Versatile iridicycle catalysts for highly efficient and chemoselective transfer hydrogenation of carbonyl compounds in water

Article abstract of DOI:10.1002/chem.201403701

Cyclometalated iridium complexes are shown to be highly efficient and chemoselective catalysts for the transfer hydrogenation of a wide range of carbonyl groups with formic acid in water. Examples include α-substituted ketones (α-ether, α-halo, α-hydroxy, α-amino, α-nitrile or α-ester), α-keto esters, β-keto esters and α,β-unsaturated aldehydes. The reduction was carried out at substrate/catalyst ratios of up to 50000 at pH 4.5 and required no organic solvent. The protocol provides a practical, easy and efficient way for the synthesis of β-functionalised secondary alcohols, such as β-hydroxyethers, β-hydroxyamines and β-hydroxyhalo compounds, which are valuable intermediates in pharmaceutical, fine chemical, perfume and agrochemical synthesis. Water wonder: Iridicycle catalysts are versatile and allow the highly efficient and chemoselective transfer hydrogenation of a variety of carbonyl compounds, including problematic and challenging ones, with formate in neat water (see scheme).

Full text of DOI:10.1002/chem.201403701

DOI: 10.1002/chem.201403701
Full Paper
&
Transfer Hydrogenation
Versatile Iridicycle Catalysts for Highly Efficient and
Chemoselective Transfer Hydrogenation of Carbonyl Compounds
in Water
Dinesh Talwar, Xiaofeng Wu, Ourida Saidi, Noemꢀ Poyatos Salguero, and Jianliang Xiao*[a]
Dedicated to Professor Takao Ikariya on the occasion of his 65th birthday
Abstract: Cyclometalated iridium complexes are shown to
be highly efficient and chemoselective catalysts for the
transfer hydrogenation of a wide range of carbonyl groups
with formic acid in water. Examples include a-substituted
ketones (a-ether, a-halo, a-hydroxy, a-amino, a-nitrile or
a-ester), a-keto esters, b-keto esters and a,b-unsaturated
aldehydes. The reduction was carried out at substrate/cata-
lyst ratios of up to 50000 at pH 4.5 and required no organic
solvent. The protocol provides a practical, easy and efficient
way for the synthesis of b-functionalised secondary alcohols,
such as b-hydroxyethers, b-hydroxyamines and b-hydroxy-
halo compounds, which are valuable intermediates in
pharmaceutical, fine chemical, perfume and agrochemical
synthesis.
Introduction
two decades, due to the products being ubiquitous in natural-
ly occurring and synthetic bioactive compounds.[6] For exam-
ple, b-hydroxyethers have been used as biological probes and
synthetic intermediates for molecular switches.[6a–c,k,m,7]
b-Aminoethers can be readily derived from b-hydroxyethers
and are important precursors in the preparation of a wide var-
iety of pharmaceutical compounds.[6a–c,k,m] A further example is
found in b-hydroxyamines, which have been demonstrated as
building blocks in many synthetic methodologies leading to
various bioactive compounds, including, for example, medi-
cines that affect the central nervous and respiratory systems
(Scheme 1).[6a–e,k–p] Of further interest are b-hydroxyhalo com-
pounds, which have found use in the preparation of numerous
compounds for pharmaceuticals, fine chemicals and functional
materials.[6b,e,i,l–m]
Transfer hydrogenation (TH) has emerged as a practical, pow-
erful alternative to hydrogenation with H2 for the reduction of
C=X (X: O, N, C) bonds. The resulting products are important
intermediates for fine chemical, pharmaceutical, agrochemical
and advanced material synthesis. The merit of TH is significant-
ly strengthened by its operational simplicity and the ready
availability of hydrogen sources with the desired properties.[1]
TH can be carried out in organic solvents or in aqueous media.
