Catalytic racemisation of chiral amines and application in dynamic kinetic resolution

Article abstract of DOI:10.1021/op060233w

A mild and efficient procedure for the racemisation of optically active amines has been developed and applied to the dynamic kinetic resolution (DKR) of a racemic amine. Pentamethylcyclopentadienyliridium (III) iodide dimer dissolved in a convenient solvent is the precatalyst that reacts in situ with primary, secondary, or tertiary amines to form what we have named a SCRAM catalyst. This is able to dehydrogenate a substrate amine to form an imine, which, depending upon the reaction conditions, is then reduced back to the amine. When an optically active amine is mixed with the iridium precatalyst, racemisation is observed. The SCRAM catalyst is used under mild conditions compatible with suitable enzymes and acyl donors, and thus the DKR of an amine has been effected, giving significantly higher yield than if the enzyme alone was used. A mixed carbonate was identified as the optimal acyl donor, giving a carbamate product that is readily removed by acidic hydrolysis.

Full text of DOI:10.1021/op060233w

Organic Process Research & Development 2007, 11, 642−648
Technical Notes
Catalytic Racemisation of Chiral Amines and Application in Dynamic Kinetic
Resolution
A. John Blacker,*,† Matthew J. Stirling,‡ and Michael I. Page‡
NPIL Pharmaceuticals, Research and DeVelopment, Leeds Road, P.O. Box 521, Huddersfield HD1 9GA, United Kingdom,
and UniVersity of Huddersfield, Department of Chemical and Biological Sciences, Huddersfield HD1 9GA,
United Kingdom
Abstract:
of process; the difficulty in achieving a consistent and
economic process that gives a product with very low catalyst
contamination; less than desired optical purity of the products
which often then require a “polishing” crystallization with
attendant loss of yield. The most common method for
manufacturing optically active amines is still by diastereo-
meric crystallization.5,6 This provides a simple, robust process
that gives a product of consistently high quality. The main
disadvantage is the low (less than 50%) yield, which is
particularly problematic if the optical resolution is carried
out on expensive or high-volume products. Whilst resolutions
are simple, it is less widely recognized that they are often
poorly productive and operationally expensive, a result of
the number and length of processing steps and isolations.
Recycling of the undesired enantiomer may be possible in
some cases if the pKa of the proton at the chiral centre is
low or can be lowered for example by formation of a Schiff
base. Most optically active amines are not amenable to this
type of racemisation; consequently, many drugs are manu-
factured, often accompanied with large waste streams of the
unwanted isomer(s).
A mild and efficient procedure for the racemisation of optically
active amines has been developed and applied to the dynamic
kinetic resolution (DKR) of a racemic amine. Pentamethylcy-
clopentadienyliridium (III) iodide dimer dissolved in a conve-
nient solvent is the precatalyst that reacts in situ with primary,
secondary, or tertiary amines to form what we have named a
SCRAM catalyst. This is able to dehydrogenate a substrate
amine to form an imine, which, depending upon the reaction
conditions, is then reduced back to the amine. When an optically
active amine is mixed with the iridium precatalyst, racemisation
is observed. The SCRAM catalyst is used under mild conditions
compatible with suitable enzymes and acyl donors, and thus
the DKR of an amine has been effected, giving significantly
higher yield than if the enzyme alone was used. A mixed
carbonate was identified as the optimal acyl donor, giving a
carbamate product that is readily removed by acidic hydrolysis.
Introduction
It is estimated that about 20% of drugs contain at least
one amine chiral centre, so there is an enormous demand
for a variety of methods for the synthesis of optically active
amines. These include manipulation of optically active
alcohols, amino acids, and amines from the chiral pool,1 use
of chiral auxiliaries to induce asymmetry,2 and catalytic
asymmetric synthesis using bio- or chemocatalysts.3 With
some notable exceptions, the catalytic asymmetric synthesis
of amines in high optical purity has rarely been achieved on
a commercial production scale.4 Reasons for this include the
following: insufficiently advanced technology and the length
of time and level of resource required to develop this type
Whilst the efficient racemisation of optically active
alcohols has now been reported with a variety of different
catalysts,7-10 there is little precedent for the racemisation of
homochiral amines. Ba¨ckvall et al.11-13 have reported the
catalytic racemisation of amines using the Shvo¨ and related
catalysts. Unfortunately, from an industrial perspective the
catalyst turnover is low, making the process not economical;
moreover, the high temperatures required for racemisation
(5) Fogassy, E.; Nogradi, M.; Kozma, D.; Egri, G.; Palovics, E.; Kiss, V. Org.
Biomol. Chem. 2006, 4 (16), 3011-3030.
(6) Sheldon, R. A. J. Chem. Technol. Biotechnol. 1996, 67 (1), 1-14.
(7) Koh, J. H.; Jeong, H. M.; Park, J. Tetrahedron Lett. 1998, 39 (31), 5545-
5548.
