U.S. patent application number 10/158559 was filed with the patent office on 2003-09-25 for process for preparing nonracemic chiral alcohols.
This patent application is currently assigned to DSM N.V.. Invention is credited to Jiang, Qiongzhong, Tucker, Charles E..
Application Number | 20030181318 10/158559 |
Document ID | / |
Family ID | 27609485 |
Filed Date | 2003-09-25 |
United States Patent
Application |
20030181318 |
Kind Code |
A1 |
Tucker, Charles E. ; et
al. |
September 25, 2003 |
Process for preparing nonracemic chiral alcohols
Abstract
The present invention provides a catalyst system and a process
for the preparation of a nonracemic chiral alcohol by hydrogenation
of a ketone using the catalyst system, wherein the catalyst system
comprises ruthenium, a nonracemic nonatropisomeric chiral
diphosphine ligand, an achiral diamine ligand, and a base.
Inventors: |
Tucker, Charles E.;
(Superior, CO) ; Jiang, Qiongzhong; (Sunnyvale,
CA) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
DSM N.V.
Heerlen
NL
|
Family ID: |
27609485 |
Appl. No.: |
10/158559 |
Filed: |
May 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10158559 |
May 21, 2002 |
|
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10057826 |
Jan 24, 2002 |
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Current U.S.
Class: |
502/162 |
Current CPC
Class: |
B01J 31/2409 20130101;
B01J 2531/821 20130101; C07F 9/3813 20130101; C07C 29/145 20130101;
B01J 31/24 20130101; B01J 2231/643 20130101; B01J 31/226 20130101;
B01J 31/1805 20130101; C07D 307/44 20130101; C07F 15/0053 20130101;
C07D 211/52 20130101; C07C 29/143 20130101; C07D 333/56 20130101;
C07B 2200/07 20130101; C07D 333/16 20130101; C07B 53/00 20130101;
C07D 277/24 20130101 |
Class at
Publication: |
502/162 |
International
Class: |
B01J 031/00 |
Claims
What is claimed is:
1. A catalyst system useful for the hydrogenation of a ketone to a
nonracemic chiral alcohol comprising ruthenium, a nonracemic
nonatropisomeric chiral diphosphine ligand, an achiral diamine
ligand, and a base.
2. The catalyst system of claim 1 wherein the nonracemic
nonatropisomeric chiral diphosphine ligand comprises at least one
stereogenic carbon atom.
3. The catalyst system of claim 2 wherein the nonracemic
nonatropisomeric chiral diphosphine ligand comprises at least one
stereogenic carbon atom in a hydrocarbyl diradical that connects
the two phosphorus atoms.
4. The catalyst system of claim 3 wherein the nonracemic
diphosphine ligand comprises a
2,2'-bis(diorganophosphino)-1,1'-bis(cyclic) structure.
5. The catalyst system of claim 4 wherein the nonracemic
diphosphine ligand is selected from enantiomers of diphosphine
ligands having the structural formula 8wherein Ar is an aryl
group.
6. The catalyst system of claim 5 wherein Ar is selected from
phenyl, monoalkylphenyl, dialkylphenyl, and trialkylphenyl.
7. The catalyst system of claim 2 wherein the nonracemic
nonatropisomeric chiral diphosphine ligand comprises a
bis(phosphacyclic) structure, wherein each phosphacycle comprises
at least one stereogenic carbon atom.
8. The catalyst system of claim 7 wherein the phosphacycle is
selected from phosphacyclopentyl and
7-phosphabicyclo[2.2.1]heptyl.
9. The catalyst system of claim 8 wherein the nonracemic
diphosphine ligand is selected from enantiomers of diphosphine
ligands having the structural formula 9wherein R.sup.a is a
hydrocarbyl diradical and R" is a substituted or unsubstituted
hydrocarbyl group selected from alkyl groups and aryl groups.
10. The catalyst system of claim 1 wherein the achiral diamine
ligand is a bis-primary amine ligand.
11. The catalyst system of claim 10 wherein the achiral diamine is
selected from meso-1,2-alkylenediamine compounds,
1,2-phenylenediamine compounds and 1,8-diaminonaphthalene
compounds.
12. The catalyst system of claim 1 wherein the base is selected
from basic inorganic and organic salts, alkylamidines,
alkylguanidines, aminophosphazenes, and proazaphosphatranes.
13. The catalyst system of claim 12 wherein the base is selected
from alkylamidines, alkylguanidines, aminophosphazenes, and
proazaphosphatranes.
14. The catalyst system of claim 13 wherein the base is an
alkylguanidine.
15. The catalyst system of claim 14 wherein the base is a
pentaalkylguanidine.
16. A process for the preparation of a nonracemic chiral alcohol
comprising hydrogenating a ketone in the presence of a catalyst
system, wherein the catalyst system comprises ruthenium, a
nonracemic nonatropisomeric chiral diphosphine ligand, an achiral
diamine ligand, and a base.
17. The process of claim 16 wherein the nonracemic nonatropisomeric
chiral diphosphine ligand comprises at least one stereogenic carbon
atom.
18. The process of claim 17 wherein the nonracemic nonatropisomeric
chiral diphosphine ligand comprises at least one stereogenic carbon
atom hydrocarbyl diradical that connects the two phosphorus
atoms.
19. The process of claim 18 wherein the nonracemic diphosphine
ligand comprises a 2,2'-bis(diorganophosphino)-1,1'-bis(cyclic)
structure.
20. The process of claim 19 wherein the nonracemic diphosphine
ligand is selected from enantiomers of diphosphine ligands having
the structural formula 10wherein Ar is an aryl group.
21. The process of claim 20 wherein Ar is selected from phenyl,
monoalkylphenyl, dialkylphenyl, and trialkylphenyl.
22. The process of claim 17 wherein the nonracemic nonatropisomeric
chiral diphosphine ligand comprises a bis(phosphacyclic) structure,
wherein each phosphacycle comprises at least one stereogenic carbon
atom.
23. The process of claim 22 wherein the phosphacycle is selected
from phosphacyclopentyl and 7-phosphabicyclo [2.2.1]heptyl.
24. The process of claim 23 wherein the nonracemic diphosphine
ligand is selected from enantiomers of diphosphine ligands having
the structural formula 11wherein R.sup.a is a hydrocarbyl diradical
and R" is a substituted or unsubstituted hydrocarbyl group selected
from alkyl groups and aryl groups.
25. The process of claim 16 wherein the achiral diamine ligand is a
bis-primary amine ligand.
26. The process of claim 25 wherein the achiral diamine is selected
from meso-1,2-alkylenediamine compounds, 1,2-phenylenediamine
compounds and 1,8-diaminonaphthalene compounds.
27. The process of claim 16 wherein the base is selected from basic
inorganic and organic salts, alkylamidines, alkylguanidines,
aminophosphazenes, and proazaphosphatranes.
28. The process of claim 27 wherein the base is selected from
alkylamidines, alkylguanidines, aminophosphazenes, and
proazaphosphatranes.
29. The process of claim 28 wherein the base is an
alkylguanidine.
30. The process of claim 29 wherein the base is a
pentaalkylguanidine.
31. The process of claim 16 wherein the nonracemic chiral alcohol
is formed in at least about 60% stereomeric excess.
Description
CROSS-REFERENCES TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of U.S. patent
application Ser. No. 10/057,826, filed Jan. 24, 2002, incorporated
herein by reference in its entirety. This application is also
related to co-filed U.S. patent application Ser. Nos. ______
(Attorney Docket No. 021153-001600US, "Process for Preparing
Nonracemic Chiral Alcohols"), and ______ (Attorney Docket No.
021153-001800US, "Process for Preparing Nonracemic Chiral
Alcohols"), incorporated herein by reference in their
entireties.
STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSORED
RESEARCH OR DEVELOPMENT
[0002] NOT APPLICABLE
REFERENCE TO A "SEQUENCE LISTING," A TABLE, OR A COMPUTER PROGRAM
LISTING APPENDIX SUBMITTED ON A COMPACT DISK.
[0003] NOT APPLICABLE
FIELD OF THE INVENTION
[0004] This invention relates generally to preparing nonracemic
chiral alcohols. It more particularly relates to preparing
nonracemic chiral alcohols by hydrogenation of ketones using
transition metal catalysts comprising nonracemic chiral ligands.
Nonracemic chiral alcohols are useful as pharmaceuticals and other
bioactive products and as intermediates for the preparation of such
products.
BACKGROUND OF THE INVENTION
[0005] Ketones can be converted to racemic chiral alcohols by
hydrogenation using certain catalyst systems of ruthenium, a
phosphine ligand, a 1,2-diamine, and an alkaline base. Aromatic and
heteroaromatic ketones can be hydrogenated to nonracemic chiral
alcohols by using certain catalyst systems of ruthenium, certain
enantiomeric atropisomeric biaryl diphosphine, an enantiomeric
1,2-diamine, and an alkaline base. Angew. Chem. Int. Ed., vol. 40,
(2001), 40-73; U.S. Pat. No. 5,763,688; J. Am. Chem. Soc., vol. 117
(1995), 2675-2676. Others have noted that such ketones can be
hydrogenated to nonracemic chiral alcohols using related catalyst
systems formed with a racemic chiral 1,2-diamine. In their catalyst
system, the active diastereomeric ruthenium catalyst is formed with
the enantiomeric atropisomeric diphosphine ligand and the "matched"
enantiomer of the racemic chiral 1,2-diamine. Interestingly, the
diastereomeric ruthenium complex with the "unmatched" enantiomer of
the racemic chiral 1,2-diamine, if it is formed, is relatively
inactive. Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; European
Patent Application 901 997; J. Am. Chem. Soc., vol. 120 (1998),
1086-1087. A catalyst system of ruthenium, the atropisomeric
diphosphine (S)-2,2'-bis-(diphenylphosphino)-1,1'-binaphthyl
(S-BINAP), achiral ethylene diamine, and potassium hydroxide in
isopropanol was reported to hydrogenate 1'-acetonaphthone to
(R)-1-(1-naphthyl)ethanol in 57% enantiomeric excess. The
corresponding catalyst system having enantiomeric
(S,S)-1,2-diphenylethylenediamine instead of achiral ethylene
diamine was reported to hydrogenate 1'-acetonaphthone under the
same conditions to (R)-1-(1-naphthyl)ethanol in 97% enantiomeric
excess. Angew. Chem. Int. Ed., vol. 40, (2001), 40-73; J. Am. Chem.
Soc., vol. 117 (1995), 2675-2676.
[0006] Aromatic ketones were similarly hydrogenated to nonracemic
chiral alcohols by using a catalyst systems of ruthenium, an
enantiomer of 2,2'-bis(diphenylphosphino)-1,1'-dicyclopentane (a
diphosphine ligand comprising stereogenic carbon atoms in the
bridge between the phosphorus atoms), certain enantiomeric
1,2-diamines, and potassium hydroxide in isopropanol. J. Org.
Chem., vol. 64 (1999), 2127-2129.
[0007] Atropisomers do not comprise a stereogenic atom, but are
chiral because of greatly hindered or prevented rotation about a
single bond. In the art, stererogenic atoms are sometimes called
asymmetric atoms. Atropisomeric biaryl diphosphine ligands comprise
a 1,1'-biaryl bond in the bridge between the phosphorus atoms,
about which rotation is sterically prohibited and which are thereby
chiral although lacking a stereogenic carbon or phosphorus atom.
