ADDITION OF POLYHALONITRILES TO FUNCTIONALIZED OLEFINS

Abstract: Novel compounds, e.g., 4-formyl-2,2,4-trichloro­ valeronitrile, method of making and cyclization to form substituted pyridines.

Description: ADDITION OF POLYHALONITRILES TO FUNCTIONALIZED OLEFINS AND NOVEL COMPOUNDS OBTAINED THEREBY European Patent 46735 (Ciba-Geigy) discloses the preparation of chloropyridines substituted by methyl, trichioromethyl or trifluoromethyl groups by the addition of trichloroacetaldehyde to methacrylonitrile or a-trifluoromethacrylonitrile, the addition of 2,2-dichloropropionaldehyde, pentachloropropionaldehyde, 2,2-dichloro-3,3,3-trifluoropropion- aldehyde to acrylonitrile or the addition of 2, 2-dichloropropionaldehyde to methacrylonitrile and cyclizing the resulting intermediate. We have now found that novel compounds having the formula EMI2.1 wherein R is CHO or COR2 where R2is halo1 alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R1 is H or lower alkyl having 1 to 6 carbon atoms; X is Br, C1 or I; Y is C1, Br, CF3, alkyl of 1 to 6 carbon atoms, substituted or unsubstituted aryl, preferably having 6 to 10 carbon atoms or a heterocyclic radical having 5 or 6 atoms in the ring; and Z is H, F or C1, are readily prepared by a process which comprises reacting an acetonitrile having the formula C(X1)3CN where X1 is any combination of H, F, C1, Br or I, with the proviso that there be no more than one H, with an olefinic compound having the formula EMI2.2 wherein R and R1 are as above-identified. The novel compounds of this invention are useful for the preparation of di- and trihalogenated pyridines, pyridinols and methylpyridines which are useful as pharmaceuticals, agricultural products and intermediates. The process of this invention utilizes polyhalogenated acetonitriles which have demonstrated increased reactivity toward acrylates and acroleins, thus enabling the use of milder reaction conditions than processes of the known art. The reaction may be carried out neat or, if desired, an inert solvent, e.g., an alkyl nitrile, may be employed. The reaction is generally carried out using equimolar amounts of the trihaloacetonitrile and olefin, e.g., acryloyl chloride, methacrolein or acrolein, although a slight excess of the lower boiling reactant may be employed as a solvent if desired. The reaction may be carried out at a temperature of from 400 to 2000 C, but is preferably carried out at a temperature of from 700 to 900C in the presence of a catalyst which is, advantageously, a complex of cuprous chloride and triphenylphosphine. Other useful catalysts include, for example, CuO, CuI, CuBr, Fe(CO)5, and complexes of, for example, ruthenium chloride or rhodium chloride and triphenyl phosphine. This invention is further illustrated by the following examples. Example 1 - Preparation of dibromoacetonitrile Cyanoacetic acid (85 g, 1.0 mole) was dissolved in 1.5 liter of H20 and cooled to 10 C. N-bromosuccinimide (356 g, 2.0 moles) was added in small portions to the stirring solution. After a brief induction period, a vigorous evolution of CO2 gas had begun. Upon completion of the addition, the reaction mixture was allowed to stir at room temperature for a period of one hour after which the reaction mixture was poured into a 2-liter separatory funnel to allow the separation of dibromoacetonitrile. The aqueous portion was then extracted with 3 x 150 ml portions of methylene chloride which were combined with the dibromoacetonitrile already separated. The combined extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was distilled to afford 167 g (84 percent yield) of dibromoacetonitrile, b.p. 600C at 20 mmEg, as a pale yellow liquid. Example 2 - Preparation of dichioroacetonitrile Cyanoacetic acid (170 g, 2.0 moles) was dissolved in 2 liters of water and cooled to lO0C. N-chlorosuccinimide (53 g, 4.0 moles) was added slowly to the stirred solution. After a brief induction period, a vigorous evolution of CO2 began. Addition of N-chlorosuccinimide was maintained such that the temperature did not exceed 350C. Upon completion of the addition, the reaction mixture was stirred at room temperature for a period of one hour and allowed to stand. The separated organic phase was removed and the aqueous phase was extracted with 3 x 200 ml portions of CH2C12. The extracts were combined with the product and dried over MgSO4. The solvent was removed in vacuo and the remaining liquid was distilled to afford 160.6 g (75 percent yield) of dichloroacetonitrile, b.p. 112 -113 C. Example 3 - Preparation of 4-formyl-2,2,4 -trichlorovaleronitrile A solution of 150 ml of CC13CN (1.5 moles) and 80 ml of methacrolein (1.0 mole) containing 10 g of CuCl and 0.5 g triphenylphosphine catalyst was heated to reflux in a 500 ml round bottomed flask equipped with a spiral condenser for a period of 4.5 hours. During that time, the reaction temperature rose from 750C to 85 C. At the end of this time the unreacted materials were removed in vacuo to afford 174 g of a dark red oil (84 percent). Distillation of this residue afforded 150 g, b.p. 750C (1.5-3.0 mm Hg) of a yellow liquid (83 percent) with greater than 95 percent purity by G.C. ENMR and CNMR. 'Hnmr (Acetone d6, TMS); 6 1.90 (S 3H -CH3); 6 3.60 (S 2H -CE2-); 6 9.58 (S 1H -CHO). IR NaCl neat 1730 cm 1 2255 cm"l, Elemental Analysis C H N Calculated for C H Cl3NO: 33.60 2.82 6.53 Found: 33.50 2.88 6.44 Example 4 - Preparation of 2,4,4-trichloro-4 -cyanopentanoyl chloride To a 100 ml round bottomed flask was added 10 ml (14.0 g) of CCl3CN, 16 ml E2C=CHCOC1 (22 g, 0.20 mole), 0.5 g Curl and 0.025 g triphenylphosphine catalyst. The flask was equipped with a spiral reflux condenser topped with a CaCl2 drying tube and the reaction mixture was heated at reflux for a period of 2h hours. At this time, G.C. analysis showed that the reaction was at 50 percent converted (by area percent), heat was removed and unreacted starting materials were stripped off in vacuo to afford a dark red viscous oil. This resulting residue was transferred to a kugelrohr apparatus and distilled at 900C/4 mm Hg to afford 5 g of product in 21.3 percent overall yield. Example 5 - Preparation of 4-cyano-2,2,4 -trichlorobutyric acid:methyl ester Methyl acrylate, 22.4 ml (0.25 ml), tri chloroacetonitrile (72 g, 50 ml, 0.5 ml), 1 g CuCl and 5 ml isopropanol were heated at 1200C overnite, the excess CCl3CN (b.p. 840C) evaporated in vacuo and the residue distilled to give product b.p. 800-850C at 0.5 mm Hg. The IR and NMR spectra are consistent with product. Elemental Analysis C H ¯ N Calculated for C6H6Cl3NO2: 31.25 2.60 6.10 Found: 30.65 2.65 6.14 Example 6 - Preparation of 2,2,4-trichloro-5 -oxypentanenitrile A) Following the above general procedures, a mixture of 56 g (1.0 mole) of acrolein and 72 g (0.5 mole) of trichloroacetonitrile was heated to reflux (600C) in the presence of 100 mg of CuCl and 100 mg of triphenylphosphine The reaction was kept at reflux for 15 hours under nitrogen by which time the temperature