Highly enantioselective hydrogenation of N-aryl imines derived from acetophenones by using Ru-pybox complexes under hydrogenation or transfer hydrogenation conditions in isopropanol

Article abstract of DOI:10.1002/chem.201405276

The asymmetric reduction of N-aryl imines derived from acetophenones by using Ru complexes bearing both a pybox (2,6-bis(oxazoline)pyridine) and a monodentate phosphite ligand has been described. The catalysts show good activity with a diverse range of su

Full text of DOI:10.1002/chem.201405276

DOI: 10.1002/chem.201405276
Communication
&
Asymmetric Hydrogenation
Highly Enantioselective Hydrogenation of N-Aryl Imines Derived
from Acetophenones by Using Ru–Pybox Complexes under
Hydrogenation or Transfer Hydrogenation Conditions in
Isopropanol**
Estefanꢀa Menꢁndez-Pedregal,[b] Mꢂnica Vaquero,[a] Elena Lastra,[b] Pilar Gamasa,*[b] and
Antonio Pizzano*[a]
procedure avoids the use of costly high-pressure equipment,
Abstract: The asymmetric reduction of N-aryl imines de-
and the nature of the by-products formed may be more favor-
rived from acetophenones by using Ru complexes bearing
able than the HCOOH/NEt3 mixture.[4] The valuable utility of
both a pybox (2,6-bis(oxazoline)pyridine) and a monoden-
isopropanol in the asymmetric transfer hydrogenation of ke-
tate phosphite ligand has been described. The catalysts
tones is well known,[5] but less success has been reported in
show good activity with a diverse range of substrates, and
the reduction of imines. Yus et al. have exploited the synthetic
deliver the amine products in very high levels of enantio-
potential of the diastereoselective reduction of N-sulfinyl
selectivity (up to 99%) under both hydrogenation and
imines by using Ru catalysts.[6] Alternatively, the groups of
transfer hydrogenation conditions in isopropanol. From
Morris[7] and Beller[8] have described the highly enantioselective
deuteration studies, a very different labeling is observed
Fe-catalyzed reduction of activated N-phosphinyl imines in the
under hydrogenation and transfer hydrogenation condi-
presence of tetradentate N2P2 chiral ligands. Notably, these cat-
tions, which demonstrates the different nature of the hy-
alysts did not show activity in the reduction of important N-
drogen source in both reactions.
aryl ketimines.[2b–j] Likewise, Cahard and Dai have described the
catalytic asymmetric transfer hydrogenation of trifluoromethyl
aryl ketimines by using a Ru–arene complex, which contained
an amino-alcoxide ligand.[9] However, low activity was ob-
The asymmetric hydrogenation of imines is a reaction of great
importance owing to the vast range of applications that chiral
amines have in the pharmaceutical and agrochemical indus-
tries.[1] This has fueled a great deal of interest in this hydroge-
nation reaction, and studies covering the application of diverse
types of Ti, Fe, Ru, Rh, and Ir catalysts have been described.[2]
Despite an apparent simplicity, the hydrogenation of imines is
a challenging transformation because the high levels of effi-
ciency and broad scope that have been achieved in the asym-
metric hydrogenation of olefins and ketones have not yet
been accomplished.
served for the reduction of the less electrophilic methyl ana-
logues with this catalyst. To the best of our knowledge, the
practical reduction of N-aryl imines by using isopropanol is lim-
ited to non-asymmetric reactions. For example, Backvall et al.
have described the application of the Shvo catalyst,[10] and re-
ductions catalyzed by [RuH(NH3)(PMe3)4] have been reported
by Yamamoto.[11] A protocol for the enantioselective transfer
hydrogenation of the N-aryl imines in isopropanol has not yet
been developed, but this would be highly desirable.
In a previous study, some of us described the extremely
high activity of Ru complexes, bearing pybox (2,6-bis(oxazol-
ine)pyridine) and monodentate P-ligands, in the transfer hydro-
genation of ketones.[12] We now describe the application of
these complexes in the highly enantioselective reduction of N-
aryl imines under both hydrogenation and transfer hydrogena-
tion conditions.
