U.S. patent application number 15/167177 was filed with the patent office on 2016-09-22 for process for hydrogenating ketones in the presence of ru(ii) catalysts.
The applicant listed for this patent is JOHNSON MATTHEY PUBLIC LIMITED COMPANY. Invention is credited to Alan Dyke, Damian Mark Grainger, Jacques Jean Marie Le Paih, Jonathan Alan Medlock, Hans Guenter Nedden, Stephen James Roseblade, Andreas Seger, Vilvanathan Sivakumar, Antonio Zanotti-Gerosa.
Application Number | 20160271599 15/167177 |
Document ID | / |
Family ID | 42629538 |
Filed Date | 2016-09-22 |
United States Patent
Application |
20160271599 |
Kind Code |
A1 |
Dyke; Alan ; et al. |
September 22, 2016 |
PROCESS FOR HYDROGENATING KETONES IN THE PRESENCE OF RU(II)
CATALYSTS
Abstract
The present invention relates to a process for hydrogenating a
substrate including a carbon-heteroatom double bond, the process
including the step of reacting the substrate with hydrogen gas in
the presence of a hydrogenation catalyst, wherein the hydrogenation
catalyst is a complex of formula (I): ##STR00001## R.sub.1-10, A
and Hal are as defined in the specification. The present invention
also provides processes for the preparation of the complex of
formula (I) and intermediates thereof.
Inventors: |
Dyke; Alan; (Cambridgeshire,
GB) ; Grainger; Damian Mark; (Cambridgeshire, GB)
; Medlock; Jonathan Alan; (Basel, CH) ; Nedden;
Hans Guenter; (Cambridgeshire, GB) ; Le Paih; Jacques
Jean Marie; (Cambridgeshire, GB) ; Roseblade; Stephen
James; (Cambridgeshire, GB) ; Seger; Andreas;
(Cambridgeshire, GB) ; Sivakumar; Vilvanathan;
(New Panvel, IN) ; Zanotti-Gerosa; Antonio;
(Cambridgeshire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JOHNSON MATTHEY PUBLIC LIMITED COMPANY |
London |
|
GB |
|
|
Family ID: |
42629538 |
Appl. No.: |
15/167177 |
Filed: |
May 27, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14458320 |
Aug 13, 2014 |
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15167177 |
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13257166 |
Jan 27, 2012 |
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PCT/GB2010/050456 |
Mar 17, 2010 |
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14458320 |
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61221690 |
Jun 30, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
B01J 2231/643 20130101;
C07C 311/07 20130101; C07C 311/18 20130101; C07C 2601/14 20170501;
C07C 2523/70 20130101; C07C 311/05 20130101; C07C 2531/18 20130101;
C07F 15/0046 20130101; C07C 311/20 20130101; B01J 2531/0238
20130101; C07C 29/145 20130101; C07F 15/0053 20130101; B01J 31/2295
20130101; C07C 2601/16 20170501; B01J 2531/821 20130101; B01J
31/1805 20130101; C07C 29/145 20130101; C07C 33/22 20130101 |
International
Class: |
B01J 31/18 20060101
B01J031/18; C07C 311/05 20060101 C07C311/05; C07F 15/00 20060101
C07F015/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 17, 2009 |
GB |
0904553.5 |
Jul 29, 2009 |
GB |
0913166.5 |
Claims
1-17. (canceled)
18. A complex selected from the group consisting of:
##STR00054##
19. A compound, or an acid addition salt thereof, selected from the
group consisting of: ##STR00055##
20. A complex of formula (I): ##STR00056## wherein, R.sub.1,
R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each independently
selected from the group consisting of hydrogen, optionally
substituted straight, branched or cyclic C.sub.1-20 alkyl,
optionally substituted straight, branched or cyclic C.sub.1-20
alkoxy, optionally substituted C.sub.6-20 aryl, optionally
substituted C.sub.6-20 aryloxy, --OH, --CN,
--NR.sub.20R.sub.21--COOH, COOR.sub.20,
--CONH.sub.2--CONR.sub.20R.sub.21 and --CF.sub.3, wherein the
substituents are selected from the group consisting of one or more
straight, branched or cyclic C.sub.1-20 alkyl, straight, branched
or cyclic C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy,
--OH, --CN, --NR.sub.30R.sub.31, --COOR.sub.30,
--CONR.sub.30R.sub.31 and --CF.sub.3; or R.sub.1 and R.sub.2,
R.sub.2 and R.sub.3, and R.sub.4 or R.sub.4 and R.sub.5 together
form an aromatic ring composed of 6 to 10 carbon atoms which is
optionally substituted with one or more straight, branched or
cyclic C.sub.1-20 alkyl, straight, branched or cyclic C.sub.1-20
alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN,
--NR.sub.20R.sub.21, --COOR.sub.20, --CONR.sub.20R.sub.21 and
--CF.sub.3, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are each
independently selected from the group consisting of hydrogen,
optionally substituted straight, branched or cyclic C.sub.1-20
alkyl, optionally substituted straight, branched or cyclic
C.sub.1-20 alkoxy, optionally substituted C.sub.6-20 aryl and
optionally substituted C.sub.6-20 aryloxy wherein the substituents
are selected from the group consisting of one or more straight,
branched or cyclic C.sub.1-20 alkyl, straight, branched or cyclic
C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN,
--NR.sub.20R.sub.21, --COOR.sub.20, --CONR.sub.20R.sub.21 and
--CF.sub.3, or R.sub.6 and R.sub.7 together with the carbon atom to
which they are bound and/or R.sub.8 and R.sub.9 together with the
carbon atom to which they are bound form an optionally substituted
C.sub.3-20 cycloalkyl or an optionally substituted C.sub.2-20
cycloalkoxy, wherein the substituents are selected from the group
consisting of one or more straight, branched or cyclic C.sub.1-20
alkyl, straight, branched or cyclic C.sub.1-20 alkoxy, C.sub.6-20
aryl, C.sub.6-20 aryloxy, --OH, --CN, --NR.sub.20R.sub.21,
--COOR.sub.20, --CONR.sub.20R.sub.21 and --CF.sub.3, or one of
R.sub.6 and R.sub.7 and one of R.sub.8 and R.sub.9 together form an
optionally substituted C.sub.5-10 cycloalkyl or an optionally
substituted C.sub.5-10 cycloalkoxy, wherein the substituents are
independently selected from the group consisting of one or more
straight, branched or cyclic C.sub.1-20 alkyl, straight, branched
or cyclic C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy,
--OH, --CN, --NR.sub.20R.sub.21, --COOR.sub.20,
--CONR.sub.20R.sub.21 and --CF.sub.3; R.sub.10 is an optionally
substituted straight, branched or cyclic C.sub.1-10 alkyl, an
optionally substituted C.sub.6-10 aryl or --NR.sub.11R.sub.12
wherein the substituents are selected from the group consisting of
one or more straight, branched or cyclic C.sub.1-10 alkyl,
straight, branched or cyclic C.sub.1-10 alkoxy, C.sub.6-10 aryl,
C.sub.6-10 aryloxy, -Hal, --OH, --ON, --NR.sub.20R.sub.21,
--COOR.sub.20, --CONR.sub.20R.sub.21 and --CF.sub.3; provided that
R.sub.10 is not a tolyl group; R.sub.11 and R.sub.12 are
independently selected from the group consisting of hydrogen,
optionally substituted straight, branched or cyclic C.sub.1-10
alkyl and optionally substituted C.sub.6-10 aryl, wherein the
substituents are selected from the group consisting of one or more
straight, branched or cyclic C.sub.1-10 alkyl groups, straight,
branched or cyclic C.sub.1-10 alkoxy, C.sub.6-10 aryl, C.sub.6-10
aryloxy, --OH, --ON, --NR.sub.20R.sub.21, --COOR.sub.20,
--CONR.sub.20R.sub.21 and --CF.sub.3, or R.sub.11 and R.sub.12
together with the nitrogen atom to which they are bound form an
optionally substituted C.sub.2-10 cycloalkylamino group wherein the
substituents are selected from the group consisting of one or more
straight, branched or cyclic C.sub.1-10 alkyl, straight, branched
or cyclic C.sub.1-10 alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy,
--OH, --CN, --NR.sub.20R.sub.21, --COOR.sub.23,
--CONR.sub.20R.sub.21 and --CF.sub.3; R.sub.20 and R.sub.21 are
independently selected from the group consisting of hydrogen,
optionally substituted straight, branched or cyclic C.sub.1-20
alkyl, optionally substituted straight, branched or cyclic
C.sub.1-20 alkoxy, optionally substituted C.sub.6-20 aryl,
optionally substituted C.sub.6-20 aryloxy, --OH, --CN,
--NR.sub.30R.sub.31, --COOR30, --CONR.sub.30R.sub.31 and
--CF.sub.3, wherein the substituents are selected from the group
consisting of one or more straight, branched or cyclic C.sub.1-20
alkyl, straight, branched or cyclic C.sub.1-20 alkoxy, C.sub.6-20
aryl, C.sub.6-20 aryloxy, --OH, --CN and --CF.sub.3; R.sub.30 and
R.sub.31 are independently selected from the group consisting of
hydrogen, optionally substituted straight, branched or cyclic
C.sub.1-20 alkyl, optionally substituted straight, branched or
cyclic C.sub.1-20 alkoxy, optionally substituted C.sub.6-20 aryl,
optionally substituted C.sub.6-20 aryloxy, --OH, --CN and
--CF.sub.3, wherein the substituents are selected from the group
consisting of one or more straight, branched or cyclic C.sub.1-20
alkyl, straight, branched or cyclic C.sub.1-20 alkoxy, C.sub.6-20
aryl, C.sub.6-20 aryloxy, --OH, --CN and --CF.sub.3; A is an
optionally substituted straight- or branched-chain C.sub.2-5 alkyl
wherein the substituents are selected from the group consisting of
one or more straight, branched or cyclic C.sub.1-10 alkyl,
straight, branched or cyclic C.sub.1-10 alkoxy, C.sub.6-10 aryl and
C.sub.6-10 aryloxy, or A is a group of formula (II): ##STR00057##
wherein p is an integer selected from 1, 2, 3 or 4; each R.sub.40
is independently selected from the group consisting of straight,
branched or cyclic C.sub.1-20 alkyl, straight, branched or cyclic
C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN
and --CF.sub.3; q and r are independently integers selected from 0,
1, 2 or 3 wherein q+r=1, 2 or 3; each R.sub.41 is independently
selected from the group consisting of hydrogen, straight, branched
or cyclic C.sub.1-20 alkyl, straight, branched or cyclic C.sub.1-20
alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN and
--CF.sub.3; and Hal is a chlorine, bromine or iodine.
21. The complex according to claim 20, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 are each independently selected from
the group consisting of hydrogen, straight-chain C.sub.1-10 alkyl
and branched-chain C.sub.1-10 alkyl.
22. The complex according to claim 21, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 are each independently selected from
the group consisting of hydrogen, methyl, ethyl, n-propyl, propyl,
n-butyl, i-butyl, s-butyl and t-butyl.
23. The complex according to claim 22, wherein R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5, are each hydrogen.
24. The complex according to claim 20, wherein R.sub.6, R.sub.7,
R.sub.8 and R.sub.9 are each independently selected from the group
consisting of hydrogen and optionally substituted C.sub.6-10,
aryl.
25. The complex according to claim 39, wherein R.sub.6, R.sub.7,
R.sub.8 and R.sub.9 are each independently selected from the group
consisting of hydrogen and phenyl.
