Chemical process for the synthesis of herbicidal pyrazolidinedione compounds

Abstract

The present invention relates to a novel process for the synthesis of herbicidal pyrazolidinedione compounds. In particular, a process for the preparation of a compound of formula (I), wherein R.sup.1, R.sup.2 and R.sup.3 are as defined herein. The present invention further relates to novel intermediate compounds utilized in said process, and methods for preparing said intermediate compounds. ##STR00001##

Claims

1. A process for preparation of a compound of formula (I) ##STR00035## wherein each R.sup.1 and R.sup.2 are independently C.sub.1-C.sub.4alkyl; R.sup.3 is selected from the group consisting of hydrogen and C.sub.1-C.sub.4alkyl; said process comprising reacting a compound of formula (II) ##STR00036## wherein X is selected from the group consisting of Br, Cl, CF.sub.3SO.sub.3—, CH.sub.3C.sub.6H.sub.4SO.sub.3— and CH.sub.3SO.sub.3—, and R.sup.1, R.sup.2 and R.sup.3 are as defined herein, with a compound of formula (III) ##STR00037## the reaction being carried out in the presence of a π-allylpalladium complex; and a phosphine ligand of the formula (IV) ##STR00038## or a suitable salt thereof, wherein R.sup.4 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.5-C.sub.6cycloalkyl, phenyl and heteroaryl, wherein the heteroaryl is a 5- or 6-membered aromatic ring which comprises 1 or 2 heteroatoms independently selected from N and O, and wherein the phenyl or heteroaryl are optionally substituted by 1, 2, 3, 4 or 5 R.sup.5 substituents, which may be the same or different; R.sup.5 is selected from the group consisting of halogen, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, N—C.sub.1-C.sub.4alkylamino, N,N-diC.sub.1-C.sub.4alkylamino and phenyl, wherein said phenyl is optionally substituted by 1, 2, 3 or 4 R.sup.6 substituents, which may be the same or different; R.sup.6 is selected from the group consisting of C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, N—C.sub.1-C.sub.4alkylamino and N,N-diC.sub.1-C.sub.4alkylamino; and a base.

2. A process according to claim 1, wherein X is Br.

3. A process according to claim 1, wherein each R.sup.1 and R.sup.2 are ethyl.

4. A process according to claim 1 wherein R.sup.3 is methyl.

5. A process according to claim 1, wherein the π-allylpalladium complex is selected from the group consisting of allylpalladium chloride, allylpalladium trifluoroacetate, (2-Butenyl) chloropalladium, palladium (π-cinnamyl) chloride and (2-methylallyl)palladium chloride.

6. A process according to claim 1, wherein the π-allylpalladium complex is allylpalladium chloride or (2-Butenyl) chloropalladium.

7. A process according to claim 1, wherein the π-allylpalladium complex is present in the amount of from 1 to 10 mol % based on the compound of formula (II).

8. A process according claim 1 wherein the molar ratio of π-allylpalladium complex to phosphine ligand or phosphine ligand salt is 1:4.

9. A process according to claim 1, wherein the π-allylpalladium complex is provided with a phosphine ligand as defined herein in a pre-formed complex.

10. A process according to claim 1, wherein the phosphine ligand of formula (IV) is 4-di-tert-butylphosphanyl-N,N-dimethyl-aniline.

11. A process according to claim 1, wherein the organic solvent is 1,4-dioxane or toluene.

12. A process according to claim 1, wherein the base is K.sub.3PO.sub.4.

13. A process according to claim 1, wherein the reaction of a compound of formula (II) with a compound of formula (III) is at a temperature of from 80° C. to 110° C.

14. A compound of formula (III): ##STR00039##

15. A process according to claim 1, wherein a compound of formula (I) is further converted to pinoxaden.

Description

EXAMPLES

(1) The following examples further illustrate, but do not limit, the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.

(2) The following abbreviations are used: s=singlet; br s=broad singlet; d=doublet; dd=double doublet; dt=double triplet; t=triplet, tt=triple triplet, q=quartet, quin=quintuplet, sept=septet; m=multiplet; GC=gas chromatography, RT=retention time, MH.sup.+=molecular mass of the molecular cation, M=molar, Q.sup.1HNMR=quantitative .sup.1HNMR, HBTU=N,N,N′,N′-Tetramethyl-O-(1H-benzotriazol-1-yl) uronium hexafluorophosphate, DIPEA=N,N-diisopropylethylamine, RT=room temperature.