A more appealing, safer approach to the hydrogenation of
imines is the use of isopropanol as the hydrogen donor.[3] This
[a] Dr. M. Vaquero, Dr. A. Pizzano
Instituto de Investigaciones Quꢀmicas (IIQ) and
Centro de Innovaciꢁn en Quꢀmica Avanzada (ORFEO-CINQA)
CSIC and Universidad de Sevilla
Amꢂrico Vespucio 49, 41092 Sevilla (Spain)
E-mail: pizzano@iiq.csic.es
Following a preliminary screen (see Table 1) we became in-
terested in a set of Ru complexes bearing pybox and mono-
dentate phosphane and phosphite ligands (Figure 1). These
complexes were simply prepared by reaction of the corre-
sponding ethylene complex trans-[Ru(Cl)2(R-pybox)(C2H4)] (R-
pybox=Ph-pybox (1a), Ind-Pybox (2a)) with an excess of the
P-ligand. By using this procedure, novel complexes 1e, 1 f, 1g,
2d, and 2g were prepared; complexes 1b–1d are already
known.[12] Examination of the NMR spectra indicated that all
the new compounds were obtained as trans-isomers.
[b] E. Menꢂndez-Pedregal, Dr. E. Lastra, Prof. P. Gamasa
Laboratorio de Compuestos Organometꢃlicos y Catꢃlisis
(Unidad Asociada al CSIC)
Departamento de Quꢀmica Orgꢃnica e Inorgꢃnica
Instituto de Quꢀmica Organometꢃlica “Enrique Moles”
Universidad de Oviedo, 33006 Oviedo (Spain)
E-mail: pgb@uniovi.es
[**] Pybox=2,6-bis(oxazoline)pyridine
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405276.
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Communication
bifunctional outer-sphere mechanism) that are used for the
highly enantioselective hydrogenation of 3a.[2j,13]
Figure 1. Ru complexes for the asymmetric reduction of imines, which con-
tain pybox (2,6-bis(oxazoline)pyridine) and monodentate phosphane and
phosphite ligands.
Table 1. Hydrogenation of 3a with complexes 1 and 2[a]
Considering that the hydrogenation reactions were per-
formed in isopropanol in the presence of base (i.e., typical
transfer hydrogenation conditions for the reduction of ke-
tones), we were also interested in examining the reactivity of
1d under the same reaction conditions, but under a nitrogen
atmosphere. Most surprisingly, we observed full conversion of
imine 3a into amine 4a with an exceedingly high level of
enantioselectivity (99% ee, Table 2, entry 1). After this unex-
Entry
Catalyst
Conv. [%]
ee of 4a [%]
(conformation)
precursor
1
2
3
1a
1b
1c
1d
1d
1e
1 f
1g
2d
2g
4
22
17
95
99
99
11
87
95
79
n.d.
n.d.
n.d.
99 (S)
99 (S)
97 (S)
n.d.
92 (S)
95 (R)
63 (R)
4
5[b]
6
7
8
9
10
Table 2. Transfer hydrogenation of 3a with complexes 1 and 2.[a]
Entry
Catalyst
precursor
Conv. [%]
ee of 4a [%]
(conformation)
[a] Conditions: 20 bar H2, 608C, iPrOH, S/C/B=100:1:5, using KOtBu as
a base, 24 h. Conversion was determined by 1H NMR analysis. Enantio-
meric excess was determined by HPLC analysis, not determined (n.d.) for
conversions below 30%. [b] Reaction performed at 708C with S/C/B=
500:1:5.
1
2
3
4
5
6
1d
1e
1g
2d
2g
1b
>99
>99
84
>99
63
99 (S)
99 (S)
95 (S)
99 (R)
76 (R)
0
Initially, the hydrogenation of imine 3a by using complexes
1 and 2 under standard reaction conditions (20 bar of hydro-
gen, 608C, S/C/B=100:1:5, iPrOH, using KOtBu as a base) was
carried out [Eq. (1)]. The results indicated that the performance
of the catalyst was very dependent upon the nature of the
ligand L. Notably, the ethylene derivative 1a (Table 1, entry 1)
and the phosphane derivatives 1b and 1c (entries 2 and 3)
gave slower reactions than their phosphite counterparts. Of
the latter, P(OMe)3 and P(OEt)3 derivatives gave very high
levels of conversion (entries 4 and 6). In contrast, the cyclic
phosphite derivative 1g offered a lower level of conversion
(entry 8), which significantly decreased for the catalyst bearing
the bulkier P(OiPr)3 ligand (entry 7). Similarly, in the set of in-
denyl catalysts, the P(OMe)3 derivative 2d offered a better
degree of activity compared to the P(OCH2)3CEt derivative 2g
(entries 9 and 10). Owing to the opposite configuration of the
pybox ligand, (R)-4a was predominantly produced in the reac-
tions with complexes 2. Regarding the enantioselectivity, com-
plexes 1d, 1e, and 2d, which contain relatively small phos-
phite ligands, delivered amines with the highest levels of enan-
tioenrichment, ranging from 95 to 99% ee. In addition, com-
plex 1d was also able to complete a reaction at 708C with an
S/C=500, to give the amine 4a in 99% ee (entry 5). Most re-
markably, catalysts that were generated from 1d, 1e, and 2d
are the first examples of Ru catalysts without reactive NH
ligand fragments (characteristic of catalysts operating by the
[a] Conditions: 608C, iPrOH, S/C/B=100:1:5, using KOtBu as a base, 24 h.
