Note: Descriptions are shown in the official language in which they were submitted.
Case 130-3938
HERBICIDAL N-THIENYL CHLOROACETAMIDES
-
The present invention relates to novel 5-membered heteroaromatic
compounds bearing at one ring C-atom a N-substituted chloroacetylamino group,
their use as herbicides, agricultural compositions for facilitating such
5 use and the preparation of the novel compounds of the invention.
Various herbicidal N-substituted a-halogenacetanilides are known.
The U.S. Patent Spec. 4,282,028 discloses N-substituted-N-2,5-dialkyl-
pyrrol-l-yl)haloacetamides having herbicidal and plant-growth-regulating
activity. The need exists for still more effective herbicides. The novel
10 5-membered heteroaromatic compounds are particularly effective herbicides
having an appropriate soil persistence.
The present invention provides compounds of formula I
COCH2Cl
Ar - N ~
wherein Ar is a 5-membered heteroaromatic group comprising 1 S heteroatom,
and linked by a C-ring atom to the N-atom of the N(Y)COCH2Cl
group to which it is bound,
and Y is a group A-O-R3,
wherein R3 is H, hydrocarbon selected from the group consisting of Cl 8alkyl,
C3 8alkenyl~ C3 8alkinyl, C3 8cycloalkyl, C5 8cycloalkenyl or
C3 8cycloalkyl-C1 5alkyl, whereby the hydrocarbon is unsubstituted
or monosubstituted by F, Cl, Br, cyano or Cl 4alkoxy;
and A is a hydrocarbon moiety, whereby the N and O atoms to which it
is bound are separated by up to 3 C-atoms.
The Ar group may be unsubstituted or substituted. Where Ar is substi-
tuted it may bear substituents in any possible position; preferred positions
25 Of such substituents are in o-position, particularly in o,o'-position of
the chloroacetamide group, whereby additional substituents may be present.
Examples of suitable substituents of Ar are halogen selected from
F, C1 and Br; C1 4alkyl unsubstituted or substituted by halogen
(F, Cl, Br), C1 4alkoxy or C3 6cycloalkyl; C2 4alkenyl unsubstituted or
30 substituted by Cl 4alkoxy; C3 6cycloalkyl; formyl or C2 4alkanoyl
and functional derivatives such as oximes, acetals and ketals
~ J~ ~e
1248S3~
~ -z- 130-3938
thereof (e.g. C~=NOCl 4alkyl)-C1 3alkyl, C(O-Cl 4alkyl)2-Cl 3alkyl, CH(O-
Cl 4alkyl)2 etc.); Cl 4alkyl-S, Cl 4alkyl-SO, Cl 4alkyl-S02; Cl 5alkoxy-
carbonyl; Cl 4alkoxy unsubstituted or substituted by halogen or C1 4alkoxy;
C2 4alkenyloxy, C2 4alkinyloxy; hydroxy and hydroxymethyl and esters
5 thereof (e.g. esters with an organic carboxylic acids, for example formic
acid, a C2 5alkane carboxylic acid or an halogenated derivative thereof,
such as acetic acid or chloroacetic acid).
Any optional substituent(s) of Ar which is not in o-position of the
N-substituted chloroacetylamino group is preferably selected from Cl 4alkyl
(e.g. CH3), halogen (e.g. Cl, Br) and Cl 4alkoxycarbonyl (e.g. COOCH3).
The N-substituted chloroacetylamino group is preferably tied to the
ring C-atom in ~-position of the ring heteroatom. A preferred sub-group of
the latter group are those compounds wherein the Ar-group is substituted
in ortho-, more preferably in ortho-ortho'-position of the N-substituted
acetylamino group, especially when the substituent(s) are selected from the
group specified hereinbefore. A particularly preferred sub-group of compounds
of formula I, are compounds wherein Ar is 3-thienyl which is at least
2,4-disubstituted, especially those 3-thienyl compounds wherein the substi-
tuents in 2- and 4-position are selected from Cl 4alkyl and Cl 4alkoxy.
Where R3 is substituted by halogen, such halogen is preferably Cl or
Br.
Where R3 is Cl 8alkyl, C3 8alkenyl or C3 8alkinyl, it preferably has
up to 5 C-atoms. Where R3 is or contains cycloalkyl or cycloalkenyl such
cyclic hydrocarbon group contains preferably up to 6 C-atoms.
Where R3 is monosubstituted hydrocarbon, it signifies e.g. CH2CH2Cl
or CH2CH2CN.
A is preferably a Cl 8alkylene moiety separating the 0- and N-atom to
which it is bound by 1 to 2 C-atoms. A suitable significance of A is a CH2
or CH2-CH2 group or monomethylated derivatives thereof, particularly CH2,
CH(CH3), CH2CH2 and CH(CH3)CH2; R3 is then especially Cl 3alkyl, such as
CH3, C2H5 and nc3H7
1;~48~3~3
3 130-3938
The present invention also provides processes for producing
a compound of formula I comprising
a) substituting in a compound of formula II
COCH OH
Ar - N < 2 II
wherein Ar and Y are as defined above.
the HO group of the N-hydroxyacetyl group by C1,
b) reacting a compound of formula III
Ar-NH-COCH2Cl III
where~n Ar is as defined above,
with a compound of formula IV
Ly IY
wherein Y is as tefined above,
and L ~s a leaving group capable of be;ng sptitt off under
the N-alkylation reaction conditions,
c) obtaining a compound of formula Ia
CO-CH Cl
Ar - N ~ 2 Ia
H - Y2
R'~
wherein R'"is H or Cl 3alkyl,
Y2 is OR3 and
Ar and R3 are as defined above,
.
~J
`''` ' ' .
- .
1~4~53~
4 130-3938
by reacting a compound of formula Y
CO-CH2Cl
Ar - N ~
CH - Cl
R"'
wherein Ar and R'Uare as defined above,
with a reactive derivatiYe of a compound of formula YI
HY2 VI
wherein Y2 is as defined above,
d) N-acylation of a compound of formula YII
Ar - NH - Y jYlI
wherein Ar and Y are as def1ned above,
w;th chloroacetyl chloride, or a react;ve functional derivatiYe thereof.
Process a) of the invent;on can be carried out by conventional
manner under conditions known for the subs~;tution of an OH group
by a Cl.
Such substitution can for example be effected by treat,ng a
compound of formula II w;th a chlorinating agent, such as th;onyl
chlor;de under cond1tions known p~r se for analogous reactions.
According to a variant of this chlorin~tion process, the
compounds of formula II are f;rst converted into the corresponding
sulphonyloxy derivatives, e.g. by O-sulphonation with the aid of a
sutphonyl halide, and such sulphonyloxy derivatives then converted
into the desired compounds of formula I by nucleophilic substitu-
tion of the sulphonyloxy group by chlorine.
Reactants supplying the Cl anions requiret for such nucleophilic
substitution are e.g. alkalimetal chlorides such as NaCl,
quaternary tetrabutylammonium chloride or 4-dimethylaminopyridine-
hydrochloride. Such substitution is conveniently carried out in
CH2Cl2 or in an aqueous/organic two-phase system, wherein the
organic phase is e.g. a hydrocarbon such as toluene, ;n the presence
of a suitable phase transfer catalyst, preferably with heating
. .
1~1853~3
-5- 130-3938
e.g. at 40~ to 120C.
Process b) may be carried out by conventional manner under
conditions known for the N-alkylation of amides. The reaction is
advantageously carried out in a solvent which is inert ur,aer the
reaction conditions e.g. dimethoxyethane or acetonitrile or in
an aqueous/organic two-phase system in the presence of a phase
transfer catalyst.
Suitable meanings of L (in formula IV) are Cl, Br or the
sulphonyloxy moiety of an organic sulphonic acid such as mesyloxy
or p-tosyloxy.
The compounds of formula llI are preferably used in salt form,
more preferably 1n alkalimetal salt form, e.g.ithe sodium salt form.
Such salts are obtained in conventlonal manner by reaction of the
compound of formula III with a base such as an alkalimetal amide,
hydride, hydroxide or alcoholate.
