Organic compounds -- part of the class 532-570 series – Organic compounds – Oxygen containing
Reexamination Certificate
2000-06-26
2001-09-18
Barts, Samuel (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Oxygen containing
C568S643000, C585S425000, C585S427000
Reexamination Certificate
active
06291722
ABSTRACT:
FIELD OF INVENTION
The invention relates to the use of phosphine oxide compounds complexed with transition metals to produce biaryls and arylamines via cross-coupling reactions with aryl halides and arylboronic acids, aryl Grignard reagents, or amines.
BACKGROUND
Chelating phosphine compounds when bound to metal atoms are generally known to be useful as catalysts. One reaction which uses palladium phosphine catalysts is the coupling of aryl halides with amines for the production of arylamines, as reviewed by Hartwig, SYNLETT, 1997, (4), pg. 329-340. An example of this reaction is the coupling of chlorobenzene and piperidine to form N-phenylpiperidine:
Another reaction in which palladium/phosphine catalysts have been used is the Suzuki reaction, where biaryls are produced through the coupling of arylboronic acids and aryl halides, as reviewed by Suzuki, A, J. Orgmet. Chem., 576 (1999), pg. 147. One example of this reaction is the preparation of biphenyl from phenylboronic acid and chlorobenzene:
Both of these products are important classes of compounds widely used in the manufacture of pharmaceuticals, advanced materials, liquid polymers and ligands, and much work has been done on their preparation. However, there is an expanding need for stable, easily prepared catalysts that result in good yields and mild reaction conditions.
Preparation of new ligands has traditionally been performed one at a time after tedious synthesis and purification protocols. Combinatorial techniques have greatly accelerated the discovery of new ligands, but new synthetic schemes are needed. One valuable technique uses solid-phase supports. This solid-phase protocol allows reactions on a polymer-bound scaffold to be driven to completion by using large excesses of reagents in solution that can be easily filtered away from the polymer support. After the scaffold has been modified, an additional cleavage step then frees the small molecule from the polymer support into solution for isolation.
Phosphine oxide compounds and libraries have been prepared using polymer scaffolds in U.S. application Ser. No. 09/415,347 (U.S. Ser. No. 99/23509) which is incorporated in its entirety by reference. Lacking is a process for the convenient preparation of stable arylamines of the formula R
1
—NR
2
R
3
or biaryls of the formula R
1
-R
6
using a stable phosphine catalyst under mild conditions and producing good yields.
SUMMARY OF THE INVENTION
This invention is directed to the use of phosphine oxide compounds complexed with transition metals to produce biaryls and arylamines via cross-coupling reactions with aryl halides and arylboronic acids or amines.
More specifically, the invention is directed to a process to prepare arylamines of the formula R
1
—NR
2
R
3
comprising contacting an amine of the formula HNR
2
R
3
with an aryl compound of the formula R
1
—X in the presence of a catalytic amount of a coordination compound comprising one or more transition metals complexed to a phosphine oxide ligand of the formula HP(O)R
4
R
5
; wherein X is a halogen; R
1
is an optionally substituted aryl; R
2
and R
3
are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R
2
and R
3
can together form a ring; and R
4
and R
5
are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQ
1
, OQ
2
, PQ
3
Q
4
, and NQ
5
Q
6
, where Q
1
, Q
2
, Q
3
, Q
4
, Q
5
, and Q
6
are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R
4
and R
5
can together form a ring.
Preferably, R
1
is an optionally substituted phenyl, and the transition metal is selected from Periodic Group VIII. More preferably, R
4
and R
5
are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, the transition metal is Pd, and R
2
and R
3
are selected from the group consisting of hydrogen, optionally substituted aryl, and wherein R
2
and R
3
are hydrocarbyl and together form a ring. Most preferably X is Cl, R
1
is selected from the group consisting of phenyl, 4-methylphenyl, 4-methoxyphenyl, and 4-trifluoromethylphenyl; R
2
and R
3
are selected from the group consisting of hydrogen, phenyl, 4-methylphenyl, and together form a piperidyl ring; and R
4
and R
5
are selected from the group consisting of t-butyl, phenyl, i-propyl, and 2,4-methoxyphenyl.
The invention is further directed to a process to prepare biaryls of the formula R
1
-R
6
comprising contacting a boronic acid of the formula R
6
—B(OH)
2
with an aryl compound of the formula R
1
—X in the presence of a catalytic amount of a coordination compound comprising one or more transition metals complexed to a phosphine oxide ligand of the formula HP(O)R
4
R
5
wherein X is a halogen; R
1
is an optionally substituted aryl; R
6
is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic; and R
4
and R
5
are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQ
1
, OQ
2
, PQ
3
Q
4
, and NQ
5
Q
6
, where Q
1
, Q
2
, Q
3
, Q
4
, Q
5
, and Q
6
are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R
4
and R
5
can together form a ring.
Preferably R
1
is an optionally substituted phenyl, and the transition metal is selected from Periodic Group VIII. More preferably R
4
and R
5
are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, the transition metal is Pd, and R
6
is an optionally substituted aryl. Most preferably X is Cl, R
1
is selected from the group consisting of of phenyl, 4-methoxyphenyl, 2-methoxyphenyl and 4-methylphenyl; R
6
is selected from the group consisting of 4-methoxyphenyl, and phenyl; and R
4
and R
5
are selected from the group consisting of t-butyl, phenyl, i-propyl, and 2,4-methoxyphenyl.
The invention is further directed to a process to prepare biaryls of the formula R
1
-R
7
comprising contacting a Grignard reagent of the formula R
7
—MgX with an aryl compound of the formula R
1
—X in the presence of a catalytic amount of a coordination compound comprising one or more transition metals complexed to a phosphine oxide compound of the formula HP(O)R
4
R
5
, wherein X is a halogen; R
1
is an optionally substituted aryl; R
7
is selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic; and R
4
and R
5
are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl, heterocyclic, organometallic, Cl, Br, I, SQ
1
, OQ
2
, PQ
3
Q
4
, and NQ
5
Q
6
, where Q
1
, Q
2
, Q
3
, Q
4
, Q
5
, and Q
6
are independently selected from the group consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbylamino, alkoxy, aryloxy, and heterocyclic, and optionally R
4
and R
5
can together form a ring.
Preferably R
1
is an optionally substituted phenyl, and the transition metal is selected from Periodic Group VIII. More preferably R
4
and R
5
are independently selected from the group consisting of hydrocarbyl, substituted hydrocarbyl and heterocyclic, the transition metal is Ni, and R
7
is an optionally substituted aryl. Most preferably X is Cl, R
1
is selected from the group consisting of 4-chloroanisole and chlorobenzene; R
7
is o-tolyl; and R
4
and R
5
are t-butyl.
Further, the invention includes the method of using phosphine oxides as ligands for homogeneous catalysis of arylamines of the formula R
1
—NR
2
R
3
or biaryls of the formula R
1
-R
6
or biaryls of the formula R
1
-R
7
comprising (1) preparing a coordination compound comprising one or more transition metals complexed to a ph
Barts Samuel
Belopolsky Inna Y.
E. I. Du Pont de Nemours and Company
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