CA2250102A1

CA2250102A1 - 1,3-oxazin-4-one derivates as herbicides, process and intermediates for their preparation

Info

Publication number: CA2250102A1
Application number: CA002250102A
Authority: CA
Inventors: Catherine Jacqueline White; Keiichi Hayashizaki; Yoshihiro Usui
Original assignee: Individual
Current assignee: Mitsubishi Chemical Corp
Priority date: 1996-04-23
Filing date: 1997-04-08
Publication date: 1997-10-30
Also published as: ZA973069B; ID16813A; EA199800942A1; AR006721A1; AU2509697A; CN1216542A; HUP9901754A1; BR9708725A; GB9608399D0; WO1997040041A1; CO4761027A1; JP2001515465A; EP0900216A1; KR20000010565A; HUP9901754A3

Abstract

1,3-oxazin-4-ones of formula (I) wherein W represents -NR6; R1 represents thiophene optionally substituted by one to three groups which may be the same or different selected from halogen, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, -S(O)nR7, -CO2R7, COR7, cyano, nitro and phenoxy; R2 represents hydrogen, lower alkyl, lower haloalkyl, alkoxyalkyl, lower alkenyl, lower haloalkenyl, alkoxyalkenyl, -CHO, -COR7, -CO2R7, -CH2NO2, and lower alkyl which is substituted by a group selected from -S(O)mR7 and -OCOR7; R3 represents phenyl optionally substituted by one to five groups which may be the same or different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, -S(O)nR7, -CO2R7,-COR7, cyano, nitro, -OH, phenoxy, -NR8R9 and -SF5; or a cycloalkyl group containing from three to six carbon atoms, optionally substituted by lower alkyl, lower haloalkyl or one or more halogen atoms which may be the same or different; R4 and R5 independently represent lower alkyl; and their use as herbicides.

Description

CA 022~0102 1998-09-2~

W097/40041 PCT~P97/01733 1,3-OXAZIN-4ONE DERIVATES AS HF~BICTr)FC. PROCESS AND INTERI'/IEDIATES FOR THEiR- PREPARAnON

This invention relates to novel 1,3-oxazin-4-one derivatives, processes and intermediates for their preparation, compositions containing the same, and their use as herbicides.

According to the present invention, there is provided a l,3-oxazin-4-one derivative of the formula (I):

V(i~ OJ
(I) wherein W represents -NR;
R1 represents thiophene optionally substituted by one to three groups which may be the same or different selected from halogen, hydroxy,lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, -S(O) nR, -CO2R, COR, cyano, nitro and phenoxy;
R2 represents hydrogen, lower alkyl, lower haloalkyl, alkoxyalkyl, lower alkenyl, lower haloalkenyl, alkoxyalkenyl, -CHO, -CoR7, -Co2R7, -CH2NO2, and lower alkyl which is substituted by a group selected from -S(O) mR and -OCOR;
R3 represents phenyl optionally substituted by one to five groups which may be the same or different selected from halogen, lower alkyl, ~lower haloalkyl, lower alkoxy, lower haloalkoxy, 3 0 ~ S (O ) nR, - CO2R, - COR, cyano, nitro, -OH, phenoxy, -NR8R9 and -SF5; or CA 022~0102 1998-09-2~

WO97/40041 PCT~Pg7/01733 a cycloalkyl group containing from three to six carbon atoms, optionally substituted by lower alkyl, lower haloalkyl or one or more halogen atoms which may be the same or different;
R4 and R5 independently represent lower alkyl;
R6 represents hydrogen;
R represents lower alkyl or lower haloalkyl;
R3 and R9 independently represent hydrogen or R ; and m and n independently represent zero, one or two;
or an agriculturally acceptable salt thereof, which possesses valuable properties.
It will be appreciated that certain substituents in the compounds of the invention may contribute to optical and/or stereoisomerism. All such forms are embraced by the present in~ention.
By the term 'agriculturally acceptable salts' is meant salts the cations or anions of which are known and accepted in the art for the formation of salts for agricultural or horticultural use. Preferably the salts are water-soluble. Suitable salts with bases include alkali metal (e.g. sodium and potassium), alkaline earth metal (e.g. calcium and magnesium), ~mmo~;um and amine (e.g.
diethanolamine, triethanolamine, octylamine, morpholine and dioctylmethylamine) salts.
Suitable acid addition salts, e.g. formed by compounds of formula (I) containing an amino group, include salts with inorganic acids, for example hydrochlorides, sulphates, phosphates CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 and nitrates and salts with organic acids for example acetic acid.
In the description the following terms are generally defined thus:-s ~lower alkyl' means a straight- or branched-chain alkyl group having one to six carbon atoms.
'lower haloalkyl' means a straight- or branched- chain alkyl group having one to six carbon atoms, substituted by one or more halogens.
'lower alkoxy' means a straight- or branched- chain alkoxy group having one to six carbon atoms.
lS 'lower haloalkoxy' means a straight- or branched- chain alkoxy group having one to six carbon atoms, substituted by one or more halogens.
~halogen' means a fluorine, chlorine, bromine or iodine atom.
~lower alkenyl' means an alkenyl group containing two to six carbon atoms.
~lower haloalkenyl' means an alkenyl group containing from two to six carbon atoms, substituted by one or more halogen atoms.
~alkoxyalkyl' means a lower alkyl group substituted by a lower alkoxy group.
~alkoxyalkenyl' means a lower alkenyl group substituted by a lower alkoxy group.
The compounds of the invention, in certain aspects of their properties, for example their control of the grass species Alopecurus mYosuroides, Avena fatua and Echinochloa crus-qalli and their selectivity in wheat, show advantages over known compounds.

CA 022~0102 1998-09-2~

.

Preferred compounds of formula (I) above include those in which:-R1 represents thiophene optionally substituted by one to three groups which may be the same or different selected from halogen, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, ~S(O)nR , -C02R , COR , cyano, nitro and phenoxy;
R2 represents hydrogen, lower alkyl, lower haloaikyl, alkoxyalkyl, lower alkenyl, lower haloalkenyl, alkoxyalkenyl, -CHO, -COR and -Co2R7;
R3 represents phenyl optionally substituted by one to five groups which may be the same or different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, -S(O)nR , -CO2R , -COR , cyano, nitro, -OH, phenoxy and -NR8R9; or a cycloalkyl group containing from three to six carbon atoms, optionally substituted by lower alkyl, lower haloalkyl or one or more halogen atoms which may be the same or different;
R4 and R5 independently represent lower alkyl;
W represents -NR6;
R6 represents hydrogen;
R represents lower alkyl or lower haloalkyl;
R8 and R9 independently represent hydrogen or R ; and n is zero, one or two.
Compounds of formula (I) above in which represents an unsubstltuted thiophene are preferred.

CA 022~0102 1998-09-2~

WO97/40~1 pcT~ps7lol733 Compounds of formula (I) above in which R4 and R5 each represent methyl are particularly preferred.
Particularly preferred compounds of formula (I) above are those in which R2 is lower alkyl, most preferably methyl.
Compounds of formula (I) in which R3 represents phenyl which is 3-monosubstituted, 3,5-disubstituted or 2,5-disubstituted are preferred (3,5-disubstituted or 2,5-disubstituted being particularly preferred).
Compounds of formula (I) in which R3 represents phenyl optionally substituted by one to three groups which may be the same or different selected from halogen, or a straight-or branched- chain alkyl group containing from one to three carbon atoms optionally substituted by one or more halogen atoms, are preferred.
Compounds of formula (I) in which R3 represents phenyl substituted by one or two groups which may be the same or different selected from halogen (especially chlorine or fluorine), Cl 3 alkyl (especially methyl) and Cl 3 haloalkyl (especially -CF3), are particularly preferred.
A preferred class of compounds of formula (I) are those wherein:
R represents methyl, halogenated methyl or methoxymethyl;
R3 represents phenyl optionally substituted by one to three groups which may be the same or different selected from halogen, a straight- or branched- chain optionally halogenated alkyl group containing from one to four carbon atoms, a straight- or branched- chain optionally CA 022~0l02 l998-09-25 W O97/40041 PCT~EP97/01733 halogenated alkoxy group containing from one to four carbon atoms, or -S(O) nR ; or cyclobutyl;
R4 and R5 each represent methyl; and R7 represents a straight- or branched- chain optionally halogenated alkyl group containing from one to four carbon atoms.
A particularly preferred class of compounds of formula (I) are those wherein:
R1 represents thiophene optionally substituted by one or two groups which may be the same or different selected from halogen, a straight- or branched- chain optionally halogenated alkyl group containing from one to four carbon atoms, a straight- or branched-chain optionally halogenated alkoxy group containing from one to four carbon atoms, or -S(o)nR7;
R2, R4 and R5 each represent methyl;
R3 represents phenyl optionally substituted by one or two groups which may be the same or different selected from halogen and optionally halogenated methyl; or cyclobutyl; and R7 represents a straight- or branched- chain optionally halogenated alkyl group containing from one to four carbon atoms.
A further particularly preferred class of compounds of formula (I) are those wherein:
Rl represents thiophene;
R2, R4 and R5 each represent methyl; and R3 represents phenyl optionally substituted by one or two groups which may be the same or different selected from halogen, optionally halogenated methyl; or cyclobutyl.

CA 022~0102 1998-09-2~

WO97/4~41 PCT~P97/01733 -A further particularly preferred class of compounds of formula (I) are those wherein:
Rl represents thiophene optionally substituted by lower alkyl, lower alkoxy or halogen;
R represents methyl or ethyl;
R4 and Rs each represent methyl; and R3 represents phenyl optionally substituted by one, two or three groups which may be the same or different selected from halogen, optionally halogenated methyl, nitro or -SF5; or cyclobutyl or cyclopropyl.
Another preferred class of compounds of formula (I) above are those having one or more lS of the following features:
Rl represents 2-thienyl; 3-thienyl; 3-methoxy-2-thienyl; 5-methyl-2-thienyl or 5-chloro-2-thienyl;
R2 represents methyl; ethyl or fluoromethyl;
R4 and R5 each represent methyl; and R3 represents cyclopropyl; cyclobutyl; 3,5-difluorophenyl;

3,5-dichlorophenyl; 2-fluoro-5-trifluoromethylphenyl; 2-fluoro-5-methylphenyl; 3-chlorophenyl;
2,5-difluorophenyl; 3-trifluoromethylphenyl;
5-chloro-2-methylphenyl;
3-pentafluorosulphanylphenyl; 2-chloro-3,5-difluorophenyl; 3,4,5-trifluorophenyl;
2-chloro-5.fluorophenyl; 5-chloro-2-fluorophenyl or 5-chloro-3-fluorophenyl .
Particularly important compounds of formula (I) include the following:-l. N-(3,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-l,3-oxazin-3-yl]-2-methylpropanamide;

CA 022~0l02 l998-09-2~

WO97/40041 PCT~P97/01733 - 2. N-(3~5-dichlorophenyl)-2-[2~3-dihydro 6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
3. N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-~,3-oxazin-3-yl]-2-~ethylpropanamide;

4. N-(2-fluoro-5-methylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

5. N-(3-chlorophenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

6. N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

7. N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

8. N-(3-chlorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

9. N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

10. N-(5-chloro-2-methylphenyl)-2-[2,3-dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

11. N-(cyclobutyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
19. N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-5-~3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
20. N-(2,5-difluorophenyl)-2-[2,3-dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

CA 022~0l02 l998-09-2~

WO97/40041 PCT~P97/01733 g 40. N-(3-trifluoromethylphenyl)-2-f2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
41. N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
42. N-(3-chlorophenyl)-2-[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
47. N-(2,5-difluorophenyl)-2-{2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
48. N-(3,5-dichlorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
49. N-(3,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
50. N-(5-chloro-2-methylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
53. N-(2,5-difluorophenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
54. N-(3-chlorophenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
55. N-(3,5-dichlorophenyl)-2-{5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
~ 56. N-(3,5-difluorophenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
57. N-(5-chloro-2-methylphenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

CA 022~0l02 l998-09-2~

WO97/40041 PCT~P97/01733 136. N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
137. N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
138. N-(3-chlorophenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
139. N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
140. N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
141. N-(5-chloro-2-methylphenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
142. N-(3,5-dichlorophenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-.-methylpropanamide;
143. N-(3,5-difluorophenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
144. N-(2,4-difluorophenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
145. N-(2-fluoro-5-trifluoromethylphenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
146. N-(3-pentafluorosulphanylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
147. N-(2-chloro-3,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;

CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 148. N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
149. N-(3,4,5-trifluorophenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
150. N-(2-methyl-5-nitrophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
151. N-(cyclopropyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
152. N-(2-chloro-5-fluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
153. N-(3-chloro-5-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
154. N-(2,4-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide;
155. N-(2-fluoro-5-trifluoromethylphenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide; and 156. N-(2-chloro-5-fluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-~3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide.