For the preparation of compounds of formula Ia according to
process c), the compounds of formula Y are suitably used in the
form of the alkalimetal salt, e.g. as sodium salt.
The reaction of process d) can likewise bè effected in
20 conventional manner, under conditions known for the N-chloroacetyla-
tion of amines. Where ClCOCH2Cl is uset as N-chloroacetylation agent
such reaction is conveniently carried out in the presence of an
acid binting agent, such as ~2C03.
The compounds of formula I may be recovered from the reaction
25 mixture in which it is formed by working according to established
procedures.
It will be appreciated that interconversion of one compound of
the invention to another, e.g. conversion of an acid group to
an ester group, of a carbonyl group to an oxime, of a halo-
alkyl group to an ether group ~or vice versa) etc., may becarried out in conventional manner. As will also be appreciated,
the compounds of the invention may possess one or more asymmetric
.,.. ~ ~,~ ,. .. .. .
lZ4~353~
-6- 130-3938
centres and may therefore exist in optically active, diasteromeric,
racemic or geometric isomer forms. In general such compounds are
employed as mixtures in the herbicide method and compositions of the
invention, even though separation may be effected by known procedures.
The compounds of for~ulae II, III, V and VII are novel and are
part of the invention.
The compounds of formula II may be obtained by ammonolysis of
an ester of the compounds of fonmula VIII
Ar NHCOCH20H VIII
wherein Ar is as defined above,
with a carboxylic acid, and subsequent introduction of the group Y
(as defined above) in the compounds of formula VIII by N-alkylation.
Such esters are obtained by acylation of the corresponding compounds
of formula IX
ArNH2 IX
wherein Ar is as defined above,
with the appropriate ester of H0-CH2COCl, e.g. with CH3C0-OCH2-COCl.
The compounds of formula III may also be obtained by acylation
of a compound of formula I% with chloroacetyl chloride.
Compounds of formula V (which are in fact a sub-group of compounds
of formula I) may be obtained by reaction of a compound of formula IX
with an appropriate aldehyde and reaction of the Schiff base thus
obtained-with chloroacetyl chloride.
The co~pounds of formula YII may be obtainet by N-alkylation of
a compound of formula IX. Such alkylation can be carried out in
conventional manner, with the corresponding alkylating agents (e.g.
halogenides~, or where appropriate, reductively via the Schiff base
or amide.
Many of the compounds of formula IX are novel.
A particular group of valuable novel compounds of formula IX
are 3-aminothiophenes substituted in 2- and 4-position by a group
selected from Cl 4alkyl and Cl 4alkoxy (compounds of formula IXa).
The compounds of formula IXa also fo m part of the invention.
lZ'~35
7 1 ~0-393
The co~pounds of formula IX may be obtained by reduction of the
corresponding N02 compounds, e.g. by catalytic hydrogenation under
hydrogen pressure in the presence of palladium. Compounds of
formula IXa having a CH3 group in 2- or 4-position may be obtained
by reduction of the corresponding thiophene-carboxylate with the
aid of a complex hydride such as sodium bis(methoxyethoxy)aluminium
hydride. Where appropriate, the compounds of formula IXa may also
be obtained from the correspsnding carbamates esters, e.y. the
benzyl carbamate, by hydrolysis. The carbamates, used as starting
10 material, may for example be obtained starting from the
corresponding acids, via their azides followed; by a Curtius reaction.
Insofar as the production of starting material is not described
herein, these compounds are known, or may be produced and purified
in accordance with known processes or in a manner analogous to
15 processes described herein or to known processes.
The compounds of formula I are useful because they control
or modify the growth of plants. By plants it is meant germinating
seeds, emerging seedlings and established vegetation including
underground pGrtions.
In particular, the compounds are useful as herbiGides as
indicated by i.a. the damage caused to both monocotyledoneous and di-
cotyledoneous plants such as Lepidium sativu~, Avena sativa,
Agrostis alba and Loliu~ perenne in tests by test dosages equivalent
to an application rate of from 1.4 to 5.6 kg/ha after pre- or post-
25 emergence application. In view of their herbicidal effect thecompounds of the lnYention are indicated for use in combatting
dicotyledoneous and grassy weeds, as confirmed by further
evaluation with representative compounds w;th test dosages
equivalent to an application rate of from 0.2 to 5.0 ks active
30 ingredient, e.g. test dosages equivalent to a rate of 0.2, 1.0
l ~'''''
:
35 3~
- 8 - 130-3938
and 5.0 kg active ingredientlha, in dicotyledoneous weeds such
as Amaranthus retroflexus, Capsella bursa-pastoris, Chenopodium
alba, Stellaria media, Senecio vulgaris and Galium aparine, and,
especially, grassy weeds such as Agropyron repens, Agrostis alba,
Alopecurus myosuroides, Apera spica-venti, Avena fatua, Echinochloa
crus-c,alli, Bromus tectorum, Sorghum halepense, Digitaria spp and
Setaria spp. Additional tests indicate a favourable soil persistence
of the compounds of the invention.
The compounds of the invention are relatively less toxic towards
lO crops than towards weeds. Selective herbicidal activity is i.a.
observed in corn (0aize), soybean, cotton, sugar beet, potato,
alfal~a, sunflower, rape, peanuts or flax, depending i.a. on the
compound ;nvolved and on the application rate. The compounds of the
invention are therefore also 1ndicated for use as selective herbicides
15 in a crop locus.
The present invention therefore also provides a method of
combatting weeds in a locus, preferably in a crop locus,particularly
in a crop locus as mentioned above, whicn comprises applying to the
tocus a herbicidally effective amount (a selective herbicidally
20 effective amount where the locus is a crop locus) of a compound of
the invention. A partlcularly preferred and advantageous embodiment of
the invention is the pre-emergence (both crops and weeds) use of a
compound of formula I in selectively combatting weeds in a crop locus.
For general herbicidal as well as for selective herbicidal use of
30 compounds of the invention, the amount to be applied to attain the
desired effect will vary depending on the particular crop if employed
for selective use and other standard variables such as the compound
employed, mode of application, conditions of treatment and the like.
The appropriate application rates can be determined by routine proce-
35 dures by those skilled in the art, or by comparing the activity of thecompounds of the invention with standards for which the application
, ~ . ~ ,~
. ~... ..
1248~3~3
-9 - 130-3938
rate is known, e.g. in greenhouse tests However. in general,
satisfactory resutls are usually obtained when the compound is
applied at a rate in the range of from about 0.1 to 5 kg/ha, prefer-
ably from about 0.2 to 4 kglha, more preferably from 0.5 to 3.0 kg/ha,
5 the application being repeated as necessary. Ilhen used in a crop locus,
the application rate should preferably not exceed 3 kg/ha.
The compounds of formula I may be and preferably are employed
as herbicidal compositions in association with herbicidally accept-
able diluent(s). Suitable formulations contain O.OlX to 99~O by
10 weight of active ingredient, from 0 to 20~ herbicidally acceptable
surfactant and 1 to 99.99X solid or liquid di,luent(s). Higher
ratios of surfactant to active ingredient are sometimes desirable
and are achieved by incorporation into the formulation or by tan~
mixing. Application forms of composition generally contain between
0.01 and 25X by weight of active ingredient. Lower or h;gher levels
of active ingredient can, of course, be present depending on the
intended use and the physical properties of the compound. Concen-
trate forms of composition intended to be diluted before use
generally contain between 2 and 90t, preferably between 10 and
80~ by weight of active ingredient.
Useful formulations of the compounds of the invention incl~de
tusts, granules, pellets, suspens~on concentrates, wettable powders,
emulsifiable concentrates and the like. They are obtained by
conventional manner, e.g. by mixing the compounds of the invention
with the dituent(s). More specifically liquid compositions are
obtained by mixing the ingredients, fine solid compositions by
blending and, usually grinding, suspensions by wet milling and
~ granules ant pellets by impregnating or coating (preformed) granular
;~ carriers with the active ingredient or by agglomeration techniques.
