U.S. patent application number 10/158560 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 | 20030181319 10/158560 |
Document ID | / |
Family ID | 27609485 |
Filed Date | 2003-09-25 |
United States Patent
Application |
20030181319 |
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 chiral diphosphine ligand, a
bidentate amine ligand, and an organic base selected from
alkylamidines, alkylguanidines, aminophosphazenes, and
proazaphosphatranes.
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.: |
10/158560 |
Filed: |
May 21, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10158560 |
May 21, 2002 |
|
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10057826 |
Jan 24, 2002 |
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Current U.S.
Class: |
502/162 |
Current CPC
Class: |
C07D 307/44 20130101;
C07D 277/24 20130101; C07F 9/3813 20130101; C07B 53/00 20130101;
C07F 15/0053 20130101; B01J 2231/643 20130101; C07C 29/143
20130101; B01J 31/2409 20130101; C07D 333/56 20130101; B01J
2531/821 20130101; C07B 2200/07 20130101; C07C 29/145 20130101;
B01J 31/1805 20130101; C07D 333/16 20130101; B01J 31/24 20130101;
C07D 211/52 20130101; B01J 31/226 20130101 |
Class at
Publication: |
502/162 |
International
Class: |
C07D 211/40 |
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 chiral
diphosphine ligand, a bidentate amine ligand, and an organic base
selected from alkylamidines, alkylguanidines, aminophosphazenes,
and proazaphosphatranes, with the proviso that when said nonracemic
chiral diphosphine is an atropisomeric diphosphine and the organic
base is selected from alkylamidines, said catalyst system is
essentially free of alkali metal salt.
2. The catalyst system of claim 1 wherein the nonracemic chiral
diphosphine ligand is a nonracemic nonatropisomeric chiral
diphosphine ligand.
3. The catalyst system of claim 2 wherein the nonracemic
nonatropisomeric chiral diphosphine ligand comprises at least one
stereogenic carbon atom.
4. The catalyst system of claim 3 wherein the nonracemic
nonatropisomeric chiral diphosphine ligand comprises at least one
stereogenic carbon atom in a hydrocarbyl diradical that connects
the two phosphorus atoms.
5. The catalyst system of claim 4 wherein the nonracemic
nonatropisomeric diphosphine ligand comprises a
2,2'-bis(diorganophosphino)-1,1'-bis(cycli- c) structure.
6. The catalyst system of claim 5 wherein the nonracemic
nonatropisomeric diphosphine ligand is selected from enantiomers of
diphosphine ligands having the structural formula 7wherein Ar is an
aryl group.
7. The catalyst system of claim 6 wherein Ar is selected from
phenyl, monoalkylphenyl, dialkylphenyl, and trialkylphenyl.
8. The catalyst system of claim 1 wherein the bidentate amine
ligand is a diamine ligand.
9. The catalyst system of claim 8 wherein the diamine amine ligand
is a bis-primary amine ligand.
10. The catalyst system of claim 8 wherein the diamine ligand is an
achiral diamine ligand.
11. The catalyst system of claim 10 wherein the achiral diamine
ligand 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 bidentate amine
ligand is an amino-thioether ligand.
13. The catalyst system of claim 12 wherein the amino-thioether
ligand is selected from 2-(alkylthio)ethylamines and
2-(alkylthio)anilines.
14. The catalyst system of claim 13 wherein the amino-thioether is
a 2-(alkylthio)aniline.
15. The catalyst system of claim 1 wherein the organic base is
selected from alkylguanidines, aminophosphazenes, and
proazaphosphatranes.
16. The catalyst system of claim 15 wherein the organic base is an
alkylguanidine.
17. The catalyst system of claim 16 wherein the base is selected
from tetraalkylguanidines and pentaalkylguanidines.
18. 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 chiral diphosphine ligand, a bidentate amine ligand, and
an organic base selected from alkylamidines, alkylguanidines,
aminophosphazenes, and proazaphosphatranes, with the proviso that
when said nonracemic chiral diphosphine is an atropisomeric
diphosphine and said organic base is selected from alkylamidines,
said catalyst system is essentially free of alkali metal salt.
19. The process of claim 18 wherein the nonracemic chiral
diphosphine ligand is a nonracemic nonatropisomeric chiral
diphosphine ligand.
20. The process of claim 21 wherein the nonracemic nonatropisomeric
chiral diphosphine ligand comprises at least one stereogenic carbon
atom.
21. The process of claim 20 wherein the nonracemic nonatropisomeric
chiral diphosphine ligand comprises at least one stereogenic carbon
atom in a hydrocarbyl diradical that connects the two phosphorus
atoms.
22. The process of claim 21 wherein the nonracemic nonatropisomeric
diphosphine ligand comprises a
2,2'-bis(diorganophosphino)-1,1'-bis(cycli- c) structure.
23. The process of claim 22 wherein the nonracemic nonatropisomeric
diphosphine ligand is selected from enantiomers of diphosphine
ligands having the structural formula 8wherein Ar is an aryl
group.
24. The process of claim 23 wherein Ar is selected from phenyl,
monoalkylphenyl, dialkylphenyl, and trialkylphenyl.
25. The process of claim 18 wherein the bidentate amine ligand is a
diamine ligand.
26. The process of claim 25 wherein the diamine amine ligand is a
bis-primary amine ligand.
27. The process of claim 25 wherein the diamine ligand is an
achiral diamine ligand.
28. The process of claim 27 wherein the achiral diamine ligand is
selected from meso-1,2-alkylenediamine compounds,
1,2-phenylenediamine compounds and 1,8-diaminonaphthalene
compounds.
29. The process of claim 18 wherein the bidentate amine ligand is
an amino-thioether ligand.
30. The process of claim 29 wherein the amino-thioether ligand is
selected from 2-(alkylthio)ethylamines and
2-(alkylthio)anilines.
31. The process of claim 30 wherein the amino-thioether is a
2-(alkylthio)aniline.
32. The process of claim 18 wherein the organic base is selected
from alkylguanidines, aminophosphazenes, and
proazaphosphatranes.
33. The process of claim 32 wherein the organic base is an
alkylguanidine.
34. The process of claim 33 wherein the base is selected from
tetraalkylguanidines and pentaalkylguanidines.
35 The process of claim 18 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 applications Ser. No. ______
(Attorney Docket No. 021153-001600US, "Process for Preparing
Nonracemic Chiral Alcohols"), and Ser. No. ______ (Attorney Docket
No. 021153-001700US, "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, an
appropriate enantiomeric diphosphine ligand, an enantiomeric
1,2-diamine, and a base. Angew. Chem. Int. Ed., vol. 40, (2001),
40-73 (a review with 211 references); U.S. Pat. No. 5,763,688; J.
Am. Chem. Soc., vol. 117 (1995), 2675-2676; J. Org. Chem., vol. 64
(1999), 2127-2129. U.S. Pat. No. 5,763,688 states, "In the bases
expressed by the general formula M.sup.2Y, for example, M.sup.2 is
an alkali metal or an alkaline earth metal, and Y is a hydroxy
group, alkoxy group, mercapto group or naphthyl group, and more
specifically, applicable ones include KOH, KOCH.sub.3,
KOCH(CH.sub.3).sub.2, KC.sub.10H.sub.8, KOC(CH.sub.3).sub.3, LiOH,
LiOCH.sub.3, LiOCH(CH.sub.3).sub.2, NaOH, NaOCH.sub.3,
NaOCH(CH.sub.3).sub.2, as well as quaternary ammonium salt." It
further states that, for solvent, "Since the product is alcohol,
alcohol type solvents are preferable. More preferably, 2-propanol
may be preferably used." The Examples of U.S. Pat. No. 5,763,688
exemplify only KOH as the base and only 2-propanol as the solvent.
