U.S. patent application number 10/114418 was filed with the patent office on 2003-05-29 for cross-metathesis reaction of functionalized and substituted olefins using group 8 transition metal carbene complexes as metathesis catalysts.
Invention is credited to Chatterjee, Arnab K., Choi, Tae-Lim, Goldberg, Steven D., Grubbs, Robert H., Love, Jennifer A., Morgan, John P., Sanders, Daniel P., Scholl, Matthias, Toste, F. Dean, Trnka, Tina M..
Application Number | 20030100776 10/114418 |
Document ID | / |
Family ID | 27540649 |
Filed Date | 2003-05-29 |
United States Patent
Application |
20030100776 |
Kind Code |
A1 |
Grubbs, Robert H. ; et
al. |
May 29, 2003 |
Cross-metathesis reaction of functionalized and substituted olefins
using group 8 transition metal carbene complexes as metathesis
catalysts
Abstract
The invention pertains to the use of Group 8 transition metal
carbene complexes as catalysts for olefin cross-metathesis
reactions. In particular, ruthenium and osmium alkylidene complexes
substituted with an N-heterocyclic carbene ligand are used to
catalyze cross-metathesis reactions to provide a variety of
substituted and functionalized olefins, including
phosphonate-substituted olefins, directly halogenated olefins,
1,1,2-trisubstituted olefins, and quaternary allylic olefins. The
invention further provides a method for creating functional
diversity using the aforementioned complexes to catalyze
cross-metathesis reactions of a first olefinic reactant, which may
or may not be substituted with a functional group, with each of a
plurality of different olefinic reactants, which may or may not be
substituted with functional groups, to give a plurality of
structurally distinct olefinic products. The methodology of the
invention is also useful in facilitating the stereoselective
synthesis of 1,2-disubstituted olefins in the cis
configuration.
Inventors: |
Grubbs, Robert H.; (South
Pasadena, CA) ; Chatterjee, Arnab K.; (Pasadena,
CA) ; Choi, Tae-Lim; (Pasadena, CA) ;
Goldberg, Steven D.; (Pasadena, CA) ; Love, Jennifer
A.; (Pasadena, CA) ; Morgan, John P.;
(Pasadena, CA) ; Sanders, Daniel P.; (Pasadena,
CA) ; Scholl, Matthias; (Cambridge, MA) ;
Toste, F. Dean; (Pasadena, CA) ; Trnka, Tina M.;
(Pasadena, CA) |
Correspondence
Address: |
REED & ASSOCIATES
800 MENLO AVENUE
SUITE 210
MENLO PARK
CA
94025
US
|
Family ID: |
27540649 |
Appl. No.: |
10/114418 |
Filed: |
April 1, 2002 |
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Current U.S.
Class: |
549/513 ;
556/465; 556/87; 558/207; 558/357; 564/463; 568/1; 568/28 |
Current CPC
Class: |
C07C 45/69 20130101;
C07D 317/24 20130101; C07C 321/14 20130101; C07C 47/21 20130101;
C07C 205/06 20130101; C07C 69/18 20130101; C07C 69/16 20130101;
C07C 69/145 20130101; C07C 69/007 20130101; C07C 69/145 20130101;
C07C 69/78 20130101; C07C 69/732 20130101; C07C 69/533 20130101;
C07C 69/78 20130101; C07C 69/56 20130101; C07C 69/157 20130101;
C07C 33/483 20130101; C07C 25/13 20130101; C07C 67/343 20130101;
C07C 67/343 20130101; C07C 67/475 20130101; C07C 67/293 20130101;
C07F 15/0046 20130101; C07C 29/40 20130101; C07C 201/12 20130101;
C07C 2531/22 20130101; C07C 67/475 20130101; C07C 2603/74 20170501;
C07C 319/20 20130101; C07D 263/14 20130101; C07D 317/20 20130101;
C07C 67/343 20130101; C07C 17/275 20130101; C07C 67/297 20130101;
C07C 2601/16 20170501; C07C 67/343 20130101; C07F 9/40 20130101;
C07F 7/1892 20130101; C07C 67/293 20130101; C07C 67/293 20130101;
C07F 9/4015 20130101; C07C 67/475 20130101; C07C 201/12 20130101;
C07C 6/04 20130101; C07C 17/275 20130101; C07C 319/20 20130101;
C07D 317/12 20130101; C07C 41/14 20130101; C07C 67/475 20130101;
C07C 2601/14 20170501; C07C 67/343 20130101; C07C 29/40 20130101;
C07C 29/46 20130101; C07C 45/69 20130101; C07C 67/293 20130101;
C07C 67/293 20130101 |
Class at
Publication: |
549/513 ; 556/87;
556/465; 558/207; 558/357; 568/1; 568/28; 564/463 |
International
Class: |
C07F 007/30; C07F
007/22; C07F 005/02; C07F 009/02 |
Goverment Interests
[0002] This invention was developed with U.S. Government support
under grant numbers 2 R01 GM31332 and 3 RO1 GM31332-16 awarded by
the National Institutes of Health, and under grant number CHE
9809856 awarded by the National Science Foundation. The Government
has certain rights in the invention.
Claims
We claim:
1. A method for synthesizing a functionalized olefin via a
cross-metathesis reaction, comprising contacting (a) a first
olefinic reactant directly or indirectly substituted with a
functional group Fn selected from phosphonato, phosphoryl,
phosphanyl, phosphino, sulfonato, C.sub.1-C.sub.20 alkylsulfanyl,
C.sub.5-C.sub.20arylsulfanyl, C.sub.1-C.sub.20 alkylsulfonyl,
C.sub.5-C.sub.20 arylsulfonyl, C.sub.1-C.sub.20 alkylsulfinyl,
C.sub.5-C.sub.20 arylsulfinyl, sulfonamido, amino, amido, imino,
nitro, nitroso, hydroxyl, C.sub.1-C.sub.20 alkoxy, C.sub.5-C.sub.20
aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.5-C.sub.20
aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl,
C.sub.1-C.sub.20 thioester, cyano, cyanato, carbamoyl, epoxy,
styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato, boryl,
stannyl, and germyl, with (b) a second olefinic reactant in the
presence of (c) a catalyst composed of a Group 8 transition metal
alkylidene complex under conditions and for a time period effective
to allow cross-metathesis to occur, wherein the catalyst has the
structure of formula (VIA) 178in which: M is a Group 8 transition
metal; X.sup.1 and X.sup.2 may be the same or different, and are
anionic ligands or polymers; R.sup.1 is selected from the group
consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, substituted
heteroatom-containing hydrocarbyl, and carboxyl; R.sup.2 is
selected from the group consisting of hydrogen, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and
substituted heteroatom-containing hydrocarbyl; L is a neutral
electron donor ligand; X and Y are heteroatoms selected from N, O,
S, and P; p is zero when X is O or S, and is 1 when X is N or P; q
is zero when Y is O or S, and is 1 when Y is N or P; Q.sup.1,
Q.sup.2, Q.sup.3, and Q.sup.4 are selected from hydrocarbylene,
substituted hydrocarbylene, heteroatom-containing hydrocarbylene,
substituted heteroatom-containing hydrocarbylene, and --(CO)--; w,
x, y and z are independently zero or 1; and R.sup.3, R.sup.3A,
R.sup.4, and R.sup.4A are independently selected from the group
consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, and substituted
heteroatom-containing hydrocarbyl, wherein any two or more of
X.sup.1, X.sup.2, L, R.sup.1, R.sup.2, R.sup.3, R.sup.3A, R.sup.4,
and R.sup.4A can be taken together to form a chelating multidentate
ligand.
2. The method of claim 1, wherein the first olefinic reactant is
directly substituted with the functional group.
3. The method of claim 1, wherein the first olefinic reactant is
indirectly substituted with the functional group.
4. The method of claim 1, wherein the second olefinic reactant is
also substituted with a functional group Fn.
5. The method of claim 1, wherein: X.sup.1 and X.sup.2 are anionic
ligands, and are optionally linked to form a cyclic group; L is a
neutral electron donor ligand that is optionally linked to R.sup.2,
X.sup.1, and/or X.sup.2 through a spacer moiety; and R.sup.3A and
R.sup.4A are optionally linked to form a cyclic group.
6. The method of claim 5, wherein w, x, y and z are zero, X and Y
are N, and R.sup.3A and R.sup.4A are linked to form -Q-, such that
the catalyst has the structure of formula (VIB) 179wherein Q is a
hydrocarbylene, substituted hydrocarbylene, heteroatom-containing
hydrocarbylene, or substituted heteroatom-containing hydrocarbylene
linker, and further wherein two or more substituents on adjacent
atoms within Q may be linked to form an additional cyclic
group.
7. The method of claim 6, wherein Q has the structure
--CR.sup.22R.sup.22A--CR.sup.23R.sup.23A-- or
--CR.sup.22.dbd.CR.sup.23--- , wherein R.sup.22 R.sup.22A,
R.sup.23, and R.sup.23A are independently selected from the group
consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, substituted
heteroatom-containing hydrocarbyl, and functional groups, and or
wherein any two of R.sup.22, R.sup.22A, R.sup.23, and R.sup.23A may
be linked together to form a substituted or unsubstituted,
saturated or unsaturated ring.
8. The method of claim 7, wherein Q has the structure
--CR.sup.22R.sup.22A--CR.sup.23R.sup.23A--, such that the catalyst
has the structure of formula (VIC) 180
9. The method of claim 8, wherein: M is Ru; X.sup.1 and X.sup.2 are
independently selected from the group consisting of hydrogen,
halide, C.sub.1-C.sub.20 alkyl, C.sub.5-C.sub.20 aryl,
C.sub.1-C.sub.20 alkoxy, C.sub.5-C.sub.20 aryloxy, C.sub.3-C.sub.20
alkyldiketonate, C.sub.5aryldiketonate, C.sub.2-C.sub.20
alkoxycarbonyl, C.sub.1-C.sub.20 aryloxycarbonyl, C.sub.2-C.sub.20
acyl, C.sub.1-C.sub.20 alkylsulfonato, C.sub.5-C.sub.20
arylsulfonato, C.sub.1-C.sub.20 alkylsulfanyl, C.sub.5-C.sub.20
arylsulfanyl, C.sub.1-C.sub.20 alkylsulfinyl, or C.sub.5-C.sub.20
arylsulfinyl, any of which, with the exception of halide, are
optionally further substituted with one or more groups selected
from halide, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, and
phenyl; R.sup.1 is hydrogen and R.sup.2 is selected from the group
consisting of C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, and
aryl; L is a neutral electron donor ligand selected from the group
consisting of phosphine, sulfonated phosphine, phosphite,
phosphinite, phosphonite, arsine, stibine, ether, amine, amide,
imine, sulfoxide, carboxyl, nitrosyl, pyridine, substituted
pyridine, imidazole, substituted imidazole, pyrazine, and
thioether; R.sup.3 and R.sup.4 are aromatic, substituted aromatic,
heteroaromatic, substituted heteroaromatic, alicyclic, substituted
alicyclic, heteroatom-containing alicyclic, or substituted
heteroatom-containing alicyclic, composed of from one to about five
rings; and R.sup.8 and R.sup.9, are hydrogen, and R.sup.3A and
R.sup.9A are selected from hydrogen, lower alkyl and phenyl, or are
linked to form a cyclic group.
10. The method of claim 9, wherein: R.sup.1 is hydrogen, and
R.sup.2 is phenyl, vinyl, methyl, isopropyl, or t-butyl, optionally
substituted with one or more moieties selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl, and a functional group Fn, wherein Fn is phosphonato,
phosphoryl, phosphanyl, phosphino, sulfonato, C.sub.1-C.sub.20
alkylsulfanyl, C.sub.5-C.sub.20arylsulfanyl, C.sub.1-C.sub.20
alkylsulfonyl, C.sub.5-C.sub.20 arylsulfonyl, C.sub.1-C.sub.20
alkylsulfinyl, C.sub.5-C.sub.20 arylsulfinyl, sulfonamido, amino,
amido, imino, nitro, nitroso, hydroxyl, C.sub.1-C.sub.20 alkoxy,
C.sub.5-C.sub.20aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl,
C.sub.1-C.sub.20 aryloxycarbonyl, carboxyl, carboxylato, mercapto,
formyl, C.sub.1-C.sub.20 thioester, cyano, cyanato, carbamoyl,
epoxy, styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato,
boryl, halogen, stannyl, or germyl; and L is a phosphine of the
formula L is a phosphine of the formula PR.sup.27R.sup.28R.sup.29,
where R.sup.27, R.sup.28, and R.sup.29 are each independently aryl
or C.sub.1-C.sub.10 alkyl.
11. The method of claim 10, wherein: Xh.sup.1 and X.sup.2 are
independently selected from the group consisting of halide,
CF.sub.3CO.sub.2, CH.sub.3CO.sub.2, CFH.sub.2CO.sub.2,
(CH.sub.3).sub.3CO, (CF.sub.3).sub.2(CH.sub.3)CO,
(CF.sub.3)(CH.sub.3),.s- ub.2CO, PhO, MeO, EtO, Tosylate, mesylate,
and trifluoromethanesulfonate; L is selected from the group
consisting of --P(cyclohexyl).sub.3, --P(cyclopentyl).sub.3,
--P(isopropyl).sub.3, --P(phenyl).sub.3, P(phenyl).sub.3,
--P(phenyl).sub.2(R.sup.7) and --P(phenyl)(R.sup.7).sub.- 2, in
which R.sup.7 is lower alkyl; and R.sup.3 and R.sup.4 are the same
and are either aromatic or C.sub.7-C.sub.12 alicyclic, if aromatic,
each having the structure of formula (XI) 181 in which R.sup.24,
R.sup.25, and R.sup.26 are each independently hydrogen, C.sub.1-Cl
alkyl, C.sub.1-C.sub.10 alkoxy, aryl, substituted aryl, halogen, or
a functional group.
12. The method of claim 11, wherein: X.sup.1 and X.sup.2 are
halide; R.sup.2 is hydrogen or 2,2-dimethylvinyl; R.sup.3 and
R.sup.4 are mesityl, diisopinocamphenyl, or
2,4,2',6'-tetramethylbiphenylyl; L is selected from the group
consisting of --P(cyclohexyl).sub.3 and --P(cyclopentyl).sub.3; and
R.sup.22 and R.sup.23 are hydrogen.
13. The method of claim 1, wherein the first olefinic reactant has
the structure of formula (VIII) 182wherein: n is zero or 1; Z is a
hydrocarbylene or a substituted and/or heteroatom-containing
hydrocarbylene linking group; and R.sup.5, R.sup.6 and R.sup.7 are
independently selected from the group consisting of hydrogen,
hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and
-(Z).sub.n-Fn.
14. The method of claim 13, wherein n is zero.
15. The method of claim 14, wherein Fn is a phosphonate.
16. The method of claim 15, wherein R.sup.5, R.sup.6 and R.sup.7
are hydrogen, such that the first olefinic reactant is a
vinylphosphonate having the structure of formula (XII) 183wherein
R.sup.27 and R.sup.28 are lower alkyl.
17. The method of claim 14, wherein n is 1.
18. The method of claim 17, wherein Fn is a phosphonate, a hydroxyl
group, or boronate.
19. The method of claim 18, wherein Z is methylene, and R.sup.5,
R.sup.6 and R.sup.7 are hydrogen.
20. The method of claim 13, wherein the second olefinic reactant
has the molecular structure
R.sup.18R.sup.19C.dbd.CR.sup.20R.sup.21wherein R.sup.18, R.sup.19,
R.sup.20, and R.sup.21are independently selected group consisting
of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, substituted
heteroatom-containing hydrocarbyl, and functional groups Fn.
21. A method for synthesizing a plurality of structurally diverse
functionalized olefins from a common olefinic reactant via a
cross-metathesis reaction, comprising: (a) contacting an olefinic
substrate with a first olefinic reactant in the presence of a
catalyst composed of a Group 8 transition metal alkylidene complex
containing an N-heterocyclic carbene ligand, under conditions and
for a time period effective to allow cross-metathesis to occur,
wherein the olefinic substrate is substituted with at least one
-(Z).sub.n-Fn moiety in which n is zero or 1, Z is a hydrocarbylene
or a substituted and/or heteroatom-containing hydrocarbylene
linking group, and Fn is selected from phosphonato, phosphoryl,
phosphanyl, phosphino, sulfonato, C.sub.1-C.sub.20 alkylsulfanyl,
C.sub.1-C.sub.20 arylsulfanyl, C.sub.1-C.sub.20 alkylsulfonyl,
C.sub.5-C.sub.20 arylsulfonyl, C.sub.1-C.sub.20 alkylsulfinyl,
C.sub.5-C.sub.20 arylsulfinyl, sulfonamido, amino, amido, imino,
nitro, nitroso, hydroxyl, C.sub.1-C.sub.20 alkoxy, C.sub.5-C.sub.20
aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.1-C.sub.20
aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl,
C.sub.1-C.sub.20 thioester, cyano, cyanato, carbamoyl, epoxy,
styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato, boryl,
stannyl, and germyl; (b) in a separate reaction, contacting the
first olefinic reactant with a second olefinic reactant having a
molecular structure that is different from that of the first
olefinic reactant, in the presence of the Group 8 transition metal
alkylidene complex, under conditions and for a time period
effective to allow cross-metathesis to occur; and (c) optionally
repeating step (b) with a plurality of olefinic reactants each
having a different molecular structure.
22. The method of claim 21, wherein the second olefinic reactant is
also substituted with at least one -(Z).sub.n-Fn moiety.
23. A method for synthesizing a directly halogenated olefin via an
olefin metathesis reaction, comprising: contacting a directly
halogenated olefinic reactant with a second olefinic species in the
presence of a catalyst composed of a Group 8 transition metal
alkylidene complex, under conditions and for a time period
effective to allow metathesis to occur.
24. The method of claim 23, wherein the olefin cross metathesis
reaction is a cross metathesis reaction.
