Fast reductive amination by transfer hydrogenation "on water"

Article abstract of DOI:10.1002/chem.201204194

Reductive amination of various ketones and aldehydes by transfer hydrogenation under aqueous conditions has been developed, by using cyclometallated iridium complexes as catalysts and formate as hydrogen source. The pH value of the solution is shown to be critical for a high catalytic chemoselectivity and activity, with the best pH value being 4.8. In comparison with that in organic solvents, the reductive amination in an aqueous phase is faster, and the molar ratio of the substrate to the catalyst (S/C) can be set as high as 1×10⁵, the highest S/C value ever reported in reductive amination reactions. The catalyst is easy to access and the reaction is operationally simple, allowing a wide range of ketones and aldehydes to react with various amines in high yields. The protocol provides a practical and environmental friendly new method for the synthesis of amine compounds. Greener amine synthesis: A versatile reductive amination protocol has been developed. By using an iridium catalyst in water, a broad range of ketones and aldehydes react with amines to afford various new amines in good yields (see scheme), with molar ratios of the substrate to the catalyst (S/C) as high as 1×10 ⁵. The pH of the reaction solution plays a key role, regulating both the catalytic activity and the selectivity. Copyright

Full text of DOI:10.1002/chem.201204194

FULL PAPER
DOI: 10.1002/chem.201204194
Fast Reductive Amination by Transfer Hydrogenation “on Water”
Qian Lei,[a] Yawen Wei,[a] Dinesh Talwar,[b] Chao Wang,*[a] Dong Xue,[a] and
Jianliang Xiao*[a, b]
Abstract: Reductive amination of vari-
ous ketones and aldehydes by transfer
hydrogenation under aqueous condi-
tions has been developed, by using cy-
clometallated iridium complexes as cat-
alysts and formate as hydrogen source.
The pH value of the solution is shown
with that in organic solvents, the reduc-
tive amination in an aqueous phase is
faster, and the molar ratio of the sub-
strate to the catalyst (S/C) can be set
as high as 1ꢀ105, the highest S/C value
ever reported in reductive amination
reactions. The catalyst is easy to access
and the reaction is operationally
simple, allowing a wide range of ke-
tones and aldehydes to react with vari-
ous amines in high yields. The protocol
provides a practical and environmental
friendly new method for the synthesis
of amine compounds.
Keywords: amination
· amines ·
to be critical for
a high catalytic
hydrogenation · iridium catalyst ·
water
chemoselectivity and activity, with the
ACHTUNGTRENNUNG
best pH value being 4.8. In comparison
Introduction
NaBH3CN and the inability to aminate aromatic ketones
with NaBH(OAc)3, two most widely used hydrides in
AHCTUNGTRENNUNG
Amine moieties are widely found in natural products, agro-
chemicals and pharmaceuticals.[1] Development of methods
for the efficient and economic production of amines has at-
tracted great attention.[1,2] One of the best ways for produc-
ing amines is the reduction of imino C=N bonds,[1a,c,2n,q,s]
which are most conveniently obtained from the condensa-
tion of carbonyl compounds with amines. However, imines
are not always easy to synthesise and have limited stability.
Reductive amination (RA) exploits imines in situ generated
from carbonyl compounds and amines, alleviating the prob-
lematic imine isolation. Tremendous efforts have been de-
voted to the development of efficient RA reactions; howev-
er, the progress is far from satisfactory.[1b,c,2h,p,s–u] In most of
the RA reactions developed, stoichiometric boron hydride
reduction and heterogeneous hydrogenation dominate the
scene.[1b,2t] Borane hydride reduction has been used in a
number of industrial applications,[3] for example, synthesis of
a CCR3 antagonist[4] and an antiangiogenic tyrosine kinase
inhibitor.[5] However, the use of a stoichiometric amount of
boron hydrides generates copious amounts of waste and is
associated with other problems, such as toxicity issues with
RA.[2t,6] Although heterogeneous catalysts have found many
applications in RA including industrial examples, they gen-
erally display poor chemoselectivity.[1b,7] Progress in devel-
oping homogeneous catalytic systems, including organome-
tallic hydrogenative,[8] organocatalytic[9] and enzymatic[10]
ones, has been made in recent years, even allowing for enan-
tioselective RA in a few cases.[8a,c–e,h–k,9,10c] However, there is
still much room for improvement in terms of substrate
scope and catalytic activity.