The following compounds of formula (I) wherein R4 and R5 represents methyl and W
represents -NH- form part of the present invention.
In the Table that follows Me means methyl, cBu means cyclobutyl, cPr means cyclopropyl, Ph means phenyl and Et means ethyl. Where subscripts do not occur in the Table it is PCT/EPg7/01733 understood that in appropriate cases they are present (for example CF3 is understood to mean CF3) CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 -Cpd no Rl R2 R~
- 1 2-thienyl Me3,5-F2 Ph 2 2-thienyl Me3,5-C12 Ph 3 2-thlenyl Me2-F-5-CF3 Ph 4 2-thienyl Me2-F-5-CH3 Ph 2-thienyl Me 3-Cl Ph 6 2-thienyl Me2,5-F2 Ph 7 2-thienyl Me 3-CF3 Ph 8 3-thienyl Me 3-Cl Ph 9 3-thienyl Me 3-CF3 Ph 2-thienyl Me2-Me-5-Cl Ph 11 2-thienyl Me cBu 12 5-OMe-2-thienyl Me 3-CF3 Ph 13 5-OMe-2-thienyl Me2,5-F2 Ph 14 5-OMe-2-thienyl Me 3-Cl Ph 15 5-OMe-2-thienyl Me3,5-C12 Ph 16 5-OMe-2-thienyl Me3,5-F2 Ph 17 5-OMe-2-thienyl Me2-Me-5-Cl Ph 18 5-OMe-2-thienyl Me cBu 19 3-OMe-2-thienyl Me 3-CF3 Ph 20 3-OMe-2-thienyl Me2,5-F2 Ph 21 3-OMe-2-thienyl Me 3-Cl Ph 22 3-OMe-2-thienyl Me3,5-C12 Ph 23 3-OMe-2-thienyl Me3,5-F2 Ph 24 3-OMe-2-thienyl Me2-Me-5-Cl Ph 25 3-OMe-2-thienyl Me cBu 26 5-SMe-2-thienyl Me 3-CF3 Ph 27 5-SMe-2-thienyl Me2,5-F2 Ph 28 5-SMe-2-thienyl Me 3-Cl Ph 29 5-SMe-2-thienyl Me3,5-C12 Ph 30 5-SMe-2-thienyl Me3,5-F2 Ph 31 5-SMe-2-thienyl Me2-Me-5-Cl Ph 32 5-SMe-2-thienyl Me cBu 33 3-SMe-2-thienyl Me 3-CF3 Ph 34 3-SMe-2-thienyl Me2,5-F2 Ph 35 3-SMe-2-thienyl Me 3-Cl Ph 36 3-SMe-2-thienyl Me3,5-C12 Ph 37 3-SMe-2-thienyl Me3,5-F2 Ph 38 3-SMe-2-thienyl Me2-Me-5-Cl Ph 39 3-SMe-2-thienyl Me cBu 5-Me-2-thienyl Me 3-CF3 Ph 41 5-Me-2-thienyl Me2,5-F2 Ph 42 5-Me-2-thienyl Me 3-Cl Ph 43 5-Me-2-thienyl Me3,5-C12 Ph 44 5-Me-2-thienyl Me3,5-F2 Ph 5-Me-2-thienyl Me2-Me-5-Cl Ph .

CA 022~0l02 l998-09-2~

- Cpd no Rl ~2 R~
465-Me-2-thienyl Me cBu 473-thienyl Me 2,5-F2 Ph 483-thienyl Me 3,5-Cl2 Ph 493-thienyl Me 3,5-F2 Ph 503-thienyl Me 2-Me-5-Cl Ph 513-thienyl Me cBu 525-Cl-2-thienyl Me 3-CF3 Ph 535-Cl-2-thienyl Me 2,5-F2 Ph 545-Cl-2-thienyl Me 3-Cl Ph 555-Cl-2-thienyl Me 3,5-Cl2 Ph 565-Cl-2-thienyl Me 3,5-F2 Ph 575-Cl-2-thienyl Me 2-Me-5-Cl Ph 585-Cl-2-thienyl Me cBu 593-Cl-2-thienyl Me 3-CF3 Ph 603-Cl-2-thienyl Me 2,5-F2 Ph 613-Cl-2-thienyl Me 3-Cl Ph 623-Cl-2-tnienyl Me 3,5-Cl2 Ph 633-Cl-2-thienyl Me 3,5-F2 Ph 643-C1-2-thienyl Me 2-Me-5-Cl Ph 653-Cl-2-thienyl Me cBu 665-F-2-thienyl Me 3-CF3 Ph 675-F-2-thienyl Me 2,5-F2 Ph 685-F-2-thienyl Me 3-Cl Ph 695-F-2-thienyl Me 3,5-Cl2 Ph 705-F-2-thienyl Me 3,5-F2 Ph 715-F-2-thienyl Me 2-Me-5-Cl Ph 725-F-2-thienyl Me cBu 733-F-2-thienyl Me 3-CF3 Ph 743-F-2-thienyl Me 2,5-F2 Ph 753-F-2-thienyl Me 3-Cl Ph 763-F-2-thienyl Me 3,5-Cl2 Ph 773-F-2-thienyl Me 3,5-F2 Ph 783-F-2-thienyl Me 2-Me-5-Cl Ph 793-F-2-thienyl Me cBu 802-thienyl CH2F 3-CF3 Ph 812-thienyl CH2F 2,5-F2 Ph 822-thienyl CH2F 3-Cl Ph 832-thienyl CH2F 3,5-Cl2 Ph 842-thienyl CH2F 3,5-F2 Ph 852-thienyl CH2F 2-Me-5-Cl Ph 862-thienyl CH2F cBu 873-thienyl CH2F 3-CF3 Ph 883-thienyl CH2F 2,5-F2 Ph 893-thienyl CH2F 3-Cl Ph go3-thienyl CH2F 3,5-Cl2 Ph 913-thienyl CH2F 3,5-F2 Ph CA 022~0l02 l998-09-2~

WO 97/40041 rCT/Er97/01733 Cpd no Rl R2 R3 92 3-thienyl CH2F 2-Me-5-Cl Ph 93 3-thienyl CH2F cBu 94 2-thienyl CH20Me 3-CF3 Ph 2-thienyl CH20Me 2,5-F2 Ph 96 2-thienyl CH20Me 3-Cl Ph 97 2-thienyl CH20Me 3,5-C12 Ph 98 2-thienyl CH20Me 3,5-F2 Ph 99 2-thienyl CH20Me 2-Me-5-Cl Ph 100 2-thienyl CH20Me cBu lO1 3-thienyl CH20Me 3-CF3 Ph 102 3-thienyl CH20Me 2,5-F2 Ph 103 3-thienyl CH20Me 3-Cl Ph 104 3-thienyl CH20Me 3,5-Cl2 Ph 105 3-thienyl CH20Me 3,5-F2 Ph 106 3-thienyl CH20Me 2-Me-5-Cl Ph 107 3-thienyl CH20Me cBu 108 3-N02-2-thienyl Me .3-CF3 Ph 109 3-N02-2-thienyl Me 2,5-F2 Ph 110 3-N02-2-thienyl Me 3-Cl Ph 111 3-N02-2-thienyl Me 3,5-C12 Ph 112 3-N02-2-thienyl Me 3,5-F2 Ph 113 3-N02-2-thienyl Me 2-Me-5-Cl Ph 114 3-N02-2-thienyl Me cBu 115 5-N02-2-thienyl Me 3-CF3 Ph 116 5-N02-2-thienyl Me 2,5-F2 Ph 117 5-N02-2-thienyl Me 3-Cl Ph 118 5-N02-2-thienyl Me 3,5-Cl2 Ph 119 5-N02-2-thienyl Me 3,5-F2 Ph 120 5-N02-2-thienyl Me 2-Me-5-Cl Ph 121 5-N02-2-thienyl Me cBu 122 3-CN-2-thienyl Me 3-CF3 Ph 123 3-CN-2-thienyl Me 2,5-F2 Ph 124 3-CN-2-thienyl Me 3-Cl Ph 125 3-CN-2-thienyl Me 3,5-Cl2 Ph 126 3-CN-2-thienyl Me 3,5-F2 Ph 127 3-CN-2-thienyl Me 2-Me-5-Cl Ph 128 3-CN-2-thienyl Me cBu 129 5-CN-2-thienyl Me 3-CF3 Ph 130 5-CN-2-thienyl Me 2,5-F2 Ph 131 5-CN-2-thienyl Me 3-Cl Ph 132 5-CN-2-thienyl Me 3,5-Cl2 Ph 133 5-CN-2-thienyl Me 3,5-F2 Ph 134 5-CN-2-thienyl Me 2-Me-5-Cl Ph 135 5-CN-2-thienyl Me cBu 136 5-Me-2-thienyl Me 2-F-5-CF3 Ph 137 2-thienyl Et 3-CF3 Ph CA 022~0l02 l998-09-2~

WO 97/40041 rCT/EP97/01733 Cpd no Rl R2 R3 138 2-thienyl Et 3-Cl Ph 139 2-thienyl Et2,5-F2 Ph 140 2-thienyl Et2-F-5-CF3 Ph 141 2-thienyl Et2-Me-5-Cl Ph 142 2-thienyl Et3,5-C12 Ph 143 2-thienyl Et3,5-F2 Ph 1445-Cl-2-thienyl Me2,4-F2 Ph 1455-Cl-2-thienyl Me2-F-5-CF3 Ph 146 2-thienyl Me 3-SF5 Ph 147 2-thienyl Me2-Cl-3,5-F2 Ph 1483-OMe-2-thienyl Me2-F-5-CF3 Ph 149 2-thienyl Me3,4,5-F3 Ph 150 2-thienyl Me2-Me-5-NO2 Ph 151 2-thienyl Me cPr 152 2-thienyl Me2-Cl-5-F Ph 153 2-thienyl Me3-Cl-5-CF3 Ph 154 3-thienyl Me2,4-F2 Ph 155 3-thienyl Me2-F-5-CF3 Ph 156 3-thienyl Me2-Cl-5-F Ph 157 3-thienyl Et2-Cl-5-F Ph 158 2-thienyl ~t2-Cl-5--F Ph 1595-Me-2-thienyl Me2-Cl-5-F Ph 1603-SMe-2-thienyl Me2-Cl-5-F Ph 1615-Cl-2-thienyl Me2-Cl-5-F Ph 1623-Cl-2-thienyl Me2-Cl-5-F Ph 1635-F-2-thienyl Me2-Cl-5-F Ph 1643-F-2-thienyl Me2-Cl-5-F Ph Compounds of formula (I) above may be prepared by the application or adaptation of known methods (i.e. methods heretofore used or described in the literature).
It is to be understood that in the descriptions of the following processes the sequences may be performed in different orders, and that suitable protecting groups may be required to achieve the compounds sought.
According to a feature of the present invention compounds of formula (I) wherein R1, R2, R3, R4, R5 and W are as defined above may be prepared by the reaction of a compound of general formula (II):

CA 022~0102 1998-09-2~

WO97/40041 pcT~ps7lol733 R2 o (II) h i Rl R2 R3 R4 and R5 are as defined above, with an amine of formula (III):
R6NH- R3 (III) wherein R3 and R6 are as defined above. The reaction is generally performed in the presence of a base, for example a tertiary amine such as triethylamine and in an inert solvent such as dichloromethane at a temperature from 0~C to the reflux temperature of the solvent.
According to a further feature of the present invention compounds of formula (I) wherein R , R , R , R , R and W are as defined above may also ~e prepared by the reaction of a compound of formula tIV):

~ R~R5 R2 o (IV) wherein Rl, R2, R4 and R5 are as defined above, with an amine of formula (III) above wherein R3 is as defined above, and in which R6 is hydrogen. The reaction is performed in the presence of a coupling reagent for example N,N'-dicyclohexylcarbodiimide (DCCI) optionally in the presence of a base for example 4-dimethylaminopyridine (DMAP) and in an inert solvent such as dichloromethane at a temperature from 0 to 60~C.