(3) .sup.1H NMR spectra are recorded at 400 MHz unless indicated otherwise and chemical shifts are recorded in ppm.

Example 1

1,2,4,5-tetrahydropyrazolo[1,2-d][1, 4, 5]oxadiazepine-7,9-dione (Compound of formula III)

(4) ##STR00031##

(5) Procedure:

(6) To a solution of malonic acid (0.39 g, 3.7 mmol, 98 mass %) in dichloromethane (12 mL) at room temperature was added portion wise HBTU (1.47 g, 3.8 mmol, 98 mass %). The solution was stirred for min at room temperature. To this solution 1,4,5-oxadiazepane (2 g, 2.9 mmol, 15 mass % in chlorobenzene) was added followed by dropwise addition of N,N-diisopropylethylamine (1.14 g, 8.64 mmol, 98 mass %) for 10 min at room temperature. The reaction mixture was stirred at room temperature for 3 h. After this time, the solvent was evaporated and product purified by column chromatography. Gradient: 2% MeOH in DCM

(7) Yield: 0.59 g (83%) as a White Solid, mp: 161-164° C.

(8) .sup.1H NMR (CDCl.sub.3): δ 3.23 (s, 2H); 3.82 (t, J=4, 4H); 3.99 (t, J=4, 4H).

Example 2

8-(2,6-diethyl-4-methyl-phenyl)-1,2,4,5-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione

(9) ##STR00032##

(10) Procedure:

(11) The reaction was conducted under a nitrogen atmosphere. To an empty oven-dried Schlenk tube (purged with N.sub.2), was added 1,2,4,5-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione 0.468 g, 2.39 mmol, 87 mass %), potassium phosphate (0.953 g, 4.35 mmol, 97 mass %), 2-bromo-1,3-diethyl-5-methyl-benzene (0.5 g, 2.17 mmol, 97 mass %) and 1,4-dioxane (15 mL). This mixture was degassed with N.sub.2 for 10 min. To this heterogeneous solution was added PdCl(crotyl) Aphos (0.051 g, 0.108 mmol, 98 mass %) and further degassed with N.sub.2 for 10 min. The resulting solution was heated with stirring to reflux for 7 h. After this time, the tube was cooled, and the reaction mixture was acidified with 2M HCl. The mixture was extracted with DCM, organic fraction was dried with Na.sub.2SO.sub.4, filtered, concentrated and purified by washing with diethyl ether yielded a yellow solid. .sup.1H NMR (400 MHz, CDCl.sub.3) σ 1.19 (t, J=7.6 Hz, 3H); 1.25 (t, J=7.6 Hz, 3H); 2.27 (q, J=7.6 Hz, 2H); 2.30 (s, 3H); 2.70 (q, J=7.6 Hz, 2H); 3.75-3.81 (m, 2H); 3.93-4.03 (m, 4H); 4.26-4.32 (m, 2H); 4.71 (s, 1H); 6.92 (s, 1H); 6.94 (s, 1H).

(12) General Procedure:

(13) A dry Schlenk flask equipped with a magnetic stir bar was charged with 1,2,4,5-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (0.459 g; 2.348 mmol; 1.07 equiv), base (1.95 equiv) and dry solvent (15 mL). This mixture was evacuated and backfilled with nitrogen. This evacuation/nitrogen backfill cycle was repeated two additional times. To this heterogeneous solution was added the palladium catalyst (0.048 equiv) and 2-bromo-1,3-diethyl-5-methyl-benzene (0.500 g; 2.179 mmol; 1.0 equiv), further degassed with N.sub.2 for 10 min. The resulting solution was heated with stirring to 105° C. for 7 h. After this time, the tube was cooled, and the reaction mixture was acidified to pH 2 with 2M HCl. The samples were then run on a GC to check conversion. The mixture was extracted with DCM, and organic extract dried over Na.sub.2SO.sub.4, filtered, concentrated and purified by wash with Diethyl ether.

(14) The above general procedure was used to obtain the results referred to in Table 1 below.