Transfer hydrogenation, which usually uses organometallic
catalysts and hydrogen sources other than hydrogen gas, is
an operationally simple and versatile method for reduction
and has been very successful in carbonyl reduction.[11] How-
ever, the development of transfer hydrogenation systems for
the reduction of C=N bonds lags behind that for carbonyl
groups.[12] Indeed, only a handful of examples of transfer hy-
drogenative RA have been reported.[13] Kitamura, Kadyrov,
Wills, Ogo and Strotman and their co-workers reported RA
using formate as hydrogen source, including asymmetric and
aqueous versions.[13a–d,f] Carbtree and co-workers attempted
RA of aldehydes with isopropanol as hydrogen source, by
using an iridium carbene catalyst.[13e] Recently, we devel-
oped a versatile and efficient transfer hydrogenation system
for RA, which exploits cyclometallated iridium complexes
as catalysts and HCOOH/Et3N as hydrogen source in alco-
holic solvents.[14]
[a] Q. Lei, Y. Wei, Prof. C. Wang, Prof. D. Xue, Prof. J. Xiao
Key Laboratory of Applied Surface and Colloid Chemistry
Ministry of Education
School of Chemistry and Chemical Engineering
Shaanxi Normal University, Xi’an, 710062 (P.R. China)
E-mail: c.wang@snnu.edu.cn
In this paper, we disclose our findings that cyclometallat-
ed iridium complexes also catalyse RA with formate under
aqueous conditions, when a suitable pH value is chosen
[Eq. (1)]. It is shown that water not only serves as a green
solvent, but also accelerates the RA reaction, affording
better activity than in organic solvents.
[b] D. Talwar, Prof. J. Xiao
Department of Chemistry, University of Liverpool
Liverpool, L69 7ZD (UK)
E-mail: jxiao@liv.ac.uk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204194.
Chem. Eur. J. 2013, 19, 4021 – 4029
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Results and Discussion
Cyclometallated iridium complexes are excellent catalysts
for a range of reactions, including RA, almost all of which
have been conducted in organic solvents.[15] It would be ap-
pealing to replace these solvents with water, because of the
economical and environmental benefits water offers.[16]
Water as solvent may also enable different activity and se-
lectivity patterns from common organic solvents.[17] Howev-
er, aqueous RA reactions are scarce in the literature. This is
not unexpected, as water is generally thought to be adverse
for RA reactions. The presence of water is expected to shift
the equilibrium of a ketone or aldehyde with an imine to
favour the former, particularly in the presence of an acid. In
fact, drying agents are sometimes used to remove water gen-
erated from the imine formation step.[9] Previously, the
groups of Ogo,[13d] Ajjou[8g] and Bhanage[8h] reported water-
soluble catalysts for aqueous RA of aldehydes and aliphatic
ketones. We were interested in learning if RA reactions
could be carried out in a “on water” fashion, by using our
water-insoluble cyclometallated iridium catalysts. We note
that no aqueous RA of aromatic ketones has been reported
thus far.
Figure 1. Effect of the pH value on the RA. Reaction conditions: aceto-
phenone (2.5 mmol), p-anisidine (3 mmol), 1a (0.0025 mmol), HCOOH/
HCOONa solution (4 mL, 10 molLÀ1), 808C, 1 h. Conversion and yield
were determined by 1H NMR spectroscopy. =total conversion,
=
&
*
~
yield of 2a, =yield of 3.
