Cobalt-Catalyzed Asymmetric Markovnikov Hydroboration of Styrenes

Article abstract of DOI:10.1021/acscatal.8b05135

A cobalt-catalyzed asymmetric hydroboration of styrenes using an imidazoline phenyl picoliamide (ImPPA) ligand was first reported to deliver the valuable chiral secondary organoboronates with good functional tolerance and high enantioselectivity (up to >9

Full text of DOI:10.1021/acscatal.8b05135

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Article
Cobalt-Catalyzed Asymmetric Markovnikov Hydroboration of Styrenes
Xu Chen, Zhaoyang Cheng, and Zhan Lu
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Cobalt-Catalyzed Asymmetric Markovnikov Hydroboration of
Styrenes
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Xu Chen, Zhaoyang Cheng, Zhan Lu*
Department of chemistry, Zhejiang University, Hangzhou 310058, China.
Supporting Information Placeholder
ABSTRACT: A cobalt-catalyzed asymmetric hydroboration of styrenes using imidazoline phenyl picoliamide (ImPPA) ligand was
firstly reported to deliver the valuable chiral secondary organoboronates with good functional tolerance and high enantioselectivity
(up to >99% ee). This protocol is operationally simple without any activator. Particularly, this method can be applied in the
asymmetric hydroboration of allylamine to afford 1, 3-amino alcohol, which is a key intermediate for the synthesis of fluoxetine
and atomoxetine. Furthermore, the control experiments, isotopic labeling experiments and qualitative and quantitative kinetic
studies were also conducted to figure out the primary mechanism.
KEYWORDS: cobalt, styrenes, asymmetric hydroboration, nitrogen ligand, chiral organoboronates
Chiral boronic esters are important building blocks in
asymmetric synthesis for their carbon-boron bond can be
easily converted to carbon–carbon or carbon–heteroatom bond
in a stereospecific fashion.1 Metal-catalyzed asymmetric
hydroboration of alkenes has shown to be one of the most
powerful methods for the synthesis of chiral boronic esters.2
To date, phosphine-ligated rhodium complexes3 have
dominated the catalyst landscape of highly enantioselective
hydroboration of styrenes. However, it also suffered from
Scheme 1. Metal-catalyzed asymmetric hydroboration of
monosubstituted styrenes
a) Previous work
BR'2

Bpin

HBpin or HBCat
HBpin
Cu, P*
Ar
Rh, P*
Ar
Ar
Hayashi, Ito, Brown,
Burgess, Knochel, Crudden,
Takacs, Aggarwal and others
Yun
b) This work
some drawbacks in some cases such as, requiring low reaction
3b
temperature (- 78 oC),3a,
limited substrate scope with
O
R
Co(OAc)2 (1.0 ~ 2.5 mol %)
moderate selectivity using stable pinacol borane (HBpin).3g
Because of the global emphasis on sustainable chemistry, the
low abundance, high cost, and toxicity of precious metals has
triggered chemists’ interest on earth-abundant metal
Ar
Bpin

N
ImPPA
(1.2 ~ 3.0 mol %)
H
R
R = H, alkyl
+
N
Ar
N
NPh
Et2O, rt, 18 h
Me
31 examples
65 ~ 99 % yield
83 ~ >99% ee
t Bu
ImPPA
HBpin
catalysis.2f, Particularly, recent years have witnessed the
4
simple styrene and β-substituted vinylarenes using imidazoline
phenyl picoliamide (ImPPA) ligand with broad substrate scope
under mild reaction conditions (Scheme 1).
growing interest in using earth-abundant metals such as
copper,5 iron,6 or cobalt7 for catalytic asymmetric
hydroboration of alkenes. However, only copper catalyst
based on chiral phosphine ligand have been employed in the
asymmetric hydroboration of simple styrenes (8 examples, 51-
95% ee) with Markvonikov selectivity in which the functional
group tolerance was not well investigated (Scheme 1).5a The
chiral iron and cobalt catalysts have only been reported for the
anti-Markvonikov selective asymmetric hydroboration of
alkenes.6-7 Thus, it is still highly desirable to develop an
efficient earth-abundant metal catalyzed asymmetric
hydroboration of styrenes with broad substrate scope and high
enantioselectivity.