~ . .
~:
,~
.
1248~3~
-10 - 130-3938
Alternatively, the compounds of the invention may be used in
microencapsu1ated form.
Herbicidally acceptable additives may be employed in the
herbicidal compositions to improve the performance of the active
ingredient and to reduce foaming, caking and corrosion.
Surfactant as used herein means a herbicidally acceptable
material which imparts emulsifiability, spreading, wetting,
dispersibility or other surface-modifying properties. Examples or
surfactants are sodium lignin sulphonate and lauryl sulphate.
Diluents as used herein mean a liquid or solid herbicidally
acceptable material used to dilute a concentrated material to a
usable or desirable strength. For dusts or granules it can be e.g.
talc, kaol;n or diatomaceous earth, for liquid concentra~e forms,
for example a hydrocarbon such as xylene or an alcohol such as
15 isopropanol, and for liquid application forms i.a. water or diesel
oil.
The compositions of this invention can also comprise other
compounds having biological activity, e.g. compounds having similar
or complementary herbicidal activity or compounds havir.g antidotal,
20 fungicidal or insecticidal activity.
,~
,J
.,,
.
.
- 11 130-3938
Specific Examples of herbicidal compositions will now be
described.
EXAMPLE A : Wettable Powder
.
25 Parts of a compound of formula I, e.g. Compound No. 25
5 here;nafter given, are mixed and milled with 25 parts of synthetic
fine silica, 2 parts of sodium lauryl sulphate, 3 parts of sodium
ligninsulphonate and 45 parts of finely divided kaolin until the mean
particle size is about 5 micron. The resulting wettable po~Jder is
diluted with water before use to a spray liquor with the desired
10 concentration.
EXAMPLE B : Emulsion Concentrate
_ j
20 Parts of a compound of formula I, e.g. Compound No. 25
hereinafter given, 40 parts of xylene, 30 parts of dimethyl
formamide and 10 parts of emulsifier (e.g. ATLOX 4851 B a blend of
15 Ca alkylarylsulphonate and a polyethoxylated trislyceride o~ Atlas
Chemie GmbH) are throughly mixed until a homoseneous solution is
obtained. The resulting emulsion concentrate is diluted with water
before use.
EXAMPLE C : Granules
_ _ _
2D 5 Kg of a compound of formula I, e.g. Compound No. 25 herein-
after given, are d;ssolved in 25 ~ methylene chloride. The solution is
then added to 95 kg of granulated attapulgite (mesh size 24/48 mesh/
inch) and thoroughly mixed. The solvent is then evaporated off under
retuced pressure.
The invention is further illustrated by the follow;ng Examples
where~n temperatures are in C, pressures are in Torr and Rf values
are on silica gel, so far not otherwise ind~cated.
FINAL COMPOUNDS
Example 1
N-~2,4-dimet_yl-thien-3-yl)-N-(1~3_dioxo1ane-2-ylmethyl2-chloro-
acetamide ~Qroce-s---a2
.
B` ,~
lZ~3S3~
-12- 130-3938
To the well stirred mixture of 1.7 9 (0.0063 mol) of N-(2,4-di-
methyl-thien^3-yl)-N-(1,3-dioxolane-2-ylmethyl)-hydroxyacetamide,
58 mg of benzyltriethylammonium chloride, 7 ml of toluene and 7 ml
of 30X NaOH are added dropwise without cooling 1.31 9 (0.0069 mol)
5 of p-toluene sulfonyl chloride in 3.5 ml of toluene. After the
exothermic reaction has subsided, stirring is continued for a further
2D houns at ambient temperature.
The toluene layer is then separated, washed with water and dried
over anhydrous Na2S04.
The crude residue left on rotevaporation of the solvent is
recrystallised from diethyl ether to give N-(?,4-dimethyl-thien-3-
yl)-N-(1,3-dioxolane-2-ylmethyl)-tosyloxyacetamide ("tosylate") having
a m.p. of 101-103
A stirred mixture of 2.16 9 (0.0051 mol) of said tosylate, 1.849
(0.0066 mol) of tetrabutylammonium chloride, 8 ml of water and
16 ml of toluene is heated at 90 over a period of 6 hours. The
toluene layer is then separated, dried (Na2S04) and evaporated in
vacuo.
The residue is chromatographed on a silica gel column. Elution
20 with hexane-ethylacetate 2:1 affords the title compound as analyti-
cally pure crystals, ha~ing a m.p. of 76-78.
Example 2
N-~2~4-t1methyl thien 3-yl) N methoxyetbyl chloroacetamide
(process a)
To a stirred solution of 2.0 9 (0.008 mol) of N-~2,4-dimethyl-
25 thien-3-yl)-N-methoxyethyl-hydroxyacetamid and 0.92 9 (0.008 mol) of
4-timethylaminopyridine (=DMAP) in 80 ml of dry methylene chloride
are added without cooling 0.93 9 (0.008 mol) of mesyl chloride in
20 ml of dry CH2C12.
The resulting mixture containing DMAP-hydrochloride and the
. ~ .
~ .
~, .:, ....
12~853~3
-~ 130-3938
methanesulphonate of the starting compound is heated under reflux
for 25 hours and then evaporated in vacuo.
The residual oil, after column chromatography on silica gel
(elution with diethylether), solidified on chilling at -20, m.p.
54-55.
Example 3 : N-~ch1Oroac~tyl2-N-~2-carbo~ethoxy-4_methyl-thien-
3 Y12 alan!ne e~hy!ester (process b)
To a well stirred suspension of 1.5 9 (0.05 mol) sodiu~hydride (80 % tispersion in mineral oil) in 250 ml of dry
10 d~methoxyethane (=D,-lE) are added portionwise, 9.9 9 (0.04 mo~)
of solid N-(2-carbomethoxy-4-methyl-thien-3:yl)-chloroacetamide.
After the addition is completed the resulting solution of the
Na-salt is stirred 2n additional hour at 50, then allowed to reach
room temperature and treated with the solution of 7.25 9 (0.04 mol)
of ethyl-2-bromopropionate in S0 ml of dry D:~E.
After a reaction period of 4 hours at 50, the mixture is
filtered and evaporated in vacuo (50/0.01 Torr.~. The residual
brown oil, after chromaSography on silica gel (elution with diethyl
ether-hexane 2:1),is sub~ected to ball tube distillat~on, giYing the
analytically pure title compound, b.p. 135/0.005 Torr.
Example 4 : N ~ yrazol l-ylmethyl2 N-~2,4 dimathyl-thien-3 yll-
chlQroacetam de (process b)
To a well stirred mixture of 19.35 9 (0.095 mol) of N-(2,4-di-
methyl-thien-3-yl)-chloroacetamide, 4.15 9 (0.01 mol) of benzyldi-
~3 ,~,
2 4~ 3~
-14_ 13C-3938
methythexadecyl-a~monium ch1Oride, 40 9 (1 mol) of sodium hydroxide,
200 ml of ~ethylene chloride and 40 ml of water are added 17 9
(0.11 mot) of solid l-chloromethyl pyrazolehydroch~oride at such a
rate, that the temperature does not rise above 25.
When the addit;on is completed, the reaction m;xture ;s
stirred an additional 21/2 hours at ambient temperature. Then 100
mt of water are added. The or~anic layer is separated,
washed with three 200 ml portions of water, dried over Na2S04 and
evaporated to dryness. The residue is chromatographed on a silica
10 gel column. Elution with hexane-diethylether 1:1 affords the title
compound as an analytically pure syrup wh kh crystallized on chilling
overnight at -20, m.p. 88-89 (recrystallized fro~ diethyl ether).
Example 5 : r~-~chloroacetvl2-~ 315-dimethyl-isoxazol-4-yl~-
_ _ _ _ .. _ _ _ ~ _ . _ _ _ _ _ _ _ _
ala~nineethylester (process b)
9.4 9 (0.05 mol) of N-(3,5-dimethyl-isoxazol-4-yl)-chlolo-
acetamide in 150 ml of dry acetonitrile (=CH3Ct~) are added drop-
wise to a well stirred suspension of 1.8 9 (0.06 mol) of sod;um
hydride (80X dispersion in mineral oil) in 25 ml of dry CH3CN.