In our initial study of the aqueous RA, acetophenone and
p-anisidine were chosen as model substrates, complex 1a as
precatalyst[14] and formate as hydrogen source (Figure 1).
Imine formation from the ketone and amine and the subse-
quent imine reduction are known to benefit from acidic con-
ditions.[8j,9,18] With this in mind, we first examined the effect
of the pH value of the solution on the model reaction, by
using HCOOH and HCOONa to adjust the pH val-
ues.[13d,17g,r,s,19] The reduction was carried out at 808C at a
molar ratio of the substrate to the catalyst (S/C) of 1000:1.
Indeed, both the catalytic activity and the selectivity were
influenced dramatically by the pH of the solution (Figure 1).
The reduction took place only at a certain pH region (ca.
pH 1.5–6), with the best activity observed at approximately
pH 3–4. However, both the desired amine product 2a and
the byproduct alcohol 3 were obtained. A bell-shaped con-
version versus pH profile was observed for the formation of
both 2a and 3, reminiscent of that commonly observed for
imine formation.[20] Pleasingly, at pH 4.8, 2a was observed as
the sole product in 26% yield.
Scheme 1. Reactions that are possible under aqueous conditions and are
affected by the pH value of the solution (H+ refers to H3O+). For the
isolation and structure of the hydride, see reference [25].
However, when the solution becomes too acidic, imine for-
mation will be inhibited and the hydride protonated, leading
to slower RA. Under basic conditions, imine formation and
reduction will both be inhibited. Offering no metal–ligand
bifunctional ability,[11c,j,22] complex 1 catalyses imine reduc-
The observation of the bell-shaped relationship may be
traced to some of the various equilibria in water, which are
tion most likely through the ionic mechanism, that is, direct
23]
affected by the pH (Scheme 1). The Ir H hydride is expect-
hydride transfer to the C=N bond.[11g,18c,
Hence, certain
À
ed to form from decarboxylation of formate.[21] A lower pH
enhances the concentration of protonated imines and hydro-
gen-bonded ketones, facilitating their reduction.[13d,17g,r,s,19]
acidic conditions will facilitate the hydrogenation of imines
by way of their protonation. The pH value of 4.8 may be a
critical point, where the imine is protonated whereas the
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Fast Reductive Amination by Transfer Hydrogenation
Table 1. Optimising reaction conditions of the RA.
FULL PAPER
Entry[a]
Catalyst
R
t
Conv.[b]
[%]
2a[b]
[%]
3[b]
[%]
[min]
1
2
3
4
5
6
1a
1b
1c
1d
1e
1 f
1g
1g
p-OMe
p-Cl
p-Br
p-CF3
p-CN
p-NO2
4,5-(CH)4
4,5-(CH)4
90
90
90
90
90
90
90
76
32
30
9
17
61
87
99
73
32
30
9
17
60
82
96 (95)
3
0
0
0
0
1
5
3
Figure 2. X-Ray diffraction structure of catalyst 1g. Selected distances
À
À
À
[ꢂ] and angles [8]: Ir1 N1 2.080(7), Ir1 C1 2.005(9), Ir1 Cl1 2.410(2);
Ir1-N1-C11 119.2(6), Ir1-C1-C10 117.6(6), N1-Ir1-C1 76.7(3).
7
8[c]
120
[a] Reaction conditions: acetophenone (2.5 mmol), p-anisidine (3 mmol),
catalyst (0.0025 mmol), HCOOH/HCOONa solution (pH 4.8, 4 mL),
808C, solution bubbled with argon for 15 min in a sealed tube. [b] Deter-
mined by 1H NMR spectroscopy. [c] Acetophenone (2.5 mmol) and p-
anisACHTUNGTRENNUNGiACHTUNGTRENNUNGdine (5 mmol). Number in brackets refers to the yield of the isolated
product.
ketone is in its free form, explaining why the reduction of
the imine is the main reaction at this condition.
