Iridium/f-Amphol-catalyzed Efficient Asymmetric Hydrogenation of Benzo-fused Cyclic Ketones

Article abstract of DOI:10.1002/adsc.201800839

Iridium/f-Amphol-catalyzed asymmetric hydrogenation of various benzo-fused five to seven-membered cyclic ketones was successfully developed, affording a series of chiral benzo-fused cyclic alcohols with excellent results (75%–99% yields, 93%–>99% ee, and TON up to 297 000). The enantioenriched products can be employed as key intermediates or motifs for the synthesis of some important biologically active compounds, such as rasagiline mesylate TVP-1012 used for the treatment of Parkinson's disease, the enantiomer of anticonvulsant drug eslicarbazepine acetate (BIA 2-093). (Figure presented.).

Full text of DOI:10.1002/adsc.201800839

Title: Iridium/f-Amphol-catalyzed Efficient Asymmetric Hydrogenation of
Benzo-fused Cyclic Ketones
Authors: Congcong Yin, Xiu-Qin Dong, and Xumu Zhang
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10.1002/adsc.201800839
Advanced Synthesis & Catalysis
VERY IMPORTANT PUBLICATION
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iridium/f-Amphol-catalyzed Efficient Asymmetric
Hydrogenation of Benzo-fused Cyclic Ketones
Congcong Yin,† Xiu-Qin Dong,*† Xumu Zhang*‡,†
† Key Laboratory of Biomedical Polymers, Engineering Research Center of Organosilicon Compounds & Materials,
Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan, Hubei, 430072, P. R.
China.
‡ Department of Chemistry, Southern University of Science and Technology, Shenzhen Grubbs Institute, Shenzhen,
Guangdong, 518055, P. R. China.
E-mail address: zhangxm@sustc.edu.cn; xiuqindong@whu.edu.cn.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Asymmetric catalytic reduction of benzo-fused
cyclic ketones and derivatives is a straightforward
and important synthetic methodology to prepare these
chiral benzo-fused cyclic alcohols,[2-6] including
Abstract. Iridium/f-Amphol-catalyzed
asymmetric
hydrogenation of various benzo-fused five to seven-
membered cyclic ketones was successfully developed,
affording a series of chiral benzo-fused cyclic alcohols with
excellent results (75%-99% yields, 93%->99% ee, and
TON up to 297 000). The enantioenriched products can be
employed as key intermediates or motifs for the synthesis
of some important biologically active compounds, such as
rasagiline mesylate TVP-1012 used for the treatment of
Parkinson’s disease, the enantiomer of anticonvulsant drug
eslicarbazepine acetate (BIA 2-093).
asymmetric
hydrogenation,[2]
asymmetric
asymmetric
hydrosilylation,[3]
hydroboration,[4]
asymmetric bioreduction,[5] and asymmetric transfer
hydrogenation[6]. Although significant advances have
been made in this research area, most of these
catalytic systems focused on the reduction of
prochiral simple ketones. Additionally, they are
generally sensitive to the structure of benzo-fused
cyclic ketones, especially for different ring sizes. To
date, there are few catalytic systems to engage in
systematical research to investigate asymmetric
hydrogenation of various benzo-fused cyclic ketones
with different ring sizes. In 2004, Noyori and
coworkers developed RuCl2(binap)(1,4-diamine)
Keywords: Asymmetric hydrogenation, Benzo-fused
cyclic ketone, Chiral benzo-fused cyclic alcohol,
Enantioselectivity, Phosphorus ligand.
complex-catalyzed
efficient
asymmetric
Optically active benzo-fused cyclic alcohols and
their derivatives are important core structures in some
biologically active compounds,[1] such as rasagiline
mesylate TVP-1012 for the treatment of Parkinson’s
disease,[1b] an anti-HIV agent,[1c] a rigid and potent
selective norepinephrine reuptake inhibitor (sNRI)
NBI 80532 as antidepressant reagent,[1d] and an
anticonvulsant drug eslicarbazepine acetate (BIA 2-
093)[1e] (Figure 1).
