Iridium-Catalyzed Highly Enantioselective Transfer Hydrogenation of Aryl N-Heteroaryl Ketones with N-Oxide as a Removable ortho-Substituent

Article abstract of DOI:10.1021/acs.orglett.7b03878

A highly enantioselective transfer hydrogenation of non-ortho-substituted aryl N-heteroaryl ketones, using readily available chiral diamine-derived iridium complex (S,S)-1f as a catalyst and sodium formate as a hydrogen source in a mixture of H₂O/i-PrOH (v/v = 1:1) under ambient conditions, is described. The chiral aryl N-heteroaryl methanols were obtained with up to 98.2% ee by introducing an N-oxide as a removable ortho-substituent. In contrast, no more than 15.1% ee was observed in the absence of an N-oxide moiety. Furthermore, the practical utility of this protocol was also demonstrated by gram-scale asymmetric synthesis of bepotastine besilate in 51% total yield and 99.9% ee.

Full text of DOI:10.1021/acs.orglett.7b03878

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium-Catalyzed Highly Enantioselective Transfer Hydrogenation of
Aryl N‑Heteroaryl Ketones with N‑Oxide as a Removable ortho-
Substituent
Qixing Liu,†,§ Chunqin Wang,†,§ Haifeng Zhou,*,†,‡ Baigui Wang,† Jinliang Lv,‡ Lu Cao,‡
and Yigang Fu*,‡
†Hubei Key Laboratory of Natural Products Research and Development, College of Biological and Pharmaceutical Sciences, China
Three Gorges University, Yichang 443002, China
‡Yichang Humanwell Pharmaceutical Co., Ltd., Yichang 443005, China
S
* Supporting Information
ABSTRACT: A highly enantioselective transfer hydrogenation of non-ortho-substituted aryl N-heteroaryl ketones, using readily
available chiral diamine-derived iridium complex (S,S)-1f as a catalyst and sodium formate as a hydrogen source in a mixture of
H2O/i-PrOH (v/v = 1:1) under ambient conditions, is described. The chiral aryl N-heteroaryl methanols were obtained with up
to 98.2% ee by introducing an N-oxide as a removable ortho-substituent. In contrast, no more than 15.1% ee was observed in the
absence of an N-oxide moiety. Furthermore, the practical utility of this protocol was also demonstrated by gram-scale asymmetric
synthesis of bepotastine besilate in 51% total yield and 99.9% ee.
nantiomeric aryl N-heteroaryl alcohols are very important
Ebuilding blocks of numerous pharmaceuticals, agrochem-
icals, and biologically active compounds.1 Therefore, various
asymmetric synthetic strategies, including biocatalytic asymmet-
ric reduction,2 chemocatalytic asymmetric reduction,3−7 as well
as asymmetric addition of aryl organometallic reagents to
heteroaryl aldehydes,8 have been reported to prepare such chiral
alcohols. Among which, the chemocatalytic asymmetric
reduction of aryl N-heteroaryl ketones is the most attractive
from the atom-economic point of view. For example, chiral Ru/
diphosphine/diamine4-catalyzed asymmetric hydrogenation,
chiral Ru/diamine5-catalyzed asymmetric transfer hydrogena-
tion, and copper/diphosphine6-catalyzed asymmetric hydro-
silylation have been developed. In all cases, the aryl N-heteroaryl
ketones bearing an ortho-substituent on the aryl ring are essential
to achieve high enantioselectivity. In fact, drugs like histamine H1
antagonists bepotastine besilate9 and carbinoxamine10 contain a
non-ortho-substituted (S)-4-chlorophenylpyridyl methanol moi-
ety (Figure 1), which has been previously produced by
hydroborylation of corresponding ketones with chiral oxazabor-
olidine.3 However, it suffered from tedious nitrogen protection
and deprotection processes, and ultralow temperature (−78 °C).
In 2015, Zhang and co-workers realized the asymmetric
hydrogenation of 2-(4-chlorobenzoyl)pyridine with [Rh(COD)-
Binapine]BF4 complexes, affording (S)-4-chlorophenylpyridyl
methanol in excellent ee.7 Until now, the asymmetric synthesis of
non-ortho-substituted aryl N-heteroaryl alcohols is very limited.
Figure 1. Drugs contain an aryl N-heteroaryl alcohol moiety.
It is highly attractive to develop effective, highly enantioselective,
and practical methods.