Examples of atropisomeric biaryl diphosphine ligands include, among
others, the enantiomers of
2,2'-bis(diphenylphosphino)1,1'-binaphthyl (BINAP), BINAP
derivatives having one or more alkyl or aryl groups connected to
one or both naphthyl rings, BINAP derivatives having one to five
alkyl substituents on the phenyl rings bonded to phosphorus, for
example 2,2'-bis-(di-p-tolylphosph- ino)-1,1'-binaphthyl
(TolBINAP), 5,6,7,8,5',6',7',8'-octahydro-BINAP (H.sub.8BINAP),
2,2'-bis(dicyclohexylphosphino)-6,6'-dimethyl-1,1'-biphen- yl
(BICHEP), 2,2'-bis(diphenylphosphino)-6,6'-dimethyl-1,1'-biphenyl
(BIPHEMP), 2,2'-bis(diphenylphosphino)-6,6'-dimethoxy-1,1'-biphenyl
(MeOBIPHEP),
[6,6'-(alkylene-.alpha.,.omega.-dioxy)biphenyl-2,2'-diyl]bis-
(diphenylphosphine) (Cn-TunaPhos; n=1,2,3, . . . for
alkylene=methylene, 1,2-ethylene, 1,3-propylene, . . . ,
respectively), 5,5'-bis(diphenylphosphino)-4,4'-bi(benzodioxolyl)
(SEGPHOS), and
2,2'-bis(diphenylphosphino)-3,3'-bi(benzo[b]thiophene)
(BITIANP).
[0008] An attempt to provide a catalyst system of ruthenium, the
atropisomeric diphosphine S-BINAP, enantiomeric
(S,S)-1,2-diphenylethylen- ediamine, and
1,8-diazabicyclo[5.4.0]undec-7-ene as the base (in the place of the
alkali base used in the references discussed above) gave no
catalytic activity for the hydrogenation of acetophenone. The
addition of selected alkali salts of
tetrakis[3,5-bis(trifluoromethyl)phenyl]borate to this attempted
catalyst system provided catalytic activity for the hydrogenation
of acetophenone to nonracemic 1-phenethanol. The investigators
conclude that alkali metal cations are required for the activity of
this catalyst system. Angew. Chem. Int. Ed., vol. 40, (2001),
3581-3585.
BRIEF SUMMARY OF THE INVENTION
[0009] The present invention provides a catalyst system and a
process for the preparation of a nonracemic chiral alcohol by
hydrogenation of a ketone using the catalyst system, wherein the
catalyst system comprises ruthenium, a nonracemic nonatropisomeric
chiral diphosphine ligand, preferably comprising a stereogenic
carbon atom, an achiral diamine ligand, and a base. Surprisingly, a
chiral diamine ligand is not required to obtain highly
enantioselective hydrogenation of a ketone to a nonracemic chiral
alcohol when using the catalyst system provided above. Accordingly,
the present invention also provides methods for the highly
enantioselective hydrogenation of a ketone to a nonracemic chiral
alcohol using an achiral diamine ligand, with a catalyst system
also comprising ruthenium, a nonracemic nonatropisomeric chiral
diphosphine ligand, preferably comprising a stereogenic carbon
atom, and a base.
[0010] In one group of embodiments the base is selected from
alkylamidines, alkylguanidines, aminophosphazenes, and
proazaphosphatranes.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] Not applicable
DETAILED DESCRIPTION OF THE INVENTION
[0012] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below:
[0013] As used herein, the term "treating", "contacting" or
"reacting" refers to adding or mixing two or more reagents under
appropriate conditions to produce the indicated and/or the desired
product. It should be appreciated that the reaction which produces
the indicated and/or the desired product may not necessarily result
directly from the combination of two reagents which were initially
added, i.e., there may be one or more intermediates which are
produced in the mixture which ultimately leads to the formation of
the indicated and/or the desired product. "Side-reaction" is a
reaction that does not ultimately lead to a production of a desired
product.
[0014] "Alkyl" means a linear saturated monovalent hydrocarbon
radical or a branched saturated monovalent hydrocarbon radical or a
cyclic saturated monovalent hydrocarbon radical, having the number
of carbon atoms indicated in the prefix. For example,
(C.sub.1-C.sub.6)alkyl is meant to include methyl, ethyl, n-propyl,
2-propyl, tert-butyl, pentyl, cyclopentyl, cyclohexyl and the like.
For each of the definitions herein (e.g. alkyl, alkenyl, alkoxy,
aralkyloxy), when a prefix is not included to indicate the number
of main chain carbon atoms in an alkyl portion, the radical or
portion thereof will have twelve or fewer main chain carbon atoms.
A divalent alkyl radical refers to a linear saturated divalent
hydrocarbon radical or a branched saturated divalent hydrocarbon
radical having the number of carbon atoms indicated in the prefix.
For example, a divalent (C.sub.1-C.sub.6)alkyl is meant to include
methylene, ethylene, propylene, 2-methylpropylene, pentylene, and
the like.
[0015] "Alkenyl" means a linear monovalent hydrocarbon radical or a
branched monovalent hydrocarbon radical having the number of carbon
atoms indicated in the prefix and containing at least one double
bond. For example, (C.sub.2-C.sub.6)alkenyl is meant to include,
ethenyl, propenyl, and the like.
[0016] "Alkynyl" means a linear monovalent hydrocarbon radical or a
branched monovalent hydrocarbon radical containing at least one
triple bond and having the number of carbon atoms indicated in the
prefix. For example, (C.sub.2-C.sub.6)alkynyl is meant to include
ethynyl, propynyl, and the like.
[0017] "Alkoxy", "aryloxy", "aralkyloxy", or "heteroaralkyloxy"
means a radical--OR where R is an alkyl, aryl, aralkyl, or
heteroaralkyl respectively, as defined herein, e.g., methoxy,
phenoxy, benzyloxy, pyridin-2-ylmethyloxy, and the like.
[0018] "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon
radical of 6 to 12 ring atoms which is substituted independently
with one to four substituents, preferably one, two, or three
substituents selected from alkyl, alkenyl, alkynyl, halo, nitro,
cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino,
di-alkylamino and heteroalkyl. More specifically the term aryl
includes, but is not limited to, phenyl, biphenyl, 1-naphthyl, and
2-naphthyl, and the substituted derivatives thereof.
[0019] "Aralkyl" refers to a radical wherein an aryl group is
attached to an alkyl group, the combination being attached to the
remainder of the molecule through the alkyl portion. Examples of
aralkyl groups are benzyl, phenylethyl, and the like.
[0020] "Heteroalkyl" means an alkyl radical as defined herein with
one, two or three substituents independently selected from cyano,
alkoxy, amino, mono- or di-alkylamino, thioalkoxy, and the like,
with the understanding that the point of attachment of the
heteroalkyl radical to the remainder of the molecule is through a
carbon atom of the heteroalkyl radical.
[0021] "Heteroaryl" means a monocyclic or bicyclic radical of 5 to
12 ring atoms having at least one aromatic ring containing one,
two, or three ring heteroatoms selected from N, O, or S, the
remaining ring atoms being C, with the understanding that the
attachment point of the heteroaryl radical will be on an aromatic
ring. The heteroaryl ring is optionally substituted independently
with one to four substituents, preferably one or two substituents,
selected from alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxy,
alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino and
heteroalkyl. More specifically the term heteroaryl includes, but is
not limited to, pyridyl, furanyl, thienyl, thiazolyl, isothiazolyl,
triazolyl, imidazolyl, isoxazolyl, pyrrolyl, pyrazolyl,
pyridazinyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl,
isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl,
isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and
the substituted derivatives thereof.
[0022] "Hydrocarbyl" is used herein to refer to an organic radical,
that can be an alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroalkyl
or heteroaryl radical, or a combination thereof which is optionally
substituted with one or more substituents generally selected from
the groups noted above.
[0023] In a general sense, the present invention provides a method
for the preparation of a chiral alcohol of formula II (shown
without stereochemistry) from a ketone of formula I. Suitable
ketones for use in the present invention are those wherein R.sup.1
and R.sup.2 are different, and optionally, one or both of R.sup.1
and R.sup.2 have a chiral center. 1
[0024] The symbols R.sup.1 and R.sup.2 in formulas I and II each
independently represent a hydrocarbyl group that can be an acyclic,
cyclic, or heterocyclic hydrocarbyl group, or a combination
thereof. Additionally, each of the hydrocarbyl groups R.sup.1 and
R.sup.2 can be saturated or unsaturated, including components
defined above as alkyl, heteroalkyl, aryl, heteroaryl, aralkyl,
alkenyl, and alkynyl groups, as well as combinations thereof. Still
further, each of R.sup.1 and R.sup.2 can be optionally substituted
with one or more substituents that do not interfere with the
reaction chemistry of the invention. In some embodiments, R.sup.1
and R.sup.2 are linked together in a cyclic structure. In a
preferred combination of R.sup.1 and R.sup.2, R.sup.1 is an
optionally substituted alkyl group and R.sup.2 is an optionally
substituted aryl or heteroaryl group.
[0025] R.sup.1 and R.sup.2 can also be, independently, chiral or
achiral. As used herein, however, the adjective "chiral" in the
term "chiral alcohol", specifically refers to the chirality at the
carbon atom bearing each of R.sup.1 and R.sup.2, which chirality is
produced by the hydrogenation of the keto group at that center. The
term is not meant to refer to the chirality that may be present in
either R.sup.1 or R.sup.2.
[0026] The ruthenium, nonracemic nonatropisomeric chiral
diphosphine ligand, and achiral diamine ligand components of the
catalyst system can be provided to the reaction mixture
individually to form the reactive catalyst complex in situ or they
can be provided as preformed complexes. Preformed complexes of
ruthenium with the nonracemic nonatropisomeric chiral diphosphine
ligand, or the achiral diamine ligand, or both can be used.
[0027] Examples of preformed complexes of the ruthenium with the
nonracemic nonatropisomeric chiral diphosphine ligand include
complexes represented by the formula RuX.sub.2LY.sub.n, wherein X
represents a halogen atom or pseudo-halide group, preferably
chloride or bromide, L represents the nonracemic nonatropisomeric
chiral diphosphine ligand, Y represents a weakly coordinating
neutral ligand, and n is an integer from 1 to 5. Examples of Y
include trialkylamines, for examples triethylamine and
tetramethylethylenediamine, and tertiary amides, for example
dimethylformamide. Such complexes can be prepared by the reaction
of the diphosphine ligand with a complex of the formula
[RuX.sub.2(arene)].sub.2- , wherein examples of the arene include
benzene, p-cymene, 1,3,5-trimethylbenzene, and hexamethylbenzene,
in a solvent comprising Y.
[0028] Examples of preformed complexes of the ruthenium with both
the nonracemic nonatropisomeric chiral diphosphine ligand and
achiral diamine ligand include complexes represented by the formula
RuX.sub.2LA, wherein A represents the achiral diamine ligand. Such
complexes can be prepared by the reaction of the achiral diamine
with a complex of the formula RuX.sub.2LY.sub.n as described
above.
