One-stage procedure of synthesis of highly reactive α-chloro-β- ketoacetals. 4-chloropyrazoles from α-chloro-β-ketodimethoxyacetals

Article abstract of DOI:10.1134/s1070428008020024

Conditions were developed where the reaction of alkyl 1,2-dichlorovinyl ketones with alcohols and 1,2-dihydroxybenzenes led to the formation of the corresponding open-chain and cyclic α-chloro-β-ketoacetals. The reaction of α-chloro-β-alkylketodimethoxyac

Full text of DOI:10.1134/s1070428008020024

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 2, pp. 184−188. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © G.V. Bozhenkov, V.A. Savosik, A.N. Mirskova, G.G. Levkovskaya, 2008, published in Zhurnal Organicheskoi Khimii, 2008,
Vol. 44, No. 2, pp. 195−199.
One-Stage Procedure of Synthesis
of Highly Reactive α-Chloro-β-ketoacetals.
4-Chloropyrazoles from α-Chloro-β-ketodimethoxyacetals
G. V. Bozhenkov, V. A. Savosik, A. N. Mirskova, and G. G. Levkovskaya
Faworsky Irkutsk Institute of Chemistry, Siberian Division, Russian Academy of Sciences, Irkutsk, 664033 Russia
e-mail: ggl@irioch.irk.ru
Received June 6, 2007
Abstract—Conditions were developed where the reaction of alkyl 1,2-dichlorovinyl ketones with alcohols and
1,2-dihydroxybenzenes led to the formation of the corresponding open-chain and cyclic α-chloro-β-ketoacetals.
The reaction of α-chloro-β-alkylketodimethoxyacetals with alkyl-, benzyl-, and arylhydrazines resulted in 1,3-
substituted 4-chloropyrazoles in 70–90% yields demonstrating that primarily formed 2,2-dimethoxy-1-chloroethyl
alkyl ketones hydrazones underwent heterocyclization.
DOI: 10.1134/S1070428008020024
CHCl
ROH + R'C(O)CCl
R'C(O)CCl CH
α-Chloro-β-ketoacetals are building blocks for
organic synthesis, promising polydentate ligands for
designing metal complex catalysts, and also models for
solving fundamental theoretical problems [1, 2]. Owing
to their high reactivity and different activity of the
reaction sites they underlie syntheses of versatile classes
of compounds [1].
NaOH
R'C(O)CClHCH(OR)2
OR
_
_
Ià Id
IIà IIc
R = Me, R' = Me (a), Et (b), Pr (c); R = Ph, R' = Pr (d)
The yields of α-chloro-β-ketoacetals sharply decreas-
ed in going from methanol to ethanol, and in the reaction
of 1,2-dichlorovinyl alkyl ketones with alcohols like
propanol and 2-methylpropanol was a mixture obtained
At the same time α-chloro-β-ketoacetals are
insufficiently used in the organic synthesis for the
methods of their preparation and isolation are very
laborous. Nowadays convenient and efficient preparation
methods are developed for α-halogen-con-taining
diketones and ketoesters [2]. α-Chloro-β-keto-acetals are
obtained mainly from very labile α-chloro-β-
ketoaldehydes, and among them only formyl deriva-tives
of aryl methyl ketones and hydroxymethylene ketones
with a substituent (alkyl or nitro group) at the α-carbon
atom are relatively stable [1, 2].
1
(as shown by H NMR data) of compounds where the
content of the target α-chloro-β-ketoacetal was 20–30%.
The distillation of these reaction mixtures led to the
decomposition of the products mixtures.
Yet the reaction of phenol with 1,2-dichlorovinyl
ketones in aprotic solvents (DMSO, DMF) without
heating stopped at the stage of the corresponding
(phenoxy)chlorovinyl propyl ketone (Id). The addition
of the second phenol molecule with simultaneous
formation of an intractable mixture of products
occurres only at heating of the reagents for 5–6 h at
50–60°C.