25. The method of claim 24, wherein the catalyst has the structure
of formula (VIA) 184wherein: M is a Group 8 transition metal;
X.sup.1 and X.sup.2 may be the same or different, and are anionic
ligands or polymers; R.sup.1 is selected from the group consisting
of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, substituted
heteroatom-containing hydrocarbyl, and carboxyl; R.sup.2 is
selected from the group consisting of hydrogen, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and
substituted heteroatom-containing hydrocarbyl; L is a neutral
electron donor ligand; X and Y are heteroatoms selected from N, O,
S, and P; p is zero when X is O or S, and is 1 when X is N or P; q
is zero when Y is O or S, and is 1 when Y is N or P; Q.sup.1,
Q.sup.2, Q.sup.3, and Q.sup.4 are selected from hydrocarbylene,
substituted hydrocarbylene, heteroatom-containing hydrocarbylene,
substituted heteroatom-containing hydrocarbylene, and --(CO)--; w,
x, y and z are independently zero or 1; and R.sup.3, R.sup.3A,
R.sup.4, and R.sup.4A are independently selected from the group
consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, and substituted
heteroatom-containing hydrocarbyl, wherein any two or more of
X.sup.1, X.sup.2, L, R.sup.1, R.sup.2, R.sup.3A, R.sup.4, and
R.sup.4A can be taken together to form a chelating multidentate
ligand.
26. The method of claim 25, wherein: X.sup.1 and X.sup.2 are
anionic ligands, and are optionally linked to form a cyclic group;
L is a neutral electron donor ligand that is optionally linked to
R.sup.2, X.sup.1, and/or X.sup.2 through a spacer moiety; and
R.sup.3A and R.sup.4A are optionally linked to form a cyclic
group.
27. The method of claim 26, wherein w, x, y and z are zero, X and Y
are N, and R.sup.3A and R.sup.4A are linked to form -Q-, such that
the catalyst has the structure of formula (VIB) 185wherein Q is a
hydrocarbylene, substituted hydrocarbylene, heteroatom-containing
hydrocarbylene, or substituted heteroatom-containing hydrocarbylene
linker, and further wherein two or more substituents on adjacent
atoms within Q may be linked to form an additional cyclic
group.
28. The method of claim 27, wherein Q has the structure
CR.sup.22R.sup.22A--CR.sup.23R.sup.23A-- or
--CR.sup.22=CR.sup.23--, wherein R.sup.22, R.sup.22A, R.sup.23, and
R.sup.23A are independently selected from the group consisting of
hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, substituted
heteroatom-containing hydrocarbyl, and functional groups, and or
wherein any two of R.sup.22, R.sup.22A, R.sup.23, and R.sup.23A may
be linked together to form a substituted or unsubstituted,
saturated or unsaturated ring.
29. The method of claim 28, wherein Q has the structure
--CR.sup.22R.sup.22CR.sup.23R.sup.23A--, such that the catalyst has
the structure of formula (VIC) 186
30. The method of claim 29, wherein: M is Ru; X.sup.1 and X.sup.2
may be the same or different, and are selected from the group
consisting of hydrogen, halide, C.sub.1-C.sub.20 alkyl,
C.sub.1-C.sub.20 aryl, C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20
aryloxy, C.sub.3-C.sub.20 alkyldiketonate, C.sub.5-C.sub.20
aryldiketonate, C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.5-C.sub.20
aryloxycarbonyl, C.sub.2-C.sub.20 acyl, C.sub.1-C.sub.20
alkylsulfonato, C.sub.5-C.sub.20 arylsulfonato, C.sub.1-C.sub.20
alkylsulfanyl, C.sub.5-C.sub.20 arylsulfanyl, C.sub.1-C.sub.20
alkylsulfinyl, or C.sub.5-C.sub.20 arylsulfinyl, any of which, with
the exception of halide, are optionally further substituted with
one or more groups selected from halide, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, and phenyl; R.sup.1 is hydrogen and R.sup.2
is selected from the group consisting of C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, and aryl; L is a neutral electron donor
ligand selected from the group consisting of phosphine, sulfonated
phosphine, phosphite, phosphinite, phosphonite, arsine, stibine,
ether, amine, amide, imine, sulfoxide, carboxyl, nitrosyl,
pyridine, substituted pyridine, imidazole, substituted imidazole,
pyrazine, and thioether; R.sup.3 and R.sup.4 are aromatic,
substituted aromatic, heteroaromatic, substituted heteroaromatic,
alicyclic, substituted alicyclic, heteroatom-containing alicyclic,
or substituted heteroatom-containing alicyclic, composed of from
one to about five rings; and R.sup.8 and R.sup.9 are hydrogen, and
R.sup.8A and R.sup.9A are selected from hydrogen, lower alkyl and
phenyl, or are linked to form a cyclic group.
31. The method of claim 30, wherein: R.sup.1 is hydrogen, and
R.sup.2 is phenyl, vinyl, methyl, isopropyl, or t-butyl, optionally
substituted with one or more moieties selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl, and a functional group Fn, wherein Fn is phosphonato,
phosphoryl, phosphanyl, phosphino, sulfonato, C.sub.1-C.sub.20
alkylsulfanyl, C.sub.1-C.sub.20 arylsulfanyl, C.sub.1-C.sub.20
alkylsulfonyl, C.sub.1-C.sub.20 arylsulfonyl, C.sub.1-C.sub.20
alkylsulfinyl, C.sub.5-C.sub.20 arylsulfinyl, sulfonamido, amino,
amido, imino, nitro, nitroso, hydroxyl, C.sub.1-C.sub.20 alkoxy,
C.sub.5-C.sub.20 aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl,
C.sub.5-C.sub.20 aryloxycarbonyl carboxyl, carboxylato, mercapto,
formyl, C.sub.1-C.sub.20 thioester, cyano, cyanato, carbamoyl,
epoxy, styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato,
boryl, halogen, stannyl, or germyl; and L is a phosphine of the
formula L is a phosphine of the formula PR.sup.27R.sup.28R.sup.29,
where R.sup.27, R.sup.23, and R.sup.29 are each independently aryl
or C.sub.1-C.sub.10 alkyl.
32. The method of claim 31, wherein: X.sup.1 and X.sup.2 are
independently selected from the group consisting of halide,
CF.sub.3CO.sub.2, CH.sub.3CO.sub.2, CFH.sub.2CO.sub.2,
(CH.sub.3).sub.3CO, (CF.sub.3).sub.2(CH.sub.3)CO,
(CF.sub.3)(CH.sub.3)..sub.2CO, PhO, MeO, EtO, tosylate, mesylate,
and trifluoromethanesulfonate; L is selected from the group
consisting of --P(cyclohexyl).sub.3, --P(cyclopentyl).sub.3,
--P(isopropyl).sub.3, --P(phenyl).sub.3, P(phenyl).sub.3,
--P(phenyl).sub.2(R.sup.7) and --P(phenyl)(R.sup.7).sub.- 2, in
which R.sup.7 is lower alkyl; and R.sup.3 and R.sup.4 are the same
and are either aromatic or C.sub.7-C.sub.12 alicyclic, if aromatic,
each having the structure of formula (XI) 187 in which R.sup.24,
R.sup.25, and R.sup.26 are each independently hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, aryl, substituted
aryl, halogen, or a functional group.
33. The method of claim 32, wherein: X.sup.1 and X.sup.2 are
halide; R.sup.2 is hydrogen or 2,2-dimethylvinyl; R.sup.3 and
R.sup.4 are mesityl; L is selected from the group consisting of
--P(cyclohexyl).sub.3 and --P(cyclopentyl).sub.3; and R.sup.22 and
R.sup.23 are hydrogen.
34. The method of claim 24, wherein the directly halogenated
olefinic reactant has the structure of formula (IX) 188wherein
X.sup.3 is halo, and R.sup.8, R.sup.9, and R.sup.10 are
independently selected from the group consisting of hydrogen,
halide, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, substituted heteroatom-containing hydrocarbyl,
-(Z).sub.n-Fn where n is zero or 1, Z is a hydrocarbylene or a
substituted and/or heteroatom-containing hydrocarbylene linking
group, and Fn is a functional group selected from the group
consisting of phosphonato, phosphoryl, phosphanyl, phosphino,
sulfonato, C.sub.1-C.sub.20 alkylsulfanyl, C.sub.5-C.sub.20
arylsulfanyl, C.sub.1-C.sub.20 alkylsulfonyl, C.sub.5-C.sub.20
arylsulfonyl, C.sub.1-C.sub.20 alkylsulfinyl, C.sub.5-C.sub.20
arylsulfinyl, sulfonamido, amino, amido, imino, nitro, nitroso,
hydroxyl, C.sub.1-C.sub.20 alkoxy, C.sub.5-C.sub.20 aryloxy,
C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.5-C.sub.20 aryloxycarbonyl,
carboxyl, carboxylato, mercapto, formyl, C.sub.1-C.sub.20
thioester, cyano, cyanato, carbamoyl, epoxy, styrenyl, silyl,
silyloxy, silanyl, siloxazanyl, boronato, boryl, stannyl, and
germyl.
35. The method of claim 34, wherein at least one of R.sup.8,
R.sup.9, and R.sup.10 is a halogen atom.
36. The method of claim 35, where X.sup.3 and at least one of
R.sup.8, R.sup.9, and R.sup.10 is chloro or fluoro.
37. The method of claim 34, where X.sup.3 is chloro or fluoro,
R.sup.8 and R.sup.9 are hydrogen or lower alkyl, and R.sup.10 is
hydrogen, lower alkyl, chloro, or fluoro.
38. The method of claim 34, wherein the second olefinic reactant
has the molecular structure
R.sup.18R.sup.19C.dbd.CR.sup.20R.sup.2wherein R.sup.18, R.sup.19,
R.sup.20, and R.sup.21 are independently selected group consisting
of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, and substituted
heteroatom-containing hydrocarbyl.
39. A method for synthesizing a substituted olefin via a
cross-metathesis reaction, comprising: contacting a substituted
olefin selected from the group consisting of geminal disubstituted
olefins and quaternary allylic olefins with an olefinic reactant in
the presence of a catalyst composed of a Group 8 transition metal
alkylidene complex containing an N-heterocyclic carbene ligand,
under conditions and for a time period effective to allow
cross-metathesis to occur.
40. The method of claim 39, wherein the catalyst has the structure
of formula (VIA) 189wherein: wherein: M is a Group 8 transition
metal; X.sup.1 and X.sup.2 may be the same or different, and are
anionic ligands or polymers; R.sup.1 is selected from the group
consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, substituted
heteroatom-containing hydrocarbyl, and carboxyl; R.sup.2 is
selected from the group consisting of hydrogen, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and
substituted heteroatom-containing hydrocarbyl; L is a neutral
electron donor ligand; X and Y are heteroatoms selected from N, O,
S, and P; p is zero when X is O or S, and is 1 when X is N or P; q
is zero when Y is O or S, and is 1 when Y is N or P; Q.sup.1,
Q.sup.2, Q.sup.3, and Q.sup.4 are selected from hydrocarbylene,
substituted hydrocarbylene, heteroatom-containing hydrocarbylene,
substituted heteroatom-containing hydrocarbylene, and --(CO)--; w,
x, y and z are independently zero or 1; and R.sup.3, R.sup.3A,
R.sup.4, and R.sup.4A are independently selected from the group
consisting of hydrogen, hydrocarbyl, substituted hydrocarbyl,
heteroatom-containing hydrocarbyl, and substituted
heteroatom-containing hydrocarbyl, wherein any two or more of
X.sup.1 , X.sup.2, L, R.sup.1, R.sup.2, R.sup.3, R.sup.3A, R.sup.4,
and R.sup.4A can be taken together to form a chelating multidentate
ligand.
41. The method of claim 40, wherein: X.sup.1 and X.sup.2 are
anionic ligands, and are optionally linked to form a cyclic group;
L is a neutral electron donor ligand that is optionally linked to
R.sup.2, X.sup.1, and/or X.sup.2 through a spacer moiety; and
R.sup.3A and R.sup.4A are optionally linked to form a cyclic
group.
42. The method of claim 41, wherein w, x, y and z are zero, X and Y
are N, and R.sup.3A and R.sup.4A are linked to form -Q-, such that
the catalyst has the structure of formula (VIB) 190wherein Q is a
hydrocarbylene, substituted hydrocarbylene, heteroatom-containing
hydrocarbylene, or substituted heteroatom-containing hydrocarbylene
linker, and further wherein two or more substituents on adjacent
atoms within Q may be linked to form an additional cyclic
group.
43. The method of claim 42, wherein Q has the structure
CR.sup.22R.sup.22ACR.sup.23R.sup.23A or CR.sup.22=CR.sup.23,
wherein R.sup.22, R.sup.22A, R.sup.23, and R.sup.23A are
independently selected from the group consisting of hydrogen,
hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and
functional groups, and or wherein any two of R.sup.22, R.sup.22A,
R.sup.23, and R.sup.23A may be linked together to form a
substituted or unsubstituted, saturated or unsaturated ring.
44. The method of claim 43, wherein Q has the structure
--CR.sup.22R.sup.22A--CR.sup.23R.sup.23A--, such that the catalyst
has the structure of formula (VIC) 191
45. The method of claim 44, wherein: M is Ru; X.sup.1 and X.sup.2
may be the same or different, and are selected from the group
consisting of hydrogen, halide, C.sub.1-C.sub.20 alkyl,
C.sub.5-C.sub.20 aryl, C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20
aryloxy, C.sub.3-C.sub.20 alkyl C.sub.5-C.sub.20 aryldiketonate,
C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.5-C.sub.20 aryloxycarbonyl,
C.sub.2-C.sub.20 acyl, C.sub.1-C.sub.20 alkylsulfonato,
C.sub.5-C.sub.2 arylsulfonato, C.sub.1-C.sub.20 alkylsulfanyl,
C.sub.5-C.sub.20 arylsulfanyl, C.sub.1-C.sub.20 alkylsulfinyl, or
C.sub.5-C.sub.20 arylsulfinyl, any of which, with the exception of
halide, are optionally further substituted with one or more groups
selected from halide, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, and phenyl; R.sup.1 is hydrogen and R.sup.2 is selected
from the group consisting of C.sub.1-C.sub.20 alkyl,
C.sub.2-C.sub.20 alkenyl, and aryl; L is a neutral electron donor
ligand selected from the group consisting of phosphine, sulfonated
phosphine, phosphite, phosphinite, phosphonite, arsine, stibine,
ether, amine, amide, imine, sulfoxide, carboxyl, nitrosyl,
pyridine, substituted pyridine, imidazole, substituted imidazole,
pyrazine, and thioether; R.sup.3 and R.sup.4 are aromatic,
substituted aromatic, heteroaromatic, substituted heteroaromatic,
alicyclic, substituted alicyclic, heteroatom-containing alicyclic,
or substituted heteroatom-containing alicyclic, composed of from
one to about five rings; and R.sup.8 and R.sup.9, are hydrogen, and
RWA and R.sup.9A are selected from hydrogen, lower alkyl and
phenyl, or are linked to form a cyclic group.
46. The method of claim 45, wherein: R.sup.1 is hydrogen, and
R.sup.2 is phenyl, vinyl, methyl, isopropyl, or t-butyl, optionally
substituted with one or more moieties selected from the group
consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
phenyl, and a functional group Fn, wherein Fn is phosphonato,
phosphoryl, phosphanyl, phosphino, sulfonato, C.sub.1-C.sub.20
alkylsulfanyl, C.sub.5-C.sub.20 arylsulfanyl, C.sub.1-C.sub.20
alkylsulfonyl, C.sub.5-C.sub.20 arylsulfonyl, C.sub.1-C.sub.20
alkylsulfinyl, C.sub.5-C.sub.20arylsulfinyl, sulfonamido, amino,
amido, imino, nitro, nitroso, hydroxyl, C.sub.1-C.sub.20 alkoxy,
C.sub.1-C.sub.20 aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl,
C.sub.1-C.sub.20 aryloxycarbonyl, carboxyl, carboxylato, mercapto,
formyl, C.sub.1-C.sub.20 thioester, cyano, cyanato, carbamoyl,
epoxy, styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato,
boryl, halogen, stannyl, or germyl; and L is a phosphine of the
formula L is a phosphine of the formula PR.sup.27R.sup.28R.sup.29,
where R.sup.27, R.sup.28, and R.sup.29 are each independently aryl
or C.sub.1-C.sub.10 alkyl.
47. The method of claim 46, wherein: X.sup.1 and X.sup.2 are
independently selected from the group consisting of halide,
CF.sub.3CO.sub.2, CH.sub.3CO.sub.2, CFH.sub.2CO.sub.2,
(CH.sub.3)..sub.3CO, (CF.sub.3).sub.2(CH.sub.3)CO,
(CF.sub.3)(CH.sub.3).sub.2CO, PhO, MeO, EtO, tosylate, mesylate,
and trifluoromethanesulfonate; L is selected from the group
consisting of --P(cyclohexyl).sub.3, --P(cyclopentyl).sub.3,
--P(isopropyl).sub.3, --(Phenyl).sub.3, P(phenyl).sub.3,
--P(phenyl).sub.2(R.sup.7) and --P(phenyl)(R.sup.7).sub.- 2, in
which R.sup.7 is lower alkyl; and R.sup.3 and R.sup.4 are the same
and are either aromatic or C.sub.7-C.sub.1.sub.2 alicyclic, if
aromatic, each having the structure of formula (XI) 192 in which
R.sup.24, R.sup.25, and R.sup.26 are each independently hydrogen,
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, aryl, substituted
aryl, halogen, or a functional group.
48. The method of claim 47, wherein: X.sup.1 and X.sup.2 are
halide; R.sup.2 is hydrogen or 2,2-dimethylvinyl; R.sup.3 and
R.sup.4 are mesityl, diisopinocamphenyl, or
2,4,2',6'-tetramethylbiphenylyl; L is selected from the group
consisting of --P(cyclohexyl).sub.3 and --P(cyclopentyl).sub.3; and
R.sup.22 and R.sup.23 are hydrogen.
49. The method of claim 39, wherein the substituted olefin is a
geminal disubstituted olefin.
