Asymmetric organocatalytic reduction of ketimines with catecholborane employing a N-triflyl phosphoramide Br?nsted acid as catalyst

Article abstract of DOI:10.1016/j.tetlet.2012.11.055

The first asymmetric reduction of ketimines with catecholborane employing an enantiopure N-triflyl phosphoramide as the organocatalyst has been developed. Five mole % of the catalyst provides the corresponding secondary amines in very good to almost quantitative yields and good enantioselectivities up to 86:14 e.r. under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2012.11.055

Tetrahedron Letters 54 (2013) 470–473
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Tetrahedron Letters
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Asymmetric organocatalytic reduction of ketimines with catecholborane
employing a N-triflyl phosphoramide Brønsted acid as catalyst
⇑
Dieter Enders , Andreas Rembiak, Matthias Seppelt
Institute of Organic Chemistry, RWTH Aachen, Landoltweg 1, 52074 Aachen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
The first asymmetric reduction of ketimines with catecholborane employing an enantiopure N-triflyl
phosphoramide as the organocatalyst has been developed. Five mole % of the catalyst provides the cor-
responding secondary amines in very good to almost quantitative yields and good enantioselectivities
up to 86:14 e.r. under mild reaction conditions.
Received 27 September 2012
Revised 9 November 2012
Accepted 14 November 2012
Available online 23 November 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Organocatalysis
Brønsted acid
Ketimine
Catecholborane
Reduction
Chiral amines are one of the most important structural motifs in
biologically active compounds.1 Furthermore they can be used for
instance as catalysts,2 chiral auxiliaries or chiral ligands3 in organic
synthesis and as resolving agents.4 Hence, numerous different
asymmetric syntheses of amines have been developed including
nitrogen C–H-insertion, hydroamination of olefins, N-acetyl ena-
mide reduction, nucleophilic addition reactions, and reductive
amination.1a Beyond these methods an important strategy is the
reduction of prochiral ketimines. There is a great variety of enan-
tioselective metal-catalyzed hydrogenations5 and many organocat-
alytic enantioselective reductions of ketimines. In the latter case
Hantzsch esters,6 benzothiazolines,7 or trichlorosilane8 are com-
monly applied as hydride sources. In contrast, only a few examples
are known utilizing boron reagents in enantioselective ketimine
reductions. While the use of stoichiometric amounts of chiral bor-
on hydrides is common, the Corey–Bakshi–Shibata (CBS) reduction,
which is known to provide an easy access to a great variety of
enantioenriched alcohols,9 has been less investigated in the field
of enantioselective reduction of imines. Furthermore, achiral
reducing agents have been rarely utilized in asymmetric reduc-
tions. Nevertheless, several examples for the enantioselective
reduction with catalytic amounts of chiral boron reagents, which
have been applied to various aliphatic as well as aromatic imines,10
oximes,11 stable N–H imines,12 or cyclic N-sulfonylimines13 are
known in the literature. Difficulties in the enantioselective borane
reduction result from the equilibrium between the E- and
Z-isomers and their differentiation by the catalyst.14 Furthermore,
oxazaborolidines can be trapped by the Lewis basic nitrogen atom
of the imine moiety and result in lower enantioselectivity, due to
their high reactivity against boron hydrides.
Chiral Brønsted acid catalysis is a rapidly growing sub-field of
organocatalysis. Since the pioneering work of Akiyama and Terada
chiral BINOL based phosphoric acids have successfully been em-
ployed in numerous organic transformations.15 Due to their great
potential, we envisaged a Brønsted acid catalyzed reduction of
ketimines utilizing catecholborane as the hydride source. During
our investigations Antilla and co-workers published the first appli-
cation of chiral phosphoric acids for the enantioselective reduction
of ketones with catecholborane,16 but to the best of our knowledge,
an analogous reduction of ketimines has not been described so far.
