Preparation of N-thienyl-chloroacetamides and tetrahydro-thien-3-ylidenimines

The invention provides compounds of formula I ##STR1## wherein R is C.sub.1-4 alkoxy-C.sub.2-4 alkyl of which the C.sub.1-4 alkoxy group is separated by at least 2 C-atoms from the N-atom to which R is bound, PA0 each of R.sub.2 and R.sub.4 independently is CH.sub.3 or C.sub.2 H.sub.5 and PA0 R.sub.5 is H or CH.sub.3, the preparation of such compounds and the use of such compounds for the preparation of N-(thien-3-yl)-chloroacetamides.

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 tetrahydrothiophenimines of 
formula I 
##STR2## 
wherein R is C.sub.1-4 alkoxy-C.sub.2-4 alkyl of which the C.sub.1-4 
alkoxy group is separated by at least 2 C-atoms from the N-atom to which R 
is bound, 
each of R.sub.2 and R.sub.4 independently is CH.sub.3 or C.sub.2 H.sub.5 
and 
R.sub.5 is H or CH.sub.3. 
It has been found that compounds of formula I can be readily dehydrogenated 
to compounds of formula II 
##STR3## 
wherein R, R.sub.2, R.sub.4 and R.sub.5 are as defined above. 
Compounds of formula II are known intermediates for the preparation of 
compounds of formula III 
##STR4## 
wherein R, R.sub.2, R.sub.4 and R.sub.5 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 materials. 
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 compounds 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 Cr.sub.2 O.sub.3 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 reaction is then suitably carried out with 
heating, preferably at a temperature above 180.degree. C., e.g. at 
220.degree. C. or higher temperature, and under an inert gas atmosphere, 
such as a N.sub.2 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. 100.degree. C. 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 conveniently 
effected in a solvent which is inert under the reaction conditions. 
Examples of suitable solvents are chlorinated hydrocarbons, such as 
CH.sub.2 Cl.sub.2 and hydrocarbons such as toluene or cyclohexane. Where 
the oxydation agent is sulphur, the oxydation reaction 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 -30.degree. C. to +80.degree. C., e.g. at room temperature (about 
20.degree. C. to 30.degree. C.). 
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 conditions 
disclosed in UK Patent Specification 2 114 566A. 
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 corresponding 
tetrahydrothiophen-3-ones of formula IV 
##STR5## 
wherein R.sub.2, R.sub.4 and R.sub.5 are as defined above, by reaction 
with an amine of formula V 
EQU H.sub.2 N--R (V) 
wherein R is as defined above. 
Such condensation 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 .ANG.. 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 N.sub.2 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 
EQU HOCO--CH(R.sub.2)--S--CH(R.sub.5)--CH(R.sub.4)COOH (VI) 
wherein R.sub.2, R.sub.4 and R.sub.5 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 Ba(OH).sub.2, MnCO.sub.3, 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 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).sub.2 and Fe(OH).sub.2 
-(acetate). 
Compounds of formula VI are also novel. They may be obtained from readily 
obtainable starting materials by addition reaction of a compound of 
formula VII 
EQU HO--CO--CH(R.sub.2)--SH (VII) 
wherein R.sub.2 is as defined above, to a compound of formula VIII 
EQU R.sub.5 --CH.dbd.C(R.sub.4)--COOH (VIII) 
wherein R.sub.4 and R.sub.5 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 cyclisized to 
compounds of formula IV without necessitating the isolation of the 
compounds of formula VI. 
R.sub.2 is preferably CH.sub.3. R.sub.4 is preferably CH.sub.3. R.sub.5 is 
preferably H. R signifies preferably CH(CH.sub.3)CH.sub.2 OCH 
.sub.3,CH.sub.2 CH.sub.2 --O--nC.sub.3 H.sub.7 or CH.sub.2 CH.sub.2 
--O--iC.sub.3 H.sub.7, more preferably CH(CH.sub.3)--CH.sub.2 --OCH.sub.3.

