Asymmetric Transfer Hydrogenation of Imines using Alcohol: Efficiency and Selectivity are Influenced by the Hydrogen Donor

Article abstract of DOI:10.1002/anie.201604025

The influence of the alcohol, as the hydrogen donor, on the efficiency and selectivity of the asymmetric transfer hydrogenation (ATH) of imines is reported for the first time. This discovery not only leads to a highly enantioselective access to N-aryl and N-alkyl amines, but also provides new insight into the mechanism of the ATH of imines. Both experimental and computational studies provide support for the reaction pathway involving an iridium alkoxide as the reducing species.

Full text of DOI:10.1002/anie.201604025

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International Edition: DOI: 10.1002/anie.201604025
German Edition: DOI: 10.1002/ange.201604025
Reduction
Asymmetric Transfer Hydrogenation of Imines using Alcohol:
Efficiency and Selectivity are Influenced by the Hydrogen Donor
Hui-Jie Pan, Yao Zhang, Chunhui Shan, Zhaoyuan Yu, Yu Lan,* and Yu Zhao*
Abstract: The influence of the alcohol, as the hydrogen donor,
on the efficiency and selectivity of the asymmetric transfer
hydrogenation (ATH) of imines is reported for the first time.
This discovery not only leads to a highly enantioselective access
to N-aryl and N-alkyl amines, but also provides new insight
into the mechanism of the ATH of imines. Both experimental
and computational studies provide support for the reaction
pathway involving an iridium alkoxide as the reducing species.
D
evelopment of efficient methods for the preparation of
chiral amines in high enantiopurity has long been an
important goal in organic synthesis because of their wide
use in fine-chemicals and pharmaceutical industries.[1] One of
the most explored reactions for this purpose is the asymmetric
reduction of imines using either molecular hydrogen [asym-
metric hydrogenation (AH)][2] or other reducing agents
including formic acid, silanes, alcohols, the Hantzsch ester,
etc. [asymmetric transfer hydrogenation (ATH)].[3] Among
these agents, alcohol is highly preferred as a convenient,
economical, and environmentally benign choice, with 2-
propanol used almost exclusively. Despite the great success
with ATH of ketones using alcohol,[4] the related ATH of
imines using alcohol proved to be extremely challenging.
Highly enantioselective variants remained elusive until recent
reports from the groups of Beller, Morris, and Yus.[5] We
report herein our recent discovery that the efficiency and
enantioselectivity of iridium-catalyzed ATH of imines can be
easily tuned by the use of different alcohols as the hydrogen
donor. Such a simple yet unprecedented modification not
only enabled a highly enantioselective ATH of N-aryl as well
as N-benzyl imines, but also provided important insights into
the mechanism of ATH of imines using alcohol.
Scheme 1. Identification of the alcohol effect in ATH. PMP=para-
methoxyphenyl.
benzyl amine only moderate enantioselectivity could be
achieved [85:15 e.r. for (S)-3a]. In an effort to better
understand this reaction and to overcome this limitation, we
decided to examine ATH of the preformed N-benzyl imine 6a
using alcohol as the hydrogen donor. After extensive
optimization using 2-propanol (1b), however, the selectivity
remained unsatisfactory (88:12 e.r.; Scheme 1b).
An intriguing discovery was made during an attempted
combination of the ATH of 6a with the desymmetrization of
a meso diol. By using 1c instead of 1b under otherwise
identical reaction conditions, the amine (S)-3a was obtained
with a much higher e.r. value of 95:5. The identity of the
hydrogen donor had a dramatic influence on the selectivity of
the transfer hydrogenation. This result is in contrast to the
well-established bifunctional catalysis mechanism of asym-
metric transfer hydrogenation, pioneered by the groups of
Noyori and Ikariya, in which the metal hydride served as the
reductant and the identity of the hydrogen donor (formic acid
or alcohol) should play no role in the enantio-determining
step.[8,9]
Recently our group reported the first example of asym-
metric amination of alcohols using the borrowing-hydrogen
methodology catalyzed by the iridium complex 4 and chiral
phosphoric acid 5 (Scheme 1a).[6,7] While it represents an
attractive redox-neutral synthesis of N-aryl amines in high
enantioselectivity (e.g. 2a), for the synthetically more flexible
Following this discovery, we decided to examine a wide
range of primary and secondary alcohols, as well as diols to
further evaluate this interesting hydrogen-donor effect. As
shown in Scheme 2, both efficiency and enantioselectivity of
the ATH of 6a were clearly affected by the alcohol used.[10]
While there is no clear trend on the influence of enantiose-
lectivity by different alcohols, benzylic alcohols in general
provided higher efficiency, and 1c remained the optimal
choice.
