 4 of the pyrazole
ring, while no signal was present in the region δ 10.00–
hydrate in 2 ml of ethanol. The mixture was stirred and
left to stand overnight. The precipitate was filtered off,
washed with 2 ml of ethanol, and recrystallized from
ethanol.
3-(1-Adamantyl)-1H-pyrazol-5-one (Va). Yield
0.54 g (63%), colorless crystals, mp 292.5–295.5°C,
Rf 0.18 (Armsorb, CHCl3−MeOH, 10:1 by volume).
IR spectrum, ν, cm–1: 1600 (C=O); 2850, 2904
(C−HAd); 3444 (N–H). 1H NMR spectrum (DMSO-d6),
δ, ppm: 1.42 m (6H, Ad), 1.75 s (6H, Ad), 1.92 s (3H,
Ad), 5.15 s (1H, CH), 10.20 br.s (2H, NH). Found, %:
C 71.49; H 8.19; N 12.90. C13H18N2O. Calculated, %:
C 71.56; H 8.26; N 12.84.
1
11.50 ppm. We failed to obtain H NMR spectra of
compounds Va and Vb in CDCl3 because of their poor
solubility in that solvent. These findings suggest that
compounds IVa, IVb, Va, and Vb in the crystalline
state and in polar solvents have structure A and that
tautomer B prevails in nonpolar solvents.
EXPERIMENTAL
3-(1-Adamantylmethyl)-1H-pyrazol-5-one (Vb).
Yield 0.44 g (47%), colorless plates, mp 306–308°C,
Rf 0.46 (Armsorb, CHCl3−MeOH, 5:1 by volume). IR
spectrum, ν, cm–1: 1604 (C=O); 2846, 2902 (C−HAd);
The IR spectra were recorded from samples pre-
pared as KBr pellets on a Shimadzu FTIR-8400S
instrument. The H NMR spectra were measured on
1
a Bruker AM-300 instrument at 300 MHz using tetra-
methylsilane as internal reference. The mass spectra
were obtained on a Finnigan Trance DCQ GC–MS
system (USA). The elemental compositions were
determined on a TermoFinnigan Flash 1112 NCH ana-
lyzer. Column chromatography was performed using
Silicagel 60 (0.063–0.200 mm). The purity of the
products was checked by TLC on Armsorb KSKG and
Silufol UV 254 plates; spots were visualized by treat-
ment with iodine vapor.
1
3421 (NH). H NMR spectrum (DMSO-d6), δ, ppm:
1.44 s (6H, Ad), 1.60 m (6H, Ad), 1.91 s (3H, Ad),
2.19 s (2H, AdCH2), 5.15 s (1H, CH), 10.20 br.s (2H,
NH). Found, %: C 72.21; H 8.77; N 11.94. C14H20N2O.
Calculated, %: C 72.38; N 8.68; N 12.06.
3-(1-Adamantyl)-1-phenyl-1H-pyrazol-5-one
(IVa) was synthesized according to the procedure
described in [4]. Yellow crystals, mp 140–141.5°C;
published data [4]: mp 138–139°C; Rf 0.39 (Silufol,
CCl4−Me2CO, 10:1 by volume). IR spectrum, ν, cm–1:
1593 (C=Ca1rom); 1716 (C=O); 2850, 2908 (C−HAd);
3448 (NH). H NMR spectrum, δ, ppm: in DMSO-d6:
1.66 s (6H, Ad), 1.82 m (6H, Ad), 1.95 s (3H, Ad),
5.34 s (1H, 4-H), 7.10 t (1H, Harom, J = 6.90 Hz), 7.30 t
(2H, Harom, J = 7.20 Hz), 7.60 d (2H, Harom, J =
7.50 Hz), 11.48 br.s (1H, NH); in CDCl3: 1.70 q (6H,
Ad), 1.81 s (6H, Ad), 2.02 s (3H, Ad), 3.35 s (2H,
Quantum-chemical calculations were performed
using HyperChem 5 software. Geometric parameters
were optimized by semiempirical methods (AM1 pa-
rameterization); analogous results were obtained in
terms of MNDO and PM3 approximations.*
Initial esters IIIa and IIIb were synthesized accord-
ing to [4, 5], and diketo esters VIIIa and VIIIb were
prepared as reported in [6].
4-H), 7.09 t (1H, Harom, J = 7.85 Hz), 7.32 t (2H, Harom
,
Reactions of keto esters IIIa and IIIb with
hydrazine hydrate. A solution of 4 mmol of ester IIIa
or IIIb in 2 ml of ethanol was added dropwise on
cooling to a solution of 0.8 g (16 mmol) of hydrazine
J = 7.80 Hz), 7.83 d (2H, Harom, J = 8.10 Hz). Found,
%: C 77.55; H 7.49; N 9.50. C19H22N2O. Calculated,
%: C 77.52; H 7.53; N 9.52.
