Chiral phosphoric acid catalyzed transfer hydrogenation: Facile synthetic access to highly optically active trifluoromethylated amines

Article abstract of DOI:10.1002/anie.201103240

Amines to an end: Highly optically active α-CF₃- functionalized amines can be obtained using metal-free reaction conditions. The method involves the transfer hydrogenation of CF₃-substituted ketimines catalyzed by 1 and reductive ami

Full text of DOI:10.1002/anie.201103240

Communications
DOI: 10.1002/anie.201103240
Synthetic Methods
Chiral Phosphoric Acid Catalyzed Transfer Hydrogenation: Facile
Synthetic Access to Highly Optically Active Trifluoromethylated
Amines**
Alexander Henseler, Masanori Kato, Keiji Mori, and Takahiko Akiyama*
Chiral amines represent an important structural motif that
can be found in a vast number of biologically active
compounds.[1] Many well-established drugs that are applicable
in a diverse number of areas rely on this prominent
pharmacophore. Among them are Cinacalcet (1) and
NPS R-568 (2; hyperparathyroidism), Rivastigmine (3; Alz-
heimerꢀs and Parkinsonꢀs disease), and Odanacatib (4;
cathepsin K inhibitor; Scheme 1).
ties, thus generally leading to increased metabolic stability as
well as improved membrane permeation by the functionalized
molecule.[2b,c,d,e] In this context, trifluoromethylated amines
became the subject of special interest since it was recently
found that they can act as nonbasic amide bond surrogates
with improved bioavailability.[2b] The application of this
strategy by Zanda et al. yielded a new kind of peptidomi-
metic, on which the development of novel cathepsin K
inhibitors for the treatment of osteoporosis were based
(Scheme 1).[3]
As a result of the constantly growing demand for new and
structurally diverse trifluoromethylated amines for pharma-
ceutical and agrochemical purposes, we envisaged the devel-
opment of a general yet efficient method for the preparation
of these compounds. Whereas several research groups have
already reported excellent contributions concerning the
asymmetric metal-[4] and organocatalyzed[5–7] reduction of
ketimines as well as the reductive amination of ketones, the
use of perfluoroalkylated ketimines and ketones as substrates
in the latter transformations has been much less investi-
gated.[8] Hughes et al. and Xu et al. developed a diastereose-
lective reductive amination of aryl trifluoromethyl ketones.[9]
During the preparation of this manuscript, the research group
of Brꢁse[10] and later that of Zhou[11] reported an achiral Lewis
acid mediated reductive amination of aromatic trifluoro-
methyl ketones and an enantioselective palladium-catalyzed
hydrogenation of perfluorinated nonactivated ketimines,
respectively. Although the yields as well as the enantioselec-
tivities are good to high, in the latter contribution the
drawbacks are the use of relatively high pressures of hydrogen
and the expensive and toxic transition-metal catalyst for the
transformation.
Scheme 1. Selected examples of a-methyl chiral amine based pharma-
ceuticals.
We report herein the first asymmetric phosphoric acid
catalyzed synthesis of aromatic and heteroaromatic trifluoro-
methylated amines and their application to the synthesis of a
perfluoroalkylated analogue of NPS R-568.
Over the last decades, fluorinated compounds have
attracted considerable attention in pharmaceutical as well as
agrochemical research.[2a–e] The incorporation of fluorine into
a biologically active molecule causes minimal steric alter-
ations yet constructively changes its physicochemical proper-
As a result of our recent finding that benzothiazolines are
=
able to reduce C N bonds efficiently, we envisaged their use
as a hydride source in this transformation.[12] At the outset of
our studies, different chiral phosphoric acid catalysts were
screened in the presence of benzothiazoline 6a and ketimine
5a, and it was revealed that the catalyst (R)-8 was the most
suitable. One of the major advantages of employing benzo-
thiazolines as the hydride donor lies in the potential to fine-
tune their electronic and steric properties. Therefore, various
benzothiazoline derivatives (6a–d) were tested for their
activity and selectivity and the results are summarized in
Table 1. Whereas high yield (68%) and good enantioselec-
[*] Dr. A. Henseler, M. Kato, Dr. K. Mori, Prof. Dr. T. Akiyama
Department of Chemistry, Gakushuin University
1-5-1 Mejiro, Toshima-ku, Tokyo 171-8588 (Japan)
E-mail: takahiko.akiyama@gakushuin.ac.jp
[**] We gratefully acknowledge the Japan Society for the Promotion of
Science (JSPS) for the support of this work and for a postdoctoral
fellowship to A.H.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103240.
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Angew. Chem. Int. Ed. 2011, 50, 8180 –8183