From the viewpoint of environmental friendliness and easy cat-
alyst/product separation, the latter is more appealing. Indeed,
since the pioneering work of Sasson and co-workers[2] and of
Benyei and Joo[3] in the 1980s, TH in water with metal catalysts
has been continuously explored. However, highly efficient and
chemoselective TH in water is still challenging.[1,4] For most of
the catalysts reported, the turnover numbers (TONs) and turn-
over frequencies (TOFs) are low, with values ranging from
a few to hundreds per hour in the case of the latter. Moreover,
only a few catalytic systems have been reported that enable
fast, selective and productive TH with inexpensive, safe reduc-
tants in water while tolerating synthetically useful functional
i,4a]
groups.[1a,c–f,h,
A case in point is the TH of a-substituted
ketones, which has been rarely studied in aqueous media.[5]
The reduction of a-substituted ketones to form b-functional-
ised secondary alcohols has drawn a lot of attention in the last
[a] D. Talwar, Dr. X. Wu, Dr. O. Saidi, N. P. Salguero, Prof. J. Xiao
Department of Chemistry, University of Liverpool
Liverpool, L69 7ZD (UK)
E-mail: jxiao@liv.ac.uk
Homepage: http://pcwww.liv.ac.uk/~jxiao
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403701.
Scheme 1. Examples of drugs containing b-functionalised secondary
alcohols.
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Given the versatility of the a-substituted ketones, a number
of reagents and methods have been developed for their selec-
tive reduction, especially the asymmetric version.[6a–m,8] How-
ever, few catalysts are known that are capable of selective TH
of a wide range of a-substituted ketones.[6a–i,l–m,9] In addition,
most of the reactions are conducted in organic solvents, which
generates unwanted waste. One way of minimising the
environmental impact caused by the use of organic solvents
would be the use of water as the reaction medium. It is cheap,
benign and readily available. However, the reduction of a-sub-
stituted ketones with TH in water is challenging, because the
substrates/products are usually acid and/or base sen-
sitive.[6c–e,l,9a,c] Thus, there is a need for a catalyst that is versa-
tile, active and chemoselective for the TH of a-substituted
ketones with diverse properties to form the corresponding
secondary alcohols.
Recently we[10] and other groups[11] have reported a series of
cyclometalated iridium complexes. Some of these have been
successfully applied to the hydrogenation of imines with H2,
the TH of ketones and imines and the reductive amination of
ketones with formate, which demonstrates the versatility of
these catalysts.[10] In particular, the TH and reductive amination
of ketones can be efficiently carried out in water, although
only simple ketones were demonstrated.[10d,h] Herein, we report
that such cyclometalated iridium complexes are also highly ef-
ficient and chemoselective for the TH of various a-substituted
ketones, keto esters and a,b-unsaturated aldehydes in water
(Scheme 2).
Scheme 3. Iridicycle catalysts examined for TH in water.
shown in Table 1, all of these six precatalysts afforded good to
excellent conversions for the TH in water at pH 4.5 in a short
reaction time of 0.5 h (Table 1, entries 3–8). Without the imino
ligand, the iridium is inactive (Table 1, entry 2). As expected, no
TH took place without a catalyst (Table 1, entry 1). It appears
that the more electronic donation of the imino ligand to the
iridium, the faster the reduction in water. This is seen by com-
paring the TH by using C2 with those by using C1 and C3. The
highly conjugated C4 and C6 gave even higher conversions,
although the anthracenyl-containing C5 was surprisingly less
active. In particular, the phenanthrenyl-ligated C6 afforded
almost full conversion in 0.5 h (Table 1, entry 8), with higher
S/C ratios being feasible. Thus, at an S/C value of 10000, the
TH was approximately complete in 2 h (Table 1, entry 9), and
Table 1. Screening of catalysts for the TH of 1-phenoxypropan-2-one in
water.[a]
Scheme 2. Transfer hydrogenation of a-substituted ketones and
a,b-unsaturated carbonyl compounds under aqueous conditions.
Entry
Catalyst
S/C[b]
t [h]
Conv. [%][c]
Results and Discussion
1
2
3
4
5
6
7
8
–
–
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
2
N.R.