In continuation of the research on the reactivity of
the synthesized 1,2-dichlorovinyl alkyl ketones [3] we
involved them into a reaction with alcohols and phenols
in the presence of an equimolar quantity of NaOH. Both
alkanols and DMSO, DMF were used as solvents.
At raising the amount of alkali to the ratio ketone :
NaOH = 1:2 the reaction carried out in alcohol involved
also the chlorine atom in the α-position with respect to
the carbonyl group. We failed to find the conditions for
selective formation of trialkoxyethyl ketones: at varying
1,2-Dichlorovinyl alkyl ketones reacted with
methanol in the presence of 1 equiv of alkali at 30–40°C
giving the corresponding ketoacetals IIa–IIc; therewith
the intermediate alkoxyvinyl ketones Ia–Ic were not
isolated in an individual state except for ketone Id.
184

ONE-STAGE PROCEDURE OF SYNTHESIS OF HIGHLY REACTIVE α-CHLORO-β-KETOACETALS.
185
1
the process temperature, the content of alkali and alcohol
we isolated only a mixture of trialkoxyethyl ketones (20–
40%) with compounds of unknown structure as showed
the data of 1H and 13C NMR spectra.
In the H NMR spectra of ketoacetals IIa–IIc the
doublet signals of protons from CHCl and CH(OR)2
groups appeared at 4.15–4.24 and 4.54–4.61 ppm
respectively. It should be noted also that the methoxy
groups of ketoacetals IIa–IIc are magnetically
nonequivalent and therefore two singlet proton and
carbon signals from OCH3 groups are observed in the
1H and 13C NMR spectra (ΔδH 0.4, ΔδC 1.15–1.40 ppm).
The carbon of the carbonyl group in the 13C NMR
spectra of obtained ketoacetals IIa–IIc, IIIa, and IIIb
gives rise to a signal in the region 200.03–203.52 ppm,
whereas the analogous carbon signal in the spectrum of
propyl phenoxyvinyl ketone Id is shifted upfield by 6–
9 ppm.
In the 1H NMR spectra of cyclic ketoacetals IIIa and
IIIb the proton signal of CHCl group is shifted downfield
(Δδ ~ 0.26 ppm) compared to the analogous signal in the
spectra of the corresponding dimethoxy-ketoacetals IIa–
IIc and similarly to the protons of CH(OR)2 group
appears as two doublets: in the spectrum of cyclic acetal
IIIa the coupling constants corresponding to the doublet
proton signals of CHCl and CH(O2X) groups equal J 4.4
O
RCCClHCH(OCH3)2 + CH3OH
O
_
55 60oC
RCCCHCH(OCH3)2 + ?
OCH3
R = CH3, C2H5, C3H7.
Alkyl 1,2-dichlorovinyl ketones reacted with 1,2-di-
hydroxybenzenes at 50–60°C in DMSO giving in good
yield 2-(acyl)chloromethylbenzo-1,3-dioxoles, cyclic
α-chloro-β-ketoacetals IIIa and IIIb.
R'
O
HO
HO
RCCCl CHCl +
R'
R'
1
Hz. In the H NMR spectrum of compound IIIb the
proton signals of groups CHCl and CH(O2X) give rise
to two doublets with a coupling constant J 4.7 Hz.
O
O
NaOH
RCCClH CH
O
R'
This magnetic nonequivalence of protons and carbons
of the methine and alkoxy groups in compounds IIa–
IIc, IIIa, and IIIb revealed by the H and 13C NMR
IIIà, IIIb
1
R = Pr, R’ = H (a); R = Et, R’ = t-Bu (b).
spectra originates from the presence in the structures of
the molecules under investigation of one (IIa–IIc and
IIIa) or two (IIIb) asymmetric centers.
The structure of compounds obtained was investigated
by IR and NMR spectroscopy, the composition was
confirmed by elemental analysis.
