Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-07-16
2003-08-05
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S134000, C548S136000, C548S202000, C548S235000, C548S560000, C548S559000, C548S438000
Reexamination Certificate
active
06603013
ABSTRACT:
BACKGROUND OF THE INVENTION
The Suzuki cross-coupling of organic electrophiles with boronic acid and boronates esters constitutes the most direct and efficient approach for the formation of carbon—carbon bonds. Generally C(sp
3
), C(sp
2
) and C(sp) boronic acids and boronate esters have been successfully employed as nucleophiles. While C(sp
2
) and C(sp) have been successfully used as the electrophilic partner, only few cases of C(sp
3
) electrophiles have been demonstrated. Homogeneous Pd catalysts such as Pd(dppf)
2
or Pd(PPh
3
)
4
are typically used for these Suzuki cross-couplings See N. Miyaura, et al.,
Chem. Rev.
1995, 95, 2457-2483; P. L. Castle et al.,
Tetrahedron Lett.
1986, 27, 6013; T. Ishiyama et al.,
Chem. Lett.
1992, 691; A. B. Charette et al.,
Tetrahedron Lett.
1997, 38, 2809-2812; N. Miyaura et al.,
J. Am. Chem. Soc.
1989, 111, 314; T. Ishiyama et al.,
Synlett
1991, 687.
This invention relates to a process wherein heterogeneous, finely dispersed Pd catalysts are used to activate alkenyl halides for cross coupling with boronic acids. The process provides for use with either electron-withdrawing or electron-donating substituents for cross coupling with boronic acids. Unlike homogeneous catalysis, the heterogeneously catalyzed Suzuki cross-coupling process provides several advantages, such as ease of product separation and recycling of the catalysts, which provide an overall simplified and cost-effective process. It also eliminate the side reactions that may occur between aryl groups of aryl phosphines (ligand) and the boronic acid. See M. G. Villeger, et al.,
Tetrahedron Lett.
1994, 35, 3277-3280; Gala, D., et al
Org. Proc. Res. Dev.
1997, 1, 163-164; V. V. Bykov, et al,
Russian Chemical Bulletin
1997, 46, 1344 and David S. Ennis, et al,
Org. Proc. Res. Dev.
1999, 3, 248.
SUMMARY OF THE INVENTION
The present invention is directed to a process for a carbon—carbon coupling reaction by using palladium heterogeneous catalysis to activate alkenyl halides for cross coupling with boronic acid to prepare a compound of formula I,
comprising reacting a boronic acid of formula II,
with an alkenyl halide of formula III,
wherein X, Y and Z are independently hydrogen, CF
3
, C
1-6
alkoxy, NO
2
, CN, halo, C
1-6
alkyl, NH
2
, COOH, COO(C
1-6
alkyl), or N[(C
1-6
alkyl]
2
,acetanilide, amide, C
2-6
alkenyl, or aryl; and Q is F, Cl, Br, or I;
in the presence of a heterogeneous palladium catalyst and a base in an aprotic solvent to produce a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a process for a carbon—carbon coupling reaction by using palladium heterogeneous catalysis to activate alkenyl halides for cross coupling with boronic acid to produce the carbon—carbon coupled compound containing aryl, heteroaryl, and alkenyl moieties.
The present invention is related to a process for synthesizing a compound of formula I:
comprising reacting a boronic acid of formula II,
with an alkenyl halide of formula III:
wherein X, Y and Z are independently hydrogen, CF
3
, C
1-6
alkoxy, NO
2
, CN, halo, C
1-6
alkyl, NH
2
, COOH, COO(C
1-6
alkyl), or N[(C
1-6
alkyl]
2
, acetanilide, amide, C
2-6
alkenyl, or aryl; and Q is F, Cl, Br, or I; in the presence of a heterogeneous palladium catalyst and a base in an aprotic solvent to produce a compound of formula I.
The process as recited above, wherein the alkenyl halide is selected from the group consisting of &agr;-bromostyrene, 1-bromo-2-methylpropene, &agr;-chlorostyrene, 1-chloro-2-methylpropene, &agr;-iodostyrene, and 1-iodo-2-methylpropene.
