U.S. patent application number 12/493043 was filed with the patent office on 2009-12-31 for sulphonylated diphenylethylenediamines, method for their preparation and use in transfer hydrogenation catalysis.
This patent application is currently assigned to BIAL - PORTELA & CA, .S.A.. Invention is credited to Beatriz Dominguez, Gabriela Alexandra Grasa, Jonathan Alan Medlock, Antonio Zanotti-Gerosa.
Application Number | 20090326274 12/493043 |
Document ID | / |
Family ID | 33548419 |
Filed Date | 2009-12-31 |
United States Patent
Application |
20090326274 |
Kind Code |
A1 |
Dominguez; Beatriz ; et
al. |
December 31, 2009 |
Sulphonylated Diphenylethylenediamines, Method for Their
Preparation and Use in Transfer Hydrogenation Catalysis
Abstract
A diamine of formula (I) is described in which A is hydrogen or
a saturated or unsaturated C1-C20 alkyl group or an aryl group; B
is a substituted or unsubstituted C1-C20 alkyl, cycloalkyl,
alkaryl, alkaryl or aryl group or an alkylamino group and at least
one of X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z is a C1-C10 alkyl,
cycloalkyl, alkaryl, aralkyl or alkoxy substituting group. The
chiral diamine may be used to prepare catalysts suitable for use in
transfer hydrogenation reactions. ##STR00001##
Inventors: |
Dominguez; Beatriz;
(Suffolk, GB) ; Zanotti-Gerosa; Antonio;
(Cambridge, GB) ; Grasa; Gabriela Alexandra;
(Mantua, NJ) ; Medlock; Jonathan Alan; (Cambridge,
GB) |
Correspondence
Address: |
CONLEY ROSE, P.C.
5601 GRANITE PARKWAY, SUITE 750
PLANO
TX
75024
US
|
Assignee: |
BIAL - PORTELA & CA,
.S.A.
S. Mamede do Coronado
PT
|
Family ID: |
33548419 |
Appl. No.: |
12/493043 |
Filed: |
June 26, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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11719478 |
Jul 17, 2007 |
|
|
|
PCT/GB2005/050190 |
Nov 1, 2005 |
|
|
|
12493043 |
|
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|
Current U.S.
Class: |
568/309 ;
502/167; 564/372 |
Current CPC
Class: |
B01J 2531/821 20130101;
B01J 2231/643 20130101; B01J 2531/827 20130101; C07C 29/143
20130101; B01J 31/1805 20130101; C07B 2200/07 20130101; C07C 29/143
20130101; B01J 2531/828 20130101; C07C 2602/10 20170501; C07C
311/18 20130101; B01J 2531/822 20130101; B01J 2531/842 20130101;
B01J 2531/847 20130101; C07C 29/143 20130101; B01J 2531/845
20130101; C07C 29/143 20130101; B01J 2531/824 20130101; C07C 33/46
20130101; C07C 35/32 20130101; C07C 33/22 20130101 |
Class at
Publication: |
568/309 ;
564/372; 502/167 |
International
Class: |
C07C 45/61 20060101
C07C045/61; C07C 211/01 20060101 C07C211/01; B01J 31/02 20060101
B01J031/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 17, 2004 |
GB |
GB 0425320.9 |
Claims
1. A diamine of formula (I) ##STR00018## in which A is hydrogen or
a saturated or unsaturated C1-C20 alkyl group or an aryl group; B
is a substituted or unsubstituted C1-C20 alkyl, cycloalkyl,
alkaryl, alkaryl or aryl group or an alkylamino group and at least
one of X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z is a C1-C10 alkyl,
cycloalkyl, alkaryl, aralkyl or alkoxy substituting group.
2. The diamine according to claim 1 wherein A is hydrogen.
3. The diamine according to claim 1 wherein B is a substituted or
unsubstituted aryl group.
4. The diamine according to claim 1 wherein X.sup.1, X.sup.2,
Y.sup.1 and Y.sup.2 are hydrogen and Z is a C1-C10 alkyl, alkaryl,
cycloalkyl, aralkyl or alkoxy substituting group.