had risen to 850C. After cooling to ambient temperature, unreacted starting materials were removed in vacuo and the residue distilled from a Kugelrohr apparatus to provide the titled product (50 g, 49.8 percent yield), purity 84 percent by gas chromatography. (B) A solution of 56 g (1.0 mole) of acrolein and 214 g (1.5 moles) of trichloroacetonitrile was heated to reflux (600C) in the presence of 100 mg of CuCl and 100 mg of triphenylphosphine. The reaction was kept at reflux for 1.5 hours under dry nitrogen by which time the temperature had risen to 850C. After cooling to room temperature, unreacted starting materials were removed in vacuo and the residue distilled through a Kugelrohr apparatus to provide 2,2,4-trichloro-5-oxopentanenitrile (170 g, 85 percent yield) as an amber liquid, b.p. 650C, 0.95 mmEg. Rnmr (Acetone d6, TMS) 6 3.39 (d.g 2H -CE2-); 6 4.94 (dd 1H -CECl); 6 9.58 (S 1" CHO). IR NaCl neat 1735 cm 1 2250 cm Elemental Analysis: C H B N Calculated for C5H4Cl3NO: 29.96 2.01 6.99 Found: 30.10 2.11 6.99 Example 7 - Preparation of 3,5-dichloro-2 -hydroxypyridine 2,2,4-Trichloro-5-oxopentanenitrile (4.0 g, 0.2 mole) was dissolved in 250 ml of acetonitrile and 500 ml of isopropylamine was added. The mixture was heated to reflux for 24 hours, the solvent removed in vacuo and the residue placed in a silica gel column and eluted with ethyl acetate. The fraction containing the 2-hydroxy-3,5-dichloropyridinol was isolated and the solvent removed in vacuo affording 15 g (61% yield) of titled product. After recrystallization from hexane the m.p. was 1790-1800C. Example 8 - Preparation of 2,4-dichloro-4 -methyl-5-oxopentanenitrile (a) By zinc reduction To a 500 ml round bottom flask containing a slurry of Zn (7.0 g, 0.11 mole) and acetonitrile (100 ml) was added dropwise a solution of 2,2,4-tri chloro-4-methyl-5-oxopentanenitrile (21.0 g, 0.1 mole) in acetonitrile (60 ml) containing 3.5 g of dry hydrogen chloride at OOC. Vigorous stirring was maintained throughout the addition. The temperature of the reaction rose to 350C during the addition. Upon completion of the addition, the reaction mixture was allowed to stir for a period of 10 minutes and was poured into 200 ml of methylene chloride and extracted with 5 x 100 ml portions of H2O. The organic portion was dried over MgSO4 and the methylene chloride was removed in vacuo. The residue was placed on a Kugelrohr apparatus and distilled at 1000C and 5 mmHg. 7.2 Grams (40 percent yield) of 2,4-dichloro -4-methyl-5-oxypentanenitrile was obtained in this manner. (b) By cadmium amalgum reduction A 5 percent cadmium amalgum was prepared by dissolving 22 g (0.20 mole) of cadmium metal in 440 g of mercury. The resulting amalgum was added to a l-liter three necked flask, equipped with a mechanical stirrer, containing 150 ml of acetonitrile. A solution of 32.2 g (0.15 mole) of 2,2,4-trichloro-4 -methyl-5-oxopentanenitrile and 21.9 g (0.2 mole) of dimethylformamide hydrochloride in 350 ml of acetonitrile was added in one portion and the resulting mixture was heated to reflux for a period of six hours. During this period, the precipitation of cadmium chloride was observed. Upon completion of the reaction, the spent mercury and some of the cadmium chloride were removed by filtration and the remaining acetonitrile solution was dissolved in 1 liter of methylene chloride and extracted with 5 x 250 ml portions of H2O. The organic portion was then dried with NgSO4 and the solvent was removed in vacuo. The residue was