(15) TABLE-US-00001 TABLE 1 Summary of results for arylation of 1,2,4,5-tetrahydropyrazolo[1,2-d] [1,4,5]oxadiazepine-7,9-dione with 2-bromo-1,3-diethyl-5-methyl-benzene Added Product Catalyst APhos formed (GC Loading/ Loading/ area % or Q Entry Precursor mol % mol % Base Solvent .sup.1HNMR)  1 Pd(OAc).sub.2 5 10 K.sub.3PO.sub.4 1,4- N/D dioxane  2 [Pd(allyl)Cl].sub.2 5 10 K.sub.3PO.sub.4 1,4- 46% (Q dioxane iHNMR)  3 [Pd(2-Butenyl)Cl].sub.2 5 10 K.sub.3PO.sub.4 1,4- 54% (Q dioxane .sup.1HNMR)  4 [Pd(cinnamyl)Cl].sub.2 5 10 K.sub.3PO.sub.4 1,4- 58% dioxane (GCarea %)  5 [Pd(2-methylallyl)Cl].sub.2 5 10 K.sub.3PO.sub.4 1,4- 53% dioxane (GCarea %)  6 [PdCl(crotyl)Aphos] 5  0 K.sub.3PO.sub.4 1,4- 85% (Q dioxane .sup.1HNMR)  7 [Pd(allyl)Cl].sub.2 5 10 K.sub.2CO.sub.3 1,4- 30% dioxane (GCarea %)  8 [Pd(allyl)Cl].sub.2 5 10 KOH 1,4- 66% powder dioxane (GCarea %)  9 [Pd(allyl)Cl].sub.2 5 10 K.sub.3PO.sub.4 DEMBB 21% (GCarea %) 10.sup.[a] [Pd(allyl)Cl].sub.2 5 10 K.sub.3PO.sub.4 1,4- 41% dioxane (GCarea %) 11.sup.[b] [Pd(allyl)Cl].sub.2 5 10 K.sub.3PO.sub.4 1,4- 16% (isolated) dioxane .sup.[a]2-chloro-1,3-diethyl-5-methy-benzene used as substrate instead of 2-bromo-1,3-diethyl-5-methyl-benzene .sup.[b]P.sup.t(Bu).sub.3 used as ligand. N/D means not detected.

Example 3

General Procedure for Palladium Catalysed α-arylation

(16) Into an oven-dried 35 mL carousel reaction tube fitted with a magnetic stirrer bar was added the palladium source, APhos (4-di-tert-butylphoshanyl-N,N-dimethyl-aniline, 0-20 mol %), 1,2,4,5-tetrahydropyrazolo[1,2-d][1,4,5]oxadiazepine-7,9-dione (1.2 equiv.) and K.sub.3PO.sub.4 (2.1 equiv.) under an atmosphere of N.sub.2 gas. A solution of 2-bromo-1,3-diethyl-5-methyl-benzene (DEMBB, 1 equiv.) and mesitylene (0.25 equiv. as an internal standard) in 1,4-dioxane (1-3 ml) was purged of oxygen by bubbling with N.sub.2 gas for 20 mins and then transferred to the reaction tube which was then placed immediately into the pre-heated carousel at 110° C. and stirred for 6 h.

(17) Sampling procedure: A small aliquot of the reaction mixture was quenched with HCl (aq, 1 M) and extracted into EtOAc. The conversion was determined by NMR spectroscopy and/or GC analysis against mesitylene as an internal standard, or 1,3,5-trimethoxybenzene as an external standard.

(18) The above general procedure (example 3) was used to obtain the results referred to in Table 2 below.

(19) TABLE-US-00002 TABLE 2 Summary of results comparing differing palladium catalysts with the APhos ligand Ratio, Added Total compound of Catalyst APhos conversion formula (la) Loading/ Loading/ [DEMBB]/ of DEMBB/ :ArH Entry Precursor mol % mol % M % (selectivity %) 1 Pd(OAc).sub.2 5 10 0.13  4 0.2:1 (17) 2 Pd(OAc).sub.2 5 20 0.4   6 0.3:1 (25) 3 [Pd(allyl)Cl].sub.2 5 10 0.13 54 1.04:1 (51)  4 [Pd(allyl)Cl].sub.2 2.5 20 0.13 50 0.9:1 (47) 5 [Pd(allyl)Cl].sub.2 2.5 20 0.4  67  4:1 (80) 6 [PdCl(crotyl)Aphos] 5 15 0.4  61  4:1 (80)

(20) [PdCl(crotyl) Aphos] is a pre-formed complex of formula (Ic) below:

(21) ##STR00033##

(22) ArH is a compound of formula (IIb) below:

(23) ##STR00034##

(24) These results demonstrate that the allylpalladium (II) chloride dimer appears to be a more efficient catalyst than palladium (II) acetate. Palladium (II) acetate is not a competent catalyst precursor for the reaction with only a 4-6% conversion of DEMBB. The palladium catalyst pre-formed complex, [PdCl (crotyl) Aphos] also demonstrated good levels of conversion to the desired product.