5. The diamine according to claim 4 wherein Z is methyl.
6. The diamine according to claim 4 wherein Z is methoxy.
7. The diamine according to claim 1 wherein the diamine is
homochiral.
8. The method for preparing a diamine of formula (I) as claimed in
claim 1 comprising the steps of a) forming a substituted
spiroimidazole from a substituted diketone of formula (II), b)
reducing the substituted spiroimidazole to form a substituted
diamine, c) optionally resolving the substituted diamine to an
enantiomerically enriched form, and d) sulphonylating the
substituted diamine. ##STR00019##
9. A catalyst comprising the reaction product of a diamine of
formula (I) as claimed in claim 1 and a compound of a metal
selected from the list consisting of Ru, Rh, Ir, Co, Ni, Fe, Pd or
Pt.
10. The catalyst according to claim 9 wherein the metal compound is
[MX.sub.2(arene)].sub.2 where M=Rh or Ru and X=halogen.
11. A method comprising contacting the catalyst according to claim
9 with a compound and performing a transfer hydrogenation
reaction.
12. The method according to claim 11 wherein the compound is a
cyclic ketone.
13. The diamine according to claim 2 wherein B is a substituted or
unsubstituted aryl group.
14. The diamine according to claim 2 wherein X.sup.1, X.sup.2,
Y.sup.1, and Y.sup.2 are hydrogen and Z is a C1-C10 alkyl, alkaryl,
cycloalkyl, aralkyl or alkoxy substituting group.
15. The diamine according to claim 3 wherein X.sup.1, X.sup.2,
Y.sup.1 and Y.sup.2 are hydrogen and Z is a C1-C10 alkyl, alkaryl,
cycloalkyl, aralkyl or alkoxy substituting group.
16. The diamine according to claim 13 wherein X.sup.1, X.sup.2,
Y.sup.1 and Y.sup.2 are hydrogen and Z is a C1-C10 alkyl, alkaryl,
cycloalkyl, aralkyl or alkoxy substituting group.
17. The diamine according to claim 14 wherein Z is methyl or
methoxy.
18. The diamine according to claim 15 wherein Z is methyl or
methoxy.
19. The diamine according to claim 16 wherein Z is methyl or
methoxy.
20. The diamine according to claim 19 wherein the diamine is
homochiral.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation application claiming priority to U.S.
patent application Ser. No. 11/719,478, filed Jul. 17, 2007, now
published as U.S. Patent Publication 2008/0081930 A1, and entitled
"Sulphonylated Diphenylethylenediamines, Method for their
Preparation and Use in Transfer Hydrogenation Catalysis." The
parent application, U.S. patent application Ser. No. 11/719,478, is
a filing under 35 U.S.C. 371 of International Application No.
PCT/GB2005/050190 filed Nov. 1, 2005, entitled "Sulphonylated
Diphenylethylenediamines, Method for their Preparation and Use in
Transfer Hydrogenation Catalysis," claiming priority of United
Kingdom Patent Application No. 0425320.9 filed Nov. 17, 2004. The
above identified applications are incorporated by reference herein
in their entirety.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] Not Applicable.
REFERENCE TO A MICROFICHE APPENDIX
[0003] Not Applicable.
BACKGROUND
[0004] This invention relates to diamines and in particular to
substituted diphenylethylenediamines and catalysts derived
therefrom. Such catalysts are useful for accelerating asymmetric
hydrogenation reactions whose products are useful, for example, as
chemical intermediates or reagents for use in the production of
fine chemicals or pharmaceutical intermediates.
[0005] Catalytic asymmetric hydrogenation involves the activation
of molecular hydrogen with chiral metal complexes. However, organic
molecules can also be applied as the hydrogen donor in the presence
of a suitable chiral catalyst in a process known as transfer
hydrogenation. A hydrogen donor such as isopropanol or formic acid
is conventionally used with catalysts of the type [(sulphonylated
diamine)RuCI(arene)] for the reduction of carbonyl groups. This
technology provides a powerful complement to catalytic asymmetric
hydrogenation. Transfer hydrogenation, in fact, is particularly
suitable for the asymmetric reduction of ketones that are difficult
substrates for hydrogenation, such as acetylenic ketones and cyclic
ketones.