placed on a Kugelrohr apparatus and distilled at 1000C at 5 mmwg. 24 Grams (90% yield) of 2, 4-dichloro-4-methyl-5-oxopentanenitrile were isolated in this manner. Physical and spectral data were in agreement with authentic material. Example 9 - Preparation of 2,4-dichloro-4 -formylvaleronitrile A solution of 11 grams (0.1 mole) of dichloroacetonitrile and 14.0 grams (0.2 mole) of methacrolein in 50 ml of propionitrile containing 100 mg of CuCl and 200 mg of triphenylphosphine was heated to reflux (850-940C) for 18 hours under a nitrogen blanket. After cooling to ambient temperature the solvent and unreacted starting materials were removed in vacuo and the residue was distilled in a Kugelrohr apparatus at 1000C and 5 mm Hg to afford 10 grams of the titled product. NMR indicated a mixture of diastereoisomers with traces of 2, 3-dichloro-5-methylpyridine. 'Hnmr (CDCl3, TMS) 6 1.78 (S 3H CH3); 6 2.3-3.10 (m 2H -CH2-); 6 4.75 (t 1H -CnCl-); 6 95 (S 1H -CHO). IR NaCl neat 2250 cm -1 1750 cm b.p. 900C at 5.0 mmEg. Example 10 - Preparation of 2,3-dichloro-5 methylpyridine (a) Direct method A solution of dichloroacetonitrile (11.0 g, "'0.1 mole) and methacrolein (14.0 g, 0.20 mole) in 50 ml of propionitrile containing 200 mg of CuCl and 200 mg of tri-n-butylphosphine was placed in a Carius tube and heated to 1300C for a period of six hours. Upon completion, the reaction was cooled to room temperature and the solvent and unreacted starting materials were removed in vacuo. The residue was distilled through a Kugelrohr apparatus at 100 -120 C at 5 ImnHg to afford a pale yellow liquid which slowly crystallized upon standing. The white crystals were washed with cold hexane and.dried to afford 6.5 g, (40 percent yield) of 2,3-dichloro-5-methylpyridine, m.p. 420-450C. Evaporation of the hexane washes afforded 2, 4-dichloro-4-methyl-5-oxopentanenitrile, 1.6 g, 10% additional yield for a total yield of 50%, cRnmr (CC14, TNS) a 2.35 (S 3H -CH3), a 7.62 (d 1H pyr C-4H); 6 8.16 (d 1H pyr C-6H). (b) By ring closure of adduct A solution of 32.1 g of 2,4-dichloro-4 -methyl-5-oxopentanenitrile in 250 ml of acetonitrile containing 30Q ml of isopropylamine and 300 mg of nickel dichlorobis(triphenylphosphine) was heated to reflux for 48 hours. The acetonitrile was then removed in vacuo and the residue was distilled through a Kugelrohr apparatus at 850-900C at 2.5-mmHg to afford 2,3-dichloro-5-methylpyridine (27.0 g, 86 percent yield) which solidified on standing, m.p. 430-450C. Example 11 - Preparation of 2,3-dibromo-5-methylpyridine by way of the in situ formation and ring closure of 2,47dibromo-4-formyl valeronitrile A solution of 19.0 g ("'0.1 mole) of dibromoacetonitrile and 14 g (0.2 mole) of methacrolein in 50 ml of propionitrile containing 100 mg of CuCl and 200 mg of tri-n-butylphosphine was heated to reflux (900C) under N2 atmosphere for 14.5 hours. After this time, the solvent and unreacted starting materials were removed in vacuo. 'Hnmr of the reaction mixture revealed the presence of 2,4-dibromo-4-formylvaleronitrile present as a mixture of diastereomers in an appropriate 1:1 ratio (by gas chromatography). lanmr (CDCl3, Thy), 6 2.55 (S 3H -CH3); 6 2.7-3.3 (M 2H -CH2); 6 4.80 (t 1H -CHBr-); 6 9.5 (S 1H -CHO). Attempts to isolate the 2,4-dibromo-4-formylvaleronitrile by vacuum distillation resulted in the conversion of this compound to 2,3-dibromo-5-methylpyridine. Thus, the residue was placed on a Kugelrohr apparatus and distilled at 1000C and 5 mm of Hg to afford 