GHEPCAP

General Method to Make a Bond in Organic Synthesis
R R' Rδ+ + R'δ–

electrophile nucleophile
R R' Rδ+ + R'δ–

δ+
δ– Br Csp3 – Csp3 Bu
Bu2CuLi +
nucleophile electrophile
Corey-Posner, Whitesides-House reaction

R R' Rδ+ + R'δ–

δ– MgBr δ+ Br Csp2 – Csp2

+
Me Me
R R' Rδ+ + R'δ–

δ– MgBr δ+ Br Csp2 – Csp2

+
Me Me
δ– MgBr δ+ Br
???
+
RO RO2C
O nucleophile electrophile
How to make this transformation occur?

Carbon–Carbon Bond Formation via Cross-Coupling Reactions
δ– MgBr δ+ Br
???
+
RO RO2C
“A coupling reaction in organic chemistry is a catch-all term for a variety of

reactions where two hydrocarbon fragments are coupled with the aid of a
metal catalyst.”
via wikipedia
Carbon–Carbon Bond Formation via Cross-Coupling Reactions
δ– MgBr δ+ Br
???
+
RO RO2C
“A coupling reaction in organic chemistry is a catch-all term for a variety of

reactions where two hydrocarbon fragments are coupled with the aid of a
metal catalyst.”
via wikipedia
2010 Nobel Prize in Chemistry was awarded to Ei-ichi Negishi, Akira Suzuki,
and Richard F. Heck for their research on cross coupling reactions.
How many cross-coupling reactions have been known?

Cross-Coupling Reaction Discovery
R–SiR3 + R'X/Pd
Hiyama coupling (1988)
R–B(OH)2+R'X/Pd, base
Suzuki reaction (1979)
R–SnR3+R'X/Pd
Stille coupling (1978)
RZnX + RX/Pd or Ni
Negishi coupling (1977)
RC≡CH+ArX/Pd, Cu
Sonogashira coupling (1975)
Alkenes+ArX/Pd, base
Heck reaction (1972)
RMgBr+ArX/Pd or Ni
Kumada coupling (1972)
ArH+ArN2X/base Alkene + RX/Pd, base R2NX + ArX/Pd
Gomberg-Bachmann Cassar reaction (1970) Buchwald–Hartwig
reaction (1924) reaction (1994)
R2CuLi + R'X
2RC≡CH/Cu, O2 Gilman reagent R–ZnI + ArCO(SEt)/Pd
Glaser coupling (1869) coupling (1967) Fukuyama
reaction (1998)
ArX/Cu, Δ RC≡CH+ArX/Cu
Ullmann (1901) Castro-Stephens R–B(OH)2+ArCO(SEt)
2RX/Na coupling (1963) /Pd, CuTC
Wurt reaction RC≡CH+RC≡CX/Cu, base Liebeskind-Srogl
(1855) Cadiot-Chodkewicz coupling (1957) coupling (2000)
1850 1900 1950 2000

R–SiR3 + R'X/Pd
R–SnR3+R'X/Pd
RZnX + RX/Pd or Ni
RC≡CH+ArX/Pd, Cu
RMgBr+ArX/Pd or Ni
R2CuLi + R'X
reaction (1998)
1850 1900 1950 2000

R–SiR3 + R'X/Pd
R–SnR3+R'X/Pd
RZnX + RX/Pd or Ni
RC≡CH+ArX/Pd, Cu
RMgBr+ArX/Pd or Ni
R2CuLi + R'X
reaction (1998)
1850 1900 1950 2000

R–SiR3 + R'X/Pd
R–SnR3+R'X/Pd
RZnX + RX/Pd or Ni
RC≡CH+ArX/Pd, Cu
RMgBr+ArX/Pd or Ni
R2CuLi + R'X
reaction (1998)
1850 1900 1950 2000

R–SiR3 + R'X/Pd
R–SnR3+R'X/Pd
RZnX + RX/Pd or Ni
RC≡CH+ArX/Pd, Cu
RMgBr+ArX/Pd or Ni
R2CuLi + R'X
reaction (1998)
1850 1900 1950 2000