[0006] Heretofore the sulphonylated diamine component of the
transfer hydrogenation catalysts has been limited to sulphonylated
diphenylethylenediamine (Dpen) and cycloalkyl-1,2-diamines such as
1,2-cyclohexane. For example transfer hydrogenation has been
applied using [(tosyl-dpen)RuCI(arene)] catalysts to pharmaceutical
products such as 10-hydroxy-dihydro-dibenz-[b,f]-azepines (see WO
2004/031155).
[0007] The sulphonylated diamine components used heretofore, while
useful, are not equally effective across the range of desirable
substrates. Thus, there is a need to expand the range of diamines
suitable for use in transfer hydrogenation catalysts that provide
catalysts of increased activity, selectivity or stability. We have
recognised that, by introducing one or more substituting groups
into the phenyl rings of diphenylethylenediamines and by variation
of the sulphonate properties, the steric and electronic properties
of the diamine component may be usefully adapted.
SUMMARY
[0008] Accordingly the present invention provides a diamine of
formula (I)
##STR00002##
in which A is hydrogen or a saturated or unsaturated C1-C20 alkyl
group or an aryl group; B is a substituted or unsubstituted C1-C20
alkyl, cycloalkyl, alkaryl, alkaryl or aryl group or an alkylamino
group and at least one of X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z
is a C1-C10 alkyl, cycloalkyl, alkaryl, aralkyl or alkoxy
substituting group.
[0009] The invention further provides a method for preparing a
diamine of formula (I) comprising the steps of forming a
substituted spiroimidazole from a substituted diketone of formula
(II), where X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 and Z are as above,
reducing the substituted spiroimidazole to form a substituted
diamine, optionally resolving the substituted diamine to an
enantiomerically enriched form, and sulphonylating the substituted
diamine.
##STR00003##
[0010] The invention also provides a catalyst comprising the
reaction product of a diamine of formula (I) and a suitable
compound of a catalytically active metal.
DETAILED DESCRIPTION
[0011] In formula (I), A is hydrogen or a saturated or unsaturated
C1-C20 alkyl group or an aryl group. The C1-C20 alkyl groups may be
branched or linear, for example may be methyl, ethyl, n-propyl,
iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl,
hexyl, cyclohexyl, ethyl-hexyl, iso-octyl, n-nonyl, n-decyl,
iso-decyl, tridecyl, octadecyl and isooctadecyl. The aryl group may
be an unsubstituted or substituted phenyl, naphthyl or
anthracylphenyl. Suitable substituting groups are hydroxy, halide
(e.g. F, Cl, Br, I), C1-C20 alkoxy, amino, amido, nitrile and
thiol. Preferably A is hydrogen, methyl ethyl, propyl or phenyl.
Most preferably A is hydrogen.
[0012] In formula (I), B is introduced by sulphonylation of the
optionally enantiomerically enriched substituted diamine. A wide
range of sulphonylation compounds may be used to alter the
properties of the sulphonylated diamine of formula (I).
Accordingly, B may be a substituted or unsubstituted C1-C20 alkyl,
cycloalkyl, alkaryl, alkaryl or aryl group, for example as
described above, or an alkylamino group. By "alkylamino" we mean
that B may be of formula --NR'.sub.12, where R' is e.g. methyl,
cyclohexyl or isopropyl or the nitrogen forms part of an alkyl ring
structure. Fluoroalkyl or fluoroaryl groups may be used, for
example B may be p-CF.sub.3--C.sub.6H.sub.4, C.sub.6F.sub.5 or
CF.sub.2CF.sub.2CF.sub.2CF.sub.3 or CF.sub.3. Preferably B is an
aryl group. The aryl group may be an unsubstituted or substituted
phenyl, naphthyl or anthracylphenyl or heteroaryl compound such as
pyridyl. Suitable substituting groups are C1-C20 alkyl as described
above, trifluoromethyl, hydroxyl, halide (e.g. F, Cl, Br, I),
C1-C20 alkoxy (especially methoxy), amino, amido, nitrile, nitro
and thiol. Hence B may be for example o-Nitrophenyl, p-nitrophenyl,
trichlorophenyl, trimethoxyphenyl, triisopropylphenyl,
o-aminophenyl, benzyl (--CH.sub.2C.sub.6H.sub.5),
2-phenylethyl(C.sub.2H.sub.4C.sub.6H.sub.5),
phenyl(C.sub.6H.sub.5), tolyl(p-CH.sub.3--C.sub.6H.sub.4),
xylyl((CH.sub.3).sub.2C.sub.6H.sub.3),
anisyl(CH.sub.3O--C.sub.6H.sub.4), naphthyl or dansyl
(5-dimethylamino-1-naphthyl). Preferably, B is tolyl and the
sulphonylation is performed with tosyl chloride (p-toluenesulphonyl
chloride).