[*] H.-J. Pan, Y. Zhang, Prof. Y. Zhao
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore 117543 (Singapore)
E-mail: zhaoyu@nus.edu.sg
Homepage: http://zhaoyu.science.nus.edu.sg
C. Shan, Z. Yu, Prof. Y. Lan
School of Chemistry and Chemical Engineering, Chongqing Univer-
sity, Chongqing, 400030 (P.R. China)
E-mail: lanyu@cqu.edu.cn
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201604025.
This catalytic system using 1c as the hydrogen donor
could be applied to the ATH of a wide range of N-benzyl
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reaction conditions, the N-PMP amine 2a was obtained in
a high yield of 88% with an excellent 97:3 e.r. (Scheme 3b).
This set of reaction conditions again proved general to
produce a range of aryl,methyl-substituted chiral amines (2a–
g) with excellent selectivity (up to 98:2 e.r.). More signifi-
cantly, the dialkyl-substituted amines 2h and 2i could also be
accessed with excellent e.r. values. This method is not limited
to chiral amines bearing a methyl substituent. The chiral
amine 2j was obtained with a high e.r. value of 93:7. Overall,
this simple and general procedure represents a rare example
of highly enantioselective transfer hydrogenation of N-aryl
and N-alkyl imines using alcohol.
Efforts were then directed towards a better understanding
of the reaction mechanism of this catalytic system. For the
ATH of ketones using alcohol and the Noyori–Ikariya-type
complexes, the concerted bifunctional catalysis mechanism
was widely accepted,[8a–d] but recent studies also point to the
alternative stepwise ion-pair mechanism for ruthenium catal-
ysis, especially by taking into consideration the protic solvent
effect.[8e–g] For the corresponding ATH of imines, in contrast,
an alternative anionic mechanism was proposed and involves
activation of the imine by an external acid cocatalyst.[9] The
original ATH of imines catalyzed by a Ru/TsDPEN complex
(e.g., 9 in Scheme 4) utilizes formic acid/Et3N as the terminal
Scheme 2. Screening of hydrogen donors for ATH. The reactions were
carried out under an N2 atmosphere. The yield of (S)-3a was
determined by GC using an internal standard. The e.r. value was
determined by HPLC. See the Supporting Information for details.
imines, the type of substrate which has proven to be highly
challenging (Scheme 3a). The substrates were directly used as
a mixture of geometrical isomers. For the aryl, methyl-
containing substrates, various substituents on the aryl ring
could be well-tolerated to yield 3a–h in high efficiencies and
good to excellent selectivities. For dialkyl-substituted chiral
amines such as 3i, the enantioselectivity dropped slightly to
87:13. In addition to N-benzyl substrates, the para-methoxy-
benzyl (PMB)-protected amine could be obtained in similar
yield and selectivity (7).
Interestingly, a similar trend with alcohols as the hydrogen
donor was observed for the ATH of N-aryl imines as well (see
the Supporting Information for details). Under the optimal
Scheme 4. Mechanistic studies for ATH of imines. See footnote of
Scheme 2. Ts=4-toluenesulfonyl.
reductant, while isopropyl alcohol was reported to be
unsuitable for this purpose.[3c] For the reduction of an imine
using the [Ru-H] complex related to 9, an acid cocatalyst was
also reported to be necessary.[9c] To provide direct evidence
for the reaction mechanism, we synthesized the iridium
hydride 8 (~ 2.4:1 d.r.), by using the procedure reported by the
group of Rauchfuss,[11] and subjected it to the stoichiometric
reduction of 6a (Scheme 4a). Similar to the case of Ru-H,[9c]
8
alone could not reduce 6a at all. Only by adding the chiral
phosphoric acid cocatalyst, a highly efficient ATH of 6a was
achieved.
Scheme 3. Scope of ATH of N-benzyl and N-aryl imines. See footnote
of Scheme 2. Yields are those of isolated products. PMB=para-
methoxybenzyl.
