Copper-Catalyzed Reactions with Diborons: From the Beginning to Recent Results

Copper-Catalyzed Reactions with
Diborons:  
From the Beginning to Recent Results
Hajime Ito, Hokkaido University, Japan

Hokkaido University in Sapporo City

Hokkaido University
Faculty Members: 4000
Hokkaido University
Undergraduate Students: 12000
Graduate Students: 6000

Hokkaido University
Faculty Members: 4000
Hokkaido University
Undergraduate Students: 12000
Graduate Students: 6000
Akira Suzuki 
2010 Nobel Prize Winner

Researches in Ito’s Group
Cu catalysis (2000−)
Si-B/base Chemistry (2012−)
J. Am. Chem. Soc., 2012, 134, 19997; Chem. Sci. 2015, 6, 2943.
Borylation Reactions
Angew. Chem., Int. Ed. 2015, 54, 8809.
J. Am. Chem. Soc. 2015, 137, 420.
J. Am. Chem. Soc. 2014, 136, 16515.
J. Am. Chem. Soc. 2013, 135, 2635.
Org. Lett. 2012, 14, 890.
Angew. Chem., Int. Ed. 2011, 50, 2778.
J. Am. Chem. Soc. 2010, 132, 11440.
J. Am. Chem. Soc. 2010, 132, 1226 .
J. Am. Chem. Soc. 2010, 132, 5990.
Angew. Chem., Int. Ed. 2010, 122, 570.
Nature Chemistry 2010, 2, 972.
J. Am. Chem. Soc. 2008, 130, 15774.
Angew. Chem., Int. Ed. 2008, 47, 7424.
J. Am. Chem. Soc. 2007, 129, 14856.
J. Am. Chem. Soc. 2005, 127, 16034.
DFT calculation: J. Am. Chem. Soc. 2015, 137, 4090.
EWG
(pin)B B(pin)
Cu cat.
EWG
(pin)B
Ito, Hosomi Tetrahedron Lett. 2000, 40, 7807.
(Ishiyama, Miyaura, Chem. Lett. 2000, 982.)
Chem. Sci., 2015, 6, 2187.
Mechano-Responsive Material
J. Am. Chem. Soc. 2008, 130, 10044.
Nature Comm. 2013, 4, 2009.
Angew. Chem., Int. Ed. 2013, 52, 12828, VIP.
Chem. Sci., 2015, 6, 1491.
Chem. Sci., 2015, 6, 2187.

Boronic Acids: Preparation and Applications in Organic Synthesis, Medicine and Materials, 2 nd revised ed.;  
Hall, D. G., Ed.; Wiley-VCH: Weinheim, 2011.
B
R1 R1
H
C
R1 R1
H
HO
R1 R1
H
H2N
R1 R1
H
Versatile Building Block
Major Synthetic Methods
・Hydroboration
・Electrophilic reactions of boron reagents
・Pd-catalyzed reactions of B2pin2 (Miyaura’s procedure)
Organoboron Compounds
No practical nucleophilic reactions of boron reagents
Low electronegativity of B (2.0) makes generation of B anion dif@icult.

・Hydroboration
Hydroboration is not the perfect solution.
■ Brown’s asymmetric hydroboration with stoichiometric chiral group
BH
2 +
H B(ipc)2 H OHoxidation
99% ee
OH
+ 2
H. C. Brown (1961)

・Hydroboration
Hydroboration is not the perfect solution.
■ Asymmetric catalytic hydroboration was limited.
Ph
[Rh(cod)2]BF4 (1 mol %)
(R)-BINAP (1 mol %)
–78°C, 6 h
O
HB
O
+ Ph
B(cat)
91%, 96.2 % ee
Hayashi, T.; Matsumoto, Y.; Ito, Y. J. Am. Chem. Soc. 1989, 111, 3426.!
■ Brown’s asymmetric hydroboration with stoichiometric chiral group
BH
2 +
H B(ipc)2 H OHoxidation
99% ee
OH
+ 2
H. C. Brown (1961)

・RLi, RMgX and Boron Electrophiles
RLi and RMgBr still have limitations.
M R X B
X
X
−MX
R B
X
X
Highly basic conditions, low functional group compatibility

・RLi, RMgX and Boron Electrophiles
RLi and RMgBr still have limitations.
M R X B
X
X
−MX
R B
X
X
Highly basic conditions, low functional group compatibility
N
Ph
O N(i-Pr)2
O
(-)-sparteine
s-BuLi
–78°C
Ph
O N(i-Pr)2
OLi
H
N
Ph
O N(i-Pr)2
OB
H
O
O
Et
Et B
O
O
MgBr2
Ph
B
O
O
Et
90%, 96% ee
R Li BX
■ Chiral Organoboron (Aggarwal et al)

Cu Cl +
NN
O
(DMI)(THF)
O
H Si
CH3
CH3
Copper-Catalyzed Hydrosilylation

no reaction
Cu Cl +
NN
O
(DMI)(THF)
O
H Si
CH3
CH3

no reaction
(DMI)nCu H(DMI)nCu
Cl
H
Si
Cu Cl +
NN
O
(DMI)(THF)
O
H Si
CH3
CH3

no reaction
(DMI)nCu H(DMI)nCu
Cl
H
Si
Ito, H.; Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetrahedron Lett. 1997, 38, 8887.
O
H Si+
cat. CuCl
DMI, rt
O
H
92%
H3O+CH3
CH3
Cu Cl +
NN
O
(DMI)(THF)
O
H Si
CH3
CH3
Catalysis
Stoichiometric Reaction

Our Preliminary Copper-Catalyzed Reactions

■ Hydorsilylaiton
CuCl / DMI / R3SiH:
O
H Si+
cat. CuCl
DMI, rt
O
H
92%
H3O+CH3
CH3
Cu
X
Si
H
Cu H
L
L
FCu(PPh3) / R3SiH: Mori, A.; Fujita, A.; Nishihara, Y.; Hiyama, T. Chem. Commun. 1997, 2159.

■ Silylation with disilanes
Si Ph+
cat. CuOTf
PBu3
DMI, rt
H3O+
O
SiPh
O
Si
Ph
Ito, H.; Ishizuka, T.; Tateiwa, J.; Sonoda, M.; Hosomi, A. J. Am. Chem. Soc. 1998, 120, 11196.
Cu
X
Si
Si
Cu Si
L
L
■ Hydorsilylaiton
CuCl / DMI / R3SiH:
O
H Si+
cat. CuCl
DMI, rt
O
H
92%
H3O+CH3
CH3
Cu
X
Si
H
Cu H
L
L
FCu(PPh3) / R3SiH: Mori, A.; Fujita, A.; Nishihara, Y.; Hiyama, T. Chem. Commun. 1997, 2159.