As an extension of our contributions in the asymmetric synthe-
sis of amines,17 herein we wish to report the first enantioselective
reduction of ketimines with catecholborane catalyzed by chiral N-
triflyl phosphoramides. Initial tests were carried out using keti-
mine 1a as the model substrate. The screening of chiral phosphoric
acids 4 was performed at À22°C in toluene with pre-cooling to
À78°C before the addition of catecholborane 2 (Table 1). First re-
sults with 5 mol % of chiral phosphoric acids 4a and 4b and
1.6 equiv of catecholborane 2 revealed that amine 3a is obtained
in high yield but only low enantioselectivity (Table 1, entries 1
and 2). Changing to the more acidic N-triflyl phoshoramide 4c
led to an increased enantioselective ratio of 76:23 with almost
quantitative conversion after 12 h (Table 1, entry 3).18 Probably
the higher reactivity of the phosporamide leads to a reaction,
which is fast enough to overcome the uncatalyzed reduction.
⇑
Corresponding author. Tel.: +49 241 80 94676; fax: +49 241 80 92127.
E-mail address: enders@rwth-aachen.de (D. Enders).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.11.055

D. Enders et al. / Tetrahedron Letters 54 (2013) 470–473
471
Table 1
1.6 equiv of hydride source provided the best results with 77:23
enantiomeric ratio (Table 2, entry 3), while lowering the amount
of borane led to a decrease of enantioselectivity (Table 2, entries
2 and 3). Interestingly, the use of only 0.9 equiv of 2 furnished
amine 3a also in good enantioselectivity, but accompanied by a
decrease in yield (Table 2, entry 1). This might be attributed to a
lower borane concentration in solution and therefore a lower
probability of a Lewis acid base reaction of the ketimine and
catecholborane. Although further decreasing the present cate-
cholborane concentration by adding 1.6 equiv of 2 over 25 min
via syringe pump increased the yield of 3a but resulted in only
72:28 e.r. Finally increasing the amount of catecholborane seems
to have no remarkable effect on either yield or enantioselectivity
(Table 2, entry 4).
Next we investigated the effect of different nitrogen protecting
groups (Table 3). We found that the enantioselectivity was highly
dependent on the steric demand of the protecting group. Generally,
higher enantiomeric ratios were obtained with benzylic than with
phenylic substituents. While substituting the benzyl group in the
4-position of the aromatic ring with an electron-donating group
led to a slight increase of enantioselectivity (Table 3, entry 4),
employing electron-withdrawing groups seems to have an oppo-
site effect on the enantioselectivity (Table 3, entry 5). Changing
to the PMP-protecting group, amine 6b was isolated in almost
quantitative yield but with low enantioselectivity (Table 4, entry
2). Decreasing the steric demand by employing a non-substituted
phenylic group gave the corresponding amine in 91% yield and also
low enantioselectivity. We assumed that the enantioselectivity is
also dependent on the E/Z ratio of the selected ketimine. Therefore
we tested the steric demanding diphenylmethyl protecting group
having the E-configuration, exclusively. Unfortunately, amine 6e
was obtained in moderate yield and low enantioselectivity (Table 4,
entry 6).
Evaluation of the chiral Brønsted acids 4 in the reduction of ketimine 1aa
N
Ph
CH3
HN
Ph
CH3
catalyst 4, toluene
−78 → −22 °C
O
1a
3a
BH
O
2
R
4a
X=O, Y=OH, R= 2,4,6-(i-Pr)3C6H2
4b X=O, Y=OH, R= 3,5-(CF3)2C6H3
4c
4d X=O, Y=NHTf, R=1-naphthyl
4e X=O, Y=NHTf, R=2-naphthyl
4f X=O, Y=NHTf, R=9-phenanthryl
4g X=S, Y=NHTf, R= 2,4,6-(i-Pr)3C6H2
O
O
X
Y
X=O, Y=NHTf, R= 2,4,6-(i-Pr)3C6H2
P
R
(R)-4
Entry
Catalyst
Time (d)
Yieldb (%)
e.r.c
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
1
1
0.5
1
1
2
0.5
3
90
89
75
91
90
84
81
81
64:36
54:46
77:23
52:48
53:47
50:50
60:40
—
4g
—
a
Reaction conditions: 1a (0.5 mmol), catalyst 4 (5 mol %), 2 (0.8 mmol), 1.0 mL
toluene at À78 ? À22 °C.
b
Yield of isolated 3a.
