Synthesis of ethophenprox

Article abstract of DOI:10.1023/A:1022562101602

An ethophenprox synthesis from easily available p-nitroneophyl chloride was developed. The reduction of the latter to aniline derivative followed by Sandmayer's and Claisen's reactions furnished p-ethoxyneophyl chloride that by condensation with 3-phenoxybenzyl alcohol in the presence KOH in DMSO yielded ethophenprox.

Full text of DOI:10.1023/A:1022562101602

Russian Journal of Organic Chemistry, Vol. 38, No. 11, 2002, pp. 1629 1634. Translated from Zhurnal Organicheskoi Khimii, Vol. 38, No. 11, 2002,
pp. 1685 1690.
Original Russian Text Copyright
2002 by Rakhimov, Galin, Tomilov, Le.
Synthesis of Ethophenprox*
R. G. Rakhimov1, F. Z. Galin1, Yu. V. Tomilov1, and V. T. Le2
1Institute of Organic Chemistry, Ufa Scientifc Center, Russian Academy of Sciences, Ufa, 450054 Russia
2Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, 197034 Russia
Received June 17, 2002
Abstract An ethophenprox synthesis from easily available p-nitroneophyl chloride was developed. The
reduction of the latter to aniline derivative followed by Sandmayer,s and Claisen,s reactions furnished
p-ethoxyneophyl chloride that by condensation with 3-phenoxybenzyl alcohol in the presence KOH in DMSO
yielded ethophenprox.
Insecticide ethophenprox [2-(p-ethoxyphenyl)-
methylpropyl m-phenoxybenzyl ether] (I) according
to mechanism of its action belongs to pyrethroids
although it does not contain cyclopropane and ester
groups[1]. It is prepared by condensation of p-ethoxy-
neophyl and m-phenoxybenzyl components.
m-Phenoxybenzyl halide and m-phenoxybenzyl
alcohol are semiproducts in production of drugs
phenotrin and permetrin [2], therefore the develop-
ment of a feasible procedure for preparation of
p-ethoxyneophyl alcohol (II) and p-ethoxyneophyl
halide (III) is an interesting problem.
The phenetole alkylation with methallyl chloride
in the presence of H2SO4 affords compound III in an
yield no more than 70% [ratio (III): (V) = 4: 1,
GLC] [10, 11].
Alcohol II is known to be obtained [3] from the
nitrile of the p-ethoxyphenylacetic acid (IV) that in
its turn is prepared from the p-chloromethylphenetole.
The phenetole chloromethylation is accomplished by
Blanc procedure [4, 5] and results in a hard-to-separate
mixture of para- and ortho-isomers [6].
The other reaction sequence starts with p-cresol:
its ethyl ether is transformed into nitrile IV by
successive treatment with N-bromosuccinimide (NBS)
[7, 8] and KCN [9].
All attempts to increase the regioselectivity and
the yield in this reaction by variation of the process
conditions and by the use of other catalysts failed.
*
We tried to synthesize p-ethoxyneophyl alcohol
The study was carried out under partial financial support of
(II) by alkylation of phenetole with methallyl alcohol
Bashkortostan Academy of Sciences (contract no. 4/2-2002).
1070-4280/02/3811-1629$27.00 2002 MAIK Nauka/Interperiodica