Hence we for the first time developed conditions for
preparation from 1,2-dichlorovinyl ketones of α-chloro-
β-ketodimethoxyacetals and cyclic α-chloro-β-keto-
acetal in 45–88% yield, that might underlie syntheses of
versatile classes of compounds. But first of all the
α-chloro-β-ketoacetals are valuable initial substances for
the synthesis of heterocyclic compounds, in particular,
of halogenated pyrazoles, similar to the other 2-halogen-
containing 1,3-dicarbonyl compounds. For instance, the
reaction of β-ketoesters, diketones, ketoaldehydes and
their acetals with hydrazine and phenylhydrazine is
known to be a convenient procedure for the synthesis of
functionalized pyrazoles [1, 4, 5], but similar reactions
of 2-haogen-containing β-dicarbonyl compounds are
poorly documented [1, 2, 4, 5], evidently because of
unavailability of the initial substances. It is known [4]
In the IR spectrum of 2-phenoxy-1-chlorovinyl propyl
ketone (Id) absorption bands appeared of C=O, C=C,
and C–H bonds of aromatic, alkyl, and olefin groups. In
1
the H NMR spectrum of ketone Id alongside the
characteristic resonances of the protons of the propyl
and phenyl groups a downfield singlet was observed
belonging to the olefin proton.
1
In the H NMR spectra of the products mixtures
obtained in reactions of 1,2-dichlorovinyl alkyl ketones
in the presence of 1 equiv of alkali with ethanol, propanol,
butanol and 2-methylpropanol also the downfield singlet
of the olefin proton was observed at 7.8–8.0 ppm.
In the IR spectra of compounds synthesized IIa–IIc,
IIIa, and IIIb the absorption bands of the C=O group
appeared in the region 1710–1720 cm–1.
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BOZHENKOV et al.
186
The structure of compounds obtained was investigated
by IR and NMR spectroscopy, the composition was
confirmed by mass spectra and elemental analysis.
that 2-chloro- and 2-bromoacetoacetate react with
phenylhydrazine to form 4-chloro-(bromo)-5-methyl-2-
phenylpyrazol-3-one. From the reaction of 2-chloro-
acetoacetate with hydrazine at the temperature not
exceeding –20°C was isolated in 35% yield 3(5)-hy-
droxy-4-chloro-5(3)-methylpyrazole [4]. Similarly
reacted with hydrazine also the fluoroalkyl-containing
2-chloro-1,3-ketoesters giving the cor-responding
pyrazolones in 35–60% yield [5]. A side reaction in this
process was a reduction by hydrazines of the halogen-
containing ketoesters and halopyrazoles and the
formation of pyrazoles without halogen in the ring and
halogen-free esters [4, 5].
In the IR spectra of 1-alkyl-4-chloropyrazoles Va–Vf
attention should be attracted by the absorption band in
the region 3125–3150 cm–1 characteristic of the stretch-
ing vibrations of the C5–H bonds of the heterocycle. The
absorption bands of C=C and C=N bonds of the hetero-
cycle appeared in the IR spectra at 1470–1575 cm–1.
In the 1H NMR spectra of pyrazoles Va–Vf the signals
of protons H5 are observed in the region 7.23–7.27 ppm.
This chemoselective reaction of formation of
1,3-substituted 4-chloropyrazoles characterizes the
potential of α-chloro-β-ketoacetals application to the
synthesis of functionalized pyrazoles. For instance, after
preliminary replacement of the chlorine in the initial
α-chloro-β-ketoacetals by other functional groups the
reaction with hydrazines can yield 4-organyloxy, -thio-,
-aminopyrazoles that are widely used as semiproducts
for production of dyes, fluorescent substances, efficient
pesticides, and pharmaceuticals. They also possess
a theoretical interest due to the wealth of the chemical
transformations.
We established that in the reaction of α-chloro-β-
ketodimethoxyacetals IIa–IIc with alkyl- and
arylhydrazines formed 1,3-substituted 4-chloropyrazoles
Va–Vf in 70–90% yield. The reaction was carried out
by heating the mixture of β-keto-α-chloroacetals IIa–
IIc with hydrazines in methanol for 5 h (see the scheme).