Early Studies on Diboron/Cu Catalysis
CuCl/KOAc: Takahashi, K.; Ishiyama, T.; Miyaura, N. Chem. Lett. 2000, 982.
CuX/PR3: Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A. Tetrahedron Lett. 2000, 41, 6821.
+
cat. CuX
PR3
DMI, rt
H3O+
O
O
B
B B
O
OO
O
O
O
87%
■ First Cu-Catalyzed Formal Nucleophilic Borylation

+
cat. CuX
PR3
DMI, rt
H3O+
O
O
B
B B
O
OO
O
O
O
87%
Cu
X
B
B
Cu B
L
L
✔ Boryl-Copper Intermediate
Boron Nucleophilicity 
Ligand Controlled Selectivity

Segawa, Y.; Yamashita, M.; Nozaki, K. Science 2006, 314, 113.
NN
B
Br
iPr
iPr iPr
iPr
NN
B
Li
iPr
iPr iPr
iPr
Li, naphthalene
THF
■ Generation of ”Boryl-Anion” was dif]icult.
+
cat. CuX
PR3
DMI, rt
H3O+
O
O
B
B B
O
OO
O
O
O
87%
Cu
X
B
B
Cu B
L
L

+
cat. CuX
PR3
DMI, rt
H3O+
O
O
B
B B
O
OO
O
O
O
87%
Cu
X
B
B
Cu B
L
L
R M X B R B
Fornmal Nucleophilic borylation
▶ ▶ Mild reaction conditions
B CuR X R B
Umpolung
▶ Catalytic asymmetric synthesis ▶
Electrophilic borylation
Highly basic conditions
Stoichiometric reaction
M R

Xantphos/Cu shows
High reactivity
High regio- and E/Z selectivity
Ito, H.; Kawakami, C.; Sawamura, M. J. Am. Chem. Soc. 2005, 127, 16034.
Cu(O-t-Bu)
/ ligand
(5 mol %)
GC yield, %
dppf
100
37
44
Xantphos
Ligand E : Z a
97 : 399 : 1
96 : 4> 99 : < 1
97 : 3> 99 : < 1
11 62 : 38> 99 : < 1
γ : α
dppe
dppp
O
PPh2Ph2P
+
2.0 equiv.
O
B
O
O
B
O
Xantphos:
Pd(dba)2 0 57 : 43
R
OCO2Me
R
B
R = (CH2)3Ph
O O
γ
THF, rt, 3 h
B
Cu
OR
L
B
Allyboron Synthesis: Xantphos/Cu

S R
2.4 equiv.
Bu
B(pin)MeO2CO Bu
(pin)B B(pin)+
THF, 0 °C, 40 h
10 mol%
Cu(O-t-Bu)ーXantphos
88%, 97% ee
γ:α = >99:1, E:Z = >99:1
97% ee
C C
R2
C
H R1
R3
OR
H
C C
B
R1
R2
H
CR3
H
C C
R2C
H R1
R3
OR
H
Cu B
L
L Cu B
■ Cu/Xantphos: anti-SN2’ reaction
Allyboron Synthesis: Asymmetric Reactions

S R
2.4 equiv.
Bu
B(pin)MeO2CO Bu
(pin)B B(pin)+
THF, 0 °C, 40 h
10 mol%
Cu(O-t-Bu)ーXantphos
88%, 97% ee
γ:α = >99:1, E:Z = >99:1
97% ee
C C
R2
C
H R1
R3
OR
H
C C
B
R1
R2
H
CR3
H
C C
R2C
H R1
R3
OR
H
Cu B
L
L Cu B
■ Cu/Xantphos: anti-SN2’ reaction
Allyboron Synthesis: Asymmetric Reactions
■ Asymmetric Cu-catalyzed Allylboron Synthesis
Ito, H.; Ito, S.; Sasaki, Y.; Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856.
N
N P
P
t-BuMe
t-Bu Me
(R,R)-QuinoxP*
R OCO2Me B B
O
OO
O
+
5 mol% Cu(O-t-Bu)
/ chiral ligand
THF, 0 °C
20 h R
B
OO
78%, 96% ee
R = PhCH2CH2

Mun, S.; Lee, J. E.; Yun, J. Org Lett. 2006, 8, 4887, Lee, J.-E.; Yun, J. Angew. Chem., Int. Ed. 2008, 47, 145.
R
EWG B B
O
OO
O
+
cat. CuCl/Na(O-t-Bu)
chiral ligand, ROH
R
EWG
B
OO Fe PPh2
PCy2
(R)-(S)-Josiphos
*
■ First Enantioselective Reactions by Yun

R
EWG B B
O
OO
O
+
chiral ligand, ROH
R
EWG
B
OO Fe PPh2
PCy2
(R)-(S)-Josiphos
*
■ First Isolation of Borylcopper Species
David S. Laitar, Peter Mu¨ller, and Joseph P. Sadighi*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts AVenue,
Cambridge Massachusetts 02139
Received September 28, 2005; E-mail: jsadighi@mit.edu
Nature uses carbon dioxide, on a massive scale, as a one-carbon
building block for the synthesis of organic molecules.1 An important
pathway for the consumption of CO2 is its reduction to CO by the
enzyme acetyl-CoA synthase/CO dehydrogenase (ACS-CODH).2
Due to the large energy input required to generate it from CO2,
CO is produced industrially from fossil fuels.3 Even with strong
reducing agents, however, overcoming the OdCO bond enthalpy
of 532 kJ/mol4 often presents kinetic difficulties.5,6
Certain metal complexes abstract oxygen readily from CO2,7 but
the resulting metal-oxygen bonds are necessarily strong, and
catalytic turnover is rare.8 Photolytic9 and photocatalytic10 ap-
proaches show promise, and synthetic electrocatalysts have achieved
impressive yields and selectivities in the reduction of CO2 to CO.11
However, the chemical processes involved are obscure, making it
difficult to improve these systems by design, and CODH remains
notably the most efficient catalyst for this reduction.12 We report
herein that a new carbene-supported copper(I) boryl complex
abstracts oxygen from CO2 and undergoes subsequent turnover
readily. Using an easily handled diboron reagent as the net oxygen
acceptor,13 these key steps permit unprecedented turnover numbers
and frequencies for the chemical reduction of CO2 to CO in a
homogeneous system.
While exploring the chemistry of organocopper(I) complexes
supported by N-heterocyclic carbene (NHC) ligands,14 we sought
to synthesize a copper(I) boryl complex and explore its reactivity
toward CO2. Metal boryls often display distinctive reactivity,15
catalyzing a number of remarkable transformations.16 Although
C-B bond-forming reactions have been achieved using diboron
compounds with catalytic17a or stoichiometric17b copper(I), well-
defined copper boryl complexes have not been described.
The known (IPr)Cu(Ot-Bu) reacts rapidly with bis(pinacolato)-
diboron (pinB-Bpin), forming a product identified as (IPr)Cu(Bpin)
(1, Scheme 1) by 1H and 11B NMR spectroscopy. Diffusion of
hexane vapor into a concentrated solution of 1 in toluene, carried
out at -40 °C to avoid thermal decomposition,18 produces single
crystals suitable for analysis by X-ray diffraction. The resulting
structure (Figure 1a) shows a monomeric, nearly linear coordination
geometry with a Cu-B distance of 2.002(3) Å.
Complex 1 reacts with CO2 under atmospheric pressure in C6D6
conversion of 1 to 2. The sole labeled products visible in the
NMR spectrum (Figure 2b) are 13CO (δ 184 ppm) and an ad
(δ 164 ppm) formed reversibly from CO and borate 2.20
Treatment of 2 in C6D6 solution with pinB-Bpin smo
regenerates 1, forming the stable byproduct pinB-O-Bpin,21
a reaction time of about 20 min. The success of this turnover
closes a catalytic cycle for the deoxygenation of CO2. Additio
a THF solution of (IPr)Cu(Ot-Bu) to a 100-fold excess of pi
Scheme 1 a
a Isolated yield, contains some 2 (5 mol % by 11B NMR); (b) react
complete in <10 min at ambient temp; (c) L ) IPr or ICy.
Figure 1. X-ray crystal structures, shown as 50% thermal ellipsoid
boryl complex 1‚C6H14 (a), and borate 2‚C7H8 (b). Hydrogen atoms (c
and solvent are omitted for clarity. Selected bond lengths (Å) and a
(deg), (a): Cu(1)-B(1) 2.002(3), Cu(1)-C(1) 1.937(2), C(1)-N(1) 1.3
C(1)-N(2) 1.363(3), C(1)-Cu(1)-B(1) 168.07(16), N(1)-C(1)-
102.97(18); (b): Cu(1)-O(1) 1.8096(16), O(1)-B(1) 1.306(3), Cu
C(1) 1.857(2), C(1)-N(1) 1.355(3), C(1)-N(2) 1.364(3), C(1)-Cu
O(1) 174.85(10), B(1)-O(1)-Cu(1) 133.61(16), N(1)-C(1)-N(2) 103.0
NN
Cu
tBuO
iPr
iPr
iPr
iPr
NN
Cu
iPr
iPr
iPr
iPr
B(pin)
(pin)B-B(pin)
Laitar, D. S.; Müller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2005, 127, 17197.

