Enantioselective Hydrogenation of Imines Using a Diverse Library of Ruthenium Dichloride(diphosphine)(diamine) Precatalysts

Article abstract of DOI:10.1002/adsc.200390011

A range of aromatic and cyclic imines were subjected to asymmetric hydrogenation with catalysts derived from complexes of the type RuCl ₂(diphosphine)(diamine). Good to high enantioselectivities were observed. For each imine, a library of chiral complexes based on different diphosphine and diamine combinations was screened. A different combination of diphosphine and diamine was required each time to obtain the optimum enantioselectivity.

Full text of DOI:10.1002/adsc.200390011

FULL PAPERS
Enantioselective Hydrogenation of Imines Using a Diverse
Library of Ruthenium Dichloride(diphosphine)(diamine)
Precatalysts
Christopher J. Cobley, Julian P. Henschke
Chirotech Technology Limited (a Subsidiary of The DowChemical Company), 321 Cambridge Science Park, Milton Road,
Cambridge, UK CB4 0WG, UK
Fax: ( ‡ 44)-1223-506-701, e-mail: CCobley@dow.com
Received: April 11, 2002; Accepted: July 11, 2002
Abstract: A range of aromatic and cyclic imines were mine combinations was screened. A different combi-
subjected to asymmetric hydrogenation with catalysts nation of diphosphine and diamine was required each
derived from complexes of the type RuCl2(diphos- time to obtain the optimum enantioselectivity.
phine)(diamine). Good to high enantioselectivities
were observed. For each imine, a library of chiral Keywords: Asymmetric hydrogenation; DuPHOS;
complexes based on different diphosphine and dia- imine hydrogenation; ruthenium
Introduction
phine in hot DMF followed by treatment with a diamine
at room temperature yielding air stable, easily handled
Enantiomerically pure amines are highly important solids.[5] The imines were purchased or prepared by
building blocks for biologically active molecules and the reaction of the requisite ketones and amines in toluene
discovery of newand efficient methods for their
at room temperature in the presence of 4 ä molecular
preparation is a matter of continued interest. Although sieves.[2i] It should be noted that we observed hydro-
numerous methods are available for their preparation, genation at lower pressures than reported, but for
the catalytic asymmetric hydrogenation of imines offers consistency in screening higher pressures were used. In a
a cheap and industrially viable process as demonstrated preliminary hydrogenation reaction using a molar sub-
by the multi-ton synthesis of (S)-metolachlor.[1] This strate-to-catalyst-to-base ratio (S/C/B) of 100/1/100 of
area, however, is still under development with progress N-(phenylethylidene)aniline (1), RuCl2[(S)-Tol-BI-
being centred around catalysts based on complexes of NAP][(S,S)-DPEN] and t-BuOK (1 M solution in t-
Rh, Ir, Ru and Ti.[2] Our own[3] recent experience in the BuOH) in i-PrOH at 50 8C under 15 bar H2 provided
area of non-olefinic hydrogenation has focused on the quantitative conversion to amine 2 with 49% ee
use of Noyori×s ruthenium(II) dichloride(diphosphi- (Scheme 1). As will be described, we were ultimately
ne)(diamine) complexes (3).[4] In i-PrOH and in the able to increase the enantioselectivity to 94% ee (vide
presence of a strong base, these complexes generate infra) by choice of appropriate catalyst and conditions.
catalysts capable of reducing ketones with very high
enantioselectivities even at extremely lowcatalyst
Concurrent to this work, Morris et al.[6] reported
the hydrogenation of a range of simple ketones and
loadings (e.g., molar substrate to catalyst ratio, S/C ˆ two imines using RuH2(PPh3)2[(R,R)-DACH] or
100,000/1).[5] Therefore, we sought to investigate their RuHCl(PPh3)2[(R,R)-DACH] but no enantioselectivi-
use in the catalytic asymmetric hydrogenation of imines. ties were reported. Very recently the same authors
We were specifically interested in this class of complex reported the use of complexes of the type RuHCl(chiral
as large libraries of structurally diverse diphosphine and
diamine ligands could be used to rapidly generate an
array of catalysts with very different stereoelectronic
domains.