CA 022~0102 1998-09-2~

WO97140041 PCT~P97/01733 Accordin~ to a further feature of the present invention compounds of formula (I) wherein R , R , R , R , R and W are as defined above, may also be prepared by the reaction of a carboxylic acid of formula (IV) above with a phenyl carbamate of formula PhO2C-N~R , wherein R is as defined above. The reaction is generally performed in the presence of a base, preferably l,8-diazabicyclo[5.4.0] undec-7-ene, in an inert solvent for example l,4-dioxan and at a temperature from 20-100~C.
According to a further feature of the present invention compounds of formula (I) wherein Rl, R2, R3, R4, R5 and W are as defined above may also be prepared by the reaction of a trimethylsilyl ester of formula (V):

~ R,<R5 R2 o (V) wherein Rl, R2, R4 and R5 are as defined above and TMS means trimethylsilyl, with an amine of formula NH2R3, wherein R3 is as defined above. The reaction is generally performed in the presence of a catalytic amount of a titanium (IV) salt, preferably prepared in situ from the reaction of titanium (IV) chloride and silver (I) trifluoromethanesulphonate, and in the presence of an anhydride, preferably 4-trifluoromethylbenzoic anhydride and in an inert solvent for example dichloromethane at a temperature from 0 to 60~C. This procedure is useful for weakly nucleophilic amines and is described in Chem. Letters (1993), 1053-1054 by M. Miyashita, I. Shirna and T. Mukaiyama.

CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 According to a further feature of the present invention compounds of formula (I) in which Rl, R3, R4, R5 and W are as defined above and R2 represents lower alkenyl optionally substituted by halogen or lower alkoxy and wherein the double bond of the alkenyl group is located between the two carbon atoms closest to the l,3-oxazin-4-one ring may be prepared by reaction of the corresponding compound of formula (I) in which R is -CHO or -COR in which R is defined above, with a phosphorane, typically generated by reaction of a phosphonium salt of formula Ph3P+-CHRl0Rll_X- in which X
represents chlorine, bromine or iodine, Rl~
represents hydrogen, alkoxy, or alkyl containing from one to four carbon atoms optionally substituted by halogen or alkoxy, and Rll represents hydrogen or alkyl containing from one to four carbon atoms optionally substituted by halogen with the proviso that the total number of carbon atoms in the combined alkyl groups R7, Rl0 and Rll does not exceed four. The reaction is generally performed in the presence of a strong base for example n-butyl lithium and in an inert solvent for example tetrahydrofuran at a temperature from 0~C to the reflux temperature, the reaction being conducted under an inert atmosphere.
According to a further feature of the present invention compounds of formula (I) wherein Rl, R3, R4, R5 and W are as defined above and R2 represents chloromethyl, bromomethyl or iodomethyl may be prepared by reaction of the correspon~;~g compound of formula (I) in which R2 is methyl with a chlorinating, brominating or iodinating agent, preferably the appropriate N-CA 022~0102 1998-09-2~

WO 97140041 P~ 57/01733 halosuccinimide, for example N-bromosuccinimide in an inert solvent e.g. carbon tetrachloride, optionally in the presence of a radical initiator e.g. azobis-isobutyronitrile or by irradiation with a tungsten light source, and at a temperature from ambient to the reflux temperature of the solvent.
According to a further feature of the present invention compounds of formula (I) in which R1, R3, R4, Rs and W are as defined above and R2 is -CF2R12a wherein R12a is C1-C5 alkyl or haloalkyl, may be prepared by reaction of the corresponding compound of formula (I) in which R2 is -COR12a with diethylaminosulphur trifluoride in an inert solvent, e.g.
dichloromethane, at a temperature of 0 to 60~C.
According to a further feature of the present invention compounds of formula (I) in which R}, R3, R4, R5 and W are as defined above and R2 is lower alkyl substituted by iodine may be prepared by iodination of the corresponding compound of formula (I) in which the iodine atom in R2 is replaced by bromine or chlorine. The transhalogenation reaction is generally performed using sodium or potassium iodide in a inert solvent preferably acetone at a temperature from ambient to the reflux temperature of the solvent.
According to a further feature of the present invention compounds of formula (I) wherein R2 represents a lower alkyl group substituted by a group -SR7, and Rl, R3, R4, R5, R7 and w are as defined abo~e, may be prepared by the reaction of the corresponding compound of formula (I) in which the -SR7 group is replaced by a leaving group, preferably chloro or bromo, .

CA 022~0102 1998-09-2~

WO 97/40041 PCr/Er97/01733 with a thiol of formula R7SH or alkali metal salt of the thiol R SM wherein M represents lithium or sodium. The reaction is generally performed in an inert solvent e.g. N,N-dimethylformamide at a temperature from 0 to 60~C.
According to a further feature of the present invention compounds of formula (I) wherein Rl, R3, R4, R5 and W are as defined above and R2 represents a lower alkyl group substituted by -SCF3 may be prepared by the reaction of the corresponding compound of formula (I) in which the -SCF3 group is replaced by an -SCN group, with trifluoromethyltrimethylsilane according to the procedure of B.R.Langlois et. al. as described in Tetrahedron Letters, Volume 38 (l), pages 65-68 (1997). The reaction is generally performed in the presence of a catalyst preferably tetrabutyl~mmo~lum fluoride in an inert solvent for example tetrahydrofuran and at a temperature of from -20 to 20~C.
According to a further feature of the present invention compounds of formula (I) wherein R1, R3, R4, R5 and W are as defined above and R2 represents a lower alkyl group substituted by -oC(o)R7 wherein R7 is as defined above may be prepared by the reaction of the corresponding compound of formula (I) in which the -oC(o)R7 group is replaced by a leaving group, with a salt of formula R7-Co2-M1+, wherein M1 represents sodium or potassium. The leaving group is preferably chlorine or bromine.
The reaction is typically performed in an inert solvent preferably N,N-dimethylformamide, at a temperature from ambient to 120~C.

CA 022~0102 1998-09-2~

WO97/40041 pcT~ps7lol733 Compounds of formula (I) in which R2 represents a lower alkyl group substituted by -oR7 and Rl, R3, R4, R5, R7 and W are as defined above, may be prepared by reaction of the correspondin~ compound of formula (I) in which -oR7 is replaced by a hydroxy group, with an alcohol of formula R OH in the presence of a trialkylphosphine, e.g. tri-n-butylphosphine and l,ll-(azodicarbonyl)piperidine, in an inert solvent (e.g. toluene at a temperature from 20~C
to the reflux temperature). The general procedure is described by J.R. Falck in Tetrahedron Letters 35, 5997 (1994).
According to a further feature of the present invention compounds of formula (I) in which R2 is - CHFR7 and Rl, R3, R , R , R and W
are as defined above, may be prepared by reaction of the corresponding compound of formula (I) in which R is -CH(OH)R with diethylaminosulphur trifluoride in an inert solvent, e.g. dichloromethane at a temperature from 0 to 60~C.
According to a further feature of the present invention compounds of formula (I) wherein Rl, R3, R4, R5 and W are as defined above and R2 represents a fluoromethyl group may be prepared by the fluorination of the corresponding compound of formula (I) in which R2 is replaced by a hydroxymethyl group, most preferably with diethylaminosulphur trifluoride in an inert solvent for example dichloromethane at a temperature from 0 to 60~C.
According to a further feature of the present invention compounds of formula (I) wherein Rl, R3, R4, R5 and W are as defined above and R2 represents a difluoromethyl group may be CA 022~0102 1998-09-2~

WO97/4~41 PCT~P97/01733 prepared by the fluorination of the corresponding compound of formula (I) in which R2 is -CHO, most preferably with diethylaminosulphur trifluoride in an inert solvent for example dichloromethane at a temperature from 0 to 60~C.
According to a further feature of the present invention compounds of formula (I) wherein Rl, R3, R4, R5 and W are as defined above and R2 represents alkoxyalkyl may be prepared by the reaction of the corresponding compound of formula (I) in which R2 is replaced by hydroxyalkyl, with an alkyl iodide in the presence of silver (I) oxide and in an inert solvent for example acetonitrile at a temperature from ambient to the reflux temperature. The general procedure is as described in J. Org.Chem. 40, 206 (1975).
According to a further feature of the present invention aldehydes of formula (I) wherein Rl, R3, R4, R5 and W are as defined above and R2 represents a -CHO group, may be prepared by oxidation of the corresponding compounds of formula (I) in which R2 is replaced by hydroxymethyl using for example pyridinium chlorochromate in dichloromethane at 0~C to the reflux temperature.
According to a further feature of the present invention compounds of formula (I) in which R2 represents -COR and Rl, R3, R4, R5, R7 and W are as defined above, may be prepared by oxidation of the corresponding compounds of formula (I) in which R2 is replaced by -CH(OH)R , using for example pyridinium chlorochromate in dichloromethane at 0~C to the reflux temperature.

CA 022~0102 1998-09-2~

WO97140041 PCT~P97/01733 According to a further feature of the present invention compounds of formula (I) in which R2 represents -CO2R and R , R3, R4, R5, R7 and W are as defined above, may be prepared by esterification of the corresponding compound of formula (I) in which R2 is replaced by -CO2H.
The reaction is preferably performed using an alcohol of formula R OH and diethylazodicarboxylate in an inert solvent for exampie ether, at a temperature from 0~C to the reflux temperature of the solvent.
Alternatively, the above conversion may be performed by chlorination of the corresponding compound of formula (I) in which R2 is replaced lS by -CO2H using for example oxalyl chloride, in an inert solvent for example dichloromethane or l,2-dichloroethane, optionally in the presence of a catalyst such as N,N-dimethylformamide at a temperature from 20~C to the reflux temperature of the mixture to give the corresponding acid chloride, which is subsequently reacted with an alcohol of formula R OH in an inert solvent for example tetrahydrofuran at a temperature from 0~C to the reflux temperature of the solvent.
According to a further feature of the present invention compounds of formula (I) in which Rl, R3, R4, R5 and W are as defined above and R2 represents -CH2NO2 may be prepared by reaction of the corresponding compound in which R2 is bromomethyl or iodomethyl, with an alkali metal nitrite preferably sodium nitrite, or silver nitrite in a solvent such as N,N-dimethylformamide or dimethylsulphoxide, and at a temperature from -20 to 50~C.
According to a further feature of the present invention compounds in which m and/or n CA 022~0102 1998-09-2~

WOg7/40041 PCT~P97/01733 - are one or two are generally prepared by the oxidation of the sulphur atom of the corresponding compounds in which m and/or n are zero or one. The oxidation of the sulphur atom is generally carried out using for example 3-chloroperbenzoic acid in an inert solvent such as dichloromethane at a temperature from -40~C
to room temperature.
Intermediates of formula (I) in which R is replaced by -CH(OH)R7 and Rl, R3, R4, R5, R and W are as defined above, may be prepared by the reaction of the corresponding compounds of formula (I) in which R represents -CHO with a Grignard reagent of formula R7Mg-Xl wherein Xl represents bromine or iodine. The reaction may be performed in an inert solvent for example ether or tetrahydrofuran at a temperature from 20 to 60~C.
Intermediates of formula (I) in which Rl, R3, R4, R5 and W are as defined above and R2 is replaced by a lower alkyl group substituted by -SCN may be prepared by the reaction of the corresponding compound of formula (I) in which -SCN is replaced by a leaving group preferably halogen such as chlorine, bromine or iodine, with an alkali metal thiocyanate or ammonium thiocyanate. The reaction is generally performed in a solvent such as ethanol or N,N-dimethylformamide and at a temperature from 0 to 60~C.
Intermediates of formula (I) in which Rl, R3, R4, R5 and W are as defined above and R2 is replaced by -CO2H, may be prepared by oxidation of the corresponding compounds of formula (I) in which R2 represents -CHO, which may be achieved by procedures reported by R.C. Larock in CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 Comprehensive Organic Transformations p.838, for example by reaction with pyridinium dichromate in N,N-dimethylformamide at a temperature from 0 to 60~C.
Acid chlorides of formula (II) may be prepared by the reaction of an acid of formula (IV) above with a chlorinating agent, for example oxalyl chloride or a mixture of triphenylphosphine and carbon tetrachloride.
The reaction with oxalyl chloride may be performed in an inert solvent for example dichloromethane optionally in the presence of a catalyst, for example N,N-dimethylformamide, at a temperature from 0 to 50~C. The reaction with triphenylphosphine and carbon tetrachloride may be performed in an inert solvent, for example toluene or excess carbon tetrachloride, and at a temperature from 20 to 120~C.
Carboxylic acids of formula (IV) may be prepared by the hydrolysis of an ester of formula (VI):

R1X~N~<CO R8a R2 o (VI) wherein R , R , R and R are as defined above and R8a represents an alkyl group, preferably methyl or ethyl. The reaction is performed in the presence of a base for example sodium or potassium hydroxide and in a solvent, e.g. aqueous alcohol at a temperature from 0~C
to the reflux temperature of the solvent.

CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 - Carboxylic acids of formula ~IV) may also be prepared by the reaction of a benzyl ester of formula (VII):

R1 ~ N ~ CO Bz R2 o (VII) wherein Rl, R2, R4 and R5 are as defined above and Bz is benzyl, with aluminium bromide and anisole in the presence of nitromethane and in an inert solvent e.g. dichloromethane at a temperature from 0 to 50~C.
Carboxylic acids of formula (IV) may also be prepared from benzyl esters of formula (VII) by catalytic hydrogenation. The reaction may be performed at normal or elevated pressure in an inert solvent, for example ethanol, preferably at room temperature and in the presence of a suitable catalyst, for example 5~ palladium or activated carbon.
Compounds of formula (II), (IV), (V), (VI) and (VII) are novel and as such constitute a further feature of the present invention.
Esters of formula (VI) or (VII) may be prepared by the reaction of a compound of formula (VIII):
o R1\~o R2 ~ O ~ Me (VIII) wherein Rl-and R2 are as defined above, with an imine of formula CH2=NC(R4)(R5)Co2R8a or of CA 022~0102 1998-09-2~
.

WO97/4~41 pcT~ps7lol733 formula CH2=NC(R )~R )CO2Bz wherein R , R5, R8 and Bz are as defined above. The reaction is generally performed in the presence or absence of solvent and at a temperature from 90 to 200~C
or the boiling point of the sol~ent. The solvent when used is inert, for example xylene, and the acetone produced is preferably removed by distillation.
Esters of formula (VI) or (VII) may also be prepared by the reaction of a compound of formula (IX):
R C(O)-CH(R )-CO2Rl2 (IX) wherein Rl and R are as defined above and Rl2 represents an alkyl group (preferably methyl or ethyl), with an imine of formula CH2=NC(R4)(R5)Co2R8a or CH2=NC(R4)(Rs)Co2Bz respectively, wherein R4 RS R8a a d B
defined above. The reaction is performed utilising similar conditions to those used for the preparation of compounds of formula (VI) or (VII) from compounds of formula (VIII) above and preferably with removal of the alcohol Rl2OH
formed in the reaction.
Intermediate alcohols of formula (I) wherein R is replaced by a hydroxymethyl group may be prepared by hydrolysis of the corresponding ester of formula (I) in which R2 is replaced by a -CH2OCOR group in which Rl3 represents lower alkyl preferably methyl. The reaction is generally performed using a base for example potassium carbonate in an aqueous alcohol solution at 0 to 50~C.
Imines of formula C~2=NC(R )(R5)Co2R8a or of formula CH2=NC(R )(RS)CO2Bz may be prepared by the reaction of an aminoacid ester of formula CA 022~0102 1998-09-2~

WO97/4~41 PCT~P97/01733 H,N-C(R4)(R5)Co2R8a or of formula H2N-C(R )(R )CO2Bz respectively, wherein R , R , R8a and Bz are as defined above, with formaldehyde, preferably as an aqueous solution and at a temperature from ambient to 60~C.
Compounds of formulae (III), (VIII) and (IX) are known or may be prepared using ~nown methods, for example see International Patent Publication No. WO 93/15064. The compounds of formula (I) can be converted into salts which can be prepared by known methods.

The following non-limiting Examples illustrate the invention.

oxalyl chloride (0.17 ml) followed by N,N-dimethylformamide (2 drops) were added to a stirred solution of 2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl~-2-methylpropanoic acid (0.51 g) in dichloromethane at ambient temperature. After 20 minutes the solution was evaporated and redissolved in dichloromethane. A solution of 3,5-difluoroaniline (0.32 g) was added at 0~C, stirring maintained at 0~C for 10 minutes, and triethylamine (0.56 ml) added. The mixture was stirred at room temperature for 2 hours, then washed in turn with hydrochloric acid (2 M), sodium carbonate solution (1 M) and brine, dried (magnesium sulphate) and evaporated. The residue was purified by column chromatography eluting with cyclohexane/ethyl acetate to give N-(3,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-CA 022~0l02 l998-09-2~

WO 97/40041 PCTlEr97101733 methylpropanamide (compound 1, 0.2 g), m.p. 178-179~C
By proceeding in a similar manner the following compounds were prepared.
N-(3,5-dichlorophenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 2), m.p. 156-158~C;
N-(2-fluoro-5-trifluoromethylphenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 3), m.p. 113.5-115.5~C;
N-(2-fluoro-5-methylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 4), m.p.
144.5-146~C;
N-(3-chlorophenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl~-2-methylpropanamide (compound 5), m.p. 125-126.5~C;
N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 6), m.p. 95-96.5~C;
N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yll-2-methylpropanamide (compound 7), m.p.
149.7-152.7~C;
N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 40) NMR 1.65(s,6H), 2.08(s,3H), 2.18(s,3H), S.22(s,2H), 6.72(m,lH), 6.85(m,lH), 7.6(m,lH), 7.8(br m,2H), 7.8(m,lH), 8.68(br s,lH);
N-(3-chlorophenyl)-2-[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-. .

CA 022~0102 1998-09-2~

- yl]-2-methylpropanamide,(compound 42) NMR
1.63(s,6H), 2.05(s,3H), 2.16(s,3H), 5.2(s,2H), 6.7(m,lH), 6.82(m,lH), 6.96(m,lH), 7.11(m,lH), 7.25(m,lH), 7.56(m,lH), 8.4(br s,lH);
N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 41) NMR 1.6(s,6H), 2.07(s,3H), 2.12(s,3H), 5.2(s,2H), 6.6(m,1H), 6.72(m,1H), 6.8(m,1H), 6.9(m,lH), 8.08(m,2H);
N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 136) NMR 1.62(s,6H), 2.08(s,3H), 2.15(s,3H), 5.22(s,2H), 6.71(m,lH), 6.81(m,lH), 7.08(m,lH), 7.22(m,lH), 8.22(br s,lH), 8.62(m,lH);
N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl~-2-methylpropanamide,(compound 137) NMR
l.l(t,3H), 1.65(s,6H), 2.35(q,2H), 5.22(s,2H), 6.86(m,lH), 6.92(m,lH), 7.25(m,2H), 7.3(m,lH), 7.58(m,lH), 7.75(m,lH), 8.5(br s,lH);
N-(3-chlorophenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-S-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 138) NMR l.l(t,3H), 1.63(s,6H), 2.35(q,2H), 5.22(s,2H), 6.85(m,lH), 6.95(m,2H), 7.1(m,lH), 7.23(m,2H), 7.55(m,lH), 8.4(br s,lH);
N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl~-2-methylpropanamide,(compound 139) NMR 1.1(t,3H), 1.61(s,6H), 2.36(q,2H), 5.23(s,2H), 6.62(m,lH), 6.9(m,3H), 7.25(m,1H), 8.1(m,2H);
N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-CA 022~0l02 1998-09-2~

WO97140041 PCT~P97/01733 oxazin-3-yl]-2-methylpropanamide,(compound 140) NMR l.l(t,3H), 1.62(s,6H), 2.36(q,2H), 5.25(s,2H), 6.9(m,2H), 7.05(m,lH), 7.25(m,2H), 8.22(br s,lH), 8.62(m,lH);
N-(5-chloro-2-methylphenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 141) NMR
l.l(t,3H), 1.65(s,6H), 2.1(s,3H), 2.36(q,2H), 5.21(s,2H), 6.86-7.0(br m,4H), 7.26(m,lH), 7.93(m,lH), 8.0(br s,lH);
N-(3,5-dichlorophenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 142) NMR l.l(t,3H), 1.62(s,6H), 2.35(q,2H), 5.2(s,2H), 6.88(m,1H), 6.95(m,2H), 7.26(m,lH), 7.4(m,2H), 8.55(br s,lH);
N-(3,5-difluorophenyl)-2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 143) NMR l.l(t,3H), 1.62(s,6H), 2.35(q,2H), 5.21(s,2H), 6.44(m,lH), 6.87(m,lH), 6.94(m,lH), 7.03(m,2H), 7.26(m,lH), 8.6(br s,lH);
N-(2,5-difluorophenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 53) NMR 1.6 (s,6H), 2.1 (s,3H), 5.2 (s,2H), 6.6 (m,2H), 6.7 (d,lH), 6.9 (m,lH), 8.1 (m,2H);
N-(3,5-difluorophenyl)-2-~5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 56) NMR 1.7 (s,6H), 2.1 (s,3H), 5.3 (s,2H), 6.5 (m,lH), 6.7 (d,lH), 6.8 (d,lH), 7.1 (m,2H), 8.5 (s,lH);
N-(2,4-difluorophenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 144) CA 022~0l02 l998-09-2~

WO97140041 PCT~P97101733 NMR 1.6 ~s,6H), 2.1 (s,3H), 5.2 (s,2H), 6.6 (d,lH), 6.7 (m,3H), 7.9 (s,lH), 8.1 (m,lH);
N-(5-chloro-2-methylphenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 57) NMR 1.6 (s,6H), 2.1 (s,3H), 2.1 (s,3H), 5.2 (s,2H~, 6.6 (d,lH), 6.7 (d,lH), 6.9 (m,2H), 7.9 (s,lH), 7.9 (s,lH);
N-(3-chlorophenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 54) NMR 1.7 (s,6H), 2.2 (s,3H), 5.2 (s,2H), 6.7 (d,lH), 6.8 (d,lH), 7.0 (d,lH), 7.2 (m,2H), 7.6 (s,lH), 8.3 (s,lH);
N-(3,5-dichlorophenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 5',) NMR 1.7 (s,6H), 2.14 (s,3H), 5.25 (s,2H), 6.68 (d,lH), 6.8 (d,lH), 7.23 (s,lH), 7.48 (d,2H), 8.48 (s,lH);
N-(2-fluoro-5-trifluoromethylphenyl)-2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide, (compound 145) NMR 1.6 (s,6H), 2.1 (s,3H), 5.2 (s,2H), 6.6 (d,lH), 6.7 (d,lH), 7.1 (t,lH), 7.2 (m,lH), 8.1 (s,lH), 8.6 (d,lH);
N-(3-pentafluorosulphanylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 146) NMR 1.65(s,6H), 2.1(s,3H), 5.3(s,2H), 7.0(m,3H), 7.28-7.95(m,4H), 8.6(s,lH);
N-(2,5-difluorophenyl)-2-[2,3-dihydro-5-~3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 20) NMR
1.6(s,6H), 2.0(s,3H), 3.7(s,3H), 5.25(s,2H), CA 022~0102 1998-09-2~

