Metal-catalyzed reactions of organoboronic acids and esters

Article abstract of DOI:10.1246/bcsj.81.1535

Metal-catalyzed B-C and C-C bond-forming reactions of organoboronic acids that have been pursued in the past three decades by our group are summarized in this article. B-C bond-forming reactions for the synthesis of organoboronic acid derivatives include metal-catalyzed addition reactions of pinacolborane or catecholborane (hydroboration), bis(pinacolato)diboron (diboration), and alkylthioboranes (thioboration) to alkenes, alkynes, 1,3-alkadienes, or 1,2-alka-dienes (allenes). Other B-C bond-forming reactions include coupling reactions of pinacolborane or bis(pinacolato)dibor-on for borylation of C-halogen bonds with palladium catalysts and C-H bonds of arenes and alkenes with iridium catalysts. These reactions have provided a convenient new access to aryl-, 1-alkenyl-, allyl-, or benzylboronates. Metal-catalyzed C-C and C-N bond-forming reactions using boronic acid derivatives include synthesis of novel cyclic triolborate salts for palladium- or copper-catalyzed cross-coupling reactions with organic halides or amines, rhodium- or palladium-catalyzed 1,4-addition reactions of arylboronic acids to α,β-unsaturated carbonyl compounds and rhodium-catalyzed addition of aryl- and 1-alkenylboronic acids to aldehydes and imines.

Full text of DOI:10.1246/bcsj.81.1535

Ó 2008 The Chemical Society of Japan
Bull. Chem. Soc. Jpn. Vol. 81, No. 12, 1535–1553 (2008) 1535
Award Accounts
The Chemical Society of Japan Award for 2007
Metal-Catalyzed Reactions of Organoboronic Acids and Esters
Norio Miyaura
Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628
Received July 2, 2008; E-mail: miyaura@eng.hokudai.ac.jp
Metal-catalyzed B–C and C–C bond-forming reactions of organoboronic acids that have been pursued in the past
three decades by our group are summarized in this article. B–C bond-forming reactions for the synthesis of organobor-
onic acid derivatives include metal-catalyzed addition reactions of pinacolborane or catecholborane (hydroboration),
bis(pinacolato)diboron (diboration), and alkylthioboranes (thioboration) to alkenes, alkynes, 1,3-alkadienes, or 1,2-alka-
dienes (allenes). Other B–C bond-forming reactions include coupling reactions of pinacolborane or bis(pinacolato)dibor-
on for borylation of C–halogen bonds with palladium catalysts and C–H bonds of arenes and alkenes with iridium cat-
alysts. These reactions have provided a convenient new access to aryl-, 1-alkenyl-, allyl-, or benzylboronates. Metal-cat-
alyzed C–C and C–N bond-forming reactions using boronic acid derivatives include synthesis of novel cyclic triolborate
salts for palladium- or copper-catalyzed cross-coupling reactions with organic halides or amines, rhodium- or palladium-
catalyzed 1,4-addition reactions of arylboronic acids to ꢀ,ꢁ-unsaturated carbonyl compounds and rhodium-catalyzed ad-
dition of aryl- and 1-alkenylboronic acids to aldehydes and imines.
1. Introduction
2. B–C Bond-Forming Reactions for Synthesis
of Organoboronic Acid Derivatives
Until recently, organoboronic acids had limited use in or-
ganic synthesis due to their inertness to ionic and radical reac-
tions. Over the past three decades, however, it has become in-
creasingly clear that they are valuable reagents capable of un-
dergoing many catalytic C–C bond formations in organic syn-
theses.1–4 Boronic acids were positioned as a mainstay of
modern synthetic chemistry by two discoveries in 1979. A dia-
stereoselective addition of allylboronates to aldehydes by
Hoffmann and Zeiss5 and a metal-catalyzed C–C bond-form-
ing reaction (Suzuki coupling)6 by our group have been widely
embraced by synthetic chemists in academia and industry
worldwide because boronic acids are convenient reagents that
are generally thermally stable and are inert to water and oxy-
gen, and because it is easy to remove the inorganic by-products
from the reaction mixture, making the reactions suitable for in-
dustrial processes. These were followed by discoveries of var-
ious C–C, C–N, and C–B bond-forming reactions over the past
two decades including Petasis Mannich reaction (1993),7 met-
al-catalyzed reactions of diborons (1993),8 rhodium-catalyzed
conjugate addition to electron-deficient alkenes (1997),9 cop-
per-promoted arylation of N–H bonds (1998),10 and iridium-
catalyzed C–H borylation of alkanes, alkenes, and arenes
(2000).11 There have also been extensive studies on biological
and medicinal applications of boronic acids for 10B carriers of
neutron capture therapy and proteasome inhibitor for cancer
therapy. Such chemistry of boronic acids is summarized in this
review,12 but this review is mainly restricted to our own efforts
in metal-catalyzed reactions.
A traditional method for the synthesis of organoboron com-
pounds is addition of B–H compounds to unsaturated hydro-
carbons (hydroboration).13 Although this method is now com-
mon for large-scale preparations, catalyzed reactions are an
interesting strategy for obtaining chemo-, regio-, and stereose-
lectivities that are different to those achieved by uncatalyzed
hydroboration.8d,14 Such a catalytic protocol that involves ox-
idative addition of an H–B bond to a low-valent transition
metal has been extended to analogous metal-catalyzed addition
reactions of B–B,8 B–S,15 B–Si,16 and B–Sn17 compounds. On
the other hand, coupling reactions of B–B8,18 or B–H19 com-
pounds with aryl, vinyl, allyl, and benzyl halides or triflates
have provided a simple method for borylation of organic elec-
trophiles without using lithium or magnesium intermediates.
Because of the availability of various electrophiles and mild
reaction conditions, this method has allowed convenient access
to organoboron compounds that have a variety of functional
groups. An extension of this methodology to aliphatic or aro-
matic C–H borylation is of significant value for direct prepara-
tion of organoboron compounds from economical hydrocar-
bons. Some key steps in putative catalytic cycles have been
established by Hartwig via stoichiometric C–H borylation of
alkanes and arenes with (boryl)metal complexes. Those dis-
coveries were followed by the rapid development of catalytic
processes for C–H borylation of hydrocarbons with bis(pinaco-
lato)diboron (B2pin2) or pinacolborane (HBpin).11 In most re-
actions, it is widely recognized that the catalytic cycle involves
Published on the web December 12, 2008; doi:10.1246/bcsj.81.1535