[0013] The diamine of the present invention has two chiral centres,
each bearing a phenyl ring having at least one substituting group
X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z. The substituting group
X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z is a C1-C10 alkyl,
cycloalkyl, alkaryl, aralkyl or alkoxy group. It will be understood
that in order to satisfy the valency of the carbon atoms in the
phenyl rings to which X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z is
bound, where X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z is not a
C1-C10 alkyl, cycloalkyl, alkaryl, aralkyl or alkoxy substituting
group, X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z will be a hydrogen
atom.
[0014] Thus at least one of X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 or Z
may independently be a C1-C10 alkyl group such as methyl,
trifluoromethyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,
sec-butyl, tert-butyl, pentyl, cyclopentyl, hexyl, cyclohexyl,
ethyl-hexyl, iso-octyl, n-nonyl, n-decyl or iso-decyl; an alkaryl
group such as benzyl or ethylphenyl; an aryl group such as phenyl,
tolyl or xylyl; or a C1-C10 alkoxy group such as methoxy, ethoxy,
n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy,
tert-butoxy, cyclopentoxy, pentoxy, hexoxy, cyclohexoxy,
ethyl-hexoxy, iso-octoxy, n-nonoxy, n-decoxy or iso-decoxy.
[0015] Preferably each phenyl ring has one or more substituents.
The phenyl rings may be substituted in one or more positions, i.e.
the rings may be mono-, di-, tri-, tetra- or penta-substituted. The
substituting group on the phenyl ring may be in the ortho (X.sup.1,
X.sup.2), meta (Y.sup.1, Y.sup.2) or para (Z) position. However,
when the substituent is at the mete-position of the phenyl ring it
minimizes the electronic effects on the amino group, which may
facilitate the synthesis of the resulting diamine. Thus one
embodiment the substituted diamine is a 1,2-di-(meta-substituted
phenyl)ethylenediamine. Where more that one substituting group is
present they are preferably the same. For example in one
embodiment, Y.sup.1, Y.sup.2 may be hydrogen and X.sup.1, X.sup.2
and Z are preferably the same alkyl, cycloalkyl, alkaryl, aralkyl
or alkoxy substituting group. In an alternative embodiment X.sup.1,
X.sup.2 and Z may be hydrogen and Y.sup.1 and Y.sup.2 are
preferably the same alkyl, cycloalkyl, alkaryl, aralkyl or alkoxy
substituting group. In a preferred embodiment X.sup.1, X.sup.2,
Y.sup.1 and Y.sup.2 are hydrogen and Z is a C1-C10 alkyl,
cycloalkyl, alkaryl, aralkyl or alkoxy substituting group. In a
particularly preferred embodiment, X.sup.1, X.sup.2, Y.sup.1 and
Y.sup.2 are hydrogen and Z is methyl. In another particularly
preferred embodiment, X.sup.1, X.sup.2, Y.sup.1 and Y.sup.2 are
hydrogen and Z is methoxy.
[0016] The substituted diamines of the present invention may be
conveniently made from substituted diketones of formula (II) where
X.sup.1, X.sup.2, Y.sup.1, Y.sup.2 and Z are as above, via a
spiro-imidazole, which is then reduced to a diamine and
sulphonylated.