J. Am. Chem. Soc., vol. 117 (1995), 2675-2676, whose authors are
inventors of U.S. Pat. No. 5,763,688, further discusses this
process of U.S. Pat. No. 5,763,688 and states, "2-propanol is the
solvent of choice. The reaction in methanol, ethanol, or
tert-butylalcohol is much slower, while THF, dichoromethane, and
toluene are not useable."
[0006] Others have noted that 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 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. European
Patent Application 901 997, having inventors in common with U.S.
Pat. No. 5,763,688 states, "With regard to the base, an inorganic
or a quaternary ammonium salt can be exemplified, preferably an
alkali metal compound or an alkaline earth metal compound and a
quaternary ammonium salt, more preferably an alkali metal or
alkaline earth metal hydroxide or a salt thereof and a quaternary
ammonium salt. Its illustrative examples include LiOH, LiOMe,
LiOEt, LiOCH(CH.sub.3).sub.2, LiOC(CH.sub.3).sub.3, NaOH, NaOMe,
NaOEt, NaOCH(CH.sub.3).sub.2, NaOC(CH.sub.3).sub.3, KOH,
KOCH.sub.3, KOCH(CH.sub.3).sub.2, KOC(CH.sub.3).sub.3,
KC.sub.10H.sub.8, and the like. A quaternary ammonium salt can also
be used." It further states that, for solvent, "Because the product
is an alcohol, alcohol solvents most preferred, and 2-propanol is
particularly preferred." The Examples of European Patent
Application 901 997 exemplify only KOH and KOC(CH.sub.3).sub.3 as
the base and only 2-propanol as main solvent. The other references
cited above in this Background of the Invention section similarly
use KOH or KOC(CH.sub.3).sub.3 as the base and 2-propanol as main
solvent.
[0007] A catalyst system of ruthenium, the atropisomeric
diphosphine (S)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl
(S-BINAP), achiral ethylenediamine, and potassium hydroxide in
2-propanol is 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 is 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.
[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) in 2-propanol
gave no catalytic activity for the hydrogenation of acetophenone.
The addition of selected alkali metal salts of
tetrakis[3,5-bis(trifluorometh- yl)-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 chiral
diphosphine ligand, a bidentate amine ligand, and an organic base
selected from alkylamidines, alkylguanidines, aminophosphazenes,
and proazaphosphatranes, with the proviso that when the nonracemic
chiral diphosphine is an atropisomeric diphosphine and the organic
base is selected from alkylamidines, the catalyst system is
essentially free of alkali metal salt. Preferably, the organic base
is selected from alkylguanidines, aminophosphazenes, and
proazaphosphatranes, and is most preferably selected from
alkylguanidines. Surprisingly, these organic bases often provide
greater enantioselectivity for the hydrogenation of a ketone to a
nonracemic chiral alcohol as compared to the basic salts preferred
in the teachings of the background references. Additionally, these
organic bases allow the inventive process to be conducted with
solvents other than the alcohol solvent preferred in the background
references, including solvents such as dichloromethane and toluene
and solvents in which the basic salts preferred in the background
references are not soluble. Even more surprisingly, by using these
organic bases to conduct the process in solvents other than alcohol
solvents, increased enantioselectivities are often provided
compared to those obtained when the process is conducted using
alcohol solvents. Still more surprisingly, in certain embodiments,
the chirality of the dominant enantiomer of the nonracemic alcohol
product can be opposite that obtained with the otherwise identical
catalyst system comprising a basic salt.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Not applicable
DETAILED DESCRIPTION OF THE INVENTION
[0011] Unless otherwise stated, the following terms used in the
specification and claims have the meanings given below:
[0012] 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.
[0013] "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.
[0014] "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.
[0015] "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.
[0016] "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.
[0017] "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.
[0018] "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.
[0019] "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.
[0020] "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, tetrahydrobenzo furanyl,
isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,
indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl,
isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and
the substituted derivatives thereof.
[0021] "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.
[0022] 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
[0023] 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.
[0024] 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.
[0025] The ruthenium, nonracemic chiral diphosphine ligand, and
bidentate amine 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 diphosphine
ligand, or the bidentate amine ligand, or both can be used.
[0026] Examples of preformed complexes of the ruthenium with the
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 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.
[0027] Examples of preformed complexes of the ruthenium with both
the diphosphine ligand and bidentate amine ligand include complexes
represented by the formula RuX.sub.2LA, wherein A represents the
bidentate amine ligand. Such complexes can be prepared by the
reaction of the bidentate amine with a complex of the formula
RuX.sub.2LY.sub.n as described above.
[0028] 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 diphosphine
ligand, the bidentate amine 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 bidentate
amine 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.
[0029] Suitable nonracemic 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, or heterocyclic hydrocarbyl groups, or combinations
thereof. Additionally, each of the hydrocarbyl groups R.sup.3,
R.sup.4 R.sup.5, R.sup.6 and R.sup.a 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.3, R.sup.4, R.sup.5, R.sup.6 and R.sup.a can be optionally
substituted with one or more substituents that do not undesirably
affect the reaction chemistry of the invention.
[0030] The chirality of the 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 radical 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. Chirality in the bridging hydrocarbyl
diradical R.sup.a may be due to the presence of one or more
stereogenic carbon atoms, or due to atropoisomerism.
[0031] Atropisomers do not comprise a stereogenic atom, but are
chiral because of greatly hindered or prevented rotation about a
single bond. 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'-di-methoxy-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).
[0032] Preferably, the nonracemic chiral diphosphine ligand is
selected from nonracemic nonatropisomeric chiral diphosphine
ligands, and more 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.
[0033] 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]ethyl-di- methylamine
(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-dimethylphos- pholano)ethylene (Me-BPE),
1,2-bis-[3,4-benzoxy-2,5-dimethylphospholanyl]b- enzene (RoPhos),
1,2-bis-[3,4-O-isopropyl-idene-3,4-dihydroxy-2,5-dimethyl-
phospholanyl]benzene (Me-KetalPhos),
1,1'-bis[3,4-O-iso-propylidene-3,4-di-
hydroxy-2,5-dimethyl-phospholanyl]ferrocene (Me-f-KetalPhos),
5,6-bis(diphenylphosphino)-2-norbornene (NORPHOS),
N,N'-bis-(diphenylphosphino)-N,N'-bis(1-phenylethyl)ethylenediamine
(PNNP), 2,2'-bis(diphenylphosphino)-1,1'-dicyclo-pentane (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-phosphabicyclo-
[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.
[0034] 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.
[0035] 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
[0036] 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
[0037] 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).
[0038] Suitable bidentate amine ligands comprise a primary amino
group and another heteroatom-containing group that is capable of
ligating to the ruthenium. Such groups are known in the art, and
include groups having a heteroatom selected from oxygen, nitrogen,
sulfur, and phosphorus. Preferred bidentate amine ligands include
diamines and amino-thioethers.
[0039] The bidentate amine ligand may be achiral, racemic chiral,
or nonracemic chiral. In certain inventive embodiments of the
invention, the bidentate amine ligand is an achiral diamine.