The corresponding 1,5-disubstituted 4-chloropyr-
azoles were not detected indicating that the intra-
molecular heterocyclization occurred in the primary
formed 2,2-dimethoxy-1-chloroethyl alkyl ketones
hydrazones IVa–IVg. Therewith the reduction of the
chlorine-containing products giving free of chlorine
ketoacetals and pyrazoles similarly to reactions of
ketoesters with hydrazines [4, 5] was not observed.
Therefore we developed a new method for the
synthesis of α-chloro-β-ketoacetals, promising semi-
products for preparation of heteroatomic multifunctional
systems and heterocyclic compounds, and for the first
time showed the possibility to synthesize pyrazoles
therefrom.
Hydrazones IVa–IVf were not isolated in pure state
save 2,2-dimethoxy-1-chloroethyl methyl ketone 2,4-di-
nitrophenylhydrazone (IVg) whose structure proved the
preliminary formation of hydrazones involving the keto
group of ketoacetals IIa–IIc followed by the cyclization
of the formed hydrazones IVa–IVf into the target
4-chloropyrazoles.
EXPERIMENTAL
1H and 13C NMR spectra were registered on a spec-
trometer Bruker DPX-400 (400.6 and 100.61 MHz
respectively) from solutions in CDCl3, 1H NMR spectrum
of compound Ivg was registered in DMSO-d6. Chemical
Pyrazoles Va–Vf were also obtained by a one-pot
procedure without isolation of chloroketoacetals from
the reaction mixture where the latter were formed.
1
shifts of H and 13C were measured with respect to
Scheme.
NHR'
Cl
Cl
R
R
N
O
RCCHClCH(OCH3)2
RCCHClCH(OCH3)2 + H2NNHR'
N
N
OCH3
_
N
N
IVà IVg
R'
R'
_
Và Ve
R= CH3, R'= C6H5 (a), C7H15 (b) C6H3(NO2)2-2,4 (IVg); R = C2H5, R'= C2H5 (c), CH2C6H5 (d); R = C3H7, R' = C2H5 (e),
C6H5 (f).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

ONE-STAGE PROCEDURE OF SYNTHESIS OF HIGHLY REACTIVE α-CHLORO-β-KETOACETALS.
187
HMDS. IR spectra were recorded on spectrophotometer
Specord IR75 from KBr pellets or thin films.
200.63 (C=O), 104.09 (CH), 61.58 (CHCl), 55.83
(OCH3), 54.68 (OCH3), 27.55 (CH3). Found, %: C 43.30;
H 6.60; Cl 21.26. C6H11ClO3. Calculated, %: C 43.26;
H 6.65; Cl 21.28.
1-Chloro-2-phenoxyvinyl propyl ketone (Id). To
a solution of 0.95 g (0.01 mol) of phenol and 0.4 g
(0.01 mol) of NaOH in 15 ml of DMSO was added
dropwise at stirring 1.67 g (0.01 mol) of propyl 1,2-di-
chlorovinyl ketone. The reaction mixture was stirred at
room temperature for 5 h and was left standing overnight,
then it was diluted with water and extracted with
dichloromethane. The extract was dried with MgSO4,
the solvent, initial ketone and phenol were distilled off
in a vacuum. Yield 0.68 g (30%), very viscous undistil-
lable substance, nD20 1.5540. IR spectrum, ν, cm–1: 3075
(HC=), 2965, 2935, 2875 (C3H7), 1685 (C=O). 1H NMR
spectrum, δ, ppm: 7.93 s (1H, =CH), 7.30 t, 7.13 t,
7.03 d (5H, C6H5), 2.63 t (2H, CH2, J 7.2 Hz), 1.60 m
(2H, CH2, J 7.2 Hz), 0.89 t (3H, CH3, J 7.2 Hz). Found,
%: C 64.35; H 5.90; Cl 15.75. C12H13ClO2. Calculated,
%: C 64.15; H 5.83; Cl 15.78.
