Organic compounds -- part of the class 532-570 series – Organic compounds – Silicon containing
Reexamination Certificate
1998-07-10
2002-05-28
Higel, Floyd D. (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Silicon containing
C564S015000, C568S013000, C568S014000, C568S017000, C568S423000
Reexamination Certificate
active
06395916
ABSTRACT:
BACKGROUND OF THE INVENTION
Transition metal catalyst complexes play important roles in many areas of chemistry, including the preparation of polymers and pharmaceuticals. The properties of these catalyst complexes are recognized to be influenced by both the characteristics of the metal and those of the ligands associated with the metal atom. For example, structural features of the ligands can influence reaction rate, regioselectivity, and stereoselectivity. Bulky ligands can be expected to slow reaction rate; electron-withdrawing ligands, in coupling reactions, can be expected to slow oxidative addition to, and speed reductive elimination from, the metal center; and electron-rich ligands, in coupling reactions, conversely, can be expected to speed oxidative addition to, and slow reductive elimination from, the metal center.
In many cases, the oxidative addition step in the accepted mechanism of a coupling reaction is deemed to be rate limiting. Therefore, adjustments to the catalytic system as a whole that increase the rate of the oxidative addition step should increase overall reaction rate. Additionally, the rate of oxidative addition of a transtion metal catalyst to the carbon-halogen bond of an aryl halide is known to decrease as the halide is varied from iodide to bromide to chloride, all other factors being equal. Because of this fact, the more stable, lower molecular weight, and arguably more easy to obtain, members of the set of reactive organic halides—the chlorides—are the poorest substrates for transition metal catalyzed coupling reactions and the like.
To date, the best halogen-containing substrates for transtion metal catalyzed carbon-heteroatom and carbon-carbon bond forming reactions have been the iodides. Bromides are often acceptable substrates, but typically required higher temperatures, longer reaction times, and give lower yields of products.
Catalyst systems that possess greater substrate flexibility, e.g., the ability to utilize organic chlorides, and/or that produce the desired products efficiently and rapidly at lower temperatures, e.g. less than about 50° C. or at room temperature, are not well precedented.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to novel, electron-rich bidentate ligands for transition metals. A second aspect of the present invention relates to the use of catalysts comprising these ligands in transition metal-catalyzed carbon-heteroatom and carbon-carbon bond-forming reactions. The subject methods provide improvements in many features of the transition metal-catalyzed reactions, including the range of suitable substrates, reaction conditions, and efficiency.
Unexpected improvements over the prior art have been realized in transition metal-catalyzed: aryl amination reactions; Suzuki couplings to give both biaryl and alkylaryl products; and &agr;-arylations of ketones. The ligands and methods of the present invention enable for the first time, the efficient use of aryl chlorides, inter alia, in the aforementioned reactions. Additionally, the ligands and methods of the present invention enable for the first time a subset of these transformations, e.g., with aryl bromides, to proceed efficiently at room temperature.
DETAILED DESCRIPTION OF THE INVENTION
I. Compounds and Methods of the Invention
In one aspect of the invention, novel, electron-rich bidentate ligands for metals, preferably transition metals, are provided. In certain embodiments, the subject ligands are represented by general structure 1:
wherein
each of A and B independently represent fused rings selected from a group consisting of monocyclic or polycyclic cycloalkyls, cycloalkenyls, aryls, and heterocyclic rings, said rings comprising from 4 to 8 atoms in a ring structure;
X and Y represent, independently for each occurrence, N, P, As, O, or S; when an occurrence of X or Y represents O or S, said occurrence of X or Y bears only one R;
R, R
1
, R
2
, R
3
, and R
4
, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH
2
)
m
—R
80
;
R
5
and R
6
, for each occurrence, independently represent halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH
2
)
m
—R
80
;
A and B independently may be unsubstituted or substituted with R
5
and R
6
, respectively, any number of times up to the limitations imposed by stability and the rules of valence;
R
1
and R
2
, and/or R
3
and R
4
, taken together may represent a ring comprising a total of 5-7 atoms in the backbone of said ring; said ring may comprise one or two heteroatoms in its backbone; and said ring may bear additional substituents or be unsubstituted;
R
80
represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
m is an integer in the range 0 to 8 inclusive; and
the ligand, when chiral, may be provided in the form of a mixture of enantiomers or as a single enantiomer.
In certain embodiments, the ligands are represented by general structure 1, and the above definitions, wherein:
X and Y are not identical;
R is selected, independently for each occurrence, from the set comprising alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, and —(CH
2
)
m
—R
80
;
R
1
, R
2
, R
3
, and R
4
are selected, independently for each occurrence, from the set comprising H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, —SiR
3
, and —(CH
2
)
m
—R
80
; and
R
5
and R
6
are selected, independently for each occurrence, from the set comprising H, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, halogen, —SiR
3
, and —(CH
2
)
m
—R
80
.
In certain embodiments, the subject ligands are represented by general structure 2:
wherein
X and Y represent, independently for each occurrence, N, P, As, O, or S; when an occurrence of X or Y represents O or S, said occurrence of X or Y bears only one R;
R, R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, and R
8
, for each occurrence, independently represent hydrogen, halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH
2
)
m
—R
80
;
any pair(s) of substituents, with an ortho-relationship therebetween, selected from the group consisting of R
1
, R
2
, R
3
, R
4
, R
5
, R
6
, R
7
, and R
8
, taken together may represent a ring comprising a total of 5-7 atoms in the backbone of said ring; said ring may comprise one or two heteroatoms in its backbone; and said ring may bear additional substituents or be unsubstituted;
R
80
represents an unsubstituted or substituted aryl, a cycloalkyl, a cycloalkenyl, a heterocycle, or a polycycle;
m is an integer in the range 0 to 8 inclusive; and
the ligand, when chiral, may be provided in the form of a mixture of
Buchwald Stephen L.
Kamikawa Ken
Old David W.
Palucki Michael
Wolfe John P.
Foley Hoag & Eliot LLP
Gordon Dana M.
Higel Floyd D.
Massachusetts Institute of Technology
Sackey Ebenezer
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