hydrogenation of 1-tetralone derivatives with
excellent results.[2a] In 2014, Rodríguez and
coworkers
bisdihydrobenzooxaphosphole
explored
chiral
(BIBOP)/
diamineruthenium complexes for the catalytic
asymmetric hydrogenation of aryl and heteroaryl six-
membered cyclic ketones with good to excellent
enantioselectivities.[2j] Therefore, it is necessary to
develop a highly efficient catalytic system for the
asymmetric hydrogenation of various benzo-fused
cyclic ketones with different ring sizes, affording
enantioenriched benzo-fused cyclic alcohols.
Recently, we developed a series of tridentate
ferrocene
aminophosphoxazoline
(f-amphox)
ligands,[7] ferrocene-based amino-phosphine acid
(f-Ampha) ligands[8] and ferrorence-based amino-
phosphine-alcohol (f-Amphol) ligands[9], which
achieved excellent results in iridium-catalyzed
asymmetric hydrogenation of prochiral simple
ketones and derivatives.[7-9] Based on these results,
we herein successfully realized Ir-catalyzed
asymmetric hydrogenation of various benzo-fused
Figure 1. Examples of biologically active compounds
containing benzo-fused cyclic alcohols and derivatives.
1
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10.1002/adsc.201800839
Advanced Synthesis & Catalysis
five to seven-membered cyclic ketones, preparing a
series of chiral benzo-fused cyclic alcohols with
Subsequently, the ratio of substrate/catalyst
loading was increased from 1 000 to 5 000 for
excellent results (Scheme 1, 75%-99% yields and further screening solvents for the asymmetric
93%->99% ee, up to 297 000 TON).
hydrogenation of benzo-fused seven-membered
cyclic ketone 6,7,8,9-tetrahydro-5H-
benzo[7]annulen-5-one 1a in the presence Ir/f-
amphox L1 catalyst and KOtBu. The reaction can
i
proceed smoothly with excellent results in PrOH,
PhMe, THF, hexane and 1,4-dioxane (97%->99%
conversions, 91%-93% ee, Table 2, entries 1-5).
iPrOH was the best choice as the reaction solvent
(>99% conversion, 93% ee, Table 2, entry 1).
This Ir-catalyzed asymmetric hydrogenation was
Scheme 1. Ir-catalyzed asymmetric hydrogenation of
benzo-fused five to seven-membered cyclic ketones.
then studied with different ligands (L1, L2 and
L3) in iPrOH with KOtBu as the base. The ligand
L3 gave the best result with >99% conversion
and 95% ee (Table 2, entry 7). Different bases
were then screened for this Ir/L3-catalyzed
asymmetric hydrogenation (seeing the Supporting
Information), and NaOtBu was found to be the
best base with >99% conversion and 98% ee
(Table 2, entry 8). To our delight, the ligand L4
with 3,5-di-tert-butylphenyl group provided
better enantioselectivity (>99% conversion,
>99% ee, Table 2, entry 9). The same result was
obtained when the amount of NaOtBu was
decreased from 5.0 mol% to 1.0 mol% (Table 2,
entry 10).
Our initial study was carried out by investigating
solvent effect for this asymmetric hydrogenation
using benzo-fused seven-membered cyclic ketone
6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one 1a as a
model substrate at room temperature with the catalyst
generated in situ by mixing [Ir(COD)Cl]2 with ligand
i
L1 (S/C = 1 000) in PrOH (Table 1). The reaction
i
proceeded well and gave excellent results in PrOH,
PhMe, THF (tetrahydrofuran), 1,4-dioxane and
hexane (>99% conversions, 91%-92% ee, Table 1,
entries 3, 5, 7, 9, 11). 78% conversion and 87% ee
were observed in CH2Cl2 (Table 1, entry 4). Poor
conversions and moderate enantioselectivities were
observed in EtOH and ClCH2CH2Cl (10%-13%
conversions, 60%-73% ee, Table 1, entries 2, 6).
Trace conversion or no reaction was observed in
MeOH, CHCl3 and CF3CH2OH (Table 1, entries 1, 8,
10).