[0029] The ruthenium component of the catalyst system, whether
provided to the reaction mixture separately from the other
components or used to form a preformed complex with the nonracemic
nonatropisomeric chiral diphosphine ligand, the achiral diamine
ligand, or both, can be provided by any ruthenium salt or complex
capable of forming the active catalyst system in combination with
the diphosphine ligand, the achiral diamine ligand, and the base.
This can be determined by routine functional testing for ketone
hydrogenation activity and enantioselectivity in the manner shown
in the Examples. A preferred source of the ruthenium component is a
complex of the formula [RuX.sub.2(arene)].sub.2 as defined
above.
[0030] Suitable nonracemic nonatropisomeric chiral diphosphine
ligands for the present invention are bis-tertiary phosphines of
the general formula R.sup.3R.sup.4PR.sup.aPR.sup.5R.sup.6, wherein
R.sup.3, R.sup.4, R.sup.5, and R.sup.6 are hydrocarbyl radicals,
which may be the same or different, and R.sup.a is a hydrocarbyl
diradical, any of which may be optionally linked in one or more
cyclic structures. Suitable hydrocarbyl groups R.sup.3, R.sup.4,
R.sup.5, R.sup.6, and diradicals thereof for R.sup.a, include
acyclic, cyclic, and heterocyclic hydrocarbyl groups, include
saturated and unsaturated hydrocarbyl groups, include alkyl,
heteroalkyl, aryl, heteroaryl, aralkyl, alkenyl, and alkynyl
groups, and can be optionally substituted with one or more
substituents that do not undesirably affect the reaction chemistry
of the invention.
[0031] The chirality of the nonracemic nonatropisomeric chiral
diphosphine ligand may reside in one or more of the hydrocarbyl
groups R.sup.3, R.sup.4, R.sup.5, R.sup.6, in the bridging
hydrocarbyl diradical R.sup.a, at phosphorus when two hydrocarbyl
radicals on phosphorus are different (R.sup.3.noteq.R.sup.4, or
R.sup.5.noteq.R.sup.6, or both), or combinations thereof, with the
proviso that when the chirality resides solely in the bridging
hydrocarbyl diradical R.sup.a, R.sup.a is not an atropisomeric
biaryl diradical. When chirality resides in the bridging
hydrocarbyl diradical R.sup.a, R.sup.a preferably comprises one or
more stereogenic carbon atoms as the source of its chirality. When
chirality resides among the hydrocarbyl groups, R.sup.3, R.sup.4,
R.sup.5, and R.sup.6, preferably one or more of R.sup.3, R.sup.4,
R.sup.5, and R.sup.6 comprises one or more stereogenic carbon atoms
in the hydrocarbyl group as the source of chirality. Preferably,
atropisomeric chiral substructures are not present in the
nonracemic nonatropisomeric chiral diphosphine ligand. Most
preferably, the nonracemic nonatropisomeric chiral diphosphine
ligand comprises one or more stereogenic carbon atoms.
[0032] Illustrative examples of nonracemic nonatropisomeric chiral
diphosphine ligands are the enantiomers of
1,2-bis-(diphenylphosphino)pro- pane (PROPHOS),
2,3-bis(diphenylphosphino)butane (CHIRAPHOS),
2,4-bis(diphenylphosphino)pentane (SKEWPHOS),
1-cyclohexyl-1,2-bis(diphen- ylphosphino)ethane (CYCPHOS),
1-substituted 3,4-bis(diphenyl-phosphino)pyr- olidine (DEGPHOS),
2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis(diphenylphos-
phino)butane (DIOP),
3,4-O-isopropylidene-3,4-dihydroxy-2,5-bis-(diphenylp-
hosphino)hexane (DIOP*),
1-[1,2-bis-(diphenylphosphino)ferrocenyl]ethyldim- ethylamine
(BPPFA), 1,2-bis[(o-methoxyphenyl)phenylphosphino]ethane (DIPAMP),
2,5-disubstituted 1,2-bis(phospholano)benzenes (DuPHOS), for
example 1,2-bis(2,5-dimethylphospholano)benzene (Me-DuPHOS),
substituted 1,2-bis(phospholano)-ethylenes (BPE), for example
1,2-bis(2,5-dimethylpho- spholano)ethylene (Me-BPE),
1,2-bis-[3,4-benzoxy-2,5-dimethylphospholanyl]- benzene (RoPhos),
1,2-bis-[3,4-O-isopropylidene-3,4-dihydroxy-2,5-dimethyl-
phospholanyl]benzene (Me-KetalPhos),
1,1'-bis[3,4-O-isopropylidene-3,4-dih-
ydroxy-2,5-dimethylphospholanyl]ferrocene (Me-f-KetalPhos),
5,6-bis(diphenylphosphino)-2-norbomene (NORPHOS),
N,N'-bis-(diphenylphosp-
hino)-N,N'-bis(1-phenylethyl)ethylenediamine (PNNP),
2,2'-bis(diphenylphosphino)-1,1'-dicyclopentane (BICP),
1,2-bis-{2,5-disubstituted-7-phosphabicyclo[2.2.1]hept-7-yl}-benzenes
(PennPhos), for example 1,2-bis-{2,5-dimethyl-7-phosphabicyclo
[2.2.1]hept-7-yl}-benzene (Me-PennPhos) and
1,2-bis-{2,5-diisopropyl-7-ph-
osphabicyclo[2.2.1]hept-7-yl}-benzene (iPr-PennPhos), and
1,2-bis{1-phosphatricyclo[3.3.0.0]undecan-1-yl}benzene
(C5-Tricyclophos), and equivalents thereto that are recognized by
those skilled in the art.
[0033] Certain preferred nonracemic nonatropisomeric chiral
diphosphine ligands comprise at least one, preferably at least two,
and most preferably four, stereogenic carbon atoms in the
hydrocarbyl diradical that connects the two phosphorus atoms
(R.sup.a in the formula above.). Illustrative examples of
nonracemic nonatropisomeric chiral diphosphine ligands wherein the
bridging hydrocarbyl diradical comprises a stereogenic carbon atom
are the enantiomers of PROPHOS, CHIRAPHOS, SKEWPHOS, DIOP, DIOP*,
and BICP ligands.
[0034] Particularly preferred nonracemic nonatropisomeric chiral
diphosphine ligands, wherein the bridging hydrocarbyl diradical
comprises a stereogenic carbon atom, comprise a
2,2'-bis-(diorgano-phosphino)-1,1'-- bis(cyclic) structure, wherein
each cycle of the bridging bis(cyclic) diradical comprises three to
eight carbon atoms, and wherein the 1,1', 2, and 2' carbon atoms in
the bis(cyclic) diradical are saturated. These ligands are
described in detail in U.S. Pat. No. 6,037,500, incorporated herein
by reference. The preferred nonracemic diphosphine ligands
comprising a 2,2'-bis-(diorgano-phosphino)-1,1'-bis(cyclic)
structure are of the formulas III and IV and their enantiomers, in
which m=1 to 6 and wherein each cycle of the bis(cyclic) structure
may be unsubstituted as shown in formulas III and IV or further
substituted with one or more substituents chosen from hydrocarbyl
substituents and heteroatom containing substituents that do not
interfere with the ketone hydrogenation chemistry, and wherein R'
is a substituted or unsubstituted hydrocarbyl group selected from
alkyl groups and aryl groups. 2
[0035] Particularly preferred nonracemic nonatropisomeric
diphosphine ligands comprising a
2,2'-bis-(diorgano-phosphino)-1,1'-bis(cyclic) structure are of the
formula V and its enantiomer, wherein Ar is an aryl group. 3
[0036] Preferred aryl groups in formula V are phenyl (the BICP
ligand) and mono-, di-, and trialkyl-phenyl, particularly wherein
alkyl is methyl, for example
2,2'-bis[di(3,5-dimethylphenyl)phosphino]-1,1'-dicyclopentane
(3,5-Me.sub.8BICP).
[0037] Certain other preferred nonracemic nonatropisomeric chiral
diphosphine ligands comprise a bis(phosphacyclic) structure,
wherein each phosphacycle comprises at least one stereogenic carbon
center, preferably at least two. The phosphacyclic structure is
selected from phosphamonocyclic structures, preferably
phosphacyclopentyl, and phosphabicyclic structures, preferably
7-phosphabicyclo[2.2.1]heptyl. Illustrative examples of nonracemic
nonatropisomeric chiral diphosphine ligands comprising a
bis(phosphacyclopentyl) structure wherein each phosphacyclopentyl
comprises at least one stereogenic carbon atom are the enantiomers
of DuPHOS, BPE, C5-Tricyclophos, RoPhos, and KetalPhos.
Illustrative examples of nonracemic nonatropisomeric chiral
diphosphine ligands comprising a bis(7-phosphabicyclo[2.2.1]heptyl)
structure wherein each phosphabicycloheptyl comprises at least one
stereogenic carbon atom are the enantiomers of PennPhos
ligands.
[0038] Particularly preferred nonracemic nonatropisomeric chiral
diphosphine ligands comprising a bis(phosphacyclic) structure,
wherein each phosphacycles comprises at least one stereogenic
carbon center, are bis(phosphabicyclic) ligands of the formula VI,
wherein R.sup.a is a bridging hydrocarbyl diradical as defined
above, R" is a substituted or unsubstituted hydrocarbyl group
selected from alkyl groups and aryl groups, and y is 1 or 2. These
ligands are described in detail in U.S. Pat. No. 6,037,500,
incorporated herein by reference. 4
[0039] Particularly preferred nonracemic nonatropisomeric
diphosphine ligands comprising a bis(phosphabicyclic) structure are
of the formula VI, wherein R" is a (C1-C3)alkyl group and y=1 (the
PennPhos ligands), for example
1,2-bis-{2,5-dimethyl-7-phosphabicyclo[2.2.1]hept-7-yl}-benze- ne
(Me-PennPhos) and
1,2-bis-{2,5-diisopropyl-7-phosphabicyclo[2.2.1]hept--
7-yl}-benzene (iPr-PennPhos).
[0040] Suitable achiral diamine ligands for the present invention
are bis-primary amines of the general formula H.sub.2NRbNH.sub.2,
wherein R.sup.b is an achiral hydrocarbyl diradical. Preferably,
the hydrocarbyl diradical comprises from 3 to 50 carbon atoms, more
preferably from 4 to 50 carbon atoms, and most preferably from 6 to
50 carbon atoms. Suitable achiral hydrocarbyl diradicals for
R.sup.b include acyclic, cyclic, and heterocyclic hydrocarbyl
diradicals, include saturated and unsaturated hydrocarbyl
diradicals, include alkyl, heteroalkyl, aryl, heteroaryl, aralkyl,
alkenyl, and alkynyl diradicals, and can be optionally substituted
with one or more substituents that do not interfere with the
reaction chemistry of the invention.
[0041] The diamine may be achiral by comprising neither
atropisomerism nor stereogenic carbon atoms or it may be achiral
comprising a meso compound. That is, the achiral hydrocarbyl
diradical may contain one or more pairs of stereogenic carbon atoms
that are related in at least one of its conformations by a plane of
symmetry. For example, while (S,S)- and
(R,R)-1,2-diphenylethylenediamine are chiral enantiomers,
(S,R)-1,2-diphenylethylenediamine is an achiral meso compound.