1,1-Dimethoxy-2-chloropentan-3-one (IIb). Yield
1.63 g (45%), bp 70–72°C (5 mm Hg), nD20 1.4685. IR
spectrum, ν, cm–1: 2975, 2935, 2835 (Alk), 1720 (C=O).
1H NMR spectrum, δ, ppm: 4.56 d (1H, CH, J 6.7 Hz),
4.20 d (1H, CHCl, J 6.7 Hz), 3.38 s (3H, OCH3), 3.34 s
(3H, OCH3), 2.60 t (2H, CH2, J 7.1 Hz), 1.01 t (3H, CH3,
J 7.1 Hz). 13C NMR spectrum, δ, ppm: 203.52 (C=O),
104.30 (OCHO), 60.66 (CHCl), 56.05, 54.60, 34.00
(CH2), 7.54 (CH3). Found, %: C 46.48; H 7.33; Cl 19.65.
C7H13ClO3. Calculated, %: C 46.55; H 7.25; Cl 19.63.
1,1-Dimethoxy-2-chlorohexan-3-one (IIc). Yield
1.94 g (50%), bp 75–80°C (5 mm Hg), nD20 1.4409. IR
spectrum, ν, cm–1: 2970, 2950, 2870, 2840 (Alk), 1720
1
(C=O). H NMR spectrum, δ, ppm: 4.54 d (1H, CH,
J 6.7 Hz), 4.14 d (1H, CHCl, J 6.7 Hz), 3.36 s (3H,
OCH3), 3.32 s (3H, OCH3), 2.50 t (2H, CH2, J 7.4 Hz),
1.54 m (2H, CH2, J 7.4 Hz), 0.83 t (3H, CH3, J 7.4 Hz).
13C NMR spectrum, δ, ppm: 202.22 (C=O), 103.56
(OCHO), 59.99 (CHCl), 55.36, 53.90, 41.82 (CH2), 16.19
(CH2), 11.01 (CH3). Found, %: C 50.26; H 7.80; Cl 18.17.
C8H15ClO3. Calculated, %: C 49.36; H 7.77; Cl 18.21.
Under similar conditions in reactions of propyl 1,2-di-
chlorovinyl ketone with methanol, ethanol, propanol,
2-methylpropanol, and butanol were isolated mixtures
1
of undistillable products whose H NMR spectra
contained groups of signals in the region 7.89–8.01 ppm
and two unresolved doublets in the region 4.20–4.60 ppm.
In the IR spectra were observed wide bands in the region
3055–3070, 2970–2880, 1685 cm–1.
2-(1-Chloro-2-oxopentyl)benzo-1,3-dioxole (IIIa).
To a solution of 1.1 g (0.01 mol) of pyrocatechol and
0.4 g (0.01 mol) of NaOH in 15 ml of DMSO was added
dropwise at stirring 1.67 g (0.01 mol) of propyl 1,2-di-
chlorovinyl ketone. The reaction mixture was stirred at
50–60°C for 3 h, then it was diluted with water and
extracted with dichloromethane. The extract was dried
with MgSO4, the solvent was distilled off in a vacuum.
Yield 1.45 g (60%), very viscous undistillable substance.
IR spectrum, ν, cm–1: 3065 (C=O), 2960, 2925, 2875
(C3H7), 1710 (C=O). 1H NMR spectrum, δ, ppm: 6.80 m
(4H, C6H4), 6.45 d (1H, CH, J 4.4 Hz), 4.46 d (1H, CHCl,
J 4.4 Hz), 2.68 t (2H, CH2, J 7.2 Hz), 1.61 m (2H, CH2,
J 7.2 Hz), 0.90 t (3H, CH3, J 7.2 Hz). 13C NMR spectrum,
δ, ppm: 202.17 (C=O), 146.69, 121.99, 120.32, 115.32,
108.62, 107.96, 61.97 (CHCl), 42.41 (CH2), 16.51 (CH2),
13.27 (CH3). Found, %: C 59.90; H 5.50; Cl 14.70.
