Diastereo- and enantioselective reductive amination of cycloaliphatic ketones by preformed chiral palladium complexes

Article abstract of DOI:10.1039/c4cy00058g

An efficient preformed chiral palladium catalyzed direct diastereo- and enantioselective reductive amination of un- and substituted cycloaliphatic ketones with primary aryl amines has been developed.

Full text of DOI:10.1039/c4cy00058g

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Diastereo- and enantioselective reductive
amination of cycloaliphatic ketones by preformed
chiral palladium complexes†
Cite this: Catal. Sci. Technol., 2014,
4, 2626
a
Armando Cabrera, Pankaj Sharma,a F. Javier Pérez-Flores,a Luis Velasco,a
Received 15th January 2014,
Accepted 7th March 2014
*
b
a
*
J. Luis Arias and Laura Rubio-Pérez
DOI: 10.1039/c4cy00058g
An efficient preformed chiral palladium catalyzed direct diastereo- and enantioselective reductive
amination of un- and substituted cycloaliphatic ketones with primary aryl amines has been developed.
www.rsc.org/catalysis
palladium catalysts in the DARA reaction (Scheme 1). Herein,
we report the general one-pot asymmetric reductive
1. Introduction
Cycloaliphatic chiral amines and their analogues are useful
compounds for the synthesis of natural products, pharma-
ceuticals, agrochemicals and material industries.1,2 The
direct asymmetric reductive amination (DARA) of carbonyl
compounds with primary amines is one of the most desired
strategies for the synthesis of chiral amines.3–6 Hence, the
development of an efficient enantioselective synthesis of
these compounds is an important task in organic chemistry.
There are only a few synthetic methods reported in the litera-
ture to access to these organic compounds from α-branched
ketones.7 The Lassaletta8 and List9 groups have developed
the asymmetric reductive amination of α-branched ketones
by dynamic kinetic resolution, employing a ruthenium cata-
lyst and organocatalysts, respectively. Thus, efficient methods
for the diastereo- and enantioselective synthesis of
substituted cycloaliphatic amines are still limited. Palladium-
based catalysts have been employed for the asymmetric
hydrogenation of imines but have not been explored much
for the reductive amination of carbonyl compounds.10 Our
group has contributed to the direct asymmetric reductive
amination of alkyl and aryl ketones, and α-diketones with
primary anilines catalyzed by stable chiral preformed palla-
dium catalysts and we were able to obtain chiral amines in
excellent yields and enantioselectivities (up to 99% ee).11
Since our initial report, we have continued to explore the
scope and limitations of the air-stable preformed chiral
amination of cycloaliphatic ketones and α- and β-branched
ketones with primary aryl amines for the non, diastereo- and
enantioselective synthesis of N-cycloalkylamines.
2. Results and discussion
A series of unsubstituted cycloaliphatic ketones were tested
for their ability to undergo direct reductive amination, using
Pd[(rac)-BINAP]Br2 as catalyst, molecular sieves (5 Å) and a
hydrogen pressure of 800 psi at 80 °C for 24 h (Table 1).12 All
showed good reactivity and gave the corresponding secondary
amines in 74–95% yields. Of all the ketones used in this
study, small aliphatic cyclic ketones, ranging from cyclo-
butanone to cyclohexanone (Table 1, entries 1–4), were the
most reactive. Larger cyclic ketones, such as cyclooctanone
and cyclododecanone, reacted somewhat slower (Table 1,
entries 9–10). Additionally, all primary aryl amines with
a Instituto de Química, Universidad Nacional Autónoma de México,
Ciudad Universitaria, Circuito Exterior, Coyoacán 04510, México D.F..
E-mail: arcaor1@unam.mx, laurarpz@unam.mx; Tel: +52 55 56224400
+52 55 56224455
b Facultad de Estudios Superiores Cuautitlán, Departamento de Química, UNAM,
Cuautitlán Izcalli, Estado de México 54700, Mexico
† Electronic supplementary information (ESI) available: Experimental,
spectroscopy data, scanned spectra and X-ray data of 1e, 1h and 1i. CCDC
980411–980413. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cy00058g
Scheme 1 Structures of non- and chiral ligands used to synthesize
palladium catalysts.