##STR00004##
[0017] Substituted diketones (benzils) of formula (II) can be
obtained commercially or can be readily prepared from substituted
benzaldehydes of formula (III) where X.sup.1, X.sup.2, Y.sup.1,
Y.sup.2 and Z are as above, by benzoin condensation followed by
oxidation of the resulting substituted benzoin. Substituted
benzaldehydes are commercially available or may be synthesised
using known substitution reactions. Benzoin condensation reactions
are well known and are typically performed by reacting a
substituted benzaldehyde in a suitable solvent in the presence of
sodium cyanide (see for example Ide et al, Org. React. 1948, 4,
269-304). The oxidation of the substituted benzoin to the diketone
may readily be performed using copper acetate and ammonium nitrate
(for example see Weiss et al, J. Am. Chem. Soc, 1948, 3666).
[0018] The spiroimidazole may be formed by treating the substituted
diketone of formula (II) with acetic acid, ammonium acetate and
cyclohexanone and heating to reflux. The reduction of the resulting
substituted benzoin to the substituted diamine may be performed by
mixing a solution of the spiroimidazole with lithium wire and
liquid ammonia at below -60.degree. C., treating the mixture with
ethanol and ammonium chloride and allowing the mixture to warm to
room temperature. The substituted diamine is sulphonylated to
provide the substituted diamines of the present invention.
[0019] The substituted diamine may then be sulphonylated by
treating the substituted diamine in a suitable solvent with the
desired sulphonyl chloride, i.e. Cl--SO.sub.2--B, and a base such
as triethylamine.
[0020] The nitrogen atoms in the substituted diamine are bonded to
chiral centres and so the substituted diamine is chiral. The
diamine may be homochiral, i.e. (R,R) or (S,S), or have one (R) and
one (S) centre. Preferably the diamine is homochiral. Whereas the
diamine may be used as a racemic mixture, the amine is preferably
enantiomerically enriched. The resolution of the chiral substituted
diamine may be performed using a chiral acid or by any other method
known to those skilled in the art. Whereas the resolution may be
performed on the sulphonylated diamine of formula (I), preferably
the resolution is performed on the substituted diamine before the
sulphonylation step. For example, the substituted diamine may be
treated with a chiral carboxylic acid such as ditoluoyltartaric
acid or dibenzoyltartaric acid in a suitable solvent. The resolved
substituted diamine preferably has an enantiomeric excess (ee
%)>70%, more preferably >90%.
[0021] Hence this route provides an efficient and cost effective
method to prepare enantiomerically enriched substituted
1,2-diphenylethylenediamines. The route is depicted below for a
preferred example where A, X.sup.1, X.sup.2, Y.sup.1 and Y.sup.2
are hydrogen, B is e.g. p-CH.sub.3--C.sub.6H.sub.5 and Z is a
C1-C10 alkyl, cycloalkyl, alkaryl, aralkyl or alkoxy substituting
group;
##STR00005##
[0022] Catalysts suitable for performing asymmetric transfer
hydrogenation reactions may be prepared by reacting the substituted
sulphonylated diamines of the present invention with a suitable
compound of a catalytically active metal. The metal compound is
preferably a compound of metals selected from the list consisting
of Ru, Rh, Ir, Co, Ni, Fe, Pd or Pt. Preferred compounds are
compounds of Ru, Rh and Ir, particularly Ru or Rh. Suitable Ru or
Rh compounds are [MX.sub.2(arene)].sub.2 compounds where M=Rh or Ru
and X=halogen, more preferably [RuCl.sub.2(arene)].sub.2. Arene
compounds are any suitable aromatic molecule, and include benzenes
and cyclopentadienes, e.g. benzene, pentamethylcylcopentadiene and
para-cymene (4-isopropyltoluene). Particularly suitable metal
compounds for preparing hydrogenation catalysts include
[RhCp*Cl.sub.2].sub.2 (where Cp* is CpMe.sub.5),
[RuCl.sub.2(benzene)].sub.2 and [RuCl.sub.2(p-cymene)].sub.2.
[0023] The catalysts may be prepared by simply combining the
diamine and the metal compound in a suitable solvent under mild
conditions (e.g. 0 to 80.degree. C. at about atmospheric pressure).
Suitable solvents include hydrocarbons, aromatic hydrocarbons,
chlorinated hydrocarbons, esters, alcohols, ethers, DMF and the
like. If desired, the reaction may be performed ex-situ and the
resulting catalyst isolated, e.g. by removal of the solvent under
vacuum. Alternatively, the catalyst may be formed in-situ, i.e. in
the presence of the substrate to be hydrogenated and the hydrogen
source, again by combining the metal compound and diamine in the
reactants, which may be diluted with a suitable solvent.
