Patent Grant
6930190
The present invention relates to a new process for preparing heterocyclic pentalenes derivatives of formula:
wherein R1, R2, R3 and R4 represent hydrogen or hydrocarbon rests and W is an oxygen atom, a sulfur atom or a NR or PR group and R is an hydrocarbon rest.
Heterocyclic pentalenes are well known in the art for various uses. For example substituted thiophenes and b, d-ortho-fused thiophenes are used as reference materials in the analysis of sulphur-containing substances of fossil raw materials, such as mineral oils, coal, carbonaceous oils, shale oils and tar sands, as model systems for studying the desulphurisation of the aforementioned fossil raw materials, also on a technical scale, as oxidation inhibitors, for example in lubricants and as active substances in the fields involving biocides.
Recently they have been used for the preparation of metallocene complexes useful as catalysts for the polymerization of olefins. For example in J. Am. Chem. Soc. 1998, 120, 10786-10787 Ewen et al. describe metallocene compounds containing thiopentalene and azapentalene derivatives. Also PCT/EP00/12406 describes metallocene compounds containing thiopentalenes ligands. Catalyst based on these compounds produce polypropylene having a high degree of isotacticity. However the synthesis of these compounds involves several steps with low yields and, moreover, some derivatives are not accessible according to the routes proposed in these documents.
Therefore, a new process that permits to obtain these compounds in higher yields and with simple steps would be desirable.
The applicant has now found a new process that permits to overcome the above drawbacks and, moreover, to obtain a broader class of compounds.
An object of the present invention is a process for preparing heterocyclic pentalene derivatives having formula (I):
wherein
W is a sulfur atom, an oxygen atom or a NR or PR group wherein R is a linear or branched saturated or unsaturated C1-C20-alkyl, C3-C20-cycloalkyl, C6-C20-aryl, C7-C20-alkylaryl or C7-C20-arylalkyl radical, optionally containing heteroatoms belonging to groups 13-17 of the Periodic Table of the Elements; preferably the group NR is N-methyl or N-phenyl; and the group PR is P-methyl or P-phenyl; more preferably W is a sulfur atom;
R1, R2, R3 and R4, equal to or different from each other, are hydrogen atoms or a linear or branched saturated or unsaturated C1-C20-alkyl, C3-C20-cycloalkyl, C6-C20-aryl, C7-C20-alkylaryl or C7-C20-arylalkyl radical, optionally containing heteroatoms belonging to groups 13-17 of the Periodic Table of the Elements; or R1 and R2 and/or R3 and R4 can form a C4-C7 ring optionally containing O, S, N, P or Si atoms, said ring optionally bearing C1-C20 alkyl substituents or being optionally fused with a C4-C7 ring optionally containing O, S, N, P or Si atoms, such as a benzene or a cyclopentadiene ring; preferably R1 is hydrogen, a C1-C20-alkyl or C7-C20-arylalkyl radical; more preferably R1 is a methyl, a phenyl or a C1-C10 alkyl substituted phenyl radical; preferably R2 is hydrogen or a C7-C20-arylalkyl radical; more preferably R2 is a phenyl or a C1-C10 alkyl-substituted phenyl radical; preferably R3 is hydrogen or a C1-C20-alkyl radical; and preferably R4 is hydrogen, a C1-C20-alkyl or C7-C20-arylalkyl radical; more preferably R4 is a methyl, or a phenyl radical;
said process comprising the following steps:
Non limitative examples of compounds of formula (I) are:
Compounds of formula (II) used in step a) can be prepared with methods generally known in the art. For example when W is a sulfur atom these compounds can be prepared according to the process described in J. Chem Soc. Perkin 1, 1976, vol. 22, 2355-2360.
Compounds of formula (III) can be easily prepared starting from the correspondent vinyl bromide or they can be purchased as such.
Step a) is carried out at a temperature range of from −78 C to 100° C., preferably from −20° C. to 20° C. Usually aprotic solvents are used, such as toluene, diethyl ether, hexane, tetrahydrofuran, dimethyl formamide, etc. The product obtained from step a) is purified by process known in the art such as filtration, crystallization, chromatography, distillation; otherwise it is used as such.