RuCl2(diphosphine)(diamine)
50 - 65 °C, 15 bar H2,
HN
N
t-BuOK, i-PrOH
overnight
(S/C/B = 100/1/100)
Results and Discussion
1
2
up to 94% ee
The precatalysts used were readily prepared under inert
Scheme 1. Hydrogenation of N-(phenylethylidene)aniline
conditions by reaction of [RuCl2C6H6]2 with a diphos- (1).
Adv. Synth. Catal. 2003, 345, No. 1+2
¹ 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 1615-4150/03/3451+2-195 201 $ 17.50+.50/0
195

Christopher J. Cobley, Julian P. Henschke
FULL PAPERS
differences in the conversion or ee was observed. When
the base was omitted no reaction occurred.
Having identified optimal conditions for the hydro-
genation of 1, we proceeded to test a larger range of
precatalysts based on different combinations of the
chiral diphosphines and chiral diamines shown in
Figure 1 (see Table 1). In entries 1 10, the DuPHOS
family of diphosphines was tested more extensively.
Although Me-DuPHOS (entry 1) gave good selectivity
it was inferior to Et-DuPHOS (entry 2) and i-Pr-
DuPHOS (entry 8) in conjunction with DPEN. A
marked stereochemical matching/mismatching effect
was observed for diphosphine/diamine combinations
(cf. entries 2 and 3). Comparison of different diamines
revealed that although DACH (entry 4) provided a
slight improvement in selectivity over DPEN (entry 2),
DAIPEN (entry 5), ANDEN (entries 6 and 7) and AMP
(entry 9) were less selective.
Figure 1. Diphosphines and diamines used to generate the
precatalyst library.
diphosphine)(chiral diamine) for the stereoselective
BINAP in combination with a variety of diamines
hydrogenation of ketones and imines.[7] Only a limited gave lowenantioselectivities and conversions (en-
range, however, of chiral diphosphines and chiral tries 11 14) for this substrate, whilst the more elec-
diamines was tested for the hydrogenation of imines tron-rich Tol-BINAP gave full conversion (entry 15).
and at best moderate selectivities obtained (up to 71% Conversely, Noyori reported[8] that the parent ketone,
ee). The hydrogenation of cyclic imines was not acetophenone, was hydrogenated in 91% ee using
reported.
RuCl2[(S)-Tol-BINAP][(S)-DAIPEN]. Generally, we
We therefore wish to report the use of a diverse library observed lower selectivities for imines as compared to
of the related RuCl2(diphosphine)(diamine) complexes those achieved in ketone hydrogenation using Noyori-
in the enantioselective catalytic hydrogenation of a type precatalysts. Moreover, diphosphine/diamine com-
range of structurally different imines and observations binations that were good for ketone hydrogenation (e.g.,
concerning the effect of different diphosphine/diamine Tol-BINAP/DPEN and PhanePHOS/DPEN) were
combinations. Crucially, we have found that for a given poor for imine hydrogenation and vice versa (e.g., Et-
imine the most appropriate diphosphine/diamine com- DuPHOS/DPEN). Several other biaryldiphosphines,
bination is best identified by extensive screening and is including the electron-rich HexaPHEMP[9] ligand were
difficult to predict.
tested (entries 16 18) and although conversions were
With the successful preliminary result in hand we generally high, enantioselectivities were moderate. The
screened a range of precatalysts and rapidly identified PhanePHOS-based family of diphosphines, that we
the Et-DuPHOS/DPEN ligand system as a more have shown[10] to be as effective as BINAP-based ligands
selective combination, providing an 89% ee for imine in ketone hydrogenation using Noyori-type precatalysts,
1. In an effort to optimise conditions before extending provided poor results for imine hydrogenation (en-
the precatalyst screen further, we examined the reaction tries 19 21). It was evident from this precatalyst screen
parameters in the hydrogenation of 1. While increased that even small electronic and steric changes in related
temperatures led to decreasing selectivities, optimum ligands were critical to the selectivities and activi-
conversion was achieved at ca. 65 8C over a 20 h period. ties obtained. Interestingly RuCl2[(R,R)-Et-Du-
At room temperature over 20 h, 48% conversion and PHOS](DMF)n, which is an intermediate in the syn-
90% ee were achieved. Although hydrogenation oc- thesis of the RuCl2[(R,R)-Et-DuPHOS](diamine), and
curred over a range of pressures from 1.5 to 15 bar, with which has been reported[11] to effect styrene hydro-
a small improvement in selectivity at higher pressures, genation in conjunction with t-BuOK in i-PrOH,
quantitative conversion was only realised at 15 bar over provided 8% conversion and 16% ee under our standard
the reaction times studied. At 5 bar a 96% conversion conditions. In theory, the complex RuCl2[(R,R)-Et-
was achieved at 65 8C over 20 h. A solvent screen using DuPHOS](2)2 could be formed under these reaction
the optimised conditions (15 bar, 65 8C, 20 h) revealed conditions by displacement of the diamine ligand with
that quantitative hydrogenation could be achieved in i- the product 2, however, separate experiments using this
PrOH, PhMe and THF. Methanol proved to be a poor prepared separately showed it was only slightly active
solvent for this reaction with 78% ee and 22% con- giving 26% conversion and 8% ee.