1536 Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) AWARD ACCOUNTS
H
>B-B<
HB<
alkene
B
B
alkene
[M] X
[M] X
RCH2CH2
B
[Pt(0)]
[Pt]
B
R
B
3
or alkyne
8
B
hydroboration
4
>B-B<
2
1
HB< -H2
diboration
B
O
O
O
B
O
O
O
O
B B
[M] X
B B
B
R
O
alkene
B
9
B2cat2
B2pin2
5
diboration
Scheme 1.
-X-B<
alkene
B
a (boryl)metal species generated by transmetalation or oxida-
tive addition.8b–8d,11g–11j The synthesis, characterization, bond-
ing, and reactivity of these catalytically important species have
recently been reviewed.8b
R
[M] B
10
6
dehydrogenative
coupling
2HB<
H2
>B-B<
2.1 Oxidative Addition of Boranes or Diborons to Low-
Valent Transition-Metal Complexes. The reaction between
Pt(PPh3)4 or Pt(C2H4)(PPh3)2 and B2pin2 or B2cat2 provides a
single crystal of 1 consisting of a distorted square-planar coor-
dination geometry for the Pt atom containing two cis-boryl and
phosphine ligands, which allows insertion of alkenes and al-
kynes into the Pt–B bond (Scheme 1).20–22 This process has
been used for catalyzed additions of B–B, B–Si, and B–Sn
compounds to alkenes and alkynes with Pd0, Pt0, or RhI com-
plexes.8,16,17
B
PhH
B
[M] B
B
11
C-H borylation
7
Scheme 2.
Reaction between rhodium(I) or iridium(I) complexes ([M]–
X, X ¼ halogen, OAc, and OR) with HBcat, HBpin, or B2pin2
yields species effective for catalyzed hydroboration of alkenes
and alkynes 4, diboration and dehydrogenative coupling of
alkenes 5 and 6 and C–H borylation of alkanes, arenes, and
alkenes 7 (Scheme 2). The oxidative addition of HBcat to
RhCl(PPh3)3 affords a coordinatively unsaturated 4,23 which
is believed to be an active species of the catalyzed hydrobora-
tion. Further oxidative addition of a borane to 4 generates
H2 and a diborylrhodium(III) complex 5,24 which undergoes
diboration 9 or dehydrogenative borylation of alkenes 10.25
H2 thus generated will hydrogenate a part of the alkenes. Thus,
catalyzed hydroboration of alkenes with HBcat often provides
a mixture of RCH(Bcat)CH2(Bcat) (9), RC(Bcat)=CH2,
RCH=CH(Bcat) (10), and RCH2CH3, along with the desired
hydroboration product 8. Interaction between a rhodium(I) or
iridium(I) complex of 6 with HBpin,26 HBcat,27 B2pin2, or
B2cat2 yields a tris(boryl) complex 7.26–28 Ir(Bpin)(PMe3)4
(6) and Ir(Bpin)3(PMe)3 (7) react cleanly with the C–H bond
of benzene to produce PhBpin and [Ir(H)(PMe3)4] or fac-
[Ir(Bpin)2(H)(PMe3)3] at room temperature, thus indicating
that both iridium(I) and iridium(III) species are viable for
aromatic C–H borylation.26 However, mechanistic studies by
Hartwig and Smith have shown that an IrIII complex 7 is a
component involved in the C–H borylation.11e,26
studies have employed HBcat, but pinacolborane (HBpin) is an
excellent alternative because it is a more stable, easily pre-
pared and stored hydroboration reagent that is convenient
for organic syntheses. Hydroboration of terminal and internal
alkenes with HBpin proceeds at room temperature in the pres-
ence of an iridium(I) catalyst (eqs 1 and 2).30 All internal al-
kenes yield single products coupled at the terminal carbons
13 via isomerization before reductive elimination.
a
R
O
ð1Þ
B
RCH=CH2
O
12
R= n-C6H13 (89%), Ph (93%), C6F5 (82%)
b
O
Ph
Ph
13 (75%)
B
ð2Þ
O
O
HBpin= H B
O
a) HBpin, [IrCl(cod)]2/2dppe, CH2Cl2, rt
b) HBpin, [IrCl(cod)]2/2dppm, CH2Cl2, rt
2.2 Additions of Boranes to Alkenes and Alkynes
(Hydroboration). Catalyzed hydroboration did not attract
much attention until a report by Mannig and Noth in 198529
that a Wilkinson complex (RhCl(PPh3)3) accelerates the addi-
tion of catecholborane (HBcat) to alkenes or alkynes.8d,14 Most
The palladium-catalyzed hydroboration of conjugate 1,3-di-
enes with a Pd, Ni, or Rh catalyst yields allylboronates via an
oxidative addition–insertion–reductive elimination process
(eq 3).31,32 The cis addition of the H–B bond to dienes affords
cis-allylboronates (Z > 99%) with selective addition of hydro-
¨
¨

N. Miyaura
Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) 1537
gen to the unsubstituted double bond to give single regioiso-
mers 14 for asymmetric dienes. The hydroboration of enynes
yields either 1,4-addition 16 or 1,2-addition products 17, the
ratio of which dramatically changes with the phosphine ligand
as well as the molar ratio of the ligand to palladium metal
(eq 4).31,33
H
HBcat
D
O
B
R
D
[RhCl(cod)]2/2iPr3P
Et3N, cyclohexane
rt
R
O
22
21
D
R1
R2
21
R1
R2
Rh(I)
R
[Rh]
a
b
O
O
23
Me
B
22
14
Et3N
Me
R1
H
R1, R2=H; 81% (syn>99%)
D
R
HBcat
D
[Rh]
Bcat
R1=H, R2=Me; 89% (syn>99%)
ð3Þ
ð4Þ
Ph
.
[Rh]
R1, R2=Me; 81%
R2 OH
R
25
15
24
•
O
O
O
B
O
O
O
B
O
c
O
B
O
O
B
B
+
Me3Si
TBSO
70% (Z>98)
17
60% (Z>99)
O
70% (Z>98)
16
a) HBcat, Pd(PPh3)4, benzene, rt; b) PhCHO
c) HBcat, Pd(PPh3)4 or NiCl2(dppe)
O
O
O
O
B
B
EtO
O
Uncatalyzed hydroboration of allenes results in the forma-
tion of a mixture of four possible isomers; however, such
regio- and stereoselectivity can be controlled by the ligands
used for catalysts (Scheme 3).34 A platinum(0)/2tBu3P com-
plex affords the internal products 19 for alkoxyallenes or
the terminal anti-Markovnikov products 18 for aliphatic and
aromatic allenes. On the other hand, a bulky and basic
67% (>99)
70% (>92%)
([Rh(cod)2]BF4/PCy3)
Scheme 4.
tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP) changes the
regioselectivity to the Markovnikov addition 20 for the repre-
sentative terminal allenes.
O
HBpin
A rhodium(I)/iPr3P complex catalyzes novel trans hydrobo-
ration of terminal alkynes giving cis-1-alkenylboron com-
pounds 22 (Scheme 4).35 The dominant factors reversing the
conventional cis hydroboration to the trans hydroboration are
the use of alkyne in excess of HBcat and the presence of more
than 1 equivalent of Et3N to HBcat for a rhodium(I) catalyst
possessing two equivalents of bulky and donating alkylphos-
phine. Since the deuterium label at the terminal carbon of 21
selectively migrates to the internal carbon, a vinylidene com-
plex 24 is proposed as a key intermediate of this formal trans
hydroboration.
The hydroboration of thioalkynes with HBcat in the pres-
ence of a nickel catalyst selectively yields ꢁ-(alkylthio)-1-al-
kenylboronates 26, in contrast to uncatalyzed hydroboration
that yields opposite ꢀ-(alkylthio) derivatives (eq 5).36 Since
the vinylic sulfide is synthetically equivalent to a carbonyl
compound, its cross-couplings with aromatic halides having
a 2-NHAc or 2-OMOM group provide valuable precursors
for the syntheses of indole and benzofuran derivatives.37 For
example, a stepwise one-pot three-step reaction affords indole
(28) in good yield (eq 5).
R1
R2
B
Pt(dba)2/2tBu3P
O
18 (R1=tBuMe2SiO, R2=H, 86%, E/Z=9/91)
HBpin
O
B
Pt(dba)2/2tBu3P
R1
R2
R1
R2
O
.
19 (R1=cyclo-C6H11, R2=H, 91%)
R1
R2
CH3
B
O
HBpin
Pt(dba)2
/2TTMPP
O
20 (R1,R2= -(CH2)5-, 76%)
Scheme 3.