3-(1-Adamantylmethyl)-1-phenyl-1H-pyrazol-5-
one (IVb) was synthesized according to the procedure
described in [5]. Yellow crystals, mp 196–197°C;
published data [5]: mp 192–193°C; Rf 0.53 (Silufol;
* The calculations were performed by E.A. Bakhmatova (Zelinskii
Institute of Organic Chemistry, Russian Academy of Sciences,
Moscow, Russia).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008

REACTIONS OF ADAMANTYL-SUBSTITUTED KETO ESTERS
1763
CCl4–Me2CO, 4:1 by volume). IR spectrum, ν, cm–1:
1593 (C=Ca1rom); 1689 (C=O); 2846, 2900 (C–HAd);
3440 (NH). H NMR spectrum, δ, ppm: in DMSO-d6:
1.53 m (12H, Ad), 1.86 s (3H, Ad), 2.15 s (2H,
AdCH2), 5.25 s (1H, 4-H), 7.15 t (1H, Harom, J =
7.65 Hz), 7.36 t (2H, Harom, J = 7.65 Hz), 7.75 d (2H,
2850, 2904 (C–HAd); 3259, 3417 (NH). 1H NMR spec-
trum (DMSO-d6), δ, ppm: 1.24 t (3H, CH3, J =
6.75 Hz), 1.62 t (12H, Ad, J = 13.05 Hz), 1.88 d (18H,
Ad, J = 16.05 Hz), 4.16 q (2H, OCH2, J = 7.00 Hz),
12.12 br.s (1H, NH). Found, %: C 76.47; H 8.82;
N 6.86. C26H36N2O2. Calculated, %: C 76.41; H 8.83;
N 6.80.
Harom, J = 8.10 Hz), 11.38 br.s (1H, NH); in CDCl3:
1.67 m (9H, Ad), 2.00 s (6H, Ad), 2.25 s (2H, AdCH2),
3.40 s (2H, 4-H), 7.20 m (1H, Harom), 7.40 m
(2H, Harom), 7.80 m (2H, Harom). Found, %: C 76.47;
H 8.82; N 6.86. C20H24N2O. Calculated, %: C 76.41;
H 8.83; N 6.80.
Reaction of diketo ester VIIIa with hydrazine
hydrate. A solution of 0.38 g (7.5 mmol) of hydrazine
hydrate in 2 ml of ethanol was mixed on cooling with
1.46 g (5 mmol) of ester VIIIa in 2 ml of ethanol, and
the mixture was stirred and left overnight. The solvent
was distilled off, and the residue was separated by
column chromatography using chloroform–methanol
(15:1 by volume) as eluent to isolate 0.16 g (11%) of
pyrazolone I, (colorless crystals, mp 220–224°C;
published data [7]: mp 223–224°C), 0.37 g (25%) of
3-(1-adamantyl)-1H-pyrazol-5-one (Va) (colorless
crystals, mp 289–291°C) and 0.35 g (24%) of adaman-
tane-1-carbohydrazide (IX) (colorless crystals, mp 154–
157°C; published data [9]: mp 156–157°C).
Ethyl 3-(1-adamantyl)-2-(1-adamantylcarbonyl)-
3-oxopropanoate (VI). Finely cut metallic sodium,
0.70 g (30 mmol), was added under stirring to a mix-
ture of 7.56 g (30 mmol) of ethyl 3-(1-adamantyl)-3-
oxopropanoate (IIIa) and 60 ml of anhydrous diethyl
ether, and the mixture was left to stand for 24 h. It was
then cooled in an ice bath, a solution of 6.00 g
(30 mmol) of adamantane-1-carbonyl chloride in 24 ml
of anhydrous diethyl ether was added dropwise, and
the mixture was stirred and left overnight. The mixture
was acidified with a small amount of 5% sulfuric acid,
~50 ml of water was added, the mixture was stirred,
and the ether layer was separated, washed with a 5%
solution of sodium hydrogen carbonate and water, and
dried over sodium sulfate. The solvent was distilled
off, and the residue was recrystallized from hexane.
Yield 4.64 g (37%), colorless crystals, mp 115–118°C,
Rf 0.76 (Armsorb, CHCl3−MeOH, 15:1 by volume).