version being obtained. A series of reactions was
We proceeded to optimise the reaction conditions for
conducted with differing amounts of base (t-BuOK in a more industrially acceptable molar substrate-to-cata-
t-BuOH from 0.1 to 2.0 equivalents) but no significant lyst-to-base ratio of 1000/1/100, with the preferred
196
Adv. Synth. Catal. 2003, 345, 195 201

Enantioselective Hydrogenation of Imines Using RuCl2(diphosphine)(diamine)
FULL PAPERS
Table 1. Precatalyst screening against N-(phenylethylidene)aniline (1).[a]
H2, precatalyst
HN
N
t-BuOK, i-PrOH
1
2
Entry
RuCl2(diphosphine)(diamine)
Conversion [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
(R,R)-Me-DuPHOS/(R,R)-DPEN
(R,R)-Et-DuPHOS/(R,R)-DPEN
(S,S)-Et-DuPHOS/(R,R)-DPEN
(R,R)-Et-DuPHOS/(R,R)-DACH
(R,R)-Et-DuPHOS/(R)-DAIPEN
(R,R)-Et-DuPHOS/(R,R)-ANDEN
(R,R)-Et-DuPHOS/(S,S)-ANDEN
(S,S)-i-Pr-DuPHOS/(R,R)-DPEN
(R,R)-i-Pr-DuPHOS/(S)-AMP
(R,R)-i-Pr-DuPHOS/(S)-BINAM
(R)-BINAP/EDA
(R)-BINAP/(R,R)-DPEN
(S)-BINAP/(S)-AMP
(R)-BINAP/(S)-AMP
(S)-Tol-BINAP/(S,S)-DPEN
(S)-HexaPHEMP/(S,S)-DACH
(R)-HexaPHEMP/(R,R)-DPEN
(R)-MeO-BIPHEP/(R,R)-DPEN
(R)-i-Pr-PhanePHOS/(S,S)-DPEN
(R)-Xylyl-PhanePHOS/(S,S)-DPEN
(S)-CF3-Ph-PhanePHOS/(R,R)-DPEN
(R,R)-Me-FerroTANE/(S,S)-DPEN
94
100
60
92
43
11
9
99
3
9
85 (S)
91 (S)
11 (R)
92 (S)
48 (S)
8 (R)
9 (R)
89 (S)
11 (R)
3
22
6
24 (S)
49 (S)
23 (R)
19 (R)
49 (R)
56 (R)
45 (S)
50 (S)
37 (R)
11 (R)
35 (S)
4
99
78
98
98
16
26
2
20
[a]
Conducted in a multi-well hydrogenation apparatus at 15 bar H2, 65 8C, for ca. 20 h, with 1 mol % RuCl2(diphos-
phine)(diamine) and 100 mol % 1 M t-BuOK in t-BuOH.
[b]
[c]
Determined by1H NMR spectroscopy.
Determined by GC analysis using a chiral DEX-CB column. Absolute configuration is in parentheses.