R
EWG B B
O
OO
O
+
chiral ligand, ROH
R
EWG
B
OO Fe PPh2
PCy2
(R)-(S)-Josiphos
*
■ Chiral NHC Ligand
Lee, Y.; Hoveyda, A. J. Am. Chem. Soc. 2009, 131, 3160.
N N
Ph Ph
i-Pr
i-Pr
i-Pr
SO3
–
Ph (pin)B B(pin)+
cat.CuCl/K(O-t-Bu)
THF, –50°C, 48 h, MeOH, 2.0 equiv
+
Ph
B(pin)
80%, 98% ee
■ First Isolation of Borylcopper Species
David S. Laitar, Peter Mu¨ller, and Joseph P. Sadighi*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts AVenue,
Cambridge Massachusetts 02139
Received September 28, 2005; E-mail: jsadighi@mit.edu
Nature uses carbon dioxide, on a massive scale, as a one-carbon
building block for the synthesis of organic molecules.1 An important
pathway for the consumption of CO2 is its reduction to CO by the
enzyme acetyl-CoA synthase/CO dehydrogenase (ACS-CODH).2
Due to the large energy input required to generate it from CO2,
CO is produced industrially from fossil fuels.3 Even with strong
reducing agents, however, overcoming the OdCO bond enthalpy
of 532 kJ/mol4 often presents kinetic difficulties.5,6
Certain metal complexes abstract oxygen readily from CO2,7 but
the resulting metal-oxygen bonds are necessarily strong, and
catalytic turnover is rare.8 Photolytic9 and photocatalytic10 ap-
proaches show promise, and synthetic electrocatalysts have achieved
impressive yields and selectivities in the reduction of CO2 to CO.11
However, the chemical processes involved are obscure, making it
difficult to improve these systems by design, and CODH remains
notably the most efficient catalyst for this reduction.12 We report
herein that a new carbene-supported copper(I) boryl complex
abstracts oxygen from CO2 and undergoes subsequent turnover
readily. Using an easily handled diboron reagent as the net oxygen
acceptor,13 these key steps permit unprecedented turnover numbers
and frequencies for the chemical reduction of CO2 to CO in a
homogeneous system.
While exploring the chemistry of organocopper(I) complexes
supported by N-heterocyclic carbene (NHC) ligands,14 we sought
to synthesize a copper(I) boryl complex and explore its reactivity
toward CO2. Metal boryls often display distinctive reactivity,15
catalyzing a number of remarkable transformations.16 Although
C-B bond-forming reactions have been achieved using diboron
compounds with catalytic17a or stoichiometric17b copper(I), well-
defined copper boryl complexes have not been described.
The known (IPr)Cu(Ot-Bu) reacts rapidly with bis(pinacolato)-
diboron (pinB-Bpin), forming a product identified as (IPr)Cu(Bpin)
(1, Scheme 1) by 1H and 11B NMR spectroscopy. Diffusion of
hexane vapor into a concentrated solution of 1 in toluene, carried
out at -40 °C to avoid thermal decomposition,18 produces single
crystals suitable for analysis by X-ray diffraction. The resulting
structure (Figure 1a) shows a monomeric, nearly linear coordination
geometry with a Cu-B distance of 2.002(3) Å.
Complex 1 reacts with CO2 under atmospheric pressure in C6D6
conversion of 1 to 2. The sole labeled products visible in the
NMR spectrum (Figure 2b) are 13CO (δ 184 ppm) and an ad
(δ 164 ppm) formed reversibly from CO and borate 2.20
Treatment of 2 in C6D6 solution with pinB-Bpin smo
regenerates 1, forming the stable byproduct pinB-O-Bpin,21
a reaction time of about 20 min. The success of this turnover
closes a catalytic cycle for the deoxygenation of CO2. Additio
a THF solution of (IPr)Cu(Ot-Bu) to a 100-fold excess of pi
Scheme 1 a
a Isolated yield, contains some 2 (5 mol % by 11B NMR); (b) react
complete in <10 min at ambient temp; (c) L ) IPr or ICy.
Figure 1. X-ray crystal structures, shown as 50% thermal ellipsoid
boryl complex 1‚C6H14 (a), and borate 2‚C7H8 (b). Hydrogen atoms (c
and solvent are omitted for clarity. Selected bond lengths (Å) and a
(deg), (a): Cu(1)-B(1) 2.002(3), Cu(1)-C(1) 1.937(2), C(1)-N(1) 1.3
C(1)-N(2) 1.363(3), C(1)-Cu(1)-B(1) 168.07(16), N(1)-C(1)-
102.97(18); (b): Cu(1)-O(1) 1.8096(16), O(1)-B(1) 1.306(3), Cu
C(1) 1.857(2), C(1)-N(1) 1.355(3), C(1)-N(2) 1.364(3), C(1)-Cu
O(1) 174.85(10), B(1)-O(1)-Cu(1) 133.61(16), N(1)-C(1)-N(2) 103.0
NN
Cu
tBuO
iPr
iPr
iPr
iPr
NN
Cu
iPr
iPr
iPr
iPr
B(pin)
(pin)B-B(pin)
Laitar, D. S.; Müller, P.; Sadighi, J. P. J. Am. Chem. Soc. 2005, 127, 17197.

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition
X X X X
X
X

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition
X X X X
X
X
Ito, 2000–
Miyaura, 2000–
Yun, 2006–
Marder, 2007–
Molander, 2008–
Kanai, 2009–
Hoveyda, 2009–
Santos, 2010–
McQuade, 2010–
Cordova, 2011–
Hall, 2010–
Carretero, 2011–
Fernandez, 2011–
Lam, 2012–
Kobayashi, 2012–
Tsuji, 2012–
de Vries, 2012–
Ma, 2010–
Zhu, 2013–
Caser, 2013–
Chun, 2013–
Yoshida, 2014–
Xiao and Fu, 2015–
Feringa, 2015–
Quiling, 2015–……
> 180 publications

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition
X X X X
X
Ito, 2000–
Miyaura, 2000–
Yun, 2006–
Marder, 2007–
Molander, 2008–
Kanai, 2009–
Hoveyda, 2009–
Santos, 2010–
McQuade, 2010–
Cordova, 2011–
Hall, 2010–
Carretero, 2011–
Fernandez, 2011–
Lam, 2012–
Kobayashi, 2012–
Tsuji, 2012–
de Vries, 2012–
Ma, 2010–
Zhu, 2013–
Caser, 2013–
Chun, 2013–
Yoshida, 2014–
Feringa, 2015–
> 180 publications

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition
X X X X
Ito, 2000–
Miyaura, 2000–
Yun, 2006–
Marder, 2007–
Molander, 2008–
Kanai, 2009–
Hoveyda, 2009–
Santos, 2010–
McQuade, 2010–
Cordova, 2011–
Hall, 2010–
Carretero, 2011–
Fernandez, 2011–
Lam, 2012–
Kobayashi, 2012–
Tsuji, 2012–
de Vries, 2012–
Ma, 2010–
Zhu, 2013–
Caser, 2013–
Chun, 2013–
Yoshida, 2014–
Feringa, 2015–
> 180 publications