Determined by chiral stationary phase HPLC of the N-acylated product.
c
Finally a survey of the solvent and the reaction temperature was
carried out (Table 4). Screening polar solvents like acetonitrile, THF
or DCM gave inferior selectivities as compared to toluene (Table 4,
entries 2–4). Due to their comparatively high Lewis basic proper-
ties these solvents may coordinate the catecholborane and so its
coordination site for the chiral acid will be blocked. Therefore, in
all further experiments exclusively non-polar and non-coordinat-
ing solvents have been used. We assumed that the high reactivity
of the ketimines combined with their strong Lewis basicity might
be the most striking problem in the case of enantioselectivity.
Therefore we suggested that a low concentration of the ketimine
in solution might suppress a direct reaction between the imine
Further screening of the catalyst showed that chiral phosphoric
acids 4d and 4e with planar substituents on the BINOL backbone
delivered 3a in high yields, albeit with only 52:48 and 53:47 e.r.,
respectively, while the sterically more demanding catalyst 4f gave
only racemic amine (Table 1, entries 4–6). The more acidic thi-
ophosphorous derivative 4g provided product 3a only with 60:40
e.r. Due to the weaker Lewis basicity of sulfur, a weaker coordina-
tion of catecholborane in the transition state might be assumed. To
evaluate the background reaction, ketimine 1a and catecholborane
2 were mixed without any catalyst under the same reaction condi-
tions. After three days 81% of the racemic amine 3a was isolated
(Table 1, entry 8).
Having identified chiral N-triflyl phosphoramide 4c to be the
best catalyst, we examined the influence of the amount of
catecholborane 2 on yield and enantioselectivity (Table 2). As it
has been expected in comparison to other reduction protocols
employing catecholborane as the reducing agent,13,16,19 the use of
Table 3
Effect of the N-protecting group on the asymmetric reduction of ketiminesa
R
R
4c (5 mol%)
N
HN
2 (1.6 eq.), toluene
∗
CH3
CH3
− 78 → −22 °C, 24 h
Table 2
Influence of the amount of 2 on the reduction of ketiminesa
6
5
Entry
2 (equiv)
Time (d)
Yieldb (%)
e.r.c
Entry
R
Product
Yieldb (%)
e.r.c
1
2
3
0.9
1.2
1.6
2.0
1.6
1
1
0.5
1
1
72
83
75
88
93
77:23
73:27
77:23
76:24
72:28
1
2
3
4
5
6
Ph
6a
6b
3a
6c
6d
6e
91
87
95
94
85
79
42:58
47:53
77:23
78:22
74:26
59:41
p-(MeO)–Ph
Bn
p-(MeO)–Bn
p-Cl–Bn
CH(Ph)2
4
5d
a
Reaction conditions: 1a (0.5 mmol), catalyst 4c (5 mol %), 1.0 mL toluene at
À78 ? À22 °C.
b
a
Yield of isolated 3a.
Determined by chiral stationary phase HPLC of the N-acylated product.
Compound 2 (in 0.5 mL toluene) was added dropwise over 25 min via syringe
Reaction conditions: 5 (0.5 mmol), catalyst 4c (5 mol %), 2 (0.8 mmol), 1.0 mL
c
toluene at À78 ? À22 °C.
d
b
Yield of isolated product.
c
pump.
Determined by chiral stationary phase HPLC of the N-acylated product.