WO 97t40041 PCT/EP97/01733 - 6.6(m,1H), 6.7(d,lH), 6.9(m,lH), 7.0(m,lH), 7.2(d,lH), 8.1(m,lH), 8.2(s,lH);
N-(3-trifluoromethylphenyl)-2-[2,3-dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 19) NMR 1.7(s,6H), 2.0(s,3H), 2.1(s,3H), 3.7(s,3H), 5.25(s,2H), 6.75(d,lH), 7.15(d,lH), 7.2-7.4(m,2H), 7.7(d,lH), 7.8(s,lH), 8.7(s,lH);
N-(2-chloro-3,5-difluorophenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 147) NMR 1.65(s,6H), 2.12(s,3H), 5.3(s,2H), 6.65(m,1H), 6.92(m,1H), 8.1(m,1H), 8.48(s,1H);
N-(2-fluoro-S-trifluoromethylphenyl)-2-[2,3-dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 148) NMR 1.65(s,6H), 2.0(s,3H), 3.07(s,3H), 5.02(s,2H), 6.75(d,1H), 7.3(m,2H), 8.3(s,lH), 8.65(d,lH);
N-(5-chloro-2-methylphenyl)-2-~2,3-dihydro-5-(2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl}-2-methylpropanamide,(compound 10) NMR
1.8(s,6H), 2.1(s,3H), 5.3(s,2H), 6.9-7.05(m,4H), 7.35(m,lH), 7.95(m,lH), 8.1(s,lH);
N-(3,4,5-trifluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 149) NMR
1.55(s,6H), 2.05(s,3H), 5.2(s,2H), 6.85(m,lH), 7.15(m,2H), 8.6(s,lH);
N-(2-methyl-5-nitrophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 150) NMR
1.7(s,6H), 2.1(s,3H), 2.3(s,3H), 5.35(s,2H), 7.0(m,3H), 7.3~m,lH), 7.4(m,lH), 8.48(s,lH), 8.8(m,1H);

CA 022~0l02 l998-09-2~

WO97140041 PCT~P97/01733 N-(cyclopropyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,~compound lSl) NMR 0.4(q, 2H), 0.65 (q, 2H), 1.5(s,6H), 2.05(s,3H), 2.6(m,lH), 5.15(s,2H), 6.1(s,lH), 6.95(m,lH);
N-(cyclobutyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 11) NMR 1.5(s,6H), 1.65(m,2H), 1.85(m,2H), 2.1(s,3H), 2.3(m,2H), 4.3(m,lH), 5.2(s,2H), 6.2(s,lH), 7.0(m,3H);
N-( 2-chloro-5-fluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 152) NMR
1.6(s,6H), 2.1(s,3H), 5.3(s,2H), 6.7(m,1H), 7.0(m,3H), 8.25(m,lH), 8.4(s,lH);
N- (3-chloro-5-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 153) NMR 1.65(s,6H), 2.05(s,3H), 5.2(s,2H), 6.9(m,3H), 7.2(m,lH), 7.65(m,2H), 8.7(s,lH);
N- (3,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 49) NMR 1.5 (s,6H), 2.0 (s,3H), 5.2 (s,2H), 6.4 (m,lH), 7.0 (m,3H), 7.2 (m,2H), 8.4 (s,lH);
N-(2,4-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 154) NMR 1.6 (s,6H), 2.0 (s,3H), 5.2 (s,2H), 6.8 (m,2H), 7.0 (d,lH), 7.2 (m,2H), 7.9 (s lH), 8.1 (m,lH);
N-( 5-chloro-2-methylphenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 50) NMR 1.6 (s,6H), 2.0 (s,3H), 2.1 (s,3H), 5.2 (s,2H), 6.9 (m,3H), 7.2 (m,2H), 7.9 (s lH), 7.9 (s lH);

CA 022~0102 1998-09-2S

' - 36 -~ N-(3,5-dichlorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 48) NMR
1.6 (s,6H), 2.0 (s,3H), 5.2 (s,2H), 7.0 (m,2H), 7.2 (m,2H), 7.4 (s 2H), 8.4 (s lH);
N-(2-fluoro-5-trifluoromethylphenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 155) NMR 1.6 (s,6H), 2.0 (s,3H), 5.2 (s,2H), 7.0 (m,2H), 7.2 (m,3H), 8.2 (s lH), 8.6 (d lH); and N-(2-chloro-5-fluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide,(compound 156) NMR 1.6 (s,6H), 2.0 (s,3H), 5.2 (s,2H), 6.6 (m,lH), 7.0 (d,lH), 7.2 (m,3H), 8.2 (d lH), 8.3 (s lH).
By proceeding in a similar manner but using a mixture of triphenylphosphine and carbon tetrachloride in dichloromethane to prepare the appropriate acid chloride the following compounds were also prepared:
N-(3-chlorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 8), m.p. 68-69.5~C;
N-(3-trifluoromethylphenyl)-2-~2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 9), m.p. 55-59 C; and N-(2,5-difluorophenyl)-2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanamide (compound 47), NMR
1.67(s,6H), 2.05(s,3H), 5.29(s,2H), 6.64-673(m,lH), 6.94-7.03( m,lH), 7.06(dd,lH), 7.25-7.3(m,2H), 8.12-8.2(m,2H).

A solution of sodium hydroxide ~1.91 g) in water (40 ml) was added to a stirred solution of CA 022~0l02 l998-09-2~

WO97/4~41 PCT~P97/01733 - ethyl 2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoate (7.37 g) in ethanol at room temperature. The mixture was then heated at 40~C for 3 hours, and s evaporated. Ether was added to the residue, which was acidified with hydrochloric acid (2 M) and extracted (ethyl acetate). The organic phase was dried (magnesium sulphate) and evaporated to give 2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoic acid (4.0 g) as a pink solid, m.p. 149-150~C.
By proceeding in a similar manner the following compounds were prepared:
2-[2,3-dihydro-6-methyl-4-oxo-5-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoic acid, m.p.
155-159~C (using a mixture of ethanol and dioxan as solvent).;
2-~2,3-dihydro-6-methyl-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoic acid, NMR 1.48(s,6H), 2.0(s,3H), 2.13(s,3H), 5.13(s,2H), 6.7(m,1H), 6.78(m,1H), 9.45(br s,lH);
2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-l~3-oxazin-3-yl]-2-methylpropanoic acid, NMR
1.14(t,3H), 1.59(s,6H), 2.38(q,2H), 5.25(s,2H), 6.95(m,lH), 6.99(m,lH), 7.3(m,lH), 9.7(br s,lH);
and 2-~2,3-dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoic acid, NMR 1.5(s,6H), l.9(s,3H), 3.7(s,3H), 5.2(s,2H), 6.75(d,lH), 7.2(d,lH), 9.3(s,lH).

A mixture o~ 2-(tributylstannyl)thiophene (11.2 g), ethyl 2-[2,3-dihydro-5-iodo-6-methyl-CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate (lO.0 g) and bis(triphenylphosphine)palladium (II) chloride (1.02 g) was heated in tetrahydrofuran at 50~C for 48 hours. Eithium s chloride (6.a3 g) was added and heating continued at 50~C for a further 3 hours. The mixture was poured into water and extracted with ether. The extract was washed ~brine) and purified by column chromatography eluting with cyclohexane/ethyl acetate to give ethyl 2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoate (7.37 g) as a white solid, m.p. 113~C.
By proceeding in a similar manner were prepared:
ethyl 2-[2,3-dihydro-6-methyl-5-(5-methyl-2-thienyl)-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate NMR 1.15(t,3H), 1.46(s,6H), 2.03(s,3H), 2.15(s,3H), 4.08(q,2H), 5.15(s,2H), 6.7(m,lH), 6.8(m,lH); and ethyl 2-[2,3-dihydro-5-(3-methoxy-2-thienyl)-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate NMR 1.6(s,6H), 2.0(s,3H), 3.85(s,3H), 4.2(q,2H), 5.3(s,2H), 6.75(s,lH), 6.8(s,lH), 7.2(s,lH), 7.25(s,lH), 7.3(s,lH), 7.4(s,lH), 7.7(s,lH).
By proceeding in a similar manner but replacing the bis(triphenylphosphine)palladium (II) chloride with a mixture of palladium (II) chloride and triphenylphosphine, and omitting the lithium chloride, there was prepared:
ethyl 2-[2,3-dihydro-6-methyl-4-oxo-s-(3-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoate, m.p. 95-98~C.

, , .

CA 022~0l02 l998-09-2~

WO97/4~41 PCT~P97/01733 A mixture of ethyl 2-[2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate (95.7g) and N-iodosuccinimide (115 g) in acetic acid was stirred at 40~C for 5 hours, and then left overnight at room temperature. The solvent was evaporated, ether added to the residue and the solution washed in turn with brine, sodium carbonate solution (2 M) and brine, until the washings were neutral. The solution was dried (magnesium sulphate), evaporated and the residue recrystallised from ethanol to give ethyl 2-[2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate (46 g) as a yellow solid, m.p. 83-85~C.

A mixture of 2,2,6-trimethyl-4H-1,3-dioxin-4-one (20.0 g) and ethyl 2-(N-methyleneamino)-2-methylpropanoate (24.2 g) was heated under reflux in toluene with distillation of solvent.
An equal volume of fresh toluene was added to replace that lost by distillation and the distillation continued. The solution was cooled and evaporated to give ethyl 2-[2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate (39 g), NMR 1.23(t,3H), 1.5(s,6H), 2.0(s,3H~, 4.17(q,2H), 5.18(s,2H), 5.22(s,lH).
RJ5~;K~ r~ ; EXAMPLE S
A stirred suspension of 2-amino-2-methylpropanoic acid (165 g) in ethanol at 0~C
was saturated with hydrogen chloride gas. The mixture was heated at reflux for 4 hours and the solvent was evaporated under reduced pressure to give ethyl 2-amino-2-methylpropanoate hydrochloride as a white solid. Sodium carbonate (100 g) was slowly added to a suspension of the CA 022~0l02 l998-09-2~

WO97/4~41 PCT~P97/01733 solid in water followed by 40% aqueous formaldehyde solution ~150 g) and the suspension was stirred for 3 hours. The mixture was extracted with ether, the organic solution was washed with water, dried (magnesium sulphate) and solvent evaporated under reduced pressure to give ethyl 2-(N-methyleneamino)-2-methylpropanoate (137.8 g) in equilibrium with its trimer, 1,3,5-tri(1-ethoxycarbonyl-1-methylethyl)hexahydro-1,3,5-triazine, as a colourless oil, ~R (liquid film) 2980(s), 1725(vs), 1250(s), 1140(vs).

A solution of lithium hexamethyldisilazide (10.6ml of a lM solution in tetrahydrofuran) was added during 35 minutes to a stirred solution of ethyl 2-[2,3-dihydro-6-methyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoate (3.22g) in tetrahydrofuran at below -70~C under nitrogen. After 6 hours under these conditions iodomethane (2ml) was added and the solution stirred for 50 minutes before allowing to warm to 20~C. Water was added after 60 hours and the ether extract washed (sodium thiosulphate solution), dried (magnesium sulphate) and evaporated to give ethyl 2-[2,3-dihydro-6-ethyl-4-oxo-5-(2-thienyl)-4H-1,3-oxazin-3-yl]-2-methylpropanoate (4.0g), NMR 1.15(t,3H), 1.21(t,3H), 1.56(s,6H), 2.4~q,2H), 4.15(q,2H), 5.25(s,2H), 6.92(m,1H), 6.98(m,1H). 7.3(m,1H).

A mixture of tert-butyl 2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-5-4H-1,3-oxazin-3-yl]-2-methylpropanoate (1.24g) and trifluoroacetic acid was stirred at 50~C for 23 hours and stood at 20~C for 4 days. Additional CA 022~0102 1998-09-2~

WO97/4~41 PCT~P97/01733 trifluoroacetic acid was added. After 2.5 hours at 60~C the mixture was evaporated to give 2-~5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoic acid (1.2g), NMR 1.5(s,6H), 2.1(s,3H), 5.2(s,2H), 6.6(d,lH), 6.7(d,lH).
REFERENCE E~AMPLE 8 A mixture of tert-butyl 2-[2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate (7.31g), 5-chlorothienylboronic acid (3.42g), tetrakis(triphenylphosphine~palladium(0) (2.2g) and sodium bicarbonate (1.61g) was stirred and heated at reflux under nitrogen in dimethoxyethane for 18 hours. The cooled mixture was diluted (2M hydrochloric acid), extracted (ether) and the extarct dried (magnesium sulphate), evaporated and purified by column chromatography on silica gel eluting with ethyl acetate/isohexane to give tert-butyl 2-[5-(5-chloro-2-thienyl)-2,3-dihydro-6-methyl-4-oxo-4H-1,3-oxazin-3-yl]-2-methylpropanoate (2.77g), NMR
1.3(s,9H), 1.5(s,6H), 2.1(s,3H), 5.1(s,2H), 6.6(d,lH), 6.7(d,lH).
R~KJSr~l_lS EXAMP~ 9 A solution of tert-butyl 2-(N-methyleneamino)-2-methylpropanoate (3.53g) and 5-iodo-2,2,6-trimethyl-1,3-dioxin-4-one (4.9g) was heated at reflux in toluene with distillation of toluene during 1 hour using a Dean and Stark apparatus.
The evaporated solution was dissolved in dichloromethane, washed (sodium thiosulphate and with 2M hydrochloric acid), dried (magnesium sulphate) and evaporated to give tert-butyl 2-[2,3-dihydro-5-iodo-6-methyl-4-oxo-4H-1,3-CA 022~0l02 l998-09-2~

WO97/4~41 PCT~Pg7/01733 oxazin-3-yl]-2-methylpropanoate (7.0g), NMR
1.35(s,9H), 1.42(s,6H), 2.22(s,3H), 5.1(s,2H).

n-Butyl lithium (33.5ml of a 2.5M solution in hexane) was added at -10~C to a stirred solution of 3-methoxythiophene (9.5g) in ether. After l hour the mixture was cooled to -70~C and stirred overnight. Tributyl tin chloride (26.lml) was added at -70~C and the mixture allowed to warm to 20~C. Water and ethyl acetate were added and the organic phase washed (brine), dried (magnesium sulphate) and evaporated.
Distillation gave 2-tributylstannyl-3-methoxythiophene (22.6g), b.p.115-122~C at 0.3mm Hg.