[0042] Illustrative examples of achiral diamine compounds
comprising at least three carbon atoms include
1,3-propylenediamine, 2-methyl-1,2-propylene-diamine,
meso-2,3-butanediamine, meso-1,2-cyclopentanediamine,
meso-1,2-cyclo-hexane-diamine, meso-1,2-cyclo-heptane-diamine,
meso-1,2-diphenylethylenediamine,
meso-2,3-dimethylbutane-1,2-diamine, 1,2-phenylenediamine,
2-aminobenzyl-amine, 1,8-diaminonaphthalene, and equivalents
thereto that are recognized by those skilled in the art, any of
which may be substituted with one or more substituents that do not
interfere with the reaction chemistry of the invention, and
provided such substitution preserves the achirality of the
diamine.
[0043] Preferred achiral diamines are selected from
1,2-alkylenediamine compounds, 1,2-phenylenediamine compounds and
1,8-diamino-naphthalene compounds, which may be substituted or
unsubstituted. Suitable substituents include alkyl (e.g.
4,5-dimethyl-1,2-phenylene-diamine), benzo (e.g.
9,10-diaminophenanthrene), and alkoxy (e.g,
1,3-benzodioxole-5,6-diamine).
[0044] Suitable bases include basic inorganic and organic salts,
preferably selected from basic salts comprising a cation selected
from an alkali metal cation, an alkaline earth cation, and
quaternary ammonium cation and a basic anion selected from
hydroxide and alkoxide anions. Examples include lithium, sodium,
potassium, and quaternary ammonium salts of hydroxide, methoxide,
ethoxide, isopropoxide, and t-butoxide.
[0045] In a further inventive embodiment of the invention, the base
is selected from alkylguanidines, aminophosphazenes,
proazaphosphatranes, and alkylamidines. In this embodiment, the
base is preferably selected from alkylguanidines,
aminophosphazenes, and proazaphosphatranes. In this embodiment, the
base is most preferably selected from alkylguanidines.
[0046] Suitable alkylguanidines have the general formula VII,
wherein R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 are
independently selected from hydrogen and alkyl groups, with the
proviso that at least one of R.sup.8, R.sup.9, R.sup.10, R.sup.11,
and R.sup.12 is an alkyl group. 5
[0047] Preferably the alkylguanidine comprises two alkyl groups,
more preferably three alkyl groups, even more preferably four alkyl
groups, and most preferably five alkyl groups. Any of the alkyl
groups R.sup.8, R.sup.9, R.sup.10, R.sup.11, and R.sup.12 may be
optionally linked in one or more cyclic structures. An illustrative
example of a suitable tetraalkylguanidine base is
1,5,7-triazabicyclo[4.4.0]dec-5-ene and tetramethylguanidine.
Illustrative examples of suitable pentalkylguanidines are
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene and
tetramethyl-2-t-butylguanidine.
[0048] Suitable aminophosphazenes have the general formula VII,
wherein R.sup.13 is selected from hydrogen and alkyl groups,
R.sup.14 is an alkyl group and the two R.sup.14 groups on each
--NR.sup.14 group may optionally be linked in a cyclic structure,
and x is an integer from zero to three.
R.sup.13N.dbd.P(--NR.sup.14.sub.2).sub.x[--N.dbd.P(NR.sup.14.sub.2).sub.3]-
.sub.(3-x) VIII
[0049] Illustrative examples of suitable aminophosphazenes include
N,N,N',N',N",N"-hexa-methyl-phosphorimidic triamide (R.sup.13=H,
R.sup.14=methyl, x=3),
N'"-t-butyl-N,N,N',N",N",N"-hexamethyl-phosphorimi- dic triamide
(R.sup.3=t-butyl, R.sup.14=methyl, x=3),
(t-butyl-imino)-tris(pyrrolidino)-phosphorane (R.sup.13=t-butyl,
--NR.sup.14.sub.2=pyrrolidino, x=3),
N'"-[N-ethyl-P,P-bis-(dimethyl-amino-
)phosphinimyl]-N,N,N',N',N",N"-hexamethyl-phosphorimidic triamide
(R.sup.13=ethyl, R.sup.14=methyl, x=2), and
t-butyl-tris[tris(dimethyl-am-
ino)-phosphoranylidene]phosphorimidic triamide (R.sup.13=t-butyl,
R.sup.14=methyl, x=0).
[0050] Suitable proazaphosphatranes are described in U.S. Pat. No.
5,051,533 and have the general formula IX, wherein R.sup.15,
R.sup.16, and R.sup.17 are independently selected from hydrogen and
alkyl groups. 6
[0051] Preferably R.sup.15, R.sup.16, and R.sup.17 are selected
from C.sub.1 to C.sub.8 alkyl groups, most preferably methyl. An
illustrative preferred proazaphosphatrane is
2,8,9-trimethyl-2,5,8,9-tetraaza-1-phosph- abicyclo[3.3.3]undecane
(R.sup.15=R=R methyl).
[0052] Suitable alkylamidines have the general formula X wherein
R.sup.18, R.sup.19, and R.sup.20 are independently selected from
alkyl groups and R.sup.21 is selected from hydrogen and alkyl
groups. Preferably, R.sup.21 is selected from alkyl groups. 7
[0053] Any of the alkyl groups R.sup.18, R.sup.19, R.sup.20, and
R.sup.21 may be optionally linked in one or more cyclic structures.
An illustrative example of a suitable alkylamidine base is
1,5-diazabicyclo[4.3.0]non-5-ene.
[0054] The components of the catalyst system are each present in a
catalytic amount, meaning less than stoichiometric relative to the
ketone reactants. The minimum amount of the catalyst system
relative to the ketone reactant may depend on the activity of the
specific catalyst system composition, the specific ketone to be
reacted, the hydrogen pressure, the gas-liquid mixing
characteristics of the reaction vessel, the reaction temperature,
the concentrations of the reactants and catalyst system components
in the solution, and the maximum time allowed for completion of the
reaction, and can be readily determined by routine experimentation.
In typical embodiments, the mole ratio of the ruthenium component
of the catalyst system to the ketone reactant is in the range from
about {fraction (1/100 )} to about {fraction (1/100,000)},
preferably in the range from about {fraction (1/500 )} to about
{fraction (1/10,000)}.
[0055] The mole ratio of the nonracemic nonatropisomeric chiral
diphosphine ligand to the ruthenium in the catalyst system is
typically in the range from about 0.5 to about 2.0, preferably from
about 0.8 to about 1.2, and most preferably is about 1. The mole
ratio of the achiral diamine ligand to the ruthenium in the
catalyst system is typically in the range from about 1 to about 50,
and preferably from about 5 to about 20. The mole ratio of the base
to the ruthenium in the catalyst system is typically in the range
from about 1 to about 100, and preferably from about 5 to about
50.
[0056] The hydrogenation reaction may be conducted without solvent
when the ketone itself is a liquid at the reaction temperature and
capable of dissolving the catalyst system. More typically, the
hydrogenation reaction is conducted in a solvent system that is
capable of dissolving the catalyst system and is reaction-inert.
The term solvent system is used to indicate that a single solvent
or a mixture of two or more solvents can be used. The term
reaction-inert it used to mean that the solvent system does not
react unfavorably with the reactants, products, or the catalyst
system. It does not mean that the solvent does not participate
productively in the desired reaction. For example, while not
wishing to be bound by theory, it is believed that when the base is
selected from alkylguanidines, aminophosphazenes, or
proazaphosphatranes and the solvent is selected from alcohol
solvents, the alcohol solvent levels the base. That is, these bases
deprotonate the alcohol to form an alkoxide base in the reaction
solution.
[0057] The solvent system need not bring about complete solution of
the ketone reactant or the chiral alcohol product. The ketone
reactant may be incompletely dissolved at the beginning of the
reaction or the chiral alcohol product may be incompletely
dissolved at the end of the reaction, or both.
[0058] Representative solvents are aromatic hydrocarbons such as
benzene, toluene, xylene; aliphatic hydrocarbons such as pentane,
hexane, heptane; halogen-containing hydrocarbon solvents such as
dichloromethane and chlorobenzene; alkyl ethers, polyethers, and
cyclic ethers such as methyl-t-butyl-ether, dibutylether,
diethoxymethane, 1,2-dimethnoxyethane, and tetrahydrofuran; ester
solvents such as ethyl acetate, organic solvents containing
heteroatoms such as acetonitrile, DMF and DMSO; and alcohol
solvents such as methanol, ethanol, 2-propanol, t-butanol, benzyl
alcohol and the like; and mixtures thereof. Preferably, the solvent
system comprises an alcohol solvent. Most preferably, the alcohol
solvent is 2-propanol.
[0059] In typical embodiments, the reaction is suitably conducted
at a temperature from about -30.degree. C. to about 100.degree. C.,
more typically from about 0.degree. C. to about 50.degree. C., and
most typically from about 20.degree. C. to about 40.degree. C. [60]
The terms "hydrogenating" and "hydrogenation" refer to reacting the
ketone with a source of hydrogen atoms under appropriate conditions
so that two hydrogen atoms are added to the carbonyl group of the
ketone to produce the hydroxyl group of the chiral alcohol. The
source of hydrogen atoms may be molecular hydrogen (H.sub.2), a
hydrogen donating organic or inorganic compound, or mixtures
thereof. Preferably the source of hydrogen atoms includes molecular
hydrogen. Hydrogen donating compounds are compounds capable of
donating hydrogen atoms via the action of the catalyst system.
[0060] Compounds capable of donating hydrogen atoms for transfer
hydrogenation reactions using ruthenium catalysts are known in the
art, and include alcohols such as methanol, ethanol, n-propanol,
isopropanol, butanol and benzyl alcohol, formic acid and salts
thereof, unsaturated hydrocarbons and heterocyclic compounds having
in part a saturated C--C bond such as tetralin, cyclohexane, and
cyclohexadiene, hydroquinone, phosphorous acid, and the like. Among
hydrogen donating compounds, alcohols are preferred and isopropanol
is most preferred.
[0061] The hydrogen pressure in the reaction is typically at least
about 1 atm., and typically in the range from about 1 atm. to about
100 atm. More typically, the hydrogen pressure is in the range from
about 5 atm to about 20 atm.
[0062] The reaction rate and time to completion are dependent on
the identities of the ketone reactant and the catalyst components,
their absolute concentrations and relative ratios, the temperature,
the hydrogen pressure, the gas-liquid mixing provided, and the
other reaction conditions. Typically, the reaction is allowed to
continue for sufficient time to complete the conversion of the
ketone reactant. For typical ketone reactants, using the preferred
catalyst systems described and the preferred reaction conditions
described herein, the reaction is typically completed in a period
of time in the range from about a few minutes to about 24 hours,
more typically in the range from about 1 hour to about 10
hours.