472
D. Enders et al. / Tetrahedron Letters 54 (2013) 470–473
Table 4
Table 5
Influence of the solvent and the temperature on the asymmetric reduction of
Substrate scope of the asymmetric reduction of ketimines with catecholboranea
ketiminesa
N
Ph
CH3
HN
Ph
CH3
4c (5 mol%), 2 (1.6 eq.)
N
Ph
CH3
HN
Ph
CH3
n-pentane, −78 → −22°C, 1 d
4c (5 mol%), 2 (1.6 eq.)
Ar
Ar
solvent, T, 24 h
1
3
Entry
Ar
Ph
Product
Yieldb (%)
e.r.c
1a
3a
1
2
3
4
5
6
7
8
3a
95
99
94
94
89
95
88
93
92
93
88
86:14
80:20
79:21
71:29
70:30
74:26
74:26
79:21
68:32
75:25
65:35
p-(MeO)–Ph
p-Me–Ph
m-(MeO)–Ph
o-Me–Ph
3b
3c
3d
3e
3f
3g
3h
3i
Entry
Solvent (M)
T (°C)
Yieldb (%)
e.r.c
1
2
3
4
5
6
7
8
Toluene (0.5)
CH3CN (0.5)
THF (0.5)
À78 ? À22 °C
À78 ? À22 °C
À78 ? À22 °C
À78 ? À22 °C
À78 ? À22 °C
À22 °C
95
72
75
99
67
77
86
83
86
38
94
77
71
81
95
77:23
50:50
50:50
56:44
70:30
83:17
86:14
81:19
80:20
83:17
85:15
71:29
67:33
61:39
86:14
p-Cl–Ph
DCM (0.5)
p-(NO2)–Ph
p-(F3C)–Ph
m-Cl–Ph
m-(F3C)–Ph
b-Naphthyl
n-Pentane (0.5)
n-Pentane (0.5)
n-Pentane (0.1)
9
10
11
À22 °C
3j
3k
n-Pentane (0.05)
n-Hexane (0.1)
Petroleum ether (0.1)
n-Pentane (0.1)
n-Pentane (0.5)
n-Pentane (0.5)
n-Pentane (0.1)
n-Pentane (0.2)
À22 °C
9
À22 °C
a
10
11
13
14
12d
15e
À22 °C
Reaction conditions: ketimine 1 (1.0 mmol), catalyst 4c (5 mol %), 2 (1.6 mmol)
in 5.0 mL n-pentane.
À15 °C
b
À22 ? 0 °C
À22 °C ? rt
À22 °C
Yield of isolated 3.
Determined by chiral stationary phase HPLC of the N-acylated product.
c
À78 ? À22 °C
a
b
c
and good enantioselectivities (Table 5). The absolute configuration
of amine 3a has been determined to be (R) by comparing its optical
rotation with the value reported in the literature.21 Aromatic keti-
mines bearing methyl or methoxy substituents as well as chlori-
nated arenes were suitable substrates in this reaction (Table 5,
entries 2–6 and 9). However, aromatic ketimines bearing substitu-
ents in the 4-position of the aromatic ring gave slightly higher
enantioselectivities than other substitution patterns. Furthermore,
nitro- and trifluoromethyl groups are tolerated and furnished the
products in excellent yields and also good enantiomeric ratios
(Table 5, entries 7, 8, and 10). Finally a b-naphthyl substituted ket-
imine could be reduced with excellent yield, albeit with slightly
lower stereoselectivity (Table 5, entry 11).22
In analogy to the proposed catalyst structure and transition
state for the reduction of ketones, recently reported by Antilla
and co-workers,16 we envisaged a possible transition state for the
reduction of ketimines (Fig. 1). We would also suppose the forma-
tion of a chiral phosphoryl borate observing the evolution of
hydrogen gas after mixing the chiral Brønsted acid with
catecholborane. This can be further confirmed by 11B NMR
spectroscopy (see Supplementary data). While the boron center
of the chiral phosphoryl borate can act as a Lewis acid coordinating
to the nitrogen of the imine moiety, the Lewis basic site of the
catalyst coordinates to another catecholborane molecule, increas-
ing its nucleophilicity. The hydride of this unreacted catecholbora-
ne can be added in a chiral environment to the Si-face of the
(Z)-ketimine, providing the (R)-configured amine. Simultaneously
the catalyst will be regenerated for another catalytic cycle.