1538 Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) AWARD ACCOUNTS
B2pin2
R1
R2
MeS
H
C4H9
R1
R2
a
b
pinB
Bpin
MeS C C C4H9
B
O
32 Pt(dba)2 for alkenes
33
O
Pt(PPh3)4 for alkynes
26
B2pin2
-L
L
L
Bpin
Bpin
L
Bpin
Bpin
C4H9
SMe
M
Pt(0)•Ln
M
C4H9
35
34
c
33
ð5Þ
32
N
NHCOMe
COMe
27 (80 %)
28 (82%)
R1
R2
L
Bpin
Bpin
M
a) HBcat, NiCl2(dppp), benzene, r.t.
b) 2-(NHAc)C6H4I, Pd(PPh3)4, aq. NaOH
c) HgCl2, MeCN-H2O
R2
pinB
37
M Bpin
R1
L
36
2.3 Addition of 9-RS-9-BBN to Terminal Alkynes
(Thioboration). ꢁ-(Alkylthio)-1-alkenylboranes 29 can be
synthesized by thioboration of terminal alkynes with 9-RS-9-
BBN (9-BBN = 9-borabicyclo[3.3.1]nonane). A selective cis
addition catalyzed by a palladium(0) complex affords 29,
which exhibits exceptionally high reactivity toward protonoly-
sis with methanol, cross-coupling reaction with organic halides
30, and nucleophilic addition to carbonyl compounds 31
(Scheme 5).15 A palladium(0) complex also works as a cata-
lyst for synthesis of 9-RS-9-BBN from RSH and 9-BBN.
2.4 Additions of Diborons to Alkenes and Alkynes
(Diboration). The addition of B2X4 (X ¼ F, Cl, and Br) to
unsaturated hydrocarbons was first discovered by Schlesinger
in 1954. Although stable alkoxo derivatives are very inert to
alkenes and alkynes, they are oxidatively added to a low-valent
transition-metal complex with the B–B bond cleavage, thus
allowing the catalyzed transfer of the B–B bond to unsaturated
organic substrates 33 (Scheme 6).8 Pt(PPh3)4, Pt(C2H4)-
(PPh3)2, Pt(CO)2(PPh3)2, and Pt(norbornene)2/P(2-MeC6H4)-
Ph2 or PCy3 catalyze the addition of B2pin2 to alkynes.20–22,38
The proposed catalytic cycle8,20–22 involves oxidative addition,
insertion and reductive elimination processes. The reaction is
accelerated significantly with an unsaturated platinum(0) com-
plex having a donating phosphine ligand and is slowed down
Scheme 6.
in the presence of PPh3 added to Pt(PPh3)4, thus suggesting
a rate-determining role of both oxidative addition and phos-
phine dissociation (34 to 35).
Phosphine-based platinum(0) catalysts are inefficient for di-
39,40
boration of alkenes, but phosphine-free Pt(dba)2
and
41
Pt(cod)2 are good catalysts allowing insertion of an alkene
into the B–Pt bond. Disubstituted alkenes result in no addition,
but the reaction proceeds smoothly for terminal alkenes and
cyclic alkenes having an internal strain such as 1-decene, sty-
rene, cyclopentene, and norbornene (eq 6). An asymmetric
version has recently been demonstrated by using B2cat2 and
chiral rhodium(I) catalyst 40 (eq 7).42
Bpin
Bpin
a
ð6Þ
38 (85%)
B
b
C4H9
C4H9
ð7Þ
C4H9
C4H9
B
41 (76%, 98%ee)
39
C4H9
a) B2pin2, Pt(dba)2, toluene, 50 oC
9-RS-9-BBN
C4H9 C C H
b) B2cat2, catalyst (40), THF
RS
B
Pd(PPh3)4
THF, 50 °C
29
Ph
P Ph
1-bromohexyne
Pd(PPh3)4, K3PO4
THF, reflux
RhX
N
hexanal
THF, reflux
40
C4H9
RS
H
C4H9
RS
The addition of diborons to 1,3-dienes affords a new class of
allylboron compounds that dramatically changes the products
between phosphine-based platinum(0) catalysts and phos-
phine-free catalysts (eqs 8 and 9).43 Pt(PPh3)4 stereoselective-
ly yields cis 1,4-addition products 42 and 44 for representative
aliphatic and alicyclic 1,3-dienes.43 In contrast, phosphine-free
Pt(dba)2 results in the formation of a 1,2-addition product 45
C5H11
HO
Bu
30 (R=Ph, 70%)
31 (R=Bu, 80%)
Scheme 5.

N. Miyaura
Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) 1539
for 1,3-pentadiene and a double insertion product 43 for iso-
prene. There have also been systematic studies on diboration
of allenes giving allylboron compounds (eq 10).44,45
B2pin2
O
O
R-X
R B
Pd catalyst, base
X=I, Br, Cl, OTf, N2BF4
a
pinB
Bpin
I
X
Cl
42 (93%)
ð8Þ
H
PS
N
FW
FW
b
O
Bpin
pinB
46
47
48
(X=Cl, Br, OTf)
43 (94%)
Pd(dba)2/2PCy3 Pd(OAc)2/NHC PdCl2(dppf)
KOAc, dioxane KOAc, THF
KOAc
a
b
80 °C
microwave
DMF, 80 °C
Bpin
Bpin
OMe
I
OTf
44 (84%)
ð9Þ
Bpin
Bpin
NHCbz
TBSO
45 (92%)
O
OMe
50
49 PdCl2(dppf), KOAc
DMSO, 80 °C
PdCl2(PPh3)2/2PPh3
K2CO3, dioxane, 80 °C
c
•
97%
ð10Þ
pinB
Bpin
O
Me
O
COMe
a) B2pin2, Pt(PPh3)4, toluene, 80 °C
b) B2pin2, Pt(dba)2, toluene, rt
c) B2pin2, Pt(dba)2/PCy3, toluene, 50 °C
Me
OTf
Br
Me
FW
OAc
51
52
53
2.5 Coupling Reactions of Diboron with C–X Bonds.
Metal-catalyzed cross-coupling reactions of disilanes and di-
stannanes with organic halides have been used for the synthe-
sis of organosilicon and -tin compounds. Although the lack of
suitable boron nucleophiles has limited this protocol for boron
compounds, tetra(alkoxo)diborons such as B2pin2 act as bor-
on-nucleophiles for palladium-catalyzed cross-coupling reac-
tions of organic halides and triflates.8,18 Analogous coupling
reaction of HBpin with aryl or vinyl halides is an economical
alternative reported by Masuda, Murata, and co-workers.19
Borylation of aryl, 1-alkenyl, allyl, and benzyl halides18,46 or
triflates47 proceeds in the presence of KOAc and a palladium
catalyst (Scheme 7). PdCl2(dppf) has been used for repre-
sentative aromatic iodides and bromides 48 and 49,18 and a
combination of a palladium precursor and an electron-donating
PCy3 4646 or N-heterocyclic carbene (NHC, 47)48 can be
advantageous for achieving high yields for aryl chlorides and
electron-rich aryl bromides or triflates. The reaction can be
further accelerated by irradiation with microwaves.48 The
borylation of 1-alkenyl halides or triflates 50 and 51 proceeds
while completely retaining their stereochemistry.49,50 Boryla-
tion of allyl acetates 52 provides a simple access to variously
functionalized allyboronic esters.51,52 Electron-rich tris(p-me-
thoxyphenyl)phosphine is effective for borylation of benzyl
halides 53.53
PdCl2(PPh3)2 Pd(dba)2/2AsPh3 Pd(dba)2
2PPh3
PhOK, toluene
50 °C
toluene, 50 °C
/P(4-MeOPh)3
KOAc, toluene
50 °C
Scheme 7.
R-X
R
L
L
Pd(0)·Ln
Pd
X
54
R-Bpin
KOAc
L
R
L
L
R
Pd
Pd
Bpin
L
OAc
B2pin2
56
55
Scheme 8.
R ¼ Ph) is obtained quantitatively when trans-PhPdBr(PPh3)2
(54, R ¼ Ph) is treated with an excess of KOAc. Indeed, reac-
tion between 55 and B2pin2 gives PhBpin, whereas no reaction
is observed between 54 and B2pin2. Thus, the coupling with
allyl acetates (52, Scheme 7) which directly generate 55 via
oxidative addition smoothly takes place in the absence of
any bases.
The presence of a base such as KOAc is critical for the cou-
pling of diborons, suggesting transmetalation occurring from
Ar–Pd–OAc generated by displacement of X on Ar–Pd–X with
an acetate anion (Scheme 8).18 trans-PhPd(OAc)(PPh3)2 (55,