C12H13ClO3. Calculated, %: C 59.88; H 5.44; Cl 14.73.
α-Chloro-β-ketodimethoxyacetals IIa–IIc. General
procedure. To a solution of 0.4 g (0.01 mol) of NaOH in
30 ml of methanol was added dropwise at stirring
0.01 mol of alkyl 1,2-dichlorovinyl ketone. The reaction
mixture was heated at 30–40°C for 3 h, and on cooling it
was diluted with 100 ml of water, extracted with CH2Cl2,
the extract was dried with MgSO4 and distilled.
At heating of a mixture of equimolar amounts of alkyl
1,2-dichlorovinyl ketones and alkali in ethanol, propanol,
2-methylpropanol, and butanol at 50–60°C for 3 h were
isolated mixtures of undistillable products whose
1H NMR spectra contained signals of groups CHCl,
CH(OAlk)2 and of protons from fragments RC(O) and
AlkO. In the IR spectra were observed wide bands in the
region 2970–2880, 1690–1710 cm–1.
1,1-Dimethoxy-2-chlorobutan-2-one (IIa). Yield
1 g (60%), bp 62–64°C (20 mm Hg), nD20 1.4340. IR
spectrum, ν, cm–1: 2935, 2830 (CH3), 1710 (C=O).
1H NMR spectrum, δ, ppm: 4.61 d (1H, CH, J 6.3 Hz),
4.24 d (1H, CHCl, J 6.3 Hz), 3.45 (3H, OCH3), 3.41
(3H, OCH3), 2.30 (3H, CH3). 13C NMR spectrum, δ, ppm:
2-(1-Chloro-2-oxobutyl)-4,6-di-tert-butylbenzo-
1,3-dioxole (IIIb) was obtained in the same way as
compound IIIa from 1.56 g (7 mmol) of 3,5-di-tert-
butylpyrocatechol, 0.28 g (7 mmol) of NaOH, and 1.07
g (7 mmol) of ethyl 1,2-dichlorovinyl ketone in 10 ml of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

BOZHENKOV et al.
188
DMSO. Yield 1.18 g (50%). IR spectrum, ν, cm–1: 3085
(C–HAr), 2950, 2900, 2870 (Alk), 1710 (C=O). 1H NMR
spectrum, δ, ppm: 6.85 s, 6.75 s (2H, C6H2), 6.43 d (1H,
CH, J 4.5 Hz), 4.48 d (1H, CHCl, J 4.5 Hz), 2.75 q (2H,
CH2, J 7.2 Hz), 1.39 s (9H, C4H9), 1.30 s (9H, C4H9),
1.09 t (3H, CH3, J 7.2 Hz). Found, %: C 68.10; H 8.20;
Cl 10.24. C19H27ClO3. Calculated, %: C 67.34; H 8.03;
Cl 10.46.
1-Heptyl-3-methyl-4-chloropyrazole (Vb). a. Yield
1.83 g (85%), viscous fluid, purified by column
chromatography on silica gel, eluent hexane. nD20 1.4800.
IR spectrum, ν, cm–1: 3140 (=C–H), 2960, 2930, 2860
1
(Alk), 1540 (C=C). H NMR spectrum, δ, ppm: 7.26 s
(1H, =C–H), 3.96 t (2H, CH2, J 7.1 Hz), 1.78 m (2H,
CH2), 1.26 m [8H, (CH2)4], 0.86 t (3H, CH3, J 7.1 Hz).
13C NMR spectrum, δ, ppm: 144.8 (C3), 126.7 (C5), 108.0
(C4), 52.3, 31.4, 30.0, 28.5, 26.2, 23.3, 13.7 (C7H15).
Found, %: C 60.78; H 8.91; Cl 12.59; N 18.54.
C11H19ClN2. Calculated, %: C 61.53; H 8.92; Cl 16.51;
N 13.05.