50. The method of claim 49, wherein the substituted olefin has the
structure of formula (X) 193wherein R.sup.11, R.sup.12, R.sup.13,
and R.sup.14 are selected from the group consisting of hydrogen,
halo, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and
-(Z).sub.n-Fn where n is zero or 1, Z is a hydrocarbylene or a
substituted and/or heteroatom-containing hydrocarbylene linking
group, and Fn is a functional group, with the proviso that R.sup.11
and R.sup.12, and/or R.sup.13 and R.sup.14, are other than
hydrogen.
51. The method of claim 50, wherein the substituted olefin is a
quaternary allylic olefin.
52. The method of claim 51, wherein the substituted olefin has the
structure of formula 194wherein R.sup.11 and R.sup.12 are selected
from the group consisting of hydrogen, halo, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl,
substituted heteroatom-containing hydrocarbyl, and -(Z).sub.n-Fn
where n is zero or 1, Z is a hydrocarbylene or a substituted and/or
heteroatom-containing hydrocarbylene linking group, and Fn is a
functional group, and R.sup.15, R.sup.16, and R.sup.17 are
nonhydrogen substituents.
53. A method for carrying out an olefin cross-metathesis reaction
so as to provide a preponderance of a cis-1,2-disubstituted olefin
in the reaction product, comprising: contacting a
cis-1,2-disubstituted olefinic reactant with a second olefinic
reactant in the presence of a catalyst composed of a Group 8
transition metal alkylidene complex containing an N-heterocyclic
carbene ligand, under conditions and for a time period effective to
allow cross-metathesis to occur, wherein the N-heterocyclic carbene
ligand is substituted with two or more bicyclic or polycyclic
moieties.
54. The method of claim 53, wherein the bicyclic or polycyclic
moieties are aliphatic.
55. The method of claim 54, wherein the bicyclic or polycyclic
moieties are selected from norbornyl, adamantyl, camphenyl, and
isobornyl, any of which may be substituted.
56. The method of claim 55, wherein the N-heterocyclic carbene
ligand is
1,3-(+)-diisopinocamphenyl-4,5-dihydroimidazol-2-ylidene.
57. The method of claim 53, wherein the bicyclic or polycyclic
moieties are aromatic.
58. The method of claim 57, wherein the bicyclic or polycyclic
moieties are biphenylyl or substituted biphenylyl.
59. The method of claim 58, wherein the N-heterocyclic carbene
ligand is
1,3-bis-[2',6'-dimethyl-3'-(2",6"-dimethylphenyl)phenyl]-4,5-dihydroimida-
zol-2-ylidene.
60. A transition metal complex comprising a transition metal center
coordinated to an N-heterocyclic carbene ligand substituted with
two or more bicyclic or polycyclic moieties.
61. The transition metal complex of claim 60, wherein the bicyclic
or polycyclic moieties are aliphatic.
62. The transition metal complex of claim 61, wherein the bicyclic
or polycyclic moieties are selected from norbornyl, adamantyl,
camphenyl, and isobornyl, any of which may be substituted.
63. The transition metal complex of claim 62, wherein the
N-heterocyclic carbene ligand is
1,3-(+)-diisopinocamphenyl-4,5-dihydroimidazol-2-yliden- e.
64. The transition metal complex of claim 60, wherein the bicyclic
or polycyclic moieties are aromatic.
65. The transition metal complex of claim 64, wherein the bicyclic
or polycyclic moieties are biphenylyl or substituted
biphenylyl.
66. The transition metal complex of claim 65, wherein the
N-heterocyclic carbene ligand is 1,3
-bis-[2',6'-dimethyl-3'-(2",6"-dimethylphenyl)pheny-
l]-4,5-dihydroimidazol-2ylidene.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C.
.sctn.119(e)(1) to the following provisional U.S. patent
applications: Serial No. 60/280,590, filed Mar. 30, 2001; Serial
No. 60/280,462, filed Mar. 30, 2001; Serial No. 60/284,213, filed
Apr. 16, 2001; Serial No. 60/285,597, filed Apr. 20, 2001; and
Serial No. 60/340,588, filed Dec. 14, 2001. The disclosures of the
aforementioned applications are incorporated by reference in their
entireties.
TECHNICAL FIELD
[0003] This invention relates generally to a method for carrying
out an olefin metathesis reaction using a Group 8 transition metal
complex as a catalyst, and more particularly relates to a method
for carrying out cross-metathesis reactions using the
aforementioned catalyst wherein at least one of the olefinic
reactants is a functionalized olefin, a geminal disubstituted
olefin, a trisubstituted olefin, and/or a quaternary allylic
olefin. Methods are also provided for the catalysis of
stereoselective olefin metathesis reactions, and for the creation
of chemical diversity by carrying out a plurality of olefin
metathesis reactions using a single olefinic substrate and
different metathesis partners, to generate a plurality of
structurally distinct products.
BACKGROUND OF THE INVENTION
[0004] To the synthetic organic or polymer chemist, simple methods
for forming carbon-carbon bonds are extremely important and
valuable tools. One method of C--C bond formation that has proved
particularly useful is transition-metal catalyzed olefin
metathesis. "Olefin metathesis," as is understood in the art,
refers to the metal-catalyzed redistribution of carbon-carbon
bonds. See Trnka and Grubbs (2001) Acc. Chem. Res. 34:18-29. Over
two decades of intensive research effort has culminated in the
discovery of well-defined ruthenium and osmium carbenes that are
highly active olefin metathesis catalysts and stable in the
presence of a variety of functional groups.
[0005] These ruthenium and osmium carbene complexes have been
described in U.S. Pat. Nos. 5,312,940, 5,342,909, 5,831,108,
5,969,170, 6,111,121, and 6,211,391 to Grubbs et al., assigned to
the California Institute of Technology. The ruthenium and osmium
carbene complexes disclosed in these patents all possess metal
centers that are formally in the +2 oxidation state, have an
electron count of 16, and are penta-coordinated. These catalysts
are of the general formula (I) 1
[0006] where M is a Group 8 transition metal such as ruthenium or
osmium, X and X' are anionic ligands, L and L' are neutral electron
donors, and R and R' are specific substituents, e.g., one may be H
and the other may be a substituted or unsubstituted hydrocarbyl
group such as phenyl or C=C(CH.sub.3).sub.2. Such complexes have
been disclosed as useful in catalyzing a variety of olefin
metathesis reactions, including ring opening metathesis
polymerization ("ROMP"), ring closing metathesis ("RCM"), acyclic
diene metathesis polymerization ("ADMET"), ring-opening metathesis
("ROM"), and cross-metathesis ("CM" or "XMET") reactions.
[0007] For the most part, such metathesis catalysts have been
prepared with phosphine ligands, e.g., triphenylphosphine or
dimethylphenylphospine, exemplified by the well-defined,
metathesis-active ruthenium alkylidene complexes (II) and (III)
2
[0008] wherein "Cy" is a cycloalkyl group such as cyclohexyl or
cyclopentyl. See U.S. Pat. No. 5,917,071 to Grubbs et al. and Trnka
and Grubbs, cited supra. These compounds are highly reactive
catalysts useful for catalyzing a variety of olefin metathesis
reactions, and are tolerant of many different functional groups.
However, as has been recognized by those in the field, the
compounds display low thermal stability, decomposing at relatively
low temperatures. Jafarpour an and Nolan (2000) Organometallics
19(11):2055-2057.
[0009] Recently, however, significant interest has focused on the
use of N-heterocyclic carbene ligands as superior alternatives to
phosphines. See, e.g., Trnka and Grubbs, supra; Bourissou et al.
(2000) Chem. Rev. 100:39-91; Scholl et al. (1999) Tetrahedron Lett.
40:2247-2250; Scholl et al. (1999) Organic Lett. 1(6):953-956; and
Huang et al. (1999) J. Am. Chem. Soc. 121:2674-2678. N-heterocyclic
carbene ligands offer many advantages, including readily tunable
steric bulk, vastly increased electron donor character, and
compatibility with a variety of metal species. In addition,
replacement of one of the phosphine ligands in these complexes
significantly improves thermal stability. The vast majority of
research on these carbene ligands has focused on their generation
and isolation, a feat finally accomplished by Arduengo and
coworkers within the last ten years (see, e.g., Arduengo et al.
(1999) Acc. Chem. Res. 32:913-921). Representative of these second
generation catalysts are the four ruthenium complexes (IVA), (IVB),
(VA) and (VB): 3
[0010] In the above structures, Cy is as defined previously, "IMes"
represents 1,3-dimesityl-imidazol-2-ylidene
IMes:
[0011] 4
[0012] and "IMesH.sub.2" represents
1,3-dimesityl-4,5-dihydroimidazol-2-yl- idene
IMesH.sub.2
[0013] 5
[0014] Other complexes formed from N-heterocyclic carbene ligands
are also known.
[0015] These transition metal carbene complexes, particularly those
containing a ligand having the 4,5-dihydroimidazol-2-ylidene
structure, such as in IMesH.sub.2, have been found to address a
number of previously unsolved problems in olefin metathesis
reactions, particularly cross-metathesis reactions. These problems
span a variety of reactions and starting materials. The following
discussion focuses on representative problems in the art that have
now been addressed by way of the present invention.
[0016] Use of Olefinic Phosphonates and Other Functionalized
Olefins as Cross-Metathesis Reactants: Olefins that contain
phosphonate functionality are used extensively in synthetic organic
chemistry. For example, allylic phosphonates are employed in the
preparation of dienes and polyenes by Horner-Emmons olefination,
providing products with improved stereoselectivity as compared to
the corresponding phosphonium salts; see Crombie et al. (1969) J.
Chem. Soc., Chem. Commun. at 1024; and Whang et al. (1992) J. Org.
Chem. 56 :7177. The reaction of organic halides with trialkyl
phosphites (Michaelis-Arbuzov reaction) is used primarily for the
synthesis of allylphosphonates; see Bhattacharya et al. (1981)
Chem. Rev. 81 :415. However, elimination and/or loss of olefin
stereochemical integrity are often competitive with product
formation. Palladium catalyzed cross-coupling of hydrogen
phosphonates to conjugated dienes and allenes has also been
developed, but requires high reaction temperatures and provide low
regioselectivity in highly substituted phosphonates products. See
Hirao et al. (1980) Tetrahedron Lett. 21:3595; Hirao et al. (1982)
Bull. Chem. Soc. Jpn. 55: 909; Imamoto et al. (1990) J. Am. Chem.
Soc. 112 :5244; Zhao et al. (2000) Organometallics 19:4196.
[0017] Vinylphosphonates are important synthetic intermediates and
have been investigated as biologically active compounds.
Vinylphosphonates have been used as intermediates in
stereoselective synthesis of trisubstituted olefins and in
heterocycle synthesis; see Shen et al. (2000) Synthesis, p. 99;
Tago et al. (2000) Org. Lett. 2:1975; Kouno et al. (1998) J. Org.
Chem. 63:6239; and Kouno et al. (2000) J. Org. Chem. 65:4326. The
synthesis of vinylphosphonates has also been widely examined and a
variety of non-catalytic approaches have been described in the
literature. Recent metal-catalyzed methods include palladium
catalyzed cross-coupling (see, e.g., Holt et al. (1989),
Tetrahedron Lett. 30:5393; Han et al. (1996), J. Am. Chem. Soc.
118:1571; Kazankova et al. (1999), Tetrahedron Lett. 40:569;
Okauchi et al. (1999), Tetrahedron Lett. 40:5337; Zhong et al.
(2000), Synth. Commun. 30:273; and Han et al. (2000), J. Am. Chem.
Soc. 122:5407) and Heck coupling of aryldiazonium salts with vinyl
phosphonates (Brunner et al. (2000) Synlett. at p. 201), but are
limited by the requirement of highly reactive functional groups in
the substrates. Therefore, a more mild, general and stereoselective
method for the synthesis of vinyl and allylphosphonates using
commercially available starting materials would be quite valuable,
and would provide an additional degree of orthogonality to the
previously reported syntheses. An ideal such method would also be
applicable in other contexts as well, for example in the synthesis
of olefins substituted with functional groups other than
phosphonates. The invention, in one embodiment, is directed to this
pressing need in the art, and provides a method that not only
accomplishes the aforementioned goals, but is also useful in a more
generalized process for creating functional group diversity in a
population of olefinic products prepared using
cross-metathesis.
[0018] Cross-Metathesis of a-Halogenated Olefins and Synthesis of
Directly Halogenated Olefins: Since the discovery of the olefin
metathesis reaction in the 1950s, the metathesis of
halogen-containing olefins has received very little attention. The
metathesis of allyl bromide, allyl chloride, and related substrates
with the heterogeneous Re.sub.2O.sub.7/Al.sub.2O.sub.3/Me.sub.4Sn
catalyst system are among the few examples. Kawai et al. (1998) J.
Mol. Catal. A 133:51; Bogolepova et al. (1992) Petrol. Chem.
32:461; Mol et al. (1979) J. Chem. Soc. Chem. Commun., at pp.
330-331 Nakamura et al. (1977) Chem. Lett., at p. 1127; Fridman et
al. (1997) Doklady Akad. Nauk S.S.S.R. 234:1354. Most recently, the
cross-metathesis of 3,3,4,4,5,5,6,6,6-nonafluoro-1-hexene with
terminal olefin and the dimerization of vinyl
gem-difluorocyclopropane derivatives have been achieved using
catalyst (VB). Chattejjee et al. (2000) J. Am. Chem. Soc. 122:3783;
International Patent Publication No. WO 02/00590 to Grubbs et al.;
Itoh et al. (2000) Org. Lett. 2:1431. In these cases, the
substrates are challenging because of the electron-withdrawing
nature of the pendent halogens. A particularly challenging
situation arises when the olefin is directly halogenated, because
the metathesis reaction will then involve a monohalo [M]=CXR or
dihalo [M]=CX.sub.2 carbene complex as the propagating species
(where X=halide), rather than the more usual alkylidene
[M]=CR.sub.2 (where R=H, alkyl, aryl). To the best of applicants'
knowledge, there has been only one report of metathesis involving
directly halogenated olefins, namely the cross-metathesis of
1-chloro- and 1-bromoethylene with propylene using
Re.sub.2O.sub.7/Al.sub.2O.sub.3/Me.sub.4Sn (Fridman et al. (1977)
Doklady Akad. Nauk S.S.S.R. 234:1354).
[0019] Accordingly, there are very few methods available for the
mild and selective synthesis of directly halogenated olefins, and
in particular, directly fluorinated olefins. The present invention
now provides a straightforward method for carrying out an olefin
metathesis reaction using an .alpha.-halogenated olefin, which may
be an .alpha.-fluorinated olefin, in order to provide a directly
halogenated (e.g., fluorinated) olefinic product.
[0020] Catalyzed Cross-Metathesis of Highly Substituted Olefins,
Including Geminal Disubstituted Olefins and Quaternary Allylic
Olefins: In prior applications of olefin metathesis, particularly
olefin cross-metathesis, there has been no method available for
generation of highly substituted olefins, such as trisubstituted
olefins (wherein the substituents may be the same or different) and
olefins that contain quaternary carbons at the allylic position.
Trisubstituted and quaternary allylic olefinic substituents are, of
course, present in a diverse array of organic molecules, including
pharmaceuticals, natural products, and functionalized polymers, and
the difficulty in generating such compounds has been a substantial
limitation. The methodology of the present invention overcomes this
limitation and now provides an efficient and versatile way to
synthesize 1,1,2-trisubstituted olefins as well as
1,2-disubstituted olefins containing one quaternary allylic carbon
atom.
[0021] Stereoselective Synthesis of 1,2-Disubstituted Olefins via
Cross-metathesis: Another limitation in known olefin metathesis
reactions is that there is no general method for controlling the
stereoselectivity of the newly formed olefins. In many cases, the
more thermodynamically stable trans olefin geometry was selectively
formed, with minimal, if any, of the cis olefin produced. See
Blackwell et al. (2000), "New approaches to olefin
cross-metathesis," J. Am. Chem. Soc. 122(1):58-71; and Chatterjee
et al. (2000), "Synthesis of functionalized olefins by cross and
ring-closing metathesis," J. Am. Chem. Soc. 122(15):3783-3784. The
present invention also addresses this need in the art by providing
a stereoselective method for synthesizing a 1,2-disubstituted
olefin in primarily the cis configuration.
SUMMARY OF THE INVENTION
[0022] The present invention is addressed to the aforementioned
needs in the art, and provides a novel process for using certain
Group 8 transition metal complexes to catalyze a variety of olefin
metathesis reactions, primarily cross-metathesis reactions. The
complexes used are metal carbenes comprised of a Group 8 transition
metal, particularly ruthenium or osmium, which preferably, although
not necessarily, contain an N-heterocyclic carbene ligand. Such
complexes are highly active catalysts of olefin metathesis
reactions, including the cross-metathesis reactions described in
detail herein. In contrast to previous catalysts used in olefin
cross-metathesis, the present complexes allow an olefinic reactant
to be substituted with a functional group without compromising the
efficiency or selectivity of a metathesis reaction involving that
olefin. The present invention also allows the second reactant,
i.e., the olefin metathesis partner, to be substituted with a
functional group. The functional group may or may not be a ligand
for the metal complex; the present method is not limited in this
regard. The olefinic reactant may also be di-substituted at one of
the olefinic carbon atoms, as is the case with 2-methyl-2-butene,
for example, or may be a quaternary allylic olefin, i.e., an olefin
directly substituted at one or both of the olefinic carbon atoms
with the moiety -CH.sub.2-CR.sub.3 where R is other than
hydrogen.