26. The complex according to claim 40, wherein one of R.sub.6 and
R.sub.7 is phenyl and the other of R.sub.6 and R.sub.7 is
hydrogen.
27. The complex according to claim 40, wherein one of R.sub.8 and
R.sub.9 is phenyl and the other of R.sub.8 and R.sub.9 is
hydrogen.
28. The complex according to claim 40, wherein R.sub.6, R.sub.7,
R.sub.8 and R.sub.9 are hydrogen.
29. The complex according to claim 35, wherein R is an optionally
substituted straight, branched or cyclic C.sub.1-10 alkyl, an
optionally substituted C.sub.6-10 aryl wherein the substituents are
selected from the group consisting of one or more straight,
branched or cyclic C.sub.1-10 alkyl, straight, branched or cyclic
C.sub.1-10 alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy, -Hal, or
--CF.sub.3.
30. The complex according to claim 35, wherein is a straight- or
branched-chain C.sub.1-10 alkyl or a C.sub.6-10 aryl optionally
substituted with one or more straight- or branched-chain C.sub.1-10
alkyl groups.
31. The complex according to claim 45, wherein is a methyl,
p-methoxyphenyl, p-chlorophenyl, trifluoromethyl,
3,5-dimethylphenyl, 2,4,6-trimethylphenyl,
2,4,6-triisopropylphenyl, 4-tert-butylphenyl, pentamethylphenyl or
2-naphthyl group.
32. The complex according to claim 35, wherein A is
--(CH.sub.2).sub.2--, --(CH.sub.2).sub.3--, --(CH.sub.2).sub.4-- or
--(CH.sub.2).sub.5--.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a division of U.S. application Ser. No.
13/257,166, filed Jan. 27, 2012, which is the 35 U.S.C. 371
National Phase of PCT International Application No.
PCT/GB2010/1050456, filed Mar. 17, 2010, which claims priority to
British Patent Application No. 0904553.5, filed Mar. 17, 2009; U.S.
Provisional Patent Application No. 61/221,690, filed Jun. 30, 2009;
and British Patent Application No. 0913166.5, filed Jul. 29, 2009,
the disclosures of all of which are incorporated herein by
reference in their entireties for all purposes.
FIELD OF THE INVENTION
[0002] The present invention relates to a process for catalytically
hydrogenating a substrate comprising a carbon-heteroatom double
bond. In particular, the present invention relates to catalytically
hydrogenating a carbonyl or iminyl compound using a .eta..sup.6
arene ruthenium monosulfonated diamine complex.
BACKGROUND OF THE INVENTION
[0003] Tethered catalysts have been used in asymmetric transfer
hydrogenation reactions (see, for example. Hayes et al, J. Am.
Chem. Soc., 2005, 127, 7318. Cheung et al, Organic Letters, 2007,
9(22), 4659, Morris et al, J. Org. Chem., 2006, 71, 7035 and
Martins et al, J. Organomet. Chem., 2008, 693, 3527). The transfer
hydrogenation conditions utilise formic acid and triethylamine. A
hydrogenation reaction differs from a transfer hydrogenation
reaction in that hydrogen gas is used and not reagents such as
formic acid and triethylamine.
SUMMARY OF THE INVENTION
[0004] In one aspect, the invention provides a process for
hydrogenating a substrate that includes a carbon-heteroatom double
bond. The process includes the step of reacting the substrate with
hydrogen gas in the presence of a hydrogenation catalyst, wherein
the hydrogenation catalyst is a complex of formula (I):
##STR00002##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, R.sub.10, A and Hal are as defined
herein.
[0005] In another aspect, the invention provides a process for the
preparation of a compound of formula (VIII):
##STR00003##
[0006] Including the steps of:
a) converting a compound of formula (IX) into a compound of formula
(X):
##STR00004##
b) reacting the compound of formula (X) with a compound of formula
(XI) in a solvent to form the compound of formula (VIII):
##STR00005##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, R.sub.10 and A are as defined
herein.
[0007] In a further aspect, the invention provides a one-pot
process for the preparation of a complex of formula (I):
##STR00006##
including the steps of: i) treating a compound of formula (VIII)
with an acid HZ, where Z is an anion
##STR00007##
ii) reacting the acid addition salt of the compound of formula
(VIII) with a Ru(Hal).sub.n complex, where Hal is a halogen and n
is a number equal to or less than the coordination number of Ru, to
form a complex of formula (XIII):
##STR00008##
iii) treating the complex of formula (XIII) with a base to form the
complex of formula (I):
##STR00009##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6,
R.sub.7, R.sub.8, R.sub.9, R.sub.10 and A are as defined
herein.
[0008] In yet another aspect, the invention provides a complex
selected from the group consisting of:
##STR00010##
[0009] In a still further aspect, the invention provides a
compound, or an acid addition salt thereof, selected from the group
consisting of:
##STR00011##
DETAILED DESCRIPTION OF THE INVENTION
Definitions of Terms and Conventions Used
[0010] The point of attachment of a moiety or substituent is
represented by "-". For example, --OH is attached through the
oxygen atom.
[0011] "Alkyl" refers to a straight-chain, branched or cyclic
saturated hydrocarbon group. In certain embodiments, the alkyl
group may have from 1-20 carbon atoms, in certain embodiments from
1-15 carbon atoms, in certain embodiments, 1-10 carbon atoms. The
number of carbon atoms is appropriate to the group e.g. a
cycloalkyl group must have at least 3 carbon atoms to form a ring.
The alkyl group may be unsubstituted or substituted. Unless
otherwise specified, the alkyl group may be attached at any
suitable carbon atom and, if substituted, may be substituted at any
suitable atom. Typical alkyl groups include but are not limited to
methyl, ethyl, n-propyl, iso-propyl, cyclopropyl, n-butyl,
iso-butyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl,
cyclopentyl, n-hexyl, cyclohexyl and the like.
[0012] "Alkoxy" refers to a --O-alkyl group wherein the alkyl group
is as described above.
[0013] "Alkenyl" refers to a straight-chain, branched or cyclic
unsaturated hydrocarbon group having at least one carbon-carbon
double bond. The group may be in either the cis- or
trans-configuration around each double bond. In certain
embodiments, the alkenyl group can have from 2-20 carbon atoms, in
certain embodiments from 2-15 carbon atoms, in certain embodiments,
2-10 carbon atoms. The alkenyl group may be unsubstituted or
substituted. Unless otherwise specified, the alkenyl group may be
attached at any suitable carbon atom and, if substituted, may be
substituted at any suitable atom. Examples of alkenyl groups
include but are not limited to ethenyl (vinyl), 2-propenyl (allyl),
1-methylethenyl, 2-butenyl, 3-butenyl, cyclobut-1,3-dienyl and the
like.
[0014] "Alkynyl" refers to a straight-chain, branched or cyclic
unsaturated hydrocarbon group having at least one carbon-carbon
triple bond. In certain embodiments, the alkynyl group can have
from 2-20 carbon atoms, in certain embodiments from 2-15 carbon
atoms, in certain embodiments, 2-8 carbon atoms. The number of
carbon atoms is appropriate to the group e.g. a cyclic group having
at least one carbon-carbon triple bond must have a sufficient
number of carbon atoms in order for the cyclic group to be formed.
The alkynyl group may be unsubstituted or substituted. Unless
otherwise specified, the alkynyl group may be attached at any
suitable carbon atom and, if substituted, may be substituted at any
suitable atom. Examples of alkynyl groups include, but are not
limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, 1-methylprop-2-ynyl,
but-1-ynyl, but-2-ynyl, but-3-ynyl and the like.
[0015] "Aryl" refers to an aromatic carbocyclic group. The aryl
group may have a single ring or multiple condensed rings. In
certain embodiments, the aryl group can have from 6-20 carbon
atoms, in certain embodiments from 6-15 carbon atoms, in certain
embodiments, 6-10 carbon atoms. The aryl group may be unsubstituted
or substituted. Unless otherwise specified, the aryl group may be
attached at any suitable carbon atom and, if substituted, may be
substituted at any suitable atom. Examples of aryl groups include,
but are not limited to, phenyl, naphthyl, anthracenyl and the
like.
[0016] "Aryloxy" refers to an --O-aryl group wherein the aryl group
is as described above.
[0017] "Hal" refers to a halogen and may be selected from the group
consisting of fluorine, chlorine, bromine and iodine.
[0018] "Heteroalkyl" refers to a straight-chain, branched or cyclic
saturated hydrocarbon group wherein one or more carbon atoms are
independently replaced with one or more heteroatoms (e.g. nitrogen,
oxygen, phosphorus and/or sulfur atoms). In certain embodiments,
the heteroalkyl group may have from 1-20 carbon atoms, in certain
embodiments from 1-15 carbon atoms, in certain embodiments, 1-10
carbon atoms. The number of carbon atoms is appropriate to the
group e.g. a heterocycloalkyl group must have a sufficient number
of carbon atoms together with the heteroatom to form a ring. The
heteroalkyl group may be unsubstituted or substituted. Unless
otherwise specified, the alkyl group may be attached at any
suitable atom and, if substituted, may be substituted at any
suitable atom. Examples of heteroalkyl groups include, but are not
limited to, ethers, amines, thioethers, epoxide, morpholinyl,
piperadinyl, piperazinyl, thirranyl and the like.
[0019] "Heteroaryl" refers to an aromatic carbocyclic group wherein
one or more carbon atoms are independently replaced with one or
more heteroatoms (e.g. nitrogen, oxygen, phosphorus and/or sulfur
atoms). In certain embodiments, the heteroaryl group may have from
3-20 carbon atoms, in certain embodiments from 3-15 carbon atoms,
in certain embodiments, 3-10 carbon atoms. The heteroaryl group may
be unsubstituted or substituted. Unless otherwise specified, the
heteroaryl group may be attached at any suitable atom and, if
substituted, may be substituted at any suitable atom. Examples of
heteroaryl groups include, but are not limited to, furanyl,
indolyl, oxazolyl, pyrrolyl, N-methyl-pyrrolyl, pyridinyl,
pyrimidinyl, pyridazinyl, thiazolyl, thiophenyl and the like.
[0020] It has been found that a substrate comprising a
carbon-heteroatom double bond may be reduced in the presence of
hydrogen gas and a tethered .eta..sup.6 arene ruthenium
monosulfonated diamine complex. In some embodiments, the
hydrogenation is asymmetric and the reduced substrate may be
obtained in high enantiomeric excess. In some embodiments, when the
substrate to be hydrogenated is polyfunctionalised, it has been
found that the tethered catalyst is resilient to the presence of
the polyfunctional groups and does not become deactivated.