Methyl 1-chloro-2,2-dimethoxyethyl ketone
2,4-dinitrophenylhydrazone (IVg). To a solution of
0.98 g (5 mmol) of 2,4-dinitrophenylhydrazine in 30 ml
of methanol and 7 ml of 25% sulfuric acid was poured at
stirring 0.83 g (5 mmol) of methyl 1-chloro-2,2-di-
methoxyethyl ketone (IIa). The reaction mixture was
stirred at room temperature for 4 h and was left standing
overnight, then it was diluted with 50 ml of water, the
separated precipitate was filtered off and dried. Yield
1.5 g (88%), mp 93–95°C. IR spectrum, ν, cm–1: 3300
(NH), 3090 (CHAr), 2930, 2840 (CH3), 1610, 1585 (C=N,
1,3-Diethyl-4-chloropyrazole (Vc). b. Yield 1.27 g
(80%), bp 77–80°C (14–15 mm Hg). IR spectrum, ν,
cm–1: 3130 (=C–H), 2960, 2940, 2860 (Alk), 1560 (C=C).
1H NMR spectrum, δ, ppm: 7.27 s (1H, =C–H), 4.03 q
(2H, CH2, J 7.3 Hz), 2.61 q (2H, CH2, J 7.7 Hz), 1.41 t
(3H, CH3, J 7.3 Hz), 1.23 t (3H, CH3, J 7.7 Hz). Found,
%: C 53.10; H 7.51; Cl 22.30; N 17.89. C7H11ClN2.
Calculated, %: C 53.00; H 6.99; Cl 22.35; N 17.66.
1
C=C), 1510, 1325 (NO2). H NMR spectrum (DMSO-
d6), δ, ppm: 10.80 (1H, NH), 8.84 d (1H, H3', 4J 2.3 Hz),
1-Benzyl-3-ethyl-4-chloropyrazole (Vd). a. Yield
1.98 γ (90%), viscous fluid, purified by column
chromatography on silica gel, eluent hexane. nD20 1.5610.
IR spectrum, ν, cm–1: 3140 (=C–H), 2970, 2940, 2870
4
8.40 d.d (1H, H5', J 2.3, 9.5 Hz), 7.89 d (1H, H6',
4J 9.5 Hz), 4.84 d (1H, CH, 3J 7.3 Hz), 4.77 d (1H, CHCl,
3J 7.3 Hz), 3.41 s (3H, OCH3), 3.34 s (3H, OCH3), 2.13
(3H, CH3). Found, %: C 41.60; H 4.26; Cl 10.25; N 16.19.
C12H15ClN4O6. Calculated, %: C 41.57; H 4.36; Cl 10.23;
N 16.16.
1
(Alk), 1520 (C=C). H NMR spectrum, δ, ppm: 7.21 s
(1H, =C–H), 7.32–7.20 m (5H, C6H5), 5.17 s (2H, CH2),
2.68 q (2H, CH2, J 7.6 Hz), 1.29 t (3H, CH3, J 7.6 Hz).
Found, %: C 67.05; H 6.00; Cl 15.27; N 12.08.
C12H13ClN2. Calculated, %: C 67.10; H 5.63; Cl 15.23;
N 12.04.
4-Chloropyrazoles Va–Vf. General procedure. a.
To a solution of 0.01 mol of an appropriate α-chloro-β-
ketoacetal in 30 ml of methanol was added dropwise
0.01 mol alkyl(aryl)hydrazine. The reaction mixture was
boiled for 5 h, diluted with water, extracted with ether,
the extract was dried with CaCl2 and subjected to
distillation.
1-Ethyl-3-propyl-4-chloropyrazole (Ve). a. Yield
1.29 g (75%), bp 70°C (5 mm Hg), nD20 1.4838. IR
spectrum, ν, cm–1: 3140 (=C–H), 2960, 2940, 2860 (Alk),
1
1520 (C=C). H NMR spectrum, δ, ppm: 7.27 s (1H,
b. To a solution of ketoacetals IIa–IIc prepared in
30–40 ml of methanol from 0.01 mol of an appropriate
alkyl 1,2-dichlorovinyl ketone in the presence of 0.4 g
(0.01 mol) of NaOH without isolation of ketoacetal from
the reaction mixture was added at stirring 0.01 mol
of alkyl(aryl)hydrazine. Further process and workup were
performed as described in procedure a.