[0024] The chiral catalysts of the present invention may be applied
to transfer hydrogenation reactions. Typically, a carbonyl compound
or imine, hydrogen source, base and solvent are mixed in the
presence of the catalyst, which may be formed in-situ. Preferred
hydrogen sources are isopropanol or formic acid (or formates). The
catalysts may be used to reduce a wide variety of carbonyl
compounds to the corresponding chiral alcohols and imines to the
corresponding chiral amines. The reactions may be carried out under
typical transfer hydrogenation conditions and in a variety of
suitable solvents known to those skilled in the art. For example,
the reaction may be performed in an ether, ester or
dimethylformamide (DMF) at 0-75.degree. C. Water may be present.
With formic acid, a base such as triethylamine, DBU or other
tertiary amine is preferably used. With isopropanol, the base is
preferably t-BuOK, KOH or iPrOK.
[0025] The invention is illustrated by the following examples.
Example 1
Preparation of Diamine Ligands
[0026] (I) Spiro-Imidazole Formation (1 to 2)
##STR00006##
[0027] a) Z=Methyl(CH.sub.3): Acetic acid (70 ml) was added to a
flask containing the commercially available diketone 1a
(dimethylbenzyl 11.9 g, 50 mmol) and ammonium acetate (27 g, 350
mmol). Cyclohexanone (5.3 ml, 51.5 mmol) was added and the reaction
mixture was heated at reflux for 1-4 hours. After cooling to room
temperature, the mixture was poured onto water and left overnight
to crystallize. The crystals were collected by filtration and dried
under reduced pressure. Recrystallization was from ethyl
acetate/hexane and gave 8.22 and 3.32 g of 2a in 2 crops. Total
yield 11.54 g, 73%.
[0028] b) Z=Methoxy(CH.sub.3O): Acetic acid (100 ml) was added to a
flask containing the commercially available diketone 1b
(dimethoxybenzil, 18.9 g, 70 mmol) and ammonium acetate (37.7 g,
490 mmol). Cyclohexanone (7.45 ml, 72.1 mmol) was added and the
reaction mixture was heated at reflux for 1-4 hours. After cooling
to room temperature, the mixture was poured onto water and left
overnight to crystallize. The crystals were collected by filtration
and dried under reduced pressure. Yield of imidazole 2b, 19.22 g,
79%. Further purification can be achieved by crystallisation from
ethyl acetate/hexane.
[0029] (II) Reduction (2 to 3)
##STR00007##
[0030] a) Z=Methyl(CH.sub.3): Ammonia gas was slowly condensed into
a solution of the spiro-imidazole 2a (6.95 g, 22 mmol) in anhydrous
THF (50 ml) at -78.degree. C. under argon. Once the volume of the
reaction mixture has approximately doubled, the gas flow was
stopped. Lithium wire (0.62 g, 88 mmol) was added slowly ensuring
that the temperature did not exceed -60.degree. C. After stirring
for 30-60 minutes ethanol (2.6 ml) was added, and 30-60 minutes
later ammonium chloride (6.2 g) was added. The mixture was allowed
to warm to room temperature and water (about 100 ml) and MTBE
(about 100 ml) were added. The layers were separated and the
aqueous layer was extracted twice with about 100 ml MTBE. The
combined organic layers were washed with brine and evaporated under
vacuum. The resulting oil was dissolved in MTBE and 10% HCl was
added (2-3 eq.). The biphasic mixture was stirred for 30-90 minutes
and was diluted with water. The layers were separated and the
organic layer was extracted with water. The combined aqueous layers
were washed with dichloromethane and then neutralised with aqueous
KOH until the pH>10. The crude diamine was extracted into
dichloromethane (3 times). The combined organic extracts dried
(Na.sub.2SO.sub.4) and evaporated to give an oil or solid. Yield of
racemic diamine 3a as a 19:1 mixture of diastereoisomers, 4.96 g,
94%. Further purification can be achieved by crystallisation from
ethyl acetate/hexane.