[0063] The nonracemic chiral alcohol product has, by definition, a
stereomeric excess greater than zero. In preferred embodiments, the
nonracemic chiral alcohol is formed in at least about 50%
stereomeric excess, more preferably at least about 60%, still more
preferably at least about 70%, still again more preferably at least
about 80%, and most preferably at least about 90%. These
stereomeric excesses refer to the chirality at the hydroxyl-bearing
carbon of the alcohol group generated by the hydrogenation of the
ketone group. When the ketone is achiral, the chiral alcohol can be
one of two enantiomers, and the enantiomer excess (e.e.) is the
measure of stereomeric excess. When the ketone reactant is already
chiral, the chiral alcohol product is a diastereomer, and
diastereomeric excess (d.e.) is the formally appropriate measure of
stereomeric excess. Accordingly, the term "nonracemic diastereomer"
when used to refer to a nonracemic chiral alcohol product, refers
to a product with an excess of one diastereomer vs. its
diastereomer with the opposite chirality at the hydroxyl-bearing
carbon. Preferably, the nonracemic diastereomer is produced in at
least about 50% d.e., more preferably at least about 60% d.e.,
still more preferably at least about 70% d.e., still again more
preferably at least about 80% d.e., and most preferably at least
about 90% d.e.
EXAMPLES OF THE INVENTION
[0064] Without further elaboration, it is believed that one skilled
in the art can, using the preceding description, utilize the
present invention to its fullest extent. The following specific
examples are intended merely to illustrate the invention and not to
limit the scope of the disclosure or the scope of the claims in any
way whatsoever.
Preparation 1
[0065] Preparation of [RuCl.sub.2(R,R,R,R-BICP)(DMF)n]: To 7.5 mg
(30 microgram-atom Ru) [RuCl.sub.2(benzene)].sub.2 and 16.2 mg (32
micromole)
(R,R,R,R)-2,2'-bis-(diphenylphosphino)-1,1'-dicyclopentane
(R,R,R,R-BICP) in a 200 ml Schlenk flask under nitrogen was added
10 ml anhydrous, deaerated dimethylformamide (DMF). The resulting
orange solution was heated at 130.degree. C. for 30 minutes, then
evaporated to dryness at 130.degree. C. under vacuum (10 mmHg). The
resulting orange-red solid residue, comprising
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n], was further dried at 80.degree.
C. under vacuum for at least an additional hour. A stock solution
of 250 micromolar [RuCl.sub.2((R,R,R,R-BICP)(DMF)n] in isopropanol
was prepared by dissolving the solid residue in 120 ml anhydrous,
deaerated isopropanol and stored under nitrogen.
[0066] This general procedure was used for the preparation of the
other [RuCl.sub.2(diphosphine)(DMF)n] complexes and the solutions
thereof used in the Examples.
Example 1
[0067] This Example illustrates the invention wherein acetophenone
is hydrogenated to nonracemic 1-phenethanol using a ruthenium
catalyst system comprising a nonracemic nonatropisomeric chiral
diphosphine ligand, an achiral diamine ligand and an alkoxide
base.
[0068] In a dry nitrogen-filled glovebox, a 20-ml glass reaction
vial was charged with 5 mL 250 micromolar (1.25 micromole)
[RuCl.sub.2((R,R,R,R-BI- CP)(DMF)n] in isopropanol, 5 mL
isopropanol, and 125 microliter 0.1M (12.5 micromole)
4,5-dimethyl-1,2-phenylene-diamine in isopropanol. After stirring
for several minutes, 73 microliter (625 micromole) acetophenone was
added, followed by 0.50 mL 0.1 M (50 micromoles) sodium
isopropoxide in isopropanol. The glass reaction vial containing the
resulting mixture was sealed in an autoclave, which was then
removed from the glovebox. The gas phase in the autoclave was
replaced by hydrogen at 18 bar and the reaction mixture was stirred
at room temperature for 6 hours under 17-18 bar hydrogen. After
releasing the hydrogen pressure, 1 ml of the resulting reaction
solution was eluted through a short column of silica gel with 9 mL
methanol. Chiral gas chromatographic analysis of the eluate showed
100% conversion of the acetophenone to give S-1-phenethanol with
71% e.e.
Example 2
[0069] This Example illustrates the process of the invention
wherein acetophenone is hydrogenated to nonracemic 1-phenethanol
using a ruthenium catalyst system comprising a nonracemic
nonatropisomeric chiral diphosphine ligand, an achiral diamine
ligand and an alkylguanidine base.
[0070] The procedure was the identical to Example 1 with the
exemptions that 0.50 mL 0.1 M (50 micromoles)
tetramethyl-2-t-butylguanidine in isopropanol was used instead of
the sodium isopropoxide solution. The analysis showed 100%
conversion of the acetophenone to give S-1-phenethanol with 77%
e.e.
Comparative Examples 1 and 2
[0071] These Comparative Examples illustrate the hydrogenation of
acetophenone to 1-phenethanol using the atropisomeric diphosphine
BINAP with an achiral diamine ligand.
[0072] The procedures were identical to Examples 1 and 2,
respectively, with the exception that an equimolar amount of
[RuCl.sub.2((R,R-BINAP)(DM- F)n] in isopropanol was substituted for
the [RuCl.sub.2((R,R,R,R-BICP)(DMF- )n] solution. The analyses
showed, respectively, 100% and 98% conversions of the acetophenone
to give S-1-phenethanol with 37% and 34% e.e.
[0073] By comparison, Examples 1 and 2 show that substantially
greater enantioselectivity (about twice as great) is obtained using
the nonatropisomeric ligand BICP ligand in combination with the
achiral diamine ligand.
Examples 3 and 4
[0074] These Examples illustrate the process of the invention
wherein 2-acetylthiophene is hydrogenated to nonracemic
1-(2-thienyl)ethanol using a ruthenium catalyst systems comprising
a nonracemic nonatropisomeric chiral diphosphine ligand, an achiral
diamine ligand and a base.
[0075] The procedures were identical to Examples 1 and 2,
respectively, with the exceptions that 68 microliter (625
micromole) 2-acetylthiophene reacted instead of the acetophenone
and the reaction mixtures were stirred under hydrogen for 4 hours.
The analyses showed 100% conversion of the 2-acetylthiophene to
S-1-(2-thienyl)ethanol with 84% e.e. in both reactions.
Comparative Example 3
[0076] This Comparative Example shows the result of omitting the
achiral diamine ligand from the catalyst system.
[0077] The procedure was identical to Examples 3 with the exception
that the 4,5-dimethyl-1,2-phenylenediamine was omitted and the
reaction mixtures were stirred under hydrogen for 10 hours. The
analysis showed 3% conversions of 2-acetylthiophene the to give
S-1-(2-thienyl)ethanol with 37% e.e.
[0078] By comparison, Example 3 shows that substantially greater
activity (conversion) and enantioselectivity (e.e.) are provided by
the catalyst systems comprising an achiral diamine ligand.
Comparative Example 4
[0079] This Example shows the result of omitting the base from the
catalyst system.
[0080] The procedure was identical to Example 3 with the exceptions
that the sodium isopropoxide solution was omitted and the reaction
mixtures was stirred under hydrogen for 10 hours. The analysis
showed only 1% conversion of the ketone.
[0081] By comparison, Example 3 shows that the activity for ketone
hydrogenation is provided by the catalyst system comprising a
base.
Examples 5 and 6
[0082] These Examples illustrate the transfer hydrogenation of
2-acetylthiophene to nonracemic 1-(2-thienyl)ethanol using
isopropanol as the hydrogen donating compound in the absence of
hydrogen.
[0083] The procedures were identical to Examples 3 and 4,
respectively, with the exception that the reaction mixtures were
stirred for 12 hours with a gas phase of nitrogen instead of 4
hours with a gas phase of hydrogen. The analyses showed,
respectively, 2% and 3% conversions of the 2-acetylthiophene to
S-1-(2-thienyl)ethanol with 41% and 24% e.e.
[0084] By comparison, Examples 3 and 4 show that the activity of
the catalyst system is greater for hydrogenation using molecular
hydrogen than for transfer hydrogenation using isopropanol as the
sole source of hydrogen atoms.
Examples 7-11 and Comparative Examples 5-7
[0085] These Examples illustrate the hydrogenation of
2-acetylthiophene to 1-(2-thienyl)ethanol using various
nonatropisomeric chiral diphosphine ligands (Examples 3 and 7-11)
and various atropisomeric biaryl diphosphine ligands (Comparative
Examples 5-7) with the achiral diamine
4,5-dimethyl-1,2-phenylenediamine.
[0086] Stock solutions of [RuCl.sub.2(diphosphine)(DMF)n] complexes
were prepared by the procedure described for
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n] in Preparation 1. The procedure
for the hydrogenation reactions was identical to Example 3 with the
exceptions that an equal molar amount the
[RuCl.sub.2(diphosphine)(DMF)n] having the diphosphine shown in
Table 1 (abbreviations are given in the Detailed Description of the
Invention) was substituted for [RuCl.sub.2(R,R,R,R-BICP)(DMF)n] and
the reaction mixtures were stirred for the time shown in Table 1.
Table 1 gives the diphosphine, the reaction time, the conversion of
the 2-acetylthiophene, the absolute configuration of the
1-(2-thienyl)ethanol, and its e.e.
1TABLE 1 Time Conv. % e.e. Example diphosphine ligand (hours) (%)
(R/S) 3 R,R,R,R-BICP 4 100 84 (S) 7 R,R-DIOP 12 100 58 (R) 8
R,R-SKEWPHOS 12 100 51 (S) 9 S,S-CHIRAPHOS 10 28 39 (R) 10
R,R-Me-PennPhos 12 14 42 (S) 11 R,R-Me-DuPHOS 6 8 31 (S) Comp. 5
R-BINAP 6 77 20 (S) Comp. 6 R-C4-TunaPhos 6 68 8 (R) Comp. 7
S-MeOBIPHEP 10 84 4 (S)
[0087] These results show that the exemplified nonatropisomeric
chiral diphosphine ligands provide greater enantioselectivities
than the comparatively exemplified atropisomeric biaryl diphosphine
ligands when used in combination with the achiral diamine ligand
4,5-dimethyl-1,2-phenylenediamine.
Examples 12-17 and Comparative Examples 8-10
[0088] These Examples illustrate the hydrogenation of
2-acetylthiophene to 1-(2-thienyl)ethanol using various
nonatropisomeric chiral diphosphine ligands (Examples 12-17) and
various atropisomeric biaryl diphosphine ligands (Comparative
Examples 8-10) with ethylenediamine as the achiral diamine.
[0089] The procedure was identical to Example 3 with the exceptions
that 125 microliter 0.1M (12.5 micromole) 1,2-ethylene diamine was
used instead of the 4,5-dimethyl-1,2-phenylenediamine solution, an
equal molar amount the [RuCl.sub.2(diphosphine)(DMF)n] having the
diphosphine shown in Table 2 was substituted for
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n], and the reaction mixtures were
stirred for the time shown in Table 2. Table 2 gives the
diphosphine, the reaction time, the conversion of the
2-acetylthiophene, the absolute configuration of the
1-(2-thienyl)ethanol, and its e.e.