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For the intriguing hydrogen-donor effect in our iridium-
A (derived from 4 via TS-A) may reduce the activated
catalyzed process, we hypothesized the following two possible
scenarios:[12] 1) the diol functionality may activate the imine
as a general acid (because of its elevated acidity relative to
simple alcohol); 2) an alternative reducing agent may be
operative instead of the iridium hydride. The corresponding
iridium alkoxide species may reduce the imine directly
through a Meerwein–Ponndorf–Verley (MPV) reduction
pathway. Such a possibility has been suggested for transfer
hydrogenation of ketones using iridium-based catalysts.[13] We
then turned our attention to the differentiation of the two
possibilities.
Different alcohols were examined for the ATH of 6a
under acid-free conditions where 8 was shown to be
unreactive (Scheme 4b). When 1b was used (even with
a higher loading), no conversion into (S)-3a was observed at
all. In contrast, benzylic alcohols such as 1a and 1d provided
the desired product in noticeable to moder-
ate yields. The diol 1g again was ineffective,
while the diols 1c, 1i, and 1j, which are
electronically modified, yielded (S)-3a in
good to excellent efficiency, with the more
electron-rich reagent providing the highest
reactivity. Clearly the trend of reactivity
(e.g., 1c versus 1i, 1j) does not correlate
with the acidity of the alcohols utilized. In
addition, as shown in Scheme 4a, by adding
1c as an additive, the ATH of the imine 8
also failed to produce the amine product in
good efficiency. All these observations
seemed to support the iridium alkoxide
pathway.
substrate 11 via TS-B to form 12 and 13 with the regeneration
of 4. Alternatively the Ir-H B which is formed from 4 (via TS-
C) may reduce the activated imine (Figure 1b; Ir-H path-
way).[17] The free-energy profiles for these processes in
toluene were calculated (in the units of kcalmolÀ1). Among
the iridium complexes, 4 was set to a relative value of zero.
As the data shows, A could be formed from 4 and 1a with
ease (TS-A; 12.3 kcalmolÀ1). The hydride transfer from A to
11 (activated by 5) could take place via the transition-state
TS-B with 26.6 kcalmolÀ1 overall activation free energy in
toluene, and results in the formation of acetophenone (12)
and chiral amine phosphate 13, together with the regener-
ation of 4 exothermally. In TS-B, the lengths for the forming
À
À
C H bond and breaking C H bond were 1.53 ꢀ and 1.31 ꢀ,
respectively. The distance between the hydrogen atom in the
reacting imine and oxygen atom in phosphoric acid moiety
It is also noteworthy that the hydrogen-
donor effect does not operate for ATH of an
imine catalyzed by the Noyori catalyst 9,
thus emphasizing the difference of the
reactivity of ruthenium- and iridium-based
catalysts (Scheme 4c).
To provide further evidence to the
iridium alkoxide pathway, the use of the
enantiopure diol (R,R)-1k for ATH of 6a
was carried out in the absence of acid
(Scheme 4d). An achiral iridium complex
10 was used in this instance, so that the diol
(R,R)-1k was the only source of chirality.[14]
As it turned out, a low but meaningful
e.r. value of 56:44 was observed for (S)-3a.
This chirality transfer lent further support
for an iridium alkoxide mechanism.
The density functional theory (DFT)
method M06-2X,[15] based on the B3LYP
optimized geometries of stationary points,
was also carried out to study the ATH of
imines. The optimization was carried out in
the presence of toluene with C-PCM solva-
tion model,[8e–g,16] and the calculated Gibbs
free energies based on the structures opti-
mized in toluene are discussed below. As
depicted in Figure 1a, the iridium alkoxide Figure 1. Free-energy profiles for the hydride transfer. TS=transition state.
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was 1.81 ꢀ, thus indicating a regular hydrogen bond. How-
ever, the distance between the hydrogen atom in the
coordinated ethanediamine ligand and the oxygen atom in
phosphoric acid moiety was as long as 3.47 ꢀ. Therefore, the
hydrogen bond between the phosphoric acid moiety and the
coordinated ethanediamine ligand could not be observed, and
could be attributed to the repulsion between phosphoric acid
and the coordinated diamine.