Asymmetric transfer hydrogenation is an efficient, safe, and
convenient method to prepare chiral alcohols without using
hazardous hydrogen gas and a pressure vessel.11 In 1995, Noyori
reported a pioneering work about the asymmetric transfer
hydrogenation of aromatic ketones with chiral N-toluenesulfon-
yl-1,2-dipenylethylenediamine ruthenium complexes.12 Since
then, various asymmetric transfer hydrogenations of simple
aryl ketones and diaryl ketones with chiral diamine-derived Ru,
Rh, or Ir complexes as catalysts have been developed.13,14 In
contrast, little attention has been focused on the asymmetric
reduction of aryl N-heteroaryl ketones with this kind of
catalyst.15 Very recently, we have developed an efficient
asymmetric transfer hydrogenation of ortho-substituted aryl N-
Received: December 13, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03878
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Organic Letters
Letter
a
heteroaryl ketones with up to 99.9% ee using a commercially
available bifunctional oxo-tethered ruthenium complex [(S,S)-
Ts-DENEB] as the catalyst. However, the non-ortho-substituted
2-(4-chlorobenzoyl)pyridine was reduced with poor ee under the
standard reaction conditions, indicating that the ortho steric
effect plays an essential role in achieving high enantioselectivity.
By introducing an N-oxide onto 2-(4-chlorobenzoyl)pyridine to
increase the steric effect, 2-(4-chlorobenzoyl)pyridine N-oxide
could be reduced with 97.8% ee. To further demonstrate this
strategy and develop a potential practical method, we reported an
asymmetric transfer hydrogenation of aryl N-heteroaryl ketones
with N-oxide as a removable ortho-substituent using readily
available iridium complex (S,S)-1f as a catalyst and sodium
formate as a hydrogen source in a mixture of H2O/i-PrOH (v/v =
1:1) at ambient conditions, followed by treatment with Zn/
NH4Cl. A variety of chiral non-ortho-substituted aryl N-
heteroaryl methanols were obtained with excellent ee. Most
importantly, the gram-scale asymmetric synthesis of bepotastine
besilate was also realized (Scheme 1).
Table 1. Optimization of Reaction Conditions
yield
(%)
ee
(%)
b
entry
cat
[H] source
solvent (v/v)
1
2
(S,S)-1a
(S,S)-1b
(S,S)-1c
(S,S)-1d
(S,S)-1e
(S,S)-1f
(S,S)-1g
(S,S)-1h
(S,S)-1i
(S,S)-1f
(S,S)-1f
(S,S)-1f
(S,S)-1f
(S,S)-1f
(S,S)-1f
F/T (1.1:1)
F/T (1.1:1)
F/T (1.1:1)
F/T (1.1:1)
F/T (1.1:1)
F/T (1.1:1)
F/T (1.1:1)
F/T (1.1:1)
F/T (5:2)
85
78
81
81
80
86
85
80
79
82
88
80
85
90
84
88.2
79.0
31.6
90.2
96.4
97.1
95.6
81.8
83.9
18.2
94.5
97.1
95.8
98.0
89.4
3
4
5
6
7
8
9
10
11
12
13
14
15
HCOONa
HCOONa
HCOONa
HCOONa
HCOONa
HCOONa
H2O/MeOH (1:1)
H2O/DMF (1:1)
H2O/DMSO (1:1)
H2O/i-PrOH (1:1)
Scheme 1. Asymmetric Transfer Hydrogenation of Aryl N-
Heteroaryl Ketones
H2O/CF3CH2OH
(1:1)
16
17
18
(S,S)-1f
(S,S)-1j
(S,S)-1k
HCOONa
HCOONa
HCOONa
H2O/HFIP (1:1)
H2O/i-PrOH (1:1)
H2O/i-PrOH (1:1)
81
87
85
68.4
95.2
95.0
a
Reaction conditions: 2-(4-chlorobenzoyl)pyridine N-oxide (0.2
mmol), catalyst (5 mol %), hydrogen source (2.0 mmol), solvent
(2.0 mL), rt, 24 h, isolated yield, the ee values were determined by
HPLC analysis. The data in brackets are molar ratio of F/T
(HCOOH/TEA).
b
Our initial studies were carried out by examining the reduction
of 2-(4-chlorobenzoyl)pyridine N-oxide in the presence of 5 mol
% of catalyst with a mixture of HCOOH/TEA (F/T = 1.1:1,
molar ratio) as both hydrogen source and solvent at room
temperature for 24 h (Table 1). First, the catalysts including
ruthenium complexes 1a−1c, rhodium complex 1d, and iridium
complexes 1e−1i were screened, and (S,S)-1f was demonstrated
to be the best in terms of yield and enantioselectivity (entries 1−
9). However, poor ee was observed when the reaction was
conducted under acidic conditions using HCOOH−NEt3
azeotrope (molar ratio F/T = 5/2) as a hydrogen source and
solvent (entry 10). Next, the reaction was investigated with
HCOONa as a hydrogen source in an aqueous solution,
including H2O/MeOH (1:1), H2O/DMF (1:1), H2O/DMSO
(1:1), H2O/i-PrOH (1:1), H2O/CF3CH2OH (1:1), and H2O/
HFIP (1:1), and it was found that 4-chlorophenylpyridyl
methanol N-oxide was obtained with up to 90% yield and 98%
ee in the mixture of H2O/i-PrOH (entries 11−16). Considering
that the counteranion effect of this kind of catalyst has been
demonstrated in the asymmetric hydrogenation,16 the anion
effect of iridium complexes was also evaluated with catalysts
(S,S)-1j and (S,S)-1k, but no apparent effect on the results was
found (entries 17 and 18). Based on these results, the optimized
reaction conditions were set as follows: 5 mol % of (S,S)-1f, 10
equiv of HCOONa, H2O/i-PrOH (v/v = 1:1), room temper-
ature, and 24 h.