2TABLE 2 Time Conv. % e.e. Example diphosphine ligand (hours) (%)
(R/S) 12 R,R,R,R-BICP 4 100 56 (S) 13 R,R-DIOP 12 54 42 (R) 14
R,R-SKEWPHOS 6 100 53 (S) 15 S,S-CHIRAPHOS 12 100 43 (R) 16
R,R-Me-PennPhos 12 100 36 (S) 17 R,R-Me-DuPHOS 12 90 54 (S) Comp. 8
R-BINAP 4 100 23 (S) Comp. 9 R-C4-TunaPhos 6 100 3 (R) Comp. 10
S-MeOBIPHEP 12 100 <1 (R)
[0090] These results show that the exemplified nonatropisomeric
chiral diphosphine ligands provide greater enantioselectivities
than the comparatively exemplified atropisomeric biaryl diphosphine
ligands when used in combination with ethylenediamine as the
achiral
Examples 18 and 19 and Comparative Examples 11-22
[0091] These Examples illustrate the hydrogenation of
2-acetylthiophene to 1-(2-thienyl)ethanol using preferred
nonatropisomeric chiral diphosphine ligands and various
atropisomeric biaryl diphosphine ligands in combinations with the
achiral (meso) and chiral stereoisomers of
1,2-cyclohexandiamine.
[0092] The procedure was identical to Example 3 with the exceptions
that 12.5 micromole of a stereoisomer of 1,2-cyclohexanediamine was
substituted for 4,5-dimethyl-1,2-phenylenediamine, an equal molar
amount the [RuCl.sub.2(diphosphine)(DMF)n] having the diphosphine
shown in Table 3 was substituted for
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n], and the reaction mixtures were
stirred for the time shown in Table 3. In all these reactions the
conversion of the 2-acetylthiophene was 100%. Table 3 gives the
diphosphine, the 1,2-cyclohexanediamine stereoisomer, the reaction
time, the absolute configuration of the 1-(2-thienyl)ethanol, and
its e.e.
3TABLE 3 cyclohexane Time % e.e. Example diphosphine ligand diamine
(hours) (R/S) 18 R,R,R,R-BICP meso 4 81 (S) Comp. 11 R,R,R,R-BICP
R,R 4 72 (S) Comp. 12 R,R,R,R-BICP S.S 6 16 (S) 19 R,R-Me-PennPhos
meso 12 76 (S) Comp. 13 R,R-Me-PennPhos R.R 12 63 (S) Comp. 14
R,R-Me-PennPhos S,S 12 28 (R) Comp. 15 R-BINAP meso 4 45 (S) Comp.
16 R-BINAP R,R 4 62 (S) Comp. 17 R-C4-TunaPhos meso 6 33 (S) Comp.
18 R-C4-TunaPhos R,R 6 40 (S) Comp. 19 R-C4-TunaPhos S.S 6 8 (S)
Comp. 20 S-MeOBIPHEP meso 10 41 (R) Comp. 21 S-MeOBIPHEP R.R 10 15
(R) Comp. 22 S-MeOBIPHEP S,S 10 47 (R)
[0093] These results show that preferred nonatropisomeric chiral
diphosphine ligands provide greater enantioselectivities than the
comparatively exemplified atropisomeric biaryl diphosphine ligands
when used in combination with meso-1,2-cyclohexanediamine as the
achiral diamine ligand. See Examples 18 and 19 vs. Comparative
Examples 15, 17, and 20.
[0094] These results also show that preferred nonatropisomeric
chiral diphosphine ligands provide greater enantioselectivity in
combination with the achiral meso-stereoisomer of
1,2-cyclohexanediamine than they do in combination with the matched
chiral enantiomer. (The "matched" enantiomer is the one that gives
greater enantioselectivity than the other.) See Example 18 vs.
Comparative Example 11 and Example 19 vs. Comparative Example
13.
[0095] In contrast, these results show that the atropisomeric
biaryl diphosphine ligands provide greater enantioselectivity in
combination with the matched chiral enantiomer of
1,2-cyclohexanediamine than they do in combination with the achiral
meso-stereoisomer. See Comparative Example 16 vs. Comparative
Example 15, Comparative Example 18 vs. Comparative Example 17, and
Comparative Example 22 vs. Comparative Example 20.
[0096] Additionally, these results show that the combinations of a
preferred nonatropisomeric chiral diphosphine ligand with the
achiral meso-stereoisomer of 1,2-cyclohexanediamine provide greater
enantioselectivities that the combinations of the atropisomeric
biaryl diphosphine ligands with their matched chiral enantiomer of
1,2-cyclohexanediamine. See Examples 18 and 19 vs. Comparative
Examples 16,18, and 22.
Examples 20-32 and Comparative Examples 23-25
[0097] These Examples illustrate the hydrogenation of
2-acetylthiophene to 1-(2-thienyl)ethanol using the
nonatropisomeric chiral diphosphine ligand BICP (Examples 20-32)
and the atropisomeric biaryl diphosphine ligand BINAP (Comparative
Examples 23-25) using a various achiral diamine ligands.
[0098] The procedure was identical to Example 3 with the exceptions
that an equal molar amount of the achiral diamine ligand shown in
Table 4 was substituted for the 4,5-dimethyl-1,2-phenylenediamine,
for the Comparative Examples an equal molar amount of
[RuCl.sub.2(R-BINAP)(DMF)n] was substituted for
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n], and the reaction mixtures were
stirred for the time shown in Table 4. Table 4 gives the achiral
amine ligand, the diphosphine (BICP or BINAP), the reaction time,
the conversion of the 2-acetylthiophene, the absolute configuration
of the 1-(2-thienyl)ethanol, and its e.e.
4TABLE 4 diphosphine Time Conv. % e.e. Example achiral diamine
ligand (hrs) (%) (R/S) 3 4,5-dimethyl-1,2-phenylenediamine
R,R,R,R-BICP 4 100 84 (S) Comp. 5 4,5-dimethyl-1,2-phenylenediamine
R-BINAP 6 77 20 (S) 12 ethylenediamine R,R,R,R-BICP 4 100 56 (S)
Comp. 8 ethylenediamine R-BINAP 4 100 23 (S) 18
meso-1,2-cyclohexanediamine R,R,R,R-BICP 4 100 81 (S) Comp. 15
meso-1,2-cyclohexanediamine R-BINAP 4 100 45 (S) 20
meso-1,2-diphenylethylenediamine R,R,R,R-BICP 4 100 81 (S) Comp. 23
meso-1,2-diphenylethylenediamine R-BINAP 4 96 16 (S) 21
1,3-propylenediamine R,R,R,R-BICP 4 100 82 (S) Comp. 24
1,3-propylenediamine R-BINAP 4 100 47 (R) 22 1,8-naphthalenediamine
R,R,R,R-BICP 4 100 85 (S) Comp. 25 1,8-naphthalenediamine R-BINAP 4
100 65 (R) 23 2,2-dimethyl-1,3-propylendiamine R,R,R,R-BICP 6 100
86 (S) 24 2-aminobenzylamine R,R,R,R-BICP 6 100 54 (S) 25
1,3-pentanediamine R,R,R,R-BICP 6 100 80 (S) 26
1,2-phenylenediamine R,R,R,R-BICP 12 100 83 (S) 27
4,5-(methylenedioxy)-1,2-phenylenediamine R,R,R,R-BICP 6 100 81 (S)
28 2-aminobenzylamine R,R,R,R-BICP 6 100 54 (S) 29
1,4-butanediamine R,R,R,R-BICP 6 14 44 (S) 30
2,3-naphthalenediamine R,R,R,R-BICP 12 49 75 (S) 31
9,10-phenanthrenediamine R,R,R,R-BICP 6 23 69 (S) 32
4-methoxy-1,2-phenylenediamine R,R,R,R-BICP 6 100 82 (S)
[0099] These results demonstrate that a variety of achiral diamine
ligands provide inventive catalyst systems having greater activity
than corresponding catalysts system lacking an achiral diamine
ligand (by comparison to the conversion in Comparative Example 3)
and provide nonracemic 1-(2-thienyl)ethanol (e.e.>0).
Comparisons between the Examples and the Comparative Examples using
the same achiral diamine ligand show that the nonatropisomeric
chiral diphosphine ligand BICP consistently provides greater
enantioselectivity for the hydrogenation of 2-acetylthiophene than
the atropisomeric biaryl diphosphine ligand BINAP.
Examples 33-39 and Comparative Examples 26-28
[0100] These Examples illustrate the hydrogenation of acetophenone
to 1-phenethanol using the nonatropisomeric chiral diphosphine
ligand BICP (Examples 33-39) and the aropisomeric biaryl
diphosphine ligand BINAP (Comparative Examples 26-28) using a
various achiral diamine ligands.
[0101] The procedure was identical to Example 1 with the exceptions
that an equal molar amount of the achiral diamine ligand shown in
Table 5 was substituted for the 4,5-dimethyl-1,2-phenylenediamine,
and for the Comparative Examples an equal molar amount of
[RuCl.sub.2(R-BINAP)(DMF)n] was substituted for
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n]. In all these reactions the
conversion of the acetophenone was 100%. Table 5 gives the achiral
amine ligand, the diphosphine (BICP or BINAP), the absolute
configuration of the 1-phenethanol, and its e.e.
5TABLE 5 diphosphine % e.e. Example achiral diamine ligand (R/S) 1
4,5-dimethyl-1,2- R,R,R,R-BICP 71 (S) phenylenediamine Comp. 1
4,5-dimethyl-1,2- R-BINAP 37 (S) phenylenediamine 33
ethylenediamine R,R,R,R-BICP 51 (S) Comp. 26 ethylenediamine
R-BINAP 47 (S) 34 meso-1,2- R,R,R,R-BICP 67 (S) cyclohexanediamine
Comp. 27 meso-1,2- R-BINAP 70 (S) cyclohexanediamine 35 meso-1,2-
R,R,R,R-BICP 73 (S) diphenylethylenediamine Comp. 28 meso-1,2-
R-BINAP 49 (S) diphenylethylenediamine 36 meso-1,2-di(4-
R,R,R,R-BICP 63 (S) methoxyphenyl)ethylenediamine 37
1,3-propylenediamine R,R,R,R-BICP 77 (S) 38 1,1-dimethyl-1,3-
R,R,R,R-BICP 57 (S) propylenediamine 39 1,8-naphthalenediamine
R,R,R,R-BICP 86 (S)
[0102] These results demonstrate that a variety of achiral diamine
ligands provide inventive catalyst systems for the hydrogenation of
acetophenone to nonracemic 1-phenethanol (e.e.>0). Comparisons
between the Examples and the Comparative Examples using the same
achiral diamine ligand show that the nonatropisomeric chiral
diphosphine ligand BICP provides similar (within 5 e.e. percentage
points) to substantially greater enantioselectivity than the
atropisomeric biaryl diphosphine ligand BINAP.
Examples 40 and 41 and Comparative Examples 29 and 30
[0103] These Examples illustrate the hydrogenation of
1'-acetonaphthone to 1-(1-napthyl)ethanol using the
nonatropisomeric chiral diphosphine ligand BICP (Examples 40 and
41) and the atropisomeric biaryl diphosphine ligand BINAP
(Comparative Examples 29 and 30) in combinations with
ethylenediamine and 4,5-dimethyl-1,2-phenylenediamine as achiral
diamine ligands.