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition
X X X
Ito, 2000–
Miyaura, 2000–
Yun, 2006–
Marder, 2007–
Molander, 2008–
Kanai, 2009–
Hoveyda, 2009–
Santos, 2010–
McQuade, 2010–
Cordova, 2011–
Hall, 2010–
Carretero, 2011–
Fernandez, 2011–
Lam, 2012–
Kobayashi, 2012–
Tsuji, 2012–
de Vries, 2012–
Ma, 2010–
Zhu, 2013–
Caser, 2013–
Chun, 2013–
Yoshida, 2014–
Feringa, 2015–
> 180 publications

Allylic Substitutions, Meso- and Propargyls

Ito, H.; Okura, T.; Matsuura, K.; Sawamura, M. Angew. Chem., Int. Ed. 2010, 49, 560.
RO
(pin)B
diboron
Cu(O-t-Bu)/
(R,R)-QuinoxP*
(5.0 mol %)
base
H2O
iPrOCO2
H
Ph
OH
PhCHO (1.0 eq.)
0 °C, 18 h
rt, 2 hRO- = i-PrOCO2 87%, 97% ee
dr >99:1
ORRO

RO
(pin)B
diboron
Cu(O-t-Bu)/
(R,R)-QuinoxP*
(5.0 mol %)
base
H2O
iPrOCO2
H
Ph
OH
PhCHO (1.0 eq.)
0 °C, 18 h
rt, 2 hRO- = i-PrOCO2 87%, 97% ee
dr >99:1
ORRO
OTIPS
N
N
N
N
NH2
Cl
Anti Virus Drug Precursor
H
OTBS
CO2Me
OH
H
97% ee, >98% ds
Four Chiral Centers

RO
(pin)B
diboron
Cu(O-t-Bu)/
(R,R)-QuinoxP*
(5.0 mol %)
base
H2O
iPrOCO2
H
Ph
OH
PhCHO (1.0 eq.)
0 °C, 18 h
rt, 2 hRO- = i-PrOCO2 87%, 97% ee
dr >99:1
ORRO
CCC
Bu
B(pin)
Me
H
74%, 97% ee
10 mol %
Cu(O-t-Bu)/Xantphos
THF, 50 °C, 5 h
97% ee
Me
C
C C Bu
OCO2Me
H
(S)
(S)
2.0 equiv.
O
B
O
O
B
O
+
■ Allenylboron compounds with high ee.
Ito, H.; Sasaki, Y.; Sawamura, M., J. Am. Chem. Soc. 2008, 130, 15774.
OTIPS
N
N
N
N
NH2
Cl
Anti Virus Drug Precursor
H
OTBS
CO2Me
OH
H
97% ee, >98% ds
Four Chiral Centers

Ito, H; Kunii, S; Sawamura, M. Nature Chem. 2010, 2, 972.
Cu(O-t-Bu)
(R,R)-QuinoxP*
(5.0 mol %)
(pin)B B(pin)
(1.5 equiv)
Et2O, 24 h
OCH3
Ph
racemic 98% yield
97% ee
Ph
B
O
O
Direct Enantio-Convergent Reaction

Cu(O-t-Bu)
(R,R)-QuinoxP*
(5.0 mol %)
(pin)B B(pin)
(1.5 equiv)
Et2O, 24 h
OCH3
Ph
racemic 98% yield
97% ee
Ph
B
O
O
OCH3
Ph
CH3O
Ph
OCH3
Ph
CH3O Ph
racemic
Cu
B
L*
Cu
B
L*
Ph
B
O
O
anti-SN2'
syn-SN2'
■ One catalyst converge two substrate enantiomers into one product  
enantiomer.

Cu(O-t-Bu)
(R,R)-QuinoxP*
(5.0 mol %)
(pin)B B(pin)
(1.5 equiv)
Et2O, 24 h
OCH3
Ph
racemic 98% yield
97% ee
Ph
B
O
O
PhCHO
Ph
B
C
O
H
Ph Ph
HO
Ph
85% yield, 97% ee
OCH3
Ph
CH3O
Ph
OCH3
Ph
CH3O Ph
racemic
Cu
B
L*
Cu
B
L*
Ph
B
O
O
anti-SN2'
syn-SN2'
■ One catalyst converge two substrate enantiomers into one product  
enantiomer.

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition
X X X

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition
X X

Cu(I) cat.
(pin)B–B(pin)
Cu BL
OR
RO
RE
RE
RO
RE
Cu B
L
B(pin)
RE
RE = SiR3, Ar
β LCuOR+
Asymmetric Borylative Cyclizations

Cu(I) cat.
(pin)B–B(pin)
Cu BL
OR
RO
RE
RE
RO
RE
Cu B
L
B(pin)
RE
RE = SiR3, Ar
β LCuOR+
(pin)B B(pin)
Cu(O-t-Bu) / ligand
R X
THF, 30 °C
B(pin)
R
R = R3Si, Ar, HetAr
B(pin)
N
Boc
B(pin)
S
B(pin)
70%, 92% ee90%, 92% ee 70%, 92% ee
X = OCO2R, OPO(OR)2
B(pin)
Me3Si
94%, 94% ee
B(pin)
BnMe2Si
83%, 94% ee
Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M. Angew. Chem., Int. Ed. 2008, 47, 7424.
Zhong, C.; Kunii, S.; Kosaka, Y.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 11440.
Asymmetric Borylative Cyclizations

a The endo-cyclization product was detected (7%).
(pin)B
4 h, 86%
(pin)B
Me
Me
4 h, 90%
(pin)B
4 h, 84%
(pin)B
6 h, 87%
d.r. = 1.1:1
Si(pin)B
Me
Me
4 h, 74%a
5 mol % CuCl
5 mol % Xantphos
(pin)B-B(pin) (1.2 equiv)
K(O-t-Bu) (1.2 equiv)
THF, 30 °C
n
C
C
Cu
(pin)B
– CuBr
C n
n = 1−3 n = 1−3
C
C
Br
Br C
(pin)B
L
complex mixtureb
Br
(pin)B
4 h, 95%
d.r. = 1.4:1
(pin)B
Me
Me
4 h, 83%
Kubota, K.; Yamamoto, E.; Ito, H. J. Am. Chem. Soc. 2013, 135, 2635.
b The six-membered ring product was detected (4%).
Borylative Cyclization of Terminal Alkenes

B
B
88%
O
O
O
O
O
B
O
B
O
O
(1.2 equiv)
Br
Br
+
10 mol % CuCl
10 mol % Xantphos
THF, 30 °C, 4 h
High exo/endo selectivity
Spiro Compounds

5 mol % CuCl / Xantphos
t-BuOK (1.2 equiv)
THF, 30 °C, 4 h, 82%
B(pin)
N
S
O O
N
S
O O
Br
Borylative cyclization
Short Synthesis of Drug Candidate