* To whom correspondence should be addressed. Fax: +44 1484 433301.
E-mail: john.blacker@NPILpharma.co.uk.
(8) Csjernyik, G.; Bogar, K.; Backvall, J. E. Tetrahedron Lett. 2004, 45 (36),
6799-6802.
(9) Ito, M.; Osaku, A.; Kitahara, S.; Hirakawa, M.; Kariya, T. Tetrahedron
Lett. 2003, 44 (40), 7521-7523.
† NPIL Pharmaceuticals.
‡ University of Huddersfield.
(1) Coppola, G. M.; Schuster, H. F. Asymmetric Synthesis. Construction of
Chiral Molecules Using Amino Acids; Wiley-Interscience: New York, 1987.
(2) Procter, G. Asymmetric Synthesis; Oxford University Press: Oxford, 1996.
(3) Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds. ComprehensiVe Asymmetric
Catalysis; Springer: Berlin; London, 1999.
(4) Blaser, H. U.; Schmidt, E. D. Asymmetric Catalysis on Industrial Scale:
Challenges, Approaches and Solutions; Wiley-VCH: Chichester; John
Wiley [distributor]: Weinheim, 2004.
(10) Fujita, K.; Furukawa, S.; Yamaguchi, R. J. Organomet. Chem. 2002, 649
(2), 289-292.
(11) Pamies, O.; Ell, A. H.; Samec, J. S. M.; Hermanns, N.; Backvall, J. E.
Tetrahedron Lett. 2002, 43 (26), 4699-4702.
(12) Samec, J. S. M.; Ell, A. H.; Backvall, J. E. Chem.sEur. J. 2005, 11 (8),
2327-2334.
(13) Ell, A. H.; Samec, J. S. M.; Brasse, C.; Backvall, J. E. Chem. Commun.
2002 (10), 1144-1145.
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10.1021/op060233w CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/04/2007

Scheme 1. Dehydrogenation and racemisation of (1S)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline using [IrCl2Cp*]2
catalyst 1a
are not compatible with some other reagents and catalysts
(for example, acyl donors and enzymes). Murahashi et al.14
reported the racemisation of optically active 2-methylben-
zylamine using palladium black although high levels of
dimeric impurities were formed. More recently, Jacobs
et al.15 have used Pearlman’s catalyst, palladium on barium
sulfate under hydrogen gas; however, the reaction is limited
to benzylic amines having substituents not susceptible to
reduction.
its removal, thereby limiting the utility of the process when
sensitive groups are present in the amine. Turner et al.20-23
have developed an interesting process for the deracemisa-
tion of amines in water using a genetically modified amine
oxidase to selectively dehydrogenate the (S)-amine to an
imine that is reduced in situ with a nonselective metal
hydride reagent to give the racemic amine. Although
elegant, the method is currently limited by the enantiose-
lectivity of the enzyme to the (S)-enantiomer. Some years
ago an elegant industrial process was developed by Celgene,
in which one enantiomer of a racemic amine is selectively
dehydrogenated and hydrolyzed to a ketone using a tran-
saminase enzyme and amine acceptor such as an R-keto
acid; in the reverse reaction the ketone is then reductively
aminated by an amine donor, such as an amino acid, to the
opposite enantiomer, resulting overall in a deracemisation
process.24
Dynamic kinetic resolution is a method that has the
advantage of combining a resolution with a racemisation.
In this way the stereoisomers within a racemate are subjected
to a fast dynamic equilibrium, and one enantiomer is
selectively removed, for example by chemical modification
using an enzyme, by physical removal, through crystalliza-
tion, or by chiral chromatography. Chemists at BASF have
developed a process for the resolution of primary and
secondary amines by enzyme-catalysed acylation using
activated acyl donors.16 Although there are few details, they
have alluded to an amine racemisation and recyle process.17
Reetz et al.18 reported the first example of an amine dynamic
kinetic resolution (DKR) in 1996. They exploited the ability
of palladium supported on carbon in a hydrogen atmosphere
to racemise (S)-1-methylbenzylamine which, when used in
conjunction with Candida antarctica lipase and ethyl acetate
in triethylamine at 50-55 °C the (R)-amide was isolated in
64% yield and 99% ee after 8 days. Jacobs et al.15 recently
extended this work to some other benzylic amines. Ba¨ckvall
has described the use of Shvo¨’s catalyst in the DKR of
primary amines.19 Use of 4 mol % of the catalyst along with
sodium carbonate, isopropyl acetate, and Candida antarctica
lipase at 90 °C for 3 days resulted in the acylation of (R)-
1-methylbenzylamine in 90% yield and 98% ee. The method
was successfully used with a number of benzylic and
aliphatic primary amines. The product of these DKR reac-
tions is an amide, which requires harsh conditions to effect
Catalyst Identification
Whilst carrying out some work on the asymmetric transfer
hydrogenation of some 1-methyl-3,4- dihydroisoquinolines
using iridium pentamethylcyclopentadienyl complexes, CATHy
catalysts,25 we noticed a reproducible and in some cases
significant fall in the enantiomeric excess of the product
amine, despite the fact that we were using a formate salt
hydrogen donor that was expected to give an irreversible
reaction. Investigation of these results led us to the finding
that this type catalyst is able to dehydrogenate amines, i.e.
that amines can serve as hydrogen donors.