[0104] The procedure was identical to Example 1 with the exceptions
that an equal molar amount of 1'-acetonaphthone was substituted for
the acetophenone, for Examples 40 and Comparative Example 29 an
equal molar amount of ethylenediamine was substituted for the
4,5-dimethyl-1,2-phenyl- enediamine, and for the Comparative
Examples an equal molar amount of [RuCl.sub.2(S-BINAP)(DMF)n] was
substituted for [RuCl.sub.2(R,R,R,R-BICP)- (DMF)n]. Table 6 gives
the achiral amine ligand, the diphosphine (BICP or BINAP), the
conversion of the 1'-acetonaphthone, and the absolute configuration
of the 1-phenethanol, and its e.e.
6TABLE 6 diphosphine Conv. % e.e. Example achiral diamine ligand
(%) (R/S) 40 ethylenediamine R,R,R,R-BICP 100 66 (S) Comp. 29
ethylenediamine S-BINAP 86 29 (S) 41 4,5-dimethyl-1,2- R,R,R,R-BICP
25 75 (S) phenylenediamine Comp. 30 4,5-dimethyl-1,2- S-BINAP 33 20
(R) phenylenediamine
[0105] These results show that, when using an achiral diamine
ligand, the nonatropisomeric chiral diphosphine ligand BICP
provides substantially greater enantioselectivity than the
atropisomeric biaryl diphosphine ligand BINAP.
Examples 42-62
[0106] Examples show the process of the invention for hydrogenation
of various ketones to nonracemic chiral alcohols using catalyst
systems of the invention.
[0107] The procedure was identical to Example 1 with the exceptions
that 625 micromole of the ketone shown in Table 7 was reacted
instead of the acetophenone, an equal molar amount of
1,8-diaminonaphthalene was substituted for the
4,5-dimethyl-1,2-phenylenediamine, and the reaction mixtures were
stirred under hydrogen for the time shown in Table 7. In each
example, the analysis showed the conversion of the ketone was 100%.
The ketone, the reaction time, the chirality of its nonracemic
chiral alcohol product, and its e.e. are in Table 7.
7TABLE 7 Time % e.e. Example ketone (hrs) (R/S) 22
2-acetylthiophene 4 85 (S) 39 acetophenone 6 86 (S) 42
propiophenone 12 91 (S) 43 4'-fluoroacetophenone 9 87 (S) 44
4'-isobutylacetophenone 9 89 (S) 45 4'-methoxyacetophenone 9 89 (S)
46 4'-methylacetophenone 9 88 (S) 47 2'-methylacetophenone 9 85 (S)
48 2'-methoxyacetophenone 9 79 (S) 49 1'-acetonaphthone 9 90 (S) 50
2'-acetonaphthone 9 86 (S) 51 2-methoxyacetophenone 9 82 (S) 52
3-acetylpyridine 9 70 (S) 53 2-acetylfuran 9 72 (S) 54
2-acetyl-3-methylthiophene 9 84 (S) 55
3-acetyl-2,5-dimethylthiophene 9 92 (S) 56 3-acetylthiophene 9 87
(S) 57 5-bromo-2-acetylthiophene 9 87 (S) 58
5-chloro-2-acetylthiophene 9 87 (S) 59
5-acetyl-2,4-dimethylthiazole 9 85 (S) 60 2-acetylbenzothiophene 9
86 (S) 61 methyl isopropyl ketone 9 33 (R) 62 methyl isobutenyl
ketone 9 66 (R)
Examples 63-70
[0108] These Examples show the process of the invention for
hydrogenation of 2-acetylthiophene to nonracemic
1-(2-thienyl)ethanol using a various bases selected from
alkylguanidines and aminophosphazenes with meso-cyclohexanediamine
as the achiral diamine ligand.
[0109] The procedure was identical to Examples 3 and 4 with the
exceptions that an equal molar amount of the base shown in Table 8
was substituted for the sodium isopropoxide (Example 3) or
tetramethyl-2-t-butylguanidine (Example 4), an equal molar amount
of meso-cyclohexanediamine was substituted for the
4,5-dimethyl-1,2-phenylene-diamine, and the reaction mixtures were
stirred under hydrogen for the time shown in Table 8. Table 8 gives
the base, the reaction time, the conversion of the
2-acetylthiophene, and the enantiomeric excess of the
S-1-(2-thienyl)ethanol product.
8TABLE 8 Ex. Time Conv. e.e. No. base (hrs) (%) (%) 18 sodium
isopropoxide 4 100 81 63 tetramethyl-2-t-butylguanidine 4 84 90 64
1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 56 90 65
7-methyl-1,5,7-triazabicyclo[4.4.0]dec- 6 34 91 5-ene 66
N,N,N',N',N",N"-hexamethyl- 6 30 90 phosphorimidic triamide 67
N"'-t-butyl-N,N,N',N',N",N"-hexamethyl- 12 100 90 phosphorimidic
triamide 68 (t-butyl-imino)-tris(pyrrolidino)phos- 12 100 85
phorane 69 N"'-[N-ethyl-P,P-bis(dimethylamino)ph- os- 12 100 79
phinimyl]-N,N,N',N',N",N"-hexamethyl- phosphorimidic triamide 70
t-butyl-tris[tris(dimethylamino)phos- 12 100 80
phoranylidene]-phosphorimidic triamide
[0110] These Examples demonstrate that a variety of bases selected
from alkylguanidines and aminophosphazenes provide
enantioselectivities at least comparable to that providedd by a
basic salt (sodium isopropoxide) as the base in the inventive
catalyst systems.
Examples 71-79
[0111] These Examples show the process of the invention for
hydrogenation of 2-acetylthiophene to nonracemic
1-(2-thienyl)ethanol using a various bases selected from
alkylamindines, alkylguanidines and aminophosphazenes with ethylene
diamine as the achiral diamine ligand.
[0112] The procedure was identical to Examples 3 and 4 with the
exceptions that an equal molar amount of the base shown in Table 9
was substituted for the sodium isopropoxide (Example 3) or
tetramethyl-2-t-butylguanidine (Example 4), an equal molar amount
of ethylenediamine was substituted for the
4,5-dimethyl-1,2-phenylenediamine, and the reaction mixtures were
stirred under hydrogen for the time shown in Table 9. Table 9 gives
the base, the reaction time, the conversion of the
2-acetylthiophene, and the enantiomeric excess of the
S-1-(2-thienyl)ethanol product.
9TABLE 9 Ex. Time Conv. e.e. No. base (hrs) (%) (%) 12 sodium
isopropoxide 4 100 56 71 tetramethyl-2-t-butylguanidine 6 100 86 72
1,5-diazabicyclo[4.3.0]non-5-ene 12 8 89 73
1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 100 88 74
7-methyl-1,5,7-triazabicyclo[4.4.0]dec- 6 95 90 5-ene 75
N,N,N',N',N",N"-hexamethyl- 6 88 89 phosphorimidic triamide 76
N'''-t-N,N,N',N',N",N"-hexamethyl- 12 100 81 phosphorimidic
triamide 77 (t-butyl-imino)-tris(pyrrolidino)phos- 12 100 61
phorane 78 N'''-[N-ethyl-P,P-bis(dimethylamino)phos- 12 100 51
phinimyl]-N,N,N',N',N",N"-hexamethyl- phosphorimidic triamide 79
t-butyl-tris[tris(dimethylamino)phosphor- 6 100 51
anylidene]-phosphorimidic triamide
[0113] These Examples demonstrate that a variety of bases selected
from alkylguanidines and aminophosphazenes provide
enantioselectivities at least comparable, and in some instances
substantially superior to that provided by a basic salt (sodium
isopropoxide) as the base in the inventive catalyst systems using
ethylenediamine as the achiral diamine ligand.
Examples 80-92
[0114] These Examples show the process of the invention for
hydrogenation of various ketones to nonracemic chiral alcohols
using ethylenediamine as the achiral diamine ligand in combination
with either sodium isopropoxide (a basic salt),
1,5,7-triazabicyclo-[4.4.0]dec-5-ene (a tetraalkylquanidine base),
or tetramethyl-2-t-butylguanidine (a pentaalkylguanidine base).
[0115] The procedure was identical to Example 1 with the exceptions
that 625 micromole of the ketone shown in Table 10 was reacted
instead of the acetophenone, an equal molar amount of
ethylenediamine was substituted for the
4,5-dimethyl-1,2-phenylene-diamine, for some Examples an equal
molar amount of 1,5,7-triazabicyclo[4.4.0]dec-5-ene or
tetramethyl-2-t-butylguanidine was substituted for the sodium
isopropoxide, and the reaction mixtures were stirred under hydrogen
for the time shown in Table 10. In each example, the analysis
showed the conversion of the ketone was 100%. Table 10 gives the
ketone, the base, the reaction time, and the enantiomeric excess of
the S-alcohol product.
10TABLE 10 Ex. Time e.e. No. ketone base (hrs) (%) 12
2-acetylthiophene sodium isopropoxide 4 56 73 2-acetylthiophene
1,5,7-triazabi- 6 88 cyclo[4.4.0]dec-5-ene 80 2-acetylthiophene
tetramethyl-2-t- 4 86 butylguanidine 33 acetophenone sodium
isopropoxide 6 51 81 acetophenone 1,5,7-triazabi- 12 83
cyclo[4.4.0]dec-5-ene 82 acetophenone tetramethyl-2-t- 6 77
butylguanidine 83 2-acetonaphthone sodium isopropoxide 9 64 84
2-acetonaphthone 1,5,7-triazabi- 12 83 cyclo[4.4.0]dec-5-ene 85
2-acetylbenzothiophene sodium isopropoxide 12 68 86
2-acetylbenzothiophene 1,5,7-triazabi- 12 82 cyclo[4.4.0]dec-5-ene
87 2-acetylfuran sodium isopropoxide 9 60 88 2-acetylfuran
1,5,7-triazabi- 9 82 cyclo[4.4.0]dec-5-ene 89 2-methoxyacetophenone
sodium isopropoxide 9 51 90 2-methoxyacetophenone 1,5,7-triazabi- 9
75 cyclo[4.4.0]dec-5-ene 91 3',5'-bis(trifluoro- sodium
isopropoxide 12 78 methyl)acetophenone 92 3',5'-bis(trifluoro-
1,5,7-triazabi- 12 76 methyl)acetophenone cyclo[4.4.0]dec-5-ene
[0116] These Examples show that for many ketones, when using
ethylene diamine as the chiral diamine ligand, alkylguanidine bases
can provide significantly greater enantioselectivity than a basic
salt like sodium isopropoxide. They also show that the degree of
the relative improvement can also depend on the identity of the
ketone.
Examples 93-98
[0117] These Examples show the process of the invention for
hydrogenation of 3-(dimethylamino)-1-(2-thienyl) 1-propanone to
nonracemic 3-(dimethylamino)-1-(2-thienyl)-1-propanol using various
achiral diamine ligands and either sodium isoproxide or
tetramethyl-2-t-butylguanidine as the base.
