Transition metal-catalyzed processes for the preparation of N-allyl compounds and use thereof
The present disclosure provides processes for the N-dealkylation of tertiary amines and the use of transition metal catalysts to prepare tertiary N-allyl amine derivatives and secondary amine derivatives thereof. The tertiary amines can be alkaloids and, more particularly, the tertiary amines can be opioids. In specific embodiments, the present disclosure provides methods for use in processes for the synthesis of naloxone and naltrexone from oripavine.
1. A method for making a compound Formula (200):
comprising:
(a) contacting a compound of Formula (45):
with a compound of Formula (93):
in the presence of a base and a solvent to provide a compound of Formula (201):
and
(b) contacting the compound of Formula (201) with a transition metal catalyst selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , Ni(PPh 3 ) 4 , Ni(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , ((pentamethylcyclopentadienyl)RuCl) 4 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , [Ni(COD) 2 ]/PPh 3 , NiCl 2 /PPh 3 , Ni[P(OEt) 3 ] 4 , and combinations of two or more thereof to provide the compound of Formula (200);
wherein:
R 4 is selected from the group consisting of —H, —(C 1 -C 6 ) alkyl, phenyl,
R 5 is selected from —H and —(C 1 -C 6 ) alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 8 groups;
R 6 and R 7 are each hydrogen or R 6 is hydrogen and R 7 is unsubstituted —(C 1 -C 6 ) alkyl;
each R 8 is independently selected from —OR 51 , —F, —Cl, —Br, —I, phenyl, and —(C 1 -C 6 ) alkyl;
R 14 and R 16 are each independently selected from —OH, —H, and —OR 17 ;
R 15 is selected from —OH, —H, —OR 17 , ═O, and ═CH 2 ;
R 17 is an oxygen protecting group;
X is selected from —Cl, —Br, and —I; and
each R 51 is independently selected from —(C 1 -C 6 ) alkyl and an oxygen protecting group.
2. The method of claim 1 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , and combinations of two or more thereof.
3. The method of claim 1 , wherein the solvent is selected from the group consisting of ether solvents, acetonitrile, benzene, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylpropionamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 1,3-dimethyl-2-imidazolidinone, 1,2-dimethoxyethane, N,N-dimethylacetamide, N-methylpyrrolidinone, ethyl acetate, ethyl formate, ethyl-methyl ketone, iso-butylmethylketone, formamide, hexamethylphosphoramide, methyl acetate, N-methylacetamide, N-methylformamide, nitrobenzene, nitromethane, propionitrile, sulfolane, tetramethylurea, tetrahydrofuran, toluene, CHCl 3 , CH 2 Cl 2 , 1,2-dichloroethane, acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene, N,N-dimethylformamide, trifluorotoluene, 1,4-dioxane, 1,2-dimethoxyethane, xylene, and combinations of two or more thereof.
4. The method of claim 3 , wherein the solvent is selected from the group consisting of CHCl 3 , CH 2 Cl 2 , 1,2-dichloroethane, toluene, tetrahydrofuran, ethyl acetate, acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene, N,N-dimethylformamide, trifluorotoluene, 1,4-dioxane, 1,2-dimethoxyethane, xylene, and combinations of two or more thereof.
5. The method of claim 1 , wherein the base is selected from the group consisting of NaBO 3 , Na 2 HPO 4 , Na 3 PO 4 , K 2 HPO 4 , K 3 PO 4 , NaHCO 3 , KHCO 3 , NaOH, KOH, Na 2 CO 3 , K 2 CO 3 , Cs 2 CO 3 , pyridine, triethylamine, di-iso-propylethylamine, N-methylmorpholine, N,N-dimethylaminopyridine, N-(2-acetamido)-2-aminoethane sulfonic acid, N-(2-acetamido)-iminodiacetic acid, N,N-bis(2-hydroxyethyl)glycine, 3-(cyclohexylamino)-1-propanesulfonic acid, 2-(cyclohexylamino)-ethanesulfonic acid, 4-(2-hydroxyethyl)-1-piperazinepropanesulfonic acid, 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid, 2-(4-morpholinyl)-ethanesulfonic acid, 4-morpholinepropanesulfonic acid, 1,4-piperazinediethanesulfonic acid, [(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]-1-propanesulfonic acid, 2-[(2-hydroxy-1,1-bis(hydroxymethyl)ethyl)amino]ethanesulfonic acid, and combinations of two or more thereof.
6. The method of claim 5 , wherein the base is selected from the group consisting of Na 2 CO 3 , NaHCO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , and combinations of two or more thereof.