1540 Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) AWARD ACCOUNTS
2.6 Coupling Reactions of B2pin2 and HBpin with C–H
Bonds (C–H Borylation). Direct borylation of arenes by
HBpin or B2pin2 is highly attractive as a convenient, econom-
ical, and environmentally benign process for the synthesis of
aromatic boron compounds, which has been studied extensive-
ly by Hartwig and Smith.11,54,55 We reported that a class of
IrI complexes possessing a 2,20-bipyridine (bpy) or 4,40-di-
tert-butyl-2,20-bipyridine (dtbpy) ligand exhibits excellent
thalene, pyrene and perylene,60 porphyrins,61 and nitrogen-
containing heterocycles.62
Mechanistic studies have shown that an IrIII–tris(boryl)
complex 7 is an active component involved in the catalytic cy-
cle as is discussed in Scheme 2.11 1H NMR spectroscopy for
the reaction of B2pin2 and 1/2[IrCl(cod)]2/dtbpy showed the
formation of a tris(boryl)IrIII complex 58, which was finally
isolated and characterized by X-ray analysis.11d When 58 is
dissolved in benzene at room temperature, 3 equivalents of pi-
nacol phenylboronate (80%) are produced instantaneously.
Thus, the reaction proceeds through a catalytic cycle analo-
gous to that proposed for the RhI-catalyzed borylation of alka-
nes11a (Scheme 10). A small steric hindrance from the planar
bipyridine ligand as well as its electron donation to the metal
center allows smooth oxidative addition of an arene C–H bond,
giving an IrV intermediate 60. The small steric influence
of the planar dioxaboryl rings (Bpin) and an aryl ring (Ar)
can also be critical for the formation of such sterically hin-
dered hepta-coordinated intermediates. These processes have
been supported by recent theoretical studies by Sakaki et al.11g
A chelation-controlled ortho selective C–H borylation of
benzoates is achieved when an IrI/2P[C6H3(CF3)2]3 complex
is used at 80 ꢀC (Scheme 11).63 Although HBpin thus generat-
ed from B2pin2 does not participate in the next catalytic cycle,
all reactions are remarkable in their high regiospecificity for
selective functionalization of ortho carbons.
activity and selectivity for aromatic C–H borylation with
11d,26,56
B2pin2
or HBpin.57 An Ir catalyst prepared from
1/2[IrCl(coe)2]2 (coe = cyclooctene) and dtbpy achieves a
maximum turnover number (8000 TON) with 0.02 mol % cat-
alyst loading at 100 ꢀC. The reaction was first demonstrated at
80–100 ꢀC using an Ir–Cl complex, but it proceeds smoothly
even at room temperature when the catalyst is prepared from
1/2[Ir(OMe)(cod)]2 (cod = 1,5-cyclooctadiene) and dtbpy
(Scheme 9).11e,56 Both 1,2- and 1,4-disubstituted arenes bear-
ing identical substituents and 1,3-disubstituted arenes afford
isomerically pure single products, whereas monosubstituted
arenes resulted in a mixture of para and meta coupling prod-
ucts. Under conditions analogous to those used for typical
arenes, heteroarenes are also borylated with B2pin2 or HBpin
(Entries 7–13). The protocol has been used successfully for
borylation of C–H bonds of azulene,58 ferrocene and Cp–metal
complexes,59 polycyclic aromatic hydrocarbons such as naph-
A simple extension of this protocol to vinylic C–H boryla-
tion of typical alkenes resulted in formation of a complex mix-
ture of boron compounds, but electron-rich vinyl ethers excep-
tionally allow selective C–H borylation. Although simple vinyl
O
O
B2pin2
B
H
[Ir(OMe)(cod)]2-2dtbpy
hexane, 25 °C
FG
FG
57
tBu
tBu
dtbpy
tBu
N
N
O
O
benzene
rt
Bpin
Bpin
N
Ph B
Cl
Ir
N
tBu
Bpin
80%
(8 h)
88%
(8 h)
Cl
kH/kD = 3.6 0.2
58
CO2Me
Cl
Cl
R=Me, 95%
(2 h)
R=Br, 91%
(2 h)
R=CN, 60%
(24 h)
HBpin
N
Bpin
Bpin
N
N
Bpin
53%
(24 h)
Ir
Ir Bpin
R
S
Bpin
Bpin
62
N
H
Cl
Cl
Bpin
59
H2
R=Me, 96%
(1 h)
R=CO2Me, 99%
(1 h)
82%
(4 h)
R
N
Bpin
H
N
N
I
Bpin
Ir
Ar-H
CF3
Bpin
R=OMe, 90%
(2 h)
R=Me, 85%
(2 h)
B2pin2
H
H
91%
(4 h)
R
O
63
Br
Br
HBpin
Bpin
Bpin
N
N
N
Bpin
Ir Bpin
Ir
88%
(0.5 h)
83%
(2 h)
N
Bpin
N
H
H
Ar
H
61
ArBpin
Scheme 10.
60
CN
Scheme 9.

N. Miyaura
Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) 1541
preparation of 1.1 equivalents of 77 is directly followed by
cross-coupling (eq 11).65
CO2Me
H
CO2Me
O
B
O
B2pin2
OTBS
OTBS
OTBS
[Ir(OMe)(cod)]2-4L
octane, 80 °C
O
O
a
FG
OTBS
FG
B
O
64
O
Me
Me
OMOM OTBS
OTBS
76
77
FG= o-CF3 (98%), o-NMe2 (97%), m-Br (64%),
m-NMe2 (99%), p-Me (99%), p-OMe (66%)
b
MeO
CF3
O
MOMO
[Ir]
O
L= P
3
78 (83%)
Me
H
ð11Þ
CF3
65
FG
HO
Me
Scheme 11.
O
MeO2C
OH
OH
OH
O
B2pin2 or HBpin
O
HO
vineomycine B2 methyl ester
O
n
X
O
O
n
X
B
[Ir(OMe)(cod)]2/2dtbpy
hexane, 25-80 °C
Me
O
a) B2pin2, Ir(OMe)(cod)/dtbpy, octane, 80 °C, 16 h
b) ArI, PdCl2(PPh3)2, K3PO4, dioxane, 80 °C, 8 h
66
X= O, CH2, CHR, CR2
n= 0, 1
67
O
A palladium on carbon (10% Pd/C) catalyzes the selective
coupling at the benzylic C–H bond (eq 12).66
O
O
Me
B
O
O
O
4-ClPh
O
a
B
O
O
B
ð12Þ
70
(73%, α/β=95/5)
CH3
B
O
O
O
R
R
69
68
(81%)
79
(75%, α/β=49/51)
a) B2pin2, Pd/C (3-6 mol%), 100 °C, 16 h.
R= H (74%), 2-Me (77%), 4-Me (72%),
3,4-Me2 (64%), 4-MeO (13%), 4-F (26%)
O
O
O
O
B
O
B
R
2.7 Synthesis of Allyl- and Benzylboron Compounds.
Allylboron compounds are valuable reagents in organic syn-
thesis since their addition to a carbon–oxygen or the carbon–
nitrogen double bond diastereoselectively provides homoallyl-
ic alcohols or amines via a chair-like, six-membered cyclic
transition state. Cross-coupling reaction of Knochel’s boryl-
methylzinc reagent with haloalkenes (eq 13)67 and borylation
of allyl acetates with diboron (eq 14)51,52 provide a variety
of 5–5, 6–5, and 7–5 cis fused exomethylene cyclopentanols
from ꢁ-ketoesters or -diketones via a cross-coupling/intramo-
lecular allylboration sequence. An alternative boron nucleo-
phile convenient for synthesis of functionalized allylboron
compounds is borylcopper(I) reagent in situ generated from
diboron and CuIOAc in DMF (eq 15).68
R'
O
72: R=H, R'=Me (61%)
73: R,R'=Me (65%)
71 (64%, α/β=75/25)
OTBS
OTBS
OTBS
O
O
O
O
O
O
B
B
74 (81%)
75 (72%)
Scheme 12.
ethers such as butyl vinyl ether resulted in ca. 30% of (E)-
BuOCH=CHBpin along with several boron-containing by-
products, cyclic vinyl ethers are substrates that achieved selec-
tive coupling at the vinylic C–H bond (Scheme 12).64,65 The
reactions with dihydrofurans 69 suffer from low regioselectiv-
ities, giving a mixture of ꢀ- and ꢁ-coupling products even for
ꢂ-disubstituted analogues 70, but dihydropyran derivatives pos-
sessing substituents at the ꢂ-position 72–74 and protected D-
glucals (75) provide single coupling products at the ꢀ-carbon.
C-Glucals are an important class of compounds due to the
frequent occurrence of these fragments in pharmaceuticals. A
key skeleton 78 previously used as a precursor of vimeomyci-
none B2 methyl ester is synthesized in 83% yield when the
O
CO2Et
O
CO2Et
a
O
B
Br
O
OH
ð13Þ
80 (71%)
CO2Et