Initial studies demonstrated that the precursor to the
CATHy catalysts pentamethylcyclopentadienyl-rhodium and
-iridium (III) chloride dimers will slowly racemise (R)- or
(S)-6,7-dimethoxy-1-methyl-1,2,3,4-tetrahydroisoquino-
line. It was found that the TsDPEN ligand inhibits the
racemisation. As shown in Scheme 1, the precatalyst pen-
tamethylcyclopentadienyliridium chloride dimer (1a) effects
(14) Murahashi, S. I.; Yoshimura, N.; Tsumiyama, T.; Kojima, T. J. Am. Chem.
Soc. 1983, 105 (15), 5002-5011.
(15) Parvulescu, A.; De Vros, D.; Jacobs, P. Chem. Commun. 2005, (42), 5307-
5309.
(16) Balkenhohl, F.; Hauer B.; Ladner, W.; Pressler, U.; Nubling, C. Resolution
of the racemates of primary and secondary amines by enzyme catalysed
acylation. U.S. Patent 5,728,876, 1996.
(21) Carr, R.; Alexeeva, M.; Enright, A.; Eve, T. S. C.; Dawson, M. J.; Turner,
N. J. Angew. Chem., Int. Ed. 2003, 42 (39), 4807-4810.
(22) Carr, R.; Alexeeva, M.; Dawson, M. J.; Gotor-Fernandez, V.; Humphrey,
C. E.; Turner, N. J. ChemBioChem 2005, 6 (4), 637-639.
(23) Dunsmore, C. J.; Carr, R.; Fleming, T.; Turner, N. J. A J. Am. Chem. Soc.
2006, 128 (7), 2224-2225.
(17) Rouhi, A. M. Chem. Eng. News 2004, 82 (24), 47-62.
(18) Reetz, M. T.; Schimossek, K. Chimia 1996, 50 (12), 668-669.
(19) Paetzold, J.; Backvall, J. E. J. Am. Chem. Soc. 2005, 127 (50), 17620-
17621.
(20) Alexeeva, M.; Enright, A.; Dawson, M. J.; Mahmoudian, M.; Turner, N.
J. Angew. Chem., Int. Ed. 2002, 41 (17), 3177-xxxxx.
(24) Stirling D. I.; Z, A. L.; Matcham, G.W.; Rozzell, J. D., Jr. Enantiomeric
enrichment and stereoselective synthesis of chiral amines. U.S. Patent 5,-
169,780, 1992.
(25) Stirling, M. Coupled Catalytic Cycles: Development of a Procedure for
the Dynamic Kinetic Resolution of Amines. Ph.D. Thesis, University of
Huddersfield, Huddersfield, U.K., 2006.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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643

Figure 2. Reaction profile of (1S)-6,7-dimethoxy-1-methyl-
1,2,3,4-tetrahydroisoquinoline (2) with [IrI2Cp*]2 catalyst 1b
according to Scheme 1.
Figure 1. Reaction profile of (1S)-6,7-dimethoxy-1-methyl-
1,2,3,4-tetrahydroisoquinoline with [IrCl2Cp*]2 catalyst 1a ac-
cording to Scheme 1.
dienylruthenium catalysts for alcohol racemisation.5b This
probably indicates that either the mechanisms or the rate-
limiting steps of the two racemisation systems are substan-
tially different. The amount of imine 3, formed is similar to
that observed with catalyst 1a. If desired, the imine can be
easily reduced back to the racemic amine, thus increasing
the overall recovery to 99%. Interestingly, the amount of
isoquinoline 4, formed was significantly less with the
iodocatalyst 1b. Use of the isolated tetra-iodo complex rather
than its preparation in situ led to very similar results. Use of
the catalyst in this way is preferred as the reaction mass is
then monophasic.
The reaction is conveniently carried out by dissolving the
precatalyst in a suitable solvent and mixing with the amine
as a homogeneous solution. Suitable solvents are aromatics,
ethers, esters, and even biphasic systems. Only dipolar aprotic
solvents such as dimethylformamide have led to poor results.
The reactions are almost thermoneutral, making them safe
but unsuitable for calorimetric monitoring. The use of a
nitrogen blanket or purge is desirable as hydrogen is slowly
evolved, although the use of a gas purge had very little effect
on the reaction profile which remained first order.