Conversion was determined by H NMR analysis. Enantiomeric excess was
determined by HPLC analysis.
1
pected result, we sought to investigate whether this reactivity
was more general by examining other catalyst precursors. Like-
wise, P(OEt)3 derivative 1e also produced full conversion to
amine 4a with a very high level of enantioselectivity (99% ee,
entry 2). On the other hand, the presence of the cyclic phos-
phite in 1g led to a small decrease in enantioselectivity
(entry 3). Regarding the indenyl complexes, 2d also produced
complete conversion to give the amine 4a with an excellent
level of enantioselectivity (entry 4); whereas, the hydrogena-
tion with 2g was achieved in lower yield and enantioselectivity
(entry 5). Notably, no reaction was observed when using phos-
phane catalyst 1b.
A comparison between the results collected in Tables 1 and
2 indicated a very close performance of P(OMe)3 and P(OEt)3
derived catalysts under both hydrogenation and transfer hy-
drogenation conditions. This similarity led us to investigate
whether the reactions that were performed under hydrogen
pressure were in fact transfer hydrogenation reactions. This
was investigated by examining various hydrogenation reac-
tions with deuterium-labeled reagents (Scheme 1).[14,15] As
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Table 3. Reduction of imines 3 with complex 1d.[a]
Entry
Substrate
Conv. [%]
ee of 4 [%]
(conformation)
1
2
3
4
3b
3c
3d
3e
3 f
3 f
3g
3h
92
95
91
98
67
79
100
100
98 (S)
97 (S)
96 (S)
99 (S)
98 (S)
93 (S)
98 (S)
99 (S)
5
6[b]
7
8
[a] See footnote [a] of Table 1 for reaction conditions. [b] Reaction per-
formed at 708C.
Scheme 1. Deuteration reactions of 3a by using 1d as a catalyst precursor.
All reactions were performed at 708C, S/C/B=100:1:5 for 24 h.
tion of several aniline and p-anisyl imines at 608C and 20 bar
H2 (Table 3). p-F imine 3b was hydrogenated with 92% conver-
sion to the amine 4b in 98% ee (entry 1). Likewise, p-tolyl sub-
strate 3c was reduced with 95% conversion to amine 4c in
97% ee, and m-MeO imine 3d produced the product 4d in
96% ee (entries 2 and 3). Imines derived from p-anisidine also
showed high levels of enantioselectivity, ranging from 98 to
99% ee (entries 4, 5, 7, and 8). Moreover, these substrates
showed high levels of conversion to the products with the ex-
ception of 3 f, which only reacted in a moderate 67% yield
(entry 5). This could be improved to 79% by carrying out the
reaction at 708C, although a decrease on enantioselectivity
was then observed (93% ee, entry 6).