1630
RAKHIMOV et al.
under acid catalysis conditions. It was established that
irrespective the reagents ratio in the presence of
H2SO4 formed a complex mixture of products; the
main among them was dimer of the methallyl alcohol
4-[(2-methyl)allyl-3-oxy]-2-methyl-n-propanol (53%)
[12]. The catalysis with ClSO3H provided product VI,
a known DDT analog [13].
In the 13C NMR spectrum of compounds VIII and
IX the chemical shifts of the gem-dimethyl groups are
different: in compound VIII axial group gives a
signal at 19.38 ppm [14], and equatorial group at
21.54ppm. In the spectrum of 5-phenoxy isomer IX
the respective signals appear at 32.30 and 33.55 ppm.
The same result was obtained with TiCl4 as catal-
yst: alkylation occurred virtually immediately, but
was accompanied with a strong tarring of the reacting
mixture. The catalysis with H3PO4 required heating
to 80 C and yielded the same product. Compound
VI was also obtained in high yield by alkylation
phenetole in the presence of ClSO3H or TiCl4 with
methallyl pentafluorobenzyl ether (VII), methallyl
acetate, methallyl chloride, and methacrolein.
1
In the H NMR spectrum of the mixture of com-
pounds VIII and IX the protons from the axial methyl
of the 5-phenoxy isomer IX give rise to a signal at
0.89 ppm whereas those from the axial methyl of the
7-phenoxy isomer VIII resonate at 0.92 ppm. The
methylene protons signals appear as complex multi-
plets in the region 3.35 3.60 and 4.46 4.56 ppm.
Ether VII was synthesized from methallyl
alcohol and pentafluorobenzyl bromide. At the use of
methallyl chloride and pentafluorobenzyl alcohol
arose high-melting yellow-brown powder of unknown
structure. Compound VII is a strong lacrimator.
We investigated the possibility to obtain p-ethoxy-
neophyl chloride (III) from the easily available
neophyl chloride.
An attempt to alkylate phenetole with methallyl
m-phenoxybenzyl ether (prepared from methallyl
alcohol and m-phenoxybenzyl bromide) in the
presence of H2SO4 as catalyst resulted in a complex
mixture of products where prevailed isochromans
VIII and IX isolated by column chromatography on
silica gels as a 1: 1 mixture (GLC) in an overall yield
46%.
It was established that sulfonation of neophyl
chloride with chlorosulfonic acid by procedure [15]
occurred in the para-position, but although alkaline
melting of the sodium salt X as in [16] resulted in
complete substitution of the sulfo group by hydroxyl,
it was accompanied by dehalogenation and partial
degradation of the carbon skeleton thus giving rise to
a mixture of p-alkylphenols.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

SYNTHESIS OF ETHOPHENPROX
1631
The reaction products did not contain chlorine
and sulfur as shown by elemental analysis. The
analysis of the complicated set of signals in the
upfield part of their H NMR spectra together with
the mass-spectral data permitted a conclusion that the
main reaction products were p-tert-butylphenol (XI)
(m/z 150) and p-iso-propylphenol (XII) (m/z 136).
The nitration of neophyl chloride under the common
conditions [17] also occurred exclusively in the
para-position in a high yield [18]. By hydrogenation
1
in the pressure reactor on Renay nickel in ethanol
[19] we obtained from p-nitroneophyl chloride (XIII)
p-aminoneophyl chloride (XIV) in 70% yield.
acid [21]) were not satisfactory. The reduction of
compound XIII with a mixture of nickel chloride and
aluminum powder in THF [22] gave rise to a complex
mixture of products. Diazotization of aniline XIV
with sodium nitrite in dilute hydrochloric acid by the
usual procedure [23] afforded p-(1-chloro-2-methyl-
iso-propyl)phenol (XV) [24] in 52% yield. The side
product of this reaction was neophyl chloride (yield
15%).
In the IR spectrum of amine XIV were observed
the stretching vibrations (as a broad hump with a
1
maximum at 2600 cm ) and bending vibrations
1
(narrow peak at 1584 cm ) of the NH group that are
characteristic of quaternary ammonium salts R2NH+2 ,
and also weak broad absorption bands with a fine
structure corresponding to the nonbonded amine at
The alkylation of phenol XV with ethyl bromide in
the presence of NaOH [25] or under conditions of the
phase-transfer catalysis is accompanied by a side
process, alkylation with the alkyl chloride moiety of
the other molecule XV. The reaction carried out
in acetone at 40 C in the presence of potassium
carbonate resulted in 67% yield of ether III, but at
boiling the yield fell to 56%.
1
1
3328 and 3240 cm . In the H NMR spectrum the
protons attached to nitrogen appear as a signal at
7.26 ppm as is common for compounds of R2NH2+
type. The elemental analysis indicated that about 95%
of chlorine in the product was present as chloride ion.
On addition of hydrochloric acid to the alcoholic
solution of the aniline no blue shift of absorption
maxima in the UV spectrum was observed. These
data indicate that aniline XIV obtained nearly
completely exists as an ammonium salt that apparent-
ly arises from intermolecular interactions.
The condensation of chloride III with m-phenoxy-
benzyl alcohol was accomplished with good yield in
solution of 1,3-dimethyl-2-imidazolidinone in the
presence of solid KOH [27]. Also the other polar
aprotic solvents (DMSO, DMF, HMPA etc.) and
It is possible that the quaternization is due to the
severe reaction conditions (high temperature and
pressure). However the attempts to reduce nitro
compound XIII under mild conditions (with iron
metal in benzene [20] and tin chloride in hydrochloric
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