RuCl2[(R,R)-Et-DuPHOS][(R,R)-DACH] precatalyst. that under these conditions an equilibrium mixture of 4
At this loading, 20% conversion and 88% ee were and its aldimine tautomer was generated (which would
obtained at 65 8C, 20 h at 20 bar H2 at 0.5 M substrate hydrogenate to give a racemic product) accounting for
concentration in i-PrOH. Although an increase in the the lowselectivities. When the amount of base was
hydrogen pressure to 100 bar had little effect, increasing reduced to 5 mol % the selectivities were greatly
the temperature to 100 8C had a detrimental effect on enhanced and 62% ee (97% conversion) was obtained
the selectivity (80% ee) and produced only a modest using RuCl2[(S)-Tol-BINAP][(S,S)-DPEN].
increase in conversion (48%). The two most important
factors leading to an increase in the conversion were
time and concentration. Thus, when the reaction was
conducted for 69 h at 65 8C in i-PrOH (4.1 M) with
N
5 mol % t-BuOK 97% conversion and 94% ee were
N
obtained. This compares favourably (ca. 23% higher ee)
to that which Morris[7] reported using a smaller set of
4
5
62% ee
88% ee
Noyori-type precatalysts and to the literature using
other catalysts.[2a,c,i,12]
MeO
MeO
N
N
A similar screening approach to that presented in
Table 1 was applied to imines 4, 5, 6, and 7 (Figure 2).
Hydrogenation of benzylimine 4 with a range of
precatalysts proceeded with low selectivities (2 29%
ee) when the reaction was conducted in the presence of
N
7
6
79% ee
69% ee
Figure 2. Other imines reduced and the ees of the corre-
100 mol % t-BuOK. A control experiment indicated sponding amine products.
Adv. Synth. Catal. 2003, 345, 195 201
197

Christopher J. Cobley, Julian P. Henschke
FULL PAPERS
Table 2. Precatalyst screening against neat 2-methylquinoxa-
In our studies we also investigated the enantioselec-
tive hydrogenation of cyclic imines. Catalyst screening
(15 precatalysts tested in a multi-well vessel) against
2,2,3-trimethylindolenine (5) revealed that RuCl2[(S)-
MeO-BIPHEP][(S,S)-ANDEN] provided the highest
selectivity (88% ee). Although the dihydroisoquinoline
(6) was screened against a smaller set of precatalysts a
large difference in selectivities was observed. Whereas
line (7) at S/C of 1000/1.[a]
H
N
N
H2, precatalyst
t-BuOK, i-PrOH
N
N
H
7
8
Entry RuCl2(diphosphine)(diamine)
Con-
version
[%]
ee [%]
RuCl2[(R,R)-Et-DuPHOS][(R,R)-DACH]
provided
79% ee and 80% conversion, with RuCl2[(S)-Hexa-
PHEMP][(S,S)-DPEN] 8% ee and 47% conversion
were obtained. The conversion with the former preca-
talyst was improved to near quantitative by raising the
reaction temperature to 80 8C.
1
2
3
4
5
6
7
8
9
10
11
12
13
(R,R)-Et-DuPHOS/(R,R)-DACH 98
40 (S)
68 (R)
69 (R)
64 (R)
65 (R)
69 (R)
66 (S)
66 (S)
61 (R)
60 (S)
39 (S)
62 (S)
37 (R)
(S)-Tol-BINAP/(S,S)-DPEN
(S)-HexaPHEMP/(S,S)-DPEN
(S)-HexaPHEMP/(R,R)-DPEN
(S)-HexaPHEMP/(S,S)-DACH
(S)-HexaPHEMP/(R,R)-DACH
(R)-BINAP/(R,R)-DPEN
(R)-BINAP/(S,S)-DPEN
(S)-BINAP/(S,S)-DACH
(R)-BINAP/(S,S)-DACH
(R)-BINAP/EDA
100
100
100
100
100
99
2-Methylquinoxaline (7), a challenging aromatic dii-
mine, was hydrogenated using a range of Noyori-type
precatalysts under our standard hydrogenation condi-
tions (15 bar H2, 65 8C, i-PrOH, S/C/B ˆ 100/1/100) with
good conversions and a range of ees being obtained.
Bianchini et al.[13] have addressed the asymmetric
hydrogenation of this aromatic diimine using iridium-
based catalysts. Although a high selectivity (90% ee)
was achieved by these workers for this substrate at 54%
conversion, a lower ee (73%) was obtained at higher
conversion (97%). In our work, biaryl BINAP-like
systems gave the highest selectivity. Given that 2-
methylquinoxaline (7) and its reduced product were
not solids under the reaction conditions we saw the
99
100
100
99
(R)-BINAP/(R)-DAIPEN
(S)-BINAP/(R)-DAIPEN
94
96
[a]
Reactions were conducted with neat 7 (5.6 M), at 30 bar
H2, 50 8C, S/C/B 1000/1/50, 20 h, 0.05 equiv. 1.0 M t-BuOK
in t-BuOH. Conversion and ees were determined by GC
analysis using a chiral DEX-CB column. Absolute config-
uration is in parentheses.