a preliminary test, we examined the behavior of a 0.15m solu-
tion of 3a in (CD3)2CDOD at 608C. Interestingly, a selective la-
beling of the methyl position was observed, with 95% incorpo-
ration of deuterium at this position after 24 h. This observation
is indicative of an exchange of the NH proton of the enamine
form of 3a with the OD deuterium of the solvent. The hydroxyl
group of the solvent also exchanges with molecular hydrogen
under the hydrogenation conditions. Thus, the deuterium con-
tent of the hydroxyl group was reduced from 95 to 40% after
the reaction of 3a with catalyst precursor 1d in (CD3)2CDOD at
20 bar of H2 and 708C. This reaction showed 20% incorpora-
tion of deuterium in the benzylic position of 4a. In contrast,
a reaction performed under the same conditions but under
a nitrogen atmosphere showed 94% deuteration in the benzyl-
ic position of 4a. On the other hand, a lower degree of deuter-
ation (70%) was observed in the reaction performed under
20 bar of D2 in (CH3)2CHOH. However, the aforementioned ex-
change between the gas phase and the solvent can reduce
the deuterium incorporation at the stereogenic carbon. We
therefore proceeded to examine the reaction under 20 bar of
D2 in (CH3)2CHOD. Accordingly, the extent of deuterium incor-
poration increased to 88%. Notably, it is interesting to com-
pare the latter result with that obtained under transfer hydro-
genation conditions in (CH3)2CHOD, which led to only 2% in-
corporation of deuterium. Therefore, the comparison of the
deuterium incorporation in reactions performed in the pres-
ence and the absence of deuterium (both in (CH3)2CHOD and
(CD3)2CDOD) indicates the profound effect that the introduc-
tion of molecular hydrogen has on the reaction. Overall, the la-
beling experiments show that, under hydrogenation condi-
tions, the main reducing agent is indeed the molecular hydro-
gen. Most importantly, despite the opposite deuterations that
were observed, minimal variation in the levels of enantioselec-
tivity (96–99% ee) were ob-
In addition, the scope of the catalyst derived from 1d under
transfer hydrogenation conditions was examined. Interestingly,
the results exceeded those obtained under hydrogenation con-
ditions. The reduction of 3b proceeded with 93% conversion,
to give the product 4b in 98% ee; while the rest of imines re-
acted with full conversion to give the corresponding amines in
99% ee [Eq. (2)].
In addition, we have observed that the catalyst generated
from 1d exhibited a high degree of chemoselectivity for the
reduction of the olefin in imine 5 [Eq. (3)].
Accordingly, under transfer hydrogenation conditions (608C,
24 h), full conversion of the substrate 5 was observed, to give
a mixture of 6 and 7 in a 95:5 ratio. At the same temperature
served in these reactions.
Following the outstanding re-
sults obtained in the hydrogena-
tion of imine 3a, we proceeded
to examine the performance of
complex 1d in the hydrogena-
Chem. Eur. J. 2015, 21, 549 – 553
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551
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Communication
under 20 bar of H2, full conversion and a 70:30 ratio of 6 and 7
was obtained. Remarkably, the allyl amine was not detected in
these experiments. In contrast, Morris et al. reported a signifi-
cant yield of the corresponding allyl amine from the hydroge-
nation of the N-phenyl analogue of 5 by using a Ru–diphos-
phine diamine catalyst.[16] This observation is in accordance
with the expected reactivity of a catalyst that is operating by
an outer-sphere bifunctional mechanism.[17] Conversely, the
data reported herein for hydrogenations catalyzed by 1 and 2
suggest an inner-sphere mechanism, which involves imine co-
ordination. Likewise, in the asymmetric transfer hydrogenation
of aryl ketones catalyzed by compounds 1, the mechanism
was proposed to involve ketone insertion (Figure 2, A).[12] Nota-
In summary, a highly enantioselective catalytic system,
based on Ru complexes bearing pybox and monodentate
phosphite ligands, for the reduction of N-aryl imines derived
from acetophenones is reported. The catalyst remarkably
shows very high levels of enantioselectivity, using either hydro-
gen gas or isopropanol as proton sources. The very similar per-
formance observed under both reaction conditions point to
a common active catalyst for the two types of transformations.
Therefore, the present study provides the first description of
an asymmetric hydrogenation/transfer hydrogenation protocol
for the reduction of imines.[25] Further studies to investigate
the mechanism and broaden the scope of this catalytic system
are currently in progress.
Acknowledgements
Junta de Andalucꢀa (2009/FQM-4832) and MICINN (CTQ2011-
26481) are acknowledged for financial support. E.M.P. thanks
the FICYT (Principado de Asturias) for a Ph.D. fellowship.
Keywords: amines · asymmetric catalysis · hydrogenation ·
ruthenium · transfer hydrogenation
Figure 2. Proposed intermediates A–D in the Ru-catalyzed hydrogenation of
ketones and imines.
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ˇ ´
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Received: September 15, 2014
Published online on November 20, 2014
Chem. Eur. J. 2015, 21, 549 – 553
www.chemeurj.org
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