[0040] Suitable diamine ligands for the present invention are of
the general formula H.sub.2NR.sup.bNH.sub.2, wherein R.sup.b is an
hydrocarbyl diradical. Preferably, the hydrocarbyl diradical
comprises at least two to fifty carbon atoms, more preferably at
least three to fifty carbon atoms, still more preferably at least
four to fifty carbon atoms, and most preferably at least six to
fifty carbon atoms, Suitable 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] Suitable chiral diamine ligands include the enantiomers and
mixtures thereof of chiral derivatives of ethylenediamine,
propylenediamines, butanediamines, cycloalkanediamines, and
phenylenediamines. Illustrative examples include chiral
stereoisomers of 1,2-diphenylethylenediamine,
1,2-cyclohexanediamine, 1,2-cycloheptanediamine,
2,3-dimethylbutanediamine, 1-methyl-2,2-diphenylethylenediamine,
1-isobutyl-2,2-diphenylethylenediam- ine,
1-isopropyl-2,2-diphenylethylenediamine,
1-methyl-2,2-di(p-methoxyphe- nyl)ethylenediamine,
1-isobutyl-2,2-di(p-methoxyphenyl)ethylenediamine,
1-isopropyl-2,2-di(p-methoxyphenyl)ethylenediamine,
1-benzyl-2,2-di(p-methoxyphenyl)ethylenediamine,
1-methyl-2,2-dinaphthyle- thylenediamine,
1-isobutyl-2,2-dinaphthylethylenediamine,
1-isopropyl-2,2-dinaphthylethylenediamine, 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. Preferred
chiral diamines are chiral stereoisomers of
1,2-diphenylethylenediamine and 1,2-cyclohexanediamine.
[0042] Suitable achiral diamines 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.
[0043] Illustrative examples of achiral diamines include
ethylenediamine, 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-dimethyl-butane-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.
[0044] 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).
[0045] Suitable amino-thioether ligands for the present invention
are of the general formula H.sub.2NR.sup.cSR.sup.7, wherein R.sup.7
is a hydrocarbyl radical and R.sup.c is a hydrocarbyl diradical and
which may be optionally linked in a cyclic structure. Suitable
hydrocarbyl groups R.sup.7 and diradicals thereof for R.sup.c
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 the reaction chemistry of the
invention. The amino-thioether ligand may be achiral, racemic
chiral, or nonracemic chiral, preferably achiral.
[0046] Preferred amino-thioether ligands are selected from
2-(alkylthio)ethylamines, 2-(alkylthio)anilines, and equivalents
thereto that are recognized by those skilled in the art. Most
preferred are 2-(alkylthio)anilines. Preferably the alkyl group
therein is selected from C.sub.1 to C.sub.4 alkyl groups. Most
preferred are methyl and ethyl. Illustrative examples include
2-(methylthio)aniline and 2-(ethylthio)aniline.
[0047] Turning next to the organic bases suitable for use in the
present methods, those bases selected from alkylamidines,
alkylguanidines, aminophosphazenes and proazaphosphatranes have
been found particularly attractive as providing, in some instances,
greater enantioselectivity and utility with solvent systems other
than the alcohols used in related processes.
[0048] Suitable alkylguanidines have the general formula VI,
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. 4
[0049] 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.
[0050] 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.sub.2 group may optionally be linked in a cyclic
structure, and x is an integer from zero to three, preferably
3.
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)
VII
[0051] 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.13=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).
[0052] Suitable proazaphosphatranes are described in U.S. Pat. No.
5,051,533 and have the general formula VIII, wherein R.sup.15,
R.sup.16, and R.sup.17 are independently selected from hydrogen and
alkyl groups. 5
[0053] 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.sup.16=R.sup.17=methyl).
[0054] Suitable alkylamidines have the general formula IX 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. 6
[0055] 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.
[0056] Preferably, the organic base is selected from
alkylguanidines, aminophosphazenes, and proazaphosphatranes. More
preferably, the organic base is an alkylguanidine, most preferably
selected from tetraalkylguanidines and pentaalkylguanidines.
[0057] Preferably, the catalyst system is essentially free of
alkali metal salt. The invention includes the proviso that for
embodiments wherein an alkylamidine base is used in combination
with a nonracemic atropisomeric diphosphine ligand, the catalyst
system is essentially free of alkali metal salt. The phrase
"essentially free of alkali metal salt" means that the
concentration of the alkali metal salt is not sufficient to
significantly increase the activity of the catalyst system. This
can be readily determined experimentally. Preferably the catalyst
system is free of alkali metal salt.
[0058] 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 1/100 to about 1/100,000, preferably in the range from about
1/500 to about 1/10,000.
[0059] The mole ratio of the nonracemic 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 bidentate amine
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.
[0060] 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.
[0061] The term reaction-inert 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
alcohol solvents level organic bases selected from the preferred
alkylguanidines, aminophosphazenes, or proazaphosphatranes. That
is, these bases deprotonate the alcohol to form an alkoxide base in
the reaction solution. However, the mere formation of an alkoxide
base in situ cannot explain the often greater enantioselectivity in
the ketone hydrogenation reaction that is provided by the organic
bases of the present invention compared to the basic alkoxide salts
preferred in the teachings of the background references. Also, the
organic bases of the present invention allow the inventive process
to be conducted using solvents other than alcohol solvents,
including solvents in which the basic alkoxide salts preferred in
the background references are not soluble.
[0062] 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.
[0063] 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-dimethoxyethane, 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.
[0064] 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.
[0065] 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. 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.
[0066] 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.
[0067] 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.
[0068] 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
[0069] 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
[0070] 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)-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.
[0071] 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 following Examples.
Example 1
[0072] This Example illustrates the process of the invention
wherein acetophenone is hydrogenated to nonracemic 1-phenethanol
using a ruthenium catalyst system comprising a nonracemic
diphosphine ligand, a bidentate amine ligand and a
pentaalkylguanidine base.
[0073] 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)
ethylenediamine in isopropanol. After stirring for several minutes,
73 microliter (625 micromole) acetophenone was added, followed by
0.50 mL 0.1 M (50 micromoles) tetramethyl-2-t-butylguanidine 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 77% e.e.
Comparative Example 1
[0074] This Comparative Example shows the result substituting an
alkoxide salt for the alkylguanidine base exemplified in Examples
1.
[0075] The procedure was the identical to Example 1 with the
exemption that 0.50 mL 0.1 M (50 micromoles) sodium isopropoxide
was used instead of the tetramethyl-2-t-butylguanidine solution.
The analysis showed 100% conversion of the acetophenone to give
S-1-phenethanol with 51% e.e.
[0076] By comparison, Example 1 shows that the enantioselectivity
for hydrogenation of acetophenone is substantially greater with the
otherwise identical catalyst comprising an alkylguanidine base.
Examples 2-7 and Comparative Examples 2-7
[0077] These Examples illustrate the process of the invention
wherein acetophenone is hydrogenated to nonracemic 1-phenethanol
using catalysts systems comprising various diamine ligands,
including achiral diamines and enantiomers of chiral diamines, in
combination with a pentaalkylguanidine base. The Comparative
Examples show the corresponding results obtained by substituting an
alkoxide salt for the alkylguanidine base.