[0023] These cross-metathesis reactions are carried out with a
catalyst having the structure of formula (VI) 6
[0024] in which
[0025] M is a Group 8 transition metal, particularly Ru or Os;
[0026] X.sup.1 and X.sup.2 may be the same or different, and are
anionic ligands or polymers;
[0027] R.sup.1 is selected from the group consisting of hydrogen,
hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and
carboxyl;
[0028] R.sup.2 is selected from the group consisting of hydrogen,
hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, and substituted heteroatom-containing hydrocarbyl;
[0029] L is a neutral electron donor ligand; and
[0030] L.sup.1 is a neutral electron donor ligand having the
structure of formula (VII) 7
[0031] In structure (VII):
[0032] X and Y are heteroatoms selected from N, O, S, and P;
[0033] p is zero when X is O or S, and is 1 when X is N or P;
[0034] q is zero when Y is O or S, and is 1 when Y is N or P;
[0035] Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are linkers, e.g.,
hydrocarbylene (including substituted hydrocarbylene,
heteroatom-containing hydrocarbylene, and substituted
heteroatom-containing hydrocarbylene, such as substituted and/or
heteroatom-containing alkylene) or --(CO)--;
[0036] w, x, y and z are independently zero or 1; and
[0037] R.sup.3, R.sup.3A, R.sup.4, and R.sup.4A are independently
selected from the group consisting of hydrogen, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and
substituted heteroatom-containing hydrocarbyl,
[0038] wherein any two or more of X.sup.1, X.sup.2, L, R.sup.1,
R.sup.2, R.sup.3, R.sup.3A, R.sup.4, and R.sup.4A can be taken
together to form a chelating multidentate ligand.
[0039] Accordingly, the complex of formula (V) may also be
represented as (VIA) 8
[0040] In a preferred embodiment, L is an N-heterocyclic carbene
having the structure of formula (VIIA) 9
[0041] wherein R.sup.3 and R.sup.4 are defined above, with
preferably at least one of R.sup.3 and R.sup.4, and more preferably
both R.sup.3 and R.sup.4, being alicyclic or aromatic of one to
about five rings, and optionally containing one or more heteroatoms
and/or substituents. Q is a linker, typically a hydrocarbylene
linker, including substituted hydrocarbylene, heteroatom-containing
hydrocarbylene, and substituted heteroatom-containing
hydrocarbylene linkers, wherein two or more substituents on
adjacent atoms within Q may also be linked to form an additional
cyclic structure, which may be similarly substituted to provide a
fused polycyclic structure of two to about five cyclic groups. Q is
often, although again not necessarily, a two-atom linkage or a
three-atom linkage. Accordingly, the metal carbene complex of
formula (VIA) may also be represented as follows: 10
[0042] In one embodiment, then, a method is provided for
synthesizing olefins substituted with a functional group by
cross-metathesis using a Group 8 transition metal catalyst having
the structure of formula (VI). At least one of the two olefinic
reactants is substituted with one or more functional groups, which
may or may not be in protected form (e.g., a hydroxyl group may be
protected as an acyloxy or benzyloxy group). More specifically, at
least one of the two olefinic reactants has the structure of
formula (VIII) 11
[0043] wherein:
[0044] Fn is a functional group such as phosphonato, phosphoryl,
phosphanyl, phosphino, sulfonato, C.sub.1-C.sub.20 alkylsulfanyl,
C.sub.5-C.sub.20arylsulfanyl, C.sub.1-C.sub.20 alkylsulfonyl,
C.sub.5-C.sub.20arylsulfonyl, C.sub.1-C.sub.20 alkylsulfinyl,
C.sub.5-C.sub.20 arylsulfinyl, sulfonamido, amino, amido, imino,
nitro, nitroso, hydroxyl, C.sub.1-C.sub.20 alkoxy, C.sub.5-C.sub.20
aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.5-C.sub.20
aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl,
C.sub.1-C.sub.20 thioester, cyano, cyanato, carbamoyl, epoxy,
styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato, or
boryl, or a metal-containing or metalloid-containing group (wherein
the metal may be, for example, Sn or Ge);
[0045] n is zero or 1;
[0046] Z is a hydrocarbylene or a substituted and/or
heteroatom-containing hydrocarbylene linking group such as an
alkylene, substituted alkylene, heteroalkylene, substituted
heteroalkene, arylene, substituted arylene, heteroarylene, or
substituted heteroarylene linkage; and
[0047] R.sup.5, R.sup.6, and R.sup.7 are independently selected
from the group consisting of hydrogen, -(Z).sub.n-Fn, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and
substituted heteroatom-containing hydrocarbyl, and, if substituted
hydrocarbyl or substituted heteroatom-containing hydrocarbyl,
wherein one or more of the substituents may be -(Z).sub.n-Fn.
[0048] In one preferred embodiment, Fn is a phosphonate and Z is
CH.sub.2, such that the reactant is an allylphosphonate (when n is
1) and a vinylphosphonate (when n is zero). The product of the
cross-metathesis reaction is also an olefin substituted with a
-(Z).sub.n-Fn group.
[0049] In another embodiment, a method is provided for synthesizing
directly halogenated olefins by cross-metathesis using a catalyst
having the structure of formula (VI). In this embodiment, at least
one of the olefinic reactants has the structure of formula (IX)
12
[0050] wherein X.sup.3 is halo, and R.sup.8, R.sup.9, and R.sup.10
are independently selected from the group consisting of hydrogen,
halo, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and
-(Z).sub.n-Fn where n, Z and Fn are as defined above.
[0051] In a further embodiment, a method is provided for
synthesizing substituted olefins, particularly trisubstituted and
quaternary allylic olefins, wherein the method comprises using the
complex of formula (VI) to catalyze a cross-metathesis reaction
between a geminal disubstituted olefin or a quaternary allylic
olefin, and a second olefin. If it is a geminal disubstituted
olefin, the first olefin has the structure (X) 13
[0052] wherein R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are
selected from the group consisting of hydrogen, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl,
substituted heteroatom-containing hydrocarbyl, and -(Z).sub.n-Fn
where n, Z and Fn are as defined above, with the proviso that
R.sup.11 and R.sup.12, or R.sup.13 and R.sup.14, are other than
hydrogen. If it is a quaternary allylic olefin, the first olefin
has the structure (XI) 14
[0053] wherein R.sup.11 and R.sup.12 are as defined previously, and
R.sup.15, R.sup.16, and R.sup.17 are any nonhydrogen substituents,
e.g., alkyl, aryl, heteroalkyl, heteroaryl, -(Z).sub.n-Fn (where n,
Z, and Fn are as defined above with respect to formula (VIII)), or
the like.
[0054] In the above-described embodiments, the second olefin has a
molecular structure given by
R.sup.18R.sup.19C.dbd.CR.sup.20R.sup.21 wherein R.sup.18, R.sup.19,
R.sup.20, and R.sup.21 may be hydrogen, hydrocarbyl, substituted
hydrocarbyl, heteroatom-containing hydrocarbyl, substituted
heteroatom-containing hydrocarbyl, -(Z).sub.n-Fn, etc. As such, it
will be appreciated that the second olefin may have a molecular
structure encompassed by any one of the above generic formulae
(VIII), (IX), (X), and (XI), or may be a simple structure such as
ethylene per se.
[0055] The invention is additionally useful in providing a method
for controlling the stereoselectivity of an olefin cross-metathesis
reaction, and in providing a cross-metathesis product in which the
thermodynamically less favored cis configuration predominates. The
reaction is carried out using selected olefinic reactants, with one
olefinic reactant substituted in a 1,2-cis configuration. The
catalyst used has the structure of formula (VI), with R.sup.3 and
R.sup.4 representing bulky ligands, e.g., bicyclic or polycyclic
ligands that may or may not be aromatic.
[0056] In a still further embodiment of the invention, complexes of
formula (VI) are used to catalyze a plurality of cross-metathesis
reactions from a common olefinic reactant to generate chemical
diversity, i.e., to provide a plurality of products having related
structures but retaining a distinguishing feature, such that each
synthesized compound is different from each other synthesized
compound. Each olefinic reactant can be substituted with functional
groups, yielding cross-metathesis products containing those groups,
and thus providing the option of further derivatization. While
prior olefin cross-metathesis reactions have been used to
synthesize alkenes bearing a range of functional groups, these
prior reactions have been limited to olefins that do not contain
any functional groups that could behave as ligands for the catalyst
employed. By contrast, the present method can be used with olefinic
starting materials in which functional groups are present that
could act as ligands for the metal complex selected as a metathesis
catalyst.
DETAILED DESCRIPTION OF THE INVENTION
[0057] I. Definitions and Nomenclature:
[0058] It is to be understood that unless otherwise indicated this
invention is not limited to specific reactants, reaction
conditions, ligands, metal complexes, or the like, as such may
vary. It is also to be understood that the terminology used herein
is for the purpose of describing particular embodiments only and is
not intended to be limiting.
[0059] As used in the specification and the appended claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a compound" encompasses a combination or mixture of
different compounds as well as a single compound, reference to "a
functional group" includes a single functional group as well as two
or more functional groups that may or may not be the same, and the
like.
[0060] In this specification and in the claims that follow,
reference will be made to a number of terms, which shall be defined
to have the following meanings:
[0061] As used herein, the phrase "having the formula" or "having
the structure" is not intended to be limiting and is used in the
same way that the term "comprising" is commonly used.
[0062] The term "alkyl" as used herein refers to a linear, branched
or cyclic saturated hydrocarbon group typically although not
necessarily containing 1 to about 20 carbon atoms, such as methyl,
ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl,
decyl, and the like, as well as cycloalkyl groups such as
cyclopentyl, cyclohexyl and the like. Generally, although again not
necessarily, alkyl groups herein contain 1 to about 12 carbon
atoms. The term "lower alkyl" intends an alkyl group of 1 to 6
carbon atoms, and the specific term "cycloalkyl" intends a cyclic
alkyl group, typically having 4 to 8, preferably 5 to 7, carbon
atoms. The term "substituted alkyl" refers to alkyl substituted
with one or more substituent groups, and the terms
"heteroatom-containing alkyl" and "heteroalkyl" refer to alkyl in
which at least one carbon atom is replaced with a heteroatom. If
not otherwise indicated, the terms "alkyl" and "lower alkyl"
include linear, branched, cyclic, unsubstituted, substituted,
and/or heteroatom-containing alkyl and lower alkyl,
respectively.
[0063] The term "alkylene" as used herein refers to a difunctional
linear, branched or cyclic alkyl group, where "alkyl" is as defined
above.
[0064] The term "alkenyl" as used herein refers to a linear,
branched or cyclic hydrocarbon group of 2 to 20 carbon atoms
containing at least one double bond, such as ethenyl, n-propenyl,
isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl,
hexadecenyl, eicosenyl, tetracosenyl, and the like. Preferred
alkenyl groups herein contain 2 to 12 carbon atoms. The term "lower
alkenyl" intends an alkenyl group of 2 to 6 carbon atoms, and the
specific term "cycloalkenyl" intends a cyclic alkenyl group,
preferably having 5 to 8 carbon atoms. The term "substituted
alkenyl" refers to alkenyl substituted with one or more substituent
groups, and the terms "heteroatom-containing alkenyl" and
"heteroalkenyl" refer to alkenyl in which at least one carbon atom
is replaced with a heteroatom. If not otherwise indicated, the
terms "alkenyl" and "lower alkenyl" include linear, branched,
cyclic, unsubstituted, substituted, and/or heteroatom-containing
alkenyl and lower alkenyl, respectively.
[0065] The term "alkenylene" as used herein refers to a
difunctional linear, branched or cyclic alkenyl group, where
"alkenyl" is as defined above.
[0066] The term "alkynyl" as used herein refers to a linear or
branched hydrocarbon group of 2 to 20 carbon atoms containing at
least one triple bond, such as ethynyl, n-propynyl, and the like.
Preferred alkynyl groups herein contain 2 to 12 carbon atoms. The
term "lower alkynyl" intends an alkynyl group of 2 to 6 carbon
atoms. The term "substituted alkynyl" refers to alkynyl substituted
with one or more substituent groups, and the terms
"heteroatom-containing alkynyl" and "heteroalkynyl" refer to
alkynyl in which at least one carbon atom is replaced with a
heteroatom. If not otherwise indicated, the terms "alkynyl" and
"lower alkynyl" include linear, branched, unsubstituted,
substituted, and/or heteroatom-containing alkynyl and lower
alkynyl, respectively.
[0067] The term "alkoxy" as used herein intends an alkyl group
bound through a single, terminal ether linkage; that is, an
"alkoxy" group may be represented as --O-alkyl where alkyl is as
defmed above. A "lower alkoxy" group intends an alkoxy group
containing 1 to 6 carbon atoms. Analogously, "alkenyloxy" and
"lower alkenyloxy" respectively refer to an alkenyl and lower
alkenyl group bound through a single, terminal ether linkage, and
"alkynyloxy" and "lower alkynyloxy" respectively refer to an
alkynyl and lower alkynyl group bound through a single, terminal
ether linkage.
[0068] The term "aryl" as used herein, and unless otherwise
specified, refers to an aromatic substituent containing a single
aromatic ring or multiple aromatic rings that are fused together,
directly linked, or indirectly linked (such that the different
aromatic rings are bound to a common group such as a methylene or
ethylene moiety). Preferred aryl groups contain one aromatic ring
or 2 to 4 fused or linked aromatic rings, e.g., phenyl, naphthyl,
biphenyl, and the like. "Substituted aryl" refers to an aryl moiety
substituted with one or more substituent groups, and the terms
"heteroatom-containing aryl" and "heteroaryl" refer to aryl in
which at least one carbon atom is replaced with a heteroatom.
Unless otherwise indicated, the terms "aromatic," "aryl," and
"arylene" include heteroaromatic, substituted aromatic, and
substituted heteroaromatic species.
[0069] The term "aryloxy" as used herein refers to an aryl group
bound through a single, terminal ether linkage. An "aryloxy" group
may be represented as --O-aryl where aryl is as defined above.
[0070] The term "aralkyl" refers to an alkyl group with an aryl
substituent, and the term "aralkylene" refers to an alkylene group
with an aryl substituent; the term "alkaryl" refers to an aryl
group that has an alkyl substituent, and the term "alkarylene"
refers to an arylene group with an alkyl substituent.
[0071] The term "alicyclic" refers to an aliphatic cyclic moiety,
which may or may not be bicyclic or polycyclic.
[0072] The terms "halo" and "halogen" are used in the conventional
sense to refer to a chloro, bromo, fluoro or iodo substituent. The
terms "haloalkyl," "haloalkenyl" or "haloalkynyl" (or "halogenated
alkyl," "halogenated alkenyl," or "halogenated alkynyl") refers to
an alkyl, alkenyl or alkynyl group, respectively, in which at least
one of the hydrogen atoms in the group has been replaced with a
halogen atom.
[0073] "Hydrocarbyl" refers to univalent hydrocarbyl radicals
containing 1 to about 30 carbon atoms, preferably 1 to about 20
carbon atoms, most preferably 1 to about 12 carbon atoms, including
linear, branched, cyclic, saturated and unsaturated species, such
as alkyl groups, alkenyl groups, aryl groups, and the like. The
term "lower hydrocarbyl" intends a hydrocarbyl group of 1 to 6
carbon atoms, and the term "hydrocarbylene" intends a divalent
hydrocarbyl moiety containing 1 to about 30 carbon atoms,
preferably 1 to about 20 carbon atoms, most preferably 1 to about
12 carbon atoms, including linear, branched, cyclic, saturated and
unsaturated species. The term "lower hydrocarbylene" intends a
hydrocarbylene group of 1 to 6 carbon atoms. "Substituted
hydrocarbyl" refers to hydrocarbyl substituted with one or more
substituent groups, and the terms "heteroatom-containing
hydrocarbyl" and "heterohydrocarbyl" refer to hydrocarbyl in which
at least one carbon atom is replaced with a heteroatom. Similarly,
"substituted hydrocarbylene" refers to hydrocarbylene substituted
with one or more substituent groups, and the terms
"heteroatom-containing hydrocarbylene" and
heterohydrocarbylene"ref- er to hydrocarbylene in which at least
one carbon atom is replaced with a heteroatom. Unless otherwise
indicated, the term "hydrocarbyl" and "hydrocarbylene" are to be
interpreted as including substituted and/or heteroatom-containing
hydrocarbyl and hydrocarbylene moieties, respectively.
[0074] The term "heteroatom-containing" as in a
"heteroatom-containing hydrocarbyl group" refers to a hydrocarbon
molecule or a hydrocarbyl molecular fragment in which one or more
carbon atoms is replaced with an atom other than carbon, e.g.,
nitrogen, oxygen, sulfur, phosphorus or silicon, typically
nitrogen, oxygen or sulfur. Similarly, the term "heteroalkyl"
refers to an alkyl substituent that is heteroatom-containing, the
term "heterocyclic" refers to a cyclic substituent that is
heteroatom-containing, the terms "heteroaryl" and heteroaromatic"
respectively refer to "aryl" and "aromatic" substituents that are
heteroatom-containing, and the like. It should be noted that a
"heterocyclic" group or compound may or may not be aromatic, and
further that "heterocycles" may be monocyclic, bicyclic, or
polycyclic as described above with respect to the term "aryl."
[0075] By "substituted" as in "substituted hydrocarbyl,"
"substituted alkyl," "substituted aryl," and the like, as alluded
to in some of the aforementioned definitions, is meant that in the
hydrocarbyl, alkyl, aryl, or other moiety at least one hydrogen
atom bound to a carbon (or other) atom is replaced with one or more
non-hydrogen substituents. Examples of such substituents include,
without limitation: functional groups such as halogen, phosphonato,
phosphoryl, phosphanyl, phosphino, sulfonato, C.sub.1-C.sub.20
alkylsulfanyl, C.sub.5-C.sub.20 arylsulfanyl, C.sub.1-C.sub.20
alkylsulfonyl, C.sub.5-C.sub.20 arylsulfonyl, C.sub.1-C.sub.20
alkylsulfinyl, C.sub.5-C.sub.20 arylsulfinyl, sulfonamido, amino,
amido, imino, nitro, nitroso, hydroxyl, C.sub.1-C.sub.20 alkoxy,
C.sub.5-C.sub.20 aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl,
C.sub.5-C.sub.20 aryloxycarbonyl, carboxyl, carboxylato, mercapto,
formyl, C.sub.1-C.sub.20 thioester, cyano, cyanato, carbamoyl,
epoxy, styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato,
or boryl, or a metal-containing or metalloid-containing group
(wherein the metal may be, for example, Sn or Ge); and the
hydrocarbyl moieties C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20
alkenyl, C.sub.2-C.sub.20 alkynyl, C.sub.5-C.sub.20 aryl,
C.sub.5-C.sub.30 aralkyl, and C.sub.5-C.sub.30 alkaryl.