=C–H), 4.03 q (2H, CH2, J 7.3 Hz), 2.56 t (2H, CH2,
J 7.5 Hz), 1.66 m (2H, CH2), 1.40 t (3H, CH3, J 7.3 Hz),
0.94 t (3H, CH3, J 7.5 Hz). 13C NMR spectrum, δ, ppm:
148.8 (C3), 126.1 (C5), 107.7 (C4), 27.5, 15.1, 13.5
(C3H7). Found, %: C 55.60; H 7.45; Cl 20.58; N 16.31.
C8H13ClN2. Calculated, %: C 55.65; H 7.59; Cl 20.53;
N 16.22.
1-Phenyl-3-methyl-4-chloropyrazole (Va). a. Yield
1.49 g (77%), bp 125°C (4 mm Hg). IR spectrum, ν,
cm–1: 3130, 3050 (=CH), 2950, 2920 (CH3), 1595 (C=C).
1H NMR spectrum, δ, ppm: 7.76 s (1H, H5), 7.55 d, 7.37 t,
7.20 t (5H, C6H5), 2.28 (3H, CH3). Found, %: C 62.30;
H 4.75; Cl 18.38; N 14.52. C10H9ClN2. Calculated, %:
C 62.35; H 4.71; Cl 18.40; N 14.54.
1-Phenyl-3-propyl-4-chloropyrazole (Ve). a. Yield
1.55 g (70%), bp 155°C (8 mm Hg), nD20 1.5766. IR
spectrum, ν, cm–1: 3140, 3050 (=CH), 2950, 2925, 2870
1
(C3H7), 1595 (C=C). H NMR spectrum, δ, ppm: 7.76
(1H, H5), 7.57 d, 7.37 t, 7.21 t (5H, C6H5), 2.65 t (2H,
CH2, J 7.4 Hz), 1.73 m (2H, CH2, J 7.4 Hz), 0.98 t (3H,
CH3, J 7.4 Hz). 13C NMR spectrum, δ, ppm: 151.46 (C3),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008

ONE-STAGE PROCEDURE OF SYNTHESIS OF HIGHLY REACTIVE α-CHLORO-β-KETOACETALS.
189
139.83 (C1'), 129.41 (C3',5'), 126.36 (C5), 124.84 (C4'),
118.59 (C2',6',4'), 27.89 (CH2), 21.89 (CH2), 13.87 (CH3).
Found, %: C 65.35; H 6.00; Cl 16.08; N 12.66.
C12H13ClN2. Calculated, %: C 65.31; H 5.99; Cl 16.06;
N 12.69.
REFERENCES
1. Kochetkov, N.K. and Nifant’ev, E.E., Zh. Org. Khim., 1961,
p. 31.
2. Meshram, H.M., Reddy, P.N., Vishnu, P., Sadashiv, K.,
Yadav, J.S., Tetrahedron Lett., 2006, vol. 47, p. 991.
3. Bozhenkov, G.V., Levkovskaya, G.G., Larina, L.I., Ushakov,
P.E., Dolgushin, G.V., Mirskova, A.N., Zh. Org. Khim.,
2004, vol. 40, p. 1632.
4. Schonbrodt, R., Lieb. Ann., 1989, vol. 253, p. 168.
5. Pashkevich, K.I., Skryabina, Z.E., and Saloutin, V.I., Izv.
Akad. Nauk SSSR, Ser. Khim., 1987, p. 2527.
The study was carried out under a financial support
of the Russian Foundation for Basic Research (grant no.
05-03-97202) and of the Russian Academy of Sciences
(program of the Presidium of the Russian Academy of
Sciences “Fundamental science for medicine”,
interdisciplinary integration project no. 54).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 2 2008