After the exothermic reaction (34~ has suhsided the solution
20 Of the sodium salt ~s allowed to reach rocm temperature 2nd then
treated with the solution of 9.05 g ~0.05 mol) of ethyl 2-bromo-
propionat~ in 25 ml of dry CH3CN.
After the addition is completed the reaction mixture ~s heated
at 50~ for three hours and then evaporated to dryness. The residue
25 is taken up with 100 ml of diethyl ether and filtered. The
residual oil left bn evaporating the filtrate is chromatographed
on a silîta gel column. Elution with diethylether-hexane 1:1
affords the title compound, having a m.p. of 49-50.
B~;~
... .
3~
-15_ 130-3938
~xample 6 : N-[l-~ -eyrazol~l-yl~ethyl~-N-~2,4-dimethyl-thien-3-yl~-
_ _ _ _ _ _
chloroacetamide (process c)
To a stirred solut;on of 12.7 9 (0.1 mol) of 2,4-dimethyl-3-
amino-th,ophene in 100 ml of dry benzene, which contains 16 9 of
5 moleculzr sieves (3A) and two drops of conc. H2504, are added dropwise
8.5 ml (0.15 mols) of acetaldehyde, taking care that the temperature
does not rise above 25.
When all the acetaldehyde has been introduced, the reaction
mixture is stirred 24 hours longer at ambient temperature and is
10 then filtered. Removal of the solvent leaves the Schiff base as a
light brown llquid.
To the stirred solution of 13 9 (0.085 mols)o~ this material
in 75 ml of dry toluene are added dropwise at -30 9.7 9 (0.086 mols)
of chloroacetyl chloride.
When the addition is complete, the reaction solution ;s
stirred for a further 30 minutes at -30 and then treated dropwise
at the same temperature with 12 9 (0.085 mols) of l-trimethylsilyl-
pyrazole. After the addition, the solid C02/acetone bath is
removed, the mixture allowed to warm to ambient temperature and
2D left to stir for a further period of 20 hours.
The reactlon mixture is then filtered and evaporatet in vacuo.
The resldual syrup is chromatographed on a s;lica gel column.
Elutlon with hexane/diethyl ether 3 : 2 affords colourless crystals
of the title compound which, upon recrystallization from diethyl
25 ether haYe a melt~ng point of 76-78.
1248538
-16- 130-~938
Exam~e 7 : N-~4 methoxy-2-methy!-thlen 3-yl2 ~ 2 ethoxyethyl2
chloroacetamide (process d)
To a well stirred mixture of 6,05 9 (0.03 mol) N-(2-ethoxyethyl)-
4-methoxyw2-methyl-thiophene-3-amine, 4.15 g (0.03 mol) o~ K2~03,
10 ml of water and 100 ml of CH2C12 is added dropwise without cooling
the solution of 3.4 9 (0.03 mol) of chloroacetyl chloride in 10 mt
of CH2C12. After the exothermic reaction t27) has subsided,
stirring is continued for a further hour at ambient temperature.
The methylene chloride layer is then separated, washed twice
10 with 100 ml of ~ater, dried ~Na2S04) and evapqrated ~n vacuo. The
residual crude title compound is analytically pure;
RF= 0.23 (hexane-diethyl ether 1:2). A small portion of this
material was sub~ected to ball tube distillation : b.p. 168-170 /
0.05 Torr.
The following compounds of formula I are obtained according to
one or more of the procedures of the Examples 1 to 7, as indicated
hereinbefore: (Me is CH3 and Et is C2H5)
TABLE A ~see next page).
... ..
: '
353~
.
-17- 130-3938
CNmOpd. Aryl Y Characterization
~ .
1 4-Me-thien-3-yl CH20C2H5 m.p. 25-26
2 ,. CH2CH20CH3 Rf=0.45(cyclohexane/
ethylacetate 1:1~
3 2-Me-thien-3-yl CH2CH20CH3 Rf=0.3(cyclohexane/
ethylacetate 6:4)
4 2,4-diMe-thien-3-yl CH2CH20H m.p. 79-80
~ CH20Et b.p.ll5/O.OOl Torr
6 " CH20C3H7n n2=1.5280
7 " CH20C4Hgn b.p.llO-11tO.OOl Torr
8 " CH(Me)OMe m.p. 48-50
g ~ CH(Et)OMe m.p. 55-57
" CH2CH20Me m.p. 54-55
11 " CH2CH20Et b.p.llO/O.Ol Torr
12 CH2CH20C3H7n Rf=0.36(diethyle.her/
hexane 1:1)
13 " CH(Me)CH20Me b.p.l48-150/0.03Torr
14 C(Me)2CH20Me
" CH~Me)OCH2CH2Cl m.p. 62-64
16 " CH2CH2CH2Me b.p.ll7-18/0.005 Torr
17 CH(Me)OCH2CH2CN m.p. 59-64
18 2-Me-4-Et-thien-
3-yl CH(Me)CH~OMe b.p.l42-44~0.2 Torr
19 ~ CH20Et m.p. 49-soo
2-Et-4-Me-thien-
3-yl CH OC H5 Rf=0.47(diethylether/
2 2 hexane 7:3)
21 -~ CH(Me)CH20Me Rf=0.47(diethylether/
hexane 7:3)
22 2,4-diEt-thien-3-yl CH2-OEt nD-1.5242
23 CH2CH20Me nD3=1.5328
~ ; B`-~
..
. . ,
3L~ 3~;3 ~.
-18 - 130-3938
Nopd. Aryl Y Characterization
24 4-OH-2-Me-thien-3-yl CH(Me)CH20Me
2-Me-4-MeO-thien-3-yl CH2-OEt m.p. 24
26 " CH2CH2-OEt b.p.l68-170/0.05 Torr
27 2-Me-4-nC4HgO-thien- CH20Et m . p . 44-45
3-yl
28 2-MeS-4-Me-thien-3-Yl CH20Et b.p. 135/0.001 Torr
29 " CH2CH20Me b.p. 148-140/0.001 Torr
2-MeS(0)-4-Me-thien- CH20Et m.p. 100
3-yl
31 2-MeS02-4-Me-thien- CH20Et
3-yl
32 2-MeCO-4-Me-thien- CH20Et m.p. 37-38
3-y1
33 2-MeC(=NOMe)-4-Me- CH20Et syn : m.p. 89-91
thien-3-yl anti: m.p. 75-76
34 2-MeC(OEt)2-4-Me- CH20Et m.p. 46-47
thien-3-yl
2-Me-4-0-COMe-thien- CH(Me)CH20Me
3-yl
36 2-COO~e-4-Me-thien-3-yl CH20Et m.p. 20-22
37 2-Et-4,5-diMe-thien- CH20Et n2=1.5273
3-yl
38 2,4-diMe-5-Cl-thien- CH20Et nD=1.5412
thien-3-yl
39 " CH20CH2CH20CH3 nD=1.5321
2,5-diBr-4-Me-thien- CH20Et m.p. 75-77
3-yl
41 2,4-diMe-5-COOMe- CH20Et b.p.l40/0.005 Torr
thien-3-yl
$
- 19 - 130-3938
INTERt~EDIATES
Example 8 : Methyl 3 5-direthyl-4-amino-thioehene-2-carboxylate
_ ~ _ _ _ _
A solution of 45.2 9 (0.21 ~ol) methyl 3,5-dimethyl-4-nitro-
thiophene-2-carboxylate in 1000 ml methanol is hydrogenated for two
hours at 10 bar in the presence of 4.5 9 pa11adium (1a X on carbon).
~ hen the retuct~on is completed the mixture is f~ltered, the
catalyst washed with methanol and the filtrate evaporated to
dryness.
