Highly Enantioselective Cobalt-Catalyzed Hydroboration of Diaryl Ketones

Article abstract of DOI:10.1021/acs.orglett.0c00293

A highly enantioselective cobalt-catalyzed hydroboration of diaryl ketones with pinacolborane was developed using chiral imidazole iminopyridine as a ligand to access chiral benzhydrols in good to excellent yields and ee. This protocol could be carried out in a gram scale under mild reaction conditions with good functional group tolerance. Chiral biologically active 3-substituted phthalide and (S)-neobenodine could be easily constructed through asymmetric hydroboration as a key step.

Full text of DOI:10.1021/acs.orglett.0c00293

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Letter
Highly Enantioselective Cobalt-Catalyzed Hydroboration of Diaryl
Ketones
Wenbo Liu,† Jun Guo,† Shipei Xing, and Zhan Lu*
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ABSTRACT: A highly enantioselective cobalt-catalyzed hydro-
boration of diaryl ketones with pinacolborane was developed using
chiral imidazole iminopyridine as a ligand to access chiral
benzhydrols in good to excellent yields and ee. This protocol
could be carried out in a gram scale under mild reaction conditions
with good functional group tolerance. Chiral biologically active 3-
substituted phthalide and (S)-neobenodine could be easily
constructed through asymmetric hydroboration as a key step.
hiral diaryl- and aryl heteroarylmethanols are present in a
acid via asymmetric transfer hydrogenation,10 have been
explored. Compared with well-investigated asymmetric reduc-
tion of aryl alkyl ketones,11 the counterpart of diaryl ketone is
challenging for the difficulty to differentiate two structurally
similar aryl groups in substrates.9 Although some elegant works
have been developed, it is still of great interest to both the
academic community and the industrial sector to develop
efficient and environmentally benign catalytic methodology for
synthesis of chiral benzhydrols.
C
large number of natural products and biologically active
compounds,1 such as isopestacin, rubiginone H, (S)-carbinox-
amin, (R)-orpheradrino, and (S)-neobenodine (Scheme 1).
Scheme 1. Selected Examples of Bioactive Molecules and
Natural Products Derived from Diaryl- or
Aryl(heteroaryl)methanols
Over the past decade, due to the abundance and
environmental friendliness, cobalt catalysis has emerged as a
hot field of organic synthesis. Using cobalt to achieve the
highly enantioselective reduction of diaryl ketones sounds
desirable from both scientific and synthetic points of view. In
2005, using ketolminatocobalt complexes, the enantioselective
borohydride reduction of benzophenones was achieved by
Yamada with good to excellent enantioselectivity.12 However,
the substrates were strictly limited to ortho-fluorinated
benzophenones, which restricted its synthetic utility. Addi-
tionally, in that case, functional group tolerance has not been
investigated. It was not until 2015 that another cobalt-
catalyzed enantioselective hydroboration reduction of diaryl
ketones was developed by us using oxazoline iminopyridine
(OIP) as a ligand; however, only two cases were reported.13
In the last 3 years, several types of chiral ligands14 were
designed and synthesized in our group, which gave us a new
chance to reinvestigate the asymmetric hydroboration
Nowadays, several strategies have been developed for the
catalytic asymmetric synthesis of diarylmethanols,2 which
could be divided into two categories: (1) the nucleophilic
addition of organometallic reagents to aromatic aldehydes3 and
(2) the catalytic reduction of prochiral diaryl ketones. For
asymmetric reduction of prochiral diaryl ketones, several
reduction reagents, including lithium aluminum hydride
modified with chiral amino alcohol derivatives,4 silanes
catalyzed by chiral rhodium5 or copper complexes,1c boranes
catalyzed by oxazaborolidine derivatives (CBS reduction),6
hydrogen mediated by Ru,7 Ir,8 or Mn9 complexes, and formic
Received: January 20, 2020
https://dx.doi.org/10.1021/acs.orglett.0c00293
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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reduction of diaryl ketones. Initially, ortho-methyl benzophe-
none 1a was chosen as the model substrate to test the activity
and selectivity of different cobalt catalysts. First, the reaction of
1a with pinacolborane (HBpin) using 2.5 mol % of La·CoCl2
as catalyst and 2.5 mol % of NaBHEt3 as activator in the
solution of THF (0.5 M) was conducted at rt for 18 h,
delivering chiral diarylmethanol 2a in 99% yield with 87% ee
(Table 1, entry 1). Using more electron-rich imidazoline
hydroboration without the existence of a cobalt complex
(entry 13) as a background reaction. The hydroboration did
not occur when no base or cobalt complex was added (entry
14). Finally, the standard conditions were confirmed as 1a (0.5
mmol), HBpin (0.6 mmol), Ld·CoCl2 (2.5 mol %), and
NaBHEt3 (2.5 mol %) in THF (0.5 M) running at rt for 18 h.