The combination of iridium and iodide ligands gives the
most active catalyst, and the addition of a bidentate ligand
destroys activity, which provides a pointer to the mechanism
of the dehydrogenation. The rhodium analogue was also
prepared but showed lower activity than iridium. The chloro
analogues were less active. Interestingly, the use of the
trifluoromethyltetramethylcyclopentadiene ligand improved
the rate of racemisation by the iodorhodium complex by a
factor of about 3, but the analogous iridium complex showed
the same racemisation rate with either the pentamethyl- or
trifluoromethyltetramethylcyclopentadiene ligand.
the dehydrogenation of the substrate amine to generate an
observable imine that can be reduced to either amine
enantiomer, thus racemising the optically active starting
material. The reaction profile is shown in Figure 1, and
noticeable is the accumulation of imine, isoquinoline, and
other unidentified impurities (likely to be dimers), as well
as hydrogen gas as the other reaction by-product.
Although a high level of impurities was formed and the
rate of racemisation low, this reaction demonstrates the ability
of the iridium dimer 1a to racemise amines under particularly
mild reaction conditions.
The rate of racemisation catalysed by the iridium complex
1a is presumably dependent on the effective positive charge
on the metal, its ability to act as a Lewis acid and to donate/
accept a hydride ion. The simplest way to modify this
effective charge and hence change catalytic activity is to
change or substitute the ligands attached to the metal. The
most convenient modification is to substitute the halide ion,
and it is known that the addition of metal halide salts to
organometallic complexes can lead to halogen exchange.26
The pentamethylcyclopentadienyliridium (III) iodide dimer
(1b) has been reported in the literature,27,28 and it was
expected that the addition of potassium iodide to the iridium
catalyst 1a would form 1b by an in situ salt-exchange
mechanism. Indeed the precatalyst was isolated, characterized
by 1H, 13C NMR, and elemental analysis, and single-crystal
X-ray diffraction confirmed the structure of the tetra-iodo
complex. The racemisation of 2 was repeated with the
addition of an equivalent of potassium iodide, but chloroform
was used instead of dichloromethane due to its higher boiling
point; tetrahydrofuran was added as a cosolvent to aid the
dissolution of potassium iodide (although the vast majority
remained insoluble).
The results in Figure 2 show that changing the anionic
ligand from chloride to iodide has a large effect on the
catalytic activity, the rate of racemisation increasing by about
120-fold. The magnitude of this was surprising as Ba¨ckvall
et al. observed no significant difference between chloride,
bromide, and iodide as anionic ligands in their cyclopenta-
Reaction Scope
The scope of the reaction has been evaluated using a range
of optically active amines shown in Scheme 2 and the half-
life (t1/2) racemisations are shown in Table 1.
Secondary amines are racemised with t1/2 22 min to 24 h
(entries 1-3, 5, 6, 8-10). Entry 10, that of the anti-
depressant drug Sertraline, is an interesting case where
epimerisation of the secondary amine is at least partially
under thermodynamic control of the remote tertiary carbon
(26) Maitlis, P. M.; Haynes, A.; James, B. R.; Catellani, M.; Chiusoli, G. P.
Dalton Trans. 2004, (21), 3409-3419.
(27) Churchill, M. R.; Julis, S. A. Inorg. Chem. 1979, 18 (5), 1215-1221.
(28) Kang, J. W.; Moseley, K.; Maitlis, P. M. J. Am. Chem. Soc. 1969, 91 (22),
5970-xxxx.
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Scheme 2. Amine substrates tested in the
SCRAM-catalysed racemisation
Scheme 3. Formation of dimeric products following the
dehydrogenation of primary amines
Table 1. Half-life (t1/2) racemisation rates of different
optically active amines with catalyst 1b
species is generated as an intermediate and supporting other
evidence that iminium salts are good substrates in transfer
hydrogenation.29 The catalyst 1b failed to racemise the
bidentate tertiary amine (S)-nicotine (entry 11), and further
studies showed that this was due to its ligation with the
iridium to give an inactive catalyst.
Whilst a variety of optically active amine substrates have
been racemised, work is still ongoing for example with amino
acids and N-heteroatom-substituted amines (e.g., oximes,
hydrazines, sulfonylamines, phosphinylamines) to test the
scope of the reaction. The mechanism of the reaction is
currently being studied, and the identity of the active catalyst
is being determined.
temp catalyst loading
racemisation
entry substrate (°C)
(mol %)
t1/2 (min-1
)
1
2
3
4
5
6
7
8
9
2
5
6
7
8
40
40
80
80
80
80
80
80
80
80
80
90
0.2
0.2
0.5
1.0
1.0
1.0
1.0
1.0
1.0
0.1
1.0
1.0
45
220
180
dimeric impuritiesa
45
250
9
10
11
12
13
14
15
dimeric impuritiesa
900
1400
22
>7200
1250
10
11
12
This mild procedure for the racemisation of optically
active amines lends itself to application in recycling the waste
enantiomer produced in a resolution process, an “end-of-
pipe” solution, and a range of applications are being
evaluated. A further refinement of the technology is to
integrate it with a resolving technique to provide a dynamic
kinetic resolution process (DKR).
a 30% of the product is the racemised amine, the remainder is a mixture of
dimers.
chiral centre. Depending upon the solvent and temperature,
the cis-isomer can be epimerised to give 90% of the trans-
isomer. The tertiary carbon chiral centre can be racemised
with base, and thus a process has been devised in which the
three waste isomers from Sertraline manufacture can be
racemised, recycled, and turned into useable drug substance.