The crystalline residue is treated with diethyl ether,
yieldin~ the analytically pure title compoundim.p. 88-89
Example 9 2 4-D;methyl-3-aminothio~hene
_~ _ _ _ _ _ _ _ ___
To 890 ml (3 mol) of sodium bis(2-methoxyethoxy)aluminium
15 hydride (70X solution in toluene)and 6C0 ml of dry toluene is
added,dropwise with vigorous stirring, a solution of lC0 9 (0.58 mol~
of methyl 3-amino-4-methy~hiophene-2-carboxylate in 7C0 ml of dry
toluene at such a rate that the temperature does not rise aboYe 55.
After the addition is completed stirring is continued for a
20 further 30 minutes and the reaction mixture then cautiously added
in small portions at 0 to 1200 ml of 20X potassium hydroxide
solut~on;
The toluene layer is separated, dried oYer MgS04 and
eYaporated in Yacuo. The residuat brown liquid is distilled under
25 diminished pressure, affording the analytical1y pure title
compound, b.p.49-52/0.01 Torr.
.
':
' `
~L~4~3~3~3
-20 -- 130-3938
Example 10: 4 Metboxy 2-methyl-3 amino-thiQehene
The well stirred mixture of 55.4 9 (0.2 mol) of benzyl N-(4-
methoxy-2-methyl-thien-3-yl)carbamate, 40 9 (0.7 mol) of ~OH, 600 ml
of ethanol and 120 ml of water is heated under reflux for two hours.
The resulting solution is then eYaporated in vacuo and the
residue diluted with 500 ml of water. The separating lisht
yellow oil is taken up in 400 ml of diethyl ether and the
aqueous phase extracted once with 400 ml of ether.
The combined etherea1 solutions are dried (Na2S04) and
10 filtered. A slow current of dry hydrogen chlorlde is then passed
through the filtrate for a period of 30 minutes, taking care - by
intermittent colling in an ice bath - that the temperature does
not rise above 10.
The prec~pitated hydrochloride of the title compound has a
15 m.p. of 230 (the free base a m.p. of 61-63).
Example 11 : 2 ~!ethylthio 4 m~thyl 3 am nothlo~hene
6 9 (0.22 gram atoms) fresnly prepared aluminium amalgam
are addet over a period of about two minutes to 18.9 g (0.1 mol)
of 2-methylthio-4-methyl-3-nitrothiophene tissolved in 200 ml of
20 moist diethylether. The vigorous reaction which sets in after
5-10 minutes is kept under control by cooling the flask in ice.
After 45 minutes, when the exothermic reaction has subsided
and all the aluminium has reacted, another six grams of amalgamated
aluminium are adted.
3L~4 ~ 3~
- 21 - 13~-3938
The reaction mixture is then gently refluxet for 2 hours;
during this period the formation of the thiophene amine is complete.
The orqanic phase is decanted and the remainder washed with two S0 ml
portions of diethy?ether. The combined ethereal solutions are dried
5 (MgS04) and eYaporated in vacuo. The residual crude title compound
is distilled under reduced pressure, having a boiling point of
79-81/0.5 Torr.
Example 12
In the following table are listed compounds of formula IX that
are obtained according to one or more of the procedures of
Examples 8 to 11.
Ex. 12.1 4-C2H5-2-CH3-3-aminothiophene, Rf=0.25 (diethylether:
Ex. 12.2 4-n-butoxy-2-methyl-3-amino-thiophene, m.p. 25;
(Rf=0.25 (diethylether/hexane 2:1)
Ex. 12.3 (3-NH2-4-Me-thien-2-yl)ethanone, m.p. 80-81
Ex. 12.4 (3-NH2-4-Et-thien-2-yl)ethanone, m.p. 68
Ex. 12.5 (3-NH2-4,5-diMb-thien-2-yl)ethanone, m.p. 120-23
Ex. 12.6 2-Et-4-Me-3-NH2-thiophene, b.p. 74-76/0.01 Torr
Ex. 12.7 2,4-diEt-3-NH2-thiophene, Rf = 0 24 (CH2C12) n2=1.5511
Ex. 12.8 2-Et-4,5-diMe-3-NH2-thiophene, nD =1.5581
~,'
~24~5~
- 22- 130-3938
Example_13 N~2~4-dime-thyl--thien-3-yll-acetoxyaceta~lde
- To 12.7 9 (0.1 mol) of 2,4-dimethyl-3-aminoth;ophene, 13.8 9(0.1 mol) of K2C03, 20 ml of water and 150 ml of methylene chloride
are added dropw1se at ambient temperature 15 9 (0.11 mol~ o~
acetoxyacetyl chloride.
After the exothermic react;on has subsided, stirring is
continued for a further hour. Then the organic layer is evapvrated,
washed with water, dried (MgS04) and evaporated in vacuo. The solid
residue is treated with hexane affording the analytlcally pure title
10 compound, m.p. 110-112.
Example 14 : N ~2~g dimethyl_tblen_3_y!~_hydrOxyacetamid2
Through a stirred solution of 15.9 9 (0.07 mol) of~2,4-di-
methyl-thien-3-yl)-acetoxyaceta~ide in 300 ml of methanol is
bubbled a gentle stream of a~monia gas for 30 minutes.
After the exothermic ~40) reaction (moderated by intermittent
cooling in cold water) has subsided, stirring is continued for
additional 30 minutes and the reaction solution then evaporated to
dryness. The resulting sol~d is recrystallized from ethylacetate,
giving the analytically pure title compound as colourless crystals,
20 m.p. 85-87.
~f ' '~: .
;
lZ4~3~3~
- 23 - 130-3938
Example 15 : N-~2-ethoxyethy1i-4-methoxy-2-methyl-thioehene-3-amine
To 70 ml (0.245 mol) of sodium bis(2-methoxyethoxy)aluminiu~
hydride (70g solution in toluene) and 30 ml of dry toluene is added
dropwise with stirring a solution of 9.4 9 (0.041 mol) of
N-~4-methoxy-2-methyl-thien-3-yl)-ethoxyacetamide in 125 ml of dry
toluene. After the exother~ic reaction has subsidedl stirring i5
continued for a further 90 minutes and the reaction sclution then
cautiously added in small portions at -10 to 100 ml of 20X KOH
solution.
The toluene layer is separated and the aqueous phase extracted
twice with 100 ml of toluene. The combined toluene solutions are
dried (Na2504) and evaporated in vacuo. The residual l~sht brown
liquid is analyt~cally pure, Rf = 0.32 (hexane-d~ethyl ether 1:2).
Example 16 : N Ç~Methoxymethy!~ethyl~ 2~4_d~methy! th~oehene-3_amine
~he solution of 6.4 9 (0.05 mo1) of 2,4-dimethyl-3-amtno-thio-
phene and 513 9 (0.06 mol) of methoxyacetone in 100 ml of dry
toluene is boiled under reflux until the ~heore~ical amount of
water has separated in the water trap (21/2 hours). The toluene
solution is then allowed to cool to ambient temperature and
20 evaporated in vacuo. ~he residual crude Schiff base is sufficiently
pure for the next step.
9.2 9 (0.048 mol) of this materiql are dissolved in 100 ml of
dry toluene and added without cooling to a well stirred solution
of 28 ml tO.098 mol) of sodium bis(2-methoxyethoxy)aluminium
25 hydr~de (70X solution in toluene) in 15 ml of dry toluene.
After the exothermic reaction (44) has subsided, stirring is
continued for a further 90 minutes and the brown reaction solution
~2(1853~
-24 - 130-3~38
then cautiously added in small portions at -10 to 40 ml of 20X
KOH solution.
The toluene layer is then separated, dried (Na2S04) and
evaporated in vacuo. The residual oil, after column chro~atography
5 on silica gal (elution with hexane-diethyl ether 3:1) is distilled
under diminished pressure ~ball tube), having a b.p. of 94-95/
0.01 Torr.
Example 17 N ~5-Et-hyl:ll3>4--ox-dlazol-2:ylmethyl~-2~4
thioehene-3-amine
The mixture of 12.7 9 (0.1 mol) of 2,4-dimethyl-3-amino-thio-
phene, 14.6 9 (0.1 mol) of 2-chloromethyl-5-ethyl-1,3,4-oxdiazole
and 13.8 9 (0.1 mol) of K2C03 in 150 ml of dry dimethylformamide
(=DMF) is stirred for 20 hours at 80.