[0076] In addition, the aforementioned functional groups may, if a
particular group permits, be further substituted with one or more
additional functional groups or with one or more hydrocarbyl
moieties such as those specifically enumerated above. Analogously,
the above-mentioned hydrocarbyl moieties may be further substituted
with one or more functional groups or additional hydrocarbyl
moieties such as those specifically enumerated.
[0077] When the term "substituted" appears prior to a list of
possible substituted groups, it is intended that the term apply to
every member of that group. That is, the phrase "substituted alkyl,
alkenyl and alkynyl" is to be interpreted as "substituted alkyl,
substituted alkenyl and substituted alkynyl." Similarly,
"optionally substituted alkyl, alkenyl and alkynyl" is to be
interpreted as "optionally substituted alkyl, optionally
substituted alkenyl and optionally substituted alkynyl."
[0078] The term "amino" is used herein to refer to the group
--NZ.sup.1Z.sup.2, where each of Z.sup.1 and Z.sup.2 is
independently selected from the group consisting of hydrogen and
optionally substituted alkyl, alkenyl, alkynyl, aryl, aralkyl,
alkaryl and heterocyclic.
[0079] The term "stereoselective" refers to a chemical reaction
that preferentially results in one stereoisomer relative to a
second stereoisomer, i.e., gives rise to a product of which the
ratio of a desired stereoisomer to a less desired stereoisomer is
greater than 1:1.
[0080] "Optional" or "optionally" means that the subsequently
described circumstance may or may not occur, so that the
description includes instances where the circumstance occurs and
instances where it does not. For example, the phrase "optionally
substituted" means that a non-hydrogen substituent may or may not
be present on a given atom, and, thus, the description includes
structures wherein a non-hydrogen substituent is present and
structures wherein a non-hydrogen substituent is not present.
[0081] In the molecular structures herein, the use of bold and
dashed lines to denote particular conformation of groups follows
the IUPAC convention. A bond indicated by a broken line indicates
that the group in question is below the general plane of the
molecule as drawn (the ".alpha." configuration), and a bond
indicated by a bold line indicates that the group at the position
in question is above the general plane of the molecule as drawn
(the ".beta." configuration).
[0082] II. The Catalyst:
[0083] The cross-metathesis reactions of the invention are carried
out catalytically, using a Group 8 transition metal complex that
preferably contains two different ligands. These transition metal
carbene complexes include a metal center in a +2 oxidation state,
have an electron count of 16, and are penta-coordinated. More
specifically, the preferred catalysts herein have the structure of
formula (VIA) 15
[0084] wherein the various substituents are as follows:
[0085] M, which serves as the transition metal center in the +2
oxidation state, is a Group 8 transition metal, particularly
ruthenium or osmium. In a preferred embodiment, M is ruthenium.
[0086] X.sup.1 and X.sup.2 are anionic ligands or polymers, and may
be the same or different, or are linked together to form a cyclic
group, typically although not necessarily a five- to eight-membered
ring. In preferred embodiments, X.sup.1 and X.sup.2 are each
independently hydrogen, halide, or one of the following groups:
C.sub.1-C.sub.20 alkyl, C.sub.5-C.sub.20 aryl, C.sub.1-C.sub.20
alkoxy, C.sub.5-C.sub.20 aryloxy, C.sub.3-C.sub.20 alkyldiketonate,
C.sub.5-C.sub.20 aryldiketonate, C.sub.2-C.sub.20 alkoxycarbonyl,
C.sub.5-C.sub.20 aryloxycarbonyl, C.sub.2-C.sub.20 acyl,
C.sub.1-C.sub.20 alkylsulfonato, C.sub.5-C.sub.20 arylsulfonato,
C.sub.1-C.sub.20 alkylsulfanyl, C.sub.1-C.sub.20 arylsulfanyl,
C.sub.1-C.sub.20 alkylsulfinyl, or C.sub.5-C.sub.20 arylsulfinyl.
Optionally, X.sup.1 and X.sup.2 may be substituted with one or more
moieties selected from the group consisting of C.sub.1-C.sub.10
alkyl, C.sub.1-C.sub.10 alkoxy, aryl, and halide, which may, in
turn, with the exception of halide, be further substituted with one
or more groups selected from halide, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, and phenyl. In more preferred embodiments,
X.sup.1 and X.sup.2 are halide, benzoate, C.sub.2-C.sub.6 acyl,
C.sub.2-C.sub.6 alkoxycarbonyl, C.sub.1-C.sub.6 alkyl, phenoxy,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylsulfanyl, aryl, or
C.sub.1-C.sub.6 alkylsulfonyl. In even more preferred embodiments,
X.sup.1 and X.sup.2 are each halide, CF.sub.3CO.sub.2,
CH.sub.3CO.sub.2, CFH.sub.2CO.sub.2, (CH.sub.3).sub.3CO,
(CF.sub.3).sub.2(CH.sub.3)CO, (CF.sub.3)(CH.sub.3).su- b.2CO, PhO,
MeO, EtO, tosylate, mesylate, or trifluoromethanesulfonate. In the
most preferred embodiments, X.sup.1 and X.sup.2 are each chloride.
The complex may also be attached to a solid support, such as to a
polymeric substrate, and this attachment may be effected by means
of X.sup.1 and/or X.sup.2, in which case X.sup.1 and/or x.sup.2 is
a polymer.
[0087] R.sup.1 is selected from the group consisting of hydrogen,
hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl,
etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl,
alkynyl, aryl, aralkyl, alkaryl, etc.), heteroatom-containing
hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl,
aryl, aralkyl, alkaryl, etc.), and substituted
heteroatom-containing hydrocarbyl (e.g., substituted
heteroatom-containing alkyl, alkenyl, alkynyl, aryl, aralkyl,
alkaryl, etc.), and carboxyl, and R.sup.2 is selected from the
group consisting of hydrogen, hydrocarbyl (e.g., alkyl, alkenyl,
alkynyl, aryl, aralkyl, alkaryl, etc.), substituted hydrocarbyl
(e.g., substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl,
etc.), heteroatom-containing hydrocarbyl (e.g.,
heteroatom-containing alkyl, alkenyl, alkynyl, aryl, aralkyl,
alkaryl, etc.), and substituted heteroatom-containing hydrocarbyl
(e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl,
aryl, aralkyl, alkaryl, etc.). R.sup.1 and R.sup.2 may also be
linked to form a cyclic group, which may be aliphatic or aromatic,
and may contain substituents and/or heteroatoms. Generally, such a
cyclic group will contain 4 to 12, preferably 5 to 8, ring
atoms.
[0088] In preferred catalysts, the R.sup.1 substituent is hydrogen
and the R.sup.2 substituent is selected from the group consisting
of C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, and aryl. More
preferably, R.sup.2 is phenyl, vinyl, methyl, isopropyl, or
t-butyl, optionally substituted with one or more moieties selected
from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, phenyl, and a functional group Fn. Still more preferably,
R.sup.2 is phenyl or vinyl substituted with one or more moieties
selected from the group consisting of methyl, ethyl, chloro, bromo,
iodo fluoro, nitro, dimethylamino, methyl, methoxy, and phenyl. In
the most preferred embodiments, the R.sup.2 substituent is phenyl
or -C=C(CH.sub.3).sub.2.
[0089] L is a neutral electron donor ligand, and may or may not be
linked to R.sup.2. Examples of suitable L moieties include, without
limitation, phosphine, sulfonated phosphine, phosphite,
phosphinite, phosphonite, arsine, stibine, ether (including cyclic
ethers), amine, amide, imine, sulfoxide, carboxyl, nitrosyl,
pyridine, substituted pyridine (e.g., halogenated pyridine),
imidazole, substituted imidazole (e.g., halogenated imidazole),
pyrazine (e.g., substituted pyrazine), and thioether. In more
preferred embodiments, L is a phosphine of the formula
PR.sup.5R.sup.6R.sup.7, where R.sup.5, R.sup.6, and R.sup.7 are
each independently aryl or C.sub.1-C.sub.10 alkyl, particularly
primary alkyl, secondary alkyl or cycloalkyl. In the most preferred
embodiments, L is selected from the group consisting of
--P(cyclohexyl).sub.3, --P(cyclopentyl).sub.3,
--P(isopropyl).sub.3, --P(phenyl).sub.3, --P(phenyl).sub.2(R.sup.7)
and --P(phenyl)(R.sup.7).sub.2, in which R.sup.7 is alkyl,
typically lower alkyl. Also preferred are weaker ligands such as
the nitrogen-containing heterocycles, which enhance catalytic
activity presumably because of the requirement that the L ligand
dissociate for initiation to occur.
[0090] Examples of complexes wherein L and R.sup.2 are linked
include the following: 16
[0091] X and Y are heteroatoms typically selected from N, O, S, and
P. Since O and S are divalent, p is necessarily zero when X is O or
S, and q is necessarily zero when Y is o or S. However, when X is N
or P, then p is 1, and when Y is N or P, then q is 1. In a
preferred embodiment, both X and Y are N.
[0092] Q.sup.1, Q.sup.2, Q.sup.3, and Q.sup.4 are linkers, e.g.,
hydrocarbylene (including substituted hydrocarbylene,
heteroatom-containing hydrocarbylene, and substituted
heteroatom-containing hydrocarbylene, such as substituted and/or
heteroatom-containing alkylene) or --(CO)--, and w, x, y and z are
independently zero or 1, meaning that each linker is optional.
Preferably, w, x, y and z are all zero.
[0093] R.sup.3, R.sup.3A, R.sup.4, and R.sup.4A are independently
selected from the group consisting of hydrogen, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and
substituted heteroatom-containing hydrocarbyl, wherein R.sup.3A and
R.sup.4A may be linked to form a cyclic group.
[0094] It should be emphasized that any two or more (typically two,
three or four) of X.sup.1, X.sup.2, L, R.sup.1, R.sup.2, R.sup.3,
R.sup.3A, R.sup.4, and R.sup.4A can be taken together to form a
chelating multidentate ligand, as disclosed, for example, in U.S.
Pat. No. 5,312,940 to Grubbs et al. Examples of bidentate ligands
include, but are not limited to, bisphosphines, dialkoxides,
alkyldiketonates, and aryldiketonates. Specific examples include
--P(Ph).sub.2CH.sub.2CH.sub.2P- (Ph).sub.2--, --As(Ph).sub.2
CH.sub.2CH.sub.2As(Ph.sub.2)--,
--P(Ph).sub.2CH.sub.2CH.sub.2C(CF.sub.3).sub.2O--, binaphtholate
dianions, pinacol dianions,
--P(CH.sub.3).sub.2(CH.sub.2).sub.2P(CH.sub.3- ).sub.2-- and
--OC(CH.sub.3).sub.2(CH.sub.3).sub.2CO--. Preferred bidentate
ligands are --P(Ph).sub.2 CH.sub.2CH.sub.2P(Ph).sub.2-- and
--P(CH.sub.3).sub.2(CH.sub.2).sub.2P(CH.sub.3).sub.2--. Tridentate
ligands include, but are not limited to,
(CH.sub.3).sub.2NCH.sub.2CH.sub.-
2P(Ph)CH.sub.2CH.sub.2N(CH.sub.3).sub.2. Other preferred tridentate
ligands are those in which any three of X.sup.1, X.sup.2, L,
R.sup.1, R.sup.2, R.sup.3, R.sup.3A, R.sup.4, and R.sup.4A (e.g.,
X, L, and any one of R.sup.3, R.sup.3A, R.sup.4, and R.sup.4A ) are
taken together to be cyclopentadienyl, indenyl or fluorenyl, each
optionally substituted with C.sub.2-C.sub.20 alkenyl,
C.sub.2-C.sub.20 alkynyl, C.sub.1-C.sub.20 alkyl, C.sub.5-C.sub.20
aryl, C.sub.1-C.sub.20 alkoxy C.sub.2-C.sub.20 alkenyloxy,
C.sub.2-C.sub.20 alkynyloxy, C.sub.5-C.sub.20 aryloxy,
C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.1-C.sub.20 alkylthio,
C.sub.1-C.sub.20 alkylsulfonyl, or C.sub.1-C.sub.20 alkylsulfinyl,
each of which may be further substituted with C.sub.1-C.sub.6
alkyl, halogen, C.sub.1-C.sub.6 alkoxy or with a phenyl group
optionally substituted with halogen, C.sub.1-C.sub.6 alkyl or
C.sub.1-C.sub.6 alkoxy. More preferably, in compounds of this type,
X, L, and any one of R.sup.3, R.sup.3A, R.sup.4, and R.sup.4A are
taken together to be cyclopentadienyl or indenyl, each optionally
substituted with vinyl, C.sub.1-C.sub.10 alkyl, C.sub.5-C.sub.20
aryl, C.sub.1-C.sub.10 carboxylate, C.sub.2-C.sub.10
alkoxycarbonyl, C.sub.1-C.sub.10 alkoxy, C.sub.5-C.sub.20 aryloxy,
each optionally substituted with C.sub.1-C.sub.6 alkyl, halogen,
C.sub.1-C.sub.6 alkoxy or with a phenyl group optionally
substituted with halogen, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
alkoxy. Most preferably, X, L, and any one of R.sup.3, R.sup.3A,
R.sup.4, and R.sup.4A may be taken together to be cyclopentadienyl,
optionally substituted with vinyl, hydrogen, Me or Ph. Tetradentate
ligands include, but are not limited to
O.sub.2C(CH.sub.2).sub.2P(Ph)(CH.sub.2).sub.2P(Ph)(CH.sub.2).sub.2CO.sub.-
2, phthalocyanines, and porphyrins.
[0095] In a preferred embodiment, the catalyst has the structure of
formula (VIB) 17
[0096] wherein R.sup.3 and R.sup.4 are defined above, with
preferably at least one of R.sup.3 and R.sup.4, and more preferably
both R.sup.3 and R.sup.4, being alicyclic or aromatic of one to
about five rings, and optionally containing one or more heteroatoms
and/or substituents. Q is a linker, typically a hydrocarbylene
linker, including substituted hydrocarbylene, heteroatom-containing
hydrocarbylene, and substituted heteroatom-containing
hydrocarbylene linkers, wherein two or more substituents on
adjacent atoms within Q may also be linked to form an additional
cyclic structure, which may be similarly substituted to provide a
fused polycyclic structure of two to five cyclic groups. Q is
often, although again not necessarily, a two-atom linkage or a
three-atom linkage, e.g., --CH.sub.2--CH.sub.2--,
--CH(Ph)--CH(Ph)-- where Ph is phenyl; .dbd.CR--N.dbd., giving rise
to an unsubstituted (when R=H) or substituted (R=other than H)
triazolyl group; and --CH.sub.2--SiR.sub.2--- CH.sub.2 (where R is
H, alkyl, alkoxy, etc.).
[0097] In a more preferred embodiment, Q is a two-atom linkage
having the structure --CR.sup.22R.sup.22A--CR.sup.23R.sup.23A-- or
--CR.sup.22.dbd.CR.sup.23--, more preferably
--CR.sup.22R.sup.22A--CR.sup- .23R.sup.23A--, in which case the
complex has the structure of formula (VIC) 18
[0098] wherein R.sup.22, R.sup.22A, R.sup.23, and R.sup.23A are
independently selected from the group consisting of hydrogen,
hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and
functional groups (i.e., Fn, as defined previously), e.g.,
C.sub.1-C.sub.20 alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20
alkynyl, aryl, C.sub.1-C.sub.20 carboxylate, C.sub.1-C.sub.20
alkoxy, C.sub.2-C.sub.20 alkenyloxy, C.sub.2-C.sub.20 alkynyloxy,
aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.1-C.sub.20
alkylthio, arylthio, C.sub.1-C.sub.20 alkylsulfonyl, and
C.sub.1-C.sub.20 alkylsulfinyl, optionally substituted with one or
more moieties selected from the group consisting of
C.sub.1-C.sub.10 alkyl, C.sub.1-C.sub.10 alkoxy, aryl, hydroxyl,
sulfhydryl, --(CO)--H, halide, and functional groups (Fn, again, as
defined previously).
[0099] Additionally, R.sup.22, R.sup.22A, R.sup.23, and R.sup.23A
may be linked to form a substituted or unsubstituted, saturated or
unsaturated ring structure, e.g., a C.sub.4-C.sub.12 alicyclic
group or a C.sub.5 or C.sub.6 aryl group, which may itself be
substituted, e.g., with linked or fused alicyclic or aromatic
groups, or with other substituents.
[0100] Examples of N-heterocyclic carbene ligands incorporated into
complex (VIC) thus include, but are not limited to, the following:
19
[0101] R.sup.3 and R.sup.4 are preferably aromatic, substituted
aromatic, heteroaromatic, substituted heteroaromatic, alicyclic, or
substituted alicyclic, composed of from one to about five cyclic
groups. When R.sup.3 and R.sup.4 are aromatic, they are typically
although not necessarily composed of one or two aromatic rings,
which may or may not be substituted, e.g., R.sup.3 and R.sup.4 may
be phenyl, substituted phenyl, biphenyl, substituted biphenyl, or
the like. In one preferred embodiment, R.sup.3 and R.sup.4 are the
same and have the structure (XII) 20
[0102] in which R.sup.24, R.sup.25, and R.sup.26 are each
independently hydrogen, C.sub.1-C.sub.20 alkyl, substituted
C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 heteroalkyl, substituted
C.sub.1-C.sub.20 heteroalkyl, C.sub.5-C.sub.20 aryl, substituted
C.sub.5-C.sub.20 aryl, C.sub.5-C.sub.20 heteroaryl,
C.sub.5-C.sub.30 aralkyl, C.sub.5-C.sub.30 alkaryl, or halogen.
[0103] In especially preferred embodiments, R.sup.24, R.sup.25, and
R.sup.26 are each independently selected from the group consisting
of hydrogen, methyl, ethyl, propyl, isopropyl, hydroxyl, halogen,
phenyl, and lower alkyl-substituted phenyl (e.g., dimethylphenyl).