Table 2. Optimization conditions for Ir-catalyzed
asymmetric hydrogenation of 6,7,8,9-tetrahydro-5H-
benzo[7]annulen-5-one (1a).[a]
Table 1. Screening solvents for the asymmetric
hydrogenation of 6,7,8,9-tetrahydro-5H-benzo[7]annulen-
5-one (1a) with Ir/L1.[a]
entry ligand solvent
base
conv.
ee
(%)[b] (%)[c]
1
2
L1
L1
L1
L1
L1
L2
L3
L3
L4
L4
iPrOH
PhMe
THF
KOtBu
KOtBu
KOtBu
KOtBu
>99
97
>99
>99
>99
73
>99
>99
>99
>99
93
91
92
92
92
93
95
98
>99
>99
3
entry
solvent
conv.
(%)[b]
trace
13
>99
78
>99
10
>99
NR
ee
(%)[c]
NA
60
92
87
92
73
91
NA
92
4
5
hexane
1,4-dioxane KOtBu
1
2
3
4
5
6
7
8
9
MeOH
6
7
8
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
KOtBu
KOtBu
NaOtBu
NaOtBu
NaOtBu
EtOH
iPrOH
CH2Cl2
PhMe
ClCH2CH2Cl
THF
9
10[d]
[a] Reaction conditions: 1.0 mmol 1a, 0.0001 mmol
[Ir(COD)Cl]2, 0.00021 mmol ligand, 1.0 mL solvent,
base (5.0 mol%). The catalyst was pre-complexed in
iPrOH (0.1 mL for each reaction vial).
CHCl3
1,4-dioxane
CF3CH2OH
hexane
>99
trace
>99
[b]
Determined by 1H NMR analysis.
10
11
NA
92
[c] Determined by HPLC analysis.
[d] NaOtBu (1.0 mol%).
[a] Reaction conditions: 0.2 mmol 1a, 0.0001 mmol
[Ir(COD)Cl]2, 0.00021 mmol ligand L1, 1.0 mL solvent,
KOtBu (5.0 mol%). The catalyst was pre-complexed in
iPrOH (0.1 mL for each reaction vial). Configuration of 2a
was determined by comparing the optical rotation data
[2b]
with reported in the literature.
not available.
NR = no reaction, NA =
[b
[c] Determined by HPLC analysis.
]
Determined by 1H NMR analysis.
2
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10.1002/adsc.201800839
Advanced Synthesis & Catalysis
Under the optimal reaction conditions, a
phenyl ring performed well in this transformation.
The challenging hetero-aromatic substrates 1t, 1u and
1v worked smoothly to prepare hydrogenation
products with >99% conversion, 91%-99% yields and
93%->99% ee. Other benzo-fused six-membered
series of benzo-fused seven-membered cyclic
ketones was hydrogenated to inspect the substrate
generality. These results were summarized in
Table 3. Various benzo-fused seven-membered
cyclic ketones proceeded well to afford the
cyclic
ketones
substrates,
such
as
2,3-
corresponding
chiral
benzo-fused
seven-
dihydroquinolin-4(1H)-one 1w, thiochroman-4-one
1x, 4,4-dimethyl-3,4-dihydronaphthalen-1(2H)-one
1y were also hydrogenated successfully with >99%
conversions, 99% yields and 98%->99% ee. It is
worth noting that the hydrogenation product 2h is the
important intermediate for the synthesis of rasagiline
mesylate TVP-1012.[1b]
membered cyclic alcohols (2a-2g) with full
conversions, high yields and excellent
enantioselectivities (>99% conversions, 93%-
99% yields and 99%->99% ee). We found that
the position and electronic property of the
substituents on the phenyl ring have a little
influence on this reaction. The electron-donating
substituent groups (1d-1g) on the phenyl ring
displayed relatively lower reactivity, which need
a little higher catalyst loading (0.1 mol%-0.4
mol%) to give full conversion.