<2
88
96
59
98
75
>99
99
96
[d]
Our previous studies have shown that the structures of the
cyclometalated iridium complexes can significantly impact on
their ability to catalyse a reaction.[10a–i] Bearing this in mind, we
firstly synthesised a series of cyclometalated iridium com-
plexes, iridicycles C1–C6 (Scheme 3), according to the reported
procedures.[10k,11d,h] These iridicycles are diverse in both the
conjugation and electronic properties of the aromatic rings co-
ordinated to the iridium metal, with some having been exploit-
ed in the hydrogenation with H2 and transfer hydrogenation
with formate of imino bonds.[10a–c,g–h,k]
[Cp*IrCl2]2
C1
C2
C3
C4
C5
C6
C6
C6
1000
1000
1000
1000
1000
1000
1000
10000
20000
50000
9
10
11
6
20
C6
82
[a] Reaction conditions: ketone (2.5 mmol), catalyst (0.01 mol%), HCO2H/
HCO2Na aqueous solution (pH 4.5; 3 mL; 14.0 mmol of HCO2H and
29.4 mmol of HCO2Na in 2.8 mL of H2O), 808C, stirred in a carousel tube
for 0.5 h. [b] S/C: substrate/catalyst molar ratio. [c] Conversion determined
by NMR spectroscopy. N.R.: no reaction. [d] Cp*: pentamethylcyclopenta-
dienyl.
To investigate the efficacy of the iridicycles in reducing
a-substituted ketones, we set out to screen the complexes
synthesised, by using 1-phenoxypropan-2-one as the bench-
mark substrate at a substrate/catalyst (S/C) ratio of 1000. As
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the catalyst delivered a conver-
sion of 82% in 20 h at the much
higher S/C value of 50000
(Table 1, entry 11).
Table 2. TH of b-keto ethers with C6 in water.[a]
The TH reactions above were
carried out at pH 4.5. Screening
of the reaction conditions with
C4 revealed that the solution pH
value plays a critical role in the
reduction. Thus, the TH occurred
only within a certain window of
acidic conditions (pH 3.0–5.0 for
greater than 50% conversions),
with the optimal pH value being
4.5, which was adopted for sub-
sequent studies. This value is
higher than that required for the
TH of acetophenone by using an
analogous catalyst,[10d] which
presumably reflects the more
electron-rich ketone being re-
duced in this study. However,
pH 4.5 is lower than that used
with the Noyori–Ikariya catalysts,
for which neutral to slightly
basic reaction conditions were
found to be optimal.[1f,4a,12] As
explained before,[10a,d,e] the iridi-
cycle catalyst is not capable of
activating the ketone through its
ligands, which renders activation
through an acidic medium
necessary, whereas the Noyori–
Ikariya type catalysts are able to
readily hydrogenate a ketone by
virtue of hydrogen bonding be-
tween the NH proton of the
ligand and the substrate.[13]
Entry
1
Substrate
Product
Yield [%][b]
93
2a
2
3
4
5
2b
2c
2d
2e
91
97
95
89
6
7
8
2 f
97
97
93
2g
2h
9
2i
87
86
98
97
91
10
11
12
13
2j
With the optimised reaction
conditions in hand, we then ex-
panded the substrate scope of
2k
2l
the reduction. Firstly,
a wide
range of b-keto ethers were ef-
fectively and chemoselectively
reduced to the desired b-hy-
droxyethers. As shown in
Table 2, the C6 catalyst is cap-
able of reducing all types of b-
keto ethers. Keto ethers featur-
ing either aromatic or aliphatic
units and aromatic, aliphatic,
heterocyclic and fluorinated
ethers were all viable and fur-
nished excellent yields at the S/C
ratio of 10000 and 2.5 mmol
substrate scale without dissocia-
tion of any ether groups. Fur-
2m
14
15
2n
2o
90
87
[a] Reaction conditions: ketone (2.5 mmol), C6 (0.01 mol%), HCO2H/HCO2Na aqueous solution (pH 4.5; 3 mL;
14.0 mmol of HCO2H and 29.4 mmol of HCO2Na in 2.8 mL of H2O), 808C, stirred in a carousel tube for 14 h.
[b] Yield of isolated product.
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thermore, for b-aryl ketone aryl
ethers, neither electron-with-
drawing substituents nor elec-
tron-donating groups on the aryl
ring of either ketones and ethers
significantly affected the produc-
tivity and selectivity of the cata-
lyst. Thus, TH of 1a and 1b af-
forded similar yields (Table 2,
entry 1 versus 2) and the reduc-
tions of 1 f, 1g and 1h all pro-
vided excellent yields (Table 2,
entries 6–8). The sterically bulky
substituent on the aryl ether 1d
also has little effect (Table 2,
entry 4). More importantly, sub-
strates containing a hexafluoro-
isopropyl group (1i) and a hepta-
fluorobutoxy group (1j) can be
reduced smoothly with 87% and
86% yields to afford highly
demanding intermediates for
pharmaceuticals and fine chem-
icals.[14] Hydrogenolysis of the
CÀO bond was not noticed. To
the best of our knowledge, there
is no literature report for the TH
of these substrates previously.