[0118] A 1.47 mM solution of [RuCl.sub.2((R,R,R,R-BICP)(DMF)n] in
isopropanol was prepared from [RuCl.sub.2(benzene)].sub.2 and 1.1
equivalents R,R,R,R-BICP following the general procedure given in
Preparation 1. For each Example, in a dry nitrogen-filled glovebox,
a 20-ml glass reaction vial was charged with 2 mL 1.47 mM (2.9
micromole) [RuCl.sub.2((R,R,R,R-BICP)(DMF)n] in isopropanol, 3 mL
isopropanol, 0.58 mL 0.1M (0.58 mmole) achiral diamine ligand in
isopropanol, 0.25 g (1.43 mmole)
3-(dimethylamino)-1-(2-thienyl)-1-propanone (free base), and 0.29
mL 0.2M (0.58 mmole) base in isopropanol. The glass reaction vial
containing the resulting mixture was sealed in an autoclave, which
was then removed from the glovebox. The gas phase in the autoclave
was replaced by hydrogen and the reaction mixture was stirred under
6.8 bar (gauge) hydrogen at room temperature for 18 hours. The
reaction mixture was sampled and analyzed by chiral HPLC. was 100%.
Table 10 gives the achiral diamine ligand, the base, the conversion
of the ketone, and the enantiomeric excess of the resulting
S-3-(dimethylamino)-1-(2-thienyl)l-p- ropanol product.
11TABLE 11 Ex. Conv. e.e. No. achiral diamine ligand base (%) (%)
93 ethylene diamine sodium isopropoxide 96 24 94 ethylene diamine
tetramethyl-2-t- 89 79 butylguanidine 95 2-methyl-1,2- sodium
isopropoxide 97 68 propylenediamine 96 2-methyl-1,2-
tetramethyl-2-t- 85 85 propylenediamine butylguanidine 97 meso-1,2-
sodium isopropoxide 96 83 cyclohexanediamine 98 meso-1,2-
tetramethyl-2-t- 77 88 cyclohexanediamine butylguanidine
[0119] These Examples further show that an alkylguanidine base can
provide significantly greater enantioselectivity than a basic salt
like sodium isopropoxide. They also show that the degree of the
relative improvement can also depend on the identity of the achiral
diamine ligand, and appears greatest with a simpler and smaller
achiral diamine, especially with ethylene diamine.
Comparative Examples 30 and 31
[0120] These Comparative Examples illustrate the hydrogenation of
hydrogenation of 3-(dimethylamino)-1-(2-thienyl)l-propanone to
nonracemic 3-(dimethylamino)-1-(2-thienyl) 1-propanol using the
atropisomeric biaryl diphosphine ligands BINAP and MeOBIPHEP in
combination with the achiral diamine ligand ethylenediamine and the
base tetramethyl-2-t-butylguanidin- e.
[0121] The procedure was identical to Example 94 with the exception
that an equal molar amount of [RuCl.sub.2(R-BINAP)(DMF)n] or
[RuCl.sub.2(S-MeOBIPHEP)(DMF)n] was substituted for
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n]. Table 12 gives the diphosphine
ligand, the conversion of the ketone, and chirality of the
resulting S-3-(dimethylamino)-1-(2-thienyl)-1-propanol, and its
enantiomeric excess.
12TABLE 12 Conv. % e.e. Example diphosphine ligand (%) (R/S) 94
R,R,R,R-BICP 89 79 (S) Comp. 30 R-BINAP 56 24 (S) Comp. 31
S-MeOBIPHEP 73 21 (R)
[0122] These results show that a preferred nonatropisomeric chiral
diphosphine ligand, BICP, provides greater activity and
substantially greater enantioselectivity than the atropisomeric
biaryl diphosphine ligands when in combination with ethylene
diamine, and even when a pentaalkylguanidine is used as the
base.
Comparative Examples 32-35
[0123] These Examples illustrate the hydrogenation of
3-(dimethylamino)-1-(2-thienyl) 1-propanone to nonracemic
3-(dimethylamino)-1-(2-thienyl)-1-propanol using the
nonatropisomeric chiral diphosphine ligand BICP and the base
tetramethyl-2-t-butylguanidin- e with enantiomeric chiral diamine
ligands.
[0124] The procedure was identical to Example 94 with the exception
that an equimolar amount of the diamine shown in Table 13 was
substituted for ethylenediamine. Table 13 gives the diamine ligand,
the conversion of the ketone, and the enantiomeric excess of the
resulting S-3-(dimethylamino)-1-(2-thienyl)1-propanol product
(ND=not determined), together with results from comparable Examples
using achiral diamine ligands.
13TABLE 12 Conv. e.e. Example diamime ligand (%) (%) 94
ethylenediamine 89 79 Comp. 32 R-1,2-propylenediamine 96 78 Comp.
33 S-1,2-propylenediamine 94 49 96 2-methyl-1,2-propylenediamine 85
85 98 meso-1,2-cyclohexanediamine 77 88 Comp. 34
R,R-1,2-cyclohexanediamine 38 74 Comp. 35 S,S-1,2-cyclohexanediami-
ne <5 ND
[0125] By comparison with Example 94, Comparative Example 32 shows
that, with a preferred nonatropisomeric chiral diphosphine ligand,
R,R,R,R-BICP, the addition of a methyl group to ethylenediamine to
make the "matched" R-enantiomer of 1,2-propylene-diamine does not
provide any greater enantioselectivity. In contrast, the addition
of a second methyl group at the same position to make the achiral
2-methyl-1,2-propylenediam- ine, in Example 96, does provide
greater enantioselectivity.
[0126] Comparison of Example 98 with Comparative Example 34 shows
that, with R,R,R,R-BICP, greater activity and enantioselectivity
are obtained with achiral meso-1,2-cyclohexanediamine than with the
"matched" R,R-enantiomer of 1,2-cyclohexanediamine as the diamine
ligand.
Example 99
[0127] This Example illustrates a preparative scale hydrogenation
of 3-(dimethylamino)-1-(2-thienyl) 1-propanone to nonracemic
3-(dimethylamino)-1-(2-thienyl) 1-propanol according to the process
of the invention.
[0128] In a dry nitrogen-filled glovebox, a 300 mL autoclave was
charged with 20.0 g (109 mmol) 3-(dimethylamino)-1-(2-thienyl)
1-propanone (free base), 90 ml isopropanol, 40 mL ethanol, 0.52 mL
(4.36 mmol) tetramethyl-2-t-butylguanidine, and 31.1 mL 7.0 mM
(0.22 mmol) [RuCl.sub.2((R,RR,R-BICP)(DMF)n] in 4:1
isopropanol:dichloromethane. The autoclave was sealed with a head
equipped for overhead stirring and removed from the glovebox. The
gas phase in the autoclave reactor was replaced by hydrogen and the
reaction mixture was stirred under 6.8 bar (gauge) hydrogen at room
temperature for 21 hours. HPLC analysis of a sample of the reaction
mixture showed 100% conversion of the ketone. The reaction mixture
was concentrated to 50 mL by rotary evaporation (25.degree. C./10
mmHg). The concentrate was diluted with 150 ml heptane and a seed
crystal was added. This mixture was concentrated again by rotary
evaporation to 50 mL and refrigerated at 4.degree. C. overnight.
The resulting crystals were collected by filtration, washed with
cold heptane and dried under high vacuum to yield 11.9 g (59%
yield) S-3-(dimethylamino)-1-(2-thienyl)l-propanol as white prisms.
Chiral HPLC analysis showed 99.7% chemical purity and 99.1%
e.e.
Example 100
[0129] This Example illustrate the process of the invention for the
hydrogenation of a enantiomeric chiral ketone to a diastereomeric
chiral alcohol.
[0130] In a dry nitrogen-filled glovebox, a glass autoclave liner
was charged with 20 ml 125 micromolar (2.5 micromoles)
[RuCl.sub.2((S,S,S,S-BICP)(DMF)n] in isopropanol, 90 ml
isopropanol, 0.5 ml 0.1 M (50 micromoles)
4,5-dimethyl-1,2-diamino-benzene in isopropanol. After stirring for
about 2 minutes, 5.2 g (12.5 millimole)
(2S)-1-(4-benzyl-oxyphenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propa-
none was added, followed by 0.5 ml 0.2 M (100 micromoles) sodium
isopropoxide in isopropanol. The glass liner containing the
resulting suspension was sealed in an autoclave, which was then
removed from the glovebox. The gas phase in the autoclave was
replaced by hydrogen at 18 bar. The gas-liquid mixture was then
stirred for 22 hours. Chiral HPLC analysis of the reaction mixture
showed 98.8% conversion of the ketone to give
(1S,2S)-1-(4-benzoxyphenyl)-2-(4-hydroxy-4-phenylpiperidin-1-yl)-l-p-
ropanol with 99.1% d.e.
[0131] The product was isolated by filtering the resulting
suspension, washing the solid with isopropanol (3.times.20 ml), and
drying it under vacuum to obtain the product as a white solid in
>80% yield, >98% purity, and >99% d.e.
Example 101
[0132] This Example illustrates the process of the invention for
producing the opposite enantiomer of the diastereomeric chiral
alcohol produced in Example 100 by using the opposite enantiomers
of the chiral ketone and the diphosphine ligand that were used in
Example 100.
[0133]
(2R)-1-(4-benzyl-oxy-phenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)--
1-propanone was hydrogenated in isopropanol solution at room
temperature under 18 bar hydrogen for one hour at using
[RuCl.sub.2((R,R,R,R-BICP)(DM- F)n],
4,5-dimethyl-1,2-diaminobenzene and sodium isopropoxide in the mole
ratios ketone:Ru:BICP:diamine:base=500:1:1:5:20. Chiral HPLC
analysis of the reaction mixture showed 98.8% conversion of the
ketone to give
(1R,2R)-1-(4-benzoxyphenyl)-2-(4-hydroxy-4-phenyl-piperidin-1-yl)-1-propa-
nol with 98.2% d.e.
[0134] This example also illustrates that because the diamine
ligand is achiral, the same diamine ligand may be used to prepare
either enantiomer of the chiral alcohol.
Example 102
[0135] This Example illustrates the process of the invention for
producing a diastereomer of the chiral alcohol enantiomers produced
in Examples 100 and 101 by using the opposite enantiomer of the
chiral ketone used in Example 101, but same enantiomer of the
diphosphine ligand used in that Example.
[0136] The procedure was identical to Example 101 with the
exception that the (2S) enantiomer of the
1-(4-benzyl-oxy-phenyl)-2-(4-hydroxy-4-phenyl--
piperidin-1-yl)-1-propanone was reacted, again using the
(R,R,R,R)-BICP ligand. Chiral HPLC analysis of the reaction mixture
showed 99.5% conversion of the ketone to give
(1R,2S)-1-(4-benzoxyphenyl)-2-(4-hydroxy-
-4-phenyl-piperidin-1-yl)-1-propanol with 92.0% d.e.
[0137] Examples 101 and 102 taken together show that the chirality
generated at the 1-carbon by hydrogenation of this ketone to the
alcohol is predominantly controlled by the chirality of the
diphosphine ligand, and only relatively weakly influenced by the
chirality already present at the 2-carbon of the this ketone.
Whether the (2R)-ketone (Example 100) or the (2S)-ketone (Example
101) is hydrogenated using the (R,R,R,R)-BICP ligand, the chirality
generated in the alcohol is predominantly (IR) by greater than 90%
d.e.
[0138] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Although
the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding,
it will be readily apparent to those of ordinary skill in the art
in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the
spirit or scope of the appended claims.
* * * * *