opportunity to conduct the hydrogenation in the ab- (EDA), however, markedly lower selectivity (entry 11)
sence of solvent. Indeed, when the reaction was was observed suggesting an electronic influence. The ee
conducted neat with RuCl2[(R,R)-Et-DuPHOS]- obtained for the product represented by entry 3 was
[(R,R)-DACH] (entry 1, Table 2) at S/C/B ˆ 1000/1/50, upgraded to 96% upon single crystallisation from i-
at 50 8C and 30 bar H2 40% ee and 98% conversion were PrOH. When precatalysts based on DAIPEN were
obtained. This was very pleasing because we have tested (entries 12 and 13) the expected diphosphine/
observed severe retardation of reaction rate in the diamine matching effect was observed.
hydrogenation of ketones using Noyori-type precata-
Finally, some deuterium labelling experiments were
lysts when conducted neat, or at very high concentra- performed in order to obtain a better understanding of
tion.[14] The use of RuCl2[(S)-Tol-BINAP][(S,S)-DPEN] the reaction (Scheme 2). When imine 1 was treated with
(entry 2) provided quantitative conversion and im- deuterium under the standard reaction conditions
proved selectivity (68% ee) suggesting that biaryldi- (5 bar, S/C/B ˆ 100/1/100, t-BuOK, 65 8C, 51 h) using
phosphines were better for this particular substrate. A RuCl2[(R,R)-Et-DuPHOS][(R,R)-DPEN], 8% deuteri-
screen against HexaPHEMP and BINAP precatalysts um was observed to have been incorporated into the
(entries 3 12) revealed an unexpected lack of diphos- benzylic position and 4% into the methyl group.
phine/diamine matching/mismatching effects. Only rel- 89% ee and 99% conversion were obtained as for the
atively small differences in selectivity were observed standard hydrogenation. These results suggest that
between the two enantiomers of either DPEN or solvent is the source of hydrogen. Although we had
DACH. This was unexpected given previous observa- initially expected almost complete deuterium incorpo-
tions with imine 1, which showed a marked matching/ ration into the benyzlic position of 2, it appears that
mismatching effect between the stereochemical ele- hydrogen or deuterium is rapidly transferred between
ments of the chiral diphosphine and diamine ligands. the solvent (e.g., i-PrOH) and ruthenium species as
This is also a characteristic of ketone hydrogenation.[10] previously suggested in the literature.[15] When the
More surprisingly, there appeared to be a reversal in the reaction was repeated using i-PrOH-d8 in the presence
usual matching/mismatching for the HexaPHEMP of hydrogen gas, 56% deuterium was incorporated
1
precatalysts bearing the DACH ligand (entries 5 and (determined by H NMR spectroscopy) into the ben-
6). These results suggested that these diamines had little zylic position, with once again an 89% ee and 99%
steric interaction with the imine substrate. When the conversion. The reproducible selectivity indicated that
chiral diamine was substituted for ethylenediamine no hydrogen/deuterium exchange occurred at the ben-
198
Adv. Synth. Catal. 2003, 345, 195 201

Enantioselective Hydrogenation of Imines Using RuCl2(diphosphine)(diamine)
FULL PAPERS
gas. For a given imine substrate a diverse range of
diphosphine/diamine combinations needs to be tested to
determine the optimum catalyst system. The imines can
be hydrogenated neat with good S/C loadings and at
reasonable pressures. In contrast to ketone reduction
using the same precatalysts, more forcing conditions for
reduction are required.
RuCl2[(R,R)-Et-DuPHOS][(R,R)-DPEN]
HN
i-PrOH, 5 bar D2, 51 h.
99% conv., 89% e.e.
4% D
8% D
i-PrOH-d8,
5 bar H2
HN
24 h
N
99% conv, 89% e.e.
76% D
56% D
Experimental Section
1
General Remarks
N
(D)HN
+
i-PrOH-d8, 0.5 bar N2.