The substrates with a N-methyl are racemised more rapidly
than with a N-benzyl substituent. Possible explanations may
be the greater steric encumbrance of the latter, the greater
difficulty in reducing benzylimine, or because the imine may
be either cis or trans, the rate of reduction of these
geometrical isomers may be different, giving a lower rate
of reaction. The cyclic amines (entries 1-3) do not give this
problem as there can only be one geometrical isomer, and
generally they tend to racemise more quickly. Some pre-
liminary work has been done on electron-donating and
-withdrawing substituents, and generally it seems that the
former racemise more quickly. From observation of the imine
concentration in solution it seems that the slow step in the
catalytic cycle is the dehydrogenation.
Dynamic Kinetic Resolution
For the DKR to be successful, both the racemisation and
resolution need to work under the same conditions in the
same reaction vessel, the former needs to be rapid, and the
resolution needs to be highly selective, and enzymes are well
suited to this task. Since our SCRAM catalysts are efficient
in the racemisation of secondary amines, we chose to use
these; however, there are few reports of enzymatic resolution
of secondary amines.16,30 Perhaps the best example is from
Breen who has devised a procedure for the resolution of
1-methyl-1,2,3,4-tetrahydroisoquinoline (5) using Candida
rugosa lipase and a novel allyl carbonate acyl donor.31 The
maximum yield achieved in this process is 46% and 99%
ee. Our target for the DKR process was to maintain the high
optical purity but to increase the yield.
The enzymatic resolution of racemic 2 was carried out
using Breen’s process but at the slightly higher temperature
of 40 °C where only minor denaturation of the enzyme and
very little uncatalyzed acylation were observed. In the next
experiment catalyst 1b was added to perform the DKR, but
From the data it is evident that primary amines are rapidly
dehydrogenated. However, as previously observed, the
reactivity of primary imines results in their rapid reaction
with substrate amine, elimination of ammonia, and the
formation of dimeric alkylated imines.6a These products can
subsequently be reduced to an isomeric mixture of dimeric
amines (Scheme 3).
(29) Blacker, A. J.; Campbell, L. Transfer Hydrogenation Process. WO00018708,
1998
(30) Alexeeva, M. V.; Enright, A.; Turner, N. J. Mahmoudian, M. Deracemi-
sation of Amines. WO03080855, 2003.
Interestingly one tertiary amine has been efficiently
racemised (entry 12), indicating that a quaternary iminium
(31) Breen, G. F. Tetrahedron Asymm. 2004, 15 (9), 1427-1430.
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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645

Scheme 4. Dynamic kinetic resolution process for racemic
secondary amine 2
although the product carbonate was formed in high ee, a large
amount of impurity was formed that was identified by NMR
and GC/MS analysis as N-allyl-1-methyl-1,2,3,4-tetrahy-
droisoquinoline. This side reaction must be catalysed by 1b
as the impurity was not observed in the absence of the
catalyst. The evidence points to catalysed allylation of the
amine by the allylcarbamate rather than reaction with
3-methoxyphenyl allyl carbonate. A simple modification of
this reagent to 3-methoxyphenyl propyl carbonate was made,
and then this reagent was tested in the DKR process as shown
in Scheme 4 and Figure 3.
A successful DKR was observed with 90% conversion
to the product carbonate in 96% ee using 0.2 mol % catalyst.
The reaction was performed at 10-g scale. and the product
carbamate was isolated in 82% yield with 96% ee.32 The
formation of a carbamate product is a useful feature of the
process since this protecting group is readily removed by
acidic hydrolysis. This can be compared to most enzyme-
catalysed amine resolutions and DKRs that involve the
formation of an amide, which is harder to remove.
Figure 3. DKR of racemic 2 using 3-methoxyphenylpropyl
carbonate as the acyl donor.
and sodium iodide (8.55 g of 99% ≡ 8.46 g ≡ 56.70 mmol)
were added to a side-armed, 1000 mL, round-bottom flask.