[0078] The procedure was identical to Example 1 with the exemptions
that an equimolar amount of the diamine ligand listed in Table 1
was substituted for the ethylene-diamine, the reaction mixture was
stirred under hydrogen for the time shown in Table 1, and for the
Comparative Examples, an equimolar amount of sodium isopropoxide
was substituted for the tetramethyl-2-t-butylguanidine. In each
example, the analysis showed the conversion of the acetophenone was
100%. Table 1 gives the diamine ligand, the base, the reaction
time, and the enantiomeric excess of the S-1-phenethanol
product.
1TABLE 1 Time e.e. Example. diamine base (hrs) (%) 1
ethylenediamine tetramethyl-2-t-butylguanidine 6 77 Comp. 1
ethylenediamine sodium isopropoxide 6 51 2 1,3-propylenediamine
tetramethyl-2-t-butylguan- idine 4 78 Comp. 2 1,3-propylenediamine
sodium isopropoxide 6 77 3 4,5-dimethyl-1,2-phenylenediamine
tetramethyl-2-t-butylguanidine 10 77 Comp. 3
4,5-dimethyl-1,2-phenylenediamine sodium isopropoxide 6 71 4
1,8-naphthalenediamine tetramethyl-2-t-butylguanidine 4 86 Comp. 4
1,8-naphthalenediamine sodium isopropoxide 8 86 5
R,R-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 6 68
Comp. 5 R,R-1,2-cyclohexanediamine sodium isopropoxide 6 62 6
S,S-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 6 14
Comp. 6 S,S-1,2-cyclohexanediamine sodium isopropoxide 6 3 7
meso-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 12 71
Comp. 7 meso-1,2-cyclohexanediamine sodium isopropoxide 6 67
[0079] The results in Table 1 show that the enantioselectivity for
hydrogenation of acetophenone is at least as good as and in many
cases better for the catalyst system comprising the
pentaalkylguanidine base compared to the otherwise identical
catalyst system comprising an the alkoxide salt for the base.
Examples 8-16 and Comparative Examples 8-16
[0080] These Examples illustrate the process of the invention
wherein 2-acetylthiophene to nonracemic 1-(2-thienyl)ethanol using
catalysts systems comprising various diamine ligands, including
achiral diamines and enantiomers of chiral diamines, in combination
with a pentaalkylguanidine base. The Comparative Examples show the
corresponding results obtained by substituting an alkoxide salt for
the alkylguanidine base.
[0081] The procedure was identical to Example 1, with the
exceptions that 68 microliter (625 micromole) 2-acetylthiophene was
reacted instead of the acetophenone, an equimolar amount of the
diamine ligand listed in Table 2 was substituted for the
ethylenediamine, the reaction mixture was stirred under hydrogen
for the time shown in Table 2, and for the Comparative Examples, an
equimolar amount of sodium isopropoxide was substituted for the
tetramethyl-2-t-butylguanidine. In each example, the analysis
showed the conversion of the acetophenone was 100%. Table 2 gives
the diamine ligand, the base, the reaction time, and the
enantiomeric excess of the 1-(2-thienyl)ethanol product.
2TABLE 2 Time e.e. Example diamine base (hrs) (%) 8 ethylenediamine
tetramethyl-2-t-butylguanidine 4 86 Comp. 8 ethylenediamine sodium
isopropoxide 4 56 9 1,3-propylenediamine tetramethyl-2-t-butylgua-
nidine 4 85 Comp. 9 1,3-propylenediamine sodium isopropoxide 4 82
10 4,5-dimethyl-1,2-phenylenediamine tetramethyl-2-t-butylguanidine
4 84 Comp. 10 4,5-dimethyl-1,2-phenylenediamine sodium isopropoxide
4 84 11 1,8-naphthalenediamine tetramethyl-2-t-butylguanidine 4 86
Comp. 11 1,8-naphthalenediamine sodium isopropoxide 4 85 12
R,R-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 4 87
Comp. 12 R,R-1,2-cyclohexanediamine sodium isopropoxide 4 72 13
S,S-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 6 62
Comp. 13 S,S-1,2-cyclohexanediamine sodium isopropoxide 6 16 14
meso-1,2-cyclohexanediamine tetramethyl-2-t-butylguanidine 4 90
Comp. 14 meso-1,2-cyclohexanediamine sodium isopropoxide 4 81 15
R-1,2-propylenediamine tetramethyl-2-t-butylguanidine 6 89 Comp. 15
R-1,2-propylenediamine sodium isopropoxide 6 77 16
2-aminobenzylamine tetramethyl-2-t-butylguanidine 6 57 Comp. 16
2-aminobenzylamine sodium isopropoxide 6 54
[0082] The results in Table 2 show that the enantioselectivity for
hydrogenation of 2-acetylthiophene is at least comparable and in
many cases significantly better for the catalyst system comprising
the pentaalkylguanidine base compared to the otherwise identical
catalyst system comprising an the alkoxide salt for the base.
Example 17
[0083] This Example illustrates the process of the invention
wherein acetophenone is hydrogenated to nonracemic 1-phenethanol
using a ruthenium catalyst system comprising a nonracemic
diphosphine ligand, a bidentate amine ligand and a
tetraaalkylguanidine base.
[0084] The procedure was the identical to Example 1 with the
exemptions that 0.50 mL 0.1 M (50 micromoles)
1,5,7-triazabicyclo[4.4.0]dec-5-ene was used instead of the
tetramethyl-2-t-butylguanidine solution and the reaction time was
12 hours. The analysis showed 100% conversion of the acetophenone
to give S-1-phenethanol with 83% e.e.
[0085] By comparison with Comparative Example 1, this Example shows
that the enantioselectivity for hydrogenation of acetophenone is
substantially greater with the catalyst system comprising the
tetraalkylguanidine base compared to the otherwise identical
catalyst system comprising an the alkoxide salt for the base.
Examples 18-25
[0086] 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
alkylamidines, alkylguanidines and aminophosphazenes with
ethylenediamine as the bidentate amine ligand.
[0087] The procedure was identical to Examples 8 with the
exceptions that an equal molar amount of the base shown in Table 3
was substituted for the tetramethyl-2-t-butyl-guanidine and the
reaction mixtures were stirred under hydrogen for the time shown in
Table 2. Table 2 gives the base, the reaction time, the conversion
of the 2-acetylthiophene, and the enantiomeric excess of the
S-1-(2-thienyl)ethanol product.
3TABLE 3 Time Conv. e.e. Example base (hrs) (%) (%) Comp. 8 sodium
isopropoxide 4 100 56 8 tetramethyl-2-t-butylguanidine 6 100 86 18
1,5-diazabicyclo[4.3.0]non-5-ene 12 8 89 19
1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 100 88 20
7-methyl-1,5,7-triazabicyclo[4.4.0] 6 95 90 dec-5-ene 21
N,N,N',N',N",N"-hexamethyl- 6 88 89 phosphorimidic triamide 22
N'''-t-butyl-N,N,N',N',N",N"- 12 100 81 hexamethyl-phosphorimidic
triamide 23 (t-butyl-imino)-tris(pyrrolidino) 12 100 61 phosphorane
24 N'''-[N-ethyl-P,P-bis(dimethylamino) 12 100 51
phosphinimyl]-N,N,N',N',N",N"- hexamethyl-phosphorimidic triamide
25 t-butyl-tris[tris(dimethylamino) 6 100 51 phosphoranylidene]-
phosphorimidic triamide
[0088] By comparison to Comparative Example 8, these Examples
demonstrate that a variety of bases selected from alkylamidines,
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 ethylene diamine as the
achiral diamine ligand.
Examples 26-32
[0089] 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-1,2-cyclohexanediamine as the bidentate amine ligand.