7. The method of claim 1 , wherein the compound of Formula (200) is a compound of Formula (205):
and the compound of Formula (201) is a compound of Formula (206):
8. The method of claim 1 , wherein the compound of Formula (200) is a compound of Formula (209):
the compound of Formula (201) is a compound of Formula (210):
and the compound of Formula (93) is a compound of Formula (21′):
9. The method of claim 1 , wherein for the compound of Formula (45), R 15 is ═O and R 16 is —OH.
10. The method of claim 9 , wherein for the compound of Formula (45), R 14 is —OH.
11. The method of claim 9 , wherein for the compound of Formula (45), R 14 is —OCH 3 .
12. A method for making a compound of Formula (41):
comprising:
(a) contacting a compound of Formula (45):
with a compound of Formula (48):
in the presence of a base and a solvent to provide a compound of Formula (95):
and
(b) contacting the compound of Formula (95) with the transition metal catalyst selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , Ni(PPh 3 ) 4 , Ni(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , ((pentamethylcyclopentadienyl)RuCl) 4 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , [Ni(COD) 2 ]/PPh 3 , NiCl 2 /PPh 3 , Ni[P(OEt) 3 ] 4 , and combinations of two or more thereof to provide the compound of Formula (41);
wherein:
X is Cl, —Br, or —I;
R 14 and R 16 are each independently selected from —OH, —H, and —OR 17 ;
R 15 is selected from —OH, —H, —OR 17 , ═O, and ═CH 2 ;
R 17 is an oxygen protecting group;
R 14′ and R 16′ are each independently selected from —OH, —H, —OR 17 , and —OC(O)OCH 2 CH═CH 2 ; and
R 15′ is selected from —OH, —H, —OR 17 , ═O, ═CH 2 and —OC(O)OCH 2 CH═CH 2 .
13. The method of claim 12 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , Ni(PPh 3 ) 4 , Ni(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , [Ni(COD) 2 ]/PPh 3 , NiCl 2 /PPh 3 , Ni[P(OEt) 3 ] 4 , and combinations of two or more thereof.
14. The method of claim 13 , wherein the base is selected from the group consisting of Na 2 CO 3 , NaHCO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , and combinations of two or more thereof.
15. The method of claim 13 , wherein the solvent is tert-amyl alcohol.
16. The method of claim 14 , wherein the solvent is selected from the group consisting of tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol, and combinations of two or more thereof.
17. The method of claim 12 , wherein the compound of Formula (45) is compound (108):
and the compound of Formula (41) is compound (104):
18. The method of claim 12 , wherein the compound of Formula (45) is compound (213):
and the compound of Formula (41) is compound (214):
19. The method of claim 1 , wherein the compound of Formula (93) is added in 3, 4, 5, 6, 7, 8, 9, 10, or more portions throughout step (a).
20. The method of claim 1 , wherein the compound of Formula (93) is added continuously throughout step (a).
21. The method of claim 1 , wherein:
the oxygen protecting group is selected from the group consisting of allyl, acetyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, —C(O)O—CH 2 —CH═CH 2 , tert-butyl-diphenylsilyl, tert-butyl-dimethylsilyl, trimethylsilyl, tri-iso-propylsilyl, tert-butyldimethylsilyloxymethyl, β-methoxyethoxymethyl, [bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, methyl, ethoxyethyl, triphenylmethyl, —C(O)(C 1 -C 4 ) alkyl, —C(O)OR 18 , and —(C 1 -C 6 ) alkyl, each said alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups;
each R 18 is independently selected from —(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkenyl, and —(C 2 -C 6 ) alkynyl, each said alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups; and
each R 21 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.
22. The method of claim 12 , wherein step (b) further comprises, after contacting a compound of Formula (95) with the transition metal catalyst, introducing an allyl scavenger selected from the group consisting of sodium 2-ethylhexonate, morpholine, dimedone, 4-methylbenzensulfinic acid, sodium hydroxymethyl sulfinate, benzenesulfinic acid, sodium toluene sulfinate, sodium 2-thiophene sulfinate, tetrabutylammonium toluene sulfinate, N,N-dimethyl barbituric acid, sodium 4-chloro-3-nitrobenzene sulfinate, formic acid, diethyl amine, methanol, ethanol, and combinations of two or more thereof.
23. The method of claim 12 , wherein R 14 and R 16 are each independently selected from —H and —OR 17 and R 15 is selected from —H, —OR 17 , ═O, and ═CH 2 .