A water condenser was fitted to the flask, and argon was
sparged through a pipet in the sidearm at 500 mL/min for
30 min. The purge of argon was then reduced to 20 mL/
min, and acetone (525 mL <100 ppm H2O) was added; the
reaction flask was then placed in an oil bath at 60 °C and
stirred using a magnetic stirrer, resulting in a dark orange
solution containing some insoluble iridium dimer. The
reaction was allowed to reflux under argon for 3 h before
being cooled to room temperature. The reaction was con-
centrated to dryness under vacuum to yield a brown/red solid
that was dissolved in dichloromethane (500 mL) and washed
with ultrapure water (250 mL, 3×), the organic layer was
separated, dried using sodium sulfate, filtered, and concen-
trated to dryness under vacuum to yield a brown solid. The
solid was recrystallized from chloroform/methanol to yield
brown needlelike crystals; the filtrates were concentrated to
dryness, and the resulting residue was recrystallized from
chloroform/methanol; this was repeated a third time, and the
three crops of catalyst combined to yield 5.102 g (78.2%
isolated yield, assuming 98% pure). The crystals were
analyzed by carbon and proton NMR, elemental analysis,
and X-ray crystallography. δH (300 MHz, solvent CDCl3,
reference SiMe4) 1.83 (s, Cp*-CH3). δC (300 MHz, solvent
CDCl3, reference SiMe4) 11.13 (Cp*-CH3), 89.3 (Cp*).
Elemental analysis: Calcd C ) 20.7, H ) 2.6. Found: C )
20.6, H ) 2.5. X-ray analysis: see Supporting Information.
General Procedure for Racemisation of Amines, Using
Pentamethylcyclopentadienyliridium (III) Chloride Dimer
(1a) and Potassium Iodide. The chosen solvent (10 vol
equiv) was charged to a nitrogen-blanketed, over-head stirred,
round-bottomed flask and warmed to between 40 °C and
110 °C. The optically active amine (1 mol equiv) was
charged in one portion and allowed to dissolve; then the
potassium iodide (1 mol equiv) and catalyst, pentamethyl-
cyclopentadienyliridium (III) chloride dimer (0.01 mol
equiv), were charged to give a transparent orange solution.
The reactions were sampled by quenching ∼100 µL into
dichloromethane (2 mL) and water (2 mL); the organic layer
was dried using sodium sulfate and concentrated to dryness
under vacuum. The resulting residue was redissolved in an
appropriate solvent to a concentration of ∼1 mg/mL and then
was analyzed by HPLC and/or GC for enantiomeric excess
Conclusion
We have developed a simple, efficient, iridium-based
catalyst system for the dehydrogenation and racemisation of
a variety of amines. The catalyst is air- and water stable and
can be used in mild conditions compatible with enzymes. A
process for the DKR of a secondary amine has been
developed, giving a product in high yield and enantiopurity.
Experimental Methods
Elemental Analyses. These were carried out by the
University of Huddersfield using standard techniques. Chro-
matography: GC data were obtained using a HP6890 series
GC; GC/MS data were obtained using a HP6890 series GC
with a HP5973 MSD detector; LC data were obtained using
either a HP1050 series or HP1100 series HPLC. Nuclear
magnetic resonance spectroscopy: NMR spectra were re-
corded using a Bruker Advance 400 MHz spectrometer.
Deuterated NMR solvents were purchased from Aldrich and
used without further purification. Catalyst (1a) was purchased
from Aldrich, Johnson-Matthey, and Heraeus. Optically
active amine substrates (2-15) were synthesized by known
literature methods.
Synthesis of Pentamethylcyclopentadienyliridium (III)
Iodide Dimer (1a). Pentamethylcyclopentadienyliridium (III)
chloride dimer (1a) (4.57 g of 96% ≡ 4.38 g ≡ 5.50 mmol)
(32) Stirling, M.; Blacker, J.; Page, M. I. Tetrahedron Lett. 2007, 48 (7), 1247-
1250.
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and impurities. When analysis was complete, the reaction
mass was quenched with acid to extract the amine and
separate it from the catalyst. The phases were separated, and
the amine was back extracted into an organic solvent by
neutralization and then concentrated to dryness to give a yield
of the crude mass.
sodium sulfate. The resulting organic layer was analyzed by
chiral and achiral GC. Analysis: gas chromatography (for
conversion). Column ) HP-5 5% Ph Me siloxane capillary
column (30 m × 320 µm × 0.25 µm). Oven temperature )
70 °C isothermal for 30 min. Inlet pressure ) 15.0 psi.
N-Methyl-1-methylbenzylamine (8) retention time ) 6.8 min.
Gas chromatography (for ee): column ) Varian Chirasil-
Dex-CB column (25 m × 250 µm × 0.25 µm). Oven
temperature ) 100 °C isothermal for 60 min. Inlet pressure
) 10.0 psi. N.B. The samples were derivatised using
trifluoroacetic anhydride prior to injection. (R)-N-Methyl-
1-methylbenzylamine (R)-(8) retention time ) 58.4 min, (S)-
N-methyl-1-methylbenzylamine (S)-(8) retention time )
54.8 min.