In the most preferred embodiments, R.sup.24, R.sup.25, and R.sup.26
are the same and are each methyl.
[0104] When R.sup.3 and R.sup.4 are alicyclic, they are generally
composed of a C.sub.7-C.sub.20, preferably a C.sub.7-C.sub.12,
alicyclic structure, e.g., diisopinocamphenyl. Complexes formed
with such ligands are exemplified by the complex containing the
diisopinocamphenyl-substitu- ted ligand shown in structural formula
(XIV). In the most preferred embodiments, R.sup.24, R.sup.25, and
R.sup.26 are the same and are each methyl. In another preferred
embodiment, R.sup.3 and R.sup.4 are each biphenylyl or substituted
biphenylyl. Catalysts formed with such ligands are exemplified by
the complex containing the 2,4,2',6'-tetramethylbiphen- ylyl-(i.e.,
2,6-dimethyl-3-(2',6'-dimethylphenyl)phenyl) substituted ligand
shown below as structural formula (XIII), preparation of which is
described in detail in as illustrated in Example 8. 21
[0105] When R.sup.3 and R.sup.4 are alicyclic, they are generally
composed of a C.sub.7-C.sub.20, preferably a C.sub.7-C.sub.12,
alicyclic structure, e.g., diisopinocamphenyl. Complexes formed
with such ligands, exemplified by the complex containing the
diisopinocamphenyl-substituted ligand shown in structural formula
(XIV), are novel compositions of matter and claimed as such herein.
22
[0106] Ligands containing bulky, electron-.donating groups such as
those illustrated in the complexes of formulae (XIII) and (XIV)
provide for very highly active olefin metathesis catalysts. Such
catalysts are thus suitable to catalyze reactions for which other,
less active catalysts are ineffective, and are also useful in
enhancing the stereoselectivity of a catalyzed cross-metathesis
reaction.
[0107] Examples of more preferred catalysts useful in conjunction
with the present methods, then, include, but are not limited to,
the following: 23
[0108] In the above molecular structures, "Mes" represents mesityl
(2,4,6-trimethylphenyl), "iPr" is isopropyl, "Ph" is phenyl, and
"Cy" is cyclohexyl.
[0109] III. Cross-metathesis of Functionalized and Substituted
Olefins:
[0110] The present invention, in one embodiment, provides a method
for using olefin cross-metathesis to synthesize olefins substituted
with functional groups. The reaction is carried out with a
functional group-substituted olefinic reactant, and may in fact be
carried out with two such functionalized olefins as
cross-metathesis reactants. The reaction is catalyzed using a
transition metal carbene complex as described in part (II) of this
section, and involves reaction between a first olefinic reactant
substituted with one or more functional groups, and a second
olefinic reactant that may or may not be substituted. With respect
to the first olefinic reactant, the functional groups may or may
not be in protected form (e.g., a hydroxyl group may be protected
as an acyloxy or benzyloxy group). More specifically, the first
olefinic reactant has the structure of formula (VIII) 24
[0111] wherein:
[0112] Fn is a functional group such as phosphonato, phosphoryl,
phosphanyl, phosphino, sulfonato, C.sub.1-C.sub.20 alkylsulfanyl,
C.sub.5-C.sub.20arylsulfanyl, C.sub.1-C.sub.20 alkylsulfonyl,
C.sub.5-C.sub.20 arylsulfonyl, C.sub.1-C.sub.20 alkylsulfinyl,
C.sub.5-C.sub.20 arylsulfinyl, sulfonamido, amino, amido, imino,
nitro, nitroso, hydroxyl, C.sub.1-C.sub.20 alkoxy, C.sub.5-C.sub.20
aryloxy, C.sub.2-C.sub.20 alkoxycarbonyl, C.sub.5-C.sub.20
aryloxycarbonyl, carboxyl, carboxylato, mercapto, formyl,
C.sub.1-C.sub.20 thioester, cyano, cyanato, carbamoyl, epoxy,
styrenyl, silyl, silyloxy, silanyl, siloxazanyl, boronato, or
boryl, or a metal-containing or metalloid-containing group (wherein
the metal may be, for example, Sn or Ge);
[0113] n is zero or 1;
[0114] Z is a hydrocarbylene or a substituted and/or
heteroatom-containing hydrocarbylene linking group slinking group
such as an alkylene, substituted alkylene, heteroalkylene,
substituted heteroalkene, arylene, substituted arylene,
heteroarylene, or substituted heteroarylene linkage; and
[0115] R.sup.5, R.sup.6, and R.sup.7 are independently selected
from the group consisting of hydrogen, -(Z).sub.n-Fn, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl, and
substituted heteroatom-containing hydrocarbyl, and, if substituted
hydrocarbyl or substituted heteroatom-containing hydrocarbyl, one
or more substituents may be -(Z).sub.n-Fn.
[0116] The functional group will generally not be directly bound to
the olefinic carbon through a heteroatom containing one or more
lone pairs of electrons, e.g., an oxygen, sulfur, nitrogen or
phosphorus atom, or through an electron-rich metal or metalloid
such as Ge, Sn, As, Sb, Se, Te, etc. With such functional groups,
there will normally be an intervening linkage Z, i.e., n is 1.
[0117] The second olefinic reactant has a molecular structure given
by R.sup.18R.sup.19C=CR.sup.20R.sup.21wherein R.sup.18, R.sup.19,
R.sup.20, and R.sup.21may be hydrogen, hydrocarbyl, substituted
hydrocarbyl, heteroatom-containing hydrocarbyl, substituted
heteroatom-containing hydrocarbyl, or -(Z).sub.n-Fn, wherein n, Z
and Fn are as defined earlier.
[0118] In a preferred embodiment, with respect to the first
reactant, R.sup.5 and at least one of R.sup.6 and R.sup.7 is
hydrogen, Fn is a phosphonate, and Z is lower alkylene, and in a
most preferred embodiment, R.sup.5, R.sup.6 and R.sup.7 are
hydrogen, and Z is methylene, such that the first olefinic reactant
is a vinylphosphonate having the structure of formula (XII) 25
[0119] when n is zero, and an allylphosphonate having the structure
of formula (XIII) 26
[0120] when n is 1. In formulae (XV) and (XVI), R.sup.27 and
R.sup.28 are hydrocarbyl, preferably lower hydrocarbyl, and most
preferably are lower alkyl such as methyl or ethyl.
[0121] With respect to the second reactant, it is preferred that
R.sup.18, R.sup.19, and R.sup.20 are hydrogen, such that reactant
has the structure H.sub.2C=C(H)R.sup.21.
[0122] The capability of the methods of the invention with respect
to such reactants are illustrated by a series of experiments
summarized in the following tables, using the ruthenium catalyst
(V) 27
[0123] in which IMesH.sub.2 is as defined previously, Cy is
cyclohexyl, and Ph is phenyl.
[0124] Terminal olefins were reacted with commercially available
diethyl vinylphosphonate as described in Example 4. As may be seen
in Table 1, cross-metathesis with an olefinic ester resulted in a
95% yield of product, almost exclusively as the (E) isomer (Table
1, Entry 1). No dimerization of the vinylphosphonate was detected
by .sup.1H-NMR, allowing for selective cross-metathesis. Alkyl
halide (Entry 2) and unprotected aldehyde functionalities (Entry 3)
were well tolerated with the ruthenium catalyst (V). Allyl benzene
also gave the desired metathesis product, without olefin
isomerization (Entry 4). The reaction also gave good yields with a
variety of styrenes, which were converted to
(E)-cinnamylphosphonates in high yield (Table 1, Entry 5).
1TABLE 1 28 Entry Cross Metathesis Partner Product Isolated
Yield.sup.a 1 29 30 95% 2 31 32 82% 3 33 34 77% 4 35 36 90% 5 37 38
97% R = H 97% R = 4-OMe 93% R = 4-Br 77% R = 2,4-(CH.sub.3).sub.2
.sup.a>20:1 E/Z as determined by .sup.1H-NMR
[0125] Second, diethylallylphosphonate was investigated as a
cross-metathesis partner. As indicated by the data in Table 2,
allylphosponates are viable cross-metathesis partners using the
present method, providing enhanced cross-metathesis ratios relative
to the predicted statistical mixture.
2TABLE 2 39 Entry Metathesis Partner Product Isolated Yield E/Z
ratio.sup.a 1 40 41 70% >20:1 2 42 43 93% >20:1 3 44 45 73%
>20:1 4 46 47 74% 5.4:1 5 48 49 85% 3.5:1 6 50 51 90% 2.5:1
.sup.aDetermined by .sup.1H-NMR
[0126] In addition, some sterically challenging styrenes proved to
be excellent CM partners (Table 2, Entry 2 and 3), providing the
E-isomer exclusively. A trisubstituted olefin is also formed in
excellent yield with modest stereoselectivity (Table 2, Entry 6).
All of the reaction products were easily separated from their
respective homodimers by column chromatography.
[0127] As noted above, the functional group Fn is not necessarily
phosphonate. A significant advantage of the present methodology is
that the olefinic reactants can be substituted with one or more of
a host of functional groups, even if those functional groups are
potential ligands for the catalyst.
[0128] For example, catalyst (V) has been used to effect
cross-metathesis reactions using allylboronates as starting
materials. Such reactions are quite useful in the stereoselective
synthesis of homoallylic alcohols. Prior to the present invention,
the accessibility of functionalized allyl boron reagents was quite
limited, and such complexes are traditionally prepared by
allylmetal addition to haloboranes or hydroboration of 1,3-dienes,
methods that can be incompatible with complex substrates and/or
many desired functional groups. The present invention, however,
enables a one pot cross-metathesis/allylboration reaction that
affords densely functionalized homoallylic alcohols, as illustrated
using pinacol allyl boronate according to the following scheme:
52
[0129] The general procedures for carrying out such reactions are
described in detail in Example 9. The effects of varying the
catalyst and the relative stoichiometries of components of the
cross-metathesis/allyla- tion reaction were explored using
(Z)-1,4-diacetoxy-2-butene and benzaldehyde (Table 3). As may be
seen, E allylboronates afforded anti products with high
diastereoselectivity, and the catalyst of the invention, complex
(V), was more E selective than the bis-tricyclohexyl-phosphine
rutheniuim alkylidene complex (II), indicating that catalyst (V)
provides the homoallylic product with greater anti selectivity. In
fact, using the complex of the invention, catalyst loading could be
reduced to 2 mol% (Table 3, entry 3) without effecting the yield or
diastereoselectivity. The fact that the homoallylic alcohol was
formed in 57% yield using a stoichiometric cross partner (Table 3,
entry 4), greater than is expected statistically (50%), indicates
that the asymetrically terminated product was favored over
symmetrical dimers.
3TABLE 3 53 54 eq of cross eq of catalyst entry partner
benzaldehyde (mol %) yield(%) anti/syn 1 3 1.5 II (5) 32 1.8/1 2 3
1.5 V (5) 75 4.5/1 3 3 1.5 V (2) 75 4.5/1 4 0.5 1.5 V (5) 57 4.7/1
5 3 0.75 V (5) 75 4.5/1
[0130] A number of experiments, summarized in Table 4, were carried
out in which the aforementioned reaction was used to generate
homoallylic alcohols with protected hydroxymethyl, protected
aldehyde, and halomethyl side chains from pinacol allyl
boronate.
4TABLE 4 entry cross partner mol % of V yield (%) anti/syn product
1 55 5 44-67 4/1 56 2 2 57 5 2 60 63 4.7/1 3.2/1 58 3 3 59 5 2 68
69 >20/1 >20/1 60 4 4 61 5 2 73 72 3.8/1 3.6/1 62 5 5 63 5 2
78 79 4.9/1 4.6/1 64 6
[0131] As may be seen in entries 1 and 2, silyl and benzyl allylic
ethers were efficiently transformed to the corresponding
homoallylic alcohols 2 and 3, respectively, indicating that the
methodology enables facile tuning of the olefinic substrate to
conform to preexisting protecting group strategies.
2-Vinyl-1,3-dioxolane was effectively converted into alcohol 4 in
69% yield as a single diastereomer (entry 3), indicating that an
increase in steric bulk at the allylic carbon atom favors the
formation of trans olefins. The present method is also effective in
achieving incorporation of a halomethyl group directly by
allylboration, a reaction that has not been achieved previously.
The bromomethyl (entry 4) and chloromethyl (entry 5) allylation
products, 5 and 6 respectively, were synthesized in good yields
from the corresponding 1,4-dihalo-2-butenes. The present method
thus enables a one-step, one-pot synthesis of halogenated targets
that would require several steps to prepare by traditional
methods.
[0132] As another example, catalyst (V) has been used to prepare
secondary allylic alcohols from other protected or unprotected
secondary allylic reactants. Examples of such reactions are
summarized in Table 5.
5TABLE 5 Isolated Allylic Substit. Olefin Cross Partner Equiv.
Product Yield(%) E/Z ratio 65 66 2.0 eq. 67 92 13:1 68 69 2.0 eq.
70 88 >20:1 71 72 2.0 eq. 73 38 18:1 74 75 2.0 eq. 76 82 11:1 77
78 0.5 eq. 79 53 6.7:1 80 81 0.5 eq. 82 61 >20:1 83 84 1.5 eq.
85 60 6:1
[0133] In addition, catalyst (V) has been used to dimerize the
allylic sulfide 3-methylsulfanyl-propene according to the following
scheme: 86
[0134] As additional examples, complex (V) has been used to
catalyze cross-metathesis reactions with other functionalized
olefins, as described in Example 6 and as indicated in Table 6:
6TABLE 6 Entry 1 87 88 2 89 90 3 91 92 4 93 94 5 95 96 6 97 98
[0135] As may be seen above, the present method is applicable not
only to dimerization of functionalized allylic olefins, but extends
to catalytic reaction of such compounds as substrates for
cross-metathesis, regardless of the oxidation state of a particular
atom in the functional group (e.g., phosphorus-containing
functional groups in the form of phosphines, protected phosphines,
and phosphonates) or the nature of the functional group (e.g., the
reaction proceeds with an allyl amine as well). This versatility is
further evidenced by applicants' use of (V) as a catalyst for the
preparation of oxazolylphenols as illustrated below: 99
[0136] In another aspect of the invention, the versatility of the
present methodology is applied to create functional diversity,
i.e., to create a plurality of different olefinic products from a
single olefinic reactant. This is carried out by conducting a
plurality of olefin metathesis reactions each employing a common
first olefinic reactant but a different second olefinic reactant.
In this way, a plurality of analogs is provided sharing some
structural commonality but having a distinguishing feature. As each
olefinic reactant may be substituted with functional groups,
cross-metathesis products result that contain those groups, thus
providing the option of further derivatization. This can be
illustrated by reference to the following schemes: 100
[0137] In the above olefins, n and Z are as defined previously, and
Fn.sup.1, Fn.sup.2, Fn.sup.3, and Fn.sup.4 are as defined for Fn or
may include other functional groups, e.g., carboxylate, alkoxy,
etc. The olefinic reactants may be further substituted on the
olefinic carbon atoms with additional -(Z).sub.n-Fn groups, or with
other moieties such as R.sup.5, R.sup.6, and R.sup.7, defined above
with respect to the olefins of formula (VIII).
[0138] As a specific example, a family of related potential
oxazolylphenol ligands was prepared by cross-metathesis of a single
olefinic reactant with a plurality of different second olefinic
reactants, again using complex (V) as catalyst, as illustrated
below: 101
[0139] It will be appreciated that the capability of the invention
in this regard enables the generation of diverse libraries of
related but structurally distinct compounds, which may then be
screened using any of various processes to ascertain utility, e.g.,
as potential ligands, reactants, biologically active agents, and
the like. The method may be generally characterized as a process
for generating a plurality of structurally diverse functionalized
olefins from a common olefinic reactant via a cross-metathesis
reaction, the method involving the following steps:
[0140] (a) contacting a functionalized olefinic substrate with a
first olefinic reactant in the presence of a catalyst composed of a
Group 8 transition metal alkylidene complex containing an
N-heterocyclic carbene ligand, under conditions and for a time
period effective to allow cross-metathesis to occur;
[0141] (b) in a separate reaction, contacting the first olefinic
reactant with a second olefinic reactant having a molecular
structure that is different from that of the first olefinic
reactant, in the presence of the Group 8 transition metal
alkylidene complex, under conditions and for a time period
effective to allow cross-metathesis to occur; and
[0142] (c) optionally repeating step (b) with a plurality of
olefinic reactants each having a different molecular structure.
[0143] In another embodiment, the present invention provides a
straightforward method for carrying out an olefin cross-metathesis
reaction using an a-halogenated olefin in order to provide a
directly halogenated olefinic product. In this embodiment, the
catalyst used may be the complex of formula (VIB), or it may be an
alternative complex of formula (VI) wherein L.sup.1 is a neutral
electron donor other than an N-heterocyclic carbene. For example,
the catalyst may be a bis(phosphine), in which case both L and
L.sup.1 of formula (VI) are phosphine ligands such as
triphenylphosphine. At least one of the olefinic reactants has the
structure of formula (IX) 102
[0144] wherein X.sup.3 is halo, and R.sup.8, R.sup.9, and R.sup.10
are independently selected from the group consisting of hydrogen,
halo, hydrocarbyl, substituted hydrocarbyl, heteroatom-containing
hydrocarbyl, substituted heteroatom-containing hydrocarbyl, and
-(Z).sub.n-Fn where n, Z and Fn are as defined previously with
respect to formula (VIII). The second olefinic reactant has the
same structure, or the structure
R.sup.18R.sup.19C.dbd.CR.sup.20R.sup.21 wherein R.sup.18, R.sup.19,
R.sup.20, and R.sup.21 are as defied previously.
[0145] The following schemes exemplify cross-metathesis reactions
of this type: 103
[0146] The reaction is straightforward and provides a facile method
for obtaining an .alpha.-halogenated olefin product.