Preferably in the compound of formula (II) T is a NR2 group; more preferably T is a N(Me)2 or a N(Et)2 radical. In the compound of formula (III) preferably the group M is MgBr or Li. Examples of Brønsted acid used in step b) are methanesulphonic acid, sulfuric acid, phosphoric acid, polyphosphoric acid or P2O5/methansulfuric acid. Preferably methanesulphonic acid or sulfuric acid are used. The reaction is preferably carried out in water or in an organic solvent such as dichloromethane, diethyl ether, tetrahydrofuran, dimethyl formamide, or in mixtures of water and organic solvents optionally in the present of a phase transfer agent. The reaction is carried out at a temperature range from 0° C. to 100° C. The amount of acid in step b) depends from the acid, usually a large excess of acid is used for example from 10 to 10000 equivalents or more.
The product obtained from step b) is purified by processes known in the art such as filtration, crystallization, chromatography, distillation; otherwise it is used as such.
Examples of reducing agents that can be used in step c) can be found in “Comprehensive Organic Transformations” ed. 1989 VCH Publishers pages 527-552. For example LiAlH4, AlH3, NaBH4 or LiHAl(OtBu)3 can be used. Preferably LiAlH4 is used.
The type of solvent used in step c) depends from the reducing agent used. In the case of LiAlH4, AlH3, NaBH4 or LiHAl(OtBu)3 the reaction is carried out in an aprotic solvent such as toluene, diethyl ether, hexane, tetrahydrofuran, dimethyl formamide, at a temperature range of from −78 C to 100° C., preferably from 0° C. to 80° C. The product obtained from step c) is purified by processes known in the art such as filtration, crystallization, chromatography, distillation; otherwise it is used as such.
Step d) is carried out by treating the alcohol of formula (VI) with a dehydrating agent. Examples of dehydrating agent can be found in “Comprehensive Organic Transformations” ed. 1989 VCH Publishers pages 151-153. Example of dehydrating agent are p-toluenesulfonic acid, sulfuric acid, hydrochloric acid and iodine. Preferably p-toulensulfonic acid and iodine are used.
The amount of dehydrating agent depends from the dehydrating agent used. It can vary from one equivalent to a large excess such as 1000 equivalents and more.
The type of solvent used in step d) depends from the dehydrating agent used. In the case of p-toulensulfonic acid the reaction is carried out in an aprotic solvent such as toluene, diethyl ether, hexane, tetrahydrofuran, dimethyl formamide, at a temperature range of from 0° C. to 100° C., preferably from 20° C. to 80° C. The product obtained from step d) is purified by processes known in the art such as filtration, crystallization, chromatography, distillation. A further method for purifying compounds obtained in step d) is treating the crude reaction product with at least one equivalent of an organolithium compound such as butylithium, methyllithium, tertbuthylithium and phenyllithium and filtering the obtained salt.
Steps a), b, c) and d) of the process of the present invention may be carried out in sequence without purification of the intermediate products.
Preferably steps c) and d) are carried out “one pot”, i.e. without purification of the alcohol of formula (VI).
Compounds of formula (I) can be used as ligands for the synthesis of metallocene complexes, such as those described in WO 01/44318. These complexes are useful as catalyst components for polymerizing alpha-olefins. The syntheses of the metallocene compounds starting from the compounds of the present invention are described in the above mentioned application. Generally, the compounds of formula (I) can be treated with a base and then contacted with a compound of formula YL′Cp wherein Y is halogen, preferably chlorine, L′ is a suitable bridge and Cp is a substituted or unsubstituted cyclopentadienyl radical. The obtained bridged ligand is then treated with two equivalents of a base and contacted with the compound of formula ML″4 wherein M is titanium, zirconium or hafnium and L is generally halogen, preferably chlorine. For unbridged metallocene compounds the compound of formula (I) is treated with a base and then the correspondent anion is contacted with a compound of formula ML″4.
The following examples are given for illustrative purposes and are not intended to limit the scope and spirit of the invention.
General Procedures.