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Table 1 Direct reductive amination of unsubstituted cycloaliphatic
ketonesa
the yields (Table 1, entries 7 and 8). Interestingly, when cyclo-
dodecanone was reacted with 3,3-difluoroaniline, the desired
secondary amine was isolated in good yield (81%, Table 1,
entry 10). The reaction of an arylamine with a –NO2 group
was also considered, but no product was obtained (Table 1,
entry 11).13
In the direct asymmetric reductive amination of
substituted cycloaliphatic ketones, 2-methylcyclopentanone
with aniline in the presence of hydrogen gas was chosen as
the model reaction to evaluate a series of diphosphine and
phosphine–nitrogen–palladium complexes (Table 2). The
structures of Pd[(R)-Tol-BINAP]Br2 (1e), Pd[(R)-PHOX]Br2 (1h)
and Pd[(R)-H8-BINAP]Br2 (1i) were confirmed by X-ray diffrac-
tion and are shown in the ESI.† In contrast to the results
reported in the literature14 for the non-diastereoselective
reactions, we have obtained only the cis-5a diastereoisomer
in all cases, probably this preference is due to equatorial
attack of the bulky hydride-complex to the cyclic imine inter-
mediate generated in situ.14 RThe relative configuration was
confirmed by NOE experiments. It is noteworthy that the
heterogeneous catalyst 1a provides 5a with a lower selectivity
(Table 2, entry 2). At room temperature, catalyst 1c provided
a low yield and enantioselectivity (Table 2, entry 4), but it was
observed that an increase in temperature highly improves the
yield and stereoselectivity (Table 2, entries 5–7). Therefore,
this catalyst turned out to be the most effective for this trans-
formation at 80 °C providing cis-5a in 90% yield with an
enantiomeric excess of 98%. A similar result was observed
with catalyst 1i at 80 °C (Table 2, entry 13), but for availability
1c was chosen for the next reactions. All other diphosphine–
palladium catalysts used were less active. Catalysts 1h and 1j,
containing a heterobidentate ligand gave the cis-5a with good
enantioselectivities (87 and 89%, respectively) but with low
yields (Table 2, entries 12 and 14).
Entry Ketone
1
Amine
Product
Yieldb
3a 95
2
3b 93
3
4
3c 89
3d 74
5
6
7
3e 92
3f 91
3g 86
8
3h 88
9
3i 88
3j 81
10
Based on these catalyst screening results, the applicability
of catalyst 1c to the asymmetric reductive amination of
2-methylcyclopentanone 4, with a range of commercially
available aryl amines were extended to obtain aminocyclo-
pentane derivatives. As shown in Table 3, rac-4 was reacted
with functionalized anilines bearing ortho, meta and para
substitutions on the aryl ring to give cis-N-(2-methyl-
cyclopentyl)amines 5b–k (Table 3, entries 1–3, 5–8 and 11) in
good yields (69–91%) and good to excellent enantiomeric
excesses (83–98%). The highest enantiomeric excess (98%)
was achieved when m-trifluoromethylaniline was used
(Table 3, entry 6). However, the reaction with o-bromo aniline
gave a lower enantiomeric excess (Table 3, entry 9) contrary
to o-trifluomethyl aniline (Table 3, entry 11). It is noteworthy
that the asymmetric reductive amination reaction is
influenced by the bulkiness of the substituents on the
anilines. For example, when sterically congested 2,4,6-
trimethylaniline and 2,3,4,5,6-pentafluoroaniline were used
under the same conditions, no reaction was observed (Table 3,
entries 4 and 10) only traces of the respective imine was
detected by GC-MS and no reduction of the cycloaliphatic
ketone was observed.
11
3k
0
a
Reaction conditions: 2.5 mol% of Pd[(rac)-BINAP]Br2, 1.0 mmol of
2, 1.3 mmol of 3, 10 mL CHCl3 and H2 (800 psi) at 80 °C for 24 h.
Isolated yield.