There are still difficulties in the
literature concerning the reduc-
tion of 1m–1o.[15] However, with
the current protocol, these sub-
strates can be translated into the
desired products smoothly with
good to excellent yields (Table 2,
entries 13–15).
Table 3. TH of a-substituted ketones with C4 in water.[a]
Entry
1
Substrate
Product
Yield [%][b]
93
4a
4b
4c
2
3
94
92
4
4d
4e
4 f
4g
4h
4i
93
87
95
96
90
92
91
5[c]
6
7
8
9
10
4j
a-Halo-, hydroxy- and nitrile-
substituted ketones are more
challenging to reduce due to the
ease of dissociation/decomposi-
tion of these a-functional groups
under acidic and/or basic condi-
tions.[6b–i,l,8,16] However, the cur-
rent reduction system over-
comes these challenges. After
modification of the reaction con-
ditions, the desired products
were obtained with excellent
yields for almost all of these
problematic ketones. As shown
in Table 3, with the cyclometalat-
ed complex C4, which is slightly
more active than C6, a-hy-
droxyacetophenone (3a) was
converted into a 1,2-diol with
93% yield at an S/C ratio of 1000
(Table 3, entry 1). a-Chloroaceto-
11
12
4k
4l
89
90
13
4m
4n
4o
4p
96
88
86
94
14
15[d]
16
[a] Reaction conditions: ketone (2.5 mmol), C4 (0.1 mol%), HCO2H/HCO2Na aqueous solution (pH 4.5; 3 mL;
14.0 mmol of HCO2H and 29.4 mmol of HCO2Na in 2.8 mL of H2O), 808C, stirred in a carousel tube for 18 h.
[b] Yield of isolated product. [c] S/C=200. [d] Yield determined by H NMR spectroscopy.
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phenone (3b) was reduced to
the a-chlorophenylethanol with
94% yield (Table 3, entry 2). For
substrates 3c and 3d, which
bear an electron-donating and
-withdrawing group, respective-
ly, the reduction afforded almost
identical yields (Table 3, entries 3
and 4). Moreover, a,a-dichloro-
acetophenone (3e) was success-
fully reduced to a,a-dichloro-
phenylethanol with 87% yield
(Table 3, entry 5), albeit at
a lower S/C ratio of 200. The re-
duction of a-chloroketones is
often problematic because they
are vulnerable to dechlorination,
which gives rise to epoxide
products. The a-fluoroketones
were also viable for this reduc-
tion system. Thus, excellent
yields were obtained for the TH
of a-fluoro- and a,a,a-trifluoro-
acetophenone (3 f and 3g, re-
spectively; Table 3, entries 6 and
7). Equally, the a-nitrile ketones
(3h–3l) were converted into the
corresponding secondary alco-
hols with excellent yields, includ-
ing examples of heterocyclic ke-
tones (Table 3, entries 8–12). Still
further, the catalytic system was
successfully applied to a-acyloxy,
a-morpholino and a-semialde-
hyde ketones (3m–3p; Table 3,
Table 4. TH of a- and b-keto esters with C4 in water.[a]
Entry
1
Substrate
Product
Yield [%][b]
6a
6b
6c
94
2
3
91
94
4
6d
92
5
6
6e
8a
95
96
7[c]
8b
8c
91
92
8
[a] Reaction conditions: keto ester (2.5 mmol), C4 (0.1 mol%), HCO2H/HCO2Na aqueous solution (pH 4.5; 3 mL;
14.0 mmol of HCO2H and 29.4 mmol of HCO2Na in 2.8 mL of H2O), 808C, stirred in a carousel tube for 14 h.
