Note: Descriptions are shown in the official language in which they were submitted.
~ ~ti3 ~3~
-1- Case 130-3982
PROCESS FOR T~ PREPARATION OF N-THIENYL-CHLOROA~ETAMIDES
The present invention relates to novel tetrahydrothien-3-ylidenimines,
their preparation and the use of such imines for the production of
N-thienyl-chloroacetamides.
More specifically, the invention provides novel tetrahydrothiophen-
imines of formula I R4 ~ NR
R5 5 R2
wherein R is Cl 4alkoxy-C2 4alkyl of which the Cl 4alkoxy group is
separated by at least 2 C-atoms from the N-atom to which
R is bound,
each of R2 and R4 independently is CH3 or C2H5
and R5 is H or CH3.
It has been found that compounds of formula I can be readily
dehydrogenated to compounds of formula II
R NH-R
4~ II
R5 S R2
15 wherein R, R2, R4 and R5 are as defined above.
Compounds of formula II are known intermediates for the preparation
of compounds of formula III R
R N ~
~ CO-CH2Cl III
R5 s 2
wherein R, R2, R4 and R5 are as defined above.
Compounds of formula III are known herbicides.
Compounds II and III are disclosed in UK Patent Specification
2 114 566A. Said specification discloses several processes for the
preparation of compounds of formula III, but none of the processes
disclosed therein, or in other literature, allows the production of
the compounds of formula III starting from readily available starting
25 materials.
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The present invention discloses a very convenient route for the
production of compounds of formula III.
One aspect of the invention is the preparation of a compound
of formula II by dehydrogenation of a compound of formula I.
Said dehydrogenation may be effected catalytically or by oxydation
with oxygen or with oxydation agents such as sulphur, sulphurylchloride
and thionylchloride; it is preferably effected catalytically or with
thionylchloride as oxydation agent. Particularly thionylchloride has
been found surprisingly suitable for the dehydrogenation of csmpounds
of formula I.
The catalytical dehydrogenation of a compound of formula I can
be effected in the presence of any dehydrogenation catalyst. Examples
of known dehydrogenation catalysts suitable for use in the dehydrogenation
reaction of the invention are noble metals such as Pt or Pd, or other
metals such as Cr203 or mixtures thereof with other metals such as
CuO. The catalytical dehydrogenation can be carried out under the
conditions known for such reactions. Where for example the catalyst
is Pt, it is conveniently finely distributed on a carrier such as
charcoal (e.g. 5% Pt/C~. The dehydrogenation reackion is then suitably
carried out with heating, preferably at a temperature above 180C,
e.g. at 220C or higher temperature, and under an inert gas atmosphere,
such as a N2 blanket.
Compounds of formula I react - even below room temperature -
with oxygen to form an intermediate product which decomposes on heating,
usually at a temperature of ca. 100C or higher, to compounds of formula
II. This conversion is conveniently performed in one step by oxydation
above the decomposition point in a suitable solvent, e.g. an aromatic
solvent such as toluene under reflux.
When applying an oxydation agent, the oxydation step is oonveniently
effected in a solvent which is inert under the reaction conditions.
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Examples of suitable solvents are chlorinated hydrocarbons, such as
CH2Cl2 and hydrocarbons such as toluene or cyclohexane. Where the
oxydation agent is sulphur, the oxydation reac~ion is suitably carried
out with heating; where the oxydation agent is sulphuryl chloride
or thionylchloride the reaction temperature is conveniently in the
range of from -30C to +80C, e.g. at room temperature (about 20C
to 30C).
Thionylchloride is surprisingly suitable for use as oxydation
agent in this reaction: the reaction can be carried out under mild
reaction conditions and undesired side reactions (such as chlorination,
further oxydation etc.) are not observed.
The thus obtained compounds of formula II are converted to compounds
of formula III by N-chloroacetylation. Said N-chloroacetylation may
be carried out according to procedures known for the preparation of
chloroacetamides from the corresponding amines, e.g. under the condi-
tions disclosed in UK Patent Specification 2 ll4 566~.
