Cyclometalated iridium complexes as highly active catalysts for the hydrogenation of imines

Article abstract of DOI:10.1055/s-0033-1340086

A robust cyclometalated iridium catalyst has been developed for highly effective hydrogenation of imines. With very low catalyst loading (down to 0.005%), good to excellent yields have been achieved for a range of substrates in a short reaction time under

Full text of DOI:10.1055/s-0033-1340086

LETTER
▌81
lCettyerclometalated Iridium Complexes as Highly Active Catalysts for the Hydro-
genation of Imines
Cyclometalated Iridium Complexes as Catalysts for Hydrogenation of Imines
Weijun Tang, Chunho Lau, Xiaofeng Wu, Jianliang Xiao*
Department of Chemistry, University of Liverpool, Liverpool, L69 7ZD, UK
Fax +44(151)7943588; E-mail: j.xiao@liv.ac.uk
Received: 20.08.2013; Accepted after revision: 04.10.2013
we report a tailor-made, more robust iridicycle, which
Abstract: A robust cyclometalated iridium catalyst has been devel-
catalyses the hydrogenation of imines with hydrogen gas
oped for highly effective hydrogenation of imines. With very low
under low catalyst loading.
catalyst loading (down to 0.005%), good to excellent yields have
been achieved for a range of substrates in a short reaction time under
mild conditions, providing an easy, efficient protocol for making
amines.
We started with preparation of the cyclometalated iridium
complexes. Using procedures reported previously,4–6 two
new cyclometalated iridium complexes were synthesised
readily from tetralone and its derivative in two steps
(Scheme 1). With the imino carbon being embedded in a
Key words: cyclometalated complexes, hydrogenation, imines,
iridium, iridicycles
ring, the resulting iridicycles C1 and C2 were expected to
be more robust in comparison with those reported before.4
Amines are important building blocks for the synthesis of
Table 1 Screening of Conditions for the Hydrogenation of Imine 1aa
numerous pharmaceutical and agrochemical substances.1
Among the various methods of synthesising amines, in-
OMe
OMe
cluding stoichiometric boron hydride and organocatalytic
reduction of C=N double bonds, transition-metal-cata-
lysed hydrogenation of imines is one of the most conve-
nient and efficient.2,3 Although significant progress has
been achieved in this area, highly efficient reduction of
C=N double bonds is still challenging. Recently, our
group4 and other groups5,6 have explored a series of cyclo-
metalated iridium compounds, some of which have been
successfully applied to transfer hydrogenation of imines
and reductive amination of ketones. More recently, we
have found that these iridicycles allow for efficient hydro-
genation of imines4f as well as N-heterocycles.4g Herein,
N
HN
C1 or C2
solvent, H2 (20 bar)
40 °C or 85 °C
2a
1a
Entry
Cat.
S/C ratio
Solvent
Temp
(°C)
Yield
(%)b
1
2
C1 or C2
C1 or C2
C1 or C2
C1 or C2
C1 or C2
C1
5000
5000
5000
5000
5000
5000
5000
5000
5000
5000
10000
20000
CH2Cl2
THF
40
40
40
40
40
40
40
40
85
85
85
85
NO
NO
NO
<2
NO
20
3
toluene
EtOH
Et2O
OMe
4
O
N
5
p-anisidine
6
TFE
4 Å MS
MW
200 °C, 4 h
L1: 61% yield
L2: 48% yield
R
R
7
C2
TFE
10
8c
9
C1
toluene
TFE
19
NaOAc
CH2Cl2
[IrCp*Cl2]2
r.t., overnight
C1
93
10c
11d
12e
C1
toluene
TFE
93
OMe
C1
90
Ir
Cl
N
C1
TFE
86
C1: R = H, 98% yield
C2: R = MeO, 98% yield
a The reaction was carried out with 1a (0.15 mmol), C1 or C2 (0.02–
0.005 mol%), solvent (0.7 mL), in reaction time of 1 h, at initial H2
pressure of 20 bar.
R
Scheme 1 Synthesis of the cyclometalated iridium complexes C1
and C2
b The yield was determined by 1H NMR with an internal standard
(1,3,5-trimethoxybenzene); NO = no reaction observed.
c NaBARF (2 equiv) was added.
SYNLETT 2014, 25, 0081–0084
Advanced online publication: 06.11.2013
d Amount of 1a used was 0.3 mmol.
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
e Amount of 1a used was 0.6 mmol, and the reaction time was 2 h.
DOI: 10.1055/s-0033-1340086; Art ID: ST-2013-D0797-L
© Georg Thieme Verlag Stuttgart · New York