1
[b] Yield of isolated product. [c] Yield determined by H NMR spectroscopy.
entries 13–16), with the a-functional groups tolerated and high
yields obtained for all of the desired products. Selective reduc-
tion of analogues of 3m by TH is difficult, because the acyl
group is prone to migration by hydrolysis.[17] Indeed, there are
only a few literature reports describing the TH of this class of
substrates; however, the catalyst loadings are high and the
yields are relatively low due to the aforementioned problem.[18]
To the best of our knowledge, this is the first time that a homo-
geneous catalyst has been reported for the TH of a-piperidyl
and a-semialdehyde ketones.
Scheme 4. Attempted chemoselective TH of a,b-unsaturated ketones in
water.
To showcase the broader utility of the catalytic system, we
also applied C4 to the reduction of keto esters.[6a,d,i,19] Both aro-
matic and aliphatic b-keto esters were reduced to afford the
corresponding alcohols with excellent yields under the cataly-
sis of 0.1 mol% of C4 (Table 4). Likewise, the analogous a-keto
esters were also reduced with ease, which demonstrates the
versatility of the cyclometalated iridium catalyst. Products 6e
and 8c are known to be important intermediates for medicines
and fine chemicals.[14b,20] Again, there appears to be no correla-
tion between the electron properties of the substituents on
the phenyl ring and the yield obtained under the conditions
employed (Table 4, entries 1–4).
The highly efficient and chemoselective reduction of a,b-un-
saturated ketones and aldehydes has been a research topic in
the last several decades.[21] Mixtures of products are frequently
obtained, because many catalysts reduce both the C=O and
C=C bonds rather than exclusively either the C=O or C=C
bond. Hence, selectivity is still an issue.[21] Therefore, we subse-
quently examined these substrates with the current reduction
system. Disappointingly, C4 was not chemoselective for the re-
duction of a,b-unsaturated ketones and catalysed the reduc-
tion of both the C=C and C=O bonds (Scheme 4).
Catalyst C4 is, however, highly chemoselective in the reduc-
tion of a,b-unsaturated aldehydes to afford only unsaturated
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alcohols (Table 5). In the case of
the aromatic a,b-unsaturated al-
dehydes, almost identical yields
of allylic alcohols were obtained
for those substrates that are
relatively sterically demanding
(9b, 9c and 9 f; Table 5,
entries 2, 3 and 6) or that bear
electron-withdrawing or -donat-
ing groups substituted on the
phenyl ring (9d versus 9e;
Table 5, entry 4 versus 5). Good
yields were also achieved for the
TH of aliphatic a,b-unsaturated
aldehydes (Table 5, entries 7–9).
The chemoselectivity observed
with the a,b-unsaturated alde-
hydes may stem from the alde-
hyde group being easier to
reduce than a ketone. Once re-
duced, the C=C bond can no
longer be hydrogenated by the
catalyst.
Table 5. TH of a,b-unsaturated aldehydes with C4 in water.[a]
Entry
1
Substrate
Product
Yield [%][b]
10a
10b
10c
10d
89
2
3
4
88
90
90
5
6
10e
10 f
92
92
7[c]
8
10g
10h
10i
90
78
85
A plausible mechanism is pro-
posed for the TH in question in
Scheme 5. Catalyst C is first con-
verted into the formate complex
I in the presence of formate.[22]
Decarboxylation of I leads to the
active, but coordinatively sat-
urated, hydride species II.[10a] The
9
[a] Reaction conditions: aldehyde (2.5 mmol), C4 (0.1 mol%), HCO2H/HCO2Na aqueous solution (pH 4.5; 3 mL;
14.0 mmol of HCO2H and 29.4 mmol of HCO2Na in 2.8 mL of H2O), stirred in a carousel tube for 6 h. [b] Yield of
isolated product. [c] E/Z=52:48.
ketone substrate, activated by the hydroxonium ion under the
acidic conditions employed,[10d] is then reduced through direct
hydride transfer from II without ketone coordination to the
metal centre, that is, by the ionic or outer-sphere mech-
anism.[23] In previous studies, we have shown that hydride spe-
cies can be easily generated from an iridicycle and formate
and transferred to protonated imines.[10a,f,h]
Scheme 5. Proposed mechanism for the TH by an iridicycle.