5 mol % CuCl / Xantphos
t-BuOK (1.2 equiv)
THF, 30 °C, 4 h, 82%
B(pin)
N
S
O O
N
S
O O
Br
Borylative cyclization
1. NaBO3/4H2O
THF/H2O, rt, 1 h
2. Jones Reagent
acetone, 0 °C, 1 h
64% (2 steps)
C-O Bond formation
Condensation
Histamine H3 Receptor Ligand
O
N
S
O O
HO
O
N
S
O O
N
N
NHN
HBTU, iPr2NEt
DMF, rt, 2 h, 91%
Short Synthesis of Drug Candidate

v
■ First Asymmetric 1,2-Monoborylation of 1,3-Dienes
Sasaki, Y.; Zhong, C.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226.
(pin)B (pin)B+
THF, MeOH (2.0 equiv)
–40°C, 24.5h
Cu(O-t-Bu)–(R,R)-Me-DuPhos
(5.0 mol %)
(pin)B B(pin) (1.5 equiv)
96%, 96% ee, dr >99:1
H
Asymmteric Monoboryaltion

v
(pin)B (pin)B+
–40°C, 24.5h
(5.0 mol %)
96%, 96% ee, dr >99:1
H
(pin)B (pin)B
96 % ee
chiral Cu catalyst
B2(pin)2(1.5 equiv)
THF, t-BuOH (5.0 equiv)
room temp.77% (dr 92:8)
chiral Cu catalyst
B2(pin)2(1.5 equiv)
–40°C 87% (dr 7:93)

v
(pin)B (pin)B+
–40°C, 24.5h
(5.0 mol %)
96%, 96% ee, dr >99:1
H
v Me
Me
BuB(pin) B(pin)
BuMe
Bu
cat. Cu(OtBu)
/diphosphine
(pin)B B(pin)
THF, MeOH
cat. Cu(OtBu)
/PPh3
(pin)B B(pin)
THF, MeOHup to 84% ee
■ Enantio- and Regioselective Borylation of 1,3-Enynes
Sasaki, Y.; Horita, Y.; Zhong, C.; Sawamura, M.; Ito, H. Angew. Chem., Int. Edit. 2011, 50, 2778.
(pin)B (pin)B
96 % ee
chiral Cu catalyst
B2(pin)2(1.5 equiv)
THF, t-BuOH (5.0 equiv)
room temp.77% (dr 92:8)
chiral Cu catalyst
B2(pin)2(1.5 equiv)
–40°C 87% (dr 7:93)

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition
X

Boryl Substitution of C(sp3)−X
Br +
CuCl / Xantphos (3 mol %)
THF, rt
B(pin)Alkyl AlkylB B
O
OO
O
1.2 equiv
B(pin)
B(pin)
4 h, 85% 5 h, 91%
B(pin)
5 h, 90%
B(pin)
44 h, 0%
B(pin)
48 h, 17%
B(pin)
5 h, 51%
B(pin)
B(pin)
24 h, 62%a
B(pin)B(pin)
30 h, 68%a
aReaction was carried out at 40°C with 15 mol % of catalyst, 2.2 equiv of B2pin2 and 2.0 equiv
of base.
B(pin)
5 h, 84%
B(pin)
4 h, 92%
Alkyl X Alkyl B
Cu cat.
B B
O
OO
O
+
X = Cl, Br, I
O
O
base
Alkyl MgX or Li
XB(pin)
CuCl / Xantphos: Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890.  
CuI / PPh3: Yang, C.-T.; Steel, P. G.; Marder, T. B.; Liu, L. et al. Angew. Chem., Int. Ed. 2012, 51, 528.
K. Kubota

Boryl Substitution of C(sp3)−X
Br +
CuCl / Xantphos (3 mol %)
THF, rt
B(pin)Alkyl AlkylB B
O
OO
O
1.2 equiv
B(pin)
B(pin)
4 h, 85% 5 h, 91%
B(pin)
5 h, 90%
B(pin)
44 h, 0%
B(pin)
48 h, 17%
B(pin)
5 h, 51%
B(pin)
B(pin)
24 h, 62%a
B(pin)B(pin)
30 h, 68%a
aReaction was carried out at 40°C with 15 mol % of catalyst, 2.2 equiv of B2pin2 and 2.0 equiv
of base.
B(pin)
5 h, 84%
B(pin)
4 h, 92%
Alkyl X Alkyl B
Cu cat.
B B
O
OO
O
+
X = Cl, Br, I
O
O
base
Alkyl MgX or Li
XB(pin)
CuCl / Xantphos: Ito, H.; Kubota, K. Org. Lett. 2012, 14, 890.  
CuI / PPh3: Yang, C.-T.; Steel, P. G.; Marder, T. B.; Liu, L. et al. Angew. Chem., Int. Ed. 2012, 51, 528.
Ni catalyst: Dudnik, A. S.; Fu, G. C. J. Am. Chem. Soc. 2012, 134, 10693.
Pd catalyst: Joshi-Pangu, A.; Ma, X.; Diane, M.; Iqbal, S.; Kribs, R. J.; Huang, R.;
Wang, C.-Y.; Biscoe, M. R. J. Org. Chem. 2012, 77, 6629.
Pd, Ni catalyst: Yi, J.; Liu, J. H.; Liang, J.; Dai, J. J.; Yang, C.-T.; Fu, Y.; Liu, L.  
Adv. Synth. Catal. 2012, 354, 1685.
Fe catalyst: Atack, T. C.; Lecker, R. M.; Cook, S. P. J. Am. Chem. Soc. 2014.
Zn catalyst: Bose, S. K.; Fucke, K.; Liu, L.; Steel, P. G.; Marder, T. B.
Angew. Chem., Int. Edit. 2014, 53, 1799.
◼ Very Simple Reaction, and Competitive!
K. Kubota

Cu B
O
O
L
C C
C C
C C
Cu B
or
C C
H B
C C
B
C C
B
X
Cu
C C
BCu
X
C C
B
n
Cu ORL
(pin)B B(pin)
C C
E B
H+
or
E
R X
Ar X
or
R B
O
O
O
C
R'R
N
C
R'R
R''
or
C
R'R
OHB
C
R'R
NHR"B
Catalysis Design
allylic 
substitution
borylative
cyclization
alkyl-, aryl-
substitution
aldehyde, imine
addition

■
Latitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006, 128, 11036.
O
H
1.0 mol % ICyCu(O-t-Bu)
(pin)B−B(pin), toluene
86%
O
B(pin)
B(pin)
Catalytic diboration
(pin)B−B(pin)
MeOH, toluene
O
H
1.5 mol %
ICyCu(O-t-Bu) OH
B(pin)
crude product
KHF2
MeOH/H2O
OH
BF3K
81%
Molander, G. A.; Wisnieski, S. R. J. Am. Chem. Soc. 2012, 134, 16856.
■ Catalytic monoborylation
N N
ICy
Copper(I)-Catalyzed Carbonyl Borylation

Enantioselective borylation
L*M
B C
R
H
B OM
Enantioenriched
α-alkoxyalkylboronates
O
C
R
H
Boryl nucleophile
Enantioselective nucleophilic borylation of a C=O double bond
has not ever been achieved.
■
Enantioselective Borylation of Aldehydes

R
O
B(pin)
B(pin)
R
OH
BF3K
Low stability Low solubility
Sadighi, J. Am. Chem. Soc. 2006 Molander, J. Am. Chem. Soc. 2012
R
O
H
L*CuCl
K(O-t-Bu)
THF
(pin)B−B(pin)
R H
BHO O
O
unstable
R H
BPGO O
Oprotection
Our approach for isolation
High stability
High solubility
■ Not suitable for HPLC analysis to determine ee values
✓
cf. Moore, C. M.; Medina, C. R.; Cannameia, P. C.; Mclntosh, M. L.; Ferber, C. J.; Roering, A. J.;
Clark, T. B. Org. Lett. 2014, 16, 6056.
alcohol
Protection for HPLC Analysis

H
B(pin)BnO
Ph H
B(pin)MeO
Ph H
B(pin)O
Ph
Ph
O
H
B(pin)O
Ph
Me2N
O
H
B(pin)Me3SiO
Ph
BnBr, NaH
26%
Me3OBF4
28%
(PhCO)2O, DMAP
20%
Me2NCOCl, pyridine
complex mixture
Me3SiCl, imidazole
64%
Ph H
O
CuCl (2 mol %)
ICy⋅HCl (2 mol %)
(pin)B−B(pin) (1.0 equiv)
K(O-t-Bu) (10 mol %)
MeOH (2.0 equiv), THF
R H
B(pin)HO
not isolated
protection
H
B(pin)PGO
isolated yield (%)
Ph
then silica gel short column
Protection for HPLC Analysis
K. Kubota