Racemisation of (S)-N-Methyl-1-methylbenzylamine
(8) Using Pentamethylcyclopentadienyliridium (III) Io-
dide Dimer (1b). 1b (24.2 mg of 96% ≡ 23.25 mg ≡
0.02 mmol), (S)-(8) (275.9 mg of 98% ≡ 270.4 mg ≡
2.00 mmol), and internal standard tridecane (186.2 mg of
99% ≡ 184.4 mg ≡ 1.00 mmol) were charged to a 5-mL
round-bottom flask. Toluene (4 mL) was added, a water
condenser was attached to the flask that was then placed in
an oil bath at 80 °C, and a timer was started. The reaction
solution immediately turned to a dark red/brown that faded
over 60 min to a dark orange solution. The color of the
solution gradually faded and was a clear orange solution after
stirring overnight. Samples were taken at regular intervals
by removing 100-200 µL and quenching into dichlo-
romethane (2 mL) and 2.5 M sodium hydroxide (2 mL); the
organic layer was separated and dried using sodium sulfate.
The resulting organic layer was analysed by chiral and achiral
GC using the conditions described in the previous experi-
ment.
3-Methoxyphenylpropyl Carbonate (16). To a three-
neck, 100-mL round-bottom flask was added 3-methoxyphe-
nol (6.47 g of 96% ≡ 6.21 g ≡ 50.00 mmol), tetrabutylam-
monium iodide (131.9 mg of 98% ≡ 129.3 mg ≡
0.35 mmol), and dichloromethane (40 mL), resulting in a
red/orange solution. A thermometer was attached and
magnetic agitation started. Sodium hydroxide solution
(20 mL of 4.0 M) was added which caused the reaction
mixture to turn a brown colour. The reaction flask was then
placed in an ice/salt bath and cooled to 0-5 °C. Propyl
chloroformate (7.06 g of 98% ≡ 6.92 g ≡ 56.50 mmol) was
added over an hour using a syringe pump, and the reaction
solution was kept between 0 and 5 °C during the addition.
A yellow precipitate formed during the addition. The reaction
was stirred for a further hour at 0-5 °C and then separated.
The aqueous layer was a dark-brown colour, and the organic
layer was yellow. The organic layer was washed with sodium
hydroxide solution (10 mL of 2.0 M), separated, dried using
magnesium sulfate, and filtered. The filtrates were concen-
trated to dryness under vacuum to leave a yellow oil
(10.67 g, 100% ) 10.51 g). The crude product was purified
using flash column chromatography with a 70/30 hexane/
ethyl acetate mobile phase, producing after vacuum distil-
lation a yellow oil (10.17 g ) 93% isolated yield). The oil
was analysed by GC, GC/MS, and NMR.
Racemisation of (S)-6,7-Dimethoxy-1-methyl-1,2,3,4-
tetrahydroisoquinoline (2). Into a 5-mL round-bottom flask
was added pentamethylcyclopentadienyliridium (III) chloride
dimer (1a) (8.30 mg of 96% ≡ 7.97 mg ≡ 0.01mmol).
Chloroform (250 µL) was added, and the catalyst solution
was stirred using a magnetic stirrer until all the catalyst had
dissolved, resulting in an orange solution. (S)-(2) (218.2 mg
of 95% ≡ 207.25 mg ≡ 1.00 mmol) and potassium iodide
(167.7 mg of 99% ≡ 166.01 mg ≡ 1.00 mmol) were added
and washed in using tetrahydrofuran (750 µL). The flask
was fitted with a water condenser and was placed into an
oil bath at 40 °C, and a timer was started. The potassium
iodide remained predominantly out of solution, and after
about 5 min at 40 °C the reaction solution had become brown
and remained this color throughout. Samples were taken at
regular intervals by adding 40 µL of the reaction solution to
dichloromethane (2 mL) and 2.5 M sodium hydroxide
solution (2 mL). The organic layer was separated and dried
using sodium sulfate. The resulting solution was analyzed
by chiral and achiral GC. Analysis: gas chromatography (for
conversion). Column ) HP Crosslinked 5% Ph Me siloxane
(25 m × 0.32 mm × 0.52 µm). Oven temperature ) 150 °C
for 7 min then ramp at 10 °C/min to 300 °C and hold for
5 min. Inlet pressure ) 12.0 psi. 6,7-Dimethoxy-1-methyl-
1,2,3,4-tetrahydroisoquinoline (2) retention time ) 12.4 min.
6,7-Dimethoxy-1-methyl-3,4-dihydroisoquinoline (3) reten-
tion time ) 12.7 min. 6,7-Dimethoxy-1-methylisoquinoline
(4) retention time ) 13.9 min. Unknown impurity retention
time ) 12.45 min. Analysis: gas chromatography (for ee).