Based our study on the iron-catalyzed Markovnikov
selective hydroboration of styrenes,10 the combination of
Co(OAc)2 with chiral oxazolinylphenyl picolinamide ligand
was tested for asymmetric transformation. The reaction of
styrene 1a with pinacolborane in the presence of L1a and
Co(OAc)2 as catalysts afforded product 2a in 68% yield but
only with 10% ee (Table 1, entry 1). A variety of amide-type
ligands L1b-L1e were then evaluated, 2a was obtained in 74-
81% yields, however, with less than 11% ee (entries 2-5). The
use of L1f bearing a methyl group at 6-position on pyridine
greatly enhanced the enantioselectivity of the reaction to 81%
ee with no deterioration in yield and regioselectivity (entry 6).
Ligands L1g-L1j containing different substituents on the
oxazoline were then investigated and no better result were
found (entries 7-10). Surprisingly, when L2a containing a
more electron-rich phenyl-protected imidazoline was used, the
ee value of 2a was increased to 94% (entry 11). Evaluation of
a serials of imidazoline ligands shown that the more bulky
Recently, we have reported cobalt-catalyzed asymmetric
isomerization/hydroboration of alkene using imidazoline
phenyl picoliamide (ImPPA) as a chiral ligand.8 However, the
cobalt catalyzed asymmetric Markovnikov hydroboration of
styrenes with high enantioselectivity has not been explored.
Based on our previous studies on asymmetric
hydrofunctionalisation of alkenes,6, 8-9 we reported an activator
free, highly enantioselective cobalt-catalyzed hydroboration of
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Table 1. Optimization conditions.a
Co(OAc)2 (2.5 mol %)
Table 2. Substrate scope.a
Bpin
Bpin
Bpin
Bpin
BPin
BPin
Ligand (3 mol %)
HBpin
1.2 eq
Ph
Ph
Ph
solvent (1.0 M), rt, 18 h
t Bu
MeO
1a
2a
3a
5
6
7
8
9
2a,
2b,
2c,
2d,
72%, 97% ee
25/1 b/lb
85%, 93% ee
23/1 b/lb
74%, 98% ee
26/1 b/lb
78%, 94% ee
42/1 b/lc
: R1 = H, R2 = Bn, X = O
: R1 = H, R2 = Ph, X = O
: R1 = H, R2 = indenyl, X = O
: R1 = H, R2 = iPr, X = O
: R1 = Me, R2 = indenyl, X = O
: R1 = Me, R2 =iPr, X = O
: R1 = Me, R2 = tBu, X = O
L1a
L1h
L1i
L1b
L1c
L1d
L1e
L1f
O
L1j
Bpin
Bpin
NH
X
Bpin
Bpin
: R1 = Me, R2 = Bn, X = NPh
: R1 = Me, R2 = Ph, X = NPh
: R1 = Me, R2 = iPr, X = NPh
: R1 = Me, R2 = tBu, X = NPh
L2a
L2b
L2c
L2d
N
R
1 = H, R2 = tBu, X = O
Bn, X = O
: R1 = Me, R2 = Ph, X = O
N
: R1 = Me, R2
=
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R2
L1, L2
AcO
F
R1
F
L1g
2e,
2f,
2g,
2h,
65%, 86% ee
42/1 b/lc
80%, 95% ee
20/1 b/ld
71%, 98% ee
30/1 b/lb
81%, 82% ee
37/1 b/l
Bpin
Entry
1
Ligand
Solvent
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
Et2O
2a/3a (%)b
Ee/(%)c
-10
-11
-5
Bpin
Bpin
Bpin
L1a
L1b
L1c
L1d
L1e
L1f
L1g
L1h
L1i
68/0.7
74/0.5
80/0.3
81/0.3
75/0.5
76/4.2
88/2.2
75/4.2
78/3.2
72/5.0
87/2.2
80/3.2
89/2.5
75/6.0
79/3.5
72/2.8
2
CF3
Cl
Br
2i,
2j,
2k,
2l,
63%, 95% ee
36/1 b/le
67%, 92% ee
25/1 b/le
64%, 88% ee
>50/1 b/le
85%, 90% ee
33/1 b/lb
3
4
-5
Bpin
Bpin
Bpin
Bpin
5
-4
6
81
F
O
N
7
87
2m,
2n,
2o,
2p,
81%, 96% ee
33/1 b/lb
68%, 86% ee
19/1 b/l
84%, 88% ee
>50/1 b/lf
81%, 98% ee
12/1 b/l
8
70
9
79
Bpin
Bpin
Bpin
Bpin
10
11
12
13
14
15
16
L1j
L2a
L2b
L2c
L2d
L2d
L2d
82
94
t Bu
2r,
Ph
MeO
91
2q,
2s,
2t,
90%, 99% ee
17/1 b/l
86%, 99% ee
26/1 b/l
94%, 98% ee
48/1 b/l
87%, 98% ee
17/1 b/l
96
Bpin
Bpin
99
Bpin
Bpin
97
97d
F3C
MeS
F
Et2O
2u,
2v,
2w,
2x,
99%, 99% ee
37/1 b/l
90%, 99% ee
13/1 b/l
87%, 99% ee
30/1 b/l
94%, 99% ee
33/1 b/l
aReactions were conducted using 1a (1.0 mmol), HBpin (1.2
mmol), Co(OAc)2 (2.5 mol %) and ligand (3.0 mol %) in a
solution of dioxane (1.0 mL) at rt under N2 atmosphere for 18 h.