Commercially available diamines, DPEN (Fluka), AMP
(Aldrich), DAIPEN (Strem), BINAM (Strem), EDA (Al-
drich), were used as received. ANDEN[16] and DACH[17] were
prepared according to literature procedures. Tol-BINAP
(Strem), BINAP (Strem) and MeO-BIPHEP (Roche) were
purchased and used as received. Me-DuPHOS, Et-DuPHOS
and i-Pr-DuPHOS were prepared as previously described.[18]
Me-FerroTANE was prepared as previously published.[19]
HexaPHEMP was prepared as described in a patent applica-
tion.[9] 2-Methylquinoxaline (7) (Aldrich), 2,3,3-trimethylin-
dolenine (5) (Aldrich) and 1-methyl-6,7-dimethoxy-3,4-dihy-
droisoquinoline (6) (Acros) were purchased and distilled
before use except for the latter which was used as received.
N-(1-Phenylethylidene)aniline (1) and N-(1-phenylethylide-
ne)benzylamine (4) were prepared as described in the liter-
ature.[2i] Racemic amines required for development of analyt-
ical methods were prepared as described in the literature.[2i]
Deuterium gas (99.98%) was purchased from Aldrich. All
imines and their corresponding amines are known compounds
and reported in the literature.
CD3
D
21 h: 24% conv., 78% e.e.
66 h: 24% conv., 75% e.e.
96% D
Scheme 2. Deuterium labelling experiments.
zylic position after reduction had occurred. The methyl
group was shown to have undergone a 76% hydrogen/
deuterium exchange. When the reaction was conducted
under a positive pressure of nitrogen gas under other-
wise standard conditions in i-PrOH-d8, a 24% conver-
sion of an essentially fully deuterated (benzylic and
methyl groups) amine with a 78% ee was produced. The
remainder of the product mixture was composed of the
starting imine 1 that was shown to have 96% deuterium
incorporated into the methyl group. The latter observa-
tion was due to base-catalysed hydrogen/deuterium
exchange and accounts for the deuterium incorporated
in the methyl position in the previous experiment. Upon
conducting the same experimental procedure for
66 hours, a 24% conversion and 75% ee were obtained
suggesting that both reactions had attained equilibrium.
These results together suggest the activated DuPHOS-
ruthenium complex catalyses both hydrogenation as
well as transfer hydrogenation, the latter being slower
and apparently providing lower selectivities. This has
not been reported for ketone hydrogenation, most likely
due to the greater reaction rates observed for hydro-
genation at the milder conditions employed. The com-
peting and lower selectivity of the transfer hydrogena-
tion could account for some erosion in enantioselectiv-
ity.
Precatalysts
The precatalysts were prepared as described in the supporting
information and as published by Noyori et al.,[5] however, the
diphosphines were generally allowed to react with the ruthe-
nium dimer for ca. 30 60 min for BINAP and BIPHEP
derivatives, and 2 3.5 h for DuPHOS and PhanePHOS
derivatives. Diamines were then reacted with the ruthenium-
diphosphine intermediates at room temperature overnight.
Hydrogenations
All hydrogenations were carried out in 50 mL Parr hydro-
genation vessels or in a Baskerville multi-welled hydrogena-
tion vessel equipped with injection ports with a rubber septum
for the addition of the solvent via syringe, a pressure gauge, a
tightly fitting removable internal glass liner and a magnetic
stirring bar. Commercially available anhydrous i-PrOH (Flu-
ka) was degassed prior to use by sparging with nitrogen for at
least 30 minutes. A commercially available 1.0 M solution of t-
Conclusion
In conclusion, we have shown that the readily prepared
Noyori-type chiral ruthenium(II)dichloride (diphos-
phine)(diamine) complexes, once activated in situ with
t-BuOK, reduce a range of aromatic and activated non-
aromatic imines to amines in the presence of hydrogen BuOK in t-BuOH (Aldrich) was used following degassing.
Adv. Synth. Catal. 2003, 345, 195 201
199

Christopher J. Cobley, Julian P. Henschke
FULL PAPERS
undergone 99% conversion with an enantioselectivity of 89%
for (S)-2-phenyl-(1-phenylethyl)amine (2). 1H NMR (CDCl3)
spectroscopy showed that the methine and methyl proton
integrations were 44%and 24% of that expected, indicating
56% and 76% incorporation of deuterium, respectively.
The deuteration experiments using i-PrOH-d8 were con-
ducted as for the general procedure except the reaction was
conducted under 0.5 bar nitrogen gas pressure in i-PrOH-d8
(2 mL) and t-BuOK (112 mg, 1.0 mmol) in i-PrOH-d8 (2 mL).