Operations moisture sensitive were performed under nitrogen by using conventional Schlenk-line techniques. Solvents were purified by degassing with N2 and passing over activated (8 hours, N2 purge, 300° C.) Al2O3, and stored under nitrogen. n-BuLi (Aldrich) was used as received.
Preparation of the Compound of Formula (II)
30.8 g (0.1 mol) of 2,3-diphenyl-5-carbetoxythiophene (prepared analogously to 2-methyl-3-phenyl-5-carbetoxythiophene with 70-80% yield from dezoxybenzoin) was treated with solution of 20 g NaOH in 50 ml water+50 ml ethanol. Resulting mixture was refluxed in 3 h and then was treated with 100 ml water. Aqueous phase was collected, added with HCl aq. up to pH=3. White solid was isolated by filtration, washed with 100 ml water and dried. Yield 100%.
1H NMR (Dimethylsulfoxide (DMSO)-d6): 7.76 (s, 1H), 7.40-7.20 (m, 10H), 3.5 (br.s., water+acidic proton)
10 g (36 mmol) of acid, 5.5 ml SOCl2 (75 mmol), 0.1 ml dimethylformamide (DMF) and 50 ml of benzene were placed into the bulb and refluxed in 2 h. Then the mixture was evaporated. Resulting oil was dissolved in 10 ml of tetrahydrofuran (THF) and this solution was added dropwise to 30 ml 33% aqueous Me2NH at 0° C. The mixture was stirred in 30 min. The precipitate was isolated, washed with water and dried. Yield 10 g (92%).
1H NMR (CDCl3): 7.45 (s, 1H), 7.40-7.20 (m, 10H), 3.40-3.20 (br.s., 6H)
Step a) 1-(4,5-Diphenyl-2-thienyl)-2-methyl-2-propen-1-on
10 g (33 mmol) of 2,3-Diphenyl-thienylcarbonic acid dimethylamide was dissolved in 15 ml THF and the resulting solution was added dropwise to solution of propenylmagnesium bromide prepared from 0.78 g Mg (33 mmol) and 4 g 2-bromopropene (33 mmol) in 50 ml THF at −40° C. The mixture warmed to r.t. and was stirred in 4 h. The resulting solution was poured into 100 ml of 5% aqueous HCl. The organic layer was collected, washed with water, dried over MgSO4 and evaporated to give yellow-reddish oil. Yield 9.5 g (100%). The product is contaminated with 5-10% of starting amide (by NMR) and can be used without further purification.
Step b) 5-Methyl-2,3-diphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on
Solution from previous experiment was poured into 80 ml methanesulphonic acid (can be replaced by H2SO4) at 65° C. After 30 min of stirring at reflux the resulting mixture was poured into 400 ml water/300 ml dichlorometane mixture. The organic phase was collected, washed with aq. NaHCO3 up to neutral reaction and dried over MgSO4. The resulting solution was evaporated to give 8.8 g viscous oil. This substance either have to be purified by chromatography on silica gel with benzene as an eluent (Rf of the product is ˜0.15) or can be used as is.
1H NMR (CDCl3): 7.40-7.20 (m, 10H), 3.20 (dd, 1H), 3.06 (quintet of doublets, 1H), 2.67 (dd, 1H), 1.44 (d, 3H)
Steps c) and d) 5-Methyl-2,3-diphenyl-4H-cyclopenta[b]thiophene
Solution of 7 g (0.023 mol) 5-methyl-2,3-diphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on in 200 ml ether was treated with 0.24 g (0.0063 mol) LiAlH4 in 100 ml ether. The mixture was stirred in 30 min and then was poured in 300 ml of 10% NH4Cl. The organic phase was collected, dried over MgSO4 and evaporated. Resulting alcohol (6.7 g, 95%) was dissolved in 350 ml benzene. To this solution 0.25 g p-toluenesulphonic acid and a few crystals of 2,6-di(tert-butyl)phenol were added. The resulting mixture was refluxed in 10 min, then was cooled to r.t., washed with saturated aq. NaHCO3 and water. The solution so-obtained was dried over MgSO4 and evaporated. The residue was recrystallized from hexane to give 4.2 g (67% from ketone) of the product as yellowish crystalline solid.