1542 Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) AWARD ACCOUNTS
Metal-catalyzed positional isomerization of the double bond
O
CO2Et
provides a simple access to ꢂ-(alkoxy)allylboronates, which
are reagents for diastereoselective preparation of 1,2-diols.
The use of a cationic iridium complex obtained via hydrogena-
tion of [Ir(cod)(PPh2Me)2)]PF6 in ethyl acetate results in a
quantitative isomerization within 10 min without stereochemi-
cal isomerization (87, E > 98%) (eq 18).71 For intramolecular
allylboration, the isomerization of 89 is followed by depro-
tection the acetal and cyclization catalyzed by Yb(OTf)3
(eq 19).72
O
CO2Et
b
O
B
OAc
O
OH
ð14Þ
81 (77%)
CO2Et
OSiR3
O
O
O
a
c
B(OiPr)2
R3SiO
B
B
B [Cu]
B(OiPr)2
O
O
O
82
R3Si=tBuMe2Si
87 (94%, E/Z = 98/2)
O
O
O
i
CO2 Pr
tartarate
R3SiO
B
O
OAc
88
O
i
B
ð15Þ
CO2 Pr
O
OH
83 (92%, E>95%)
a) IZnCH2Bpin, Pd(OAc)2/3PPh3
b) B2pin2, Pd(dba)2/2AsPh3, toluene, 50 °C
c) CuCl, LiCl, KOAc, DMF, r.t.
CHO
ð18Þ
MS-4A, toluene
R3SiO
-78 °C
85%, 91%ee
Allylboration of carbonyl compounds with these bulky pina-
col esters is very slow at room temperature, but the reaction
can be catalyzed by Lewis acids. Addition of pinacol (E)-
and (Z)-crotylboronate to benzaldehyde diastereoselectively
proceeds at ꢁ78 ꢀC in the presence of AlCl3 or Sc(OTf)3
(10 mol %) (eq 16).69
OMe
OMe
OMe
O
OMe
a
O
B
O
O
B
O
O
89
Yb(OTf)3
MeCN, H2O
90
OH
PhCHO
H
O
O
ð16Þ
Me
B
Ph
84
92% (anti=99%)
ð19Þ
a
77%
O
Me
OH
H
AlCl3
Sc(OTf)3 94% (anti=98%)
a) [IrH2(PPh2Me)2]PF6, AcOEt, r.t.
a) catalyst (10 mol%), toluene, -78 °C, 4 h
The synthesis of benzylboronates via coupling reactions of
B2pin2 is shown in Scheme 7 (53) and eq 12 (79). ortho-Acyl-
benzylboronates synthesized by cross-coupling reaction of
Knochel’s borylmethylzinc reagent with haloarenes work as
stable ortho-quinodimethane precursors that can be trapped
by dienophiles (eq 20).73
Ruthenium-catalyzed olefin cross-metathesis has resulted in
a one-pot three-component coupling for the synthesis of homo-
allylic alcohols. The utility of this protocol was demonstrated
in enantioselective allylboration (eq 17).70
i
CO2 Pr
R
CO2Me
Ru catalyst
R
O
B
i
CO2 Pr
b
a
O
O
O
O
O
B
i
I
CO2 Pr
91
CHO
H+
O
CO2Me
O
i
CO2 Pr
B
NPh
OH
O
B
R
O
H
85
O
O
ð20Þ
NPh
R
H
N
N
O
O
93a :R = H, 87%
93b :R = CH3, 92%
Cl
Cy3P
92
ð17Þ
Ru
Ph
O
Cl
a) IZnCH2Bpin, PdCl2(PPh3)2, THF
b) 100 °C or h
86
Ru catalyst
ν
78%, 82%ee

N. Miyaura
Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) 1543
M'+
3. C–C and C–N Bond-Forming Reactions
[M]-R
+ [B(OH)4]M'
+ M'X
OH
-
[M]-X
OH-
M'OH
OH
R B
OH
3.1 Transmetalation to Transition-Metal Complexes.
Transmetalation between organometallic reagents and transi-
tion-metal complexes is a fundamental process involved in
metal-catalyzed bond-forming reactions. It is the first step in
metal-catalyzed 1,4-addition of organic electrophiles to ꢀ,ꢁ-
unsaturated carbonyl compounds9 and the second step in palla-
dium- or nickel-catalyzed cross-coupling reactions of organo-
boron compounds with nucleophiles.6 Main group nonmetallic
compounds such as boron and silicon compounds are attractive
for use in organic syntheses due to their high degrees of ther-
mal stability and air stability for isolation or handling and due
to their compatibility with a wide range of functional groups,
but transmetalation is very slow due to low nucleophilicity
of the nonmetal organoelement compounds. However, they
transfer the organic groups to transition-metal complexes by
one of the following three processes (eqs 21, 22, and 23).6,74
The addition of a base such as alkoxy, hydroxy, or fluoride
anion exerts a remarkable accelerating effect on the cross-
coupling reactions of organoboron and -silicon compounds
(eq 21).6h,75,76 Thereby, the coordination of a negatively charg-
ed base enhances the nucleophilicity of the organic group so
that ligand exchange between [M]–X (X ¼ halogen) and an
organometallic reagent proceeds via a four-centered ꢃ-bond
metathesis (94).
R B OH
OH
95
stability constants for OH- (log K at 25 °C)
Li+
0.36
Na+
-0.2
K+
Cs+
-
-0.5
stability constants for X- (log K at 25 °C)
K+
Cs+ Ba2+ Bu4N+ Tl+ Cu+ Ag+
Cl-
Br-
I-
-0.7 -0.39 -0.13 0.40 0.49 2.7 3.3
-
0.03
-
-
0.49 0.91 5.9 4.7
0.78 8.9 6.6
-0.19 -0.03
-
Scheme 13.
proceed under neutral conditions for organic electrophiles, di-
rectly yielding RO–Pd complexes via oxidative addition. Re-
actions of boron or silicon compounds with allylic acetates,78
allylic carbonates,79 1,3-butadiene monoxide,80 propargyl car-
bonates,81 acetic anhydrides,82 and phenyl trifluoroacetate83
have been carried out in the absence of a base.
OH
H
O
-
R'
R B OH
RB(OH)2
-
B
O
OH
OH
OH
OH
ð21Þ
[M]−R
+ B(OH)4
+ X-
[M] X
X
[M]
ð22Þ
[M]−R
+ R'OB(OH)2
[M] OR'
[M]
B
-
R
94
OH
R
96
[M]=Pd(II), Ni(II), Rh(I); X=halogen
[M]=Pd(II), Rh(I), Re(I); R'=H, Me, COMe
The effects of bases and counter cations on such a base-as-
sisted transmetalation can be roughly estimated by the basic
strength, affinity of counter cations for halide ions (stability
constant)77 and solubility of M0X (Scheme 13). The transmeta-
lation is a reversible process that involves nucleophilic dis-
placement of [M]–X (M ¼ PdII and NiII) with [RB(OH)3]M0
95 to yield [M]–R, B(OH)3, and M0X. The concentration of
hydroxyborate anion 95, which exists in an alkaline solution
in equilibrium with a free organoboronic acid, increases by
Although the transmetalation shown in eq 22 takes place
under neutral conditions, there is a strong accelerating effect
of bases (Scheme 14).84 For example, addition of KOH to a
mixture of p-tolylboronic acid, 2-cyclohexenone, and a rhodi-
um complex in aqueous DME at 5 ꢀC exerts a remarkable ac-
celerating effect. The RhOH complex, that is believed to be an
active species for transmetalation ( ), is a better catalyst than
the RhCl complex ( ), but addition of aqueous KOH results in
completion of both reactions within 1 h ( and ). Thus, quar-
ternization of arylboronic acids with a base greatly facilitates
transmetalation to both RhCl and RhOH complexes.
increasing the basic strength (OHꢁ > MPO4 > MCO3
>
ꢁ
ꢁ
HCO3ꢁ). For each series of bases, cesium may yield a higher
concentration of 95 than do the corresponding smaller alkali
metals because the stability constant of OHꢁ becomes smaller
The third process is transmetalation to cationic metal com-
plexes (eq 23). Cross-coupling reactions of organoboron and
as we move down the periodic table (Csþ < Kþ < Naþ
Liþ). Transmetalation can be fast for counter cations (M0þ
that have a high stability constant for halide ions (Agþ
<
)
>
85
silicon compounds with Ph2IBF4 or ArN2BF4,86 which af-
fords an Ar–[Pd]þ intermediate via oxidative addition, have
been carried out in the absence of a base because transmetala-
tion takes place smoothly under neutral conditions.
Tlþ > R4Nþ > Ba2þ > Csþ > Kþ). Precipitation of insoluble
AgX, TlX, and BaX2 is also a strong driving force of transme-
talation.
The second process is transmetalation to [M]–OR0 (M ¼ Pd,
Rh, and Re; R0O ¼ OAc, OMe, and OH) complexes (eq 22).
Due to the high oxophilicity of boron and silicon compounds
and high basicity of [M]–OR0 complexes, transmetalation
takes place without any assistance of a base for these Pd,
Rh, and Re complexes. Thus, cross-coupling reactions often
H
H
B
+
O
R
RB(OH)2
H2O
OH
OH
[M]+
[M]−R
+ B(OH)3
ð23Þ
[M]
97
[M]+=Pd2+, RPd+, Pt2+ , Rh+