The reaction 0ixture is then cooled to ambient temperature
15 poured into 400 ~1 of water and the water-DMF solution extracted
with three 150 ml portions of diethyl ether. The combined ethereal
extracts are dried over anhydrous Na2S04 and evaporated in vacuo.
The residual brown oil is chromatographed on a silica ge1 column,
elution with hexane/diethyl ether 1:1 affords the title compound as
20 an analytically pure orange liquid, R~-0.2 (ether-hexane 1:1).
Example 18 : N~l214-dimetbyl tbien 3-yl2glycine hydrazide
82 g (0.412 mol) N-(2,4-dimethyl-thien^3-yl)glycine-methylester
and 42 g ~1.3 mol) hydrazine hydrate in 350 ml alcohol are stirred
for 24 hours at room temperature. The mixture is evaporated in
25 vacuo. After adding 150 ml water the residue is treated with
4 x 500 ml portions of ether. The ether phase is dried over Na2S04
and evapora~ed to dryness gi~ing the analytically pure title
compound, m.p. 68-70C
3'~, "
.
~L Z 4 ~3~j~3
- 25 - 130-393~
Example 19 : N-~2,4-dimethyl-thien-3-yl2-N-I4-methyl-5-merca~to-
lL2,4-triazol-3-yl-methyl~-amine
A mixture of 15 9 (0.075 mol) N-(2,4-dimethyl-thien-3-yl)glycine
hydrazide and 5.59 (0.075 mol) methylisothiocyanate in 100 ml ethanol
5 is refluxed for 4 hours. The reaction mixture is cooled to 6C and
the precipitate formed separated by filtration giving the pure com-
pound, m.p. 184-87C.
Example 20 : N-~2~4-dimethyl-thien-3-yl~-N-~4-methyl-5-methylmercaeto-
1~2~4 tria3ol-3 yl methyl~-am ne
To a mixture of 9.5 9 (0.037 mol) N-(2,4-dimethyl-thien-3-yl)-
N-(4-methyl-5~mercapto-1,2,4-triazol 3-yl-methyl)-amine, 1.19 tri-
ethyl-benzyl ammonium chloride in 100 ml toluene and 30 ml aqueous
50X sodium hydroxide solution are added 4.79 (0.037 mol) dimethyl-
sulfate. The reaction mixture is stirred at room temperature for 5
15 hours, the organic layer is separated, washed with three 100 ml
portions of water, dried over Na2S04 and evaporated to dryness. The
residue is recrystallized ~ice from ether giving the pure title
compound, m.p. 92-96C.
Example 21 : N-~2~4 dimetbyl-th en-3 yll N ~5 metbyl 1~3~g tb_adiazol
2-yl_methyl~ am ne
To 109 (0.05 mol) N-(2,4-dimethyl-thien-3-yl)-glycine hydrazide
in 175 ml methylene chloride is added dropwise 5.59 (0.05 mol) acetic
acid anhydride. The mixture is stirred for 1 hour at 20C and
evaporated to dryness. The oily residue is dissolved in 150 ml
pyridlne and 11.19 (0.05 mol) phosphorous pentasulfide is added ;n
small portions. During the course of the addition the temperature
reached 48C. The mixture is refluxed for two hours and stirred at
room temperature for another 16 hours. After evaporation to dryness
. . .
38
-26 - 130-3938
the residue is dissolved in methylene chloride and the solution
treated successively with ice water, diluted cold sodium hydroxide
solution and water, dried over Na2S04 and evaporated to dryness.
Chromatography on a silica gel column afforded the pure compound as
5 an oil, Rf = 0.23 (ethylacetate/hexane 6:4).
Example 22 N-(2~4-dimethyl-th~en-3-yll-N- S-methyl-l ,2,4-triazol-3-
yl-methyl2amine
To a stirred solution of 2.29 (0.055 mol) NaOH in 125 ml
methano1 is added 5 9 (0.05 mol) acetamidine hydrochloride. After
15 minutes 10 9 (0.05 mol) N-(2,4-dimethyl-thien-3-yl)-glycine
hydrazide is added and the mixture refluxed for 18 hours. After
evaporation to dryness the residue is treated with methylene chloride
and freed from insoluble by-products by filtration. Evaporation of
the methylene chloride gives the title compound, m.p. 8S-87~C.
5 Example 23: N ~2?4 dimethyl-th en 3 yl291ycine soero~yl_dene-
hydrazide
_
79 (0.035 mol) N-(2,4-dimethyl-thien-3-yl)-glycine hydra~ide in
50 ml acetone is stirred at room temperature for 2 hours. The pure
title compound which crystallized was obtained by filtration, m.p.
20 126-28C.
Example 24
The follcwing compounds of formula VII are obtained according
to one or more of the preceding Examples 13 to 23:
4b~53~3
-27 - ~30-3938
Ex. Ar y Characteriza-
tion
_ _ _
24.1 2,4-di-CH3-thien-3-yl CH2CH2 OCH3 Rf=0.~2(diethyl
ether-hexane
3:1)
24.2 ~ C2H5 Rf=0.23(diethyl
ether-hexane
1 : 1 )
24.3 2,4-di-CH3-thien-3 yl CH2CH2C2H5 Rf-0 48(diethyl
24. 4 " CH2CH20C3H7-n Rf-0 57(diethyl
24- 5 2,4-di-C2H5-thien-3-yl CH2CH20CH3 n2D=1.5238
24. 6 2-CH -4-C H -thien-3-yl CH ~ CH20CH3 b.p. 98-100/
3 2 5 0.09 Torr
CH3
24.7 2-C2 H5-4-CH3-thien-3-yl CH - CH20CH3 Rf=0.52 (ether-hexane
Example 25 : N-~2 carbomethoxy-3~5-dimet~ thien-4 yl)-chloro-
acetamide
_ ____ ____
To 12.25 g (0.066 mol) of methyl 3,5-dimethyl-4-aminothiophene-
2-carboxylate, 9.1 9 (0.066 mol) of K2C03, 25 ml of water and 150 ml
of methylene chloride are added without cooling 7.5 9 (0.066 mol) of
chloroacetyl chloride.
After the exothermic reaction (36) ~as subsided stirring is
continued for a further hour. Then the organic layer is separatet~
washed with water and dried over anhydrous Na2S04. After removal of
the solvent the desired product is obtained as colourless crystals,
m.p. 157-58.
J
~3S 3~3
-28- 130-3938
Example 26 : N-~2-chloro-3,5-dimethyl-thien-4-yl2-chloroacetamide
_ . _ _ _ _ _ _ _ .. _ _ _
To the stirred solution of S.Og (0.0245 mol) of N-~2,4-dimethyl-
thien-3-yl)-chloroacetamide in 50 ml o~ dry CH2C12 are added dropwise
at 0 3.39 (0.0245 mol) of sulfuryl chloride.
When the addition is complete, the reaction mixture is allowed
to warm to ambient temperature and stirred for a further period of
20 hours. Then the solvent is removed in vacuo and the crystalline
residue triturated with hexane, yielding the analyticalty pure title
compound, m.p. 166, decomp.
0 Example 27 : N-~2-~111-d ethoxy2ethyl 4-methyl-thien 3 yl ] cbloro-
acetamide
15 9 (0.065 mol) of N-(2-acetyl-4-methyl-thien-3-yl)-chloro-
acetamide are dissolved in the warm (50) mixture of 60 9 of dry ethyl
alcohol, 60 9 of triethyl orthoformate and 7 drops of concentrated
15 HCl.
Upon standing for 30 hours at room temperature thé reaction
mixture is evaporated in vacuo (50/0.01 Torr) and the residual
brown syrup chromatographed on a sil~ca gel column. Elution with
hexane-diethylether 2:1 afforts the title compound as colourless
20 crystals, having a m.p. of 57-58.