Knowing the best pH value for the RA, we set out to fur-
ther optimise the reaction by screening various cyclometal-
lated iridium catalysts. The results are summarised in
Table 1. Catalyst 1a afforded 76% conversion in 1.5 h at S/
C=1000, with a 2a/3 ratio of >24. The para-Cl and para-Br
substituents on the ligand effected lower conversions than
1a, although the chemoselectivities were excellent (Table 1,
entries 2 and 3). Interestingly, although the electron-defi-
cient substituents para-CF3 and para-CN gave quite low con-
versions (Table 1, entries 4 and 5), the catalyst with the
para-NO2 group demonstrated good activity and selectivity
(Table 1, entry 6). The most active catalyst is that derived
from 1g, which contains a naphthyl group, affording 87%
conversion with a 2a/3 ratio of 16. The structure of 1g was
confirmed by X-ray diffraction (Figure 2).
Further studies showed that the reduction with catalyst 1g
was very fast before reaching approximately 80% conver-
sion under the conditions given in Table 1 (Figure 3). A
turnover frequency (TOF) of 1.1ꢀ103 h was observed in the
first 30 min. Thereafter (at ꢀ60 min), the reaction became
sluggish, however, and this was accompanied with more sig-
nificant hydrogenation of acetophenone to give alcohol 3
(Figure 3). Bearing this in mind, we increased the ratio of p-
anisidine to acetophenone. This led to 99% conversion in
2 h and a higher 2a/3 ratio of 32 (Table 1, entry 8). Under
this condition, the amine 2a was isolated in an excellent
yield of 95%.
Figure 3. Reaction profile of the RA with catalyst 1g. Conditions: aceto-
phenone (2.5 mmol), p-anisidine (3 mmol), catalyst (0.0025 mmol),
&
HCOOH/HCOONa solution (pH 4.8, 4 mL), 808C. =conversion of the
ketone, =yield of 2a, =yield of 3, determined by 1H NMR spectro-
~
*
scopy.
ous conditions with that in MeOH and DMF (the volume of
the organic solvent was determined such that when it is re-
placed with the same volume of water the resulting aqueous
solution would display pH 4.8). As is shown in Figure 4, the
initial rate under aqueous condition is about six times of
that in MeOH and DMF. More strikingly, the reaction in
the organic media became sluggish, showing little progress
after the first 30 min.
The rate of the RA reaction in the aqueous solution of
pH 4.8 was faster than in our previously reported alcohol
system.[14] We compared the rate of reduction under aque-
Interestingly, we noted that the reaction under the aque-
ous condition was heterogeneous or biphasic, whereas that
in the organic solvents was homogeneous (Figure 5). Thus,
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C. Wang, J. Xiao et al.
The substrate scope of the aqueous HCOOH/HCOONa
system with catalyst 1g was firstly examined in the reactions
of aromatic ketones with various amines. The results are
summarised in Table 2. Aromatic ketones with electron-
withdrawing or electron-donating substituents all react well
with p-anisidine, affording excellent yields in 2 h at S/C of
1000 (Table 2, entries 1–10). The electronic effects of these
substituents on the RA are not obvious for these substrates
under the conditions employed. A b-ketoester also reacted,
allowing direct access to amino acids; but it needed lower
pH (pH 4.2) and showed lower activity (Table 2, entry 11).
The RA is more significantly affected by the amine partners,
however. For aromatic amines, relatively lower yields were
obtained for substituents other than p-OMe (Table 2, en-
tries 12–16). The p-Cl- and p-Br-substituted anilines were
particularly less reactive, requiring longer time or higher
catalyst loading to reach acceptable yields. This appears to
suggest that the RA is rate limited by the step of the imine
formation. Benzyl amine reacted quite well with acetophe-
none to afford 87% yield at S/C of 2000 in 4 h. However,
aliphatic amines provided lower yields, although they are
good substrates when using MeOH as solvent (Table 2,
entry 18).[14] A chiral amino acid ester could also act as
amine source, providing excellent diastereoselectivity, albeit
with low yield (Table 2, entry 19).