IR spectrum, ν, cm–1: 1691, 1706 (C=O, ketone); 1730
(C=O, ester); 2905, 2850 (C–HAd). 1H NMR spectrum,
δ, ppm: 1.17 t (3H, CH3, J = 5.35 Hz), 1.68 s (12H,
Ad), 1.75 s (12H, Ad), 2.00 s (6H, Ad), 4.15 q
(2H, OCH2, J = 5.39 Hz), 5.75 s (1H, CH). Found, %:
C 75.64; H 8.66. C26H36O4. Calculated, %: C 75.73;
H 8.74.
Following an analogous procedure, reactions of
VIIIa with 1.50 g (30 mmol) and 2.25 g (45 mmol) of
hydrazine hydrate were performed.
Reaction of diketo ester VIIIb with hydrazine
hydrate. Hydrazine hydrate, 1.50 g (30 mmol), was
added to a solution of 1.53 g (5 mmol) of ester VIIIb
in 15 ml of ethanol, and the mixture was heated for 4 h
under reflux. The solvent was distilled off under
reduced pressure (water-jet pump), and the residue was
recrystallized from ethanol. Yield of Vb 0.45 g (39%),
colorless plates, mp 306–308°C.
Reactions of diketo esters VIIIa and VIIIb with
phenylhydrazine. A mixture of 5 mmol of ester VIIIa
or VIIIb and 0.65 g (6 mmol) of phenylhydrazine was
heated for 2 h at 70°C on a water bath, 2 ml of ethanol
was added to the hot mixture, and the mixture was left
overnight. The precipitate was filtered off and washed
with 3 ml of ethanol.
Reaction of diketo ester VI with hydrazine
hydrate. A solution of 0.15 g (3 mmol) of hydrazine
hydrate in 2 ml of ethanol was mixed on cooling with
0.80 g (2 mmol) of ester VI in 5 ml of ethanol. The
mixture was stirred and left overnight, additional 5 ml
of ethanol and 0.15 g (3 mmol) of hydrazine hydrate
were added, and the mixture was again stirred and left
overnight. The solvent was distilled off, the residue
was treated with a small amount of water, and the
precipitate was filtered off and recrystallized from
ethanol. Yield of ethyl 3,5-di(1-adamantyl)-1H-pyra-
zole-4-carboxylate (VII) 0.68 g (86%), colorless crys-
tals, mp 270–273°C, Rf 0.23 (Armsorb, CHCl3–MeOH,
15:1, by volume). IR spectrum, ν, cm–1: 1712 (C=O);
In the reaction with ester VIIIa, the product was
N-phenyladamantane-1-carbohydrazide (X). Yield 1 g
(74%), colorless crystals, mp 226–228°C, Rf 0.29
(Silufol, CCl4−Me2CO, 10:1 by volume). IR spectrum,
ν, cm–1: 1600 (C=Carom); 1641 (C=O); 2850, 2900
1
(C–HAd); 3298, 3344 (NH). H NMR spectrum, δ,
ppm: 1.70 s (6H, Ad), 1.88 m (6H, Ad), 2.00 s (3H,
Ad), 6.70 d (3H, Harom, J = 6.00 Hz), 7.10 t (2H, Harom
,
J = 6.30 Hz), 7.45 br.s (1H, NH), 9.35 s (1H, NH).
Found, %: C 71.05; H 8.09; N 10.45. C17H22N2O. Cal-
culated, %: C 71.11; H 8.15; N 10.37.
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BORMASHEVA et al.
1764
3. Seidel, F., Chem. Ber., 1935, vol. 68, p. 1913.
The residue obtained after evaporation of the
4. Stetter, H. and Rauscher, E., Chem. Ber., 1960, vol. 93,
p. 2054.
5. Stepanov, F.N., Sidorova, L.I., and Dovgan’, N.A.,
Zh. Org. Khim., 1972, vol. 8, p. 1834.
filtrate was (according to the GC–MS data) a mixture
of 86% of ethyl 3-(1-adamantyl)-5-methyl-1-phenyl-
1H-pyrazole-4-carboxylate and 14% of unidentified
substances.
6. Bormasheva, K.M., Nechaeva, O.N., Lyzhov, V.V., Pozd-
nyakov, V.V., and Moiseev, I.K., Izv. Vyssh. Uchebn.
Zaved., Ser. Khim. Khim. Tekhnol., 2005, vol. 48, no. 10,
p. 47.
In the reaction with ester VIIIb we isolated 0.42 g
(27%) of compound IVb as yellow crystals with
mp 196–197°C; published data [5]: mp 192–193°C.
7. Jae-Chul Jung, Watkins, B.E., and Avery, M.A., Tetra-
hedron, 2002, vol. 58, p. 3639.
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8. Joule, J.A. and Mills, K., Heterocyclic Chemistry,
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 12 2008