[0031] b) Z=Methoxy(CH.sub.3): Ammonia gas was slowly condensed
into a solution of the spiro-imidazole 2b (6.96 g, 20 mmol) in
anhydrous THF (40 ml) at -78.degree. C. under argon. Once the
volume of the reaction mixture has approximately doubled, the gas
flow was stopped. Lithium wire (0.56 g, 80 mmol) was added slowly
ensuring that the temperature did not exceed -60.degree. C. After
stirring for 30-60 minutes ethanol (2.4 ml) was added, and 30-60
minutes later ammonium chloride (2.8 g) was added. The mixture was
allowed to warm to room temperature and water (about 100 ml) and
MTBE (about 100 ml) were added. The layers were separated and the
aqueous layer was extracted twice with about 100 ml MTBE. The
combined organic layers were washed with brine and evaporated under
vacuum: The resulting oil was dissolved in MTBE and 10% HCl was
added (2-3 eq.). The biphasic mixture was stirred for 30-90 minutes
and was diluted with water. The layers were separated and the
organic layer was extracted with water. The combined aqueous layers
were washed with dichloromethane and then neutralised with aqueous
KOH until the pH>10. The crude diamine was extracted into
dichloromethane (3 times). The combined organic extracts dried
(Na.sub.2SO.sub.4) and evaporated to give an oil or solid. Yield of
racemic diamine 3b as a 19:1 mixture of diastereoisomers, 4.69 g,
86%. Further purification can be achieved by crystallisation from
ethyl acetate/hexane.
[0032] (III) Chiral Resolution of Diamines
##STR00008##
[0033] a) Resolution of diamine 3a. Formation of a salt with
ditoluoyltartaric acid in methanol and crystallisation from
methanol initially gave (R,R) 4a in 94% ee. This can be increased
to >99% with one further crystallisation.
[0034] b) Resolution of diamine 3b. Formation of a salt with
ditoluoyltartaric acid in methanol and crystallisation from
methanol initially gave (S,S) 4b in 74% ee. It should be possible
to increase the ee by further crystallisation. Formation of a salt
with dibenzoyltartaric acid in methanol and crystallisation from
methanol initially gave 4b in 98% ee.
[0035] (IV) Synthesis of Mono-Sulfonylated Diamines
##STR00009##
[0036] a) Tosyl-5a (Z=CH.sub.3, B=4-CH.sub.3--C.sub.6H.sub.4).
Triethylamine (210 .mu.l, 1.5 mmol) was added to a solution of the
diamine 4a (180 mg, 0.75 mmol) in anhydrous dichloromethane (8 ml)
and the solution was cooled to 0.degree. C. A solution of the tosyl
chloride (p-toluenesulphonyl chloride, 148 mg, 0.77 mmol) in
anhydrous dichloromethane (4 ml) was added slowly. The mixture was
stirred at 0.degree. C. for 30-120 minutes and allowed to warm to
room temperature over 1-24 hours. Water was added and the layers
separated. The aqueous layer was extracted twice with
dichloromethane and the combined organic layers were washed with
brine, dried (Na.sub.2SO.sub.4) and evaporated. The crude
mono-sulfonated diamine could be purified by column chromatography.
Purification by column chromatography gave 270 mg (91%) of Ts-5a as
a white solid.
[0037] b) Tosyl-5b (Z=OCH.sub.3, B=4-CH.sub.3--C.sub.6H.sub.4).
Triethylamine (190 .mu.l, 1.3 mmol) was added to a solution of the
diamine 4b (175 mg, 0.65 mmol) in anhydrous dichloromethane (8 ml)
and the solution was cooled to 0.degree. C. A solution of the tosyl
chloride (p-toluenesulphonyl chloride, 1428 mg, 0.67 mmol) in
anhydrous dichloromethane (5 ml) was added slowly. The mixture was
stirred at 0.degree. C. for 30-120 minutes and allowed to warm to
room temperature over 1-24 hours. Water was added and the layers
separated. The aqueous layer was extracted twice with
dichloromethane and the combined organic layers were washed with
brine, dried (Na.sub.2SO.sub.4) and evaporated. The crude
mono-sulfonylated diamine could be purified by column
chromatography. Purification by column chromatography gave 270 mg
(91%) of Ts-5b as a white solid.