Example 28 : N-S2-(l-methQxyiminolethyl-4-methyl thien-3 yl~ chlQro-
ac_tamlde
The s~lut~on of 1.5 9 (0.0065 mol) of N-(2-acetyl-4-methyl-thien-
3-yl)-chloroacetamide and 6.6 9 (0.14 mol) of methoxyamine in 50 ml
25 of try toluene, which contains 5 9 of molecular sieves (3A) is
refluxed for 7 hours.
The yellow reaction solution is then filtered and evaporated
in vacuo. The resulting crude syn~anti isomer mixture is separated by
chromatography with hexane-diethylether as the mobile phase.
~ .. . .
~ ~ J
~91853~
- 29 - 130-3938
First are eluted 0.69 of the pure iso~er (syn isomer) with the
m.p. of 101-102 (Rf=0.33, hexane-ether 1:1). Continued elution of
the silica gel column affords the other analytically pure anti isomer
(0.4 9) having a melting point of 87-~9 (Rf=0.21).
Example 29
.
S The following compounds of formula III are obtained according
to one or more of the Examples 25 to 28:
Ex. Ar Characterization
_
29.1 2-COOCH3-4-CH3-thien-3-yl m.p. 118-119
29.2 2-CH3S - 4-CH3-thien-3-yl m.p. 105-106
10 29.3 2,4-di-CH3-thien-3-yl m.p. 128-129
29.4 4-CH3-thien-3-yl m.p. 93-96
29.5 2-cH3-4-c2H5-thien-3-yl m.p. 114
29.6 2-CH3-4-OCH3-thien-3-yl m.p. 144-45
29.7 2-C2H5-4-CH3-thien-3-yl m.p. 105
29.8 2,4-di-C2H5-thien-3-yl m.p. 145
29.9. 2-COCH3-4-CH3-thien-3-yl m.p. 110
29.10 2-CH3-4-OC4Hgn-thien-3-yl m.p. 129-30
29.11 2-c2H5-4~5-dicH3-thien-3-yl m-p- 147-48
5;3~
30- l30-3938
Example 30 : N-~2,4-d~eth~!thien-3-yl~-N-~ethoxyethyl hydroxy-
acetam1de
18.4 9 (O.l mol) of N-~2,4-dimethylthien-3-yl)-hydroxyacetamide
;n 50 ml of dry d;methylformamide (=D~F) are added dropwise to a well
stirred suspension of 3.0 9 (O.l mol) of sodium hydroxide ~80
dispersion in mineral oil) in S0 ml of dry DMF.
After the exothermic reaction (50) has subsided, the solution
of the Na-salt is allowed to reach room temperature and then
treated with the solution of 10.4 g (O.ll mol) of 2-chloroethyl-
lO methylether in 20 ml of dry DMF. When the addition is completed,
the resùlting mixture is heated at 100 for 4 hours and then
evaporated to dryness (40/O.l Torr).
The residue is taken up with 200 ml of diethyl ether, washed
with 250 ml of water, dried (MgS04) and filtPred. The residual
lS oil left on evaporating the filtrate is chromatographed on a
silica gel column. Elution with ether affords the desired
product asan analytically pure viscous liquid (Rf=0.25/ether).
.
Example 3l : N-~g Methoxy-2-methyl-thien-3-yl2etho~yacetamide
To 9.8 g (0.068 mol) 4-methoxy-2-methyl-3-amino-thiophene,
9.45 9 (0.068 mol) K2C03, 35 ml of water and lG0 ml of CH2Cl2 is
addet without cooling the solution of 8.4 9 (0.069 mol) of ethoxy-
- acetyl chloride in 20 ml of CH2Cl2.
After the exothermic reaction (32) has subsided, stirring is
continued for a further hour. Then the organic layer is separated,
washed twice with 150 ml of water and dried over anhydrous Na2S04.
The residue left on rotevaporation of the solvent is subjected
to column chromatography on silica gel. Elution with hexane-diethyl-
ether l:l affords the analytically pure title compound having a
m.p. of 40-41.
~;r~
~ 35 3~
_31 - 130-3938
Example 32
Analogous to the procedure of Example 33, the following am;des
of formula ArNHCOY3 are obtained.
Ex. Ar Y3 Characterization
32.1 2,4-di-CH3-thien-3-yl -CH2-OCH3 m.p.62-63
32.2 1,3,5-tri-CH3-pyrazol-4-yl -CH20CH3 m.p.85-87
32.3 1-CH3-3,5-di-C2H5- " b.p.l20/0.001 Torr
pyrazol-4-yl
32-4 3-CH3-s-0c2H5- -CH20CH3 m.p.l23-30
pyrazol-4-yl
32.5 2,4-di-CH3-thien-3-yl -CH20C2H5 m.p. 37-38
32.6 ~ -CH20C3H7-n m.p. 43-45
32.7 2,4-di-C2H5-thien-3-yl -CH20CH3 m.p. 48-49
Example 33 : Benzyl ~y-4-methoxy-2-meth~thien 3-yl~carbam_te
63.6 9 (0.23 mol) of diphenylphosphoryl azide and 24.4 9
(0.23 mol) of triethylamine are added all at once to the stirred
susPenSion of 36.5 9 (0.21 mol) of 4-methoxy-2-methyl-thiophene-3-
carboxylic acid in 300 ml of dry benzene.
The resulting mixture i5 refluxed for one hour and then
treated with 25 9 (0.?3 mol) of benzyl alcohol.
12~853~3
-32 - 130-3938
After a reaction period of 3Y2 hours at 78 the reaction
mixture is cooled to ambient temperature, diluted with diethyl
ether (350 ml) and washed successively with 250 ~1 of 5X HCl,
250 ml of saturated NaHC03 solution and 200 ~1 of saturated NaCl
solution. The crystalline residue left on rotevaporation of the dried
(Na2S04) solvent is triturated with pentane, yielding the
analytically pure title compound, m.p. 107-108.
Example 34
Following the procedure of Example 33, employing the appropriate
carboxylic acid, the following carbamate is obtained.
10 Ex. 3~.1 Benzyl (N-4-n-butoxy-2-methy~thien-3-yl)carbamate, m.p. 83.
Example 35 : 4 Metboxy 2-methyl thioehene 3 carboxyliç acid
The title compound is obtained by saponification (KOH) of the
corresponding ethyl ester; m.p. 127.
Example 36
Analogous to the procedure of Example 35 is obtained
4-n-butoxy-2-~ethyl-thiophene-3-carboxyl;c acid, m.p. 66-68.
Example 37 : Ethyl 4-methox~-2-methyl-thiophene-3-carboxy!ate
_ _ ____ _ __ _ _
20 ml of 50X sodium hydroxide solution are added dropwise to
a mixture of 18.6 9 (0.1 mol) of ethyl 4-hydroxy-2-methyl-thiophene-
3-carboxylate, 10 ml (0.105 mol) of dimethyl sulphate and 2.3 9
~0.01 mol) of benzyltriethylammonium chloride in 100 ml of CH2C1
at ambient temperature.
After about 15 minutes of reflux, the reaction mixture is
worked up to give the title compound, Rf = 0.36 (diethyl ether:hexane
2 : 1).
B~
~L~ 8 S ~3~
- 33 - 130-3938
Example 38 : Methyl 3,5-dimethyl-4-nitrothioehene-2-rarboxylate
To a wel1 stirred, c.hilled (0) solution of 51.4 g (0.3 mol) of
methyl 3,5-dimethylthiophene-2-carboxylate in 200 ml of glacial
5 acetic acid are added dropwise over a period of 40 minutes, a
mixture of 30 ml of fuming nitric acid (specific gravity = l.S) and
120 ml of acetic anhydride. After the addition is completed the
resulting brown solution is stirred a further two hoùrs at 5 and
then poured into 3000 ml of ice water.
The aqueous phase is extractet twice with l500 ml of diethyl
ether. The ethereal extracts are washed with water and 3Z sodium
bicarbonate solution, dried (Na2S04) and evaporated in vacuo.