[0021] In one aspect, therefore, the present invention provides a
process for hydrogenating a substrate comprising a
carbon-heteroatom double bond, the process comprising the step of
reacting the substrate with hydrogen gas in the presence of a
hydrogenation catalyst, wherein the hydrogenation catalyst is a
complex of formula (I):
##STR00012##
wherein, R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
optionally substituted straight, branched or cyclic C.sub.1-20
alkyl, optionally substituted straight, branched or cyclic
C.sub.1-20 alkoxy, optionally substituted C.sub.6-20 aryl,
optionally substituted C.sub.6-20 aryloxy, --OH, CN,
--NR.sub.20R.sub.21, --COOH, COOR.sub.20, --CONH.sub.2,
--CONR.sub.20R.sub.21 and --CF.sub.3 wherein the substituents are
selected from the group consisting of one or more straight,
branched or cyclic C.sub.1-20 alkyl, straight, branched or cyclic
C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN,
--NR.sub.30R.sub.31, --COOR.sub.30, --CONR.sub.30R.sub.31 and
--CF.sub.3: R.sub.1 and R.sub.2, R.sub.2 and R.sub.3, R.sub.3 and
R.sub.4 or R.sub.4 and R.sub.5 together form an aromatic ring
composed of 6 to 10 carbon atoms which is optionally substituted
with one or more straight, branched or cyclic C.sub.1-20 alkyl,
straight, branched or cyclic C.sub.1-20 alkoxy, C.sub.6-20 aryl,
C.sub.6-20 aryloxy, --OH, --CN, --NR.sub.20R.sub.21, --COOR.sub.20,
--CONR.sub.20R.sub.21 and --CF.sub.3; R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are each independently selected from the group consisting
of hydrogen, optionally substituted straight, branched or cyclic
C.sub.1-20 alkyl, optionally substituted straight, branched or
cyclic C.sub.1-20 alkoxy, optionally substituted C.sub.6-20 aryl
and optionally substituted C.sub.6-20 aryloxy wherein the
substituents are selected from the group consisting of one or more
straight, branched or cyclic C.sub.1-20 alkyl, straight, branched
or cyclic C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy,
--OH, --CN, --NR.sub.20R.sub.21, --COOR.sub.20,
--CONR.sub.20R.sub.21 and --CF.sub.3, or R.sub.6 and R.sub.7
together with the carbon atom to which they are bound and/or
R.sub.8 and R.sub.9 together with the carbon atom to which they are
bound form an optionally substituted C.sub.3-20 cycloalkyl or an
optionally substituted C.sub.2-20 cycloalkoxy, wherein the
substituents are selected from the group consisting of one or more
straight, branched or cyclic C.sub.1-20 alkyl, straight branched or
cyclic C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy,
--OH, --CN, --NR.sub.21R.sub.21, --COOR.sub.20,
--CONR.sub.20R.sub.21 and --CF.sub.3, or one of R.sub.6 and R.sub.7
and one of R.sub.8 and R.sub.9 together form an optionally
substituted C.sub.5-10 cycloalkyl or an optionally substituted
C.sub.5-10 cycloalkoxy, wherein the substituents are independently
selected from the group consisting of one or more straight,
branched or cyclic C.sub.1-20 alkyl, straight, branched or cyclic
C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN,
--NR.sub.20R.sub.21, --COOR.sub.20, --CONR.sub.20R.sub.21 and
--CF.sub.3, or R.sub.10 is an optionally substituted straight,
branched or cyclic C.sub.1-10 alkyl, an optionally substituted
C.sub.6-10 aryl or --NR.sub.11R.sub.12 wherein the substituents are
selected from the group consisting of one or more straight branched
or cyclic C.sub.1-10 alkyl, straight, branched or cyclic C.sub.1-10
alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy, -Hal, --OH, --CN,
--NR.sub.20R.sub.21, --COOR.sub.20, --CONR.sub.20R.sub.21 and
--CF.sub.3; R.sub.11 and R.sub.12 are independently selected from
the group consisting of hydrogen, optionally substituted straight,
branched or cyclic C.sub.1-10 alkyl and optionally substituted
C.sub.6-10 aryl, wherein the substituents are selected from the
group consisting of one or more straight, branched or cyclic
C.sub.1-10 alkyl groups, straight, branched or cyclic C.sub.1-10
alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy, --OH, --CN,
--NR.sub.20R.sub.21, --COOR.sub.20, --CONR.sub.20R.sub.21 and
--CF.sub.3, or R.sub.11 and R.sub.12 together with the nitrogen
atom to which they are bound form an optionally substituted
C.sub.2-10 cycloalkyl-amino group, wherein the substituents are
selected from the group consisting of one or more straight,
branched or cyclic C.sub.1-10 alkyl, straight, branched or cyclic
C.sub.1-10 alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy, --OH, --CN,
--NR.sub.20R.sub.21, --COOR.sub.20, --CONR.sub.20R.sub.21 and
--CF.sub.3; R.sub.20 and R.sub.21 are independently selected from
the group consisting of hydrogen, optionally substituted straight,
branched or cyclic C.sub.1-20 alkyl, optionally substituted
straight, branched or cyclic C.sub.1-20 alkoxy, optionally
substituted C.sub.6-20 aryl, optionally substituted C.sub.6-20
aryloxy, --OH, --CN, --NR.sub.30R.sub.31, --COOR.sub.30,
--CONR.sub.30R.sub.31 and --CF.sub.3, wherein the substituents are
selected from the group consisting of one or more straight,
branched or cyclic C.sub.1-20 alkyl, straight, branched or cyclic
C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN
and --CF.sub.3; R.sub.30 and R.sub.31 are independently selected
from the group consisting of hydrogen, optionally substituted
straight, branched or cyclic C.sub.1-20 alkyl, optionally
substituted straight, branched or cyclic C.sub.1-20 alkoxy,
optionally substituted C.sub.6-20 aryl, optionally substituted
C.sub.6-20 aryloxy, --OH, --CN and --CF.sub.3, wherein the
substituents are selected from the group consisting of one or more
straight, branched or cyclic C.sub.1-20 alkyl, straight, branched
or cyclic C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy,
--OH, --CN and --CF.sub.3; A is an optionally substituted straight-
or branched-chain C.sub.2-5, alkyl wherein the substituents are
selected from the group consisting of one or more straight,
branched or cyclic C.sub.1-10 alkyl, straight, branched or cyclic
C.sub.1-10 alkoxy, C.sub.6-10 aryl and C.sub.6-10 aryloxy, or A is
a group of formula (II):
##STR00013##
wherein p is an integer selected from 1, 2, 3 or 4; each R.sub.40
is independently selected from the group consisting of straight,
branched or cyclic C.sub.1-20 alkyl, straight, branched or cyclic
C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN
or --CF.sub.3; q and r are independently integers selected from 0,
1, 2 or 3 wherein q+r=1, 2 or 3; each R.sub.41 is independently
selected from the group consisting of hydrogen, straight, branched
or cyclic C.sub.1-20 alkyl, straight, branched or cyclic C.sub.1-20
alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN and
--CF.sub.3; and Hal is a halogen.
[0022] The carbon atoms to which R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are bound may be asymmetric. The complex of formula (I)
therefore may be chiral and the hydrogenation process of the
invention an asymmetric hydrogenation process. It is envisaged that
chiral catalysts and asymmetric hydrogenation processes are within
the scope of the invention.
[0023] In one embodiment, the process is suitable for selectively
hydrogenating a carbonyl group to provide the corresponding
alcohol.
[0024] A suitable substrate to be hydrogenated includes, but is not
limited to, a carbonyl of formula (III):
##STR00014##
wherein, R.sub.50 and R.sub.51 are each independently selected from
the group consisting of hydrogen, an optionally substituted
straight, branched or cyclic C.sub.1-20 alkyl, an optionally
substituted straight, branched or cyclic C.sub.2-20 alkenyl, an
optionally substituted C.sub.2-20 alkynyl, an optionally
substituted C.sub.6-20 aryl, an optionally substituted straight,
branched or cyclic C.sub.1-20 heteroalkyl, an optionally
substituted C.sub.3-20 heteroaryl, --NR.sub.60R.sub.61,
--COR.sub.60, --COOR.sub.60, --CONR.sub.60R.sub.61, an optionally
substituted --C.sub.1-20-alkyl-COOR.sub.60, an optionally
substituted --C.sub.1-20-alkyl-COR.sub.60, an optionally
substituted --C.sub.1-20-alkyl-CONR.sub.60R.sub.61, optionally
substituted --C.sub.2-20-alkynyl-C.sub.6-20-aryl and optionally
substituted --C.sub.2-20-alkynyl-C.sub.1-20-alkyl; or R.sub.50 and
R.sub.51 are bound by an optionally substituted C.sub.1-20 alkyl,
an optionally substituted C.sub.1-20 alkoxy or an optionally
substituted C.sub.2-20alkenyl; or R.sub.50 and R.sub.51 are bound
to form a 5, 6 or 7 membered ring by an optionally substituted
--(CH.sub.2).sub.t-(ortho-C.sub.5-6-aryl)-(CH.sub.2).sub.u-- chain,
an optionally substituted
--(CH.sub.2).sub.t-(ortho-C.sub.5-6-aryl)-Q-(CH.sub.2).sub.u--
chain or an optionally substituted
--(CH.sub.2).sub.t-(ortho-C.sub.5-6-heteroaryl)-(CH.sub.2).sub.u--
chain, wherein t is an integer selected from 0 or 1. u is an
integer selected from 2, 3 or 4, Q is selected from the group
consisting of --O--, --N-- and --SO.sub.2--, wherein the
substituents are selected from the group consisting of one or more
of straight, branched or cyclic C.sub.1-20 alkyl, straight,
branched or cyclic C.sub.1-20alkoxy, C.sub.6-20 aryl, C.sub.6-20
aryloxy, straight, branched or cyclic C.sub.1-20 heteroalkyl,
C.sub.6-20 heteroaryl, straight or branched
tri-C.sub.1-20-alkylsilyl-, -Hal, --OH, --CN, --NR.sub.60R.sub.61,
--COR.sub.60, --COOR.sub.60, --CONR.sub.60R.sub.61 and --CF.sub.3,
wherein R.sub.60 and R.sub.61 are independently selected from the
group consisting of hydrogen, straight branched or cyclic
C.sub.1-20 alkyl, straight branched or cyclic C.sub.1-20 alkoxy,
C.sub.6-20 aryl, C.sub.6-20 aryloxy and --OH.
[0025] In one embodiment, when R.sub.50 and R.sub.51 are bound to
form a 5, 6 or 7 membered ring, Q is preferably --O-- or
--SO.sub.2--. In another embodiment, the substrate to be
hydrogenated may be selected from an optionally substituted
1-indanone, an optionally substituted 2-indanone, an optionally
substituted .alpha.-tetralone, an optionally substituted
.beta.-tetralone, an optionally substituted
6,7,8,9-tetrahydro-5-benzocycloheptenone, an optionally substituted
5,7,8,9-tetrahydro-6H-benzo[A]cyclohepten-6-one, an optionally
substituted benzofuran-3(2H)-one, an optionally substituted
4-chromanone and an optionally substituted
3,4-dihydro-1-benzoxepin-5(2H)-one. In one embodiment, the
substituents are selected from the group consisting of one or more
of straight branched or cyclic C.sub.1-20 alkyl and -Hal. In
another embodiment, the substituents are selected from methyl,
ethyl, n-propyl, is-propyl, fluorine, chlorine, bromine and
iodine.
[0026] In yet another embodiment, the process is suitable for
selectively hydrogenating an iminyl group to provide the
corresponding amine.