With the optimized conditions in hand, the substrate scope
of diaryl ketones was investigated and is shown in Scheme 2.
a
a
Table 1. Optimizations
Scheme 2. Substrate Scope
b
entry
[Co]
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
La·CoCl2
Lb·CoCl2
Lc·CoCl2
Ld·CoCl2
Le·CoCl2
Lf·CoCl2
Lg·CoCl2
Ld·CoBr2
Ld·CoI2
99
85
98
99
77
82
48
99
98
99
99
trace
72
87
90
91
91
87
89
28
89
84
68
63
c
Ld·CoCl2
Ld·CoCl2
Ld·CoCl2
d
e
f
ef
,
14
ND
a
The reactions were conducted using 1a (0.5 mmol), HBpin (0.6
mmol), cobalt complex (2.5 mol %), and NaBHEt3 (2.5 mol %) in a
solution of THF (1 mL) at rt under the atmosphere of nitrogen for 18
1
h. Yields were determined by H NMR using 1,3,5-trimethylbenzene
b
as an internal standard. Enantiomeric excess value was determined
c
d
e
by HPLC. NaBHEt3 (5 mol %). NaBHEt3 (7.5 mol %). Without
f
NaBHEt3. Without a cobalt complex.
iminopyridine (IIP)-ligated cobalt complex Lb·CoCl2, 2a was
obtained in 85% yield with 90% ee (entry 2). Changing the
tert-butyl group on imidazoline to benzyl gave a high yield, and
the enantioselectivity was slightly increased (entry 3). When
the R1 was changed to isopropyl, 1a could almost be converted
completely into 2a with the same enantioselectivity (entry 4).
When steric bulky imide-derived catalysts were used, the ee
values of 2a were decreased to varying degrees (entries 5−7).
In particular, when 2,6-di(diphenylmethyl)aniline-derived Lg·
CoCl2 was used, the yield and enantioselectivity of 2a were
sharply decreased (entry 7). Further investigation of the effect
of counterion showed that the chloride was the best in terms of
the enantioselectivity. It should be noted that the enantiose-
lectivity was dramatically decreased when 2 or 3 equiv of
NaBHEt3 was used (entries 10 and 11), indicating the critical
impact of the amount of reductant in this catalytic system. In
addition, the reaction almost did not occur in the absence of
reductant (entry 12), implying that Ld·CoCl2 has no catalytic
activity. The reductant itself was able to catalyze the
a
Standard conditions: unless otherwise noted, diaryl ketone (0.5
mmol), HBPin (1.2 equiv), Ld·CoCl2 (2.5 mol %), NaBHEt3 (2.5
b
c
mol %), THF (1 mL), rt, 18 h. Isolated yields. HBpin (2 equiv). Ld·
d
CoCl2 (5 mol %). Diaryl ketone (0.25 mmol), HBPin (1.2 equiv),
Ld·CoCl2 (10 mol %), NaBHEt3 (10 mol %), THF (1 mL), 0 °C, 48
h. 1-Cyclohexylethanone (1.0 mmol), THF (2 mL), 22 h.
e
First, the ortho-substituents were examined. Halides, such as
fluoro (1b), chloro (1c), bromo (1d), and even iodo (1e),
which could easily undergo oxidative addition in noble metal
catalysis, were tolerated well to afford the corresponding diaryl
methanols 2b−2e in 70−99% yields with 88−98% ee. It is
worth noting that 2b−2e could be easily functionalized
through halide transformations, which demonstrated their
synthetic utilities. Substrates containing electron-donating (2-
OEt) or electron-withdrawing group (2-CF3) participated to
yield 2f in 78% yield with 83% ee or 2g in 99% yield with 96%
ee. Next, using an ortho-chloro phenyl group as a partner,
B
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substituents at the other phenyl ring were also investigated.
Usually, due to the challenge in differentiating the enantiotopic
faces, it was difficult to achieve highly enantioselective
reduction of a substrate having a nearly symmetric structure.
To our delight, substrate 1h containing 2-chloro and 2′-methyl
on the two phenyl rings was afforded in excellent yield with a
good enantioselectivity. Substrates containing substituents at
the 3′- or 4′-position were suitable for this catalytic system,
giving 2i−2m in excellent yield and enantioselectivity. Phenol
(1n), ester (1o), and amide (1p) could also be tolerated to
deliver 2n−2p in 44−86% yields and 96−98% ee. Substrates
with disubstituents were good partners to give 2q−2t in 93−
99% yields with 89−98% ee. N-Methyl-protected indole could
also be tolerated to obtain 2u in 81% yield with 95% ee.