1H NMR (C6D6): 7.45 (d, 2H), 7.31 (d, 2H), 7.15-6.90 (m, 6H), 6.20 (quintet, 1H); 2.73 (br.s, 2H); 1.80 (s, 3H)
Preparation of the Compound of Formula (II)
0.375 mol (35 mL) of POCl3 was added at 0° C. to a 0.45 mol (35 mL) of DMF. At the end of the addition, the mixture was allowed to warm up to room temperature and stirred for 30 min. Then it was cooled again to 0° C. and carefullly treated with 0.15 mol (20.1 g) of phenylacetone. The resulting reaction mixture was stirred at the same temperature for 1 h and then at 60-70° C. in additional 4 hours (the reaction was monitored by NMR). The resulting viscous solution was poured into a mixture of ice and aqueous sodium acetate (150 g). Product was extracted with CH2Cl2 (3×50 mL). The organic phase was separated, washed with water until neutral pH, dried over MgSO4 and evaporated to dryness. The residue represents chloroaldehyde as a mixture of two forms (ratio of forms depends on the duration of chlorocarbonylation). It was used without further purification. Yield 19.2 (71%).
1H-NMR (CDCl3): 10.47(s) and 10.15(s) (1H, CHO); 7.40-7.00 (group of multiplets, 5H, aromatic CH); 2.79(s) and 2.32(s) (3H, CH3).
Note: do not use distillation to purify the product!
Ethyl-2-mercaptoacetate (45.8 mmol, 5.0 mL) was added at 0° C. to a solution of sodium ethoxide (46 mmol, 3.13 g) in 50 mL of ethanol and the resulting mixture was stirred at the same temperature for 30 min. Then 3-chloro-2-phenyl-2-butenal (45.8 mmol, 8.3 g) was added and stirring was continued overnight. The resulting product was refluxed for 2 h, cooled to room temperature and diluted in 100 mL of water. The organic layer was collected and the water layer was extracted with CH2Cl2 (3×50 mL). The combined organic layers were dried over MgSO4, evaporated to dryness and the residue was used in the next step without further purification.
The 5-methyl-4-phenyl-2-thiophene-ethylcarboxylate coming from the previous step was added to a 30% solution of sodium hydroxide in 100 mL of ethanol and the resulting mixture was refluxed for 2 h. Then it was diluted in water and extracted with 50 mL of benzene. The water phase was isolated, acidified and the mixture was filtered. The precipitate was dried under P2O5. Yield 9.5 g (95% towards 3-chloro-2-phenyl-2-butenal).
1H-NMR (CDCl3): 12.00-10.00 (br.s, 1H, COOH); 7.87 (s, 1H, thiopheneCH); 7.50-7.35 (m, 5H, phenylCH); 2.58 (s, 3H, CH3).
21.8 g (0.1 mol) of acid, 10.9 ml SOCl2 (0.5 mmol), 0.5 ml DMF and 150 ml of dichloromethane were placed into the bulb and refluxed in 2 h. Then the mixture was evaporated. Resulting oil was dissolved in 20 ml THF and this solution was added dropwise to 50 ml 33% aqueous Me2NH at 0° C. The mixture was stirred in 30 min. The resulting emulsion was poured into 500 ml of water. Product was extracted with 2×50 ml dichloromethane. Solution was washed with water, dried over magnesium sulfate and evaporated to give brown viscous liquid that tends to crystallize. Yield 28 g (81%).
1H NMR (CDCl3): 7.45 (s, 1H), 7.40-7.20 (m, 10H), 3.40-3.20 (br.s., 6H)
Step a) 1-(5-Methyl-4-phenyl-2-thienyl)-2-phenyl-2-propen-1-on
23.3 g (100 mmol) of 2-methyl-3-phenyl-thienylcarbonic acid dimethylamide was mixed with 100 ml ether and the resulting suspension was added in some portions at 0° C. to solution of 1-stiryllitium prepared from 62 ml 1.6M BuLi in hexane (100 mmol) and 27 g 1-bromostyrene (150 mmol) in 200 ml ether. The mixture warmed to r.t. and was stirred in 1 h. The resulting solution was poured into 500 ml of 5% aqueous HCl. The organic phase was collected, separated from insoluble impurities (these impurities presumably are due to the use of Li-derivative instead of Mg derivative in the previous case), washed with water, dried over MgSO4 and evaporated to give yellow oil. Yield of crude product 15 g (52%). The product can contaminated with 5-10% of starting amide (by NMR) and can be used without further purification.