[0027] A suitable substrate to be hydrogenated includes, but is not
limited to, a compound of formula (IV) or (V):
##STR00015##
R.sub.50 and R.sub.51 are as described above with regard to the
carbonyl of formula (III); R.sub.52 is selected from the group
consisting of hydrogen, an optionally substituted straight,
branched or cyclic C.sub.1-20 alkyl, straight, branched or cyclic
C.sub.1-20alkoxy, an optionally substituted straight, branched or
cyclic C.sub.2-20 alkenyl, an optionally substituted C.sub.6-20
aryl, an optionally substituted C.sub.6-20 aryloxy, an optionally
substituted --C.sub.1-20-alkyl-C.sub.6-20-aryl, an optionally
substituted straight, branched or cyclic C.sub.1-20 heteroalkyl, an
optionally substituted C.sub.3-20 heteroaryl, --NR.sub.70R.sub.71,
--COR.sub.70, --COOR.sub.70, --CONR.sub.70R.sub.71, an optionally
substituted --C.sub.1-20-alkyl-COOR.sub.70, an optionally
substituted --C.sub.1-20-alkyl-COR.sub.70, an optionally
substituted --C.sub.1-20-alkyl-CONR.sub.70R.sub.71, --SOR.sub.70,
--SO.sub.2R.sub.70, --P(O)(R.sub.70).sub.2, or R.sub.52 and one of
R.sub.50 and R.sub.51 are bound to form an optionally substituted
C.sub.1-20-heteroalkyl group, wherein the substituents are selected
from the group consisting of one or more straight, branched or
cyclic C.sub.1-20 alkyl, straight, branched or cyclic C.sub.1-20
alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, straight branched or
cyclic C.sub.1-20 heteroalkyl, C.sub.6-20 heteroaryl, -Hal, --OH,
--CN, --NR.sub.70R.sub.71--COOR.sub.70, --CONR.sub.70R.sub.71 or
--CF.sub.3, and wherein R.sub.70 and R.sub.71 are independently
selected from the group consisting of hydrogen, straight, branched
or cyclic C.sub.1-20 alkyl, straight, branched or cyclic C.sub.1-20
alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH,
--C(O)--(C.sub.1-20-alkyl) and --C(O)O--(C.sub.1-20-alkyl).
[0028] When the substrate to be hydrogenated is a compound of
formula (V), any suitable anion may be present.
[0029] When R.sub.50, R.sub.51 and/or R.sub.52 are different, the
compounds of formulae (III), (IV) or (V) are prochiral and the
hydrogenation catalysed by the metal complex of formula (I) is
enantioselective. The enantiomeric excess is preferably greater
than 80% ee. In certain embodiments, the enantiomeric excess is
greater than 85% ee, in certain embodiments greater than 90% ee, in
certain embodiments greater than 93% ee.
[0030] The process according to the invention may be carried out
either in the absence of a solvent or in presence of a solvent. In
one embodiment therefore the process further comprises a
solvent.
[0031] Preferably, the solvent comprises water, an alcohol, an
aromatic solvent (such as benzene or toluene), an ether (cyclic or
open chain, such as tetrahydrofuran (THF) or methyl tert-butylether
(MTBE)), an ester (such as ethyl acetate) or a combination thereof.
When the solvent comprises an alcohol, preferred alcohols have
boiling points at atmospheric pressure (i.e. 1.0135.times.10.sup.5
Pa) below 160.degree. C., more preferably below 120.degree. C. and
even more preferably below 100.degree. C. Preferred examples are
methanol, ethanol, n-propanol, isopropanol, n-butanol or
combinations thereof. More preferably, the alcohol is methanol,
isopropanol or a combination thereof. Particular preference is
given to methanol.
[0032] The concentration range of the complex of formula (I) may
vary widely. In general, a substrate/complex ratio of about
50.000:1 to about 25:1, preferably from about 2000:1 to about 50:1,
more preferably about 1000:1 to about 100:1 can be achieved.
[0033] The hydrogenation process may be carried out at typical
pressures of about 1 bar to about 100 bar. Advantageously, about 20
bar to about 85 bar and, in particular, about 15 bar to about 35
bar can be used.
[0034] The hydrogenation process may be carried out at temperatures
between about 0.degree. C. to about 120.degree. C. Suitably, the
process can be carried out at about 20.degree. C. to about
80.degree. C. and, most suitably, at about 30.degree. C. to about
60.degree. C.
[0035] The process of the present invention may further comprise a
silver salt. Without wishing to be bound by theory, it is believed
that the silver salt removes the halogen (Hal) from the complex of
formula (I) to form a ruthenium complex of formula (VI) and/or
formula (VII). It is further believed that suitable silver salts
are those which are more soluble than the formed AgHal.
##STR00016##
[0036] Y is an anion from the silver salt. Preferably, the
conjugate acid of the anion Y has a pKa in water below about 4,
more preferably below about 2 and most preferably below about
0.
[0037] Suitable silver salts include silver perfluorinated
alkanesulfonates (such as silver triflate) or silver
(perfluorinated alkanesulfonate)amides. Alternatively, silver
hexafluorophosphate, silver tetrafluoroborate or silver perchlorate
can be used. The silver salt may be present in any suitable mol %,
for example, from about 0.2 to 500 mol % to the amount of ruthenium
complex used.
[0038] In another embodiment, the process of the present invention
may further comprise a fluorinated sulfonic acid, preferably
trifluoromethanesulfonic acid. The fluorinated sulfonic acid may be
used in any suitable mol %, for example, 2 mol %.
[0039] Examples of anion Y therefore may include, but are not
limited to, trifluoromethanesulphonate, tetrafluoroborate,
hexafluorophosphate and perchlorate.
[0040] The ruthenium catalyst and the substrate, as well as the
solvent and/or additive if present, can be mixed in any suitable
order before the hydrogen gas is applied to the reaction
mixture.
[0041] The hydrogenation process may be carried out for any
suitable period of time and this period of time will depend upon
the reaction conditions under which the hydrogenation is conducted
e.g. substrate concentration, catalyst concentration, pressure,
temperature and the like. Once the hydrogenation process has been
determined to be complete, the product may be isolated and purified
using conventional techniques.
[0042] In one embodiment, the hydrogenation catalyst is metal
complex of formula (I):
##STR00017##
wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
straight branched or cyclic C.sub.1-20 alkyl, straight, branched or
cyclic C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy,
--OH, --CN, --NR.sub.20R.sub.21, --COOH, COOR.sub.20, --CONH.sub.2,
--CONR.sub.20R.sub.21 and --CF.sub.3, in another embodiment.
R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 are each
independently selected from the group consisting of hydrogen,
straight- or branched-chain C.sub.1-10 alkyl, straight- or
branched-chain C.sub.1-10 alkoxy, C.sub.6-10 aryl, C.sub.6-10
aryloxy and --OH. Preferably, R.sub.1, R.sub.2, R.sub.3, R.sub.4
and R.sub.5 are each independently selected from the group
consisting of hydrogen, straight-chain C.sub.1-10 alkyl and
branched-chain C.sub.1-10 alkyl. More preferably, R.sub.1, R.sub.2,
R.sub.3, R.sub.4 and R.sub.5 are each independently selected from
the group consisting of hydrogen, methyl, ethyl, n-propyl,
i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. Particular
preference is given to R.sub.1, R.sub.2, R.sub.3, R.sub.4, and
R.sub.5 each being hydrogen.
[0043] In yet another embodiment, R.sub.6, R.sub.7, R.sub.8 and
R.sub.9 are each independently selected from the group consisting
of hydrogen, optionally substituted straight- or branched-chain
C.sub.1-10 alkyl, optionally substituted straight- or
branched-chain C.sub.1-10 alkoxy, optionally substituted C.sub.6-10
aryl and optionally substituted C.sub.6-10 aryloxy wherein the
substituents are selected from the group consisting of straight- or
branched-chain C.sub.1-10 alkyl, straight- or branched-chain
C.sub.1-10 alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy and --OH.
The groups R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are preferably
each independently selected from the group consisting of hydrogen
and optionally substituted C.sub.6-10 aryl. Preferably, R.sub.6,
R.sub.7, R.sub.8 and R.sub.9 are each independently selected from
the group consisting of hydrogen or phenyl. Preferably, one of
R.sub.6 and R.sub.7 is phenyl and the other of R.sub.6 and R.sub.7
is hydrogen. Preferably, one of R.sub.8 and R.sub.9 is phenyl and
the other of R.sub.8 and R.sub.9 is hydrogen.
[0044] In one embodiment, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are
each hydrogen.
[0045] In another embodiment, R.sub.6 and R.sub.7 together with the
carbon atom to which they are bound and/or R.sub.8 and R.sub.9
together with the carbon atom to which they are bound form an
optionally substituted C.sub.5-10 cycloalkyl or an optionally
substituted C.sub.5-10 cycloalkoxy, wherein the substituents are
selected from the group consisting of straight- or branched-chain
C.sub.1-10 straight- or branched-chain C.sub.1-10 alkoxy,
C.sub.6-10 aryl, C.sub.6-10 aryloxy and --OH.
[0046] In yet another embodiment, one of R.sub.6 and R.sub.7 and
one of R.sub.8 and R.sub.9 together form an optionally substituted
C.sub.5-10 cycloalkyl or an optionally substituted C.sub.5-10
cycloalkoxy, wherein the substituents are selected from the group
consisting of straight- or branched-chain C.sub.1-10 alkyl,
straight- or branched-chain C.sub.1-10 alkoxy, C.sub.6-10 aryl,
C.sub.6-10 aryloxy and --OH.
[0047] In yet another embodiment, R.sub.10 is an optionally
substituted straight, branched or cyclic C.sub.1-10 alkyl, an
optionally substituted C.sub.6-10 aryl wherein the substituents are
selected from the group consisting of one or more straight,
branched or cyclic C.sub.1-10 alkyl, straight, branched or cyclic
C.sub.1-10 alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy, -Hal, --OH,
--CN, --NR.sub.20R.sub.21, --COOR.sub.20, --CONR.sub.20R.sub.21 and
--CF.sub.3. In another embodiment, the substituents are selected
from the group consisting of one or more straight, branched or
cyclic C.sub.1-10 alkyl, straight, branched or cyclic C.sub.1-10
alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy, -Hal, or --CF.sub.3.
In another embodiment, R.sub.10 is a straight- or branched-chain
C.sub.1-10 alkyl or a C.sub.6-10 aryl optionally substituted with
one or more straight- or branched-chain C.sub.1-10 alkyl groups.
Examples of R.sub.10 include, but are not limited to, p-tolyl,
methyl, p-methoxyphenyl, p-chlorophenyl, trifluoromethyl,
3,5-dimethylphenyl, 2,4,6-trimethylphenyl,
2,4,6-triisopropylphenyl, 4-tert-butylphenyl, pentamethylphenyl and
2-naphthyl. Preferably, R.sub.10 is methyl or a tolyl group.
[0048] In another embodiment, R.sub.10 is --NR.sub.11R.sub.12
wherein R.sub.11 and R.sub.12 are independently selected from the
group consisting of straight- or branched-chain C.sub.1-10 alkyl
and C.sub.6-10 aryl optionally substituted with one or more
straight- or branched-chain C.sub.1-10 alkyl groups.
[0049] In yet another embodiment, R.sub.11 and R.sub.12 together
with the nitrogen atom to which they are bound form an optionally
substituted C.sub.5-10 cycloalkyl-amino group wherein the
substituents are selected from the group consisting of straight- or
branched-chain C.sub.1-10 alkyl, straight- or branched-chain
C.sub.1-10 alkoxy, C.sub.6-10 aryl, C.sub.6-10 aryloxy and
--OH.
[0050] In one embodiment, A is an optionally substituted straight-
or branched-chain C.sub.2-5alkyl, preferably an optionally
substituted straight- or branched-chain C.sub.3-5 alkyl, wherein
the substituents are selected from the group consisting of
straight- or branched-chain C.sub.1-10 alkyl, straight- or
branched-chain C.sub.1-10 alkoxy, C.sub.6-10 aryl and C.sub.6-10
aryloxy. Preferably, A is --(CH.sub.2).sub.2--,
--(CH.sub.2).sub.3--, --(CH.sub.2).sub.4-- or --(CH.sub.2).sub.5--.
Particular preference is given to --(CH.sub.2).sub.3-- or
--(CH.sub.2).sub.4--.
[0051] Alternatively, A can be a group of formula (II) i.e. the
--[C(R.sub.41).sub.2].sub.q-- and --[C(R.sub.41).sub.2].sub.r--
groups are ortho to each other.