Under the optimized reaction conditions, a variety of aryl N-
heteroaryl ketone N-oxides were reduced, followed by treatment
with Zn/NH4Cl (Scheme 2). The phenyl 2-pyridyl ketone N-
oxides 2a−2l bearing electron-donating or electron-withdrawing
groups at the para- or meta-position on the benzene ring gave the
corresponding aryl 2-pyridyl methanols 3a−3l in 78−98% ee and
good yields. For example, the asymmetric transfer hydrogenation
of 2-(4-chlorobenzoyl)pyridine N-oxide 2d afforded (S)-3d in
90% yield and 98.2% ee after removing the N-oxide moiety.17 By
contrast, the meta-disubstituted phenyl 2-pyridyl methanols 3j−
3l were obtained in relatively lower ee. Note that the steric effects
not only impact the enantioselectivity but also determine the
reactivity. Regarding the sterically hindered 2-tolyl 2-pyridyl
ketone N-oxide (2m), α-naphthyl 2-pyridyl ketone N-oxide
(2n), and α-naphthyl 2-isoquinolinyl N-oxide (2r), the transfer
B
DOI: 10.1021/acs.orglett.7b03878
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Letter
a
effect plays an essential role in achieving high enantioselectiv-
ity.18,19
Scheme 2. Substrate Scope
To demonstrate the practical utility of this protocol, the key
intermediate of bepotastine besilate (S)-3d was synthesized
successfully in a gram scale, which was then subjected to the
reaction with compound 4, followed by hydrolysis, salification,
and recrystallization. Finally, the bepotastine besilate (5) was
obtained with 51% total yield and up to 99.9% ee (Scheme 3).20
Scheme 3. Asymmetric Synthesis of Bepotastine Besilate in a
Gram Scale
In summary, we have developed an effective method for the
asymmetric transfer hydrogenation of non-ortho-substituted aryl
N-heteroaryl ketones by introducing N-oxide as a removable
ortho-substituent with a readily available chiral diamine-derived
iridium complex as a catalyst and sodium formate as a hydrogen
source in an aqueous solution at ambient conditions. A range of
non-ortho-substituted aryl N-heteroaryl methanols were ob-
tained with excellent yields and high enantioselectivities. The
great potential of this protocol in practical use was also
demonstrated by the gram-scale synthesis of bepotastine besilate.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03878.
a
Experimental details and characterization data (PDF)
Reaction conditions: aryl N-heteroaryl ketone N-oxide 2 (0.2 mmol),
(S,S)-1f (5 mol %), HCOONa (2.0 mmol), H2O/i-PrOH (2.0 mL, v/
v = 1:1), rt, 24 h; isolated yield; the ee values were determined by
AUTHOR INFORMATION
Corresponding Authors
■
b
HPLC analysis. The corresponding substrates without an N-oxide
moiety were used. NR: no reaction.
c
*E-mail: zhouhf@ctgu.edu.cn.
*E-mail: fuyigang@renfu.com.cn.
ORCID
hydrogenation did not occur. For methyl-substituted 2-pyridyl
phenyl ketone N-oxides 2o and 2p, both gave excellent ee and
yields. In the case of substrates 2q and 2s bearing a bulky
isoquinolinyl or quinolinyl moiety, relatively lower ee values were
obtained. Finally, substrates 2t and 2u that have substituents on
both aromatic and N-heteroaromatic ring moieties were also
examined, affording the corresponding alcohols with more than
75% yield and 89% ee. Moreover, the asymmetric transfer
hydrogenation of substrates such as 2a, 2d, 2h, 2f, and 2o without
an N-oxide proceeded smoothly, giving the corresponding aryl
N-heteroaryl methanols in good yield but with no more than
15.1% ee (Scheme 2, data in the brackets). It means that the N-
oxide moiety acts as an ortho-substituent, and the ortho steric
Haifeng Zhou: 0000-0002-2710-9570
Author Contributions
§Q.L. and C.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the financial support by grants from the
National Natural Science Foundation of China (21202092), the
Project of Scientific Research of Hubei Provincial Education
Department (B2016024), China Three Gorges University
C
DOI: 10.1021/acs.orglett.7b03878
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(KJ2014H008, KJ2014B084), and a joint research fund from
Yichang Humanwell Pharmaceutical Co., Ltd. (SDHZ2015003).
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DOI: 10.1021/acs.orglett.7b03878
Org. Lett. XXXX, XXX, XXX−XXX