[1] For selected recent reviews, see: a) Chiral Amine Synthesis:
Methods, Developments and Applications (Ed.: T. C. Nugent),
Wiley-VCH, Weinheim, 2010; b) T. C. Nugent, M. El-Shazly,
Adv. Synth. Catal. 2010, 352, 753 – 819; c) C. Wang, B. Villa-
Marcos, J. Xiao, Chem. Commun. 2011, 47, 9773 – 9785.
[2] For selected reviews, see: a) N. Fleury-Brꢁgeot, V. de la Fuente,
S. Castillꢂn, C. Claver, ChemCatChem 2010, 2, 1346 – 1371; b) J.-
H. Xie, S.-F. Zhu, Q.-L. Zhou, Chem. Rev. 2011, 111, 1713 – 1760;
For selected recent examples, see: c) C. Moessner, C. Bolm,
Angew. Chem. Int. Ed. 2005, 44, 7564 – 7567; Angew. Chem. 2005,
117, 7736 – 7739; d) S.-F. Zhu, J.-B. Xie, Y.-Z. Zhang, S. Li, Q.-L.
Zhou, J. Am. Chem. Soc. 2006, 128, 12886 – 12891; e) Q. Yang, G.
Shang, W. Gao, J. Deng, X. Zhang, Angew. Chem. Int. Ed. 2006,
45, 3832 – 3835; Angew. Chem. 2006, 118, 3916 – 3919; f) M. T.
Reetz, O. Bondarev, Angew. Chem. Int. Ed. 2007, 46, 4523 –
4526; Angew. Chem. 2007, 119, 4607 – 4610; g) C. Li, C. Wang,
B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2008, 130, 14450 –
14451; h) C. Li, B. Villa-Marcos, J. Xiao, J. Am. Chem. Soc. 2009,
131, 6967 – 6969; i) Z. Han, Z. Wang, X. Zhang, K. Ding, Angew.
Chem. Int. Ed. 2009, 48, 5345 – 5349; Angew. Chem. 2009, 121,
Alternatively, B could be formed from 4 and 1a with the
release of 12 via the transition-state TS-C with an activation
free energy of 28.7 kcalmolÀ1 (higher than that of TS-B). In
our system, the possible intermediates/TSs for the stepwise
mechanism of the formation of B[8e–g] could not be allocated.
The use of an iridium-based catalyst and aprotic solvent of
toluene is believed to be the key factors. Once formed, B can
reduce the activated imine with a very low barrier of
12.2 kcalmolÀ1 (TS-D) to form 13 and regenerate 4. In TS-
D hydrogen-bond interaction between the acid to the imine
could be located, but similar to TS-B, the hydrogen-bond
interaction between the oxygen atom in the phosphoric acid
and the ethanediamine ligand on iridium could not be located.
Overall, Ir-H is more effective for the reduction, but the
formation of Ir-H requires a higher activation barrier. The
direct hydride transfer from the iridium alkoxide to the
activated imine is thus believed to be operative in this
iridium-catalyzed ATH of imines. As to the stereoselectivity
of this ATH system, it is possible that hydrogen-bond
interactions between the optimal diol 1c and the catalyst
and substrate may partially contribute to the enhanced
selectivity. More detailed computations on the comparison
of alcohols/diols (with or without the acid co-catalyst) are
ongoing to gain more insight into the origin of the stereose-
lectivity.
´
5449 – 5453; j) N. Mrsic, A. J. Minnaard, B. L. Feringa, J. G.
de Vries, J. Am. Chem. Soc. 2009, 131, 8358 – 8359; k) G. Hou, F.
Gosselin, W. Li, J. C. McWilliams, Y. Sun, M. Weisel, P. D. Shea,
C.-Y. Chen, I. W. Davies, X. Zhang, J. Am. Chem. Soc. 2009, 131,
9882 – 9883; l) G. Hou, R. Tao, Y. Sun, X. Zhang, F. Gosselin, J.
Am. Chem. Soc. 2010, 132, 2124 – 2125; m) D. S. Wang, Q. A.
Chen, W. Li, C. B. Yu, Y. G. Zhou, X. M. Zhang, J. Am. Chem.
Soc. 2010, 132, 8909 – 8911; n) Q. A. Chen, D. S. Wang, Y. G.
Zhou, Y. Duan, H. J. Fan, Y. Yang, Z. Zhang, J. Am. Chem. Soc.