1H NMR (CDCl3): 7.61 (s, 1H), 7.55-7.35 (m, 10H), 6.03 (s, 1H), 5.82(s, 1H), 2.59 (s., 3H)
Step b) 2-Methyl-3,5-diphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on
Vinyl-ketone obtained in previous experiment was dissolved in 20 ml of dichloromethane and resulting was poured into 50 ml methanesulphonic acid heated to 65° C. After 30 min of stirring at reflux the resulting mixture was poured into the mixture 0.31 water/ice/200 ml dichlorometane. The organic phase was collected, washed with water, then with aq. NaHCO3 up to neutral reaction and dried over MgSO4. The resulting solution was evaporated to give 14 g of viscous oil. This oil crystallizes on standing. This substance can be used for further steps (reduction by LiAlH4 followed by dehydration without special purification.
1H NMR (CDCl3): 7.55-7.20 (m, 10H), 4.15 (dd, 1H); 3.50 (dd, 1H); 3.07 (dd, 1H), 261 (s., 3H)
Steps c) and d) 2-Methyl-3,5-diphenyl-4H-cyclopenta[b]thiophene
Solution of 14 g (47 mmol) 2-Methyl-3,5-diphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on in 150 ml ether was treated with 0.63 g (16 mmol) LiAlH4 in 100 ml ether. The mixture was stirred in 30 min and then was poured in 300 ml of 10% NH4Cl. The organic phase was collected, dried over MgSO4 and evaporated. Resulting alcohol (13.4 g, 95%) was poured into solution 1 g p-toluenesulphonic acid in 11 toluene at 65° C. The resulting mixture was stirred in 20 min at 80° C., then it was cooled to r.t., washed with saturated aq. NaHCO3 and water. The solution so-obtained was dried over MgSO4 and evaporated. The residue was isolated by chromatography on silica-gel (hexane/CH2Cl2 3/1) to give 6.5 g (53% from ketone) of yellowish crystalline solid. This solid consists of two isomers of position of double bond.
1H NMR (CDCl3): 7.60-7.20 (m, 10H), 7.21(m) and 7.14(m) (1H), 3.83 (br.s) and 3.68 (br.s) 2H); 2.60 (s, 3H)
Preparation of the Compound of Formula (II)
2,3-diphenyl-thienylcarbonic acid dimethylamide was prepared in analogous manner to 2-Methyl-3-phenyl-thienylcarbonyc dimethylamide with the exception that the starting compound was dibenzyl ketone instead of phenylacetone.
Step a) 1-(4,5-Diphenyl-2-thienyl)-2-phenyl-2-propen-1-on
30.7 g (100 mmol) of 2,3-diphenyl-thienylcarbonic acid dimethylamide was mixed with 100 ml ether and the resulting suspension was added in some portions at 0° C. to solution of 1-stiryllitium prepared from 62 ml 1.6M BuLi in hexane (100 mmol) and 27 g 1-bromostyrene (150 mmol) in 200 ml ether. The mixture warmed to room temperature (r.t.) and was stirred for 1 h. The resulting solution was poured into 500 ml of 5% aqueous HCl. The organic phase was collected, separated from insoluble impurities, washed with water, dried over MgSO4 and evaporated to give 20.9 g (57%) of crystalline solid. The product can be contaminated with 5-10% of starting amide (by NMR) and can be used without further purification.
1H NMR (CDCl3): 7.82 (s, 1H), 7.70-7.30 (m, 15H), 6.16 (s, 1H), 5.96(s, 1H)
Note: only technical-grade 1-bromo-styrene is available. It was distilled before reaction and was taken in 50% excess.