[0147] For example, using the procedures described in Example 5, an
olefin metathesis catalyst
(L)(L.sup.1)X.sup.1X.sup.2Ru.dbd.CR.sup.1R.sup.2 such as
(H.sub.2IMes)(PCy.sub.3)Cl.sub.2Ru.dbd.CHPh reacts with
1,1-difluoroethylene to yield the corresponding methylidene
(H.sub.2IMes)(PCy.sub.3)Cl.sub.2Ru.dbd.CH.sub.2 and difluorocarbene
(H.sub.2IMes)(PCy.sub.3)Cl.sub.2Ru.dbd.CF.sub.2 complexes. At
elevated temperatures, greater than 98% of the difluorocarbene
complex forms, and it can be isolated in pure form by column
chromatography. Although this reaction is not catalytic, the
H.sub.2C.dbd.CF.sub.2 double bond is cleaved in a metathesis
fashion, and as such, it is the first example of metathesis
involving a directly halide-substituted olefin. In addition, it
should be emphasized that
(H.sub.2IMes)(PCy.sub.3)Cl.sub.2Ru=CF.sub.2 is active for
subsequent metathesis reactions, such as the ring-closing
metathesis of diethyl diallylmalonate and the ring-opening
metathesis polymerization of norbornene derivatives. The activity
of (H.sub.2IMes)(PCy.sub.3)Cl.sub.2Ru.dbd.CF.sub.2 can be enhanced
by the addition of HCl or CuCl, which aid in the dissociation of
PCy.sub.3 from the metal center. The bis(pyridine) derivative of
the catalyst, (H.sub.2IMes)(py).sub.2Cl.sub.2Ru.dbd.CF.sub.2, is
somewhat more active for subsequent metathesis reactions than the
PCy.sub.3 complex, presumably because the pyridine ligands are less
basic and thus more labile. Likewise, the bis(phosphine) olefin
metathesis catalyst (PCy.sub.3).sub.2Cl.sub.2Ru.dbd.CHPh reacts
with 1,1-difluoroethylene to yield the corresponding methylidene
(PCy.sub.3).sub.2Cl.sub.2Ru.dbd.CH.su- b.2 and difluorocarbene
(PCy.sub.3).sub.2Cl.sub.2Ru.dbd.CF.sub.2 complexes.
[0148] In a further embodiment, a method is provided for
synthesizing substituted olefins, particularly geminal
disubstituted olefins, 1,1,2-trisubstituted olefins and quaternary
allylic olefins, wherein the method comprises using the complex of
formula (VI) to catalyze a cross-metathesis reaction between a
geminal disubstituted olefin, a 1,1,2-trisubstituted olefin, or a
quaternary allylic olefin, and a second olefin. If it is a geminal
disubstituted olefin or a 1,1,2-trisubstituted olefin, the first
olefin has the structure (X) 104
[0149] wherein R.sup.11, R.sup.12, R.sup.13, and R.sup.14 are
selected from the group consisting of hydrogen, halo, hydrocarbyl,
substituted hydrocarbyl, heteroatom-containing hydrocarbyl,
substituted heteroatom-containing hydrocarbyl, and -(Z).sub.n-Fn
where n, Z and Fn are as defined above, with the provisos that
R.sup.11 and R.sup.12, or R.sup.13 and R.sup.14 are other than
hydrogen for a geminal disubstituted olefin, and that R.sup.11,
R.sup.12, and R.sup.13 are other than hydrogen for a
1,1,2-trisubstituted olefin. If it is a quaternary allylic olefin,
the first olefin has the structure (XI) 105
[0150] wherein R.sup.11 and R.sup.12 are as defined previously, and
R.sup.15, R.sup.16, and R.sup.17 are nonhydrogen substituents.
[0151] In the aforementioned cross-metathesis reaction, the second
olefin has a molecular structure given by
R.sup.18R.sup.19C.dbd.CR.sup.20R.sup.2- 1 wherein R.sup.18,
R.sup.19, R.sup.20, and R.sup.21 may be hydrogen, hydrocarbyl
substituted hydrocarbyl, heteroatom-containing hydrocarbyl, or
substituted heteroatom-containing hydrocarbyl.
[0152] Generally, the reaction is carried out with the two olefinic
reactants in a mole ratio in the range of about 1:3 to 3:1, at a
temperature in the range of about 20.degree. C. to about 40.degree.
C., for a time period in the range of about 4 to 16 hours.
Typically, about 0.01 to 7.5 mole % catalyst is used. However, the
reaction is also viable if there is a large excess of one reactant,
such as is the case when one reactant serves as a solvent for the
reaction mixture.
[0153] Another example of such a reaction is the synthesis of
1,1-dimethyl olefins through a cross-metathesis reaction of
a-olefins with isobutylene or 2-methyl-2-butene. The capability of
the methods of the invention with respect to such a reaction is
illustrated by a series of experiments summarized in Table 7, using
2-methyl-2-butene as the geminal disubstituted olefin and
(MesH.sub.2)(PCy.sub.3)Cl.sub.2RuC(H)Ph (complex (V)) as the
catalyst.
7TABLE 7 Entry Terminal .alpha.-Olefin Product Yield 1 106 107 97 2
108 109 97 3 110 111 96 4 112 113 91 5 114 115 91 6 116 117 99 7
118 119 80 8 120 121 83
[0154] Additional experiments, summarized in Table 8, were carried
out using catalyst (V) to generate trisubstituted olefins from
symmetrical 1,1-disubstituted olefins as starting materials.
8TABLE 8 1,1-Disubstituted Metathesis Entry Olefin Temp(.degree.
C.) Partner Product Isolated Yield 1 122 40 123 124 97 2 125 40 126
127 88 3 128 40 129 130 48 4 131 40 132 133 65 5 134 40 135 136 96
6 137 40 138 139 42 7 140 40 141 142 83
[0155] Further experiments illustrating the versatility of the
present methodology were carried out in order to generate
1,2-disubstituted olefins with quaternary allylic carbons using the
catalyst (V), the results of which are summarized in Table 9.
9TABLE 9 Quat. Entry Allylic Olefin Equiv. CM Partner Product Yield
1 143 0.5 eq. 144 145 95 2 146 2.0 eq. 147 148 97 3 149 0.5 eq. 150
151 66 4 152 2.0 eq. 1.0 eq. 153 154 90 69 5 155 3 eq. 156 157 88 6
158 .about.50 eq. 159 160 93 7 161 3 eq. 162 163 44 8 164 2 eq. 165
166 93 9 167 1 eq. 168 169 95 10 170 2 eq. 171 172 71
[0156] These reactions were stereoselective, resulting in virtually
exclusive formation of the trans olefin isomer, as may be seen
under the column heading "E/Z Ratio" in the figure. This
stereoselectivity is an important feature of the method, insofar as
prior to the present invention, there was no general method for
controlling the stereoselectivity of newly formed olefins.
[0157] In a related embodiment of the invention, a stereoselective
method for carrying out an olefin cross-metathesis reaction is
provided, wherein the stereochemistry of the olefinic product may
be either cis or trans, as desired. The catalyst used has the
structure of formula (VIB), wherein the nitrogen atoms of the
N-heterocyclic carbene ligand are substituted with bulky
substituents, i.e., R.sup.3 and R.sup.4 are aromatic, substituted
aromatic, heteroaromatic, substituted aromatic, alicyclic, or
substituted alicyclic. For a stereoselective synthesis that will
preferentially result in a cis-1,2-disubstituted olefin, bulky
R.sup.3 and R.sup.4 substituent are preferred, e.g., bicyclic or
polycyclic ligands that may or may not be aromatic. If R.sup.3 and
R.sup.4 are aromatic, they are generally composed of two to five
aromatic rings that may be fused or linked (e.g., biphenyl or
substituted biphenyl), and if R.sup.3 and R.sup.4 are alicyclic,
they are generally composed of a C.sub.7-C.sub.20, preferably a
C.sub.7-C.sub.12, alicyclic structure that may or may not be
substituted. Representative such R.sup.3 and R.sup.4 groups thus
include the alicyclic groups norbornyl, adamantyl, camphenyl,
isobornyl, any of which may be substituted, e.g., with a lower
alkyl group (as in diisopinocamphenyl, as shown in the structure of
formula (XIV)), and the bicyclic groups biphenylyl and
2',6'-dimethyl-3'-(2",6"-d- imethylphenyl (as shown in the
structure of formula (XIII)).
[0158] It is to be understood that while the invention has been
described in conjunction with the preferred specific embodiments
thereof, that the foregoing description as well as the examples
that follow are intended to illustrate and not limit the scope of
the invention. Other aspects, advantages and modifications within
the scope of the invention will be apparent to those skilled in the
art to which the invention pertains.
[0159] All patents, patent applications, and publications mentioned
herein are hereby incorporated by reference in their
entireties.
EXPERIMENTAL
[0160] IMesH.sub.2Cl was prepared according to a modified version
of the procedure described in Scholl et al. (1999) Org. Lett.
1:953-956 and Jafarpour et al. (2000) Organometallics 19:2055-2057.
Unless otherwise specified, all other reagents were purchased from
commercial suppliers and used without further purification. All
other solvents were purified by passage through a solvent column
(containing activated A-2 alumina; see Pangborn et al. (1996)
Organometallics 15:1518-1520.). Analytical thin-layer
chromatography (TLC) was performed using silica gel 60 F254
precoated plates (0.25 mm thickness) with a fluorescent indicator.
Flash column chromatography was performed using silica gel 60
(230-400 mesh) from EM Science. .sup.1H, .sup.13C, and .sup.31P NMR
spectra were obtained on a Varian 300 MHz Fourier Transform
spectrometer (300 MHz .sup.1H, 75.4 MHz .sup.13C, 121.4
MHz.sup.31P). All chemical shift values are given in parts-per
million (.delta.) and are referenced with respect to residual
solvent (.sup.1H and .sup.13C) or phosphoric acid (.sup.31P).
[0161] Preparation of IMesH.sub.2Cl: IMesH.sub.2Cl, used as a
starting material in Examples 1 through 3, was synthesized
according to the following scheme: 173
[0162] To a solution of glyoxal (9 mL, 79 mmol, 40% wt in H.sub.2O)
in isopropanol (100 mL) and H.sub.2O (200 mL) was added
mesitylamine (25 mL, 2.2 eq.) at 0.degree. C. The reaction mixture
was stirred while allowing to warm to room temperature. Immediately
upon addition of amine, yellow precipitates were formed. After 24
hrs of stirring at ambient temperature, the precipitates were
filtered and washed with H.sub.2O (1.times.100 mL) and hexanes
(3.times.100 mL). The yellow precipitates obtained were dried in
vacuo to yield the diimine (20.6 g, 89%).
[0163] To a solution of diimine (8.0 g, 27.3 mmol) in THF (100 mL)
was added NaBH4 (4.24 g, 112.1 mmol) at 0.degree. C. Concentrated
HCl (4.5 mL, 2 eq.) was added dropwise over 30 minutes. After the
HCl addition, the reaction mixture was stirred at 0.degree. C. for
20 min. Then, 3 M HCl (250 mL) was added carefully to the flask at
0.degree. C. and the mixture was stirred for an additional 1 hr,
allowing the temperature to rise to ambient temperature. The
resulting white precipitates were filtered and washed with water
(200 mL) and 5% acetone-ether (150 mL). The product (9.4 g, 93%)
was obtained as a white solid and dried in vacuo. To a suspension
of the HCl salt (8.5 g, 23 mmol) in HC(OEt)3 (35 mL, 162 mmol) was
added 2 drops of HCO.sub.2H (adding about 1 mol %). The reaction
mixture was then heated at 120.degree. C. for 5 hr under Ar. Then,
the reaction mixture was cooled to an ambient temperature and
hexane (200 mL) was added. The mixture was stirred for 1 hr and the
white precipitates were filtered, washed with hexane (.about.200
mL) and dried in vacuo to yield the IMesH.sub.2HCl salt (7.6 g,
96%).
EXAMPLE 1
Representative Procedure for Synthesis of Ruthenium Alkylidene
Catalysts
[0164] Synthesis of
RuCl.sub.2(.dbd.CH--CH.dbd.C(CH.sub.3).sub.2)(IMesH.su-
b.2)(PCy.sub.3) (complex (2), Scheme 1): 174
[0165] [Ru(COD)Cl.sub.2].sub.n. (300 mg, 1 mmol), IMesH.sub.2Cl
(1.47 g, 4 mmol), tricyclohexylphosphine (300 mg, 1 mmol), and
KN(SiMe.sub.3).sub.2 (540 mg, 2.5 mmol) were weighed directly into
a 600 mL Schlenk tube. The flask was evacuated and filled with dry
argon (2.times.). Degassed benzene (300 mL) was added and the flask
was pressurized to 30 psi with H.sub.2. The suspension was
vigorously stirred for 12 hours at 90.degree. C., yielding a bright
yellow solution and white precipitate (1). After cooling the
reaction to 5.degree. C., propargyl chloride (0.3 mL, 4 mmol) was
slowly added via syringe and the reaction mixture was allowed to
warm to room temperature. The resulting brown benzene solution was
washed with degassed 1M HCl (2.times.), degassed brine (2.times.),
filtered through Celite and concentrated in vacuo to afford
compound (2) as a brown solid in 90% yield (.about.95% purity). The
brown solid displayed catalytic behavior identical with previously
synthesized second-generation catalysts. Analytically pure (2) was
obtained by column chromatography on silica gel (degassed 3:1
hexanes/Et.sub.2O). .sup.1H NMR (CD.sub.2Cl.sub.2): .delta.18.49
(d, J=11.1 Hz, 1H), 7.26 (d, J=10.9 Hz, 1H), 6.97 (s, 2H), 6,77 (s,
2H), 3.92 (m, 4H), 2.58 (s, 6H), 2.37 (s, 6H), 2.29 (s, 3H), 2.23
(s, 3H), 0.88-1.584 (m, 33H), 1.06 (s, 3H), 1.08 (s, 3H). .sup.31P
NMR (CD.sub.2Cl.sub.2): .delta.28.9. The reaction was repeated
several times with one or more reaction conditions modified so as
to optimize the yield of the product. It was found that the yield
could be increased to greater than 95% by reducing the reaction
temperature from 90.degree. C. to 80.degree. C.
[0166] Analogous ruthenium alkylidene complexes can be prepared
using the aforementioned protocol and differently substituted
phosphines, alkynes, etc., as indicated in the following two
examples.
EXAMPLE 2
Synthesis of
RuCl.sub.2(.dbd.CH--CH.dbd.C(CH.sub.3).sub.2)(IMesH.sub.2)(PP-
h.sub.3) (complex (4), Scheme 2)
[0167] 175
[0168] The procedure of Example 2 was employed using
[Ru(COD)Cl.sub.2].sub.n (300 mg, 1 mmol), IMesH.sub.2Cl (0.74 g, 2
mmol), triphenylphosphine (280 mg, 1 mmol), and
KN(SiMe.sub.3).sub.2 (380 mg, 1.9 mmol), giving 550 mg (68%) of
complex (3). .sup.31P NMR (CD.sub.2Cl.sub.2): .delta.24.0. .sup.1H
NMR (CD.sub.2Cl.sub.2): .delta.18.49 (d, J=11.1 Hz, 1H).
EXAMPLE 3
Synthesis of RuCl.sub.2(.dbd.CH--CH--Ph)(IMesH.sub.2)(PCy.sub.3)
(complex (5), Scheme 3)
[0169] 176
[0170]
RuCl.sub.2(.dbd.CHPh)(PCy.sub.3).(phenylmethylene-bis(tricyclohexyl-
phosphine) ruthenium dichloride, "catalyst (I)") (6.00 g, 7.29
mmol, 1.0 eq.), IMesH.sub.2HCl salt prepared above (2 eq.), and
potassium t-butoxide (2 eq.) were placed in a Schlenk flask. 60 mL
of anhydrous degassed hexanes (Aldrich SureSeal boffle) were added.
A vacuum was applied to further degas the reaction mixture, which
was then heated to 60.degree. C. for 24 hours. The suspension
changed color from purple to orange-brown over the reaction time.
After approximately 24 hr, the mixture was cooled to room
temperature, and an excess of 1:1 isopropanol:water (180 mL) was
added. The mixture was stirred rapidly in air for 30 min., then
filtered using a medium porosity frit, and washed with
isopropanol-water (3.times.100 mL) and hexanes (3.times.100 mL).
The solids were dried in in vacuo, and the yield was approximately
75%. .sup.1H NMR (CD.sub.2C.sub.2, 400 MHz) .delta.19.16 (s, 1H),
7.37-7.05 (m, 9H), 3.88 (s, 4H), 2.56-0.15 (m, 51H); .sup.31P NMR
(CD.sub.2Cl.sub.2, 161.9 MHz) .delta.31.41; HRMS (FAB)
C.sub.45H.sub.65Cl.sub.2N.sub.2PRu [M.sup.+] 848.3306, found
848.3286.
EXAMPLE 4
Representative Procedures for Cross-metathesis Reactions Used to
Synthesize Functionalized Olefins
[0171] Preparation of Olefinic Phosphonates (Tables 1 and 2):
Terminal olefin (0.75 mmol) and diethyl vinylphosphonate (Aldrich)
or diethyl allylphosphonate (Acros Organics, 0.51 mmol) were added
simultaneously via syringe to a stirring solution of (5) (21 mg,
0.026 mmol, 5.2 mol %) in CH.sub.2Cl.sub.2 (2.5 mL, 0.2M in
phosphonate) under a nitrogen atmosphere. The flask was fitted with
a condenser and refluxed under nitrogen for 12 hours. The reaction
mixture was then reduced in volume to 0.5 mL and purified directly
on a silica gel column (2.times.10 cm), eluting with 1:1
hexane:ethyl acetate to provide cross products as viscous oils.