[0090] The procedure was identical to Example 14 with the
exceptions that an equal molar amount of the base shown in Table 4
was substituted for the tetramethyl-2-t-butyl-guanidine and the
reaction mixtures were stirred under hydrogen for the time shown in
Table 4. Table 4 gives the base, the reaction time, the conversion
of the 2-acetylthiophene, and the enantiomeric excess of the
S-1-(2-thienyl)ethanol product.
4TABLE 4 Time Conv. e.e. Example base (hrs) (%) (%) Comp. 14 sodium
isopropoxide 4 100 81 14 tetramethyl-2-t-butylguanidine 4 84 90 26
1,5,7-triazabicyclo[4.4.0] 6 56 90 dec-5-ene 27
7-methyl-1,5,7-triazabicyclo[4.4.0] 6 34 91 dec-5-ene 28
N,N,N',N',N",N"-hexamethyl- 6 30 90 phosphorimidic triamide 29
N'''-t-butyl-N,N,N',N',N",N"- 12 100 90 hexamethyl-phosphorimidic
triamide 30 (t-butyl-imino)-tris(pyrrolidino) 12 100 85 phosphorane
31 N'''-[N-ethyl-P,P-bis 12 100 79 (dimethylamino)phosphinimyl]-
N,N,N',N',N",N"-hexamethyl- phosphorimidic triamide 32
t-butyl-tris[tris(dimethylamino) 12 100 80 phosphoranylidene]-
phosphorimidic triamide
[0091] By comparison to Comparative Example 14, these Examples
demonstrate that a variety of bases selected from alkylguanidines
and aminophosphazenes provide enantioselectivities at least
comparable, and in some superior, to that provided by a basic salt
(sodium isopropoxide) as the base in the inventive catalyst
systems.
Examples 33-36
[0092] These Examples show the process of the invention for
hydrogenation of 2-acetylthiophene to nonracemic
1-(2-thienyl)ethanol using various bases selected from
alkylguanidines and aminophosphazenes in combinations with
enantiomers of chiral 1,2-cyclohexanediamine as the bidentate amine
ligand.
[0093] The procedure was identical to Examples 12 and 13, for R,R-
and S,S-1,2-cyclohexanediamine respectively, with the exceptions
that an equal molar amount of the base shown in Table 5 was
substituted for the tetramethyl-2-t-butylguanidine and the reaction
mixtures were stirred under hydrogen for the time shown in Table 5.
Table 5 gives the chirality of the 1,2-cyclohexane diamine, the
base, the reaction time, the conversion of the 2-acetylthiophene,
and the enantiomeric excess of the S-1-(2-thienyl)ethanol
product.
5TABLE 5 c-hexane Time Conv. e.e. Example diamine base (hrs) (%)
(%) Comp. 12 R,R- sodium isopropoxide 4 100 72 12 R,R-
tetramethyl-2-t- 4 100 87 butylguanidine 33 R,R- 7-methyl-1,5,7- 12
99 92 triazabicyclo[4.4.0] dec-5-ene 34 R,R- N'''-t-butyl- 12 100
85 N,N,N',N',N",N",- hexamethyl- phosphorimidic triamide Comp. 13
S,S- sodium isopropoxide 6 100 16 13 S,S- tetramethyl-2-t- 6 100 62
butylguanidine 35 S,S- 7-methyl-1,5,7- 12 92 72
triazabicyclo[4.4.0] dec-5-ene 36 S,S- N'''-t-butyl- 12 100 56
N,N,N',N',N",N"- hexamethyl- phosphorimidic triamide
[0094] The results in Table 5 demonstrate, for each enantiomer of
chiral 1,2-cyclohexanediamine, that bases selected from
alkylguanidines and aminophosphazenes can provide substantially
greater enantioselectivities to that provided by an alkoxide
salt.
[0095] In all these Examples, the chirality of the dominant
enantiomer of the nonracemic alcohol product is the same, S,
showing that it is controlled by the chirality of the diphosphine
enantiomer. Among these results, the chirality of the
1,2-cyclohexanediamine affects only the degree of
enantioselectivity toward the S-alcohol. Comparisons between the
results that use the same base consistently show that that the
R,R-1,2-cyclohexanediamine is matched to the chirality of the
R,R,R,R-BICP, their combination giving higher enantioselectivities
than the combination of the S,S-1,2-cyclohexanediamine with
R,R,R,R-BICP.
[0096] Surprisingly, Example 35 shows that the unmatched
combination of S,S-1,2-cyclohexanediamine with R,R,R,R-BICP when
used with an alkylguanidine base can provide in an
enantioselectivity on par with the matched combination of
R,R-1,2-cyclohexanediamine with R,R,R,R-BICP when used with the
alkoxide salt base (Comparative Example 2).
Examples 37-45 and Comparative Examples 15 and 17
[0097] These Examples show the process of the invention for
hydrogenation of 2-acetylthiophene to nonracemic
1-(2-thienyl)ethanol using various bases selected from
alkylguanidines and aminophosphazenes in combinations with the
enantiomers of 1,2-propylenediamine as the bidentate amine
ligand.
[0098] The procedure was identical to Example 15 with the
exceptions that S-1,2-propylenediamine was substituted for
R-1,2-propylenediamine in some of the Examples, an equal molar
amount of the base shown in Table 6 was substituted for the
tetramethyl-2-t-butylguanidine, and the reaction mixtures were
stirred under hydrogen for the time shown in Table 6. Table 6 gives
the chirality of the 1,2-propylenediamine, the base, the reaction
time, the conversion of the 2-acetylthiophene, and the enantiomeric
excess of the S-1-(2-thienyl)ethanol product.
6TABLE 6 diamine Time Conv. e.e. Example chirality base (hrs) (%)
(%) Comp. 17 S- sodium isopropoxide 6 100 35 37 S-
tetramethyl-2-t-butylguanidine 6 85 70 38 S-
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 88 75 Comp. 15 R-
sodium isopropoxide 6 100 77 15 R- tetramethyl-2-t-butylguanidine 6
100 89 39 R- 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 100 94
40 R- 1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 100 93 41 R-
N,N,N',N',N",N"-hexamethyl-phosphorimidic 6 96 94 triamide 42 R-
N'''-t-butyl-N,N,N',N',N",N"-hexamethyl- 12 100 89 phosphorimidic
triamide 43 R- (t-butyl-imino)-tris(pyrrolidino)pho- sphorane 12
100 81 44 R- N'''-[N-ethyl-P,P-bis(dimethylamino)- 12 100 76
phosphinimyl]-N,N,N',N',N",N"-hexamethyl- phosphorimidic triamide
45 R- t-butyl-tris[tris(dimethylamino)- 6 100 76
phosphoranylidene]phosphorimidic triamide
[0099] The results in Table 6 demonstrate, for each enantiomer of
1,2-propylenediamine, that bases selected from alkylguanidines and
aminophosphazenes can provide substantially greater
enantioselectivities to that provided by an alkoxide salt.
[0100] In all these Examples, the chirality of the dominant
enantiomer of the nonracemic alcohol product is the same, S,
showing that it is controlled by the chirality of the diphosphine
enantiomer. Among these results, the chirality of the
1,2-propylenediamine affects only the degree of enantioselectivity
toward the S-alcohol. Comparisons between the results that use the
same base consistently show that that the R-1,2-propylenediamine is
matched to the chirality of the R,R,R,R-BICP, their combination
giving higher enantioselectivities than the combination of the
S-1,2-propylenediamine with R,R,R,R-BICP.