24. The method of claim 12 , wherein:
the oxygen protecting group is selected from the group consisting of allyl, acetyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, —C(O)O—CH 2 —CH═CH 2 , tert-butyl-diphenylsilyl, tert-butyl-dimethylsilyl, trimethylsilyl, tri-iso-propylsilyl, tert-butyldimethylsilyloxymethyl, β-methoxyethoxymethyl, [bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, methyl, ethoxyethyl, triphenylmethyl, —C(O)(C 1 -C 4 ) alkyl, —C(O)OR 18 , and —(C 1 -C 6 ) alkyl, each said alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups;
each R 18 is independently selected from —(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkenyl, and —(C 2 -C 6 ) alkynyl, each said alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups; and
each R 21 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.
25. The method of claim 1 , wherein:
R 4 is selected from hydrogen and unsubstituted —(C 1 -C 6 ) alkyl;
R 5 is selected from hydrogen and —CH 3 ; and
R 7 is hydrogen.
26. The method of claim 7 , wherein:
R 4 is selected from hydrogen and unsubstituted —(C 1 -C 6 ) alkyl; and
R 5 is selected from hydrogen and unsubstituted —(C 1 -C 6 ) alkyl.
27. The method of claim 7 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , and combinations of two or more thereof.
28. The method of claim 7 , wherein the solvent is selected from the group consisting of CHCl 3 , CH 2 Cl 2 , 1,2-dichloroethane, toluene, tetrahydrofuran, ethyl acetate, acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene, N,N-dimethylformamide, trifluorotoluene, 1,4-dioxane, 1,2-dimethoxyethane, xylene, and combinations of two or more thereof.
29. The method of claim 7 , wherein the base is selected from the group consisting of Na 2 CO 3 , NaHCO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , and combinations of two or more thereof.
30. The method of claim 7 , wherein for the compound of Formula (45), R 15 is ═O and R 16 is —OH.
31. The method of claim 30 , wherein for the compound of Formula (45), R 14 is —OH.
32. The method of claim 30 , wherein for the compound of Formula (45), R 14 is —OCH 3 .
33. The method of claim 8 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , and combinations of two or more thereof.
34. The method of claim 8 , wherein the solvent is selected from the group consisting of CHCl 3 , CH 2 Cl 2 , 1,2-dichloroethane, toluene, tetrahydrofuran, ethyl acetate, acetone, tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol, acetonitrile, benzene, carbon tetrachloride, chlorobenzene, 1,2-dichlorobenzene, N,N-dimethylformamide, trifluorotoluene, 1,4-dioxane, 1,2-dimethoxyethane, xylene, and combinations of two or more thereof.
35. The method of claim 8 , wherein the base is selected from the group consisting of Na 2 CO 3 , NaHCO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , and combinations of two or more thereof.
36. The method of claim 8 , wherein for the compound of Formula (45), R 15 is ═O and R 16 is —OH.
37. The method of claim 36 , wherein for the compound of Formula (45), R 14 is —OH.
38. The method of claim 36 , wherein for the compound of Formula (45), R 14 is —OCH 3 .
39. The method of claim 1 , wherein:
R 4 is selected from hydrogen and unsubstituted —(C 1 -C 6 ) alkyl;
R 5 is selected from hydrogen and unsubstituted —(C 1 -C 6 ) alkyl; and
R 7 is hydrogen.
40. The method of claim 17 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , and combinations of two or more thereof.
41. The method of claim 17 , wherein the base is selected from the group consisting of Na 2 CO 3 , NaHCO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , and combinations of two or more thereof.
42. The method of claim 40 , wherein the solvent is tert-amyl alcohol.
43. The method of claim 41 , wherein the solvent is selected from the group consisting of tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol, and combinations of two or more thereof.
44. The method of claim 18 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , and combinations of two or more thereof.
45. The method of claim 18 , wherein the base is selected from the group consisting of Na 2 CO 3 , NaHCO 3 , KHCO 3 , K 2 CO 3 , Cs 2 CO 3 , and combinations of two or more thereof.
46. The method of claim 44 , wherein the solvent is tert-amyl alcohol.
47. The method of claim 45 , wherein the solvent is selected from the group consisting of tert-amyl alcohol, tert-butyl alcohol, 3-methyl-3-pentanol, 2,3-dimethyl-3-pentanol, 3-ethyl pentanol, 2-methyl-2-hexanol, and combinations of two or more thereof.
48. The method of claim 7 , wherein:
the oxygen protecting group is selected from the group consisting of allyl, acetyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, —C(O)O—CH 2 —CH═CH 2 , tert-butyl-diphenylsilyl, tert-butyl-dimethylsilyl, trimethylsilyl, tri-iso-propylsilyl, tert-butyldimethylsilyloxymethyl, β-methoxyethoxymethyl, [bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, methyl, ethoxyethyl, triphenylmethyl, —C(O)(C 1 -C 4 ) alkyl, —C(O)OR 18 , and —(C 1 -C 6 ) alkyl, each said alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups;
each R 18 is independently selected from —(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkenyl, and —(C 2 -C 6 ) alkynyl, each said alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups; and
each R 21 is independently selected from —Cl, —Br, —I, —NH 2 , —CN, and phenyl.