2011, 133, 6126 – 6129; o) Q.-A. Chen, M.-W. Chen, C.-B. Yu, L.
Shi, D.-S. Wang, Y. Yang, Y.-G. Zhou, J. Am. Chem. Soc. 2011,
133, 16432 – 16435; p) M. Rueping, R. M. Koenigs, Chem.
Commun. 2011, 47, 304 – 306; q) S. Zhou, S. Fleischer, K.
Junge, M. Beller, Angew. Chem. Int. Ed. 2011, 50, 5120 – 5124;
Angew. Chem. 2011, 123, 5226 – 5230; r) Z.-Y. Ding, F. Chen, J.
Qin, Y.-M. He, Q.-H. Fan, Angew. Chem. Int. Ed. 2012, 51, 5706 –
5710; Angew. Chem. 2012, 124, 5804 – 5808.
In conclusion, we have developed a highly selective ATH
of N-aryl and N-alkyl ketimines, using alcohol as the hydro-
gen donor, catalyzed by a chiral iridium complex in cooper-
ation with a chiral phosphoric acid. The discovery of the
hydrogen-donor effect on the reactivity and enantioselectivity
was key to the success of this system. Based on the
experimental evidence and DFT calculations, a mechanism
involving an iridium alkoxide as the reducing agent is
proposed.
[3] For selected reviews, see: a) S. Gladiali, E. Alberico, Chem. Soc.
Rev. 2006, 35, 226 – 236; b) M. Rueping, E. Sugiono, F. R.
Schoepke, Synlett 2010, 852 – 865; For selected examples using
formic acid, see: c) N. Uematsu, A. Fujii, S. Hashiguchi, T.
Ikariya, R. Noyori, J. Am. Chem. Soc. 1996, 118, 4916 – 4917;
d) J. Mao, D. C. Baker, Org. Lett. 1999, 1, 841 – 843; e) R.
Kadyrov, T. H. Riermeier, Angew. Chem. Int. Ed. 2003, 42,
5472 – 5474; Angew. Chem. 2003, 115, 5630 – 5632; for selected
examples using hydrosilane: f) X. Verdaguer, U. E. W. Lange,
S. L. Buchwald, Angew. Chem. Int. Ed. 1998, 37, 1103 – 1107;
Angew. Chem. 1998, 110, 1174 – 1178; g) B. H. Lipshutz, H.
Shimizu, Angew. Chem. Int. Ed. 2004, 43, 2228 – 2230; Angew.
Chem. 2004, 116, 2278 – 2280; h) K. A. Nolin, R. W. Ahn, F. D.
Toste, J. Am. Chem. Soc. 2005, 127, 12462 – 12463; i) A. V.
Malkov, A. Mariani, K. N. MacDougall, P. Kocovsky, Org. Lett.
2004, 6, 2253 – 2256; for selected examples using Hantzch ester:
j) M. Rueping, E. Sugiono, C. Azap, T. Theissmann, M. Bolte,
Org. Lett. 2005, 7, 3781 – 3783; k) S. Hoffmann, A. M. Seayad, B.
List, Angew. Chem. Int. Ed. 2005, 44, 7424 – 7427; Angew. Chem.
2005, 117, 7590 – 7593; l) M. Rueping, A. P. Antonchik, T.
Theissmann, Angew. Chem. Int. Ed. 2006, 45, 3683 – 3686;
Angew. Chem. 2006, 118, 3765 – 3768; m) M. Rueping, A. P.
Antonchik, T. Theissmann, Angew. Chem. Int. Ed. 2006, 45,
6751 – 6755; Angew. Chem. 2006, 118, 6903 – 6907; n) R. I.
Storer, D. E. Carrera, Y. Ni, D. W. C. MacMillan, J. Am. Chem.
Soc. 2006, 128, 84 – 86; o) S. Hoffmann, M. Nicoletti, B. List, J.
Am. Chem. Soc. 2006, 128, 13074 – 13075; p) G. Li, Y. Liang, J. C.
Antilla, J. Am. Chem. Soc. 2007, 129, 5830 – 5831.
Acknowledgments
We are grateful for the generous financial support from
Singapore National Research Foundation (R-143-000-477-
281) and the Ministry of Education of Singapore (R-143-000-
613-112). The computation part was supported by the
National Science Foundation of China (Grant No. 21372266).