Table 4. Scope study for Ir/f-Amphol L4-catalyzed the
asymmetric hydrogenation of benzo-fused five/six-
membered cyclic ketones.[a]
Table 3. Scope study for Ir/f-Amphol L4-catalyzed
asymmetric hydrogenation of benzo-fused seven-
membered cyclic ketones.[a]
[a] Reaction conditions: 1.0 mmol substrate, 0.0001 mmol
[Ir(COD)Cl]2, 0.00021 mmol ligand, NaOtBu (1.0 mol%),
i
i
1.0 mL PrOH. The catalyst was pre-complexed in PrOH.
1
Conversion was determined by H NMR analysis, yield
reported is the isolated yield, ee was determined by HPLC
analysis.
[b] S/C = 1 000, 0.2 mmol substrate, 0.0001 mmol
[Ir(COD)Cl]2, 0.00021 mmol ligand, NaOtBu (1.0 mol%),
1.0 mL iPrOH.
[a] Reaction conditions: 1.0 mmol substrate, 0.0001
mmol [Ir(COD)Cl]2, 0.00021 mmol ligand, 1.0 mL
iPrOH, NaOtBu (1.0 mol%). The catalyst was pre-
[c] S/C = 250, NaOtBu (5.0 mol%), 0.2 mmol substrate,
0.0004 mmol [Ir(COD)Cl]2, 0.00084 mmol ligand, 1.0 mL
iPrOH.
i
complexed in PrOH. Conversion was determined by
1H NMR analysis, yield reported is the isolated yield,
ee was determined by HPLC analysis.
Encouraged by these excellent results, we turned
our attention to investigate the asymmetric
hydrogenation of benzo-fused five/six-membered
cyclic ketones. As shown in Table 4, various benzo-
fused five/six-membered cyclic ketones were
hydrogenated smoothly, affording the corresponding
chiral alcohols with excellent results (>99%
conversions, 91%-99% yields and 93%->99% ee).
The ring size of substrates have little effect on the
reactivity and enantioselectivity. The benzo-fused
five or six-membered cyclic ketones substrates with
electron-donating (1i-1l, 1p-1r) or electron-
withdrawing (1m-1n, 1s) substituent groups on the
[b] S/C = 500, NaOtBu (5 mol%), 0.2 mmol substrate,
0.0002 mmol [Ir(COD)Cl]2, 0.00042 mmol ligand, 1.0
mL iPrOH.
[c] S/C = 1 000, 0.2 mmol substrate, 0.0001 mmol
[Ir(COD)Cl]2, 0.00021 mmol ligand, 1.0 mL iPrOH.
The gram-scale asymmetric hydrogenation of
benzo-fused six-membered cyclic ketone 3,4-
dihydronaphthalen-1(2H)-one 1o performed smoothly
with S/C = 300 000, affording the product (R)-
1,2,3,4-tetrahydronaphthalen-1-ol 2o with 99%
conversion, 97% yield and >99% ee (up to 297 000
3
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10.1002/adsc.201800839
Advanced Synthesis & Catalysis
TON, Scheme 2). It displayed that our Ir/f-Amphol
L4 catalytic system owned extremely high activity in
this asymmetric hydrogenation.
Scheme 2. Gram-scale asymmetric hydrogenation of
benzo-fused
six-membered
cyclic
ketone
3,4-
dihydronaphthalen-1(2H)-one 1o with high TON.
In addition, racemic α-substituted benzo-fused
five to seven-membered cyclic ketones were
investigated, which involved dynamic kinetic
resolution process.[2a, 2j, 6g, 10] As shown in Scheme 3,
racemic α-methyl substituted benzo-fused five/six-
membered cyclic ketones (3a-3b) worked well,
providing the hydrogenation products (4a-4b) with
high conversions, excellent enantioselectivities and
good to excellent diastereoselectivities (98%->99%
conversions, 95%-96% yields, 99% ee, 81:19-95:5
dr). Although racemic α-methyl substituted benzo-
fused seven-membered cyclic ketone (3c) provided
Scheme 4. Synthetic application for the preparation of key
intermediate of (R)-BIA 2-093.