bYields were determined using TMSPh as an internal standard.
Bpin
Bpin
Bpin
Bpin
d
cEe values were determined by chiral HPLC analysis. 1 mol%
F
Cl
catalyst.
2y,
2z,
2aa,
2ab,
79%, 98% ee
20/1 b/l
84%, 98% ee
25/1 b/l
96%, 97% ee
37/1 b/l
85%, 96% ee
22/1 b/l
L2d was the best ligand to give product 2a in 99% ee but with
a slight decrease in regioselectivity (12/1 b/l) (entries 12-14).
Next, various solvents were investigated in which Et2O was
found to be the best solvent to give the product 2a in 97% ee
with 25/1 b/l (entry 15). The reaction could occur smoothly
using 1 mol % of catalyst to give 72% yield and 97% ee (entry
16). The standard conditions are identified as 1 mmol of
alkene, 1.2 mmol of HBpin, 2.5 mol % of Co(OAc)2, 3 mol %
of L2d in 1.0 mL of Et2O for 18 h.
Bpin
Bpin
5
CO2Et
Bpin
OH
5
Bpin
6
g
2ac,
83%, 99% ee
2ad
: 65% yield, 99% ee
2af
: 90% yield, 10% ee
2ae
: 92% yield
aStandard conditions: unless otherwise noted, Co(OAc)2 (2.5
mol%), L2d (3.0 mol %), alkene (1 mmol), HBPin (1.2 equiv),
Et2O (1 mL), rt, 18 h; Yields referred to the isolated yields; Ee
values were determined by chiral HPLC analysis;
1
Regioselectivities were determined by H NMR analysis analysis
With the standard conditions in hand, various styrenes were
investigated (Table 2). Styrenes containing both electron-
donating and electron-withdrawing groups could participate to
give the corresponding chiral boronic esters in 63-85% yields
with high regioselectivity and 82-98% ee. Styrenes with
acetoxyl, fluro, chloro, bromo and trifluoromethyl group can
be tolerated which show the good functional group tolerance
of this reaction system. The styrenes containing heterocycle
and polycyclic ring, such as 3-pyridyl (1n) and 2-naphthyl
(1o), could be converted to the correponding product in 68%
b
of crude mixture of products. Co(OAc)2 (1.0 mol%), L2d (1.2
mol %). cCo(OAc)2 (1.0 mol %), L2c (1.2 mol %), 36 h.
dCo(OAc)2 (1.0 mol %), L2d (1.2 mol %), 36 h. Co(OAc)2 (2.5
e
mol %), L2d (3.0 mol %), 36 h. fCo(OAc)2 (2.5 mol %), L2c (3.0
mol %). gIsolated yield for corresponding alcohol.
yield with 86% ee and 84% yield with 88% ee, respectively.