49. The method of claim 8 , wherein:
the oxygen protecting group is selected from the group consisting of allyl, acetyl, benzoyl, benzyl, β-methoxyethoxymethyl, dimethoxytrityl, methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, tetrahydropyranyl, trityl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldimethylsilyloxymethyl, tri-iso-propylsilyl, methyl, ethoxyethyl, —C(O)O—CH 2 —CH═CH 2 , tert-butyl-diphenylsilyl, tert-butyl-dimethylsilyl, trimethylsilyl, tri-iso-propylsilyl, tert-butyldimethylsilyloxymethyl, β-methoxyethoxymethyl, [bis-(4-methoxyphenyl)phenylmethyl)], methoxymethyl, para-methoxybenzyl, methylthiomethyl, pivaloyl, methyl, ethoxyethyl, triphenylmethyl, —C(O)(C 1 -C 4 ) alkyl, —C(O)OR 18 , and —(C 1 -C 6 ) alkyl, each said alkyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups;
each R 18 is independently selected from —(C 1 -C 6 ) alkyl, —(C 2 -C 6 ) alkenyl, and —(C 2 -C 6 ) alkynyl, each said alkyl, alkenyl, and alkynyl being unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 21 groups; and
each R 21 is independently selected from —CI, —Br, —I, —NH 2 , —CN, and phenyl.
50. A method for making a compound Formula (200):
comprising:
(a) contacting a compound of Formula (45):
with a compound of Formula (93):
in the presence of a base and a solvent to provide a compound of Formula (201):
and
(b) contacting the compound of Formula (201) with a transition metal catalyst to provide the compound of Formula (200);
wherein:
the transition metal in the transition metal catalyst consists essentially of Pd[0], Pd[II], Ni[0], Ni[II], or Ru[II];
R 4 is selected from the group consisting of —H, —(C 1 -C 6 ) alkyl, phenyl,
R 5 is selected from —H and —(C 1 -C 6 ) alkyl, wherein said alkyl is unsubstituted or substituted with 1, 2, 3, 4, or 5 independently-selected R 8 groups;
R 6 and R 7 are each hydrogen or R 6 is hydrogen and R 7 is unsubstituted —(C 1 -C 6 ) alkyl;
each R 8 is independently selected from —OR 51 , —F, —Cl, —Br, —I, phenyl, and —(C 1 -C 6 ) alkyl;
R 14 and R 16 are each independently selected from —OH, —H, and —OR 17 ;
R 15 is selected from —OH, —H, —OR 17 , ═O, and ═CH 2 ;
R 17 is an oxygen protecting group;
X is selected from —Cl, —Br, and —I; and
each R 51 is independently selected from —(C 1 -C 6 ) alkyl and an oxygen protecting group.
51. The method of claim 50 , wherein the transition metal in the transition metal catalyst consists essentially of Pd[0], Pd[II], Ni[0], or Ni[II].
52. The method of claim 50 , wherein the transition metal in the transition metal catalyst consists essentially of Pd[0] or Pd[II].
53. The method of claim 52 , wherein the transition metal catalyst is selected from the group consisting of Pd(PPh 3 ) 4 , Pd(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , [Pd(DBA) 2 ]/PPh 3 , [Pd(OAc) 2 ]/PPh 3 , and combinations of two or more thereof.
54. The method of claim 50 , wherein the transition metal in the transition metal catalyst consists essentially of Ni[0] or Ni[II].
55. The method of claim 54 , wherein the transition metal catalyst is selected from the group consisting of Ni(PPh 3 ) 4 , Ni(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 , [Ni(COD) 2 ]/PPh 3 , NiCl 2 /PPh 3 , Ni[P(OEt) 3 ] 4 , and combinations of two or more thereof.
56. The method of claim 1 , wherein R 7 is selected from the group consisting of —H and —CH 3 .
57. The method of claim 56 , wherein R 5 is selected from the group consisting of —H and —CH 3 .
58. The method of claim 57 , wherein R 4 is selected from the group consisting of —H, —CH 3 , and phenyl, wherein said phenyl is unsubstituted.
59. The method of claim 50 , wherein R 7 is selected from the group consisting of —H and —CH 3 .
60. The method of claim 59 , wherein R 5 is selected from the group consisting of —H and —CH 3 .
61. The method of claim 60 , wherein R 4 is selected from the group consisting of —H, —CH 3 , and phenyl, wherein said phenyl is unsubstituted.