[0101] Surprisingly, Example 38 shows that the unmatched
combination of S-1,2-propylenediamine with R,R,R,R-BICP when used
with an alkylguanidine base can provide in an enantioselectivity
comparable with the matched combination of R-1,2-propylenediamine
with R,R,R,R-BICP when used with the alkoxide salt base
(Comparative Example 15).
Examples 46-50 and Comparative Examples 18-22
[0102] These Examples show the hydrogenation of various ketones
using either the tetraalkylguanidine
1,5,7-triazabicyclo[4.4.0]dec-5-ene (the Examples) or sodium
isopropoxide (the Comparative Examples) in combination with
ethylenediamine as the bidentate amine ligand.
[0103] 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 equimolar amount of either
1,5,7-triazabicyclo[4.4.0]dec- -5-ene or sodium isopropoxide was
substituted for the tetramethyl-2-t-butylguanidine, and the
reaction mixture was stirred under hydrogen for the time shown in
Table 7. In each example, the analysis showed the conversion of the
ketone was 100% and that the chirality of the product alcohol was
predominantly S. Table 7 gives the ketone, the base, the reaction
time, and the enantiomeric excess of the S-alcohol product.
7TABLE 7 Time e.e. Example ketone base (hrs) (%) 2 acetophenone
1,5,7-triazabicyclo[4.4.- 0]dec-5-ene 12 83 Comp. 1 acetophenone
sodium isopropoxide 6 51 8 2-acetylthiophene
1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 88 Comp. 8 2-acetylthiophene
sodium isopropoxide 4 56 46 2'-acetonaphthone
1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 83 Comp. 18
2'-acetonaphthone sodium isopropoxide 9 64 47
2-acetylbenzothiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 82
Comp. 19 2-acetylbenzothiophene sodium isopropoxide 12 68 48
2-acetylfuran 1,5,7-triazabicyclo[4.4.0]dec-5-ene 9 82 Comp. 20
2-acetylfuran sodium isopropoxide 9 60 49 2-methoxyacetophenone
1,5,7-triazabicyclo[4.4.0]dec-5-ene 9 75 Comp. 21
2-methoxyacetophenone sodium isopropoxide 9 51 50
3',5'-bis(trifluoromethyl)- 1,5,7-triazabicyclo[4.4.0]dec-5-ene 9
76 acetophenone Comp. 22 3',5'-bis(trifluoromethyl)- sodium
isopropoxide 12 78 acetophenone
[0104] These Examples show that for many ketones, when using
ethylene diamine as the achiral diamine ligand, 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
ketone.
Examples 51-56 and Comparative Examples 23-28
[0105] These Examples show the hydrogenation of various ketones
using either 1,5,7-triabicyclo[4.4.0]dec-5-ene (the Examples) or
sodium isopropoxide (the Comparative Examples) in combination with
R-propylenediamine as the bidentate amine ligand.
[0106] The procedure was identical to Example 1 with the exceptions
that 625 micromole of the ketone shown in Table 8 was reacted
instead of the acetophenone, an equimolar amount R-propylenediamine
was substituted for the ethylenediamine, an equimolar amount of
either 1,5,7-triazabicyclo[4.4.0]dec-5-ene or sodium isopropoxide
was substituted for the tetramethyl-2-t-butylguanidine, and the
reaction mixture was stirred under hydrogen for the time shown in
Table 8. In each example, the analysis showed the conversion of the
ketone was 100% and that the chirality of the product alcohol was
predominantly S. Table 8 gives the ketone base, the reaction time,
and the enantiomeric excess of the S-alcohol product.
8TABLE 8 Time e.e. Example ketone base (hrs) (%) 51 acetophenone
1,5,7-triazabicyclo[4.4.- 0]dec-5-ene 12 87 Comp. 23 acetophenone
sodium isopropoxide 9 68 52 2-acetylthiophene
1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 93 Comp. 15 2-acetylthiophene
sodium isopropoxide 6 77 53 2'-acetonaphthone
1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 87 Comp. 24
2'-acetonaphthone sodium isopropoxide 9 77 54
2-acetylbenzothiophene 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 88
Comp. 25 2-acetylbenzothiophene sodium isopropoxide 12 81 55
2-acetylfuran 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 87 Comp. 26
2-acetylfuran sodium isopropoxide 9 74 55 2-methoxyacetophenone
1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 81 Comp. 27
2-methoxyacetophenone sodium isopropoxide 9 60 56
3',5'-bis(trifluoromethyl)- 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12
79 acetophenone Comp. 28 3',5'-bis(trifluoromethyl)- sodium
isopropoxide 12 78 acetophenone
[0107] These Examples show that for many ketones, when using
R-propylenediamine as the achiral diamine ligand, 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
ketone.
Examples 57-67 and Comparative Examples 29-33
[0108] These Examples show the hydrogenation of various ketones
using either an alkylguanidine base (the Examples) or sodium
isopropoxide (the Comparative Examples) in combination with
meso-cyclohexanediamine as the bidentate amine ligand.
[0109] The procedure was identical to Example 7 with the exceptions
that 625 micromole of the ketone shown in Table 9 was reacted
instead of the acetophenone, in some reactions an equimolar amount
of either 1,5,7-triazabicyclo[4.4.0]dec-5-ene or sodium
isopropoxide was substituted for the
tetramethyl-2-t-butylguanidine, and the reaction mixture was
stirred under hydrogen for the time shown in Table 9. In each
example, the chirality of the product alcohol was predominantly S.
Table 9 gives the ketone base, the reaction time, the conversion of
the ketone and the enantiomeric excess of the S-alcohol
product.
9TABLE 9 Time Conv. e.e. Example ketone base (hrs) (%) (%) 57
acetophenone 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 73 7
acetophenone tetramethyl-2-t-butylguanidine 12 100 71 Comp. 7
acetophenone sodium isopropoxide 6 100 67 26 2-acetylthiophene
1,5,7-triazabicyclo[4.4.0]dec-5-ene 6 56 90 14 2-acetylthiophene
tetramethyl-2-t-butylguanidine 4 84 90 Comp. 14 2-acetylthiophene
sodium isopropoxide 4 100 81 58 2-acetonaphthone
1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 81 59 2-acetonaphthone
tetramethyl-2-t-butylguanidine 12 100 80 Comp. 29 2-acetonaphthone
sodium isopropoxide 9 100 78 60 2-acetylbenzothiophene
1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 93 61
2-acetylbenzothiophene tetramethyl-2-t-butylguanidine 12 100 92
Comp. 30 2-acetylbenzothiophene sodium isopropoxide 12 100 89 62
2-acetylfuran 1,5,7-triazabicyclo[4.4.0]dec-5-ene 9 84 83 63
2-acetylfuran tetramethyl-2-t-butylguanidine 12 100 83 Comp. 31
2-acetylfuran sodium isopropoxide 9 100 79 64 2-methoxyacetophenone
1,5,7-triazabicyclo[4.4.0]dec-5-ene 12 100 71 65
2-methoxyacetophenone tetramethyl-2-t-butylguanidine 8 84 67 Comp.