b
electron-donating or electron-withdrawing groups were used
successfully in these reactions. For the same cycloaliphatic
ketone, such as cyclohexanone, the direct reductive
amination proceeds well with both aniline (89%, Table 1,
entry 3) as the disubstituted aryl amine containing two differ-
ent halogen atoms (74% yield, Table 1, entry 4). Reaction of
cycloheptanone with an arylamine containing an electron-
donating substituent showed similar reactivity with aniline
(Table 1, entries 5 and 6). Reactions with substituted anilines
either at the ortho or meta position with an electron-
withdrawing group such as –CF3 led to a slight decrease in
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Table 2 Catalyst screening for the direct asymmetric reductive amination of 4a
Entry
Catalyst precursor
T (°C)
Yieldb (%)
d.r.c
eed (%)
1
2
3
4
5
6
7
8
None
Pd/C (1a)
Pd[(R)-BINAP]Cl2 (1b)
Pd[(R)-BINAP]Br2 (1c)
80
80
80
rt
0
77
87
70
88
90
90
89
81
82
82
63
90
68
0
0
62 : 38
97 : 3
94 : 6
96 : 4
98 : 2
98 : 2
98 : 2
95 : 5
94 : 6
92 : 8
91 : 9
98 : 2
93 : 7
—
92
78
80
98
91
95
89
93
96
87
98
89
60
80
100
80
80
80
80
80
80
80
Pd[(S)-BINAP]Br2 (1d)
9
Pd[(R)-Tol-BINAP]Br2 (1e)
Pd[(S)-Tol-BINAP]Br2 (1f)
Pd[(S,S)-CHIRAPHOS]Br2 (1g)
Pd[(R)-PHOX] Br2 (1h)e
Pd[(R)-H8-BINAP]Br2 (1i)
Pd[(R)-QUINAP]Br2 (1j)
10
11
12
13
14
a
b
Reaction conditions: 2.5 mol% of catalyst, 1.0 mmol of 2, 1.3 mmol of 3a, 10 mL CHCl3 and H2 (800 psi) at 80 °C for 24 h. Isolated yield of
c
d
major cis product. Relative stereochemistry determined by NMR. Determined by NMR analysis of crude product. Determined by GC-MS (EI)
using a chiral column Cyclodex-β. Here abbreviated as PHOX = 2-[2-(diphenylphosphino)phenyl]-4-isopropyl 1,3-oxazoline.
e
For
the
asymmetric
reductive
amination
of
we achieved the formation of trans-3-methylcyclohexylamine
derivatives 9a–d with excellent enantioselectivity up to 99%
(Table 5, entries 1–4).15
2-methylcyclohexanone 6, only cis-N-(2-methylcyclohexyl)
amines 7a–h were obtained in good yields (Table 4, entries
1–8, 71–91%) and with good to excellent enantioselectivities
(62–99%). The highest enantioselectivity was observed when
p-methoxyaniline was used (Table 4, entry 5). From these
experiments, it was concluded that the steric factor has an
effect on the stereocontrol of the reaction.
The potential of the palladium catalytic system was
extended to other substituted cyclic ketones (Scheme 2).
2- and 4-arylsubstituted cyclohexanones (10 and 12) were reduc-
tively aminated with aniline to give the cis product in excel-
lent yield and moderate enantioselectivity for 10. It is also
possible to transform bicyclic ketones such as norcamphor,
which led to the exclusive formation of 15 with 87% ee.
The asymmetric induction may be explained by the fact
that the substituent on the cycloaliphatic imine must be
On the other hand, for the reaction of (R)-(+)-3-methyl-
cyclohexanone with selected anilines using catalyst 1c (Table 5),
Table 3 Asymmetric reductive amination of 2-methyl cyclopentanone
with anilinesa
Table 4 Asymmetric reductive amination of 2-methyl cyclohexanone
with anilinesa
Entry
R
Product
Yieldb (%)
d.r.c
eed (%)
1
2
3
4
5
6
7
8
m-CH3
p-CH3
p-C2H5
2,4,6-CH3
p-CH3O
m-CF3
m-Cl
p-Cl
o-Br
2,3,4,5,6-F
o-CF3
5b
5c
5d
5e
5f
5g
5h
5i
90
91
86
0
78
80
86
88
75
0
97 : 3
97 : 3
98 : 2
—
99 : 1
96 : 4
98 : 2
97 : 3
93 : 7
—
93
95
83
—
96
98
91
84
18
—
95
Entry
R
Product
Yieldb
d.r.c (%)
eed (%)
1
2
3
4
5
6
7
8
H
7a
7b
7c
7d
7e
7f
91
91
74
83
85
90
82
71
91 : 9
94 : 6
90 : 10
92 : 8
93 : 7
91 : 9
91 : 9
89 : 11
79
p-CH3
p-C2H5
o-CH3O
p-CH3O
m-Cl
75d
62
98
>99
93
9
10
11
5j
5k
5l
p-Cl
p-Br
7g
7h
89
83e
69
92 : 8
a
The reaction conditions were the same as those in Table 2.
Isolated yield of major diastereomer.
a
b
c
The reaction conditions were the same as those in Table 2.