1544 Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) AWARD ACCOUNTS
[Pd]+
[Pd]+
(HO)2B
O
CH3
H
H
H
H
X
X
+
O
4-MeC6H4
O
1.5 equiv
B
B
HO
O
OH
HO OH
Rh catalyst (3 mol%)
base (if used, 1 equiv)
DME-H2O, 5 °C
103
102
0.8
p-MeO
p-Me
0.4
0
ρ = -0.54
yield/%
p-CH3CO
100
80
60
40
20
0
H
-0.4
-0.8
p-CF3
[RhOH(cod)]2/KOH
[RhCl(cod)]2/KOH
[RhOH(cod)]2/Et3N
-0.4
-0.2
0
0.2
0.4
0.6
σ
Effect of substituents in the reaction between
[CH3CH=CHCH2BF3]K (100) and para substituted
arylboronic acids (eq 25)
Scheme 15.
[RhOH(cod)]2
stituted arylboronic acids shows a negative ꢄ value (ꢁ0:54),
demonstrating that the donating substituents accelerate the re-
action (Scheme 15).75 Aromatic C–B or C–Si bond cleavage
with water or halogens and cleavage of aromatic main met-
al–carbon bonds with cationic palladium or platinum com-
plexes are believed to proceed through a chelated Wheland in-
termediate 102.88 However, the observed effect is ca. 10-times
smaller than that of protonolysis or halogenolysis of aromatic
C–B and C–Si bonds via this transition state. For example, the
ꢄ value reported for bromonolysis of aromatic C–B bonds is
ꢁ3:87.89 Thus, this effect of substituents can be best interpret-
ed by assuming interaction of an empty d orbital of palladium
with the ꢃ C–B bond rather than with the ꢅ-orbital of the
aromatic ring 103.
We reported the efficiency of D-t-BPF for ꢂ-selective cou-
pling of potassium allyltrifluoroborates 104 with bromoarenes
and asymmetric reaction using (R,S)-CyPF-t-Bu as the chiral
auxiliary (eq 26).90,91 It is interesting that kinetic and theoret-
ical studies have revealed a hitherto unknown process that in-
volves the formation of cationic palladium(II) species before
transmetalation.92
[RhCl(cod)]2
0
1
2
3
time/h
Scheme 14.
It has been reported that a stoichiometric reaction between
[Pt(S)2(PEt3)2][CF3SO3]2 (98, S ¼ MeOH or H2O) and
[Ph4B]Na, Ph3B, or PhB(OH)2 gives [Pt(Ph)(S)(PEt3)2]2þ
(99) without any assistance of bases (eq 24).87 Another exam-
ple reported in this category is interaction of [Pd(dppe)-
(PhCN)2](BF4)2 (100) with PhB(OH)2 to provide a mono-
cationic [Pd(Ph)(dppe)(S)]þ (101, S ¼ H2O and PhCN)
(eq 25). Isolation of this intermediate failed due to its thermal
instability, but addition of PPh3 (1 equiv) gives 101 (X ¼ H),
which is identical to an authentic material obtained from trans-
[Pd(Ph)(Br)(PPh3)2], dppe and AgBF4.75
+
2+
PEt3
Ph
PhB(OH)2
S
S
S
Et3P
Et3P
BF3K
Pt
Pt
ð24Þ
ð25Þ
104
Br
Et3P
Pd(OAc)2/L
98
99
K2CO3
FG
FG
THF or MeOH-H2O
2+
105
Me
P(t-Bu)2
Ph
Ph
Ph
Ph
PH
Pd
+
PPh3
NCPh
ð26Þ
P
4-XC6H4B(OH)2
PPh3, rt
P(t-Bu)2
Pd
NCPh
Ph
P
P
PCy2
C6H4X-4
Fe
Fe
Ph
Ph
Ph
101
P(t-Bu)2
100
(R,S)-CyPF-tBu
D-t-BPF
Transmetalation is a critical process involved in various
metal-catalyzed bond-forming reactions; however, little is
known about the mechanistic features, including its kinetics.
The electronic effect on transmetalation of a series of para sub-
The reaction between (E)-CH3CH=CHCH2BF3K (104) and
para substituted bromoarenes with Pd0/D-t-BPF in refluxing
THF showed
a negative linear Hammett’s correlation

N. Miyaura
Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) 1545
cones, and -stannanes. The reaction has been reviewed exten-
sively.6 In view of space limitation, this review is restricted to
other metal-catalyzed bond-forming reactions of organoboron-
ic aids. The mechanism of cross-coupling is discussed in
Section 3.1 and some synthetic application are shown in
eqs 5, 11, 26, 28, and 29 and in Schemes 5, 7, and 20.
3.3 Cyclic Triolborates for C–C and C–N Bond-Forming
Reactions. The C–B bond of organoboronic acids is totally
covalent which is inert to ionic reactions, but nucleophilicity
of organic groups on a boron atom are significantly enhanced
by quaternarization by an anionic ligand. Thus, tetracoordinat-
ed ate-complexes are a key species that has been successfully
used for addition and coupling reactions of organoboron com-
pounds, including metal-catalyzed reactions of organoboronic
acids.6,9 Air- and water-stable trifluoroborates [RBF3]Mþ
(M ¼ K and NR3) are typical ate-complexes that are advanta-
geous over boronic acids in preparation and handling of pure
and water-stable crystalline materials.94 However, their met-
al-catalyzed bond-forming reactions are very slow in the ab-
sence of bases because of the low nucleophilicity of organic
groups due to high electronegativity of fluorine atoms. Thus,
sodium trihydroxyborates [RB(OH)3]Na were recently synthe-
sized as isolated discrete species for cross-coupling in anhy-
drous solvents.95 We reported novel cyclic triolborates 110
and 111 that have exceptionally high levels of stability in air
and water and higher solubility in organic solvents than that
of potassium trifluoroborates.96 High performance of lithium
or potassium triolborates for transmetalation is demonstrated
in palladium- and copper-catalyzed C–C and C–N bond-form-
ing reactions (eqs 28 and 29).96,97 The cross-coupling reactions
of arylboronic acids in aqueous solvents often suffers from low
yields due to competitive hydrolytic B–C bond cleavage. 2-
Pyridylboronic acid is a typical boron compound that results
in such cleavage with water during couplings. It is remarkable
that 2-pyridineboronate (111) affords a high yield of the cou-
pling product (eq 29).
log(kX/kH)
0.4
0.2
p-OPh
p-Me
H
0
p-Cl
-0.2
ρ= -1.1
-0.4
-0.6
p-CF3
-0.4 -0.2
0
0.2
0.4 0.6
σp
Effect of substituents in the reaction between 104
and para substituted bromoarenes with
Pd0/D-t-BPF in refluxing THF (eq 26)
Scheme 16.
(Scheme 16).92 Among steps involved in the catalytic cycle of
cross-coupling, oxidative addition exhibits a positive correla-
tion accelerated by withdrawing groups. It is also difficult to
conclude that it is due to the rate-determining role of reductive
elimination. A possible mechanism which accounts for the
electronic effect of substituents is one proceeding through a
cationic palladium(II) species by elimination of a bromine li-
gand before reaction with CH3CH=CHCH2BF3K (104)
(eq 27). A donating ability of D-t-BPF strongly stabilizing cat-
ionic palladium(II) species was previously demonstrated by
Hartwig in the equilibrium formation of [Pd(Ar)(D-t-BPF)]þ
107 from Pd(Ar)(D-t-BPF)(Br) 106 in polar solvents such
as THF.93 Indeed, the reaction between 104 and [Pd(4-
MeO2CPh)(D-t-BPF)]BF4 shows a perfect ꢂ-selectivity. Theo-
retical calculation suggested transmetalation proceeding
through a chelated cyclic transition state 108 analogous to
97 in eq 23.
K+
HO
1. HO
HO
toluene
O
B
-
B(OH)2
O
O
2. KOH
110
(88%)
F
OMe
Br
-
F B
S
Br
Pd
Ar
106
MeO
L
L
L
L
S
F
104
Pd+
L
+
ð28Þ
Pd
Ar
107
Pd(OAc)2 (3 mol%)
L
Ar
DMF-H2O (5/1), rt, 5 h
98%
O
108
L2=D-t-BPF S=solvent
Li+
Ar
L
Pd
L
1. BuLi
B(OiPr)3
-
B
105
ð27Þ
O
O
HO
2. HO
HO
N
Br
109
N
111 (82%)
3.2 Cross-Coupling Reactions.
In 1979, we reported
cross-coupling reactions of organoboron compounds, which
involve transmetalation to palladium(II) halides as a key step.
The protocol has been proved to be a general reaction for a
wide range of selective C–C bond formations, in addition to
related coupling reactions of organomagnesiums, -zincs, -sili-
NH
ð29Þ
N
N
Cu(OAc)2, O2
4Å MS, DMF
80°C
70%