Reaction conditions: 1a (0.5 mmol), catalyst 4c (5 mol %), 2 (0.8 mmol).
Yield of isolated 3a.
Determined by chiral stationary phase HPLC of the N-acylated product.
Reaction was performed with 3 Å molecular sieve.
d
e
Catalyst 4c and 2 were stirred at rt for 20 min before the solution was cooled to
À78 °C. Then the imine 1a was added in one portion.
and catecholborane. Since ketimine 1a can be recrystallized from
n-pentane we thought that the ketimines would slowly dissolve
effecting a low current concentration. First attempts of conducting
the reaction in a 0.5 M solution of n-pentane with pre-cooling pro-
vided the amine in moderate yield and a slight decrease in enanti-
oselectivity (Table 4, entry 5). Realizing that the catalyzed reaction
is too slow at this temperature, the amine was added at À22°C and
further stirred at this temperature. To our delight the selectivity
could be improved to 83:17 e.r. and further increased to 86:14
enantiomeric ratio and 86% yield by lowering the concentration
of ketimine 1a (Table 4, entries 6 and 7). Reducing the concentra-
tion further led to a considerable drop in enantioselectivity (Ta-
ble 4, entry 8). Other aliphatic non-polar solvents such as n-
hexane or petroleum ether gave comparable results, although with
a slight decrease in selectivity (Table 4, entries 9 and 10). A de-
crease of the reaction temperature to À15°C led to an increase of
the yield but did not affect the selectivity (Table 4, entry 11), while
pre-cooling to À22°C and then conducting the reaction at elevated
temperatures led to a remarkable decrease in selectivity (Table 4,
entries 12 and 13). The addition of molecular sieves to the reaction
has been reported to improve the selectivity several times in the
literature,20 unfortunately the enantioselectivity was decreased
to 61:39 e.r. in our case. Various other basic as well as acidic addi-
tives were tested in this reaction (see Supplementary data), but
none of them proved to be beneficial with respect to the enantiose-
lectivity. Based on NMR-studies Antilla and co-workers postulated
a chiral phosphoryl borate as active species in the reduction of ke-
tones with catecholborane.16 We investigated the effect of pre-
forming this kind of species by stirring catalyst 4c with 2 in n-
pentane at room temperature before cooling the system to
À78°C. To our delight this provided amine 3a with almost quanti-
tative yield and good enantioselectivity (Table 4, entry 15).
O
O
B
Tf
N
N
Ph
O
P
O
*
O
CH3
O
H
B
With the optimized reaction conditions in hand we investigated
the substrate scope of the asymmetric reduction of ketimines. Sev-
eral electron rich and electron deficient aromatic ketimines with
various substitution patterns were reduced with excellent yields
O
Figure 1. Proposed transition state of the asymmetric reduction of ketimines with
catecholborane.

D. Enders et al. / Tetrahedron Letters 54 (2013) 470–473
473
8. For recent examples, see: (a) Kanemitsu, T.; Umehara, A.; Haneji, R.; Nagata, K.;
In conclusion, we have developed the first asymmetric reduc-
tion of aromatic ketimines with catecholborane, catalyzed by chiral
N-triflyl phosphoramides with good enantiomeric ratios up to
86:14 and overall excellent yields under mild reaction conditions.
Further applications and mechanistical investigations are currently
in progress in our laboratories and will be reported in due course.
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We thank BASF SE for the donation of chemicals.
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
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22. For experimental details, see Supplementary data.