According to a further feature of the present invention, there are provided compositions suitable for herbicidal use comprising one or more of the 1,3-oxazin-4-one derivative of formula (I) or an agriculturally acceptable salt thereof, in association with, and preferably homogeneously dispersed in, one or more compatible agriculturally- acceptable diluents or carriers and/or surface active agents Li.e.
diluents or carriers and/or surface active agents of the type generally accepted in the art as being suitable for use in herbicidal compositions and which are compatible with compounds of formula (I)]. The term llhomogeneously dispersed" is used to include compositions in which the compounds of formula (I) are dissolved in other components. The term llherbicidal compositions" is used in a broad sense to include not only compositions which are ready for use as herbicides but also CA 022~0102 1998-09-2~

WO97/4~41 PCT~P97/01733 concentrates which must be diluted before use.
Preferably, the compositions contain from 0.05 to 90% by weight of one or more compounds of formula (I).
The herbicidal compositions may contain both a diluent or carrier and surface-active (e.g.
wetting, dispersing, or emulsifying) agent.
Surface-active agents which may be present in herbicidal compositions of the present invention may be of the ionic or non-ionic types, for example sulphoricinoleates, quaternary ~on;um derivatives, products based on condensates of ethylene oxide with alkyl and polyaryl phenols, e.g. nonyl- or octyl-phenols, or carboxylic acid esters of anhydrosorbitols which have been rendered soluble by etherification of the free hydroxy groups by con~ensation with ethylene oxide, alkali and alkaline earth metal salts of sulphuric acid esters and sulphonic acids such as dinonyl- and dioctyl-sodium sulphonosuccinates and alkali and alkaline earth metal salts of high molecular weight sulphonic acid derivatives such as sodium and calcium lignosulphonates and sodium and calcium alkylbenzene sulphonates.
Suitably, the herbicidal compositions according to the present invention may comprise up to 10% by weight, e.g. from 0.05% to 10% by weight, of surface-active agent but, if desired, herbicidal compositions according to the present invention may comprise higher proportions of surface-active agent, for example up to 15~ by weight in liquid emulsifiable suspension concentrates and up to 25~ by weight in liquid water soluble concentrates.

CA 022~0l02 l998-09-2~

WO97/40041 pcT~ps7lol733 Examples of suitable solid diluents or carriers are aluminium silicate, microfine silicon dioxide, talc, chalk, calcined magnesia, kieselguhr, tricalcium phosphate, powdered cork, adsorbent carbon black and clays such as kaolin and bentonite. The solid compositions (which may take the form of dusts, granules or wettable powders) are preferably prepared by grinding the compounds of formula ~I) with solid diluents or by impregnating the solid diluents or carriers with solutions of the compounds of formula (I) in volatile solvents, evaporating the solvents and, if necessary, grinding the products so as to obtain powders. Granular formulations may be prepared by absorbing the compounds of formula (I) (dissolved in suitable solvents, which may, if desired, be volatile) onto the solid diluents or carriers in granular form and, if desired, evaporating the solvents, or by granulating compositions in powder form obtained as described above. Solid herbicidal compositions, particularly wettable powders and granules, may contain wetting or dispersing agents (for example of the types described above), which may also, when solid, serve as diluents or carriers.
~iquid compositions according to the invention may take the form of aqueous, organic or aqueous-organic solutions, suspensions and emulsions which may incorporate a surface-active agent. Suitable liquid diluents for incorporation in the liquid compositions include water, glycols, glycol ethers, tetrahydrofurfuryl alcohol, acetophenone, cyclohexanone, isophorone, N-alkyl pyrrolidones, toluene, xylene, mineral, animal and vegetable oils, esterified vegetable oils and light CA 022~0102 1998-09-2~

WO97/4~41 PCT~P97/01733 aromatic and naphthenic fractions of petroleum ~ (and mixtures of these diluents). Surface-active agents, which may be present in the liquid compositions, may be ionic or non-ionic (for example of the types described above) and may, when liquid, also serve as diluents or carriers.
Powders, dispersible granules and liquid compositions in the form of concentrates may be diluted with water or other suitable diluents, for example mineral or vegetable oils, particularly in the case of liquid concentrates in which the diluent or carrier is an oil, to give compositions ready for use.
When desired, liquid compositions of the compound of formula (I) may be used in the form of self-emulsifying concentrates containing the active substances dissolved in the emulsifying agents or in solvents containing emulsifying agents compatible with the active substances, the simple addition of such concentrates to water producing compositions ready for use.
Liquid concentrates in which the diluent or carrier is an oil may be used without further dilution using the electrostatic spray technique.
Herbicidal compositions according to the present invention may also contain, if desired, conventional adjuvants such as adhesives, protective colloids, thickeners, penetrating agents, spreading agents, stabilisers, se~uestering agents, anti-caking agents, colouring agents and corrosion inhibitors. These adjuvants may also serve as carriers or diluents.
Unless otherwise specified, the following percentages are by weight. Preferred herbicidal CA 022~0102 1998-09-2~

WO 97/40041 PCI~/EPg7101733 compositions according to the present invention are:
aqueous suspension concentrates which comprise from 10 to 70% of one or more compounds of formula (I), from 2 to 10% of surface-active agent, from 0.1 to 5% of thickener and from 15 to 87.9% of water;
wettable powders which comprise from 10 to 90% of one or more compounds of formula (I), from 2 to 10% of surface-active agent and from 8 to 88% of solid diluent or carrier;
water dispersible granules which comprise from 1 to 75%, e.g. 50 to 75% of one or more compounds of formula (I), from 2 to 10% of surface-active agent and from 1 to 20%, e.g. 5 to 15%, of water soluble binder;
liquid emulsifiable suspension concentrates which comprise from 10 to 70% of one or more compounds of formula (I) from 5 to 15% of surface-active agent, from 0.1 to 5% of thickener and from 10 to 84.9% of organic solvent;
granules which comprise from 1 to 90%, e.g.
2 to 10% of one or more compounds of formula (I) from 0.5 to 7%, e.g. 0.5 to 2%, of surface-active agent and from 3 to 98.5%, e.g. 88 to 97.5% of granular carrier and emulsifiable concentrates which comprise 0.05 to 90%, and preferably from 1 to 60% of one or more compounds of formula (I), from 0.01 to 10%, and preferably from 1 to 10%, of surface-active agent and from 9.99 to 99.94%, and preferably from 39 to 98.99~, of organic solvent.
Herbicidal compositions according to the present invention may also comprise the CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 compounds of formula (I) in association with, and preferably homogeneously dispersed in, one or more other pesticidally active compounds and, if desired, one or more compatible pesticidally acceptable diluents or carriers, surface-active agents and conventional adjuvants as hereinbefore described.
Examples of other pesticidally active compounds which may be included in, or used in conjunction with, the herbicidal compositions of the present invention include herbicides, for example to increase the range of weed species controlled for example alachlor [2-chloro-2,6~-diethyl-N-(methoxy-methyl)-acetanilide], atrazine [2-chloro-4-ethylamino-6-isopropylamino-l,3,5-triazine], bromoxynil [3,5-dibromo-4-hydroxybenzonitrile], chlortoluron [N~-(3-chloro-4-methylphenyl)-N,N-dimethylurea], cyanazine [2-chloro-4-(l-cyano-l-methylethylamino)-6-ethylamino-l,3,5-triazine], 2,4-D [2,4-dichlorophenoxy-acetic acid], dicamba [3,6-dichloro-2-methoxybenzoic acid], difenzoquat [l,2- dimethyl-3,5-diphenyl-pyrazolium salts], flampropmethyl [methyl N-2-(N- benzoyl-3-chloro-4-fluoroanilino)-propionate], fluometuron [N'-(3-trifluoro-methylphenyl)-N,N-dimethylurea], isoproturon [N'-(4-isopropylphenyl)-N,N-dimethylurea], diclofop { (RS)-2-[4-2,4-dichlorophenoxy)phPnoxy]propionic acid}, fenoxaprop and fenoxaprop-P { 2-[4-(6-chloro-l,3-benzoxazol-2-yloxy)phenoxy]propionic acid}, diflufenican{N-(2,4-difluorophenyl)-2-[3-(trifluoromethyl)phenoxy]-3-pyridinecarboxamide}, tralkoxydim {2-[l-(ethoxyimino)propyl]-3-hydroxy-5-CA 022~0l02 l998-09-2~

WO97/40041 PCT~P97/01733 mesitylcyclohex-2-enone}, clodinafop {2-[4-(5-chloro-3-fluoro-2-pyridyloxy)phenoxy]propionic acid~, sulcotrione [2-(2-chloro-4-methylsulphonylbenzoyl)cyclohexane-l,3-dione], flurtamone {5-methylamino-2-phenyl-4-[3-(trifluoromethyl)phenyl]-3(2H)-furanone}, aclonifen (2-chloro-6-nitro-3-phenoxyaniline), and sulfonylureas (e.g. nicosulfuron);
insecticides, e.g. synthetic pyrethroids, e.g.
permethrin and cypermethrin, and fungicides, e.g. carbamates, e.g. methyl N-(l-butyl-carbamoyl- benzimidazol-2-yl)carbamate, and triazoles e.g. l-(4-chloro-phenoxy)-3,3- dimethyl-l-(l,2,4-triazol-l-yl)-butan-2-one.
Pesticidally active compounds and other biologically active materials which may be included in, or used in conjunction with, the herbicidal compositions of the present invention, for example those hereinbefore mentioned, and which are acids, may, if desired, be utilised in the form of conventional derivatives, for example alkali metal and amine salts and esters.
According to a further feature of the present invention there is provided an article of manufacture comprising at least one of the l,3-oxazin-4-one derivative of formula (I) or, as is preferred, a herbicidal composition as hereinbefore described, and preferably a herbicidal concentrate which must be diluted before use, comprising at least one of the l,3-oxazin-4-one derivative of formula ~I) within a container for the aforesaid derivative or derivatives of formula (I), or a said herbicidal composition, and instructions physically CA 022~0102 1998-09-2~

WO97/40041 PCT~7/01733 associated with the aforesaid container setting out the manner in which the aforesaid derivative or derivatives of formula (I) or herbicidal composition contained therein is to be used to control the growth of weeds. The containers will normally be of the types conventionally used for the storage of chemical substances which are solid at normal ambient temperatures and herbicidal compositions particularly in the form of concentrates, for example cans and drums of metal, which may be internally lacquered, and plastics materials, bottles or glass and plastics materials and, when the contents of the container is a solid, for example granular, herbicidal compositions, ~oxes, for example of cardboard, plastics materials and metal, or sacks. The containers will normally be of sufficient capacity to contain amounts of the N-substituted pyrazole derivative or herbicidal compositions sufficient to treat at least one acre of ground to control the growth of weeds therein but will not exceed a size which is convenient for conventional methods of handling.
The instructions will be physically associated with the container, for example by being printed directly thereon or on a label or tag affixed thereto. The directions will normally indicate that the contents of the container, after dilution if necessary, are to be applied to control the growth of weeds at rates of application between 0.5 g and 5000 g of active material per hectare in the manner and for the purposes hereinbefore described.
The following Examples illustrate herbicidal compositions according to the present invention.
The following trademarks appear in these CA 022~0102 1998-09-2~