Additionally, reaction of aryl heteroaryl ketones like 1v and 1w
afforded corresponding heteroarylmethanols 2v and 2w in 69
and 53% yield and 85 and 93% ee, respectively, with increased
catalyst loading. The absolute configurations of 2a−2d and 2h
were verified by comparison of their optical rotation with
previously reported data.3f,15,16a The configuration of 2z was
verified by X-ray diffraction, and other products were then
assigned by analogy.
blocks broadly present in many natural products and
biologically active compounds.1a,b,16 The ortho-methyl-ester-
substituted diaryl ketone 1z could smoothly undergo
sequential asymmetric hydroboration/lactonization reactions
to afford (S)-3-phenylisobenzofuran-1(3H)-one (2z) in 66%
yield with 92% ee (Scheme 3b). The structure and absolute
configuration of (S)-2z were determined via X-ray diffraction
analysis.17 Benzhydrol 2aa can be obtained with 95% yield and
98% ee via hydroboration of 1aa under standard conditions.
Further debromination of 2aa delivered 3aa in 91% yield and
98% ee, which was used to synthesize the (S)-neobenodine in
60% overall yield and 97% ee.
Based on the previous work of Chirik,18 we considered that
it was cobalt chloride LCoCl that generated rather than cobalt
hydride LCoH when 1 equiv of NaBHEt3 was used as the
activator. So the key catalytic species is LCoCl rather than
LCoH, which is so common for catalysis based on cobalt.
Meanwhile, given the possibility that LCoCl might undergo
other transformations, such as oxidative addition, it could also
be the precursor of real catalytic species. It should be noted
that the actual chemical valence of cobalt is not confirmed. The
IIP ligand is proposed as a redox-active ligand.19 As mentioned
in Table 1, excess NaBHEt3 led to lower ee and higher yield.
We owed that to the generation of IIP·Co(I)H when more
than 1 equiv of NaBHEt3 was used as IIP·Co(I)H might lead
to another type of catalytic mechanism. This mechanism based
on IIP·Co(I)H might be similar to that described by Gade’s
group in 2018, which was based on Mn20 and resulted in lower
ee in this case. Meanwhile, given that the isomerization of
terminal alkene was observed under standard conditions when
terminal alkene was contained in the substrate, the mechanism
based on IIP·Co(I)H could not be simply ruled out.
To showcase the utility of this transformation, a gram-scale
reaction was carried out to give the corresponding chiral
alcohol 2c in 93% yield with 96% ee under the standard
conditions (Scheme 3a). Chiral 3-substituted phthalide
frameworks (1(3H)-isobenzofuranones) are versatile building
Scheme 3. Gram-Scale Reaction and Further Derivatizations
In summary, a cobalt-catalyzed highly enantioselective
hydroboration of diaryl ketones with pinacolborane was
developed using chiral imidazole iminopyridine as a ligand to
deliver chiral benzhydrols in good to excellent yield and ee.
Various functional groups such as halides, ethers, phenol,
esters, and amides are well-tolerated under the mild conditions.
The developed methodology could also be utilized to construct
the biologically active 3-substituted phthalide in an asymmetric
hydroboration/lactonization sequence. Additionally, the asym-
metric reduction could be easily carried out in a gram scale
without any decrease in yield and ee. Further studies on the
mechanism and asymmetric catalysis via ligand design are
underway in our laboratory.
ASSOCIATED CONTENT
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The Supporting Information is available free of charge at
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Experimental procedures and characterization data for
all compounds (PDF)
Accession Codes
CCDC 1962316 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
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AUTHOR INFORMATION
Corresponding Author
■
Zhan Lu − Department of Chemistry, Zhejiang University,
Hangzhou 310058, China; orcid.org/0000-0002-3069-
079X; Email: luzhan@zju.edu.cn
Authors
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Asymmetry 1991, 2, 339−342.
Wenbo Liu − Department of Chemistry, Zhejiang University,
Hangzhou 310058, China
Jun Guo − Department of Chemistry, Zhejiang University,
Hangzhou 310058, China
Shipei Xing − Department of Chemistry, Zhejiang University,
Hangzhou 310058, China
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Complete contact information is available at:
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Author Contributions
†W.L. and J.G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was provided by Zhejiang Provincial Natural
Science Foundation of China (LR19B020001), NSFC
(21772171), Center Chemistry for Frontier Technologies,
and the Fundamental Research Funds for the Central
Universities (2019QNA3008). Dr. Xu Chen, Mr. Xiang Ren,
Mr. Tao Han, and Mr. Huangzhe Lu at Zhejiang University are
thanked for the help with the synthesis of some starting
materials. Prof. Longwu Ye at Xiamen University is thanked for
helpful discussions.
(10) Touge, T.; Nara, H.; Fujiwhara, M.; Kayaki, Y.; Ikariya, T.
Efficient Access to Chiral Benzhydrols via Asymmetric Transfer
Hydrogenation of Unsymmetrical Benzophenones with Bifunctional
Oxo-Tethered Ruthenium Catalysts. J. Am. Chem. Soc. 2016, 138,
10084−10087.
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