EXAMPLE 5
Representative Procedures for Synthesis Directly Halogenated
Olefins
[0172] 177
[0173] Synthesis and characterization of
[(IMesH.sub.2)(PCy.sub.3)(Cl).sub- .2Ru.dbd.CF.sub.2]: A solution
of 0.32 g (0.37 mmol)
[(IMesH.sub.2)(PCy.sub.3)(Cl).sub.2Ru.dbd.CHPh] (5) in dry,
degassed benzene (15 mL) in a thick-walled glass ampule was put
under .about.1.5 atm of 1,1-difluoroethylene. The reaction was
heated at 60.degree. C. for 12 hrs, during which time it changed
from reddish to brown in color. The solution was then concentrated
to 5 mL and purified by column chromatography in air (silica gel,
5:1 pentane/THF). The orange fraction was stripped of solvent and
dried under vacuum: yield 0.26 g (86%). .sup.1H NMR (499.852 MHz,
25.degree. C., CD.sub.2Cl.sub.2): .delta.1.118 [br, 15H,
PCy.sub.3], 1.626 [br, 15H, PCy.sub.3], 2.248 [s, 3H, p-CH.sub.3 of
Mes], 2.285 [s, 3H, p-CH.sub.3 of Mes], 2.385 [m, 3H PCy.sub.3],
2.480 [s, 6H, o-CH.sub.3 of Mes], 2.551 [s, 6H, o-CH.sub.3 of Mes],
4.003 [s, 4H, NCH.sub.2CH.sub.2N], 6.921 [s, 4H, m-H of Mes].
.sup.13C {.sup.1H} NMR (125.705 MHz, 30.degree. C.,
C.sub.6D.sub.6): .delta.19.44 [s, CH.sub.3 of Mes], 20.65 [s,
CH.sub.3 of Mes], 21.49 [s, CH.sub.3 of Mes], 21.50 [s, CH.sub.3 of
Mes], 26.92 [d, J=1.3 Hz, PCy.sub.3], 28.50 [d, J=10 Hz,
PCy.sub.3], 30.14 [s, PCy.sub.3], 33.34 [d, J=18 Hz, PCy.sub.3],
51.86 [d, .sup.4 J.sub.PC=2.6 Hz, NCH.sub.2CH.sub.2N], 52.61 [d,
.sup.4J.sub.PC=3.5 Hz, NCH.sub.2CH.sub.2N], 127.30 [s, Mes], 128.17
[s, Mes], 129.26 [s, Mes], 129.51 [s, Mes], 130.11 [s, Mes], 130.52
[s, Mes], 134.68 [d, .sup.4 J.sub.PC=0.7 Hz, ipso-C of Mes], 136.85
[s, ipso-C of Mes], 138.91 [s, Mes], 138.93 [s, Mes], 139.03 [s,
Mes], 139.67 [s, Mes], 217.23 [d, .sup.2J.sub.CP=87 Hz, NCN],
218.09 [td, .sup.2J.sub.CP=12 Hz, .sup.1J.sub.CF=430 Hz,
Ru=CF.sub.2]. .sup.19F NMR (282.192 MHz, 25.degree. C.,
CD.sub.2Cl.sub.2): .delta.133.74 [d,.sup.3J.sub.FP=4.5 Hz].
.sup.31P{.sup.1H} NMR (121.392 MHz, 25.degree. C.,
CD.sub.2Cl.sub.2): .delta.32.15 (t, .sup.3J.sub.PF=4.4 Hz]. IR (KBr
pellet): 1167 and 1172 (.nu..sub.C-F)
[0174] When the reaction is performed at room temperature, the
product mixture contains approximately 40% methylidene and 60%
difluorocarbene, as well as styrene (H.sub.2C.dbd.CHPh) and
.beta.,.beta.-difluorostyrene (F.sub.2C.dbd.CHPh). The amount of
difluorocarbene complex formed increased to greater than 98% when
the reaction was carried out at 60.degree. C. instead. In a similar
fashion, the bis(phosphine) olefin metathesis catalyst
[(PCy.sub.3).sub.2Cl.sub.2Ru.dbd.CHPh] reacts with 1,1
-difluoroethylene to yield the corresponding methylidene
[(PCy.sub.3).sub.2Cl.sub.2Ru.dbd.CH.sub.2] and difluorocarbene
[(PCy.sub.3).sub.2Cl.sub.2Ru.dbd.CF.sub.2] complexes.
EXAMPLE 6
Representative Procedures for Synthesis of Substituted Allylic
Olefins
[0175] Allyldiphenylphosphine oxide (53 mg, 0.22 mmol) and catalyst
(5) (14 mg, 0.165 mmol) were weighed directly into a dried 25 mL
round bottom flask with a Teflon stirbar. Dry methylene chloride
(1.5 mL, 0.3M) and cis-2-butene-1,4-diacetate (TCI) (70 L, 0.44
mmol) were added via syringe under a nitrogen atmosphere. The flask
was fitted with a condenser and refluxed under nitrogen for 12
hours. The reaction mixture was then reduced in volume to 0.5 mL
and purified directly on a silica gel column (2.times.10 cm),
eluting with 1:1 hexane:ethyl acetate to provide the cross product
(62 mg, 90% yield) as viscous oil/semi solid as confirmed by
.sup.1H and .sup.13C-NMR.
EXAMPLE 7
Representative Procedures for Synthesis of Trisubstituted and
Quaternary Allylic Olefins
[0176] General procedure for isobutylene CM: To an oven dried, 100
mL Fischer-Porter bottle with Teflon stir bar, ruthenium metathesis
catalyst (15.0 mg, 0.018 mmol, 0.01-0.02 equiv.) was added. The
bottle was capped with a rubber septum and flushed with dry
nitrogen and cooled to -78.degree. C. (or temperature sufficient to
freeze substrate). Substrate (0.9-1.9 mmol) was injected into the
bottle. Once the substrate was frozen, a pressure regulator was
attached to the bottle. The bottle was evacuated and backfilled
with dry nitrogen 3 times. Subsequently, isobutylene (5-10 mL,
50-100 equiv.) was condensed into the bottle. The bottle was
backfilled to .about.2 psi with nitrogen, sealed, and allowed to
slowly warm to room temperature, at which time it was transferred
to an oil bath at 40.degree. C. After stirring for 12-18 hours, the
bottle was removed from the oil bath and allowed to cool to room
temperature. The isobutylene was slowly vented off at room
temperature until the pressure apparatus could be safely
disassembled. The remaining mixture was taken up in organic solvent
for subsequent silica gel chromatography and/or spectrographic
characterization.
[0177] Representative procedure for CM with 2-methyl-2-butene
(Table 7, Entry 5): Pw Pentafluoroallylbenzene (225 .mu.L, 1.468
mmol) from Aldrich Chem. Co. and 2-methyl-2-butene (3.2 nL) from
Aldrich Chem. Co. were added simultaneously via syringe to a
stirring solution of catalyst (5) (12.5 mg, 0.015 mmol, 1.0 mol %)
under a nitrogen atmosphere. The reaction mixture was allowed to
stir at room temperature for 12 hours, and was then reduced in
volume to 0.5 mL and purified directly on a silica gel column
(2.times.10 cm), eluting with 20:1 hexane:ethyl acetate to provide
the cross-metathesis product (316 mg, 1.337 mmol, 91% yield) as a
viscous oils.
[0178] Representative procedure for CM with 3,3-dimethyl-1-butene
(Table 8, Entry 6): Cis-2-butene-1,4-diacetate (50 .mu.L, 0.3168
mmol) from TCI America and 3,3-dimethyl-1-butene (3.2 mL, 0.15M)
from Aldrich Chem. Co. were added simultaneously via syringe to a
stirring solution of catalyst (5) (10 mg, 0.012 mmol, 3.7 mol %)
under a nitrogen atmosphere. The flask was allowed to stir at room
temperature for 12 hours. The reaction mixture was then reduced in
volume to 0.5 mL and purified directly on a silica gel column
(2.times.10 cm), eluting with 50:1 hexane:ethyl acetate to provide
the cross-metathesis product (92 mg, 0.5891 mmol, 93% yield) as a
viscous oils.
[0179] Representative 40.degree. C. procedure with
3,3-dimethyl-1-hexene (Table 8, Entry 5): Allylbenzene (40 .mu.L,
0.30 mmol) from Aldrich Chem. Co. and 3,3-dimethyl-1-hexene (140
.mu.L, 0.90 mmol, 3 equiv.) from Aldrich Chem. Co were added
simultaneously via syringe to a stirring solution of catalyst (5)
(20 mg, 0.024 mmol, 7.8 mol %) in CH.sub.2Cl.sub.2 (2.0 mL, 0.15M
in allylbenzene) under a nitrogen atmosphere. The flask was fitted
with a condenser and refluxed under nitrogen for 12 hours at 40C.
The reaction mixture was then reduced in volume to 0.5 mL and
purified directly on a silica gel column (2.times.10 cm), eluting
with 20:1 hexane:ethyl acetate to provide the cross product (54 mg,
0.27 mmol, 88% yield) as a viscous oils.
EXAMPLE 8
Representative Procedures for Synthesis of Cis-1,2-disubstituted
Olefins
[0180] (a) General considerations: All manipulations were performed
using a combination of glovebox, high vacuum, and Schlenk
techniques under a nitrogen atmosphere, unless otherwise specified.
Solvents were dried and degassed by standard procedures. .sup.1H
and .sup.13C NMR spectra were measured on a Varian 300 or an Inova
500 spectrometer. Chemical shifts are reported in ppm relative to
SiMe.sub.4 (.delta.=0) and were referenced internally with respect
to the protio solvent impurity (.delta.=5.32 for CDHCl.sub.2) and
the .sup.13C resonances (.delta.=54.00 for CD.sub.2Cl.sub.2).
Coupling constants are in hertz. The silica gel used for the
purification of organometallic complexes was obtained from TSI
Scientific, Cambridge, Mass. (60 .ANG., pH 6.5-7.0).
[0181] (b) Preparation of representative catalysts useful for
stereoselective synthesis of cis-1,2-disubstituted olefins: The
ligand precursors 1,3-(+)diisopinocamphenyl-4,5-dihydroimidazolium
tetrafluoroborate salt [IPCimid(H)][BF.sub.4] and
1,3-bis[2',6'-dimethyl--
3'-(2",6"-dimethylphenyl)phenyl]-4,5-dihydroimidazolium chloride
salt were prepared by analogy to the method of Kaloustian et al.
(see Saba et al. (1991) Tet. Lett. 32:5031-34).
[0182] (b-i) In a nitrogen-filled glovebox, a large Schlenk flask
was charged with 0.475 g [IPCimid(H)][BF.sub.4] (1.120 mmol), 0.131
g potassium tert-butoxide (1.120 mmol), and 30 mL anhydrous,
degassed benzene. This mixture was stirred at room temperature for
6 hrs. Then, a solution of 0.400 g [(PCy.sub.3).sub.2(Cl).sub.2
Ru.dbd.CHPh] (0.486 mmol) in 15 mL benzene was added, and the
reaction was stirred for 30 min at room temperature, during which
time the mixture changed from purple to brown. The reaction was
concentrated to a third of its original volume under vacuum and
transferred to a silica gel column (1.5.times.16"). The product was
quickly eluted with 5:1 heptane:ether. The second, brown band was
collected and stripped of solvent. The oily residue that remained
was redissolved in a minimum amount of benzene and lyophylized to
yield 0.080 g of the desired product as a brown powder (19%).
.sup.1H NMR (299.817 MHz, 20.degree. C., CD.sub.2Cl.sub.2): 20.583
and 20.577 [two s, two orientations of Ru.dbd.CH.sup..alpha.], 8.54
[br s], 7.60 [t, J=7.3], 7.34 (t, t=7.8], 5.16 (qt, J=5.1],
3.46-3.96 [m], 2.86 (t, J=12.4], 2.34-2.50 [m], 1.44-2.20 [m], 1.43
(s), 1.41 (s), 0.82-1.31 [m], 1.26 [s], 1.12 [s], 1.01 [s], 0.57
[d, J=6.9], 0.25 [s]. .sup.1H NMR (299.817 MHz, -70.degree. C.,
CD.sub.2Cl.sub.2): 20.32 [s, Ru.dbd.CH.sup..alpha.], 9.07 [d,
J=7.8], 7.87 [t, J=7.1], 7.59 [t, J=7.4], 7.35 [m], 4.92 [br],
3.30-3.90 [m], 2.69 [m], 2.44-0.78 [m], 1.33 [s], 1.16 [s], 1.02
[s], 0.90 [s], 0.88 [s], 0.86 [s], 0.80 [s], 0.78 [s], 0.43 [s],
0.11 [br d, J=5.7]. .sup.31P{.sup.1H} MR (121.39 MHz, 25.degree.
C., CD.sub.2Cl.sub.2): 21.72 [s]. .sup.31P{.sup.1H} NMR (121.39
MHz, -65.degree. C., CD.sub.2Cl.sub.2): 21.95 [s], 21.16 [s].
[0183] (b-ii)
2-tert-butoxy-1,3-bis[2',6'-dimethyl-3'-(2",6"-dimethylpheny-
l)phenyl]-4,5-dihydroimidazol-2-ylidene was prepared by stirring a
suspension of potassium tert-butoxide (9 mg, 0.080 mmol) and
1,3-bis[2',6'-dimethyl-3'-(2",6"-dimethylphenyl)-phenyl]-4,5-dihydroimida-
zol-2-ylidene (50 mg, 0.079 mmol) in benzene (1 mL) for 1 h at room
temperature. To this suspension was added
phenylmethylene-bis(tricyclohex- ylphosphine) ruthenium dichloride
(65 mg, 0.079 mmol) in benzene (1 mL). The solution, which
immediately became pinkish purple, was stirred at 50.degree. C. for
16 h. After this time, the solution was cooled and the solvent was
evaporated to near dryness. The residue was passed through a plug
of TSI silica gel, using 1:1 ether/pentane as the eluant. After
concentrating, the solids were washed with pentane (5.times.1 mL).
The solid material was dissolved in benzene (1 mL) and was frozen
(dry ice/acetone). The solvent was removed by sublimation to give
phenylmethylene
1,3-bis[2',6'-dimethyl-3'-(2",6"-dimethyl-phenyl)phenyl]--
4,5-dihydroimidazol-2-ylidene (50 mg, 62%) as a pink solid. .sup.1H
NMR (500 mHz, toluene-d.sub.8): .delta.=19.46 (s, 1H), 9.59 (br s,
1H), 7.35-6.18 (multiple peaks, 14H), 3.68-3.22 (multiple peaks,
4H), 2.98 (s, 3H), 2.61 (s, 3H), 2.46 (s, 3H), 2.35 (s, 3H), 2.19
(s, 3H), 1.98 (s, 3H), 1.92 (s, 3H), 2.09-1.10 (multiple peaks,
36H) ppm. .sup.31P NMR (202 mHz, toluene-d.sub.8): .delta.=34.54
ppm (s).
[0184] The same procedures may be followed for preparation of a
ruthenium catalyst containing other ligands.
[0185] Representative cross-metathesis reactions using the
catalysts prepared in (b-i) and (b-ii):
[0186] (c-i) Upon isolation of the catalyst prepared with the
1,3-(+)diisopinocamphenyl-4,5-dihydroimidazole-2-ylidene ligand as
described in (b), a representative cross-metathesis reaction can be
conducted with 5 mol % of the catalyst in a reaction with a 2:1
ratio of cis-2-butene-1,4-diacetate and an .alpha.-terminal olefin
at 40.degree. C. in methylene chloride for 12 hours to generate the
cross-metathesis allylic acetate product as a 1.3:1 mixture of
trans and cis isomers in 85% overall yield. Upon isolation of the
second catalyst prepared as described in (a), i.e., phenylmethylene
1,3-bis[2',6'-dimethyl-3'-(2",6"--
dimethylphenyl)phenyl]-4,5-dihydroimidazol-2-ylidene
tricyclohexylphosphine ruthenium dichloride, a representative
cross-metathesis reaction can be conducted with 5 mol % of the
catalyst in a reaction with a 2:1 ratio of
cis-2-butene-1,4-diacetate and an .alpha.-terminal olefin at
40.degree. C. in methylene chloride for 6 hours to generate the
cross-metathesis allylic acetate product as a 2.2:1 mixture of
trans and cis isomers in 60% overall yield.
[0187] (c-ii) Allylbenzene (15 mg, 0.13 mmol),
cis-1,4-diacetoxy-2-butene (45 mg, 0.26 mmol), and phenylmethylene
1,3-bis[2',6'-dimethyl-3'-(2",6"--
dimethylphenyl)phenyl]-4,5-dihydroimidazol-2-ylidene (4 mg, 0.004
mmol) were dissolved in CD.sub.2Cl.sub.2 (0.7 mL) and added to a
screw-cap NMR tube. The tube was heated at 40.degree. C. and the
reaction progress was monitored periodically by NMR. After 12 h at
40.degree. C., NMR analysis indicated that the reaction had
proceeded to 77% completion. The tube was cooled to room
temperature and the solution was transferred to a 5 mL flask and
the solvent was removed in vacuo. The residue was taken up in
CH.sub.2Cl.sub.2 and passed through a small plug of silica. The
solution was concentrated and the residue was taken up in
CDCl.sub.3 and was added to an NMR tube. NMR analysis indicated a
2.4:1 (E:Z) ratio of E/Z-1-acetoxy-4-phenyl-2-butene.
EXAMPLE 9
Allylboronates as Cross-metathesis Substrates
[0188] General procedures for carrying out cross-metathesis
reactions with pinacol allyl boronate: A flame-dried round-bottomed
flask was charged with pinacol allyl boronate (1 eq.) and the
olefin cross partner CH.sub.2.dbd.CHR (3.0 equiv.). a rubber septum
was attached, dichloromethane was added (0.2-0.3 N in pinacol allyl
boronate), and argon was bubbled through the resultant solution for
10 min. Under a stream of argon, catalyst (5) (0.050 equiv.) was
added to the degassed solution as a solid. A reflux condenser was
attached immediately, and the entire system was flushed with argon
for 2 min. The colored solution was then heated at reflux for 2-12
h, and the reaction was monitored by thin-layer chromatography.
Upon consumption of the allylboronate reactant, the aldehyde R'CHO
(1.5 eq.) was added to the reaction mixture through a syringe, and
the resultant solution was stirred at 23.degree. C. in vacuo, and
the residue was purified by means of silica gel chromatography to
yield the allylic alcohol product having the structure
CH.sub.2.dbd.CHR--CH(OH)--R'.
* * * * *