The following examples illustrate the invention. Temperatures are given in 
centigrade. 
EXAMPLE 
N-(1-Methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine 
A reaction flask is fitted with a thermometer, a water cooler and a column 
charged with 31 g molecular sieve (5 .ANG.). 
A reaction flask is charged with a mixture of 0.2 mol of 
2,4-dimethyltetrahydrothiophen-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 g 
molecular sieve (5 .ANG.) in such a way, that the condensate of the 
boiling reaction mixture is directed continuously through the molecular 
sieve. The apparatus is protected by N.sub.2 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.degree.-80.degree.. 
EXAMPLE 2 
N-(1-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.degree.-20.degree. to a solution of 0.1 mol 
N-(1-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 
compound, b.p. 70.degree.-72.degree.. 
EXAMPLE 3 
N-(-1-Methoxyprop-2-yl)-2,4-dimethylaminothiophene 
0.01 Mol N-(1-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine 
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.degree.-170.degree., whereby the title compound is obtained 
as a clear distillate. 
EXAMPLE 4 
N-(1-Methoxyprop-2-yl)-2,4-dimethylaminothiophene 
0.1 Mol N-(1-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine 
are heated under N.sub.2 atmosphere with 2 g 5% Pt/charcoal at 200.degree. 
, 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.degree.-71.degree.. 
EXAMPLE 5 
N-(2,4-Dimethylthien-3-yl)-N-(1-methoxyprop-2-yl)-chloroacetamide 
(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-(1-methoxyprop-2-yl-)-2,4-dimethyltetrahydrothien-3-ylidenimine, 
dissolved in 10 ml of toluene at 20.degree. . 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.degree.-150.degree./0.03 Torr. 
(b) Involving use of a compound of formula II in base form. 
To a mixture of 315 g (1.58 mol) 
N-(1-methyl-2-methoxy-ethyl)2,4-dimethyl-3-aminothiophene in 1500 ml 
CH.sub.2 Cl and 240 g (1.75 mol) of K.sub.2 CO.sub.3 in 250 ml H.sub.2 O 
are added dropwise, at room temperature, and while stirring vigorously, 
200 g (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.times.200 ml), dried over Na.sub.2 SO.sub.4 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.degree.-150.degree./0.03 Torr. 
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.degree.-220.degree. with 7.5 parts of iron powder. The thus obtained 
distillate is dissolved in CH.sub.2 Cl.sub.2, washed with saturated 
aqueous NaHCO.sub.3 solution, dried over Na.sub.2 SO.sub.4. The title 
compound is distilled at 2 Torr, at a temperature of 
39.degree.-40.degree.. 
(b) With Ba (OH).sub.2. 
A mixture of 0.94 mol of 2,5-dimethyl-3-thiaadipic acid and 10 g of 
Ba(OH).sub.2 is heated during 24 hours in a distillation flask, at 
230.degree.-250.degree., with stirring. The distillate is extracted with 
diethylether, the ether solution dried (over MgSO.sub.4) and distilled 
under reduced pressure b.p. 39.degree.-40.degree. 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 4 g LiCl is stirred for 6 hours at 120.degree. . The crude mixture is 
poured onto ice, and 10 cm.sup.3 H.sub.2 SO.sub.4 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.sub.4 and concentrated by evaporation. The residue is distilled over 
a Vigreux column to give the title compound b.p. 81.degree.-88.degree. at 
20 Torr. 
EXAMPLE 7 
2,5-Dimethyl-3-thiaadipic acid 
To a solution of 320 g (8 mol) NaOH in 1300 ml water are added within 15 
minutes, 424 g (4 mol) of thiolactic acid. After decay of the exothermic 
reaction (35.degree. ) are added 344 g (4 mol) of methacrylic acid and the 
reaction mixture is then stirred for 18 hours at 80.degree. . 
The mixture is cooled to 50.degree. , poured onto a mixture of 3 kg of ice 
and 750 ml of concentrated HCl and extracted with 4 1000 ml portions of 
CH.sub.2 Cl.sub.2. The CH.sub.2 Cl.sub.2 extracts are dried with Na.sub.2 
SO.sub.4 and the organic phase then concentrated by rotary flash 
evaporation, yielding the title compound of m.p. 78.degree.-80.degree. 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.degree. . The reaction mixture is then heated for 1 hour at 
150.degree.-160.degree. and thereafter at 210.degree.-220.degree.. Under 
these conditions distills a mixture of the title compound, water and 
tributylamine at 150.degree.-170.degree. over, which is dissolved in ethyl 
acetate, diluted with water and neutralised with 10% HCl. 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.degree.-73.degree.. 
(b) With Fe(II) acetate 
A mixture of 85.9 g thiolactic acid, 70.0 g methacrylic acid and 0.8 g Fe 
acetate is stirred and heated to 150.degree.-160.degree. for 1 hour. Then 
another 0.8 g Fe acetate are added and the temperature is raised to 
200.degree.-210.degree. C. for 2 hours to yield 103.9 g 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 MgSO.sub.4 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 
MgSO.sub.4, evaporated at 15 Torr to yield 10.6 g of a mixture of 
methacrylic acid and thiolactic acid in the ratio 2:1. 
EXAMPLE 9 
N-(1-methoxyprop-2-yl)-2,4dimethyl-3-aminothiophene 
A solution of 2 g (0.01 mol) 
N-(1-methoxyprop-2-yl)-2,4-dimethyltetrahydrothien-3-ylidenimine in 3 g 
carbon tetrachloride is stirred for 1 hour at room temperature under an 
atmosphere of oxygen. 200 ml of O.sub.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.degree.-180.degree. air 
temperature to yield the title compound.