Column ) Varian Chirasil-Dex-CB column (25 m ×
250 µm × 0.25 µm). Oven temperature ) 165 °C isothermal
for 60 min. Inlet pressure ) 10.0 psi. N.B. Samples were
derivatised using trifluoroacetic anhydride prior to injection.
(R)-(2) retention time ) 41.6 min. (S)-(2) retention time )
42.5 min.
Racemisation of (S)-N-Methyl-1-methylbenzylamine
(8). Pentamethylcyclopentadienyliridium (III) chloride dimer
(1a) (16.6 mg of 96% ≡ 15.9 mg ≡ 0.02 mmol), (R)-N-
methyl-R-methylbenzylamine (R)-(8) (275.9 mg of 98% ≡
270.4 mg ≡ 2.00 mmol), potassium iodide (335.4 mg of 99%
≡ 332.0 mg ≡ 2.00 mmol), and internal standard biphenyl
(155.0 mg of 99.5% ≡ 154.2 mg ≡ 1.00 mmol) were charged
to a 5-mL round-bottom flask. Toluene (4 mL) was added,
a water condenser was attached to the flask which was then
placed in a oil bath at 80 °C, and a timer was started. The
reaction solution immediately turned to a dark red/brown
that faded over 60 min to a dark orange solution. The colour
of the solution gradually faded and was a clear orange
solution after stirring overnight. Samples were taken at
regular intervals by removing 100-200 µL and quenching
into dichloromethane (2 mL) and 2.5 M sodium hydroxide
(2 mL); the organic layer was separated and dried using
Vol. 11, No. 3, 2007 / Organic Process Research & Development
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647

Analysis: gas chromatography (for conversion). Column
) Chirasil-Dex-CB column (25.0 m × 250 µm × 0.25 µm).
Oven temperature ) 140 °C for 20 min then ramp at
10 °C/min to 190 °C and hold for 20 min. Inlet pressure )
10.0 psi. 3-Methoxyphenylpropylcarbonate (16) retention
time ) 22.8 min.
reaction time of 48 h the reaction solution was filtered
through Celite to remove any enzyme. The filtrates were
added to dichloromethane (100 mL) and washed with
hydrochloric acid (2 × 50 mL of 1.0 M) and sodium
hydroxide solution (2 × 50 mL of 1.0 M). The organic layer
was removed, dried using sodium sulfate, filtered, and
concentrated to dryness under vacuum to yield a brown oil
(6.10 g) which was purified through a silica column using a
hexane/ethyl acetate gradient elution system. The fractions
containing only the product were combined and concentrated
to dryness under vacuum to yield a yellow oil (3.53 g, 100%
yield ) 4.24 g; therefore, isolated yield ) 81.6%, assuming
the product is 98% pure). The product was analyzed by GC,
dissolved in hexane/propan-2-ol (70/30), and analyzed by
chiral HPLC and dissolved in CDCl3 for NMR analysis
(H1, C13, and HMQC) (see Supporting Information).
Dynamic Kinetic Resolution of Racemic 6,7-Dimethoxy-
1-methyl-1,2,3,4-tetrahydroisoquinoline (2). Prior to the
reaction a stock solution of toluene saturated with water was
prepared by vigorously stirring a toluene/water mixture for
1 h and then allowing the two layers to separate; the toluene
layer was used for the reaction solvent. To a two-neck,
50-mL round-bottom flask was added 6,7-dimethoxy-1-
methyl-1,2,3,4-tetrahydroisoquinoline (2) (3.093 g of 97%
≡ 3.00 g ≡ 14.47 mmol), Candida rugosa lipase (1.5 g,
1410 units/mg), pentamethylcyclopentadienyliridium (III)
iodide (1b) (34.3 mg of 98% ≡ 33.6 mg ≡ 0.03 mmol), and
toluene saturated with water (25 mL), resulting in an orange
solution containing some insoluble amine. The reaction vessel
was placed in an oil bath at 40 °C and connected to a second
flask containing saturated brine at 50 °C. 3-Methoxyphe-
nylpropyl carbonate (16) (4.657 g of 98% ≡ 4.564 g ≡
21.71 mmol) was added and washed in using toluene
saturated with water (5 mL), resulting in an orange/brown
solution containing brown insoluble material (enzyme). The
reaction flask was sealed so that the system was closed and
was stirred overnight. After 24 h additional aliquots of 16
(1.55 g 98% ≡ 1.52 g ≡ 7.23 mmol) and Candida rugosa
lipase (600 mg of 1410 units/mg) were added. After a total
Acknowledgment
We thank the Royal Commission for the Exhibition of
1851 for a scholarship to Matthew Stirling.
Supporting Information Available
X-ray analysis. This material is available free of charge
via the Internet at http://pubs.acs.org.
Received for review November 14, 2006.
OP060233W
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