In summary, we successfully developed the Ir/f-
amphol L4-catalyzed asymmetric hydrogenation of a
series of benzo-fused five to seven-membered cyclic
ketones to prepare the corresponding chiral alcohols
with high yields and excellent enantioselectivities
(75%-99% yields and 93%->99% ee, up to 297 000
TON). In addition, our Ir/f-Amphol L4-catalyzed
asymmetric hydrogenation of benzo-fused cyclic
ketones can be applied to provide the key
intermediate for the synthesis of the enantiomer of an
anticonvulsant drug eslicarbazepine acetate (BIA 2-
093) with excellent result (full conversion, 99% yield
and >99% ee).
lower
conversion,
excellent
diastereo-
/enantioselectivity was obtained (83% conversion, 75%
yield, 99% ee, 97:3 dr).
Experimental Section
General procedure for the asymmetric hydrogenation
with S/C = 5 000: To a 4.0 mL vial was added the metal
precursor [Ir(COD)Cl]2 (1.4 mg, 2.0×10-3 mmol), ligand
i
L4 (3.4 mg, 4.2×10-3 mmol) and anhydrous PrOH (2.0
mL) in the argon-filled glovebox. The mixture was stirred
o
for 2.0 h at 25 C giving an orange solution. Then 1.0
mmol of benzo-fused cyclic ketones were added into a 5.0
mL hydrogenation vessel. Dissolve NaOtBu (1.0 mg, 0.01
i
mmol) in 1.0 mL anhydrous PrOH was added and a
i
solution of Ir/f-amphol L4 in anhydrous PrOH (100 μL)
Scheme 3. The asymmetric hydrogenation of racemic α-
methyl substituted benzo-fused five to seven-membered
cyclic ketones.
was added via an injection port. Then the vessel was
placed in an autoclave, closed it and moved it out from
glovebox. The autoclave quickly purged with hydrogen gas
for three times, then pressurized to 50 atm H2. The reaction
This Ir/f-amphol L4-catalyzed asymmetric
hydrogenation of benzo-fused cyclic ketones can be
applied to construct some important intermediates of
biologically active compounds. As shown in Scheme
4, the benzo-fused seven-membered cyclic ketone
5,11-dihydro-10H-dibenzo[b, f]azepin-10-one 6 was
easily obtained with 93% yield,[1e] which went
through highly efficient asymmetric hydrogenation in
the presence of 0.2 mol% (S/C = 500) Ir/f-amphol L4
catalyst. The chiral alcohol product 7 was obtained
with full conversion, 99% yield and >99% ee, which
is the key intermediate of the enantiomer of an
anticonvulsant drug eslicarbazepine acetate (BIA 2-
093).[1e]
o
o
solution was stirred at room temperature (25 C-30 C)
until for 12 h, then released pressure carefully. The
solution of reaction mixture was purified by a flash
chromatography on a silica gel with ethyl acetate and the
solvent was removed under reduced pressure. The ee value
was determined by chiral HPLC analysis of the
hydrogenation product chiral benzo-fused cyclic alcohols
directly.
Acknowledgements
We are grateful for financial support from the National
Natural Science Foundation of China (Grant No. 21432007,
21502145), the Natural Science Foundation of Hubei Province
(Grant No. 2016CFB449), Wuhan Morning Light Plan of Youth
Science and Technology (Grant No. 2017050304010307) and the
Fundamental Research Funds for and the Central Universities
(Grant No. 2042018kf0202). The Program of Introducing Talents
of Discipline to Universities of China (111 Project) is also
appreciated.
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10.1002/adsc.201800839
Advanced Synthesis & Catalysis
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10.1002/adsc.201800839
Advanced Synthesis & Catalysis
COMMUNICATION
Iridium/f-Amphol-catalyzed Efficient Asymmetric
Hydrogenation of Benzo-fused Cyclic Ketones
Adv. Synth. Catal. 2018, Volume, Page – Page
Congcong Yin,† Xiu-Qin Dong,*† Xumu Zhang*‡,†
6
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