1546 Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) AWARD ACCOUNTS
3.4 Conjugate Additions to ꢀ,ꢁ-Unsaturated Carbonyl
Compounds.
1,4-Additions of electrophiles to ꢀ,ꢁ-un-
PPh2
PPh2
saturated carbonyl compounds are a versatile methodology
for forming carbon–carbon bonds. Since the reaction yields a
stereogenic center at the ꢁ-carbon, considerable efforts have
been devoted to the development of asymmetric syntheses
via metal-catalyzed 1,4-addition of organometallic and nonme-
tallic compounds. In this field, we developed a new catalytic
cycle starting from transmetalation to give an aryl- or 1-al-
kenylrhodium(I) or -palladium(II) intermediate for 1,4-addi-
tion of organoboronic acids to electron-deficient alkenes
(eq 30).9a,9b,84,98–106 1,4-Additions of aryl- or 1-alkenylboron,
-silicon, -tin, -titanium, -zinc, -zirconium, and -indium com-
pounds to ꢀ,ꢁ-unsaturated carbonyl compounds and to other
activated or unactivated C–C, C–O, and C–N double bonds
or triple bonds are efficiently catalyzed by rhodium(I) com-
plexes.9c–9h The corresponding reactions using palladium cata-
lysts are rare; however, we reported that arylboronic acids
easily transmetalate to dicationic palladium(II) complexes
such as [Pd(dppe)(PhCN)2]2þ, in which 1,4-addition of
ArB(OH)2, [ArBF3]K, ArSiF3, and Ar3Bi to enones smoothly
took place in an aqueous solvents.75,107–116
PPh2
PPh2
115 (binap)
116 (chiraphos)
OMe
P
P
O
O
MeO
P
N
117 (dipamp)
118
X
R1
R1
R3
O
O
R3 [m]
O
P
O
P
ð30Þ
R2
R2
N
Me
Me
N
Pd or Rh catalyst
H2O
Me
O
O
Me
119a: X=O (Me-BIPAM)
119b: X=NMe (N-Me-BIPAM)
112
113
R1
Scheme 17.
m=B(OH)2, BF3K,
Si(OMe)3, SiF3, BiAr2
R1=alkyl, alkenyl, aryl
R2=1-alkenyl, aryl
R2
R3
aryl metal reagents to ꢁ-aryl unsaturated carbonyl compounds.
The catalyst in situ prepared from [Rh(nbd)2]BF4 and chira-
phos achieves enantioselectivities in the range of 83–89%
for ꢁ-aryl ketone derivatives 126 (Method E)105 and in the
range of 78–94% for t-butyl ꢁ-arylacrylate derivatives (e.g.,
128–130) (Method F).105
O
114
The rhodium(I)–binap 115 catalyst was first introduced
for enantioselective 1,4-addition of aryl- and 1-alkenylboronic
acids to cyclic and acyclic enones (Scheme 17).9b Other
ligands effective for rhodium(I) catalysts are bisphosphine
ligands of chiraphos (116)117 and diphosphonites,118 P–N
ligands of amidomonophosphines,119 bis(alkene) ligands based
on a norbornadiene skeleton,120 monophosphine ligands of
phosphoramidites 118,103,121 and bidentate phosphoramidite
(119a, Me-BIPAM)104,106 synthesized from linked-(R)-
BINOL. For the corresponding palladium-catalyzed reactions
of organoboron, -silicon, and -bismuth compounds, bisphos-
phines bridged by two carbons, such as chiraphos (116) and di-
pamp (117), result in high yields and high enantioselectivi-
ties.75,107–116
Performance of these chiral ligands for enantioselectivities
is shown in Scheme 18. The binap ligand 115 achieves high
enantioselectivities for both cyclic and acyclic substrates.
For example, it gives enantioselectivities of up to 99% ee for
cyclic enones (e.g., 120–122), 83–97% ee for acyclic enones
(e.g., 124 and 125), 94% ee for acyclic esters 127, and 92%
ee for amides 131 (Methods A and B).84 Monodentate (Meth-
od C)103 and bidentate phosphoramidite (Method D)104,106 also
achieve high selectivities under analogous conditions. The tra-
ditional chiraphos ligand 116 is better than binap for introduc-
ing two different aryl-fragments at the ꢁ-carbon via addition of
Results of palladium-catalyzed asymmetric 1,4-additions
are shown in Scheme 19. Since the catalyst efficiency is spe-
cific for bisphosphines bridged by two carbon atoms, dipamp
(117) and chiraphos (116) are ligands that meet this require-
ment. Enantioselectivities giving ꢁ-aryl ketones up to 99%
are achieved when using chiraphos for 2-cyclopentenone 133
and acyclic (E)-enones 124–134, whereas dipamp results in
the best selectivities for 2-cyclohexenone 121 and 2-cyclohep-
tenone 123 (89–96% ee). Addition of boronic acids require the
presence of a silver co-catalyst (Method A)112 whereas
[ArBF3]K smoothly add to enones without any such an addi-
tive (Method B).110,111 The palladium–chiraphos complex cat-
alyzes the addition of PhSiF3 at 0 ꢀC in the presence of ZnF2
(0.5 equiv) (Method C).111 The corresponding reaction of
Ar3Bi suffers from decomposition of the catalyst, resulting
in the formation of a homo-coupling biaryl with precipitation
of palladium black. Thus, the presence of a reoxidant such
as Cu(BF4)2 is critical to recycle the precipitated palladium(0)
species (Method D).109
High performance of a chiraphos ligand for ꢁ-arylenones is
demonstrated in the enantioselective synthesis of carbonyl
compounds possessing two aryl groups at the ꢁ-carbon. 1,4-

N. Miyaura
Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) 1547
O
O
O
O
O
O
Ph
133
121
L=117
123
120
121
122
OMe
Cl
L=116
L=117
A: 99%, 97%ee A: 99%, 99%ee A: 98%, 99%ee
D: 99%, 96%ee C: 95%, 98%ee D: 90%, 99.5%ee
D: 99%, 99.6%ee
A: 94%, 94%ee A: 90%, 92%ee B: 92%, 89%ee
B: 60%, 95%ee B: 95%, 93%ee C: 76%, 76%ee
C: 83%, 94%ee C: 83%, 92%ee D: 89%, 76%ee
D: 85%, 95%ee D: 92%, 92%ee
O
OMe
OMe
O
O
O
O
O
Ph
n-C5H11
123
124
125
R
Ph
)
n-Bu Ph
Ph
D: 90%, 98%ee A: 98%, 83%ee B: 75%, 97%ee
C: 95%, 1%ee D: 80%, 92%ee
D: 87%, 74%ee
124 (R=n-C5H11
L=116
A: 99%, 80%ee A: 66%, 99%ee A: 86%, 97%ee
B: 99%, 83%ee B: 91%, 99%ee B: 94%, 97%ee
C: 93%, 82%ee C: 73%, 99%ee C: 88%, 97%ee
D: 80%, 80%ee
134
126
L=116
L=116
OMe
OMe
O
O
A: ArB(OH)2, [Pd(L)(PhCN)2](SbF6)2, AgBF4,
acetone-H2O, 0 °C.
B: [ArBF3]K, [Pd(L)(PhCN)2](SbF6)2, MeOH-H2O,
O
126
127
E: 99%, 86%ee
A: 93%, 94%ee
-15~5 °C.
OMe
O
C: ArSiF3, [Pd(L)(PhCN)2](SbF6)2, ZnF2,
MeOH-H2O, 0~5 °C.
O
D: Ar3Bi, [Pd(L)(PhCN)2](SbF6)2, Cu(BF4)2,
O
MeOH-H2O, -5~10 °C.
O
Ot-Bu
Scheme 19.
Ot-Bu
128
129
F: 95%, 90%ee
F: 94%, 94%ee
OH
PhB(OH)2
OMe
O
O
O
MeO
MeO
[Pd(S,S-chiraphos)
(PhCN)2](SbF6)2
acetone-H2O, 0 °C
O
135
O
Ph
NHBn
O
Me
OH
O
Me
Ot-Bu
130
131
132
MeO
N
ð31Þ
TsOH
F:90%, 89%ee B:97%, 92%ee D:61%, 91%ee
All reactions were conducted in dioxane-H2O.
A: [Rh(binap)(nbd)]BF4, Et3N, rt, 6 h.
136 (99%, dr 16:1)
137 (94%, 95%ee)
B: [Rh(binap)(nbd)]BF4, Et3N, 50 °C, 16 h
C: Rh(acac)(C2H4)2, 118, KOH, 50 °C, 6 h.
D: [Rh(nbd)2]BF4, 119a, Et3N, rt, 1-16 h.
E: [Rh(nbd)2]BF4, 116, K2CO3, 20 °C, 5 h.
F: [Rh(nbd)2]BF4, 116, KOH, 50~60 °C, 6 h.
O
CHO
Ph
MeO
B(OH)2
Scheme 18.
[Pd(S,S-chiraphos)
(PhCN)2](SbF6)2
acetone, aq. HBF4
0 °C
OH
OH
Addition of arylboronic acids to 135 affords a diastereomeric
mixture of hemi acetals 136, which give optically active chro-
mens with 95% ee via acid-catalyzed dehydration (eq 31).112
1,4-Addition to unsaturated aldehydes is very slow due to
the formation of hemi acetal in aqueous solution. The reaction
with trans-ꢁ-arylenals proceeds smoothly in the presence of
HBF4 to afford optically active 3,3-diarylalkanals with high
enantioselectivities in the range of 86–97% ee. The protocol
provided a method for short-step synthesis of optically active
(+)-(R)-CDP 840 (eq 32).113
Ph
OMe
OMe
O
O
ð32Þ
CHO
N
138 (70%, 94%ee)
(+)-(R)-CDP 840