##STR00018##
wherein p is an integer selected from 1, 2, 3 or 4; each R.sub.40
is independently selected from the group consisting of straight,
branched or cyclic C.sub.1-20 alkyl, straight, branched or cyclic
C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy, --OH, --CN
or --CF.sub.3; q and r are independently integers selected from 0,
1, 2 or 3 wherein q+r=1, 2 or 3: and each R.sub.41, is
independently selected from the group consisting of hydrogen,
straight, branched or cyclic C.sub.1-20 alkyl, straight, branched
or cyclic C.sub.1-20 alkoxy, C.sub.6-20 aryl, C.sub.6-20 aryloxy,
--OH, --CN or --CF.sub.3.
[0052] In one embodiment, p is 0. The phenyl ring therefore is not
substituted by any R.sub.40 groups.
[0053] In another embodiment, each R.sub.41 are independently
selected from the group consisting of hydrogen, straight-chain
C.sub.1-10 alkyl and branched-chain C.sub.1-10 alkyl. More
preferably, each R.sub.41 are each independently selected from the
group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, s-butyl and t-butyl. Particular preference is
given to each R.sub.41 being hydrogen.
[0054] Examples of A include, but are not limited to, the
following:
##STR00019##
[0055] In one embodiment, Hal is chlorine, bromine or iodine,
preferably chlorine.
[0056] Preferred metal complexes of formula (I) are shown
below:
##STR00020## ##STR00021##
[0057] Complex (B) may be prepared according to Wills et al. J. Am.
Chem. Soc., 2005, 127(20), 7318. The Wills method involves five
steps:
##STR00022##
[0058] Step 1 is a Birch reduction of 3-phenyl-propanol to
3-cyclohexa-1,4-dienyl-propan-1-ol. Step 2 involves a Swern
oxidation of 3-cyclohexa-1,4-dienyl-propan-1-ol to produce
3-cyclohexa-1,4-dienyl-propionaldehyde. This stage is
disadvantageous as a change in oxidation state occurs and, for the
subsequent reduction, the reagent lithium aluminium hydride is used
which is unsuitable for larger scale reactions. Step 3 is a
reductive amination reaction to form the desired (R,R)-TsDPEN.
However, a by-product is also formed during the course of the
reductive amination which complicates the subsequent purification
of (R,R)-TsDPEN. Steps 4 and 5 relate to the synthesis of the
ruthenium dimer and monomer respectively.
[0059] The inventors of the present case have overcome the above
disadvantages to provide an improved process for the preparation of
the complexes of formula (I).
[0060] The present invention therefore provides a process for the
preparation of a compound of formula (VIII):
##STR00023## [0061] comprising the steps of: [0062] (a) converting
a compound of formula (IX) into a compound of formula (X):
[0062] ##STR00024## [0063] (b) reacting the compound of formula (X)
with a compound of formula (XI) in a solvent to form the compound
of formula (VIII):
[0063] ##STR00025## [0064] wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10 and
A are as defined above, and X is an electrophilic group.
[0065] The process of the invention provides a process for the
production of a compound of formula (VIII) which does not involve a
change in oxidation state. Moreover, a reductive amination step is
not required and, as such, the use of lithium aluminium hydride is
avoided. This means that the process of the invention is suitable
for large scale manufacturing procedures.
[0066] Step (a) preferably comprises reacting the compound of
formula (IX) with a base and a compound of formula (XII):
X-LG (XII)
wherein LG is a leaving group.
[0067] The base is preferably an amine, for example, lutidine or
triethylamine. Desirably, the reaction is carried out under an
inert atmosphere (such as nitrogen or argon). Suitably, a solvent
may be used, for example, any suitable aprotic polar solvent (such
as, dichloromethane). The solvent may be anhydrous, although this
is not essential.
[0068] The compound of formula (IX), the base, the solvent and the
compound of formula (XII) may be added in any suitable order. In a
preferred process of the invention, however, the compound of
formula (IX) and the base is placed in a reaction vessel, together
with the solvent, and then the compound of formula (XII) is
added.
[0069] The compound of formula (XII) may also be present as a
solution in a solvent. In this case, the solvent may be any
suitable polar aprotic solvent (such as dichloromethane). The
solvent may the same or different to the solvent used to prepare
the reaction mixture of the compound of formula (XII) and the base,
although in a preferred embodiment of the invention, the solvents
are the same.
[0070] The compound of formula (XII) is preferably selected from
the group consisting of trifluoromethane sulfonic anhydride,
trifluoromethane sulfonic acid, methanesulfonyl chloride and
p-toluenesulfonyl chloride. X therefore may be --SO.sub.2CF.sub.3
(for trifluoromethane sulfonic anhydride and trifluoromethane
sulfonic acid), --SO.sub.2Me (for methanesulfonyl chloride) or
--SO.sub.2--C.sub.6H.sub.4-p-CH.sub.3 (for p-toluenesulfonyl
chloride). In these instances, LG may be --O--SO.sub.2CF.sub.3 (for
trifluoromethane sulfonic anhydride), --OH (for trifluoromethane
sulfonic acid) or --Cl (for methanesulfonyl chloride or
p-toluenesulfonyl chloride).
[0071] While the compound of formula (XII) is added to the reaction
mixture, it is preferred that the temperature range of the reaction
is maintained at one or more temperatures between about -10.degree.
C. to about 35.degree. C. In a preferred embodiment the reaction
mixture is maintained at a temperature of less than about 5.degree.
C. In order to keep the temperature of the reaction mixture within
these ranges, the compound of formula (XII) together with the
solvent (if used) may be added slowly over a period of time.
[0072] The reaction may be continued for a period of from about 30
minutes to about 72 hours, preferably 30 minutes to about 24 hours.
During this time, the reaction temperature may be varied one or
more times between about -10.degree. C. and about 25.degree. C. If
desired, on completion of the reaction, the compound of formula (X)
may be separated from the reaction mixture by any appropriate
method. Alternatively, the reaction mixture comprising the compound
of formula (X) may be used directly without isolation in step (b)
of the process of the invention.
[0073] In step (b), the compound of formula (X) is reacted with the
compound of formula (XI) in a solvent to form the compound of
formula (VIII).
[0074] In one embodiment, the compound of formula (VIII) is the
compound of formula (G):
##STR00026##
[0075] In another embodiment, the compound of formula (VIII) is
selected from the group consisting of:
##STR00027##
[0076] The compounds of formulae (G), (H), (L) and (M) may be
present as enantiomers or diastereoisomers. It is envisaged that
enantiomers and diastereoisomers are within the scope of the
invention.
[0077] Desirably, the reaction is carried out under an inert
atmosphere (such as nitrogen or argon). Desirably, a suitable
solvent is used, for example, an aprotic polar solvent (such as
dichloromethane or 1,2-dimethoxy ethane). The solvent may be
anhydrous, although this is not essential. The reaction is
preferably carried out at one or more temperatures in the range of
between about -10.degree. C. to about 65.degree. C.
[0078] Step (b) preferably further comprises a base. More
preferably, the base is an amine, for example, triethylamine.
[0079] The compound of formula (X), the compound of formula (XI),
the base (if used) and the solvent may be added in any suitable
order. In one embodiment, the compound of formula (XI) is placed in
a reaction vessel, together with the solvent and the base (if
used), heated if necessary and the compound of formula (X) added,
either alone or as a solution in solvent. Alternatively, the
compound of formula (X) and the solvent may be present in a
reaction vessel, cooled or heated if necessary and then the
compound of formula (XI), the base (if used) and the solvent may be
added.
[0080] The reaction may be continued for a period of from about 30
minutes to about 24 hours. During this time, the reaction
temperature may be varied one or more times between about
-10.degree. C. and about 100.degree. C., preferably between about
0.degree. C. and about 85.degree. C. On completion of the reaction,
the compound of formula (VIII) may be separated from the reaction
mixture by any appropriate method and if necessary purified.
[0081] Preferably, the process of the invention further comprises
the steps of: [0082] c) treating the compound of formula (VIII)
with an acid HZ, where Z is an anion: and [0083] d) reacting the
acid addition salt of the compound of formula (VIII) with a
Ru(Hal).sub.n complex, where Hal is a halogen and n is a number
equal to or less than the coordination number of Ru, to form a
complex of formula (XIII):
##STR00028##
[0084] Step c) is preferably carried out in the presence of a
solvent. The solvent may be any suitable solvent, for example, a
polar protic solvent (such as water, methanol, ethanol, n-propanol
or isopropanol), a polar aprotic solvent (such as dichloromethane
or dichloroethane) or an aromatic hydrocarbon (such as toluene).
Preferably, the solvent is selected from the group consisting of at
least one of water, ethanol, isopropanol, dichloroethane and
toluene.
[0085] Preferably, the acid HZ is selected from the group
consisting of hydrochloric acid, hydrobromic acid and hydroiodic
acid. More preferably, the acid is hydrochloric acid. Z therefore
may be a chloride, bromide or iodide anion, preferably a chloride
anion. In a preferred embodiment, the acid HZ is a concentrated
aqueous acid.
[0086] The halogen Hal is preferably selected from the group
consisting of chlorine, bromine and iodine. In a preferred
embodiment, Ru(Hal).sub.n is RuCl.sub.3, for example,
RuCl.sub.3.H.sub.2O or an aqueous solution of RuCl.sub.3, including
coordination complexes of RuCl.sub.3 such as
[RuCl.sub.3.(H.sub.2O).sub.3], [RuCl.sub.2.(H.sub.2O).sub.4]Cl etc.
n therefore is 3. There is a commercial advantage in using an
aqueous solution of RuCl.sub.3 in that it is much cheaper than the
isolated complex RuCl.sub.3.
[0087] In one embodiment, the acid addition salt of the compound of
formula (VIII) is isolated before reaction with the Ru(Hal).sub.n
complex.
[0088] In another embodiment, the acid addition salt of the
compound of formula (VIII) is prepared in situ before reaction with
the Ru(Hal).sub.n complex. In this case, it is desirable that the
solution of the acid addition salt of the compound of formula
(VIII) is warmed to one or more temperatures in the range from
about 50.degree. C. to about 80.degree. C. and more preferably
about 50.degree. C. to about 75.degree. C. before the addition of
the Ru(Hal).sub.n complex.
[0089] The Ru(Hal).sub.n complex may added as a solution or a
suspension in a solvent. The solvent may be any suitable solvent,
for example, a polar protic solvent (such as water, methanol,
ethanol, n-propanol or isopropanol), a polar aprotic solvent (such
as dichloromethane or dichloroethane) or an aromatic hydrocarbon
(such as toluene). Preferably, the solvent is selected from the
group consisting of at least one of water, ethanol, isopropanol,
dichloroethane and toluene. The solvent or solvent mixture may be
the same or different to the solvent used in step c).
[0090] The reaction is preferably carried out at a temperature in
the range from about 50.degree. C. to about 100.degree. C. and more
preferably about 50.degree. C. to about 85.degree. C. It is
preferred that the reaction temperature is maintained below the
decomposition temperatures of the RuL.sub.n and the complex of
formula (XIII). As such, when it is known that RuL.sub.n or the
complex of formula (XIII) decompose within the temperature ranges
given above, the reaction temperature should be maintained below
the decomposition temperatures.
[0091] Preferably, the compound of formula (VIII) is present in the
reaction mixture in stoichiometric excess. Preferably the amount of
the compound of formula (VIII) in the reaction mixture is
calculated to provide a molar excess of at least 5% over the amount
required for the stoichiometric reaction, more preferably an excess
of at least 9%.