Step b) 2,3,5-triphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on
Vinyl-ketone obtained in previous experiment was dissolved in 20 ml of dichloromethane and resulting was poured into 50 ml methanesulphonic acid heated to 65° C. After 30 min of stirring at reflux the resulting mixture was poured into the mixture 0.31 water/ice/200 ml dichlorometane. The organic phase was collected, washed with water, then with aq. NaHCO3 up to neutral reaction and dried over MgSO4. The resulting solution was evaporated to give 20 g of crystalline product. This substance can be used for further steps (reduction by LiAlH4 followed by dehydration) without special purification.
1H NMR (CDCl3): 7.55-7.20 (m, 15H), 4.25 (dd, 1H); 3.61 (dd, 1H); 3.20 (dd, 1H)
Steps c) and d) 2,3,5-Triphenyl-4H-cyclopenta[b]thiophene
Solution of 3.7 g (10 mmol) 2,3,5-triphenyl-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on in 20 ml ether was treated with 130 mg (16 mmol) LiAlH4 in 10 ml ether. The mixture was stirred in 30 min and then was poured in 50 ml of 10% NH4Cl. The organic phase was collected, dried over MgSO4 and evaporated. Resulting alcohol was poured into solution of 300 mg p-toluenesulphonic acid in 300 ml toluene at 65° C. The resulting mixture was refluxed in 20 min, then it was cooled to r.t., washed with saturated aq. NaHCO3 and water. The solution so-obtained was dried over MgSO4 and evaporated. The residue was isolated by chromatography on silica-gel (hexane/CH2Cl2 3/1) to give 2.1 g (60% from ketone) of yellowish crystalline solid.
1H NMR (CDCl3): 7.60 (m, 2H), 7.45-7.25(m, 14H); 3.72 (d, 2H)
Preparation of the Compound of Formula (II)
34 g (0.224 mol) (4-chloro-phenyl)benznitryl and 33 ml (0.337 mol) ethylacetate was added to the hot solution of 24 g (0.3 mol) sodium isopropilate in 150 ml isopropanol. Reaction mixture was stirred at reflux in 3 hours then it was cooled to r.t., treated with 20 g (0.3 mol) acetic acid and finally diluted with 500 ml water. Organic precipitate was extracted with 100 ml dichloromethane. Resulting solution was evaporated to give yellowish solid of p-Cl-phenylacetone that was used without purification.
1H-NMR (CDCl3): 7.44 (AA′BB′ component, 2H); 7.36 (AA′BB′ component, 2H); 4.68 (s, 1H); 2.31 (s, 3H).
p-Cl-phenylacetone prepared in previous experiment was added in small portions to 50 ml of concentrated sulfuric acid at 0-5° C. then the mixture was heated at stirring to 100° C. in 10 min. Then the reaction mixture was cooled to 0° C., was treated quickly with 250 ml water and was stirred at 100° C. in 3 hours. The resulting mixture was cooled to r.t., the organic layer was separated and distilled at 108-110/10 torr to give 24.5 g (65% from p-Cl-phenylacetone).
1H-NMR (CDCl3): 7.34 (AA′BB′ component, 2H); 7.16 (AA′BB′ component, 2H); 3.71 (s, 2H); 2.20 (s, 3H).
17.5 ml (0.19 mol) of POCl3 was added at 0° C. to a 32 ml (0.44 mol) of DMF. At the end of the addition, the mixture was allowed to warm up to room temperature and stirred for 30 min. Then it was cooled again to 0° C. and carefully treated with 24.5 g (0.145 mol) of p-Cl-phenylacetone. The resulting reaction mixture was stirred at the same temperature for 1 h and then at 60-70° C. in additional 4 hours. The resulting viscous solution was poured into a mixture of ice and aqueous sodium acetate (150 g). Product was extracted with CH2Cl2 (3×50 mL). The organic phase was separated, washed with water until neutral pH, dried over MgSO4 and evaporated to dryness. The residue represents 21.5 g (68%) of crude chloroaldehyde that was used as is.