Ph
O
1. CuCl / L* (5 mol %)
MeOH (2.0 equiv)
THF, 30 °C, 6 h
2. BnMe2SiCl, imidazole
CH2Cl2, 3 h
Ph HH
BnMe2SiO B
(S)
NMR yield (%)
B B
O
O O
O
+
1.0 equiv
O
O
Chiral Ligand Screening

Ph
O
1. CuCl / L* (5 mol %)
MeOH (2.0 equiv)
THF, 30 °C, 6 h
2. BnMe2SiCl, imidazole
CH2Cl2, 3 h
Ph HH
BnMe2SiO B
(S)
NMR yield (%)
B B
O
O O
O
+
1.0 equiv
O
O
O
O
O
O
P
P
tBu
OMe
tBu
tBu
OMe
tBu
2
2
(R)-DTBM-SEGPHOS
72%, 96% ee
O
O
O
O
P
P
Me
Me
Me
Me
2
2
(R)-DM-SEGPHOS
71%, 32% ee
(R)-SEGPHOS
74%, 24% ee
O
O
O
O
P
P
2
2
larger steric hinderance
higher enantioselectivity
Chiral Ligand Screening

coordination
σ-bond
metathesis
protonation
enantioselective
insertion
P
P
= (R)-DTBM-SEGPHOS
DFT: Kubota, K.; Jin, M.; Ito, H. Organometallics, under revision.
cf. Zhao, H.; Dang, L.; Marder, T. B.; Lin, Z. J. Am. Chem. Soc. 2008, 130, 5586.
Cu B(pin)
P
P
Cu
B(pin)
P
P
O C
H
R
O C
Cu
R
B(pin)
H
P
P
Cu OR
P
P R = OMe or
O-t-Bu
O C
H
R
(pin)B−B(pin)
MeOH
(pin)B−OR
A
B
C
DO C
R
B(pin)
H
H
Points not elucidated
1. Mechanism of enantioselection
2. Effect of proton source
Proposed Reaction Mechanism
M. Jing
K. Kubota

Cu
B
P P
O
H
H
H
Cu
B
P P
O
H
H
H
Ph Ph
Ph Ph
Ph
Ph Ph
Ph
Si-face TS (favored) Re-face TS (disfavored)
０ kcal/mol +1.04 kcal/mol
<
B3PW91/cc-PVDZ , Relative G value (kcal/mol) at 298 K, 1.0 atm, gas phase.
Observed result
24% ee
Enantioselection Models [(R)-SEGPHOS]

Cu
B
P P
O
H
H
H
Cu
B
P P
O
H
H
H
Ar
Ar
Ar Ar
Ar
Ar Ar
Ar
Si-face TS (favored) Re-face TS (disfavored)
０ kcal/mol +1.97 kcal/mol
<
observed result
96% ee
Models for [(R)-DTBM-SEGPHOS]
B3PW91/cc-PVDZ , Relative G value (kcal/mol) at 298 K, 1.0 atm, gas phase.

R
O
1. 5 mol % CuCl/
(R)-DTBM-SEGPHOS
MeOH (2.0 equiv)
THF, 30 °C, 6 h
2. R3SiCl, imidazole
CH2Cl2, 3 h
H
B B
O
O O
O
+
1.0 equiv
R H
R3SiO B
(S)
isolated yield (%)
O
O
B(pin)Me3SiO
H
B(pin)Me3SiO
H
B(pin)Me3SiO
H
51%, 96% ee 61%, 95% ee 84%, 95% ee 61%, 96% ee
B(pin)HO
H
B(pin)BnMe2SiO
H
N
B(pin)Me3SiO
H
N
Boc Ts
81%, 95% ee 52%, 91% ee
B(pin)BnMe2SiO
H
69%, 90% ee
BzO
B(pin)BnMe2SiO
H
69%, 95% ee
BnO
Borylation of Various Aldehydes

H
O
H
B(pin)HO
CuCl / L* (5 mol %)
MeOH (2.0 equiv)
THF (0.5 M), 30 °C, 6 h
Ph2MeSiCl
imidazole
CH2Cl2, 3 h
>99% conversion
L* = (R)-DTBM-SEGPHOS
H
B(pin)Ph2MeSiO
22% yield
99% ee
H
BF3KHO
KHF2 (4.0 equiv)
MeOH/H2O, 30 min
71% yield
■ Poor stability of the product toward silica gel column
Good isolated yield (71%) by converting into tri]luoroborate■
Aromatic Aldehyde Case: Unstable

CuCl / ligand (5 mol %)
MeOH (2.0 equiv)
solvent, 30 °C, 18 h
then Me3SiCl
imidazole, 3 h (R,S)
H
O
Me
TBSO
B(pin)
OSiMe3
Me
TBSO
(R,R)
B(pin)
OSiMe3
Me
TBSO
+
(R)
α-Stereocenter
ICy⋅HCl (2 mol %), toluene: 69%, (R,S):(R,R) = 30:70
(R)-DTBM-SEGPHOS, THF: 73%, (R,S):(R,R) = 89:11
(S)-DTBM-SEGPHOS, THF: 77%, (R,S):(R,R) = 5:>95
■ Catalyst-controlled selectivity over substrate vias
Catalyst Controlled Reaction

For a review of Matteson homologation chemistry: Matteson, D. S. Tetrahedron 1998, 54, 10555.
cf. Sadhu, K. M.; Matteson, D. S. Organometallics 1985, 4, 1687.
Stereospeci@ic C(sp3)-C(sp3) bond formation;
One-carbon homologation
Larouche-Gauthier, R.; Elfold, T. G.; Aggarval, V. K. J. Am. Chem. Soc. 2011, 133, 16794.
Ph H
B(pin)BnMe2SiO
96% ee
ClCH2Br
n-BuLi
THF
−78 °C→rt
3 h
Ph H
BnMe2SiO B(pin)
92%, 96% ee
H2O2
NaOH Ph H
HO OH
77%, 96% ee
chiral 1,2-diol
chiral 1,2-haloalcohol
Ph H
R3SiO Br
80%, 96% ee
3,5-(CF3)2C6H3Li
then NBS, −78 °C
Useful intermediate
chiral β-alkoxyboron
Stereospeci]ic Functionalization

H
(pin)B OSiMe3
95% ee
(S)
Benzofuran (1.2 equiv)
n-BuLi (1.2 equiv)
THF, −78 °C, 1 h
NBS (1.2 equiv)
−78 °C, 1 h
then TBAF, 2 hH
Li
H
52%, 95% ee
(pin)B OSiMe3
O
OH
O
(R)
Bonet, A.; Odachowski, M.; Leonori, D.; Essafi, S.; Aggarwal, V. K. Nature. Chem. 2014, 6, 584.
Stereospeci@ic C(sp3)-C(sp2) bond formation;
Cross-coupling with a heteroaromatic compound
Aggarwal Arylation

Chiral NHC/copper(I)
complex catalyst
HO B O
O
Ph *
59%, 9% ee
HO B O
O
*Ph
62%, 9% ee
HO B O
O
*
no reaction
Unsuccessful
substrates
O
B B
O
O O
O
+
1.0 equiv
5 mol % CuCl / L*
NNL* =
BF4
HO B O
O
*
47%, 98% ee
10 mol % K(O-t-Bu)
MeOH (2.0 equiv)
toluene/THF, rt, 4 h
Enantioselective Borylation of Ketones

N
H
F
O
O
O
(−)-paroxetine N
N
N
N
N
OPh
NH2
O ibrutinib
WAY-163909
N
N
H
N
OH
(−)-preclamol
N
N
Me
H
Me
Me
O
H
N
O
Me
(−)-Physostigmine
Novel Boron Reagents for Alkaloid Synthesis
N OH
(–)-preclamol
N
O
Ph
PhO
O zamifenacine
ibrutinib
Pyridine and its Derivatives in Heterocycles in Natural Product Synthesis, Majumdar, K. C.; Chattopadhyay, S. K., Ed.;
Wiley-VCH, Weinheim, 2011, Chap. 8, pp. 267.