Where the compounds of formula I are oxydized with the aid of
sulphurylchloride or thionylchloride, the compounds of formula II
will be obtained in the form of the hydrochloride acid addition salt.
Said hydrochloride can be reacted with chloroacetylchloride without
prior isolation from the reaction mixture, and in the absence of a
base, giving practically quantitative yields of compounds of formula
III.
The compounds of formula I are readily obtained from the corres-
ponding tetrahydrothiophen-3-ones of formula IV
R4 ~ IV
R5 2
wherein R2, R4 and R5 are as defined above,
by reaction with an amine of formula V
H2N-R (V)
wherein R is as defined above.
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Such condensakion reaction is conveniently effected in a solvent
which is inert under the reaction conditions, such as cyclohexane
or toluene. The reaction is preferably carried out with heating, e.g.
at reflux temperature. The reaction product is suitably dried e.g.
with the aid of a water trap or by an appropriate molecular sieve,
e.g. of 5 A. This may be done continuously, by using a cooler, e.g.
a water cooler, and directing the condensate through a column comprising
a molecular sieve, which is preferably protected by N2 to exclude
atmospheric oxygen.
The above disclosed reaction route for the preparation of compounds
of formula III from compounds of formula IV - via compounds of formula
I and II may be effected in one and the same reaction vessel, i.e.
compounds of formula I and II may be obtained in good yields and need
not be isolated from the reaction vessel for the next reaction step.
Compounds of formula IV are novel. They are readily obtained
by cyclisation of compounds of formula VI
HOC0-CH(R2)-S-CH(R5~-CH(R4)COOH (VI)
wherein R2, R4 and R5 are as defined above.
Such cyclisation can be carried out under the conditions of a
Ruzicka cyclisation or modifications thereof.
The cyclisation is conveniently effected with heating; the presence
of a condensation agent, such as 3a(0H)2, MnC03, Fe powder, acetates
of Fe, CO(II) or Ni(II), acetic acid anhydride/LiCl or a tertiary
amine e.g. a trialkylamine, promotes cyclisation. The use of Fe powder
2s or of acetates of Fe, CO(II) or Ni(II) as condensation agent is
particularly advantageous.
The term acetates of Fe as used herein is intended to comprise
Fe(II) and Fe(III) acetate compounds such as Fe(acetate)2 and Fe(OH)2-
(acetate).
Compounds of Formula VI are also novel. They may be obtained
from readily obtainable starting materials by addikion reaction of
a compound of formula VII
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H0-C0-CH(R2)-SH (VII)
wherein R2 is as defined above,
to a compound of formula VIII
R5-CH=C(R4)-COOH (VIII)
wherein R4 and R5 are as defined above.
The addition of a compound of formula VII to a compound of formula
VIII is conveniently effected under the conditions of a Michael addition
or modifications thereof. The addition is conveniently effected with
heating. The compound of formula VII may be used for example in its
salt form (carboxylate salt), e.g. alkali metal salt form such as
the Na carboxylate form. The compound of formula VII may however also
be used in its free acid form, in which case the addition is conveniently
effected in the presence of a tertiary amine, e.g. a trialkylamine
such as tri(n-butyl)amine or of an acetate of Fe, CO(II) or Ni(II).
The latter process variante can be carried out in the absence of a
solvent, the reaction proceeds fast with high yields, nonreacted starting
material may be recovered and the compounds of formula VI may be cycli-
sized to compounds of formula IV without necessitating the isolation
of the compounds of formula VI.
R2 is preferably CH3. R4 is preferably CH3. R5 is preferably
H. R signifies preferably CH(CH3)CH20CH3, CH2CH2-0-nC3H7 or
CH2CH2-0-iC3H7, more preferably CH(CH3)-CH2-OCH3.
The following examples illustrate the invention. Temperatures
are given in centigrade.
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EXAMPLE 1 : N-(l-Methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-yliden-
imine
A reaction flask is fitted with a thermometer, a water cooler
and a column charged with 31 9 molecular sieve (5 ~).