Ethyl-2-mercaptoacetate (12 g, 0.1 mol) was added at 0° C. to a solution of sodium ethoxide (6.8 g, 0.1 mol) in 150 mL of ethanol and the resulting mixture was stirred at the same temperature for 30 min. Then chloroaldehyde from the previous experiment (21.5 g, 0.1 mol) was added and stirring was continued overnight. The resulting product was refluxed for 2 h, cooled to room temperature and then was treated with solution of 12 g (0.3 mol) NaOH in 20 ml water. The resulting mixture was refluxed in 1 hour, then it was cooled to r.t. and finally was poured into 500 ml of water. The resulting mixture was neutralized by aqueous HCl, the precipitate was isolated, washed twice with 200 ml water and dried. Yield 15.3 g (60%).
1H-NMR (DMSO): 7.52 (s, 1H, thiopheneCH); 7.47 (m, 4H, phenylCH); 2.46 (s, 3H, CH3).
15.3 g (0.06 mol) of acid, 7.1 ml SOCl2 (0.1 mmol), 0.1 ml DMF and 100 ml of dichloromethane were placed into the bulb and refluxed in 30 min. Then the mixture was evaporated. Resulting oil was dissolved in 20 ml THF and this solution was added dropwise to 50 ml 33% aqueous Me2NH at 0° C. The mixture was stirred in 30 min. The resulting emulsion was poured into 500 ml of water. Product was extracted with 2×50 ml dichloromethane. Solution was washed with water, dried over magnesium sulfate and evaporated to give brown viscous liquid. Yield 14.4 g (86%).
1H-NMR (CDCl3): 7.45-7.30 (m, 5H); 3.25 (br.s, 6H); 2.50 (s, 3H).
Step a) 1-[5-Methyl-4-(4-chloro-phenyl)-2-thienyl]-2-methyl-2-propen-1-on
7.2 g (26 mmol) of 2-methyl-3-(p-Cl-phenyl)-thienylcarbonic acid dimethylamide was dissolved in 15 ml THF and the resulting solution was added dropwise to solution of 2-propenylmagnesium bromide prepared from 1 g Mg (42 mmol) and 3.7 g 2-bromopropene (31 mmol) in 20 ml THF at 0° C. The mixture warmed to r.t. and was stirred in 4 h. The resulting solution was poured into 100 ml of 5% aqueous HCl. The organic layer was collected, washed with water, dried over MgSO4 and evaporated to give quantitative amount yellow-reddish oil that was used without further purification.
1H NMR (CDCl3): 7.56 (s, 1H); 7.39 (AA′BB′ component, 2H); 7.29 (AA′BB′ component, 2H); 5.79 (m, 1H), 5.74(m, 1H), 2.51 (s., 3H); 2.04 (m, 3H)
Step b) 2,5-Dimethyl-3-(4-chloro-phenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on
Vinyl-ketone obtained in previous experiment was dissolved in 10 ml of dichloromethane and resulting solution was poured into 25 ml methanesulphonic acid heated to 65° C. After 20 min of stirring at reflux the resulting mixture was poured into the mixture 0.21 water/ice/50 ml dichlorometane. The organic phase was collected, washed with water, then with aq. NaHCO3 up to neutral reaction and dried over MgSO4. The resulting solution was evaporated and was purified by chromatography (hexane/ether 3/1) to give 2.2 g (31%) of viscous oil.
1H NMR (CDCl3): 7.41 (AA′BB′ component, 2H); 7.23 (AA′BB′ component, 2H); 3.13 (dd, 1H), 2.94 (quintet of doublets, 1H); 2.50 (s, 3H); 2.49 (dd, 1H), 1.31 (d, 3H)
Steps c) and d) Synthesis of 2,5-dimethyl-3-(4-chloro-phenyl)-6H-cyclopenta[b]thiophene
Solution of 2.2 g (8 mmol) 2,5-dimethyl-3-(4-chloro-phenyl)-4,5-dihydro-6H-cyclopenta[b]thiophen-6-on in 20 ml ether was treated with 0.1 g (2.6 mmol) LiAlH4 in 20 ml ether. The mixture was stirred in 30 min and then was poured in 30 ml of 10% NH4Cl. The organic phase was collected, dried over MgSO4 and evaporated. Resulting alcohol was dissolved in 150 ml benzene. To this solution 0.1 g p-toluenesulphonic acid. The resulting mixture was refluxed in 10 min, then was cooled to r.t., washed with saturated aq. NaHCO3 and water. The solution so-obtained was dried over MgSO4 and evaporated to give 1.4 g (67% from ketone) of the solid product.