1548 Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) AWARD ACCOUNTS
OTf
RO
B(OH)2
[Rh(nbd)2]BF4
(R,R)-chiraphos
KOH, dioxane-H2O
60 °C
CO2Me
CO2t-Bu
O
RO
CO2t-Bu
O
RO
CO2Me
1. NaHMDS
THF, -78 °C
2. NaH
CO2t-Bu
O
143
R= n-C3H7
O
O
O
3. Tf2O
144 (88%, 89% ee)
145 (55 %)
OMe
OMe
OMOM
O
OMOM
RO
O
RO
1. H2, Pd(OH)2
CO2t-Bu
CO2t-Bu
PdCl2(dppf)
K3PO4
2. LiOH, THF, 60 °C
toluene-H2O
60 °C
O
O
147
O
146 (90%)
O
OMe
O
OH
O
known method
CO2H
SmithKline Beecham's
endothelin receptor antagonist
O
O
Scheme 20.
Although the palladium-catalyzed protocol has been limit-
edly used for unsaturated ketone and aldehyde derivatives, ad-
ditions to aryl esters (139, R ¼ Ph and 4-MeCOPh)122 and N-
acylamides (141)115 exceptionally provide 1,4-addition prod-
ucts (eqs 33 and 34). The dicationic palladium–chiraphos cat-
alyst is again recognized to be the best catalyst to afford opti-
cally active esters 140 with enantioselectivities of up to 97%
ee and amides 142 of up to 98% ee.
1,3-Diarylindane-2-carboxylic acids such as 147 are highly
potent antagonists, selective for endothelin receptors among
non-peptide antagonists reported by SmithKline Beecham123
and Merck–Banyu.124 The first catalytic synthesis was accom-
plished by 1,4-addition catalyzed by a rhodium–chiraphos
complex (Scheme 20).105 The strategy has a structural flexibil-
ity for both top and bottom aryl groups for parallel synthesis of
drug candidates.
One-step enantioselective synthesis of optically active 1-
aryl-1H-indenes 149 is achieved by tandem 1,4-addition and
aldol condensation using a palladium(II)–chiraphos catalyst
in acidic media (Scheme 21).114,122 The desired 149 are pro-
vided in 60–99% yields and with 90–97% ee in the presence
of HBF4. The protocol provides a simple, short-step access
to an indene intermediate 146 employed for the total synthe-
sis of an endothelin receptor antagonist 147 shown in
Scheme 20.
3.5 Nucleophilic Additions to C=O and C=N. Less
attention has been paid to Grignard-type reactions of
nonmetal element compounds, but metal-catalyzed reactions
of B and Si compounds are of interest due to their compatibil-
ity with a wide range of functional groups and their potential
applications to asymmetric synthesis. In this field, the rho-
dium(I)-catalyzed addition of arylstannanes to ketones and
aldehydes was first reported by Oi, Inoue, and co-worker in
1997.125 This discovery was followed by reports of analogous
reactions of B, Si, and Bi compounds with aldehydes,102,126–129
ketones, and aldimines.130,131 The reaction of arylboronic acids
Me
O
a
ð33Þ
ð34Þ
O
Ph
OR
Ph
OR
140 (71%, 97%ee)
139 (R=4-AcPh)
OMe
O
O
b
O
O
R
N
Ph
Ph
R
N
Ph
Ph
142
141
R= Ph (74%, 98%ee), CH3 (96%, 92%ee)
n-C3H7 (77%, 90%ee)
a) 4-MeC6H4B(OH)2, [Pd(S,S-chiraphos)
(PhCN)2](SbF6)2, acetone-H2O, 50 °C
b) 3-MeOC6H4B(OH)2, [Pd(S,S-chiraphos)
(PhCN)2](SbF6)2, DMF-H2O, 50 °C

N. Miyaura
Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) 1549
OMe
O
O
OMOM
O
Scheme 4
O
B
HO
CHO
Br
4 steps
RO
O
O
EtO
EtO
O
153
O
154 (67%)
Me
HO
CO2Ph
148 (R= n-C3H7)
ð37Þ
[Rh(cod)Cl]2
K2CO3
THF-H2O, rt
OMe
Me
155 (79%)
CO2Et
OMOM
The addition of arylboronic acids to N-phenylsulfonyl
aldimines, RCH=NSO2Ph (R = alkyl, aryl, and 1-alkenyl),
takes place at 95 ꢀC in the presence of a rhodium catalyst
(eq 38).130–132 [Rh(cod)(MeCN)2]BF4 (3 mol %) is recognized
to be the best catalyst for aryl aldimines and Rh(acac)(coe)2/
i-Pr3P for alkyl and 1-alkenyl aldimines. Analogous reactions
of arylboronic esters, such as 1,2-ethanediol and 1,3-propane-
diol esters, are slower than those of arylboronic acids, but they
smoothly occur in the presence of two equivalents of Et3N.
For enantioselective addition, the bidentate phosphoramidite
(119b, N–Me–BIPAM) results in high enantioselectivities of
up to 99% ee (eq 39).133
O
RO
B(OH)2
O
CO2Ph
O
[Pd(R,R-chiraphos)
(PhCN)2](SbF6)2
AgSbF6
O
O
DMF-iPrOH, 45 °C
149 (70%)
OMe
O
OMOM
RO
MeO
CO2Ph
H2, Pd/C
MeO
a
ð38Þ
Ph
NSO2Ph
N
H
O
SO2Ph
O
150 (88%, 95%ee)
156 (99%)
Scheme 21.
O
COOMe
NTs
NTs
is catalyzed by rhodium(I)–bisphosphine complexes having a
large P–Rh–P angle such as dppf,126 but bulky and donating
monophosphines such as i-Pr3P and t-Bu3P remarkably accel-
erate the reaction when one equivalent of phosphine to a
rhodium metal complex is used (eqs 35 and 36).102,127 The re-
action is used for a catalytic ring closure via the intramolecular
addition of 156 to a !-keto carbonyl group (eq 37).102,128 The
required key intermediates 155 are available by Z selective
hydroboration of the corresponding terminal alkynes shown
in Scheme 4.
b
ð39Þ
H
O
O
157 (96%, 99%ee)
a) PhB(OH)2, [Rh(cod)(MeCN)2]BF4, dioxane, 95 °C
b) 1) ArB(OH)2, Rh(acac)(=)2/(R)-N-Me-BIPAM
(119b), DME, 50°C, 2) K2CO3
O
O
I would like to express my sincere gratitude to all of the
staff, research associates, and students who greatly contributed
to the research discussed here, especially Associate Professor
Tatsuo Ishiyama and Assistant Professor Yasunori Yamamoto.
Also, I am greatly indebted to Professor John F. Hartwig at
University of Illinois, Fumiyuki Ozawa at Kyoto University
and Ilya D. Gridnev aty Tokyo Institute Technology for their
contributions to the elucidation of the mechanisms of catalytic
cycles and their helpful discussion.
PhB(OH)2
ð35Þ
DME-H2O
Ph
CHO
151
HO
Rh(acac)(coe)2, t-Bu3P, 25 °C 98%
Rh(acac)(CO)2, dppf, 80 °C 93%
Ph
Ph
OH
PhB(OH)2
Ph
H
ð36Þ
References
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t-Bu3P
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2

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preparation.

N. Miyaura
Bull. Chem. Soc. Jpn. Vol. 81, No. 12 (2008) 1553
Norio Miyaura was born in Hokkaido, Japan 1946. He received his B.S. and Ph.D. degrees from
Hokkaido University in 1969 and 1976, respectively, under the guidance of Professor Akira
Suzuki. In 1981, he joined to J. K. Kochi group at Indiana University to study the catalytic
epoxidation of alkenes with metal salen complexes. He was promoted to Assistant Professor in
1971 and an Associate Professor in 1991 and Professor at Hokkaido University in 1994. His
current interests are mainly in the field of transition-metal-catalyzed reactions of organoboron
compounds with emphasis of applications to organic synthesis. For these studies, he received the
Chemical Society of Japan Award for Creative Work in 1996, the Japan Synthetic Organic Chem-
istry Award in 2007, and the Chemical Society of Japan Award in 2007.