[0092] The reactants may be added in any suitable order, but in a
preferred process of the invention the diluted aqueous solution of
the Ru(Hal).sub.n complex is added to the solution of the acid
addition salt of the compound of formula (VIII). It is desirable
that the diluted aqueous solution of the Ru(Hal).sub.n complex is
added to the solution of the acid addition salt of the compound of
formula (VIII) slowly in order to avoid an uncontrollable
exotherm.
[0093] The reaction may be carried out for a period from about 30
minutes to about 24 hours. On completion, the complex of formula
(XIII) may be isolated from the reaction mixture. In this case, the
complex is separated by any appropriate method which is dependent
on the physical form of the product. Purification of the complex of
formula (XIII) is not normally required, although if necessary it
is possible to purify the complex using conventional
procedures.
[0094] Alternatively, it may be desirable to prepare the complex of
formula (XIII) in situ.
[0095] Preferably, the present invention further comprises the step
of treating the complex of formula (XIII) with a base to form the
complex of formula (I):
##STR00029##
[0096] The complex of formula (XIII) is preferably present in a
solvent. The solvent may be any suitable solvent, for example, a
polar protic solvent (such as methanol, ethanol, n-propanol or
isopropanol), a polar aprotic solvent (such as dichloromethane or
dichloroethane) or an aromatic hydrocarbon (such as toluene).
Preferably, the solvent is selected from the group consisting of at
least one of ethanol, isopropanol, dichloromethane, dichloroethane
and toluene. The solvent or solvent mixture may be the same or
different to the solvents used in step c) and/or step d).
[0097] The base is preferably an amine, for example, triethylamine
or N,N-diisopropylamine. In a preferred embodiment, the base is
N,N-diisopropylamine.
[0098] The reaction may be continued for a period of from about 20
minutes to about 24 hours. During this time, the reaction
temperature may be varied one or more times between about
-10.degree. C. and about 100.degree. C. preferably between about
0.degree. C. and about 85.degree. C. It is preferred that the
reaction temperature is maintained below the decomposition
temperature of the complex of formula (I). As such, when it is
known that the complex of formula (I) decomposes within the
temperature ranges given above, the reaction temperature should be
maintained below the decomposition temperature.
[0099] On completion of the reaction, the compound of formula
(VIII) may be separated from the reaction mixture by any
appropriate method which is dependent on the physical form of the
product. In particular, solid complexes may be recovered by
filtering, decanting or centrifuging. If purification is necessary,
the complexes may be obtained in high purity by conventional
methods.
[0100] In another aspect, the present invention provides a one-pot
process for the preparation of a complex of formula (I):
##STR00030## [0101] comprising the steps of: [0102] i) treating a
compound of formula (VIII) with an acid HZ, where Z is an anion
[0102] ##STR00031## [0103] ii) reacting the acid addition salt of
the compound of formula (VIII) with a Ru(Hal).sub.n complex, where
Hal is a halogen and n is a number equal to or less than the
coordination number of Ru, to form a complex of formula (XIII):
[0103] ##STR00032## [0104] iii) treating the complex of formula
(XIII) with a base to form the complex of formula (I):
[0104] ##STR00033## [0105] wherein R.sub.1, R.sub.2, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10 and
A are as defined above, and wherein the acid addition salt of the
compound of formula (VIII) and the complex of formula (XIII) are
prepared in situ.
[0106] In yet another aspect, the present invention provides a
complex of formula (I) or formula (XIII):
##STR00034## [0107] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10, A, Hal
and Z are as defined above. [0108] provided that the complex of
formula (I) is not:
[0108] ##STR00035## [0109] and the complex of formula (XIII) is
not:
##STR00036## ##STR00037##
[0110] Preferably, the complex of formula (I) selected from the
group consisting of:
##STR00038##
[0111] In another aspect, the present invention provides a compound
of formula (VIII), or an acid addition salt thereof.
##STR00039## [0112] wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4,
R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9, R.sub.10 and A are as
defined above, provided that the compound of formula (VIII) is
not:
[0112] ##STR00040## or the hydrogen chloride salt thereof, [0113]
or
##STR00041##
[0114] Preferably, the compound of formula (VIII), or an acid
addition salt thereof, is selected from the group consisting
of:
##STR00042##
[0115] The invention is further illustrated by reference to the
following non-limiting Examples.
Example 1
Birch reduction of 3-phenyl-propanol
[0116] Ammonia is condensed in a round-bottomed flack with four
necks (thermometer, a cold finger connected to ammonia lecture
bottle, argon inlet with silicone oil bubbler, inlet closed with a
stopper). The cold finger is cooled with dry ice and the flask is
cooled in a dry ice-EtOH bath. When between 50 and 100 mL of
ammonia have been collected (a slow flow of argon is maintained
throughout the reaction), 3-phenyl-propanol (5.0 g, MW 136.2, 36.7
mmol) in EtOH (20 mL) are added. Portions of lithium wire are added
(.about.1.0 g) so that the reaction is maintained dark green. After
2 hours at -78.degree. C. the reaction is allowed to warm up to
room temperature and the ammonia to evaporate. The reaction is then
quenched with a saturated solution of ammonium chloride (200 mL)
and extracted with dichloromethane (2.times.200 mL). The combined
dichloromethane fractions are washed with 200 mL of HCl 2N, then
dried over Na.sub.2SO.sub.4. The solvent is removed at the
rotavapor to give a clear colourless oil (4.77 g, 95% yield).
Purity is determined by .sup.1H NMR.
Example 2
Synthesis of tethered (R,R)-TsDPEN
##STR00043##
[0118] A solution of 3-(1,4-cyclohexadien-1-yl)-1-propanol (MW:
138.21; 22.1 g, 0.16 mol, 1.6 eq.) and 2,6-lutidine (MW: 107.16, d:
0.92 g/ml; 24.5 ml, 0.21 mol, 2.10 eq.) in anhydrous
CH.sub.2Cl.sub.2 (500 ml) was cooled to 0.degree. C. under N.sub.2.
A solution of triflic anhydride (MW: 281.14, d: 1.67/; 29.1 ml,
0.17 mol, 1.7 eq.) in anhydrous CH.sub.2Cl.sub.2 (100 ml) was added
slowly, keeping the internal temperature below 5.degree. C. The
resulting amber solution was stirred for 30 min at 0.degree. C. 60
min at room temperature, and cooled back to 0.degree. C. A solution
of (R,R)-TsDPEN (MW: 366.48; 36.6 g, 0.10 mol) and triethylamine
(MW: 101.19, d: 0.726; 33.5 ml, 0.24 mol, 2.4 eq.) in anhydrous
CH.sub.2Cl.sub.2 (100 ml) was added slowly, keeping the internal
temperature below 5.degree. C. At the end of the addition, stirring
was continued for 30 min at 0.degree. C. and then at room
temperature over night (17.5 h). The reaction mixture was diluted
with CH.sub.2Cl.sub.2 (500 ml), washed with sat. aq. NaHCO.sub.3
(2.times.500 ml, 1.times.250 ml), water (2.times.300 ml), brine
(250 ml), dried over MgSO.sub.4, and concentrated under reduced
pressure to give a highly viscous, amber oil. Ethanol (250 ml) was
added, and the mixture was stirred until a solid formed. Additional
ethanol (450 ml) was added, and the mixture was heated to
70.degree. C. until a clear solution was obtained, which was
allowed to cool to room temperature over night. The thick
suspension (solvent not visible, voluminous product) was filtered,
and the off-white precipitate was washed with ethanol, hexane, and
dried under high vacuum. Yield: 34.10 g (70%), NMR purity >98%
(.sup.1H NMR).
Example 3
Synthesis of tethered (S,S)-MsDPEN
##STR00044##
[0120] A solution of 3-(1,4-cyclohexadien-1-yl)-1-propanol (MW:
138.21; 8.3 g, 60.0 mmol, 1.20 eq.) and 2,6-lutidine (MW: 107.16,
d: 0.92 g/ml; 8.3 ml, 70.0 mmol, 1.40 eq.) in anhydrous
CH.sub.2Cl.sub.2 (250 ml) was cooled to 0.degree. C. under N.sub.2.
A solution of triflic anhydride (MW: 281.14, d: 1.677; 10.7 ml,
62.5 mmol, 1.25 eq.) in anhydrous CH.sub.2Cl.sub.2 (40 ml) was
added slowly, keeping the internal temperature below 5.degree. C.
The resulting amber solution was stirred for 30 min at 0.degree.
C., 90 min at room temperature, and cooled back to 0.degree. C. A
solution of (S,S)-MsDPEN (MW: 290.39; 14.52 g, 50.0 mmol) and
triethylamine (MW: 101.19, d: 0.726; 11.2 ml, 80.0 mmol, 1.6 eq.)
in anhydrous CH.sub.2Cl.sub.2 (90 ml) was added slowly, keeping the
internal temperature below 5.degree. C. At the end of the addition,
stirring was continued for 30 min at 0.degree. C. and then at room
temperature over night (20.5 h). The reaction mixture was diluted
with CH.sub.2Cl.sub.2 (total volume: ca. 500 ml), washed with sat.
aq. NaHCO.sub.3 (2.times.250 ml, 1.times.150 ml), water
(2.times.200 ml), brine (200 ml), dried over MgSO.sub.4, and
concentrated under reduced pressure to give a highly viscous, amber
oil (26.5 g). The crude product was filtered through a layer of
silica gel (7 cm thick, 9 cm in diameter) with EtOAc/hexane 2/1 as
eluent. The product was obtained with the first two fractions (200
ml each) but still contained an impurity, which eluted first (TLC
in EtOAc, R.sub.t(impurity): 0.76, R.sub.f(tethered MsDPEN): 0.66;
visualised with UV @254 nm or with basic KMnO.sub.4). Evaporation
of the solvents under reduced pressure yielded the crude product as
a yellow-to-orange oil, which slowly solidified (20.2 g).
[0121] The solid was dissolved in MTBE (500 ml) and the solution
was cooled to ca. 0.degree. C. A 1.25 M solution of HCl in MeOH
(120 ml, 150 mmol) was added with vigorous stirring. After 45 min
at 0.degree. C. the thick suspension was filtered, the solid was
washed with MTBE, and dried under high vacuum. Yield: 17.13 g
(77%), NMR purity >98% (.sup.1H NMR).
[0122] A second batch of product was obtained by working up the
mother liquor: The combined filtrate and washings were evaporated
to dryness under reduced pressure until a solid was obtained, which
was triturated with ethyl acetate (40 ml) at 70.degree. C. for 1
hour. After cooling to room temperature, the mixture was filtered
and the filter cake was washed with EtOAc. The off-white solid was
then dried under high vacuum. Yield: 1.66 g (7%), NMR purity
>98% (H NMR).
Example 4
Synthesis of Ts-DPEN Ru dimer
##STR00045##
[0123] Procedure 1.
[0124] To a stirred suspension of (R,R)-tethered-diamine (11.68 g,
24 mmol) in EtOH (500 mL) was added concentrated HCl (3 mL, 37%, 36
mmol) at 60.degree. C. and solution stirred for 30 minutes. The
solution was then heated to 75.degree. C. and to this was added
RuCl.sub.3 in H.sub.2O (Assay 19.23% in Ru, 6.46 mL, 20 mmol) in
EtOH (50 mL) added dropwise over 1 hour. The solution was then
stirred at 75.degree. C. overnight. The solution was then cooled,
hexane (600 mL) added with vigorous stirring and solution filtered.