The process as recited above, wherein and the boronic acid is selected from the group consisting of phenyl boronic acid, 2-phenylvinylboronic acid, and phenylethenylboronic acid.
The process as recited above, wherein the heterogeneous palladium catalyst is finely dispersed palladium on a solid support.
The process as recited above, wherein the solid support is selected from the group consisting of carbon (Pd/C), silica, alumina, titania, and mesopourous zeolitic materials.
The process as recited above, wherein the heterogeneous palladium catalyst is finely dispersed palladium without a solid support.
The process as recited above, wherein the finely dispersed palladium is finely dispersed palladium metal (Pd Black) or finely dispersed palladium generated from homogeneous palladium acetate.
The process as recited above, wherein the heterogeneous palladium catalyst is finely dispersed palladium (colloidal) stabilized by organic polymers.
The process as recited above, wherein the aprotic solvent selected from the group consisting of N,N-dimethylacetamide (DMA), N,N-dimethylformamide (DMF), N-methylpyrrolidinone (NMP), dioxane, ethylene glycol dimethyl ether (DME), diethoxymethane (DEM), tetrahydrofuran (THF) or a combination of one or more of the above with water is added.
The process as recited above, wherein the solvent is NMP or DMA in combination with water.
The process as recited above, wherein a ratio of solvent to water is about 30:0.5 to about 5:0.5, preferably from about 25:1 to about 5:1, and most preferably from about 20:1 to about 10:1.
The process as recited above, wherein the base is selected from the group consisting of triethylamine, trimethylamine, ethyldimethylamine, tri-n-propylamine, 1,8-diazabicyclo [5.4.0.]undec-7-ene (DBU), pyridine, lutidine, collidine, 4-dimethylaminomethyl-pyridine, sodium carbonate, sodium bicarbonate, potassium bicarbonate, potassium carbonate, potassium sodium tartrate, potassium tartrate, potassium bitartrate, sodium tartrate, and sodium bitartrate. The preferred base is pyridine, potassium sodium tartrate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, or potassium carbonate.
The present invention is described herein in detail using the terms defined below unless otherwise specified.
As used herein, the term “alkyl” refers, unless otherwise indicated, includes those alkyl groups of designated number of carbon atoms of either a straight, branched or cyclic configuration. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl and cyclohexyl and the like.
The term “alkenyl” refers to a hydrocarbon radical straight, branched or cyclic containing a specified number of carbon atoms and at least one unsaturation. Preferred alkenyl groups include ethenyl, propenyl, butenyl, cyclohexenyl and the like.
Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and the like, as well as rings which are fused, e.g., naphthyl, phenanthrenyl and the like. An aryl group thus contains at least one ring having at least 6 atoms, with up to five such rings being present, containing up to 22 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms or suitable heteroatoms. The preferred aryl groups are phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise be substituted with substituents selected from the group consisting of CF
3
, C
1-6
alkoxy, NO
2
, CN, halo, C
1-6
alkyl, NH
2
, N[(C
1-6
alkyl)]
2
, acetanilide, amide, COOH and COO(C
1-6
alkyl), and C
2-6
alkenyl. Preferred aryls are phenyl and naphthyl.
The term “heteroaryl” refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms containing at least one heteroatom selected from O, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one or two additional carbon atoms is optionally replaced by a heteroatom selected from 0 or 5, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms, the heteroaryl group being optionally substituted as recited above in aryl group. Examples of heteroaryl are pyrrole, pyridine, oxazole, and thiazole. Additional nitrogen atoms may be present together with the first nitrogen and oxygen or sulfur, giving, e.g., thiadiazole.
represents aryl or heteroaryl group as defined above, and aryl or heteroaryl may be optionally substituted with substitue
LeBlond Carl
Sowa, Jr. John R.
Sun Yongkui
Camara Valerie J.
Daniel Mark R.
McKenzie Thomas
Merck & Co. , Inc.
Parr Richard S.
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