32 2-methoxyacetophenone sodium isopropoxide 9 100 55 66
3',5'-bis(trifluoromethyl)- 1,5,7-triazabicyclo[4.4.0]dec-5-ene 12
100 64 acetophenone 67 3',5'-bis(trifluoromethyl)-
tetramethyl-2-t-butylguanidine 12 100 64 acetophenone Comp. 33
3',5'-bis(trifluoromethyl)- sodium isopropoxide 12 100 70
acetophenone
[0110] These Examples show that for many ketones, when using
meso-cyclohexanediamine as the achiral diamine ligand, an
alkylguanidine base can provide greater enantioselectivity than a
basic salt like sodium isopropoxide. They also show that the
relative improvement can also depend on the identity of the
ketone.
Examples 68-73 and Comparative Examples 34-39
[0111] These Examples illustrate the hydrogenation of
2-acetylthiophene to 1-(2-thienyl)ethanol using various chiral
diphosphine ligands in combinations with ethylendiamine as the
bidentate amine ligand and either tetramethyl-2-t-butylguanidine
(the Examples) or sodium isopropoxide (the Comparative Examples) as
the base.
[0112] 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 8 with the
exceptions that an equal molar amount the
[RuCl.sub.2(diphosphine)(DMF)n] having the diphosphine shown in
Table 10 (abbreviations are given in the Detailed Description of
the Invention) was substituted for
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n], for the Comparative Examples an
equimolar amount of sodium isopropoxide was substituted for the
tetramethyl-2-t-butylguanidine and the reaction mixtures were
stirred for the time shown in Table 10. Table 10 gives the
diphosphine, the base, the reaction time, the conversion of the
2-acetylthiophene, the absolute configuration of the
1-(2-thienyl)ethanol, and its e.e.
10TABLE 10 Time Conv. e.e. (%) Example diphosphine base (hrs) (%)
(R/S) 8 R,R,R,R-BICP tetramethyl-2-t-butylguanidine 4 100 86 (S)
Comp. 8 R,R,R,R-BICP sodium isopropoxide 4 100 56 (S) 68
S,S-CHIRAPHOS tetramethyl-2-t-butylguanidine 8 17 64 (S) Comp. 34
S,S-CHIRAPHOS sodium isopropoxide 12 100 43 (R) 69 R,R-SKEWPHOS
tetramethyl-2-t-butylguanidine 8 29 55 (S) Comp. 35 R,R-SKEWPHOS
sodium isopropoxide 6 100 53 (S) 70 R,R-Me-PennPhos
tetramethyl-2-t-butylguanidine 8 49 61 (S) Comp. 36 R,R-Me-PennPhos
sodium isopropoxide 12 100 36 (S) 71 R-BINAP
tetramethyl-2-t-butylguanidine 6 21 23 (S) Comp. 37 R-BINAP sodium
isopropoxide 4 100 23 (S) 72 R-C4-TunaPhos tetramethyl-2-t-butylgu-
anidine 12 69 12 (R) Comp. 38 R-C4-TunaPhos sodium isopropoxide 6
100 3 (R) 73 S-MeOBIPHEP tetramethyl-2-t-butylguanidine 12 54 <1
(R) Comp. 39 S-MeOBIPHEP sodium isopropoxide 6 100 <1 (R)
[0113] These Examples show that for many chiral diphosphines, when
using ethylenediamine as the bidentate amine ligand, an
alkylguanidine base can provide greater enantioselectivity than a
basic salt like sodium isopropoxide. They also show that the
improvement can also depend on the identity of the chiral
diphosphine. Among these chiral diphosphines, the greater such
improvements as well as the greater absolute enantioselectivities
are obtained among the nonatropisomeric chiral diphosphines
(Examples 8, 69, and 70), while the lesser such improvements and
lesser absolute enantioselectivities are obtained among the
atropisomeric chiral diphosphines (Examples 71, 72, and 73).
[0114] Examples 68 and Comparative Example 34, using CHIRAPHOS show
the surprising result of the chirality of the dominant enantiomer
of the nonracemic alcohol being switched upon using the
tetramethyl-2-t-butylgua- nidine instead of sodium
isopropoxide.
Examples 74-80 and Comparative Examples 40-46
[0115] These Examples illustrate the hydrogenation of
2-acetylthiophene to 1-(2-thienyl)ethanol using various chiral
diphosphine ligands in combinations with meso-cyclohexanediamine as
the bidentate amine ligand and either
tetramethyl-2-t-butyl-guanidine (the Examples) or sodium
isopropoxide (the Comparative Examples) as the base.
[0116] The procedure was identical to Example 14 with the
exceptions that an equal molar amount the
[RuCl.sub.2(diphosphine)(DMF)n] having the diphosphine shown in
Table 10 (abbreviations are given in the Detailed Description of
the Invention) was substituted for [RuCl.sub.2(R,R,R,R-BIC-
P)(DMF)n], for the Comparative Examples an equimolar amount of
sodium isopropoxide was substituted for the
tetramethyl-2-t-butylguanidine and the reaction mixtures were
stirred for the time shown in Table 11. Table 11 gives the
diphosphine, the base, the reaction time, the conversion of the
2-acetylthiophene, the absolute configuration of the
1-(2-thienyl)ethanol, and its e.e.
[0117] These Examples show that, when using meso-cyclohexanediamine
as the bidentate amine ligand, the greater enantioselectivities are
obtained when using the preferred nonatropisomeric chiral
diphosphine ligands (Examples 14, 74-77) as compared to the
atropisomeric chiral diphosphine ligands (Examples 78-80). The
Examples using the most preferred chiral diphosphine ligands,
comprising four stereogenic carbon atoms in the hydrocarbyl
diradical that connects the two phosphorus atoms (Examples 14 and
74) show substantial improvements in enantioselectivity using
tetramethyl-2-t-butylguanidine as compared to using sodium
isopropoxide. Examples 74 and Comparative Example 40, using
CHIRAPHOS show the surprising result of the chirality of the
dominant enantiomer of the nonracemic alcohol being switched upon
using the tetramethyl-2-t-butylgua- nidine instead of sodium
isopropoxide. A similar switch in chirality, though lesser in e.e.
points, is shown by Examples 79 and Comparative Example 45, using
R-C4-TunaPhos. For a number of the other chiral diphosphines, the
enantioselectivity with tetramethyl-2-t-butylguanidine was no
better than that with sodium isopropoxide. The data in Tables 10
and 11, collectively, show that the enantioselectivity advantages
which may be provided by the alkylguanidine bases in the present
invention is dependent on both the diphosphine ligand and the
bidentate amine ligand, and can be determined by routing
experimentation.
11TABLE 11 Time Conv. e.e. (%) Example diphosphine base (hrs) (%)
(R/S) 14 R,R,R,R-BICP tetramethyl-2-t-butylguanidine 4 84 90 (S)
Comp. 14 R,R,R,R-BICP sodium isopropoxide 4 100 81 (S) 74
S,S-CHIRAPHOS tetramethyl-2-t-butylguanidine 8 18 64 (S) Comp. 40
S,S-CHIRAPHOS sodium isopropoxide 10 100 58 (R) 75 R,R-SKEWPHOS
tetramethyl-2-t-butylguanidine 8 10 52 (S) Comp. 41 R,R-SKEWPHOS
sodium isopropoxide 12 90 56 (S) 76 R,R-Me-PennPhos
tetramethyl-2-t-butylguanidine 8 63 77 (S) Comp. 42 R,R-Me-PennPhos
sodium isopropoxide 12 100 76 (S) 77 R,R-DIOP
tetramethyl-2-t-butylguanidine 8 5 52 (R) Comp. 43 R,R-DIOP sodium
isopropoxide 12 94 57 (R) 78 R-BINAP tetramethyl-2-t-butylguanidin-
e 6 12 34 (S) Comp. 44 R-BINAP sodium isopropoxide 4 100 45 (S) 79
R-C4-TunaPhos tetramethyl-2-t-butylguanidine 12 25 24 (R) Comp. 45
R-C4-TunaPhos sodium isopropoxide 6 100 33 (S) 80 S-MeOBIPHEP
tetramethyl-2-t-butylguanidine 12 20 34 (R) Comp. 46 S-MeOBIPHEP
sodium isopropoxide 10 100 41 (R)
Examples 81-83 and Comparative Examples 47-49
[0118] These Examples show the hydrogenation of
3-(dimethylamino)-1-(2-thi- enyl)-1-propanone to nonracemic
3-(dimethylamino)-1-(2-thienyl)-1-propanol using various diamine
ligands and either tetramethyl-2-t-butylguanidine (the Examples) or
sodium isopropoxide (the Comparative Examples) as the base.