11.5 g (49% isolated yield) of a pale yellow oil which slowly solidified upon standing. Recrystallization from hexane afforded 2,3-dibromo-5-methylpyridine as colorless platelets, m.p. 530-550C. Elemental Analysis: C H N Calculated for C H Br2N: 28.72 2.01 5.58 Found: 29.00 2.00 5.58 Example 12 - Preparation of 2,2,4-trichloro-5 -oxo-hexanenitrile A solution of 28 grams (0.2 mole) trichloroacetonitrile and 20 grams (0.3 mole) methylvinylketone in 50 ml of propionitrile containing 1.0 gram of CuCl and triphenylphosphine (1:1 ratio by weight) was refluxed overnight. Solvent was removed in vacuo and the residue distilled in a Xugelrohr apparatus to afford 30 grams of titled product having a boiling point of 1000C at 3 mm Hg. 'Hnmr (Acetone d6 Thy); 6 2.42 (S 3H CE3); 6 3.34 (dq 2E -CE2-); 6 4.90 (dd 1E -CHCl-). b.p. 720-730C; 0.8 mmHg. IR NaCl neat 1725 cm 1 2255 cm 1. Elemental Analysis: C H N Calculated for C6H6C13NO: 33.60 2.82 6.53 Found: 33.50 2.75 6.70 Example 13 - Preparation of 2,4-dibromo-2-fluoro-4 -formylvaleronitrile and its conversion to 2-bromo-3-fluoro-5-methylpyridine and 2 -bromo-3 - fluoro-5-methylpyridine hydrobromide Dibromofluoroacetonitrile (5.0 g, 0.025 mole) and 3.5 g (0.05 mole) of methacrolein were dissolved in 50 ml of propionitrile containing 50 mg of CuCl, 50 p1 of n-Bu3P and 50 pl of triethylamine. This solution was placed in.a Carius tube and heated at 1000C for a period of 9 hours. Upon completion, the solvent and unreacted starting material were removed under reduced pressure. An 'Hnmr spectrum of the material showed the presence of diastereomeric 2,4-dibromo-2-fluoro -4-formylvaleronitrile along with trace amounts of 2-bromo-3-fluoro-5-methylpyridine. 'Enmr (acetone d6): 6 1.95, 2.0 (singlets, 3H, -CE3); 6 3.2-3.65 (m, 24, -CH2); a 9.20, 9.35 (doublets, 1H, CHO). Distillation -of-this residue through a Kugelrohr apparatus at 1200C and 3 miwg afforded only a mixture of pyridines. The distillate which contained a precipitate was taken up in hot hexane and filtered to remove the precipitate. This precipitate was dried and purified by sublimation (500-800C at 0.5 mm Hg) to afford 0.795 g (11.7 percent yield) of 2-bromo-3-fluoro-5-methylpyridine hydrobromide, m.p. 1980-2030C (sublimed). 'Hnmr. (acetone d6: D2O; 1:1): 6 2.45 (s, 3H, -CE3); 6 7.75 (double doublet, 1H, pyr-4H); J1'F 9.4 He; 6 8.15 (broad singlet, 1H, pyr-6H). Removal of the hexane in vacuo afforded a colorless oil which solidified on standing. Sublimation of this material (300C at 0.3 mm Hg) gave 0.95 g (20.0 percent yield) of 2-bromo-3-fluoro-5-methylpyridine, m.p. 32 -33 C. IRnmr (acetone d6): 6 2.35 (s, 3H, 6 7.50 (double doublet, 1H, pyr-4H), JHF 9.3 Hz; 6 8.10 (broad s, 11', pyr-6H). Elemental analysis Calc'd for C6H6 Br2FN: C, 26.59; H, 2.23; N, 5.17. Found: C, 26.30; H, 2.54; N, 5.29. Calc'd for C6H5BrFN: C, 37.92; H, 2.65; N, 7.37. Found: C, 37.24; H, 2.85; N, 6.98. Example 14 - Preparation of 4-formyl-2,4-dichloro -2-fluorovaleronitrile The above general procedures were repeated except to employ 12.8 grams (0.1 mole) of dichlorofluoroacetonitrile and 14.0 grams (0.2 mole) of methacrolein. The catalyst comprised 100 mg CuCl, 50 microliters of tri-n-butylphosphine and 50 microliters of triethylamine. After 9 1/2 hours at 1100C, the unreacted starting materials and solvent were removed in vacuo and the residue distilled from a Kugelrohr apparatus (950C at 3.0 mm Hg) to provide 12 grams of the title product. NMR revealed the sample to be a mixture of