1632
RAKHIMOV et al.
bases (NaOH, tert-BuOK, NaH etc.) are also used
[28]. It should be taken into consideration that the
condensation of 2-(4-ethoxyphenyl)-2-methylpropyl
chloride (III) with 3-phenoxybenzyl alcohol proceeds
under severe conditions and is usually accompanied
with hydrolysis of the ethoxy group and formation of
meta and para-isomers in 4: 1 ratio was separated by
column chromatography on silica gel L 40 100,
eluent hexane ethyl acetate, 9: 1.
1-Chloro-2-(2-ethoxyphenyl)-2-methylpropane
1
(V). HNMR spectrum, , ppm: 1.42 t (3H, CH2CH3,
J 1.7), 1.59 s [6H, C(CH3)2], 3.02 s (2H, CH2Cl),
4.04q (2H, CH2CH3, J1.7), 6.50 7.35s (4H, C arom
H). Found, %: C 67.12; H8.27; Cl16.55. C12H17ClO.
Calculated, %: C 67.75; H 8.07; Cl 16.66.
2-(4-hydroxyphenyl)-2-methylpropyl
3-phenoxy-
benzyl ether (XVI). The latter compound requires
repeated ethylation [29].
We chose reaction conditions suppressing the side
process. Thus, at 1: 1 molar ratio of chloride III to
3-phenoxybenzyl alcohol (KOH/DMSO) at 130
140 C in 5 h compounds I and XVI arise in the ratio
2: 3 in an overall yield of 56%, i.e. the yield of
ethophenprox attains 22%.
1,1-Di(h-ethoxy)phenyl-2-methylpropane (VI).
(a)The alkylation of phenetole with 0.26g of
methallyl chloride in the presence of 0.23 g (2 mmol)
of chlorosulfonic acid afforded 0.4 g (64%) of com-
pound VI. (b). Reaction catalyzed with 0.38 g
(2 mmol) of TiCl4 occurred virtually immediately and
with strong tarring of the reaction mixture. Yield
0.38 g (60%). (c). With 0.25 g (2 mmol) of 80%
H3PO4 as catalyst the reaction mixture was heated to
80 C. Yield 0.9 g (63%).
At 110 120 C in 15 h was obtained mainly
ethophenprox (I), and its yield reached 42.5% [(I):
(XVI) ratio was 5: 1, overall yield 51%].
Thus we developed a procedure for ethophenprox
synthesis from the available neophyl chloride.
2-Methylallyl pentaflyorobenzyl ether (VII). In a
flask equipped with a reflux condenser and a
mechanical stirrer was mixed 11.3 g (43.3 mmol) of
pentafluorobenzyl bromide, 3.12 g (43,3 mmol) of
methallyl alcohol, 15 ml of anhydrous THF, 2.85 g
(43.3 mmol) of 80% KOH, and 0.05 g of Bu4NI. The
stirring at reflux was continued for 6 h, then the reac-
tion mixture was filtered through a thin bed of silica
gel and subjected to distillation to give 10.14 g (93%)
of ether VII, bp 60 C (5 mm Hg), n1D9.1 1.5495. IR
EXPERIMENTAL
IR spectra were measured on spectrometer UR-20
1
from films. H and 13C NMR spectra were registered
on Bruker AM-300 instrument at operating frequ-
encies 300.13 and 75.75 MHz respectively, solvent
CDC3. Chemical shifts are given in
scale from
TMS. Mass spectra were obtained on MKh-1303 and
MKh-1320 devices at the temperature in the ioniza-
tion chamber 100 180 C, ionizing voltage 70 eV.
UV spectra were recorded on spectrophotometer
Specord M-40 from solutions in ethanol. GLC ana-