The residue is subjected to column chromatography on silica
gel. Elution with hexane-diethylether (10:1) afforded the ti~le
lS compound having a melting point of 87-88.
Example 39
Analogous to the process of Example 38 but employing
1,3-dimethyl-5-ethoxypyrazole as starting material is obtained
1,3-dimethyl-5-ethoxy-4-nitropyrazole; Rf = 0.37 with diethylether
on silica gel.
~',''
3LZ~3~3~
-34- 130-3938
Herbic~dal Tests
Example 4~ : Weed control - Pre-emersence trqatment
Seed pots (7 cm diameter) are filled with a mixture of peat
culture substrate and sand. The exposed surface of the peat
5 culture substrate and sand mixture is sprayed with a test liquid
of a test compound (e.g. formulated in accordancè with Example 8)
and seeds of Lepidium sativum, Agrostis alba, Avena sativa and
Lolium perenne are sown in each pot, whereby the Avena sativa and
Lolium perenne seeds are, after sowing covered with a thin layer
10 (0.5 cm) of peat culture substrate/sand mixture. The pots are kept
for 21 days at room temperature with 14 to 17 hours light (daylight
or its equivalent) per day.
Determination of the herbicidal effect of the particular
herbicide is made after the 21 day period. The determination
lS involves a visual evaluation of the degree and quality of dam3ge
to the various seed plants.
,, ,J
, . .~ O` '
~L~4 ~ S 3~3
-35 130-3938
The compounds of formula I are applied in the above manner at
dosages equivalent to 1.4 and 5.6 kg of active agent/hectare.
Herbicidal activity, that is to say, significant
damage to the test plants is observed.
Example 41 : Weed control - Post-emergence treatment
A procedure similar to that employed in Example 40 is followed
with the exception that the test compounds (herbicides) are applied
hen the plants are at the 2-4 leaf stage, the sowing of the plant
seeds being st2ggered to ensure that the plants reach the 2-4 leaf
10 stage at about the same time.
Again the compounds of formula I are applied
in the above manner at dosages corresponding to 1.4 kg/ha and
5.6 kg/ha. The determination of the herbicidal effe t is made 21
days after application of the test compounds and involYes an
15 analogous evaluation as described in Example 40. Heroicldal
activity is observed.
Example 42
Representative compounds of the invention are evaluated in the
following pre-emergence test procedure.
Seed dishes measuring 30 x 40 cm are filled to a depth of 6 cm
with a mixture of peat culture substrate and sand. The exposed surCace
of the peat culture substrate and sand mixture is sprayed with an
aqueous test liquid (e.g. formulated in accordance with Example B)
comprising a compound of the invention in a given concentration. The
s?ray volume corresponds to 600~ aqueous test liquidtha. The same
test is repeated with various concentrations of test l;quid, whereby
tbe concentrations are selected in such a manner that the desired
B~
-36- 130-3938
application rates are realized. Six species of seed are then sown in
each dish. The number of seeds sown for each plant species depends
on the seed germination potential and also the initial growth size
of the particular seed plant. After sowing of the seeds, the
treated surface is covered with a thin layer about 0.5 cm deep of
the peat culture substrate and sand mixture.
The prepared seed dishes are kept for 28 days at a temperature
of 20 to 24C and 14 to 17 hours light each day.
Determination of the herbicidal effect of the particular
compound of the invention is made after the 28 day period. The
determination involves a visual evaluation ofithe degree and
quality of damage to the various plants. Particular advantageous
herbicidal properties are i.a. observed with the Compound Nos. 5, 6,
13, 19 and 26 of Table A. Some of the results
obtained with an application rate corresponding to 1 kg active
ingredient/hectare are summarised in the follow;ng Table B.
Example 43: Post-emergence Treatment
_ _ _ _ _ _ _ _
A further evaluation of representative compounds of the formula I
is effec~ed in a post-emergence test procedure similar t~ that of the
pre-emergence test described in Example 42. except that the herbicide
test tiquid is appliet when the plants are at a 2 - 4 leaf stage. For
that purpose the various plants species are sown in time-staggered
relationship. The greenhouse conditions (temperature, light) are as in
Example 42. Determination of the herbicidal effect is also effect~d
28 days after application according to the method of Example 40.
Particular advantageous herbicidal properties are i.a. observed
with the Compound Nos. 5, 6, 13, 19 and 26 of Table A.
Some of the results obtained with application rates corresponding to
5 kg active ingredient/hectare are summarised in the following
Table C.
'
lZ~353~
37- 1 30-3938
T~ B Pre-emergence application 1 kg/ha
Compound Tested - ~ damage
Plant _
treated _ 5 6 13 19 26
Amaran.re~rofl._ _ 100 100 100 100 90
Capsella b.p. 100 80 90 70 90
_ __ _ _ _ _ __ ~ _ r--
Chenop. alb, _ 90 50 20 50 _ 60
Galium aparine - 50 O 10 10 10
. _ _
Senecio vulg. 80 80 80 100 100
,_
Stellarla medla 70 80 50 50 90
_
Alfalfa 60 50 80 10 90
............ . . . _
Bean 20 20 0 - O 10
Carrot 90 90 70 100 _ 90
Cotton _ 10 0 0 0 0
~'lax = = 6 ~ 50 30 0 = 10
Potato 1O 0 0 ; 0¦ 'J
. _ _
so~a 30 30 0 lO 30
.
Sugar ~eet 10 0 0 0 30
_ _
l~ape _ _ 20 0 0 0 10
Sunflower 30 50 0 0 10
~gropyron repen~ 90 60 80 90 _ 70
.grositi~i alba _ 100 100 100 100 _ 1OO
Alopec. myos.80 20 50 ao so
Apera sp.ventl. _ 100 100 100 1OO 100
. l
Avena fatua 80 40 80 90 90
. . .
Echinochloa c.g. 90 90 90 100 90
_, _ l . . _
Corn 50 30 0 50 60
_ _ _
Wheat 90 90 0 100 70
__ . I .
?
"~ ,,
3~.~
-38 ~ 130 3938
~E C Post-emergence apolication 5 ~g~ha
Compound Tested - % damage
treated 1 6 13* 19 26*
_ .
~maran.retrofl. _ _ 70 50 80 60 . 90
Capsella b.p. 20 20 80 50 60
.. .. _ _
Chenop. alb. _ 40 20 20 40 60
Galium aparlne 40 30 80 20 60
. .
Senec~o vulg. 70 80 90 90 90
Stellarla medla 60 10 30 40 40
_ _ . _ _
Alfalfa . 20 10 50 20 70
_ _
Bean 30 20 20 30 50
Carrot _ _ 30 100 80 100 80
Cotton _ 50 40 50 60 ~ 70
Flax 90 100 8C 90 80
_ _ __ __ __ .
Potato _ 20 1010 10 . 10
So~a -- _ 30 30 20 30
_ .
Sugar beet 70 0. 10 10 10
... _
nape _ 10 10 30 60 40
Sunflower 30 80 40 60 50
. ...... _ .. _ _
~gropyron repens _ 70 50 50 50 _ 50
P~rostis alba _ _ _ _ _ _ ~
Alope~. myos. 80 70 60 90 90
l _ _ . .
Apera sp.ventl. 100 100 100 10090
. _ _ _
Avena fatua 90 80 90 100 . 100
Echinochloa c.g. 1~ _ _ 80 80 90 70 _ 90
2) 80 S0 100 80 100
. .. _
Corn _ 100 90 30 30 80
Wheat 80 50 10 60 80
Rice 2) 10 50 30 30 40
* 4 kg/ha 1) upland conditionsi 2) paddy conditions
~,.'1
3~
- 39 - 130-3~38
The above results indicate an herbicidal activity which is
equal or superior to that tound with commercially available
standards against monocotyledonous weeds, and is superior to that
of such standards against dicotyledonous weeds. The herbicidal
activity is selective in soybean, cotton and at the lowest
application rate also in corn.