Examples:- Arylan CA, Synperonic, Solvesso, Arylan SX8S, Arkopon T, Sopropon T36, Tixosil 38, Soprophor FL, Ethylan BCP, Attagel, Rhodorsil.
Exam~le C1:
An emulsifiable concentrate is formed from:
Active ingredient (Compound 1) 20% w/v N-Methylpyrrolidone (NMP) 25% w/v Calcium dodecylbenzenesulphonate (CaDDBS) (Arylan CA) 4% w/v Nonylphenol ethylene oxide propylene oxide condensate (NPEOPO)(Synperonic NPE 1800) 6% w/v Aromatic solvent (Solvesso) to 100 volumes by stirring NMP, active ingredient (Compound 1), CaDDBS, NPEOPO and 90% Aromatic solvent until a clear solution is formed, and adjusting to volume with Aromatic solvent.
ExamPle C2 A wettable powder is formed from:
Active ingredient (Compound 1) 50% w/w Sodium dodecylbenzenesulphonate (Arylan SX85) 3% w/w Sodium methyl oleoyl taurate (Arkopon T) 5% w/w Sodium polycarboxylate (Sopropon T36) l~ w/w Microfine silicon dioxide (Tixosil 38) 3% w/w China clay 38% w/w by blending the above ingredients together and grinding the mixture in an air jet mill.
Exam~le C3 CA 022~0102 1998-09-2~

WOg7/40041 PCT~P97/01733 A suspension concentrate is formed from:
Active ingredient (Compound 1~ 50~ w/v Antifreeze (Propylene glycol) 5% w/v Ethoxylated tristyrylphenol phosphate(Soprophor FL) 0.5% w/v Nonyl phenol 9 mole ethoxylate (Ethylan BCP) 0.5% w/v Sodium polycarboxylate (Sopropon T36) 0.2% w/v Attaclay (Attagel) 1.5% w/v Antifoam ~Rhodorsil AF426R) 0.003% w/v Water to 100 volumes by stirring the above ingredients together and milling in a bead mill.~5 Exam~le C4 A water dispersible granule is formed from:
Active ingredient (Compound 1) 50% w/w Sodium dodecylbenzenesulphonate (Arylan SX 85) 3% w/w Sodium methyl oleoyl taurate (Arkopon T) 5% w/w Sodium polycarboxylate (Sopropon T36) 1% w/w Binder ~Sodium lignosulphonate) 8% w/w China clay 30~ w/w Microfine silicon dioxide (Tixosil 38) 3% w/w by blending the above ingredients together, grinding the mixture in an air jet mill and granulating by addition of water in a suitable granulation plant (e.g. Fluid bed drier) and drying. Optionally the active ingredient may be ground either on its own or admixed with some or all of the other ingredients.

CA 022~0102 1998-09-2~

WO97140041 PcT~Ps7to1733 Similar compositions may be prepared by replacing compound 1 in each of Examples C1 to C4 above with other compounds of formula (I).
According to a feature of the present invention, there is provided a method for controlling the growth of weeds (i.e. undesired vegetation) at a locus which comprises applying to the locus a herbicidally effective amount of at least one l,3-oxazin-4-one derivative of formula (I) or an agriculturally acceptable salt thereof. For this purpose, the 1,3-oxazin-4-one derivatives are normally used in the form of herbicidal compositions (i.e. in association with compatible diluents or carriers and/or surface active agents suitable for use in herbicidal compositions), for example as hereinafter described.
The compounds of formula (I) show herbicidal activity against dicotyledonous (i.e. broad-leafed) and monocotyledonous (e.g. grass) weeds by pre- and/or post-emergence application.
By the term "pre-emergence application" -is meant application to the soil in which the weed seeds or seedlings are present before emergence of the weeds above the surface of the soil. By the term "post-emergence application" is meant application to the aerial or exposed portions of the weeds which have emerged above the surface of the soil. For example, the compounds of formula (I~ may be used to control the growth of:
broad-leafed weeds, for example, Abutilon theophrasti, Amaranthus retroflexus, Bidens pilosa, Chenopodium album, Galium aparine, Ipomoea sPP . e.g. Ipomoea purpurea, Sesbania CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 exaltata, Sinapis arvensis, Solanum niqrum and Xanthium strumarium, and grass weeds, for example Alopecurus mYosuroides, Avena fatua, Diqitaria sanquinalis, s Echinochloa crus-qalli, Eleusine indica and Setaria spp, e.g. Setaria faberii or Setaria viridis, and sedges, for example, C~perus esculentus.
The compound of formula (I) are particularly preferred as pre-emergence herbicides and for their control of grass species, in particular Echinochloa crus-qalli.
The amounts of compounds of formula (I) applied vary with the nature of the weeds, the compositions used, the time of application, the climatic and edaphic conditions and (when used to control the growth of weeds in crop-growing areas) the nature of the crops. When applied to a crop-growing area, the rate of application should be sufficient to control the growth of weeds without causing substantial permanent damage to the crop. In general, taking these factors into account, application rates between l g and lO00 g of active material per hectare give good results. However, it is to be understood that higher or lower application rates may be used, depending upon the particular problem of weed control encountered.
The compounds of formula (I) may be used to control selectively the growth of weeds, for example to control the growth of those species hereinbefore mentioned, by pre- or post-emergence application in a directional or non-directional fashion, e.g. by directional or non-directional spraying, to a locus of weed infestation which is an area used, or to be CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 used, for growing crops, for example cereals, e.g. wheat, barley, oats, maize and rice, soya beans, field and dwarf beans, peas, lucerne, cotton, peanuts, flax, onions, carrots, cabbage, oilseed rape, sunflower, sugar beet, and permanent or sown grassland before or after sowing of the crop or before or after emergence of the crop. For the selective control of weeds at a locus of weed infestation which is an area used, or to be used, for growing of crops, e.g.
the crops hereinbefore mentioned, application rates between lO g and 500 g, and preferably between 25 g and 250 g, of active material per hectare are particularly suitable.
The compounds of the invention are especially useful for controlling small seeded grass species, such as Alo~ecurus mYosuroides, Poa annua, and Apera spica-venti.
The compounds of formula (I) may also be used to control the growth of weeds, especially those indicated above, by pre- or post-emergence application in established orchards and other tree-growing areas, for example forests, woods and parks, and plantations, e.g. sugar cane, oil palm and rubber plantations. For this purpose they may be applied in a directional or non-directional fashion (e.g. by directional or non-directional spraying) to the weeds or to the soil in which they are expected to appear, before or after planting of the trees or plantations at application rates between 50 g and 5000 g, and preferably between 50 g and 2000 g, most preferably between lO0 g and lO00 g of active material per hectare.
The compounds of formula (I) may also be used to control the growth of weeds, especially CA 022~0102 1998-09-2~

WO97/40041 PCT~P97/01733 those indicated above, at loci which are not crop-growing areas but in which the control of weeds is nevertheless desirable.
Examples of such non-crop-growing areas include airfields, industrial sites, railways, roadside verges, the verges of rivers, irrigation and other waterways, scrublands and fallow or uncultivated land, in particular where it is desired to control the growth of weeds in order to reduce fire risks. When used for such purposes in which a total herbicidal effect is frequently desired, the active compounds are normally applied at dosage rates higher than those used in crop-growing areas as hereinbefore described. The precise dosage will depend upon the nature of the vegetation treated and the effect sought.
Pre- or post-emergence application, and preferably pre-emergence application, in a directional or non-directional fashion (e.g. by directional or non-directional spraying) at application rates between 50 g and 5000 g, and preferably between 50 g and 2000 g, most preferably between lO0 g and lO00 g of active material per hectare are particularly suitable for this purpose.
When used to control the growth of weeds by pre-emergence application, the compounds of formula (I) may be incorporated into the soil in which the weeds are expected to emerge. It will be appreciated that when the compounds of formula I are used to control the growth of weeds by post-emergence application, i.e. by application to the aerial or exposed portions of emerged weeds, the compounds of formula I will also normally come into contact with the soil CA 022~0102 l998-09-2~

WO97/40041 PCT~P97/01733 -and may also then exercise a pre-emergence control on later-germinating weeds in the soil.
Where especially prolonged weed control is required, the application of the compounds of formula (I) may be repeated if required.
The compounds of the invention have been used in herbicidal applications according to the following procedures.

METHOD OF USE OF HERBICIDA~ CONPO~lNDS:
TEST M~:THOD A
a) General Appropriate quantities of the compounds used to treat the plants were dissolved in acetone to give solutions equivalent to application rates of up to lOOOg test compound per hectare (g/ha).
These solutions were applied from a standard laboratory herbicide sprayer delivering the equivalent of 290 litres of spray fluid per hectare.
b) Weed control : Pre-emerqence The seeds were sown in 70 mm square, 75 mm deep plastic pots in non-sterile soil . The quantities of seed per pot were as follows:-Weed sPecies A~prox number of seeds/pot 1) Broad-leafed weeds Abutilon theophrasti 10 Amaranthus retroflexus 20 Galium aparine 10 Ipomoea purpurea 10 Sinapis arvensis 15 Xanthium strumarium 2 2) Grass weeds Alopecurus myosuroides 15 Avena fatua 10 Echinochloa crus-galli 15 CA 022~0l02 l998-09-2~

WO97/4~41 PcT~ps7lol733 Setaria viridis 20 3) Sedqes Cyperus esculentus 3 Crop l) Broad-leafed Cotton 3 Soya 3 2) Grass Maize 2 Rice 6 Wheat 6 The compounds of the invention were applied to the soil surface, containing the seeds, as described in (a~. A single pot of each crop and each weed was allocated to each treatment, with unsprayed controls and controls sprayed with acetone alone.
After treatment the pots were placed on capillary matting kept in a glass house, and watered overhead. Visual assessment of crop damage was made 20-24 days after spraying. The results were expressed as the percentage reduction in growth or damage to the crop or weeds, in comparison with the plants in the control pots.
c) Weed control : Post-emerqence The weeds and crops were sown directly into John Innes potting compost in 75 mm deep, 70 mm square pots except for Amaranthus which was pricked out at the seedling stage and transferred to the pots one week before spraying. The plants were then grown in the greenhouse until ready for spraying with the compounds used to treat the plants. The number of plants per pot were as follows :-CA 022~0102 1998-09-2~

WO97/4~41 PCT~P97/01733 1) Broad leafed weeds Weed sPecies Number of Plants per pot Growth staqe Abutilon theophrasti 3 1-2 leaves Amaranthus retroflexus 4 1-2 leaves Galium aparine 3 lSt whorl Ipomoea purpurea 3 1-2 leaves Sinapis arvensis 4 2 leaves Xanthium strumarium 1 2-3 leaves 2) Grass weeds Weed sPeciesNumber of plants per Pot Growth staqe Alopecurus myosuroides 8-12 1-2 leaves Avena fatua 12-18 1-2 leaves Echinochloa crus-galli 4 2-3 leaves Setaria viridis 15-25 1-2 leaves.
3) Sedqes Weed sPeciesNumber of plants per Pot Growth staqe Cyperus esculentus 3 3 leaves.
1) Broad leafed CroPs Number of plants Per pot Growth staqe Cotton 2 1 leaf Soya 2 2 leaves.