Keywords: amines · cooperative effects · enantioselectivity ·
hydrogenation · iridium
[4] R. Noyori, S. Hashiguchi, Acc. Chem. Res. 1997, 30, 97 – 102.
4
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[5] a) S. Zhou, S. Fleischer, K. Junge, S. Das, D. Addis, M. Beller,
Res. Dev. 2006, 10, 457 – 463; e) J. E. D. Martins, G. J. Clarkson,
Angew. Chem. Int. Ed. 2010, 49, 8121 – 8125; Angew. Chem.
2010, 122, 8298 – 8302; b) A. A. Mikhailine, M. I. Maishan, R. H.
Morris, Org. Lett. 2012, 14, 4638 – 4641; c) W. Zuo, A. J. Lough,
Y. F. Li, R. H. Morris, Science 2013, 342, 1080 – 1083; d) O.
Pablo, D. Guijarro, G. Kovꢃcs, A. Lleds, G. Ujaque, M. Yus,
Chem. Eur. J. 2012, 18, 1969 – 1983.
M. Wills, Org. Lett. 2009, 11, 847 – 850; f) R. Soni, F. K. Cheung,
G. C. Clarkson, J. E. D. Martins, M. A. Graham, M. Wills, Org.
Biomol. Chem. 2011, 9, 3290 – 3294; g) J. S. M. Samec, A. H. Ell,
J. B. ꢀberg, T. Primalov, L. Eriksson, J.-E. Bꢄckvall, J. Am.
Chem. Soc. 2006, 128, 14293 – 14305; h) C. P. Casey, T. B. Clark,
I. A. Guzei, J. Am. Chem. Soc. 2007, 129, 11821 – 11827; i) S. À y.
Shirai, H. Nara, Y. Kayaki, T. Ikariya, Organometallics 2009, 28,
802 – 809.
[6] a) Y. Zhang, C.-S. Lim, D. S. B. Sim, H.-J. Pan, Y. Zhao, Angew.
Chem. Int. Ed. 2014, 53, 1399 – 1403; Angew. Chem. 2014, 126,
1423 – 1427; b) Z.-Q. Rong, Y. Zhang, H. B. R. Chua, H.-J. Pan,
Y. Zhao, J. Am. Chem. Soc. 2015, 137, 4944 – 4947; for more
recent diastereo- or enantioselective amination of alcohols, see:
c) N. J. Oldenhuis, V. M. Dong, Z. Guan, J. Am. Chem. Soc. 2014,
[10] The reactions were complicated by a small amount of amine side
product, which was formed by transfer of the amino group in 6 to
the ketones generated from the alcohol 1 followed by reduction.
[11] C. S. Letko, Z. M. Heiden, T. B. Rauchfuss, S. R. Wilson, Inorg.
Chem. 2011, 50, 5558 – 5566.
ˇ
136, 12548 – 12551; d) M. Pena-Lꢂpez, H. Neumann, M. Beller,
Angew. Chem. Int. Ed. 2016, 55, 7826 – 7830; Angew. Chem.
2016, 128, 7957 – 7961.
[12] A third possibility could be operative: the use of different
alcohols may lead to the formation of [Ir-H] with a different
d.r. value, which in turn results in the difference in ee value of the
chiral amine product. By following the stoichiometric reactions,
using NMR spectroscopy, of 4 and either 1b or 1c in the absence
of imine, however, we observed the [Ir-H] formation in a small
amount and with the similar d.r. value of 2.1:1 and 2.3:1 (see the
Supporting Information). This observation ruled out this possi-
bility for the alcohol effect.
[7] For selected reviews on the borrowing-hydrogen methodology,
see: a) M. H. S. A. Hamid, P. A. Slatford, J. M. J. Williams, Adv.
Synth. Catal. 2007, 349, 1555 – 1575; b) T. D. Dixon, M. K.