After 21 h, the reaction was analysed by GC and shown to have
undergone 24% conversion with an enantioselectivity of 78%
for (S)-2-phenyl-(1-phenylethyl)amine (2). 1H NMR (CDCl3)
spectroscopy showed that the methine and methyl positions
had essentially full incorporation of deuterium. The methine
proton integration was 4% of that expected, indicating 96%
incorporation of deuterium.
General Procedure
The catalyst (0.01 mmol) and imine substrate (1 mmol) were
placed in a glass liner and the vessel assembled. This was
purged with nitrogen and then with hydrogen at least three
times, by pressurising to 5 bar and releasing the pressure. i-
PrOH (4 mL) was added and the reaction was purged a further
three times with hydrogen. A solution of t-BuOK in t-BuOH
(1.0 M, 1.0 mL, 1.0 mmol) was added and the reaction purged a
further three times with hydrogen. Finally, the vessel was
pressurised to 15 bar of hydrogen and stirred at 50 65 8C (oil
bath) for 18 21 h. The hydrogenations conducted in the mutli-
welled vessel were conducted on half this scale. When the
pressure was released a sample of the crude reaction was
analysed (derivatised or underivatised) by chiral GC (DEX-
CB column) for conversion and enantiomeric purity. Con-
versions were supported by 1H NMR spectroscopy. Liquid
imines were added to the catalyst in the purged vessel as a
solution in i-PrOH. The absolute configurations of the hydro-
genation products of N-(1-phenylethylidene)aniline 1 were
determined by optical rotation on a doubly distilled sample of
the product prepared using RuCl2[(R,R)-Et-DuPHOS][(R,R)-
DACH]. [a]D25: ‡ 18.08 (c 1.0, MeOH)) {lit.[20] [a]D24: À 168 (c 1.0,
MeOH) for (R)-2-phenyl-(1-phenylethyl)amine (2)}.
Acknowledgements
We thank Drs. Guy Casy, Ian Lennon, Raymond McCague,
James Ramsden and Antonio Zanotti-Gerosa for their helpful
suggestions and David Baldwin, Natasha Cheeseman and Cath
Rippe ofthe ChiroTechanalytical team for their skilled technical
assistance.
Hydrogenation of Neat 2-Methylquinoxaline 7
The catalyst (0.008 mmol) was placed in a glass liner and the
vessel assembled. This was purged with nitrogen and then with
hydrogen at least three times, by pressurising to 5 bar and
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releasing the pressure. 2-Methylquinoxaline
7 (1.15 g,
8.0 mmol) was added and the mixture was purged three times
with hydrogen. A solution of t-BuOK in t-BuOH (1.0 M,
0.40 mL, 0.40 mmol) was added and the reaction was purged a
further three times with hydrogen. Finally, the vessel was
pressurised to 30 bar of hydrogen and stirred at 50 8C (oil bath)
for 20 hours. The absolute configurations of the enantiomeric
products were determinedby optical rotation measurementsof
upgraded (crystallised from i-PrOH) product samples pre-
pared by hydrogenation of 2-methylquinoxaline (7) using
RuCl2[(S)-HexaPHEMP][(S,S)-DACH] {[a]D24: ‡ 23.18 (c 1.0,
EtOH)} and RuCl2[(R)-BINAP][(R)-DAIPEN] [[a]D24: À 23.18
(c 1.0, EtOH)} {lit.[21] [a]D24: À 35.88 (c 1.0, EtOH) for (S)-2-
methyl-1,2,3,4-tetrahydroquinoxaline (8)}.
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The deuteration experiment using D2 in i-PrOH was conducted
as for the general procedure except the reaction was conducted
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was analysed by GC and shown to have undergone 99%
conversion with an enantioselectivity of 89% for (S)-2-phenyl-
(1-phenylethyl)amine (2). 1H NMR (CDCl3) spectroscopy
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incorporation of deuterium, respectively.
The deuteration experiment using H2 in i-PrOH-d8 was
conducted as for the general procedure except the reaction was
conducted under 5 bar hydrogen gas pressure in i-PrOH-d8
(2 mL) and t-BuOK (112 mg, 1.0 mmol) in i-PrOH-d8 (2 mL).
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