Table 1: Optimization of the reaction conditions.[a]
Table 2: Substrate scope for the chiral phosphoric acid catalyzed transfer
hydrogenation of trifluoromethyl ketimines.[a]
Entry
Imine
R1
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5 f
5g
5h
5i
Ph
89
91
89
77
89
97
94
99
72
96 (+)
98 (+)
97 (+)
97 (+)
97 (+)
97 (+) (S)[d]
98 (+)
97 (+)
97 (+)
4-ClC6H4
4-BrC6H4
4-CF3C6H4
4-MeC6H4
3-MeOC6H4
4-MeOC6H4
2-naphthyl
2-thienyl
Entry
Thiazoline
R
Solvent
Yield [%][b]
ee [%][c]
1
2
3
4
5
6a
6b
6c
6d
6d
Ph
toluene
toluene
toluene
toluene
CH2Cl2
28[d]
51
84
82
87
92
96
4-MeOC6H4
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
68[d]
44
89
[a] Reaction conditions: trifluoromethyl ketimine 5a–i (0.2 mmol),
benzothiazoline 6d (0.24 mmol), (R)-8 (10 mol%), CH2Cl2 (2 mL) at
reflux temperature. [b] Yields are of the isolated products 7a–i after
preparative TLC. [c] Determined by HPLC analysis on a chiral stationary
phase. [d] The absolute configuration was determined by comparison to
data reported in the literature.[8h]
[a] Reaction conditions: trifluoromethyl ketimine 5a (0.2 mmol), ben-
zothiazoline 6a-d (0.24 mmol), (R)-8 (10 mol%), solvent (2 mL) at reflux
temperature. [b] If not otherwise noted, the yield is of the isolated
product 7a after preparative TLC. [c] Determined by HPLC analysis on a
chiral stationary phase. [d] Determined from the H NMR spectrum of
the crude reaction mixture. PMP=para-methoxyphenyl.
1
tivity (87% ee) could be obtained with benzothiazoline 6c
(entry 3, Table 1), the use of the more-electron-deficient
4-nitrophenyl benzothiazoline 6d resulted in a lower yield
(44%), albeit with a better enantioselectivity (92% ee;
entry 4, Table 1). To our delight, changing the solvent from
toluene to dichloromethane improved both the yield and
enantioselectivity significantly (entry 5, Table 1).
Interestingly, employing the commonly used transfer
hydrogenation agent, the Hantzsch ester (9), under the
same reaction conditions resulted in only a trace amount of
7a (4%) with diminished enantioselectivity (45% ee;
Scheme 2). This result clearly points to the distinct differences
in the reactivity between 6d and 9, and shows that an
appropriate choice of hydride source is crucial for the
outcome of this transformation.[13]
Heteroaromatic imine 5i is viable for this transformation
although its use results in a lower reactivity (72% yield) and
high enantioselectivity (97% ee; entry 10, Table 2).
Next, we investigated the possibility of creating the
required N-PMP-protected ketimines in situ in the manner
of a direct reductive amination; a simpler and more practical
version of this protocol. To our delight, subjecting 2,2,2-
trifluoromethyl acetophenone (10a) and p-anisidine (11) in
the presence of MgSO4 to the optimized reaction conditions
(10 mol% (R)-8, CH2Cl2, reflux) resulted in the formation of
7a in very good yield (92%) and with excellent enantiose-
lectivity (95% ee; entry 1, Table 3). Although this trans-
formation requires a longer reaction time (3 d), the yields and
the enantioselectivities are as high as those for the reduction
of the preformed imines (entries 1–3, Table 3).
In additional experiments, we focused on the synthesis of
a perfluoroalkylated analogue of NPS R-568, (S)-14, to
underscore the synthetic utility of this method. NPS R-568
Table 3: Chiral phosphoric acid catalyzed reductive amination of tri-
fluoromethyl ketones.[a]
Scheme 2. Transfer hydrogenation of trifluoromethyl ketimine with
Hantzsch ester (9).
With the optimized reaction conditions in hand, a range of
trifluoromethyl ketimines 5a–j were tested in this reaction
(Table 2). Whereas the yields and enantioselectivities were
similar for halogenated ketimines 5b (entry 2, Table 2) and 5c
(entry 3), the employment of substrate 5d, which bears a
stronger electron-withdrawing aromatic substituent (entry 4),
resulted in a diminished yield (77%) but similar enantiose-
lectivity (97% ee). The electron-rich ketimines 5e–g showed
good to excellent results (89–99% yield) and overall excellent
enantioselectivities (97–98% ee; entries 5–7, Table 2).
Entry
Ketone
R1
Yield [%][b]
ee [%][c]
1
2
3
10a
10 f
10h
Ph
92
82
95
95 (+)
93 (+)-(S)
96 (+)
3-MeOC6H4
2-naphthyl
[a] Reaction conditions: trifluoromethyl ketone 10a,f, or h (0.2 mmol),
benzothiazoline 6d (0.24 mmol), (R)-8 (10 mol%), CH2Cl2 (2 mL) at
reflux temperature. [b] Yields are of the isolated products 7a,f, and h
after preparative TLC. [c] Determined by HPLC analysis on a chiral
stationary phase.
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8181