The solids obtained were then washed with hexane, collected and
dried under high vacuum to give a light brown solid (.about.15 g,
carried forward). The isolated product was shown to be >95% pure
by .sup.1H NMR (CDCl.sub.3). No further purification was attempted
and this material was carried forward to the next step.
Procedure 2.
[0125] To a stirred suspension of (R,R)-diamine (2.9 g, 6 mmol) in
DCE (20 mL) was added HCl (3 mL, 37%, 36 mmol) at 50.degree. C. and
solution stirred for 30 minutes. The resulting suspension was then
heated to 75.degree. C. and to this was added RuCl.sub.3 in
H.sub.2O (Assay 19.23% in Ru, 1.62 mL, 5 mmol) in IPA (20 mL) added
dropwise over 1 hour. The solution was then stirred at 75.degree.
C. overnight. The solution was then cooled, hexane (100 mL) added
with vigorous stirring and solution filtered. The solids obtained
were then washed with hexane, collected and dried under high vacuum
to give a light brown solid (.about.6 g, carried forward). The
dimer was isolated as a crude solid and shown to be >90% pure by
.sup.1H NMR (CDCl.sub.3).
Procedure 3.
[0126] To a stirred suspension of (R,R)-diamine (2.9 g, 6 mmol) in
Toluene (20 mL) was added HCl (3 mL 37%, 36 mmol) at 50.degree. C.
and the solution was stirred for 30 minutes. The resulting
suspension was then heated to 75.degree. C. and to this was added
RuCl.sub.3 in H.sub.2O (Assay 19.23% in Ru, 1.62 mL 5 mmol) in IPA
(20 mL) dropwise over 1 hour. The solution was then stirred at
75.degree. C. overnight. The solution was then cooled, hexane (100
mL) added with vigorous stirring and solution filtered. The solids
obtained were then washed with hexane, collected and dried under
high vacuum to give a light brown solid (.about.6 g, carried
forward). The dimer was isolated as a crude solid and shown to be
>90% pure by .sup.1H NMR (CDCl.sub.3).
Example 5
Synthesis of [Ts-teth-DPEN Ru Cl] (monomer)
##STR00046##
[0127] Procedure 1.
[0128] To a stirred solution of the (R,R)-dimer (carried forward,
.about.20 mmol) in DCM (300 mL) at 0.degree. C. was added
N,N-diisopropylethylamine (20.9 mL, 120 mmol) and solution stirred
at room temperature for 1 hour. The solution was then filtered over
celite, IPA (300 mL) added and the DCM removed by rotary
evaporation. The resulting suspension was then filtered and solid
collected as a dark orange solid. The solid was then further dried
under high vacuum over night to give a fine orange powder (10.6 g,
83%). Isolated product was shown to be >95% pure by .sup.1H NMR
(CDCl.sub.3).
Procedure 2.
[0129] To a stirred solution of the (R,R)-dimer (14 g, .about.20
mmol) in IPA (1 L) at 50.degree. C. was added
N,N-diisopropylethylamine (20.9 mL, 120 mmol) and solution stirred
at 85.degree. C. for 2 hours. The solution was then cooled,
evaporated to a third of its original volume and then filtered to
give a dark orange solid. The solid was then further dried under
high vacuum over night to give a fine orange powder (8.5 g, 67%).
Isolated product was shown to be >95% pure by .sup.1H NMR
(CDCl.sub.3).
Example 6
Synthesis of [Ts-teth-DPEN Ru Cl] one-pot
##STR00047##
[0130] Procedure 1.
[0131] To a stirred suspension of (R,R)-diamine (2.9 g, 6 mmol) in
Toluene (20 mL) was added HCl (0.75 mL, 37%, 9 mmol) at 50.degree.
C. and solution stirred for 30 minutes. The resulting suspension
was then heated to 75.degree. C. and to this was added RuCl.sub.3
in H.sub.2O (Assay 19.23% in Ru, 1.62 mL, 5 mmol) in IPA (10 mL)
added dropwise over 1 hour. The solution was then stirred at
75.degree. C. overnight (16 h). The solution was then cooled to
0.degree. C., toluene (30 mL) added and N,N-diisopropylethylamine
(4.35 mL, 25 mmol) added dropwise with stirring. The solution was
then allowed to warm to room temperature and then heated to
80.degree. C. for 30 mins. The solution was then cooled, diluted
with DCM (50 mL), filtered over neutral alumina (1 g/mmol) and pad
washed with further portions of DCM (2.times.20 mL). The filtrate
was evaporated to remove the DCM/toluene, IPA (50 mL) added and
solution stirred at room temperature for 1 h. The resulting slurry
was then filtered to give an orange solid, which was dried under
high vacuum for 2 hours (2 g, 63%). No exotherm was observed at
this scale, but care should be taken, as this could be possible at
larger scale. After the initial heating phase a thick precipitate
formed which resulted in the stirring of the solution failing.
Addition of the toluene and Hunigs base however resulted in
re-dissolution of the solids as the monomer formation proceeded.
Isolated product was shown to be >95% pure by .sup.1H NMR
(CDCl.sub.3).
##STR00048##
Procedure 2.
[0132] To a stirred suspension of (S,S)-diamine (14.5 g, 30 mmol)
in Toluene (100 mL) under nitrogen was added HCl (3.75 mL 37%, 45
mmol) at 50.degree. C. and solution stirred for 30 minutes. The
resulting suspension was then heated to 75.degree. C. and to this
was added RuCl.sub.3 in H.sub.2O (Assay 19.23% in Ru, 8.1 mL 25
mmol) in IPA (50 mL) added dropwise over 1 hour. The solution was
then stirred at 75.degree. C. overnight (16 h). The solution was
then cooled to 0.degree. C., DCM (100 mL) added and
N,N-diisopropylethylamine (21.75 mL, 125 mmol) added dropwise with
stirring. The solution was then allowed to warm to room temperature
and then stirred for 2 h. The solution was then filtered over
neutral alumina (1 g/mmol) and pad washed with further portions of
10% IPA/DCM (2.times.50 mL). The filtrate was evaporated to remove
the DCM/toluene, IPA (200 mL) added and solution stirred at room
temperature for 2 h. The resulting slurry was then filtered to give
an orange solid, which was washed with cold IPA (30 mL) and dried
under high vacuum for 2 hours (12.3 g, 77%). After the initial
heating phase a thick precipitate formed which resulted in the
stirring of the solution failing. Addition of the DCM and Hunigs
base however resulted in re-dissolution of the solids as the
monomer formation proceeded. Crude Isolated product was shown to be
>95% pure by .sup.1H NMR (CDCl.sub.3). Further purification can
be undertaken by dissolution with DCM (100 mL) and IPA (100 mL),
followed by removal of the DCM by rotary evaporation. The resulting
slurry could then be filtered as before and solids dried to give
pure material.
Example 7
Synthesis of [Ms-teth-DPEN Ru Cl] one-pot
##STR00049##
[0133] Procedure 1.
[0134] To a stirred suspension of (S,S)-diamine.HCl (2.67 g, 6
mmol) in Toluene (20 mL) at 75.degree. C. under nitrogen was added
RuCl.sub.3 in H.sub.2O (Assay 19.23% in Ru, 1.62 mL, 5 mmol) in IPA
(10 mL) dropwise over 1 hour. The solution was then stirred at
75.degree. C. overnight (16 h). The solution was then cooled to
0.degree. C. DCM (30 mL) added and N,N-diisopropylethylamine (4.35
mL, 25 mmol) added dropwise with stirring. The solution was then
allowed to warm to room temperature and stirred for 2 h. The
solution was then diluted with DCM (50 mL), filtered over neutral
alumina (1 g/mmol) and pad washed with further portions of DCM
(2.times.20 mL). The filtrate was evaporated to remove DCM/toluene,
IPA (50 mL) added and solution stirred at room temperature for 1 h.
The resulting slurry was then filtered to give an orange solid,
which was dried under high vacuum for 2 hours (1.8 g, 64%); After
the initial heating phase a thick precipitate was not observed in
comparison to the Ts example. Isolated product was shown to be
>95% pure by .sup.1H NMR (CDCl.sub.3).
##STR00050##
Procedure 2.
[0135] To a stirred suspension of (R,R)-diamine.HCl (8.03 g, 18
mmol) in Toluene (60 mL) at 75.degree. C. under nitrogen was added
RuCl.sub.3 in H.sub.2O (Assay 19.23% in Ru, 4.86 mL, 15 mmol) in
IPA (30 mL) dropwise over 1 hour. The solution was then stirred at
75.degree. C. overnight (16 h). The solution was then cooled to
0.degree. C., DCM (100 mL) added and N,N-diisopropylethylamine
(15.66 mL, 90 mmol) added dropwise with stirring. The solution was
then allowed to warm to room temperature and stirred for 2 h. The
solution was then filtered over neutral alumina (1 g/mmol) and pad
washed with further portions of 10% IPA/DCM (2.times.50 mL). The
filtrate was evaporated to remove the DCM/toluene. IPA (200 mL)
added and solution stirred at room temperature for 2 h. The
resulting slurry was then filtered to give an orange solid, which
was washed with cold IPA (30 mL) and dried under high vacuum for 2
hours (5.0 g, 60%); After the initial heating phase a thick
precipitate was not observed in comparison to the Ts example. Crude
Isolated product was shown to be >95% pure by .sup.1H NMR
(CDCl.sub.3). Further purification could be undertaken by
dissolution with DCM (100 mL) and IPA (100 mL), followed by removal
of the DCM by rotary evaporation. The resulting slurry could then
be filtered as before and solids dried to give pure material.
Example 8
Synthesis of Achiral Tethered Catalysts
##STR00051##
[0136] Synthesis of the Ligand (Steps 1 and 2)
[0137] To a stirred solution of
3-(1,4-cyclohexadien-1-yl)-1-propanol (MW: 138.21; 1.21 g, 9.18
mmol) in 25 mL of DCM 2.7 mL of NEt.sub.3 (19.28 mmol) was added
and cooled to 0.degree. C. A solution of methane sulfonyl chloride
(1.1 mL, 13.8 mmol) was added over a period of 20 min by keeping
the internal temperature below 5.degree. C. After 30 min the
reaction mixture was allowed to warm up to RT and stirred
overnight. The reaction was quenched with saturated NaHCO.sub.3
solution. The reaction was worked up with water, brine and dried
over Na.sub.2SO.sub.4. The mesylate derivative (96% yield) was
isolated was carried forward to the next step. To a stirred
solution of monotosylated ethylenediamine (1.98 g, 9.25 mmol) in 20
mL of 1,2-dimethoxy ethane and NEt.sub.3 (2.7 mL, 19.43 mmol) at
60.degree. C. a solution of the mesylate derivative in 10 mL of DME
was added slowly over a period of 5 min. Then the solution was
heated to 80.degree. C. and stirred overnight. The reaction was
quenched with saturated NaHCO.sub.3 solution. The reaction was
worked up with water, brine and dried over Na.sub.2SO.sub.4. The
desired ligand was isolated by column chromatography with EtOAc as
eluent (R.sub.f value 0.1 in EtOAc; visualised with UV @254 nm or
with basic KMnO.sub.4). Isolated yield of the ligand was 1.0 g (33%
based on the starting alcohol). .sup.1H NMR: (300 MHz, CDCl.sub.3)
7.77-7.73 (2H, m, ArH), 7.32-7.27 (2H, m, ArH), 5.71 (2H, br s,
CH.dbd.CH), 5.34 (2H, br s, .dbd.CH), 3.04-3.00 (2H, m,
CH.sub.2NH), 2.82-2.73 (2H, m, CH.sub.2NH), 2.72-2.68 (2H, m,
--CH.sub.2--C.dbd. or .dbd.CH--CH.sub.2--CH.dbd.), 2.56-2.51 (4H,
m, --CH.sub.2--C.dbd. or .dbd.CH--CH.sub.2--CH.dbd.), 2.42 (3H, s,
CH.sub.3), 1.95-1.90 (2H, m, --NH--CH.sub.2--), 1.53-1.48 (2H, m,
--CH.sub.2--CH.sub.2--CH.sub.2).