Figure 4. Comparison of the effect of water, MeOH and DMF on the
RA. Reaction conditions: acetophenone (5 mmol), p-anisidine (6 mmol),
&
1g (0.005 mmol), 808C.
=aqueous HCOOH/HCOONa solution
~
*
(pH 4.8, 8 mL); =MeOH (1 mL), Et3N/HCOOH (v/v 2:1, 7 mL);
=
DMF (1 mL), Et3N/HCOOH (v/v 2:1, 7 mL). Conversions were deter-
1
The reactions of aliphatic ketones with various amines
were investigated next. 4-Phenylbutan-2-one was chosen as
a model substrate to react with different amines initially.
Aliphatic ketones generally showed higher activity than aro-
matic ketones. An S/C of 2000 can be employed for most of
the substrates. As can be seen in Table 3, aromatic amines
reacted quite well with 4-phenylbutan-2-one, apart from p-
Br- and the electron-withdrawing p-CF3-substituted aniline
(Table 3, entries 1–7). Benzylamine was also a good sub-
strate for 4-phenylbutan-2-one (Table 3, entry 8). However,
aliphatic amines, particularly the sterically more demanding
ones, were again poorer substrates (Table 3, entries 9–11). A
slightly higher pH of 5.0 was used for cyclohexylamine
(Table 3, entry 11). Likewise, secondary amines displayed
lower activity, probably again due to their steric hindrance.
Thus, only 64% yield were obtained for methylphenylamine
at S/C of 200 for 24 h (Table 3, entry 12). The methyl ester
of phenylalanine reacted much faster with 4-phenylbutan-2-
one than with acetophenone, affording 95% yield at S/C of
2000 in 3 h, with a d.r. of 79:21 (Table 3, entry 13). An a,b-
unsaturated ketone reacted with p-anisidine to give a fully
reduced product in good yield (Table 3, entry 14). Water-in-
soluble long-chain or cyclic ketones all reacted with p-anisi-
dine, furnishing good to excellent yields at S/C of 2000 in
2 h (Table 3, entries 16–18).
mined by H NMR spectroscopy.
Figure 5. Photos of the RA of acetophenone with p-anisidine in water
and organic solvent under the conditions given in Figure 4. Top) Reaction
in aqueous HCOOH/HCOONa solution. Bottom) Reaction in MeOH.
From left to right: before reaction, during reaction and after reaction.
Despite its water solubility, acetone was also a viable sub-
strate for the water-insoluble p-anisidine (Table 3, entry 15).
However, little reaction took place when the ketone and
amine were both water soluble, for example, acetone with n-
butylamine. These results show the importance of phase sep-
aration in the RA studied, supporting the “on water” nature
of the catalysis.
the faster rate associated with the aqueous conditions may
stem from an increased concentration of substrates as a
result of the reaction happening “on water”.[16e,17f,l] Alterna-
tively, water molecules may participate in the transition
states of the rate-determining step.[17r, 24]
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Fast Reductive Amination by Transfer Hydrogenation
Table 2. RA of aromatic ketones with different amines.
FULL PAPER
Table 2. (Continued)
Entry[a] Ketone
Amine
S/C t [h] Yield [%][b]
19
500 24
44 (>99:1)[d]
Entry[a] Ketone
Amine
S/C t [h] Yield [%][b]
[a] Reaction conditions: ketone (2.5 mmol), amine (5 mmol), 1g,
HCOOH/HCOONa solution (pH 4.8, 4 mL), 808C. [b] Yield of the iso-
lated product. [c] pH 4.2. [d] The diastereomeric ratio (d.r.) is given in
brackets.