A reaction flask is charged with a mixture of 0.2 mol of 2,4-di-
methyltetrahydrothiophen-3-one, 0.225 mol of 1-methoxy-2-aminopropane
and 50 ml of cyclohexane. The reaction flask is fitted with a thermometer
a water cooler and a column charged with 31 9 molecular sieve (5 ~)
in such a way, that the condensate of the boiling reaction mixture
is directed continuously through the molecular sieve. The apparatus is
protected by N2 to exclude atmospheric oxygen.
The reaction mixture is boiled during 9 hours. The title compounds
is then vacuum distilled at 0.5 Torr at the boiling range of 65~0.
EXAMPLE 2: N-(l-Methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene
0.1 Mol thionylchloride dissolved in 20 ml toluene are added
dropwise with stirring and cooling at 10-20 to a solution of 0.1
mol N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine
in 80 ml.
The reaction mixture is stirred for 1 hour and then rendered
alkaline with a conc. solution of caustic soda. The aqueous phase is
separated off, the organic phase washed with water, dried and the
toluene distilled off in vacuum. The residue is distilled at 0.2 Torr
and yields the title cornpound, b.p. 70-72.
EXAMPLE 3: N-(-l-Methoxyprop-2-yl)-2,4-dimethylaminothiophene
0.01 Mol N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-yliden-
imine are added dropwise, within 5 minutes to 0.013 mol sulphur powder
in 2 ml boiling toluene (under reflux). The mixture is stirred under
reflux for another 5 minutes and the crude residue distilled in a
bulb tube, at 0.5 Torr and 150-170, whereby the title compound is
obtained as a clear distillate.
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EXAMPLE 4 : N-(l-Methoxyprop-2-yl)-2,4-dimethylaminothiophene
0.1 Mol N-(l-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-yliden-
imine are heated under N2 atmosphere with 2 9 5% Pt/charcoal at 200,
during 11 hours. The catalyst is filtered off and the filtrate distilled
at 0.1 Torr. The title compound is obtained at the boiling range of
68-71.
EXAMPLE S : N-(2,4-Dimethylthien-3-yl)-N-(l-methoxyprop-2-yl)-chloro
acetamide
a) Involving use of compound of formula II in salt form
0.02 Mol thionylchloride in 5 ml toluene are added dropwise,
within 40 minutes, to 0.02 mol N-(l-methoxyprop-2-yl-)-2,4-dimethyltetra-
hydrothien-3-ylidenimine, dissolved in 10 ml of toluene at 20. The
reaction mixture is stirred for 2 hours whereby the hydrochloride
of N-(-1-methoxyprop-2-yl)-2,4-dimethyl-3-aminothiophene is obtained.
Then are added 0.02 mol of chloroacetylchloride dissolved in 5 ml
toluene. This mixture is heated during 1 hour at reflux, whereby HCl
escapes. The title compound is obtained by column chromatography on
silica gel with cyclohexane/ethyl acetate (8:2), b.p. 148-150/0.03
Torr.
b) Involving use of a compound of formula II in base form.
To a mixture of 315 9 (1.58 mol) N-(l-methyl-2-methoxy-ethyl)-
2,4-dimethyl-3-aminothiophene in 1500 ml CH2Cl and 240 9 (1.75 mol)
of K2C03 in 250 ml H20 are added dropwise, at room temperature, and
while stirring vigorously, 200 9 (1.77 mol) of chloroacetylchloride.
After half an hour's reaction time at room temperature, the organic
phase is separated off, washed with water (2 x 200 ml), dried over
Na2S04 and concentrated by evaporation.
The title compounds is obtained by chromatography on silica gel
with hexane/diethylether 85:15.Rf = 0.3 (silica gel; diethylether/hexane
2:1) b.p. 148-150/0.03 Torr.
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EXAMPLE 6 : 2,4-Dimethyltetrahydrothiophen-3-one
Cyclisation of 2,5-dimethyl-3-thiaadipic acid
a) With Fe powder
100 Parts of 2,5-Dimethyl-3-thiaadipic acid are heated at 180-220
with 7.5 parts of iron powder. The thus obtained distillate is dissolved
in CH2C12, washed with saturated aqueous NaHC03 solution, dried over
Na2504. The title compound is distilled at 2 Torr, at a temperature
of 39 40o.
b) With Ba (OH)2.