Whittlesey, J. M. J. Williams, Dalton Trans. 2009, 753 – 762;
c) G. E. Dobereiner, R. H. Crabtree, Chem. Rev. 2010, 110,
681 – 703; d) G. Guillena, D. J. Ramꢂn, M. Yus, Chem. Rev. 2010,
110, 1611 – 1641; e) A. J. A. Watson, J. M. J. Williams, Science
2010, 329, 635 – 636; f) S. Bꢄhn, S. Imm, L. Neubert, M. Zhang,
H. Neumann, M. Beller, ChemCatChem 2011, 3, 1853 – 1864;
g) S. Pan, T. Shibata, ACS Catal. 2013, 3, 704 – 712. The Krische
[13] J.-W. Handgraaf, J. N. H. Reek, E. J. Meijer, Organometallics
2003, 22, 3150 – 3157.
[14] The iridium complex 10 was reported by the group of Xiao group
to be an effective AH catalyst. See: W. Tang, S. Johnston, J. A.
Iggo, N. G. Berry, M. Phelan, L. Lian, J. Bacsa, J. Xiao, Angew.
Chem. Int. Ed. 2013, 52, 1668 – 1672; Angew. Chem. 2013, 125,
1712 – 1716. While 1k could in principle lead to an enantiose-
lective generation of [Ir-H] (chiral at iridium) from 10, such
a hydride species was reported to be inactive without acid
activation of the imine substrate.
[15] Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215 – 241.
[16] a) A. Pavlova, E. J. Meijer, ChemPhysChem 2012, 13, 3492 –
3496; b) M. C. Carriꢂn, M. R. CastaÇeda, G. Espino, C. Aliende,
L. Santos, A. M. Rodrꢅguez, B. R. Manzano, F. A. Jalꢂn, A.
Lledꢂs, ACS Catal. 2014, 4, 1040 – 1053.
À
group has developed highly enantioselective catalytic C C
coupling involving transfer hydrogenation: h) J. F. Bower, M. J.
Krische, Top. Organomet. Chem. 2011, 34, 107 – 138; i) J. Moran,
M. J. Krische, Pure Appl. Chem. 2012, 84, 1729 – 1739.
[8] For selected reports, see: a) M. Yamakawa, H. Ito, R. Noyori, J.
Am. Chem. Soc. 2000, 122, 1466 – 1478; b) D. A. Alonso, P.
Brandt, S. J. M. Nordin, P. G. Andersson, J. Am. Chem. Soc.
1999, 121, 9580 – 9588; c) T. Ikariya, K. Murata, R. Noyori, Org.
Biomol. Chem. 2006, 4, 393 – 406; d) T. Ikariya, A. J. Blacker,
Acc. Chem. Res. 2007, 40, 1300 – 1308; e) P. A. Dub, T. Ikariya, J.
Am. Chem. Soc. 2013, 135, 2604 – 2619; f) P. A. Dub, N. J.
Henson, R. L. Martin, J. C. Gordon, J. Am. Chem. Soc. 2014, 136,
3505 – 3521; g) P. A. Dub, J. C. Gordon, Dalton Trans. 2016, 45,
6756 – 6781.
[9] For selected reviews and examples, see: a) S. E. Clapham, A.
Hadzovic, R. H. Morris, Coord. Chem. Rev. 2004, 248, 2201 –
2237; b) J. S. M. Samec, J.-E. Bꢄckvall, P. G. Andersson, P.
Brandt, Chem. Soc. Rev. 2006, 35, 237 – 248; c) J. B. ꢀberg,
J. S. M. Samec, J.-E. Bꢄckvall, Chem. Commun. 2006, 2771 –
2773; d) D. G. Blackmond, M. Ropic, M. Stefinvic, Org. Process
[17] The Ir-H B could also be formed from the iridium alkoxide A by
b-hydride elimination. However this TS-E was shown to be
prohibitively high in energy (52.5 kcalmolÀ1).
Received: April 26, 2016
Revised: June 14, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Reduction
The influence of alcohol, as the hydrogen
donor, on the efficiency and enantio-
selectivity of the asymmetric transfer
hydrogenation (ATH) of imines is
reported. This discovery not only leads to
a highly enantioselective access to N-aryl
as well as N-alkyl chiral amines, but also
provides new insight into the mechanism
of iridium-catalyzed ATH of imines using
alcohol.
H.-J. Pan, Y. Zhang, C. Shan, Z. Yu,
Y. Lan,* Y. Zhao*
&&&& — &&&&
Asymmetric Transfer Hydrogenation of
Imines using Alcohol: Efficiency and
Selectivity are Influenced by the
Hydrogen Donor
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!