Experimental Section
Typical procedure for the TH of b-keto ethers in water
Conclusion
b-Keto ether (2.5 mmol) and C6 (0.17 mg, 2.5ꢂ10À4 mmol) were
placed in a carousel reaction tube. The tube was degassed and
charged with nitrogen. An aqueous solution of HCO2Na/HCO2H at
pH 4.5 (3 mL) was then introduced, and the mixture was stirred at
808C for 14 h under nitrogen. The reaction mixture was cooled to
room temperature and quenched with saturated sodium bicarbon-
ate solution. The aqueous layer was extracted with ethyl acetate
(3ꢂ25 mL), and the combined organic layers were washed with
brine (25 mL). The organic layer was collected and dried over anhy-
drous sodium sulfate. Filtration, followed by evaporation of the sol-
vent under reduced pressure, gave the crude mixture. Flash
column chromatography of the crude mixture afforded the desired
b-hydroxyether product.
In summary, this paper has demonstrated that cyclometalated
iridium complexes, iridicycles, catalyse the highly efficient and
chemoselective TH of a wide variety of carbonyl groups, in-
cluding a series of a-substituted ketones, a- and b-keto esters
and a,b-unsaturated aldehydes. With the reduction feasible in
water at S/C ratios of 1000–50000, the current protocol pro-
vides a practical, easy and efficient synthesis of b-functional-
ised secondary alcohols, especially b-hydroxyethers, b-amino-
ethers, b-hydroxyamines and b-hydroxyhalo compounds,
which are bioactive and/or of value for the synthesis of
pharmaceuticals, fine chemicals, perfumes and agrochemicals.
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Typical procedure for the TH of a-functionalised aromatic
ketones in water
Ketone (2.5 mmol) and C4 (1.6 mg, 2.5ꢂ10À3 mmol) were placed in
a carousel reaction tube. The tube was degassed and charged with
nitrogen. An aqueous solution of HCO2Na/HCO2H at pH 4.5 (3 mL)
was then introduced, and the mixture was stirred at 808C for 18 h
under nitrogen. The reaction mixture was cooled to room tempera-
ture, quenched with saturated NaCl solution (20 mL) and extracted
with ethyl acetate (3ꢂ25 mL). The combined organic layer was
dried over anhydrous sodium sulfate. Filtration, followed by evapo-
ration of the solvent under reduced pressure, gave the crude mix-
ture. Flash column chromatography of the crude mixture
afforded the desired product.
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water
Keto ester (2.5 mmol) and C4 (1.6 mg, 2.5ꢂ10À3 mmol) were
placed in a carousel reaction tube. The tube was degassed and
charged with nitrogen. An aqueous solution of HCO2Na/HCO2H at
pH 4.5 (3 mL) was then introduced, and the mixture was stirred at
808C for 14 h under nitrogen. The reaction mixture was cooled to
room temperature, quenched with saturated NaCl solution (20 mL)
and extracted with ethyl acetate (3ꢂ25 mL). The combined organic
layer was dried over anhydrous sodium sulfate. Filtration, followed
by evaporation of the solvent under reduced pressure, gave the
crude mixture. Flash column chromatography of the crude mixture
afforded the desired hydroxyester product.
Typical procedure for the TH of a,b-unsaturated aldehydes
in water
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Acknowledgements
We thank the University of Liverpool for support (D.T. and
X.W.). We are also grateful to Angela Gonzalez De Castro, Anto-
nio David Conde and Ho Yin Li for technical assistance and
useful discussions. Mass spectrometry data were acquired at
the EPSRC UK National Mass Spectrometry Facility at Swansea
University.
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Keywords: carbonyl groups · cyclometalated complexes ·
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Received: June 1, 2014
Published online on && &&, 0000
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ÝÝ These are not the final page numbers!

Full Paper
FULL PAPER
&
Transfer Hydrogenation
D. Talwar, X. Wu, O. Saidi, N. P. Salguero,
J. Xiao*
&& – &&
Versatile Iridicycle Catalysts for Highly
Efficient and Chemoselective Transfer
Hydrogenation of Carbonyl
Water wonder: Iridicycle catalysts are
versatile and allow the highly efficient
and chemoselective transfer hydrogena-
tion of a variety of carbonyl com-
pounds, including problematic and chal-
lenging ones, with formate in neat
water (see scheme).
Compounds in Water
Chem. Eur. J. 2014, 20, 1 – 9
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers! ÞÞ