82
W. Tang et al.
LETTER
Having obtained these precatalysts, the hydrogenation of
ketoimine 1a was then examined. The reduction was car-
ried out at a high substrate to catalyst (S/C) ratio of 5000
with 20 bar initial hydrogen pressure at 40 °C. As shown
in Table 1, little reaction was observed with both of the
catalysts in either polar or nonpolar common organic sol-
vents, such as CH2Cl2, THF, toluene, EtOH, and Et2O
(Table 1, entries 1–5). However, to our satisfaction, some
conversion was obtained for the reduction by using triflu-
oroethanol (TFE) as solvent (Table 1, entries 6 and 7).
This is probably due to the dissociation and/or solvation
of the chloride ion of the catalyst by the strongly ionising
TFE.7 This significant solvent effect has been noted in our
previous studies.4f,g Indeed, promoting the dissociation of
chloride with NaBARF makes the reaction work in the
nonpolar toluene (Table 1, entry 8). Full conversion was
obtained with C1 at a high temperature of 85 °C (Table 1,
entries 9 and 10). The hydrogenation reaction proceeded
well at even a higher S/C ratio of 20000 in TFE (Table 1,
entries 11 and 12). The screening indicates that C1 is
more active than C2 (Table 1, entries 6 and 7).
Table 2 Hydrogenation of Imines with C1a
R
R
N
HN
C1
TFE, H2 (20 bar)
85 °C
S/C 10000
Ar
Ar
1a–l
2a–l
Entry
Substrate Product
Yield
(%)b
OMe
HN
1
1a
90
OMe
HN
2
3
4
5
1b
1c
1d
1e
90
90
85
93
With the optimal reaction conditions in hand, the scope of
substrates was explored subsequently with C1 and the re-
sults are listed in Table 2. In general, most of the imines
were fully hydrogenated at a high S/C ratio of 10000, af-
fording good to excellent isolated yields. However, a sig-
nificant electronic effect arising from the substituents on
the aryl rings of the substrates was observed, with elec-
tron-donating groups favouring hydrogenation. Thus ex-
cellent yields were obtained for imines with methyl and
methoxy groups on the aryl rings (Table 2, entries 1–7).
However, for substrates with electron-withdrawing sub-
stituents on the aryl rings, good yields could only be ob-
tained at a higher catalyst loading (Table 2, entries 10–
12). For weakly electron-withdrawing substituents (e.g.,
Cl on one aryl ring), a good yield was afforded under the
standard conditions (Table 2, entries 8 and 9). It is worth
noting that the hydrogenation can be readily scaled up.
Thus, 1a was fully converted on a two-gram scale into the
desired amine product in two hours under the optimised
conditions, affording 93% isolated yield.
OMe
HN
OMe
HN
OMe
HN
MeO
OMe
In summary, we have synthesised a new type of robust cy-
clometalated iridium catalysts, and the catalyst has been
shown to be effective for the hydrogenation of imines at
high S/C ratios under mild conditions.8 The high activity,
air-stability and ease of preparation make the catalyst
attractive for imine hydrogenation and possibly for other
reactions as well.
HN
6
7
1f
89
91
OMe
HN
Acknowledgment
1g
MeO
MeO
We thank EPSRC for a postdoctoral fellowship (W.J.T.) and the
University of Liverpool for funding (X.F.W.). Thanks also go to the
EPSRC UK National Mass Spectrometry Facility at Swansea Uni-
versity for mass analysis.
Synlett 2014, 25, 81–84
© Georg Thieme Verlag Stuttgart · New York