A mixture of 0.94 mol of 2,5-dimethyl-3-thiaadipic acid and 109
of Ba(OH)2 is heated during 24 hours in a distillation flask, at 230-250,
with stirring. The distillate is extracted with diethylether, the
ether solution dried (over MgS04) and distilled under reduced pressure
b.p. 39-40 at 2 Torr.
c) With acetic acid anhydride.
0.5 Mol of 2,5-dimethyl-3-thiaadipic acid, 300 ml of acetic acid
anhydride and 49 LiCl is stirred for 6 hours at 120. The crude mixture
is poured onto ice, and 10 cm3 H2S04 conc. are added thereto. The
mixture is then stirred overnight, rendered alkaline with conc. NaOH
solution, while cooling with pieces of ice, and extracted several
times with diethylether. The ether phase is washed with water, dried
over MgSO~ and concentrated by evaporation. The residue is distilled
over a Vigreux column to give the title compound b.p. 81-88 at 20
Torr.
EXAMPLE 7 : 2,5-Dimethyl-3-thiaadipic acid
To a solution of 320 9 (8 mol) NaOH in 1300 ml water are added within
lS minutes, 424 g (4 mol) of thiolactic acid. After decay of the exother-
mic reaction (35) are added 344 g (4 mol) of methacrylic acid and
the reaction mixture is then stirred for 18 hours at 80.
The mixture is cooled to 50, poured onto a mixture of 3 kg of
ice and 750 ml of concentrated HCl and extracted with 4 1000 ml portions
,6
-9- 130-3982
of CH2C12. The CH2C12 extracts are dried with Na2S04 and the organic
phase then concentrated by rotary flash evaporation, yielding the
title compound of m.p. 78-80 in the form of colourless crystals.
EXAMPLE 8 : 2,5-Dimethyltetrahydrothiophen-3-on
a) With tertiary amine
To a mixture of 0.2 mol thiolactic acid and 0.2 mol methacrylic
acid are added dropwise 0.2 mol tributylamine, whereby the reaction
temperature rises up to 60. The reaction mixture is then heated for
1 hour at 150-160 and thereafter at 210-220. Under these conditions
distills a mixture of the title compound, water and tributylamine
at 150-170 over, which is dissolved in ethyl acetate, diluted with
water and neutralised with 10 % ~Cl. The organic phase is extracted
with 2N NaOH, washed neutral, dried and concentrated by evaporation.
The residue is distilled at 15 Torr, yielding the title compound at
the boiling range of 70-73.
b) With Fe(II) acetate
A mixture of 85.9 9 thiolactic acid, 70.0 9 methacrylic acid
and 0.8 9 Fe acetate is stirred and heated to 150-160 for 1 hour.
Then another 0.8 9 Fe acetate are added and the temperature is raised
to 200-210C for 2 hours to yield 103.9 9 of a distillate. This is
dissolved in 200 ml cyclohexane, made alkaline with sodium hydroxide
and separated in a separation funnel. The aqueous phase is extracted
with 100 ml cyclohexane. The combined organic layers are washed with
water, dried over MgS04 and evaporated at 15 Torr to yield the title
compound.
The aqueous layer is acidified with hydrochloric acid and extracted
with methylenechloride. The extract is washed with water, dried with
MgS04, evaporated at 15 Torr to yield 10.6 9 of a mixture of methacrylic
acid and thiolactlc acid in the ratio 2:1.
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EXAMPLE 9 : N^(l-methoxyprop-2-yl)-2,4dimethyl-3-aminothiophene
A solution of 2 9 (0.01 mol) N-(l-methoxyprop-2-yl)-2,4-
dimethyltetrahydrothien-3-ylidenimine in 3 9 carbon tetrachloride
is stirred for 1 hour at room temperature under an atmosphere of oxygen.
200 ml of 2 are consumed. The NMR-spectrum of the solution shows
no signals for aromatic protons. Then the product is distilled in
a bulb tube at 0.2 Torr and 150-180 air temperature to yield the
title compound.