1
1000
1000
1000
2
2
2
95
98
95
2
3
4
5
6
7
We also explored the RA of another type of carbonyl
group, that is, aldehydes. Aldehydes were more reactive
than ketones in general (Table 4). Over 90% yield were ob-
tained for most of the aromatic aldehydes with different
substituents reacting with p-anisidine at S/C of 2000 in 2 h
(Table 4, entries 1–9). The only exception was found for
para-chlorobenzaldehyde, which gave a lower yield of 79%
(Table 4, entry 5). Switching to other aromatic amines with
varying substituents showed that they reacted smoothly with
benzaldehyde affording high yields (Table 4, entries 10–14).
Aliphatic amines generally showed better activity in reac-
tions with aldehydes than with ketones (Table 4, entries 16–
18). Thus, a high yield of 97% was achieved for n-octyl-
1000
1000
1000
1000
1000
2
2
2
2
2
94
98
98
98
96
93
AHCTUNGTREGaNNNU mine at S/C of 2000 in 2 h (Table 4, entry 16). In particular,
the lower steric hindrance of the aldehydes compared with
the ketones renders their reaction with secondary amines
much easier (Table 4, entries 19). Similarly, N-methylbenzyl-
amine reacted with benzaldehyde to afford an excellent
yield of 98% (Table 4, entry 20). The methyl ester of
8
9
phenyl
ACHTUNGTERNNaUNG lanine is also a good amine donor (Table 4,
entry 19).
1000
1000
2
2
In the RA of aldehydes, a slow background reaction was
observed for the reaction of benzaldehyde with p-anisidine.
As shown by the conversion–time profiles in Figure 6, the
RA does happen in the absence of 1g; but it is much slower
than the RA catalysed with 0.05 mol% 1g.
10
11[c]
12
13
14
15
16
17
18
92
71
82
91
93
77
59
87
82
200 12
To explore the potential application of the catalytic iridi-
um system in the practical synthesis of amines, we studied
the RA of benzaldehyde with p-anisidine at higher S/C
ratios. A pH value of 4.6 was used for these reactions to
ensure the quantity of the hydrogen source to be sufficient.
The results are shown in Table 5. As can be seen, at S/C=
1ꢀ104, where 25 mmol of aldehyde were used, the RA af-
forded a conversion of 91% within 10 h, with the amine iso-
lated in 76% yield (Table 5, entry 1). At higher S/C ratios of
2ꢀ104 and 5ꢀ104 corresponding to a scale of 50 and
125 mmol of aldehyde, respectively, the reaction also
worked quite well, affording yields of 91 and 88% in 16 and
36 h, respectively (Table 5, entries 2 and 3). Impressively,
the reaction still proceeded well at still higher S/C of 1ꢀ105
(250 mmol scale), the highest S/C ratios ever reported for
RA reactions (Table 5, entry 4).[8a]
1000
2
2
2
1000
1000
1000 10
200 24
2000
4
200 64
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C. Wang, J. Xiao et al.
Table 3. RA of aliphatic ketones with different amines.
Table 4. RA of various aldehydes with different amines.
Entry[a] Ketone
Amine
S/C
t [h] Yield [%][b]
Entry[a] Aldehyde
1
Amine
S/C
t [h] Yield [%][b]
2000
2
2
2
2
2
2
98
98
95
97
79
92
1
2000
2
2
2
2
2
2
2
2
2
6
98
99
98
98
99
96
79
97
54
85
52
64
2
3
4
5
6
2000
2000
2000
2000
2000
2
2000
2000
2000
2000
1000
2000
2000
2000
1000
3
4
5
6
7
8
2000
2000
2
2
97
96
7
9
2000
2000
2000
2000
4
5
2
2
97
97
94
98
8
10
11
12
9
10
11[c]
12[c]
200 48
200 24
13
14
2000
1000
2
2
99
95
15
16
17
18
2000
2000
1000
1000
2
2
4
4
96
97
83
93
13
14
2000
3
4
95 (=79:21)[d]
1000
93
15
16
17
1000
2000
2000
2
2
2
98
88
98
19
20
1000
1000
5
2
72
98
21
500
2
99
18
2000
2
95
[a] Reaction conditions: aldehydes (5 mmol), amine (10 mmol), 1g,
HCOOH/HCOONa solution (pH 4.8, 8 mL), 808C. [b] Yield of the iso-
lated product.