LETTER
Cyclometalated Iridium Complexes as Catalysts for Hydrogenation of Imines
83
Table 2 Hydrogenation of Imines with C1a (continued)
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R
R
N
HN
C1
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Wang, Z. J.; Fan, Q. H.; Pan, J.; Xu, L. J. Org. Lett. 2008, 22,
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TFE, H2 (20 bar)
85 °C
S/C 10000
Ar
Ar
1a–l
2a–l
Entry
Substrate Product
Yield
(%)b
OMe
HN
8
1h
89
91
53
OMe
HN
9
10
11
12
1i
Cl
OMe
HN
1j
Br
Br
HN
45
1k
1l
(91)c
OMe
HN
11
(91)c
O2N
a The reaction was carried out with imine (0.3 mmol), C1 (0.01
mol%), solvent (0.7 mL), in reaction time of 1 h, at initial H2 pressure
of 20 bar.
b Isolated yield.
(5) Davies, D. L.; Al-Duaij, O.; Fawcett, J.; Giardiello, M.;
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2013, 4, 2760. (b) Djukic, J. P.; Iali, W.; Pfeffer, M.; Le
Goff, X. F. Chem. Eur. J. 2012, 18, 6063. (c) Jerphagnon, T.;
Haak, R.; Berthiol, F.; Gayet, A. J. A.; Ritleng, V.; Holuigue,
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Commun. 1996, 2105.
c Amount of C1 used was 0.1 mol%.
References and Notes
(1) For reviews, see: (a) Breuer, M.; Ditrich, K.; Habicher, T.;
Hauer, B.; Keßeler, M.; Sturmer, R.; Zelinski, T. Angew.
Chem. Int. Ed. 2004, 43, 788. (b) Blacker, J.; Martin, J. In
Asymmetric Catalysis on Industrial Scale: Challenges,
Approaches and Solutions; Blaser, H. U.; Schmidt, E., Eds.;
Wiley-VCH: Weinheim, 2004, 201.
(2) For recent reviews, see: (a) Nugent, T. C.; El-Shazly, M.
Adv. Synth. Catal. 2010, 352, 753. (b) Xie, J. H.; Zhu, S. F.;
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Zhu, S. F.; Zhou, Q. L. Chem. Rev. 2011, 111, 1713.
(d) Fleury-Bregeot, N.; de la Fuente, V.; Castillon, S.;
(8) General Procedure for the Synthesis of the
Cyclometalated Iridium Complexes: An oven-dried
Schlenk tube containing a magnetic stirrer bar was charged
with [Cp*IrCl2]2 (1 equiv), imine ligand5 (2 equiv) and
NaOAc (10 equiv). Following degassing with N2 (3 ×),
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 81–84

84
W. Tang et al.
LETTER
170.7, 162.3, 157.5, 144.7, 143.5, 138.4, 124.8, 117.6,
114.2, 113.8, 113.5, 106.9, 88.7, 55.6, 55.0, 30.2, 29.5, 23.9,
8.7. Anal. Calcd for C28H33ClIrNO2: C, 52.28; H, 5.17; N,
2.18. Found: C, 52.43; H, 5.48; N, 1.94.
Procedure for the Hydrogenation of Imines with
Cyclometalated Iridium Complex C1: A glass liner
containing a stirrer bar was charged with the requisite imine
(0.3 mmol) and TFE (0.75 mL). The mixture was stirred
until the imine was dissolved and catalyst C1 was then added
(10 μL stock solution, made by dissolving C1 in TFE: 0.03
mmol C1 in 10 mL TFE). The glass liner was then placed
into an autoclave followed by degassing with H2 (3 ×). The
hydrogenation was carried out at 20 bar H2 with stirring at 85
°C for 1 h. After the reaction was finished, the autoclave was
allowed to cool to r.t. The hydrogen gas was then carefully
released in the fume hood, the solution transferred to a flask
and concentrated in vacuo to afford the crude product. Flash
chromatographic purification with a column of silica gel
eluted with petroleum ether–EtOAc (20:1 → 5:1) yielded the
desired amine product.
freshly distilled CH2Cl2 was injected. The resulting mixture
was stirred at r.t. overnight. The reaction mixture was then
filtered through Celite®, washed with CH2Cl2 and the
combined organic solvents were concentrated in vacuo. The
resulting solid was washed with Et2O–hexane and
recrystallised from CH2Cl2–hexane.
C1: orange powder (90.5 mg, 98%). 1H NMR (400 MHz,
CDCl3; 258 K): δ = 7.79 (br, 1 H), 7.62–7.64 (d, J = 7.6 Hz,
1 H), 7.12–7.16 (m, 1 H), 6.92–6.99 (m, 3 H), 6.76–6.78 (d,
J = 7.2 Hz, 1 H), 3.85 (s, 3 H), 2.63–2.97 (m, 4 H), 1.87–1.88
(m, 2 H), 1.43 (s, 15 H). 13C NMR (100 MHz, CDCl3; 258
K): δ = 182.9, 168.4, 157.4, 144.6, 143.4, 143.0, 132.7,
132.4, 125.2, 123.3, 121.2, 115.0, 112.3, 88.9, 55.7, 30.4,
29.2, 23.8, 15.5, 8.9. Anal. Calcd for C27H31ClIrNO: C,
52.88; H, 5.10; N, 2.61. Found: C, 52.69; H, 5.12; N, 2.09.
C2: pale orange powder (31.7 mg, 98%). 1H NMR (400
MHz, CDCl3; 258 K): δ = 7.76–7.79 (m, 1 H), 7.15–7.16 (d,
J = 1.6 Hz, 1 H), 6.82–6.93 (m, 3 H), 6.33 (s, 1 H), 3.86 (s,
3 H), 3.84 (s, 3 H), 2.56–2.93 (m, 4 H), 1.84–1.85 (m, 2 H),
1.42 (s, 15 H). 13C NMR (100 MHz, CDCl3): δ = 181.4,
Synlett 2014, 25, 81–84
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