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shown that aqueous media of lower pH favour the ketone re-
duction over the imine formation.[17,18]
Table 1. Optimising reaction conditions of DRA.
The substrate scope was examined with catalyst 1i under
the optimised conditions (0.1 mol% 1i, 808C in MeOH). The re-
sults of DRA of aromatic ketones are summarised in Table 2. All
the phenyl derivatives, regardless of the nature of the substitu-
ents and their positions, gave excellent yields (Table 2, en-
tries 3–16). The naphthyl derivatives also reacted well giving
high yields (entries 1 and 2). Disubstituted aromatic ketones
and those with increasing chain length at the a-position did
not affect the yields of the product (entries 17–19). When an
a,b-unsaturated ketone was subjected to the DRA under the
present conditions, reduction of the carbon double bond was
observed as well (entry 20). This suggests that when a double
bond is present next to a carbonyl, 1,4-reduction pathway is
favoured over 1,2-reduction, and it is not surprising, as 1,4-re-
duction is frequently observed in transfer hydrogenation.[23]
The cyclic substrates, 1-indanone and 1-tetralone, both gave
their corresponding amines in excellent yields (entries 21 and
22). In contrast to the a,b-unsaturated ketone, when 2-acetyl-
benzofuran was used, the double bond was retained, with 1-
(benzofuran-2-yl)ethanamine obtained in 91% yield (entry 23),
a result that reflects the aromaticity of the substrate. A thio-
phene ring was also tolerated well, affording 1-(2,5-dimethylth-
iophen-3-yl)ethanamine in an excellent yield (entry 24). It was
found that a prolonged reaction time increases the concentra-
tion of N-formyl derivatives in these reactions. In fact, reaction
times of 4–12 h were sufficient for the completion of the DRA.
Reactions of aliphatic ketones with HCO2NH4 are summar-
ised in Table 3. As can be seen, 4-phenylbutan-2-one and its
variant 4-(3,4-methylenedioxy)phenyl-2-butanone both were
converted to their corresponding amines in excellent yields
(Table 3, entries 1 and 2). Cyclohexanamine and 1-cyclohexyle-
thanamine were also obtained in good yields (entries 3 and 4).
Interestingly, a bulkier substrate, cyclododecanone, was also
aminated in a high yield without any predicament (entry 5).
Long-chain aliphatic substrates worked well, furnishing good
yields regardless of the position of the carbonyl unit (entries 6
and 7). Still interestingly, 6-methylhept-5-en-2-one gave its cor-
responding amine in a very good yield, leaving its C=C double
bond intact. This shows the selectivity of the catalyst towards
C=N bond reduction over a C=C bond. Indeed, the reduction
of C=C double bond is only observed when it is present at
a position a to the C=O group. 3,3-Dimethyl-1,5-dioxaspiro-
[5.5]undecan-9-one, a useful monoprotected form of the
dione, was selectively aminated in excellent yield without the
hydrolysis of its 1,3-dioxane being observed (entry 9). Thus, the
catalytic system offers a simple and efficient way of obtaining
aminocyclohexanones, which are useful intermediates, espe-
cially for the synthesis of Pramipexole, a dopamine agonist of
the non-ergoline class used for the treatment of signs and
symptoms of idiopathic Parkinson’s disease.[24] 2-Aminotetralin,
another key precursor, was also obtained in a very good yield
from its corresponding b-tetralone (entry 10). 2-Aminotetralins
are used in the synthesis of many therapeutic agents and have
also been known to possess other pharmacological activities,
including dopamine receptor activity.[25]
Entry[a]
Cat.
Solvent
Conv. [%][b] 3a[b] 4[b] 5[b] 6[b]
1
2
3
4
5
6
7
8
[IrCl2(Cp*)]2 MeOH
6
36
9
–
28
5
1
5
1
–
1
1
1
1
2
2
2
1
2
–
3
2
3
–
1
2
2
3
5
2
2
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1i
1i
1j
1k
1i
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
H2O
38
12
70
86
98
42
99
54
82
93
65
99
35
7
–
3
2
2
3
4
1
–
9
1
4
98
3
2
1
2
3
3
3
2
1
5
6
5
–
64
79
90
34
94
53
65
84
53
1
9
10
11[c]
12[d]
13
14
15
16
17
18
19
1i
1i
1i
1i
toluene 15
4
7
DMF
EtOAc
TFE
18
35
96
3
1
81
–
13
4
13
19
8
[a] Reaction conditions: 2-acetonaphthone (0.5 mmol), HCO2NH4
(5 mmol), catalyst (5ꢂ10À4 mmol), HCO2H/Et3N (5:2) azeotrope (0.5 mL)
and solvent (3 mL), stirred at 808C in a carousel tube for 4 h. [b] Deter-
mined by 1H NMR spectroscopy (%). [c] In the absence of F/T azeoptrope.
[d] Five equivalents of ammonium formate used.
ic rings, such as naphthyl and phenanthryl, which offer more
extensive conjugation. To our delight, catalyst 1i, which con-
tains a naphthyl ring gave excellent results, with 99% conver-
sion and a very high selectivity towards primary amines
(entry 10).
Addition of the formic acid–triethyl amine (F/T) azeotrope
was found to promote the reaction. In its absence, the 1i-cata-
lysed reaction proceeded in only 54% conversion in 4 h
(Table 1, entry 11). The F/T azeotrope increases the acidity of
the reaction medium, and indeed it is known that the imine
formation and its subsequent reduction benefits from the
acidic conditions.[22] When the reaction was conducted with
five equivalents of ammonium formate, the conversion de-
creased and formation of more byproducts was observed
(entry 12). In contrast, the more conjugating catalysts 1j and
1k, bearing an anthracene and phenanthrene ring, respective-
ly, gave lower conversions (entries 13 and 14). This is at least
partly due to their low solubility in the reaction medium. It
was confirmed that the reaction did not proceed in the ab-
sence of a catalyst.
Next, we investigated the reaction in various solvents. MeOH
was found to be the best medium, giving high selectivity to-
wards the primary amine relative to other solvents (Table 1, en-
tries 16–19). Interestingly, when the reaction was conducted in
water, the reduction of ketone dominated, with the alcohol
product observed in 98% ratio (entry 15). We have recently
Chem. Eur. J. 2014, 20, 245 – 252
247
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