diastereoisomers. Example 15 - Preparation of 2,4-dichloro-2-fluoro -4-formylbutyronitrile Employing the above general procedures a mixture of 12.8 grams (0.1 mole) of dichlorofluoroacetonitrile and 14.2 grams (0.2 mole) of acrolein in 50 ml of propionitrile containing 100 mg of CuCl and 50microliters of triethylamine was heated to 1000C for 9 hours, unreacted starting materials and solvent were removed in vacuo and the residue distilled from a Kugelrohr apparatus (1000C at 5.0 mm Hg) to afford 50 grams of the titled product as a mixture of diastereomers. The yield was 27.2 percent, b.p. 430-440C; 0.55 mm Hg. Rnmr (Acetone d6) 6 1.75 (s,. 3H, CH3); 6 2.70-3.40 (m, 2H, -CH2); 6 9.3-9.5 (m, 1H, -CEO). Ir NaCl neat 2260 cm1, 1740 cm1, 1450 cm1, 1125 cml, 1050 cm1, 910 cm1. Chemical Ionization Mass Spec. (CH4) MH+ m/e 198 (100%); . MH+ + 2 m/e 200 (62%), m/e 226 (M + C2H5) , m/e 238 (M + C3H5)

Claims: WE CLAIM: 1. A compound having the formula EMI15.1 wherein R is CEO or COR2 where R2 is halo, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R1 is H or lower alkyl having 1 to 6 carbon atoms; X is Br, C1 or I; Y is Cl, Br, CF3, alkyl of 1 to 6 carbon atoms, substituted or unsubstituted aryl, preferably having 6 to 10 carbon atoms or a heterocyclic radical having 5 or 6 atoms in the ring; and Z is H, F or Cl. 2. Compound of Claim 1 wherein X, Y and Z are chloro, R is CHO and R1is CE3. 3. Compound of Claim 1 wherein X, Y and Z are chloro, R is COR2 wherein R2 is chloro and R1 is H. 4. Compound of Claim 1 wherein X, Y and Z are chloro, R is COR2 where R2 is OCE3 and R1 is H. 5. Compound of Claim 1 wherein X, Y and Z are Cl, R is COR2 where R2 is CH3 and R1is H. 6. Compound of Claim 1 wherein X and Z are Cl, R is CEO and R1 is CH3. 7. Compound of Claim 1 wherein X and Z are Br, Y is H, R is CHO and R1 is CE3. 8. Compound of Claim 1 wherein X and Y are Cl, Z is F, R is CEO and R' is H. 9. Compound of Claim 1 where X and Y are Br, Z is F, R is CEO and R' is C. 10. A process for making a compound having the formula EMI16.1 wherein R is CEO or COR2 where R2 is halo, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms; R1 is H or lower alkyl having 1 to 6 carbon atoms; X is Br or Cl; Y is Cl, Br, I, CF3, alkyl of 1 to 6 carbon atoms, substituted or unsubstituted aryl, preferably having 6 to 10 carbon atoms or a heterocyclic radical having 5 or 6 atoms in the ring; and Z is H, F or Cl, which comprises reacting an acetonitrile having the formula C(X1)3CN where X1is any combination of H, C1, Br, I or F, with the proviso that there be no more than one H, with an olefinic compound having the formula EMI17.1 wherein R1 is H or lower alkyl having 1 to 6 carbon atoms and R2 is halo, alkyl having 1 to 6 carbon atoms or alkoxy having 1 to 6 carbon atoms. 11. Process of Claim 10 wherein the reaction is carried out at a temperature of from 400 to 2000C. 12. Process of Claim 11 wherein the reaction is carried out in the presence of a catalyst. 13. Process of Claim 12 wherein the catalyst is a complex of cuprous chloride and triphenylphosphine. 14. Process of Claim 13 wherein the reaction is carried out neat. 15. Process of Claim 14 wherein the temperature is from 700 to 900C. 16. Process of Claim 10 wherein the reactants are employed in approximately equal molar proportions.

Inventors: LYSENKO, ZENON, PEWS, RICHARD GARTH
Applicants: THE DOW CHEMICAL COMPANY
Application year: 1984
Main classification: C07C121
IPC codes: B01J31, C07C255, C07B61, C07D213, C07C67, C07C253