lysis were performed on chromatograph Chrom-5,
stationary phase 5% SE-30 on carrier N-AW-DMCS,
column 1200 mm, oven programming from 50 to
300 C at a rate 14 deg/min, carrier gas helium.
1
1
spectrum, , cm : 1666 C=C. H NMR spectrum,
, ppm: 1.72 s (3H, CH3), 3.97 s (2H, CH2C= ),
4.61 s (2H, CH2C arom), 4.90 s (1H, cis HC=C),
4.98 s (1H, trans HC=C). Found, %: C 52.51; H
3.24; F 37.00. C11H9F5O. Calculated, %: C 52.39;
H 3.60; F 37.67.
4,4-Dimethyl-7-phenoxyisochroman (VIII) and
1
4,4-dimethyl-5-phenoxyisochroman (IX). H NMR
spectrum, , ppm: 0.89 s (3H, CH3, ax, IX), 0.90s
(3H, CH3, ax, VIII), 0.91 s (3H, CH3, eq, IX), 0.92s
(3H, CH3, eq, VIII), 3.35 3.60 m (4H, 2C3H2),
4.46 4.56 m (4H, 2C1H2), 6.91 7.42 m (16H,
Carom, H). 13C NMR spectrum, , ppm: 19.38 (CH3,
VIII, ax), 21.54 (CH3, VIII, eq), 32.30 (CH3, IX,
ax), 33.66 (CH3, IX, eq), 64.78 (C_ H2C arom, VIII),
65.79 (C_ H2C arom, IX), 71.72 (C_ H2CMe2, VIII),
72.91 (_CH2cme2, IX), 114.19 (C8arom, VIII), 116.66
(C6arom, IX), 117.04 (C2 arom, IX), 118.51(C6arom,
VIII), 118.80 (C8arom, IX), 118.97 (C2 arom, VIII),
121.44 (C4 arom, IX), 123.62 (C4 arom, VIII),
128.72 (C5arom, VIII), 129.08 (C3 arom, IX),
129.69 (C3 arom, VIII), 129.86 (C5arom, IX),
General procedure for phenetole alkylation.
To a mixture of 1.69 g (13.85 mmol) of phenetole
and 2.77 mmol of olefin stirred by magnetic stirrer
was added at room temperature 2 mmol of a catalyst.
After 5 h the reaction mixture was treated with
Na2CO3 solution till pH 8 and extracted with ethyl
acetate. The extract was dried over MgSO4, filtered,
the excess phenetole was distilled off at 80 C and
2 mm Hg, and the product obtained was when neces-
sary subjected to distillation.
1-Chloro-2-[2(4)-ethoxyphenyl]-2-methyl-
propanes (III) and (V) were obtained in overall yield
94% by phenetole alkylation with methallyl chloride
in the presence of H2SO4. The obtained mixture of
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 38 No. 11 2002

SYNTHESIS OF ETHOPHENPROX
1633
134.20 (C_ arom CH2, VIII and IX), 140.48 (C_ arom
CMe2, IX), 141.00 (C_ arom CMe2, VIII), 152.10
(C5aromO, IX), 156.31 (C1 arom O, VIII and IX),
157.41 (C7arom O, VIII). Found, %: C 80.19; H 7.09.
C17H18O2. Calculated, %: C 80.29; H 7.15. m/z:
ether, 10: 1. We obtained 0.28 g (42,5%) of com-
pound I with physical constants consistent with the
published data[1], and 0.07 g (8.5%) of 2-(4-hydr-
oxyphenyl)-2-methylpropyl phenoxybenzyl ether
1
(XVI). H NMR spectrum (XVI), , ppm: 1.30 s
+
254 M+ , 224 (M CH2O ).
[6H, C(C_H3)2], 3.44 s (2H, C_H2CMe2), 4.47 s (2H,
C_H2Ar), 4.80 s (1H, HOAr), 6.71 7.37 m (13H,
C arom H).
p-(1-Chloro-2-methyl-2-propyl)benzenesulfonic
acid sodium salt (X) was prepared by procedure
from [15] in 1.05 g (66%) yield, light gray crystals.
1
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