[a] Reaction conditions: ketone (5 mmol), amine (10 mmol), 1g,
HCOOH/HCOONa solution (pH 4.8, 8 mL), 808C. [b] Yield of the iso-
lated product. [c] pH 5.0. [d] The d.r. value is given in brackets.
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Fast Reductive Amination by Transfer Hydrogenation
FULL PAPER
into a Schlenk tube. The tube was then degassed and recharged with
argon three times. Dichloromethane was then added and the resulting
mixture was stirred at room temperature overnight. The reaction mixture
was filtered through celite and dried over MgSO4. Following removal of
the solvent under vacuum, the resulting solid was washed with diethyl
ether/hexane. Single crystals suitable for X-ray analysis were obtained by
diffusion of hexane into a solution of dichloromethane. The imine ligands
were prepared according to the literature.[12e]
Typical procedure for the RA: A reaction tube was charged with a mag-
netic stir bar and p-anisidine (5 mmol). Acetophenone (2.5 mmol) was
then introduced with a syringe, followed by catalyst 1g (0.0025 mmol).
To the mixture was injected a water solution of HCOOH/HCOONa
(4 mL, pH 4.8), prepared from HCOOH (88%, 0.4 mL), HCOONa·
2H2O (2.45 g) and water (3.6 mL). The resulting mixture was bubbled
with argon for 15 min and stirred at 808C for 2 h. After cooling to room
temperature, the solution was adjusted to pH 2–3 with HCl (4m), stirred
for 10 min and then basified with aqueous NaOH solution (6m) to pH 9–
10. The resulting solution was extracted with ethyl acetate and dried over
anhydrous Na2SO4. After removing the solvent in vacuum, the product
was purified by flash column chromatography (petroleum ether (m.p.=
60–908C)/ethyl acetate 30:1).
Figure 6. Comparison of catalysed RA with the background RA. Reac-
tion conditions: benzaldehyde (5 mmol), p-anisidine (6 mmol), 1g
&
*
(0.0025 mmol), 808C. =catalysed reaction,
=background reaction
without catalyst.
Table 5. RA at high S/C ratios.
Acknowledgements
Entry[a]
S/C
10000
20000
50000
t [h]
Yield [%][b]
91 (76)[c]
The work was supported by the Program for Changjiang Scholars and In-
novative Research Team in University (IRT 1070), the National Science
Foundation of China (21103102), the Cheung Kong Scholar Programme,
the Fundamental Research Funds for the Central Universities
(GK200902009) and the Distinguished Doctoral Research Fund of the
Shaanxi Normal University (S2011YB02). We are grateful to Dr. Tom
Emge and Dr. Manrong Li of Rutgers University for solving the X-Ray
structure of catalyst 1g.
1
2
3
4
10
16
36
48
91
88
95
100000
[a] Reaction conditions: aldehydes (1 equiv; see the text for the amount
used), amine (2 equiv), 1g, HCOOH/HCOONa solution, 808C. [b] Deter-
mined by 1H NMR spectroscopy by using 1,3,5-trimethoxybenzene as in-
ternal standard. [c] Number in brackets refers to the yield of the isolated
product.
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with a range of amines has been realised with iridium-cata-
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and less toxic formic acid as hydrogen source. The pH of the
solution is shown to play an important role in regulating the
activity and chemoselectivity of the RA, with certain acidic
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in a heterogeneous manner, providing another example of
transition-metal-catalysed “on water” reactions, is faster
than that in organic solvents, where the reaction is homoge-
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the cyclometallated iridium complex 1g, which catalysed
“on water” RA, offers an efficient, green and practical new
method for accessing amines.
Experimental Section
General procedure for the preparation of the cyclometallated complex-
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[{Cp*IrCl2}2]
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Received: November 23, 2012
Published online: February 10, 2013
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4029