N
H
F
O
O
O
(−)-paroxetine N
N
N
N
N
OPh
NH2
O ibrutinib
WAY-163909
N
N
H
N
OH
(−)-preclamol
N
N
Me
H
Me
Me
O
H
N
O
Me
(−)-Physostigmine
N OH
(–)-preclamol
N
O
Ph
PhO
O zamifenacine
ibrutinib
N-Heterocyclic borons
N
H
B
R
N
H
R1
B
R

N
H
F
O
O
O
(−)-paroxetine N
N
N
N
N
OPh
NH2
O ibrutinib
WAY-163909
N
N
H
N
OH
(−)-preclamol
N
N
Me
H
Me
Me
O
H
N
O
Me
(−)-Physostigmine
*LCu B
N
R3
R1
R2
N
R1
R2
Novel enantioselective
borylation
Abundant, cheap and
readily available
N OH
(–)-preclamol
N
O
Ph
PhO
O zamifenacine
ibrutinib
N-Heterocyclic borons
N
H
B
R
N
H
R1
B
R

Hydrogenation
Electrophilic allylic substitution
Kuwano, R.; Sato, K.; Kurokawa, T.; Karube, D.; Ito, Y. J. Am. Chem. Soc. 2000, 122, 7614.
Trost, B. M.; Quancard, J. J. Am. Chem. Soc. 2006, 128, 6314.
Trost ligand
(S,S)-(R,R)-PhTRAP
Fe
Fe
PPh2PPh2
O
N
H
HN O
Ph2P
PPh2
2.5 mol % Pd2(dba)3CHCl3
7.5 mol % chiral ligand
9-BBN-C6H13 (1.05 equiv)
CH2Cl2, 4 °C
N
H
N
+
HO
MeO
MeO
3 equiv
92%, 85% ee
1.0 mol % [Rh(nbd)2]SbF6
1.05 mol % PhTRAP
10 mol % Cs2CO3
i-PrOH, H2 (5.0 MPa)
60 °C, 2 h
N
Ac
N
Ac
91%, 91% ee
Asymmetric Dearomatizations

Kubota, K.; Hayama, K.; Iwamoto, H.; Ito, H. Angew. Chem., Int. Ed. 2015, 30, 8809.
The ﬁrst enantioselective carbon-boron bond forming dearomatization by copper(I) catalysis✓
Direct synthesis of chiral boryl-indolines from readily available indoles✓
N
O
OMe
Cbz
+ B B
2.0 equiv
O
OO
O
10 mol % Cu(O-t-Bu) / L*
10 mol % Na(O-t-Bu)
t-BuOH (2.0 equiv)
THF, 30 °C, 20 h
N
Cbz
B(pin)
OMe
O
98%, d.r. 97:3
93% ee
P P
Me
Me
Me
Me
Me
Me
Me
Me
L* = (R,R)-xyl-BDPP
Enantioselective Borylative Dearomatization

Coordinationσ-Bond
metathesis
Diastereoselective
protonation
3,4-Addition and
toutomerization
Steric
repulsion
Cu B
P
P
P
P
= (R,R)-xyl-BDPP
(pin)B−(O-t-Bu)
N
Cbz
O
OMe
Cu B
PP
N
Cbz
O
OMeB
P
P
N
Cbz
O
OMeB
H
O
H
O
Cu(O-t-Bu)
P
P
diboron
substrate
HO
disfavored
favored
Cu
Cu
P
P
A
B
C
D
E
N
Cbz
B(pin)
OMe
OH

Coordinationσ-Bond
metathesis
Diastereoselective
protonation
3,4-Addition and
toutomerization
Steric
repulsion
Cu B
P
P
P
P
= (R,R)-xyl-BDPP
(pin)B−(O-t-Bu)
N
Cbz
O
OMe
Cu B
PP
N
Cbz
O
OMeB
P
P
N
Cbz
O
OMeB
H
O
H
O
Cu(O-t-Bu)
P
P
diboron
substrate
HO
disfavored
favored
Cu
Cu
P
P
A
B
C
D
E
N
Cbz
B(pin)
OMe
OH
MeOH: 94%, 94% ee
d.r. 75:25
t-BuOH: 98%, 93% ee
d.r. 97:3

10 mol % Cu(O-t-Bu)
10 mol % chiral ligand
10 mol % Na(O-t-Bu)
N
O
OMe
Cbz
N
O
OMe
Cbz
B(pin)
0.5 mmol
+
O
B
O
B
O
O
2.0 equiv
t-BuOH (2.0 equiv)
THF, 30 °C, 18−48 h
NMR yield (%)
PP
Me
Me
Me
Me
Me
Me
Me
Me PP
P
P
Me
Me
Me
Me
(R,R)-BenzP*
77%, d.r. 91:9
61% ee
(R,R)-Me-Duphos
71%, d.r. 97:3
37% ee
P
P
Me
tBu
tBu
Me
N
N P
P
Me
tBu
tBu
Me
(R,R)-3,5-xyl-BDPP
98%, d.r. 97:3
93% ee
(R,R)-BDPP
98%, d.r. 89:11
74% ee
(R,R)-QuinoxP*
93%, d.r. 90:10
27% ee
Ligand Screening
Kubota, K.; Hayama, K. Ito, H. Angew. Chem., Int. Ed. 2015, 54, 8809.

N
Cbz
B(pin)
OMe
OF
93% yield
d.r. 97:3, 95% ee
N
Cbz
B(pin)
OMe
OCl
93% yield
d.r. 93:7, 95% ee
N
Cbz
B(pin)
OMe
OBr
96% yield
d.r. 97:3, 92% ee
N
Cbz
B(pin)
OMe
OMeO
99% yield
d.r. 97:3, 97% ee
N
Cbz
B(pin)
OMe
O
88% yield
d.r. 97:3, 93% ee
MeO N
Cbz
B(pin)
OMe
O
99% yield
d.r. 93:7, 86% ee
Br N
Cbz
B(pin)
OMe
O
82% yield
d.r. 83:17, 89% ee
N
O
OMe
Cbz
10 mol % Cu(O-t-Bu)
10 mol % (R,R)-xyl-BDPP
B2(pin)2 (2.0 equiv)
10 mol % Na(O-t-Bu)
t-BuOH (2.0 equiv)
THF, 30 °C, 4−18 h
N
Cbz
B(pin)
OMe
O
R1
R2
R1
R2
Borylative Dearomatization of Various Indoles