The moderate yields got in some cases attributed to the
formation of the hydrogenated product. It should be noted that
various β-substituted vinylarenes can participate in the
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reaction to give the corresponding products in 65-99% yields
L2d •CoCl2 and NaOAc as an additive could give 2a in 80%
yield with 97% ee (Scheme 3b). The control experiments
demonstrated two possibilities: one was that metal complex
with weak coordinated counter ion from ligand exchange was
easier to be reduced, the other was that weak base could
deprotonate the proton from metal complex to accelerate the
formation of active pincer-type metal complex.
with 96-99% ee. The electronic nature of the substituents on
the aromatic ring has little effect on the enantioselectivity of
this reaction. Particularly, alkene 1ad with primary alcohol
could also participate in the reaction to afford 2ad in 65%
yield with 99% ee. The reaction of oct-1-ene with HBpin
afforded the linear product 2ae in 92% yield which indicated
that aromatic ring may contribute to the formation of benzylic
metal-complex and determine the regioselectivity and
enantioselectivity.11 When α-methylstyrene was subjected to
this reaction system, the anti-Markovnikov addition product
2af was obtained in 90% yield with 10% ee and benzylic
boronate was not observed.
Scheme 3. (a) Deuterium experiment. (b) Reaction
conducted using complex L2d•CoCl2.
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BPin
OH
1
Co(OAc)2 (5 mol %)
2
1
2
L2d
(6 mol %)
3
D
3
D
a
(
)
+
DBpin
Et2O, rt, 20 h
2q
d- : 92% yield,
99% ee, 16/1 b/l
1 position: 6%
1q
A gram scale reaction of 1a could be performed to afford 2a
in 92% yield with 97% ee using 1.0 mol % of Co(OAc)2 and
1.2 mol % of ligand (Scheme 2a). Cinnamyl amine (1ag)
could be converted to 1,3-amino alcohol 3ag in 65% yield
with 98% ee, which is a key intermediate for the synthesis of
the antidepressant drug fluoxetine,12 as well as the attention
2 position: 70%
3 position: 11%
L2d
-CoCl2 (2.5 mol %)
BPin
Ph
NaOAc (7.5 mol %)
HBpin
1.2 eq
b
(
)
Ph
1a
Et2O (1.0 M), rt, 18 h
2a:
80% yield, 97% ee
20/1 b/l
13
deficit hyperactivity disorder (ADHD) drug atomoxetine
(Scheme 2b). Traditionally, asymmetric hydrogenation of
ketones is the main method for the synthesis of chiral 1,3-
amino alcohol, which needs noble-metal catalyst and the high
pressure of hydrogen atmosphere. This method embraces the
benefits of earth-abundant metal catalysis and mild reaction
conditions. To the best of our knowledge, this is also the first
example of metal-catalyzed asymmetric hydroboration of
cinnamyl amine.
Figure 1. X-ray structure of L2d•CoCl2.
Scheme 2. Gram scale reaction and synthesis of 1,3-amino
alcohol
Co(OAc)2 (1.0 mol %)
BPin
L2d
(1.2 mol %)
a
( )
HBpin
Ph
Ph
2a
Et2O (2.0 M), rt, 24 h
: 2.13 g
10.0 mmol
12.0 mmol
92% yield, 97% ee
28/1 b/l
Figure 2. (a) A plot of Kin vs. HBpin concentrations. (b) A
plot of Kin vs. catalyst concentrations. (c) A plot of Kin vs.
styrene concentrations. (d) Time course studies.
OH
H2O2/NaOH
Et2O, rt, 2 h
Standard conditions
cat. (5 mol %)
Bn
b
(
)
Bn
Ph
N
Ph
3ag
N
1ag
, 65% yield, 98% ee
a
CF3
b
OH
Ref.12
Ref.13
O
O
Bn
Ph
N
Ph
N
Ph
N
3ag
H
H
Fluoxetine
(antidepressant)
Atomoxetine
(ADHD drug)
To probe the mechanism of this hydroboration reaction, the
deuterium experiment of alkene 1q with DBpin was conducted
to give d-2q in 92% yield with 70% D-incorporation in 2-
position and 6% D-incorporation in 1-position (Scheme 3a).
11% D-incorporation in 3-position showed that the occurrence
of alkene-isomeration during the process which illustrated the
formation of cobalt hydride species. Although the structure of
L2d•Co(OAc)2 was difficult to be obtained, we got the x-ray
d
c
Quantitative kinetic studies were also performed to
determine the roles of HBpin, styrene and catalyst.