Isolated yield of major diastereomer. Determined by NMR analysis.
Determined by GC-MS (EI) using a chiral column Cyclodex-β.
Determined by NMR
b
d
c
d
analysis. Determined by GC-MS (EI) using a chiral column Cyclo-
dex-β. e Realized with catalyst 1d.
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Table
5
Asymmetric
reductive
amination
of
(R)-3-
methylcyclohexanone with selected anilinesa
Entry
R
Product
Yieldb (%)
d.r.
eec (%)
Fig. 1 Suggested arrangement of the palladium–hydride complex for
the obtained stereochemistry in the products.
1
2
3
4
H
9a
9b
9c
9d
87
90
84
89
98 : 2
98 : 2
99 : 1
96 : 4
91
95
>99
>99
p-C2H5
m-CF3
m-Cl
a
The reaction conditions were the same as those in Table 2.
Isolated yield. Determined by GC-MS (EI) using a chiral column
b
c
Cyclodex-β.
oriented far from the equatorial phosphinic phenyl groups of
the BINAP ligand in order to avoid steric hindrance.16 This
promotes the preferential hydride attack on the Si face of the
substrate. In the case when the Re face is attacked by the
hydride, the R1 group on the cyclic imine would present a
greater repulsion from the equatorial phenyl (Eq) group.
Fig. 1 shows the favored arrangement.
The suggested arrangement shown in Fig. 1 also explains
the increment in ee due to higher fluxionality. Thus, there
will be more steric congestion in the hydride species at
higher temperatures.
On the other hand, the diastereomeric excess found in
this reaction can be explained by the steric influence exerted
by the large hydride palladium species, which in turn facili-
tates the equatorial attack14 preferentially on the iminic bond
(Fig. 2). This results in a 1,2- or 1,4-cis-amino methyl product,
as the methyl group is in the β-equatorial position on the
ring. In the case of 1,3-di substitution, the methyl group at
the α-equatorial position generates the trans-1,3-reduced
product.
Fig. 2 Preferential hydride attack on the iminic bond.
3. Conclusion
In summary, the preformed chiral palladium catalysts pro-
vides a direct and efficient route towards the diastereo- and
enantioselective synthesis of N-cycloalkylamines from
substituted cycloaliphatic ketones in good yields with good to
excellent enantiomeric excess. This catalytic system shows
versatility with different substituents on the aniline deriva-
tives. The steric bulkiness of the aniline derivatives has an
important effect on the stereocontrol of the process. The
Scheme 2 Other ring sizes for asymmetric reductive amination.
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diastereoselective preparation of either of the two possible
chiral diastereomers represents a significant challenge for
organic synthesis. Further investigations to expand the scope
of other substrates and to further understand the mechanism
of this reaction are in progress.
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Acknowledgements
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This work was supported by CONACyT (166350) and DGAPA-
UNAM (PAPIIT IN203209).
Notes and references
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see: (a) R. P. Triphathi, S. S. Verma, J. Pandey and
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12 The starting primary aromatic amine was used in 30%
excess in order to control the selectivity toward alkylation.
The addition of molecular sieves (MS 5 Å) was necessary to
absorb water molecules, which are generated by the
condensation between the cycloaliphatic ketone and aniline
derivatives. Without MS 5 Å, the reaction proceeds with low
yield.
3 For organocatalytic reductive amination using Brønsted
acids in combination with
a Hantzsch ester, see. (a)
R. I. Storer, D. E. Carrera, Y. Ni and D. W. C. Macmillan,
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I. Lavandera, D. Clay, G. M. Guebitz, D. Rozzell and
W. Kroutil, Angew. Chem., Int. Ed., 2008, 47, 9337–9340.
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13 Only reduction of the –NO2 group on aniline to –NH2 was
detected by GC-MS.
14 Conformational studies over stereoselective reduction of
cyclopentyl and cyclohexyl imines by hydride reagents, see:
(a) R. O. Hutchins, W. Y. Su, S. Ramachandran, F. Cistone
and Y. P. Stercho, J. Org. Chem., 1983, 48, 3412–3422; (b)
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15 The synthesis of 3-substituted cyclohexylamines with chiral
phosphoric acids gives the corresponding cis-diastereomers,
see ref. 3b.
16 T. Ohkuma, M. Kitamura and R. Noyori, New Frontiers in
Asymmetric Catalysis, ed. K. Mikami and M. Lautens J. Wiley
& Sons Inc., 2007, ch. I.
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