2) Grass Crops Number of Plants per Pot Growth staqe Maize 2 2-3 leaves Rice 4 2-3 leaves Wheat 5 2-3 leaves.
The compounds used to treat the plants were applied to the plants as described in (a). A
single pot of each crop and weed species was CA 022~0102 1998-09-2~

WOg7/40041 PCT~P97/01733 allocated to each treatment, with unsprayed controls and controls sprayed with acetone alone.
After treatment the pots were placed on capillary matting in a glass house, and watered overhead once after 24 hours and then by controlled sub-irrigation. Visual assessment of crop damage and weed control was made 20-24 days after spraying. The results were expressed as the percentage reduction in growth or damage to the crop or weeds, in comparison with the plants in the control pots.
TEST METHOD B
PaddY ~ost-emerqence a~lication in qreenhouse Paddy field soil was filled in 170 cm2 plastic pots, a suitable amount of water and chemical fertilisers were added thereto and kneaded to convert it to a state of a paddy.
Paddy rice plants (variety; Koshihikari), that had been grown in advance in a greenhouse to a stage of two leaves, were transplanted to each pot (two seedlings per pot). Then in each pot there were sown predetermined amounts of seeds of Echinochloa oryzicola, Monochoria vaqinalis, Lindernia procumbens and Scir~us juncoides respectively, and water was added to a depth of 3 cm.
After having grown the plants in a greenhouse until Echinochloa oryzicola reached a stage of 1.5 leaves, solutions were prepared in 100% acetone using compounds described in the Examples so that they contained active ingredients in an amount equivalent to 75, 300 and 1200 g/ha. The solutions were applied by dropping with a pipette.

CA 022~0l02 l998-09-2~

WO97140041 PCT~P97/01733 After 21 days from the application with the chemicals, herbicidal effects on each weed and phytotoxicity on paddy rice plants were visually assessed, and the results expressed as the percentage reduction in growth or damage to the crop or weeds in comparison with the plants in the control pots.
When applied pre- or post-emergence in Test Method A at lOOOg/ha or less compounds 1 to 8, 10, 11, 19, 20, 40-42, 48-50, 53, 54, 56 and 136-156 gave at least 90~ reduction in growth of one or more of the weed species.
When applied pre- or post-emergence in Test Method A at 250g/ha or less compound 57 gave at least 80% reduction in growth of one or more of the weed species.
At levels of application toxic to the weeds these compounds were selective in at least one of the crop species.
When applied at 1200g/ha or less, in Test Method B, compounds 1-4, 6-ll, 19, 20, 40-42, 47-50, 53-57, 136-140, 143-156 of the invention gave at least 90% reduction in growth of one or more of the weed species listed above.

Claims

1. A 1,3-oxazin-4-one derivative of formula (I):
wherein:
W represents -NR6;
R1 represents thiophene optionally substituted by one to three groups which may be the same or different selected from halogen, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, -S(O)n R7, -CO2R 7, COR 7, cyano, nitro and phenoxy;
R2 represents hydrogen, lower alkyl, lower haloalkyl, alkoxyalkyl, lower alkenyl, lower haloalkenyl, alkoxyalkenyl, -CHO, -COR7, -CO2R7, -CH2NO2, and lower alkyl which is substituted by a group selected from -S(O)m R7 and -OCOR7;
R3 represents phenyl optionally substituted by one to five groups which may be the same or different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, -S(O)n R7, -CO2R7, -COR7, cyano, nitro, -OH, phenoxy, -NR8R9 and -SF5; or a cycloalkyl group containing from three to six carbon atoms, optionally substituted by lower alkyl, lower haloalkyl or one or more halogen atoms which may be the same or different;
R4 and R5 independently represent lower alkyl;
R6 represents hydrogen;

R7 represents lower alkyl or lower haloalkyl;
R8 and R9 independently represent hydrogen or R7; and m and n independently represent zero, one or two;
or an agriculturally acceptable salt thereof.

2. A compound according to claim 1 in which:
R1 represents thiophene optionally substituted by one to three groups which may be the same or different selected from halogen, hydroxy, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, -S(O)n R7, -CO2R7, COR7, cyano, nitro and phenoxy;
R2 represents hydrogen, lower alkyl, lower haloalkyl, alkoxyalkyl, lower alkenyl, lower haloalkenyl, alkoxyalkenyl, -CHO, -COR7 and -CO2R7;
R3 represents phenyl optionally substituted by one to five groups which may be the same or different selected from halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, -S(O)n R7, -CO2R7, -COR7, cyano, nitro, -OH, phenoxy and -NR8R9; or a cycloalkyl group containing from three to six carbon atoms, optionally substituted by lower alkyl, lower haloalkyl or one or more halogen atoms which may be the same or different;
R4 and R5 independently represent lower alkyl;
W represents -NR6;
R6 represents hydrogen;

R7 represents lower alkyl or lower haloalkyl;
R8 and R9 independently represent hydrogen or R7; and n is zero, one or two.

3. A compound according to claim 1 or 2 in which R1 represents unsubstituted thiophene.

4. A compound according to claim 1, 2 or 3 in which R4 and R5 each represent methyl.

5. A compound according to claims 1 to 4 in which R2 represents lower alkyl.

6. A compound according to claim 5 in which R2 represents methyl.

7. A compound according to any one of claims 1 to 6 in which R3 represents phenyl optionally substituted by one to three groups which may be the same or different selected from halogen and a straight- or branched- chain alkyl group containing from one to three carbon atoms optionally substituted by one or more halogen atoms.

8. A compound according to claim 1 or 2 in which R2 represents methyl, halogenated methyl or methoxymethyl;
R3 represents phenyl optionally substituted by one to three groups which may be the same or different selected from halogen, a straight- or branched- chain optionally halogenated alkyl group containing from one to four carbon atoms, a straight- or branched- chain optionally halogenated alkoxy group containing from one to four carbon atoms, or -S(O)n R7; or cyclobutyl;
R4 and R5 each represent methyl; and R7 represents a straight- or branched- chain optionally halogenated alkyl group containing from one to four carbon atoms.

9. A compound according to claim 1 or 2 in which:
R1 represents thiophene optionally substituted by one or two groups which may be the same or different selected from halogen, a straight- or branched- chain optionally halogenated alkyl group containing from one to four carbon atoms, a straight- or branched-chain optionally halogenated alkoxy group containing from one to four carbon atoms, or -S(O)n R7;
R2, R4 and R5 each represent methyl;
R3 represents phenyl optionally substituted by one or two groups which may be the same or different selected from halogen and optionally halogenated methyl; or cyclobutyl; and R7 represents a straight- or branched- chain optionally halogenated alkyl group containing from one to four carbon atoms.

10. A compound according to claim 1 or 2 in which:
R1 represents unsubstituted thiophene;
R2, R4 and R5 each represent methyl; and R3 represents phenyl optionally substituted by one or two groups which may be the same or different selected from halogen, optionally halogenated methyl; and cyclobutyl.

11. A compound according to claim 1 in which:
R1 represents thiophene optionally substituted by lower alkyl, lower alkoxy or halogen;
R2 represents methyl or ethyl;
R4 and R5 each represent methyl; and R3 represents:
phenyl optionally substituted by one, two or three groups which may be the same or different selected from halogen, optionally halogenated methyl, nitro and -SF5;
cyclobutyl or cyclopropyl.

12. A compound according to claim 1 having one or more of the following features:
R1 represents 2-thienyl; 3-thienyl;
3-methoxy-2-thienyl; 5-methyl-2-thienyl or 5-chloro-2-thienyl;
R2 represents methyl; ethyl or fluoromethyl;
R4 and R5 each represent methyl; and R3 represents cyclopropyl; cyclobutyl;
3,5-difluorophenyl; 3,5-dichlorophenyl;
2-fluoro-5-trifluoromethylphenyl;
2-fluoro-2,5-difluorophenyl; 3-trifluoromethylphenyl;
5-chloro-2-methylphenyl;
3-pentafluorosulphanylphenyl;
2-chloro-3,5-difluorophenyl; 3,4,5-trifluorophenyl;
2-chloro-5-fluorophenyl; 5-chloro-2-fluorophenyl or 5-chloro-3-fluorophenyl.

13. A herbicidal composition comprising an effective amount of a 1,3-oxazin-4-one derivative according to any one of claims 1 to 12 or an agriculturally acceptable salt thereof, in association with an agriculturally acceptable diluent or carrier and/or surface acting agent.

14. A method for the control of weeds at a locus which comprises applying to said locus an effective amount of a 1,3-oxazin-4-one derivative according to any one of claims 1 to 12 or an agriculturally acceptable salt thereof.

15. A method according to claim 14 wherein the locus is an area to be used, or to be used for the growing of crops and the 1,3-oxazin-4-one derivative is applied at an application rate of from 0.001 to 1.0 kg/ha.

16. A process for the preparation of a 1,3-oxazin-4-one derivative of formula (I) as defined in claim 1 which comprises:
(a) the reaction of a compound of formula (II):

wherein R1, R2, R4 and R5 are as defined in claim 1, with an amine of formula (III):
R6NH~R3 (III) wherein R3 and R6 are as defined in claim 1;
(b) the reaction of a compound of formula (IV):

wherein R1, R2, R4 and RS are as defined in claim 1, with an amine of formula (III) above wherein R3 and R5 are as defined in claim 1 in the presence of a coupling agent;
(c) the reaction of a compound of formula (IV) above wherein R1, R2, R4 and R5 are as defined in claim 1, with a phenyl carbamate of formula PhO2C-NHR3, wherein R3 is defined in claim 1;
(d) the reaction of a compound of formula (V):

wherein R1, R2, R4 and R5 are as defined in claim 1 and TMS means trimethylsilyl, with an amine of formula NH2R3, wherein R3 is defined in claim 1;
(e) where R2 represents chloromethyl, bromomethyl or iodomethyl, the chlorination, bromination or iodination of the corresponding compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and R2 represents methyl;
(f) where R represents fluoromethyl, the fluorination of the corresponding compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and R2 is replaced by hydroxymethyl;
(g) where R represents difluoromethyl, the fluorination of the corresponding compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and R2 represents -CHO;
(h) where R2 represents alkoxyalkyl, the alkylation of a compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim and R2 is replaced by hydroxyalkyl;
(i) where R2 represents a -CHO group, the oxidation of the corresponding compound of formula (I) ) wherein R1, R3, R4, R5 and W are as defined in claim 1 and R2 is replaced by hydroxymethyl;
(j) where R2 represents -COR7, the oxidation of a compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and R2 is replaced by -CH(OH)R7;
(k) where R2 represents -CO2R7, the esterification of a compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and R2 is replaced by -CO2H;
(1) where R2 represents alkenyl optionally substituted by halogen or alkoxy and wherein the double bond of the alkenyl group is located between the two carbon atoms closest to the 1,3-oxazin-4-one ring, the reaction of a compound of formula (I) wherein R represents -CHO or -COR7 and R1, R3, R4, R5, R7 and W are as defined in claim 1, with a phosphorane;
(m) where m and/or n is one or two, the oxidation of the corresponding compound of formula (I) in which m and/or n are zero or one;
(n) where R2 represents -CF2R12a wherein R12a represents C1-C5 alkyl or haloalkyl, the fluorination of the corresponding compound of formula (I) wherein R1, R3, R4, R5 and w are as defined in claim 1 and R2 represents -COR12a;
(o) where R2 is lower alkyl substituted by iodine, the iodination of the corresponding compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and the iodine atom in R2 is replaced by bromine or chlorine;
(p) where R2 represents a lower alkyl group substituted by a group -SR7, the thioalkylation of the corresponding compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and the -SR7 group is replaced by a leaving group, preferably chloro or bromo;
(q) where R2 represents a lower alkyl group substituted by -SCF3 the trifluoromethylation of the corresponding compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and the -SCF3 group is replaced by an -SCN group;
(r) where R2 represents a lower alkyl group substituted by -OC(O)R7 wherein R7 is as defined in claim 1, the reaction of the corresponding compound of formula (I) wherein R1, R3, R4, R5 and W are as defined in claim 1 and the -OC(O)R7 group is replaced by a leaving group, with a salt of formula R7-CO2-M1+, wherein M1 represents sodium or potassium;
(s) where R2 represents -CHFR wherein R7 is as defined in claim 1, the fluorination of the corresponding compound of formula (I) in which R1, R3, R4, R5 and W are as defined in claim 1 and R2 is -CH(OH)R7;
(t) where R2 represents -CH2NO2, the reaction of the corresponding compound of formula (I) in which R1, R3, R4, R5 and W are as defined in claim 1 and R2 is bromomethyl or iodomethyl with an alkali metal nitrite or silver nitrite;
optionally followed by conversion of the corresponding compound of formula (I) thus obtained into an agriculturally acceptable salt thereof.

17. A compound of formula (II), (IV), (V), (VI) or (VII) wherein R1, R2, R4 and R5 are as defined in claim 1, R8a is an alkyl group, TMS means trimethylsilyl and Bz is benzyl.