Example 2
Preparation of Transfer Hydrogenation Catalyst
[0038] A mixture of [Ru(p-cymene)Cl.sub.2].sub.2 (0.5 eq.),
triethylamine (2 eq.), mono-sulfonated diamine (1 eq.) 5b in
anhydrous isopropanol was heated at 70-90.degree. C. for 1-4 hours
under an inert atmosphere. After cooling to room temperature the
solution was concentrated under reduced pressure and the orange
solid collected by filtration. The solid was washed with degassed
water and a small amount of methanol then further dried under
reduced pressure. Further purification can be performed by
precipitation/crystallisation from hot methanol.
Example 3
Use of Mono-Sulfonated Diamines 5 for Asymmetric Transfer
Hydrogenation Test of Transfer Hydrogenation Catalysts on a Mixture
of Ketones
[0039] Transfer hydrogenation catalysts bearing diamines 5 were
prepared in situ and tested on pre-formed mixture of ketones in
DMF. [Ru(p-cymene)Cl.sub.2].sub.2 (0.0025 mmol) or
[RhCp*Cl.sub.2].sub.2 (0.0025 mmol) mono-sulfonated diamine (0.0055
mmol) 5 in anhydrous DMF (2 mL) were heated at 40.degree. C. for 10
minutes under inert atmosphere (argon). A solution of five ketones
(0.5 mL, 1 mmol in total, 0.2 mmol each) in DMF was added (S/C 40
with respect to each substrate), followed by 0.6 mL of formic
acid/trietylamine 1/1 mixture and 1 mL of DMF. The reaction was
heated overnight (20 hrs) at 60.degree. C. and analysed by CG
(ChiraDex CB column, 10 psi He, 100.degree. C. for 12 min, then to
180.degree. C. at 1.5.degree. C./min, then to 200.degree. C. at
5.degree. C./min).
[0040] For reference, the diamines tested were as follows:
TABLE-US-00001 ##STR00010## 5b, (S,S)-TsDAEN ##STR00011##
5a,(R,R)-TsDTEN ##STR00012## (S,S)-TsDPEN Ketone ##STR00013##
##STR00014## ##STR00015## ##STR00016## ##STR00017##
(S,S)-Ts-DAEN-Ru >95% conv 33% conv >95% conv >95% conv
>95% conv S/C 100/1 55% ee 40% ee 96% ee 29% ee 92% ee
(S,S)-Ts-DAEN-Ru >95% conv 10% conv >95% conv >95% conv
>95% conv S/C 200/1 57% ee 42% ee 98% ee 27% ee 94% ee
(R,R)-Ts-DTEN-Ru >95% conv 11% conv >95% conv >95% conv
>95% conv S/C 200/1 53% ee 35% ee 96% ee 28% ee 91% ee
(S,S)-Ts-DAEN-Ru >95% conv 48% conv 51% conv >95% conv 47%
conv S/C 100/1 72% ee 13% ee 98% ee 13% ee 90% ee conv = conversion
ee enantlomeric excess
[0041] The results show particularly high conversions and ee's are
obtained for the cyclic ketone, i.e. where the ketone is part of a
ring structure, such as .alpha.-tetralone.
Example 4
Activity of TsDAEN vs. TsDPEN
[0042] The activity of (S,S)-TsDAEN vs the conventional
(S,S)-TsDPEN in asymmetric transfer hydrogenation was tested using
.alpha.-tetralone as a substrate. The reaction was performed on a
15 mmol scale, at S/C 500/1, using [RUCl.sub.2(p-cymene)].sub.2 as
metal precursor and DMF as solvent at 60.degree. C. One equivalent
of triethylammonium formate was added at the beginning of the
reaction and more HCOOH was added during the course of the reaction
to maintain the pH at 8.2. The results shown below indicate that
(S,S)-TsDAEN is more active than (S,S)-TsDPEN.
TABLE-US-00002 Diamine Ligand Time (h) Conversion (%) e.e. (%)
Example 4 (S,S)-TsDAEN 1.5 36 98 5 71 22 90 Comparative
(S,S)-TsDPEN 1 11 98 Example 2 25 3 31 4 36 6 45 22 70
* * * * *