CuCl (5 mol %)
Xantphos (5 mol %)
ClCO2Me (1.0 equiv)
K(O-t-Bu)/THF (1.0 equiv)
MeOH (2.0 equiv), rt,
N
+ B B
1.2 equiv
O
OO
O
N
MeO
O
B
O O
detected by GC-Mass
decomposed during purification
predicted structures
N
MeO
O
B
O
O+Possible intermediate
NO
MeO
Cl
O
P
P
Ph Ph
Ph Ph
CuBvia
Kubota, K.; Watanabe, Y.; Hayama, K.; Ito, H. Submitted.
Initial Attempt for Chiral Boryl-Piperidine

cat. Cu/L*
B2(pin)2
alkoxide base
alcohol
N N
RO
O
ClCO2R
hydride
source
N
RO
O
N
RO
O
B(pin)
B(pin)
N
RO
O
(pin)B
N
RO
O
B(pin)
*
*
*
*
Regioselective? Enantioselective?
No examples of selective borylation
of conjugated dienamines
ClCO2R
NaBH4 or
LiBH4
✓
✓
cat. Cu(I)/L*
B2(pin)2
alkoxide base
alcohol
Alternative Strategy: Sequencial Method

cat. Cu/L*
B2(pin)2
alkoxide base
alcohol
N N
RO
O
ClCO2R
hydride
source
N
RO
O
N
RO
O
B(pin)
B(pin)
N
RO
O
(pin)B
N
RO
O
B(pin)
*
*
*
*
Regioselective? Enantioselective?
No examples of selective borylation
of conjugated dienamines
ClCO2R
NaBH4 or
LiBH4
✓
✓
cat. Cu(I)/L*
B2(pin)2
alkoxide base
alcohol
MeOH (2.0 equiv)
THF,−20 °C, 22 h
5 mol%
Cu(O-t-Bu)/
(R,R)-Me-Duphos
90%, 95% ee
B(pin)
P
P
Me
Me
Me
Me
(R,R)-Me-Duphos
+ B B
1.5 equiv
O
OO
O
cf. Enantioselective monoborylation of carbocyclic dienes
10 mol %
Cu(O-t-Bu)/
(R,R)-Me-Duphos
MeOH (1.0 equiv)
THF, –20 °C, 22 h
90%, 95% ee
P
P
Me
Me
Me
Me
(R,R)-Me-Duphos
Alternative Strategy: Sequencial Method

Pyridines to 3-Substituted Piperidines
CuCl (5 mol %)
chiral ligand (5 mol %)
3 (1.2 equiv)
MeOH (2 equiv)
THF, temp., 2-4 h2a (R)-4a
NaBH4
ClCO2Me
MeOH
−78 °C
1 h, 71%1a
N
NO
MeO
NO
MeO
B(pin)
P
P
Me tBu
tBu Me
(R,R)-BenzP*
92%, 98% ee
N
N P
P
Me tBu
tBu Me
(R,R)-QuinoxP*
93%, 99% ee
O
O
O
O
PPh2
PPh2
(R)-SEGPHOS, <5%
P
P
Me
Me
Me
Me
(R,R)-Me-Duphos
83%, 93% ee
PPh2
PPh2
(R)-SEGPHOS, <5%

NaBH4 or
LiBH4
ClCO2R3
MeOH
−78 °C
N
R3O
O
R1
R2 5 mol % CuCl/
(R,R)-QuinoxP*
MeOH (2.0 equiv)
THF, –10 °C, 2 h
N
R3O
O
R1
R2
B(pin)
76%, 97% ee
N
BnO
O
B(pin)
N
MeO
O
B(pin)
93%, 99% ee
N
O
O
B(pin)
88%, 98% ee
N
O
O
B(pin)
90%, 97% ee
N
PhO
O
B(pin)
84%, 93% ee
N
O
O
B(pin)
91%, 97% ee
N
MeO
O
B(pin)
86%, 92% ee
N
MeO
O
B(pin)
67%, 96% ee
Me Me
N
MeO
O
B(pin)
Me
no reaction
76%, 97% ee
N
N P
P
Me tBu
tBu Me
(R,R)-QuinoxP*
93%, 99% ee 88%, 98% ee 90%, 97% ee 76%, 97% ee 84%, 93% ee
91%, 97% ee 86%, 92% ee 67%, 96% ee
Unprecedented Regio- and Enantioselective

CO2Me
eOH
78 °C
N
MeO
O
aBH4
Ar
5 mol % CuCl/
(S)-SEGPHOS
t-BuOH (2.0 equiv)
toluene/DME
0 °C, 2 h
N
MeO
O
Ar
B(pin)
(R)-SEGPHOS
O
O
O
O
PPh2
PPh2
(R)-SEGPHOS
5 mol % CuCl/
(R)-SEGPHOS
t-BuOH (2.0 equiv)
toluene/DME/THF
(6:6:1), 0 °C, 2 h
N
MeO
O
B
O
O
Me
91%, d.r. 98:2
95% ee
N
MeO
O
B
O
O
OMe
82%, d.r. 96:4
96% ee
90%, d.r. 97:3
92% ee
N
MeO
O
B
93%, d.r. 99:1
39% ee
*(R,R)-QuinoxP*
was used.
O
O
N
MeO
O
B
O
O
F
91%, d.r. 96:4
96% ee
*(S)-SEGPHOS
was used.
Diastereo- and Enantioselective Borylation

(−)-Paroxetine
Antidepressant drug
3. MsCl (1.5 equiv)
Et3N (3.0 equiv)
CH2Cl2, 0 °C→rt
1. LiCH2Cl (1.5 equiv)
−78 °C→rt, 3 h
2. NaBO3•4H2O
(4.0 equiv), rt, 1 h
N
MeO
O
B
O
O
d.r. 95:5
96% ee
F
N
MeO
O
F
OMs
77% (3 steps)
d.r. 95:5
O
O
HO
(2 equiv)
Cs2CO3 (4.0 equiv)
MeCN, 90 °C, 2 h
then Pd/C, H2, 12 h
N
MeO
O
F
O
67% (2 steps)
d.r. >95:5, 94% ee
O
O
KOH (30 equiv)
EtOH/H2O (4:1)
100 °C, 42 h
HN
F
O
61% O
O
d.r. 96:4
96% ee
77% (3 steps)
d.r. 96:4
67% (2 steps)
d.r. >95:5, 94% ee
61%
Hynes, P. S.; Stupple, P. A.; Dixon, D. J. Org. Lett. 2008, 10, 1389.
Krautwald, S.; Schafroth, M. A.; Sarlah, D.; Carreira, E. M. J. Am. Chem. Soc. 2014, 136, 3020.
KOH (30 equiv)
EtOH/H2O (4:1)
reflux, 42 h
d.r. 96:4
96% ee
77% (3 steps)
d.r. 96:4
67% (2 steps)
d.r. >95:5, 94% ee
61%
Diastereo- and Enantioselective Borylation

Cu-Catalyzed Borylation from Our Group
+
cat. CuX
PR3
DMI, rt
H3O+
O
O
B
B B
O
OO
O
O
O
87%

Cu-Catalyzed Borylation from Our Group
R
B
OO
J. Am. Chem. Soc. 2005
B
OR
O
O
Angew. Chem., Int. Ed. 2010
BR O
O
(rac)-
R
B
O
O
C C C
B
Bu
Me
H
O
O
B
O
O
B
O
O
or
B
B
O
O
O
O
B(pin)
Org. Lett. 2012
R
B
O
O
Nature Chem. 2010
Bu
B
O
O
RO
B
OO
B
RSi
O
O
Ph
Ph
Org. Lett. 2010
B(pin)HO
H
N
B(pin)
CO2R

￥Funding￥
MEXT
PRESTO
NEXT
MMC
FCC
Dr. Tatsuo Ishiyama
Dr. Yasunori Yamamoto
Dr. Tomohiro Seki
Dr. Ikuo Sasaki
Dr. Eiji Yamamoto
Prof. Akira Hosomi
Prof. Tsuneo Imamoto
Prof. Masaya Sawamura
Prof. Tetsuya Taketsugu
Prof. Satoshi Maeda
Tomoko Ishizuka
Chika Kawakami
Yuki Kosaka
Shin-ichiro Ito
Kou Mtsuura
Kosuke Nonoyaam
Takashi Toyoda
Dr. Chongmin Zhong
Dr. Yusuke Sasaki
Takuma Okura
Shun Kunii
Koji Kubota
Taichi Ozaki
Yuta Takenouchi
Yuko Horita
Kiyotaka Izumi
Ryoto Kojima
Hiroaki Iwamoto
Satoshi Ukigai
Dr. Ryohei Uematsu
Acknowledgements

Copper-Catalyzed Reactions with Diborons: From the Beginning to Recent Results

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Copper-Catalyzed Reactions with Diborons: From the Beginning to Recent Results