Measurements of the initial rates (Kin) for the reaction of
styrene with different concentrations of HBpin and the catalyst
showed a corresponding rise in the rates of the reactions. Plots
of Kin versus the concentrations of HBpin and the catalyst
14
crystal structure of L2d •CoCl2 which indicated that both
pyridine and amide coordinated with cobalt (Figure 1). It
should be noted that the proton on amide was shifted to
imidazoline which inhibited the formation of tridendate cobalt
complex. The reaction of 1a with HBpin using L2d•CoCl2
did not occur. However, the reaction using cobalt complex
gave linear curves (slope = 1.24 ×10-5 M s-1; 1.00 × 10-3 M s-1)
indicating a first order rate dependence on HBpin and the
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catalyst (Fig. 2a-b). Similar kinetic studies on styrene showed
AUTHOR INFORMATION
Corresponding Author
that a first order rate dependence on styrene, however, the
reaction rates were slightly affected negatively with the
increasing concentrations of styrene (Fig. 2c). These kinetic
studies showed that the σ-bond metathesis with HBpin is rate-
limiting step. The phenomenon that the increased
concentration of styrene decreased initial rates may attribute to
the multiple ligation of alkene to catalyst, which depletes the
coordination sites of catalyst and precluded it from
approaching the HBpin.
*E-mail: luzhan@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by NSFC (21772171), Zhejiang
Provincial natural Science Foundation of China (LR19B020001)
and the Fundamental Research Funds for the Central Universities.
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Based on these mechanistic studies, a possible mechanism
is illustrated in Scheme 4. First, ligand LH* coordinates to
cobalt(II) acetate to form cobalt (II) precatalyst A and releases
a molecule of acetic acid.15 Then cobalt precursor A enters the
catalytic cycle to generate cobalt (II) hydride species B
through σ-bond metathesis with HBpin. Alkene undergoes
coordination and insertion to cobalt hydrogen bond to form
cobalt(II) species D or D’.15 Finally, species D undergoes a
rate- limiting σ-bond metathesis with HBpin to regenerate
cobalt (II) hydride species B and afford chiral organoboronic
ester.
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(2-Diphenylphosphino-1-Naphthyl)Isoquinoline. J. Chem. Soc., Chem.
Commun. 1993, 1673-1674. (d) Schnyder, A.; Hintermann, L.; Togni,
A. Strong Electronic Effects on Enantioselectivity in Rhodium-
Catalyzed Hydroborations with Novel Pyrazole-Containing
Ferrocenyl Ligands. Angew. Chem., Int. Ed. 1995, 34, 931-933. (e)
Demay, S.; Volant, F.; Knochel, P. New C2-Symmetrical 1,2-
Diphosphanes for the Efficient Rhodium-catalyzed Asymmetric
Hydroboration of Styrene Derivatives. Angew. Chem., Int. Ed. 2001,
40, 1235-1238. (f) Blume, F.; Zemolka, S.; Fey, T.; Kranich, R.;
Schmalz, H. G. Identification of Suitable Ligands for a Transition
Metal-catalyzed Reaction: Screening of a Modular Ligand Library in
the Enantioselective Hydroboration of Styrene. Adv. Synth. Catal.
Scheme 4. Possible mechanism.
HOAc
Co(OAc)2
L*CoOAc
A
LH*
HBPin
AcOBpin
BPin
L*Co-H
Ph
Ph
B
CoL*
RDS
Ph
C
CoL*
HBPin
CoL*
Ph
D
D'
In summary, we have developed the cobalt-catalyzed highly
enantioselective asymmetric hydroboration of styrenes and β-
substituted vinylarenes using an imidazoline phenyl
picoliamide (ImPPA) ligand. Various vinylarenes are
subjected to this reaction system to afford the chiral secondary
organoboronates in good to excellent enantioselectivity (up to
>99% ee). Featuring earth-abundant catalysis, additional
activator free, simple operation and good functional group
tolerance, this protocol will be a practical method for
preparing synthetic useful chiral organoboronates. Developing
other cobalt-catalyzed asymmetric transformations is ongoing
in our laboratory.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental details, characterization data of all new compounds,
and copies of 1H and 13C NMR spectra (PDF).
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Table of contents (TOC)
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ImPPA
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O
R
Ar
R = H, alkyl
N
Bpin
H
N
N
NPh
R
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+
Ar
Me
t Bu
Co(OAc)2
HBpin
31 examples
up to 99% yield
up to 99% ee
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