1H NMR (CD2Cl2): 7.37 (AA′BB′ component, 2H); 7.32 (AA′BB′ component, 2H); 6.38 (quintet, 1H); 3.06 (br.s., 2H); 2.43 (s, 3H); 2.10 (br.s, 3H).
15.3 g (0.06 mol) of acid, 7.1 ml SOCl2 (0.1 mmol), 0.1 ml DMF and 100 ml of dichloromethane were placed into the bulb and refluxed in 30 min. Then the mixture was evaporated. Resulting oil was dissolved in 20 ml THF and this solution was added dropwise to 50 ml 33% aqueous Me2NH at 0° C. The mixture was stirred in 30 min. The resulting emulsion was poured into 500 ml of water. Product was extracted with 2×50 ml dichloromethane. Solution was washed with water, dried over magnesium sulfate and evaporated to give brown viscous liquid.
Viscous liquid so-obtained was dissolved in 15 ml THF and the resulting solution was added dropwise to solution of 2-propenylmagnesium bromide prepared from 2 g Mg (42 mmol) and 7.4 g 2-bromopropene (62 mmol) in 40 ml THF at 0° C. The mixture warmed to r.t. and was stirred in 4 h. The resulting solution was poured into 200 ml of 5% aqueous HCl. The organic layer was collected, washed with water, dried over MgSO4 and evaporated to give yellow-reddish oil of vinyl-ketone.
Vinyl-ketone obtained in previous experiment was dissolved in 20 ml of dichloromethane and resulting solution was poured into 50 ml methanesulphonic acid heated to 65° C. After 20 mm of stirring at reflux the resulting mixture was poured into the mixture 0.41 water/ice/100 ml dichlorometane. The organic phase was collected, washed with water, then with aq. NaHCO3 up to neutral reaction and dried over MgSO4. The resulting solution was evaporated, then was dissolved in 50 ml ether was treated with 675 mg (15 mmol) LiAlH4 in 50 ml ether. The mixture was stirred in 30 mm and then was poured in 30 ml of 10% NH4Cl. The organic phase was collected, dried over MgSO4 and evaporated. Resulting alcohol was dissolved in 300 ml toluene. To this solution 0.2 g p-toluenesulphonic acid was added. The resulting mixture was heated under stirring at 80° C. in 10 mm, then was cooled to r.t., washed with saturated aq. NaHCO3 and water. The solution so-obtained was dried over MgSO4 and evaporated to give 10.4 g of crude ligand.
This crude product was dissolved in the mixture of 30 ml ether and 100 ml hexane and then was treated with 38 ml of 1.6M BuLi in hexane (60 mmol). The precipitate was isolated, washed with hexane and dried. Yield 7.5 g.
| Number | Date | Country | Kind |
|---|---|---|---|
| 01202930 | Aug 2001 | EP | regional |
This application is the U.S. national phase of International Application PCT/EP02/07680, filed Jul. 10, 2002.
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP02/07680 | 7/10/2002 | WO | 00 | 1/30/2004 |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO03/01410 | 2/20/2003 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 4496742 | Smith | Jan 1985 | A |
| 4532236 | Nickolson et al. | Jul 1985 | A |
| 4853149 | Krause et al. | Aug 1989 | A |
| 5136081 | Briner | Aug 1992 | A |
| 5252749 | Badorc et al. | Oct 1993 | A |
| 5747531 | Matsumura et al. | May 1998 | A |
| 6057316 | Wrobel et al. | May 2000 | A |
| 6423870 | Langlois et al. | Jul 2002 | B1 |
| 6444833 | Ewen et al. | Sep 2002 | B1 |
| 6762316 | Chand et al. | Jul 2004 | B1 |
| Number | Date | Country |
|---|---|---|
| 0144318 | Jun 2001 | WO |
| Number | Date | Country | |
|---|---|---|---|
| 20040192931 A1 | Sep 2004 | US |