Synthesis of Dimer (Step 3)
[0138] To a stirred solution of tethered ethylenediamine ligand
(MW: 334.17, 0.270 g, 0.808 mmol) in EtOH (15 mL) was added
concentrated HCl (0.12 mL, 35%, 1.212 mmol) at 0.degree. C. The
solution was heated at 60.degree. C. for 30 minutes. After this the
solution was heated to 75.degree. C. and a solution of RuCl.sub.3
(0.110 g, 0.533 mmol) in EtOH (15 mL) and water (0.5 mL) added
dropwise over 20 min. The solution was then stirred at 75.degree.
C. overnight. The solution was then cooled, hexane (60 mL) added
with vigorous stirring and filtered. The solids obtained were then
washed with hexane, collected and dried under high vacuum to give a
dark brown solid (0.006 g). The filtrate was concentrated to give
orange powder (0.040 g). Both these solids were combined for the
next reaction. The isolated product was shown to be >95% pure by
.sup.1H NMR: .sup.1H NMR (300 MHz, DMSO-d6) 8.50 (2H, br s,
NH.sub.2), 7.82 (2H, br s, NH), 7.71-7.68 (2H, m, ArH), 7.44-7.42
(2H, m, ArH), 6.02 (2H, br s, Ru--ArH), 5.79 (3H, br s, Ru--ArH),
2.98 (5 or 6H, br s, CH.sub.2), 2.30 (3H, s, CH.sub.3), 1.92 (2H,
br s, --CH.sub.2--).
Synthesis of Monomer (Step 4)
[0139] To a stirred solution of the dimer (MW: 1081.80, 0.238 g,
0.220 mmol) in DCM (50 mL) at 0.degree. C. was added
N,N-diisopropylethylamine (3.0 mL, 1.696 mmol) and the solution was
stirred at room temperature for 2 hours. The solution was then
filtered over celite and the DCM was removed by rotary evaporation.
EtOH was added to the resulting paste and stored in the freezer for
3 hours and the cold solution was filtered and an orange
precipitate was collected. The dark precipitate was washed with
further portions of cold EtOH. The desired ruthenium complex was
isolated by column chromatography with EtOAc (R.sub.f value 0.2 in
EtOAc; visualised with UV @254 nm and phosphomolybdic acid).
.sup.1H NMR (300 MHz, DMSO-d6) 7.68 (1H, br s, NH), 7.82 7.59 (2H,
d, ArH), 7.13 (2H, d, ArH), 5.91 (1H, m, Ru--ArH), 5.79-5.71 (2H,
m, Ru--ArH), 5.26-5.20 (2H, m, Ru--ArH), 2.29 (3H, s,
CH.sub.3).
Example 9
Hydrogenation of Acetophenone Using Tethered-Ts/MsDPENRuCl
Catalysts and Optional Additives
##STR00052##
[0141] Experimental Procedure: Ru catalyst (1.2 mg,
1.9.times.10.sup.6 mol) and silver salt (3.8.times.10.sup.-6 mol)
(if present) were weighed into a glass reaction tube. MeOH (3 mL)
added, followed by acetophenone. The vessel was placed in a Biotage
Endeavour and flushed with nitrogen, then hydrogen gas. The
reaction was heated to 50.degree. C. under 30 bar (450 PSI) H.sub.2
for 16 hours and analysed by TLC and GC.
[0142] See Table 1 for the results of the hydrogenation
experiments.
Example 10
Hydrogenation of acetophenone with [(R,R)-Ts-teth-DPEN Ru Cl] and
[(S,S)-Ts-teth-DPEN Ru Cl]
[0143] Experimental Procedure: Ru catalyst (0.005 mol) weighed into
a glass reaction tube. The vials were placed in a Biotage Endeavour
and flushed with nitrogen. Acetophenone was added, followed by
MeOH. The reaction was purged with hydrogen gas, heated and
pressurised. The reaction was heated and pressurised with H.sub.2
for 16 hours and analysed by GC.
[0144] See Table 2 for the results of the hydrogenation of
acetophenone with [(R,R)-Ts-teth-DPEN Ru Cl]
[0145] See Table 3 for the results of the hydrogenation of
acetophenone with [(S,S)-Ts-teth-DPEN Ru Cl]
Example 11
Hydrogenation of Acetophenone
Comparative Experiments in MeOH
[0146] Experimental Procedure: Ru catalyst weighed into a glass
reaction tube. The vials were placed in a Biotage Endeavour and
flushed with nitrogen. Acetophenone was added, followed by MeOH
(total reaction volume: 4 mL). The reaction was purged with
hydrogen gas, heated and pressurised. The reaction was heated under
30 bar (435 psi) H.sub.2 for 16 hours and analysed by and GC.
[0147] See Table 4 for the results of the comparative
experiments.
[0148] As can be seen, the non-tethered catalyst is less active
than the tethered catalyst when the catalyst loading was reduced to
S/C 1000/1.
Example 12
Hydrogenation of Acetophenone with Tethered TsEn-Ru Catalyst
##STR00053##
[0150] See Table 5 for the results of the hydrogenation of
acetophenone with the tethered TsEn-Ru catalyst.
TABLE-US-00001 TABLE 1 Conver- Substrate/ AgX sion Ee Expt Catalyst
Catalyst (mol %) (%).sup.a (%).sup.a 1 Ts-DPEN Teth RuCl 100/1 --
70 94 2 Ts-DPEN Teth RuCl 100/1 AgOTf (2).sup.b 84 90 3 Ts-DPEN
Teth RuCl 100/1 AgPF.sub.6 (2) 16 87 4 Ts-DPEN Teth RuCl 100/1
AgBF.sub.4 (2) 69 92 5 Ts-DPEN Teth RuCl 200/1 AgOTf (1) 80 94 6
Ts-DPEN Teth RuCl 400/1 AgOTf (0.5) 63 92 7 Ts-DPEN Teth RuCl 100/1
TfOH (2) 24 90 8 Ms-DPEN Teth RuCl 100/1 -- 38 82 9 Ms-DPEN Teth
RuCl 100/1 AgOTf (2) 94 92 10 Ms-DPEN Teth RuCl 100/1 AgPF.sub.6
(2) 41 92 11 Ms-DPEN Teth RuCl 100/1 AgBF.sub.4 (2) 25 84
.sup.aDetermined by GC. .sup.b--OTf is trimethanesulfonate.
TABLE-US-00002 TABLE 2 hydrogenation of acetophenone with
[(R,R)-Ts-teth-DPEN Ru Cl] Scale Alcohol ee Expt. S/C Solv. [S]
Press. Temp. Time (%).sup.a (%).sup.a 12 200/1 MeOH 1 mmol [0.5M]
30 bar 50.degree. C. 16 h >99% .sup. 95% (R) 13 250/1 MeOH 1
mmol [0.4M] 30 bar 50.degree. C. 16 h >99% 94.5% (R) 14 500/1
MeOH 2 mmol [0.5M] 30 bar 50.degree. C. 16 h 67% 92.5% (R) 15 500/1
MeOH 2 mmol [0.5M] 30 bar 60.degree. C. 16 h >99% 94.5% (R) 16
500/1 MeOH 10 mmol [1M] 15 bar 60.degree. C. 24 h 97% 91.5% (R)
.sup.aDetermined by GC (ChromPack CP-Chirasil-Dex-CB 25 m .times.
0.25 mm .times. 0.25 .mu.m. 100.degree. C. for 10 min, then to
200.degree. C. @ 10.degree. C./min, 10 psi He flow, injector:
200.degree. C.; detector (FID): 210.degree. C.
TABLE-US-00003 TABLE 3 hydrogenation of acetophenone with
[(S,S)-Ts-teth-DPEN Ru Cl] Scale Alcohol ee Expt. S/C Solv. [S]
Press. Temp. Time (%).sup.a (%).sup.a 17 100/1 MeOH 2 mmol [0.5M]
30 bar 40.degree. C. 16 h 100% 94% (S) 18 250/1 MeOH 2 mmol [0.5M]
30 bar 50.degree. C. 16 h 100% 94% (S) 19 500/1 MeOH 2 mmol [0.5M]
30 bar 60.degree. C. 16 h 100% 93.5% (S).sup. 20 1000/1 MeOH 2 mmol
[0.5M] 30 bar 60.degree. C. 16 h 100% 93% (S) 21 2000/1 MeOH 4 mmol
[1M].sup. 30 bar 60.degree. C. 16 h 49% 93% (S) .sup.aDetermined by
GC (ChromPack CP-Chirasil-Dex-CB 25 m .times. 0.25 mm .times. 0.25
.mu.m. 100.degree. C. for 10 min, then to 200.degree. C. @
10.degree. C./min, 10 psi He flow, injector: 200.degree. C.;
detector (FID): 210.degree. C.
TABLE-US-00004 TABLE 4 hydrogenation of acetophenone: comparative
experiments in MeOH Scale Alcohol ee Expt. S/C Catalyst [S] Press.
Temp. Time (%).sup.a (%).sup.a 22 100/1 [(S,S)Ts-teth- 2 mmol
[0.5M] 30 bar 40.degree. C. 16 h >99% 94% (S) DPEN Ru Cl] 22
100/1 [(S,S)-TsDPEN 2 mmol [0.5M] 30 bar 40.degree. C. 16 h >99%
92% (S) (Comparative) Ru(p-cym)Cl] 23 500/1 [(S,S)Ts-teth- 2 mmol
[0.5M] 30 bar 60.degree. C. 16 h >99% 93.5% (S).sup. DPEN Ru Cl]
23 500/1 [(S,S)-TsDPEN 2 mmol [0.5M] 30 bar 60.degree. C. 16 h
>99% 93.5% (S).sup. (Comparative) Ru(p-cym)Cl] 24 1000/1
[(S,S)Ts-teth- 2 mmol [0.5M] 30 bar 60.degree. C. 16 h >99% 94%
(S) DPEN Ru Cl] 24 1000/1 [(S,S)-TsDPEN 2 mmol [0.5M] 30 bar
60.degree. C. 16 h 77% 93% (S) (Comparative) Ru(p-cym)Cl]
.sup.aDetermined by GC (ChromPack CP-Chirasil-Dex-CB 25 m .times.
0.25 mm .times. 0.25 .mu.m. 100.degree. C. for 10 min, then to
200.degree. C. @ 10.degree. C./min, 10 psi He flow, injector:
200.degree. C.; cetector (FID): 210.degree. C.
TABLE-US-00005 TABLE 5 Hydrogenation of acetophenone with Ru
catalyst A..sup.a S/C Temperature Expt. Catalyst (molar ratio)
(.degree. C.) Conv. to 2 (%) 25 [Ts-teth-EN Ru Cl] 100 30 100 26
[Ts-teth-EN Ru Cl] 250 40 100 27 [Ts-teth-EN Ru Cl] 1000 50 50
.sup.aReaction conditions: Endeavor catalyst screening system;
Catalyst, 1 (3.0 mmol), MeOI- (1.0 ml/mmol), 31 bar H.sub.2, 16 h.
.sup.bAnalysed by GC (Column: CP-Sil 5 CB, 30 m, 0.25 mm, 1
.mu.m).
* * * * *