[0119] 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) 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 12 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) 1-propanol product.
12 Conv. e.e. Example diamine ligand base (%) (%) 81 ethylene
diamine tetramethyl-2-t- 89 79 butylguanidine Comp. 47 ethylene
diamine sodium isopropoxide 96 24 82 2-methyl-1,2- tetramethyl-2-t-
85 85 propylenediamine butylguanidine Comp. 48 2-methyl-1,2- sodium
isopropoxide 97 68 propylenediamine 83 meso-1,2- tetramethyl-2-t-
77 88 cyclohexanediamine butylguanidine Comp. 49 meso-1,2- sodium
isopropoxide 96 83 cyclohexanediamine
[0120] These Examples further show that an alkylguanidine base can
provide significantly greater enantioselectivity than a basic salt
like sodium isopropoxide in the process of the invention. They also
show that the degree of the relative improvement can also depend on
the identity of the diamine ligand, and appears greatest with a
simpler and smaller achiral diamine, especially with ethylene
diamine.
Examples 83-90
[0121] These Examples illustrate the inventive process for
hydrogenation of 3',5'-bis-(trifluoromethyl)acetophenone to
nonracemic 3',5'-bis(trifluoromethyl)-1-phenethanol in various
solvents using tetramethyl-2-t-butylguanidine as the base. They
also illustrate the use of an amino-thioether as the bidentate
amine ligand in the present invention.
[0122] Stock solutions of 556 micromolar
[RuCl.sub.2((R,R,R,R-BICP)(DMF)n] in various anhydrous, deaerated
solvents were prepared analogous to the procedure in Preparation 1
by dissolving the solid residue comprising
[RuCl.sub.2(R,R,R,R-BICP)(DMF)n] in the desired solvent instead of
isopropanol. In the same manner as described in Example 1,
solutions prepared from 0.2843 g (1.11 mmol)
3',5'-bis(trifluoromethyl)acetophenone- , 10 mL 556 micromolar
(5.56 micromoles) [RuCl.sub.2(R,R,R,R-BICP)(DMF)n] in the solvent,
0.22 mL 0.1 M (22 micromole) 2-(ethylthio)aniline in the solvent,
and 0.20 mL 0.1 M (20 micromoles) tetramethyl-2-t-butylguanidine in
the solvent were stirred under 100 psi hydrogen for 19 hours at
room temperature. Table 13 gives the solvent, the conversion of the
3',5'-bis-(trifluoromethyl)acetophenone, and the e.e of the
(S)-3',5'-bis(trifluoromethyl)-1-phenethanol product.
13TABLE 13 Conv. Example solvent (%) % e.e. 83 isopropanol 100 72
84 toluene 100 77 85 dibutyl ether 100 75 86 dichloromethane 100 75
87 chlorobenzene 100 78 88 ethylacetate 37 74 89 1,2-dimethoxy
ethane 58 78 90 methyl t-butyl ether 24 70
[0123] These results show that that an organic base selected from
alkylamidines, alkylguanidines, aminophosphazenes, and
proazaphosphatranes allows the inventive process to be conducted
using solvents other than alcohol solvents and in which basic salts
such as sodium isopropoxide are not soluble, and that many solvents
provide for higher enantioselectivities than the alcohol
solvent.
[0124] Examples 84 and 86 may be compared to the report in J. Am.
Chem. Soc., vol. 117 (1995), 2675-2676 that toluene and
dichloromethane are not useable in the disclosed process using KOH
or (CH.sub.3).sub.2CHOK as the base.
Examples 91-99 and Comparative Examples 50-52
[0125] These Examples illustrate the process of the invention for
the hydrogenation of a enantiomeric chiral ketone to a
diastereomeric chiral alcohol. The Comparative Examples show
results obtained using certain organic bases that are not selected
from alkylamidines, alkylguanidines, aminophosphazenes, and
proazaphosphatranes.
[0126] For each example,
(2S)-1-(4-benzyl-oxy-phenyl)-2-(4-hydroxy-4-pheny-
l-piperidin-1-yl)-1-propanone was hydrogenated in isopropanol
solution at room temperature under 18 bar hydrogen for four hours
using [RuCl.sub.2((S,S,S,S-BICP)(DMF)n],
4,5-dimethyl-1,2-diamino-benzene and a base in the mole ratios
ketone:RuBICP:diamine:base=500:1:5:20. The reaction mixture was
analyzed by chiral HPLC. Table 14 gives the base, the conversion of
the ketone and the chemical yield of the (1S,2S)-diastereomer of
1-(4-benzoxy-phenyl)2-(4-hydroxy-4-phenyl-piperid-
in-1-yl)-1-propanol.
14 Conv. yield Example base (%) (%) Comp. 50 guanidine 1.4 1.4
Comp. 51 4,7,13,16,21-pentaoxa-1,10-diazabicyclo 0.1 0.1
[8.8.5]tricosane Comp. 52 sodium isopropoxide 98.6 93.2 91
N'''-[N-ethyl-P,P-bis(dimethylamino) 99.5 95.1
phosphinimyl]-N,N,N',N',N",N"- hexamethyl-phosphorimidic triamide
92 N'''-t-butyl-N,N,N',N',N",N"- 99.5 96.5
hexamethyl-phosphorimidic triamide 93 N,N,N',N',N",N"-hexamethyl-
99.6 95.2 phosphorimidic triamide 94
t-butyl-tris[tris(dimethylamino) 99.6 96.4
phosphoranylidene]-phosphorimidic triamide 95
2,8,9-trimethyl-2,5,8,9-tetraaza-1- 98.6 93.2 phosphabicyclo[3.3
.3]undecane 96 1,5,7-triazabicyclo[4.4.0]dec-5-ene 99.6 96.2 97
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene 99.5 96.7 98
tetramethyl-2-t-butylguanidine 99.5 97.1 99 tetramethylguanidine
60.7 58.8
[0127] Examples 91-99 show that organic bases selected from
alkylamidines, alkylguanidines, aminophosphazenes, and
proazaphosphatranes provide high activity and diastereoselectivity
in the process of the invention. Comparative Examples 50 and 51
show that certain other organic bases provide insignificant
catalytic activity. By comparison to Comparative Example 50 using
guanidine, Examples 98 and 99 show that the N-alkyl substitution in
the alkylguanidine bases is required for catalyst system activity.
Comparative Example 50 shows that a trialkylamine base does not
provide any significant catalyst activity.
[0128] 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.
* * * * *