Communications
(2) belongs to the drug class of type II calcimetics and has
ketones, respectively. The corresponding a-trifluoromethy-
lated amines could be obtained in good to excellent yields
(72–99%) with overall excellent enantioselectivities (96–
98%), and represent important synthetic building blocks as
well as valuable pharmaceutical intermediates. Furthermore,
the synthetic applicability of the developed method was
been approved for use in the treatment of hyperparathyroid-
ism in patients with kidney disease as well as hypercalcemia in
patients with parathyroid carcinoma.[14] The deprotection of
7 f with orthoperiodic acid[15] worked smoothly and resulted in
the primary amine 12 in a quantitative yield (99%). The
absolute configuration was determined to be S by comparing
the optical rotation of 12 to that reported in the literature.[8h,16]
Next, the reductive amination of (S)-12 with aldehyde 13
afforded compound (S)-14 in 78% yield without significant
loss of enantioselectivity (95% ee; Scheme 3). Notably, the
synthesis of the NPS R-568 trifluoromethyl analogue (S)-14
was accomplished by this route without the use of any
expensive and toxic transition-metal catalysts or reagents.
demonstrated in
a short yet efficient synthesis of a
CF3 analogue of the pharmaceutical compound NPS R-568.
In additional experiments it could be shown that the
developed method is also suitable for the enantioselective
incorporation of deuterium into prochiral trifluoromethyl
ketimines.
Experimental Section
Typical procedure for the transfer hydrogenation of trifluoromethyl
ketimines: In a dry, nitrogen-flushed Schlenk tube, trifluoromethyl
ketimine (0.2 mmol), 2-(4-nitrophenyl)-2,3-dihydrobenzothiazoline
(6d; 62 mg, 0.24 mmol), and chiral phosphoric acid (R)-8 (15 mg,
0.02 mmol) were dissolved in absolute CH2Cl2 (2 mL). After being
stirred for 24 h at 558C, the reaction mixture was quenched with aq.
10% NaHCO3 (2 mL) and extracted three times with ethyl acetate
(5 mL). The combined organic phases were dried and concentrated
in vacuo. The resulting crude reaction mixture was purified by
preparative TLC (eluent: n-hexane/ethyl acetate 15:1) to yield the
corresponding trifluoromethylated amine.
Typical procedure for the reductive amination of trifluoromethyl
ketones: In a dry, nitrogen-flushed Schlenk tube, trifluoromethyl
ketone (0.2 mmol), 4-methoxyaniline 11 (25 mg, 0.2 mmol), 2-(4-
nitrophenyl)-2,3-dihydrobenzothiazoline (6d; 62 mg, 0.24 mmol),
and chiral phosphoric acid (R)-8 (15 mg, 0.02 mmol) were dissolved
in 2 mL of absolute CH2Cl2. MgSO4 (24 mg, 0.2 mmol) was added and
the reaction mixture was stirred for 3 d at 558C after which the typical
work-up procedure was performed.
Scheme 3. Synthesis of the trifluoromethylated analogue [(S)-14] of
NPS R-568 (2).
Received: May 12, 2011
Published online: July 11, 2011
Despite the possibility of fine-tuning the reactivity of
benzothiazoline to enable the adaptation to the steric and
electronic demands of the catalytic system, the use of
deuterated benzothiazoline for the enantioselective incorpo-
ration of deuterium in a molecule represents another
synthetic advantage of the present method. Treatment of
trifluoromethyl ketimine 5g and the readily available deu-
terated benzothiazoline 6e[17] with 8 (10 mol%) furnished the
a-deuterio-a-trifluoromethylated amine 7j in slightly dimin-
ished yield (72%) and with excellent enantioselectivity
(97%) under somewhat modified standard reaction condi-
tions (Scheme 4).[18] This outcome strongly supports the
hydride (deuteride) mechanism for the transfer hydrogena-
tion of ketimines with benzothiazoline.[7h,i,12]
Keywords: asymmetric catalysis · fluorine · hydrogenation ·
.
organocatalysis · reductive amination
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benzothiazoline 6e see the Supporting Information.
[18] Reaction conditions: trifluoromethyl ketimine 5g (0.13 mmol),
benzothiazoline 6e (0.16 mmol), (R)-8 (10 mol%), CH2Cl2
(2 mL) at reflux temperature.
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