R–SiR3 + R'X/Pd
R–SnR3+R'X/Pd
RZnX + RX/Pd or Ni
RC≡CH+ArX/Pd, Cu
RMgBr+ArX/Pd or Ni
R2CuLi + R'X
reaction (1998)
1850 1900 1950 2000

R–SiR3 + R'X/Pd
R–SnR3+R'X/Pd
RZnX + RX/Pd or Ni
RC≡CH+ArX/Pd, Cu
RMgBr+ArX/Pd or Ni
R2CuLi + R'X
reaction (1998)
1850 1900 1950 2000

Which metals have been used in cross-coupling reaction?
Cross-Coupling Reaction: Metal Catalysts
Cross-Coupling Reaction: Metal Catalysts
This talk briefly mentions some cross-coupling reactions including Kumada,

Negishi, Suzuki; and Mizoroki-Heck reactions and their synthetic applications
Cross-Coupling Reaction: How Does It Work?
Cl NiCl2(dppe), 1 mol%
Me MgBr Me
Et2O
Csp 3
Csp2 Kumada JACS 1972, 94, 4374 98% yield
What is the reaction mechanism?

Organometallic Chemistry: The 18 Electron Rule
Organometallic Chemistry: Bonding with Ligands
Bonding with Ligands: Electron Counting
Bonding and Reactions in Transition Metal Complexes
Reactions in Transition Metal Complexes: Oxidative Addition
Reactions in Transition Metal Complexes: Oxidative Addition
Reactions in Transition Metal Complexes: Reductive Eliminations
Reactions in Transition Metal Complexes: Migratory Insertion
Reactions in Transition Metal Complexes: Migratory Insertion
Reactions in Transition Metal Complexes: CO Incorporation
Reactions in Transition Metal Complexes: Reversible Insertions
Palladium: The Most Widely Used Metal in Homogeneous Catalysis
Palladium: The Most Widely Used Metal in Homogeneous Catalysis
Mirozoki–Heck: an Organometallic Reagent Free Cross-Coupling
I I
PdCl2, 10 mol% PdCl2, 10 mol%
AcOK, MeOH nBu N
3
120 °C, 2 hrs 100 °C, 2 hrs

90% yield 75% yield
Mizoroki Bull. Chem. Soc. Jp. 1971, 44, 581 Heck J. Org. Chem. 1972, 37, 2320
Tsutomu Mizoroki succumbed to Richard Fred Heck (born August 15,

pancreatic cancer only nine years after his 1931) is an American chemist noted for
breakthrough discovery of the palladium- the discovery and development of the
catalyzed reaction. Heck reaction. (U. of Delaware)
http://cenblog.org/newscripts/2010/05/in-search-of-mizoroki-heck/
I I
AcOK, MeOH nBu N
3
120 °C, 2 hrs 100 °C, 2 hrs

90% yield 75% yield
“Unfortunately, Mizoroki died quite young, before he could do much

chemistry with palladium,” Heck says. “Maybe if he’d lived, it might’ve
been called the Mizoroki reaction instead.”
http://cenblog.org/terra-sigillata/2010/10/06/nobel-prize-in-chemistry-2010-to-heck-negishi-
and-suzuki-for-pd-catalyzed-cross-couplings/
I I
AcOK, MeOH nBu N
3
120 °C, 2 hrs 100 °C, 2 hrs

90% yield 75% yield
The good: well functional group tolerance, no organometallic reagent, no need dry
solvent and no need to fully deoxygenate solvents.
The bad: β–H elimination.
How the reaction works?

HX RX
LnPd(0)
reductive elimination oxidative addtition
base
X X
LPd H LPd R
(II) (II)
R'
R syn β–H elimination R'

migratory insertion
X H R'
X H R'
LPd
R LPd
(II) H
H (II)
H H
R
C–C bond rotation

HX RX
LnPd(0)
base
X X
LPd H LPd R
(II) (II)
R'

migratory insertion
X H R'
X H R'
LPd
R LPd
(II) H
H (II)
H H
R
C–C bond rotation

HX RX
LnPd(0)
base
X X
LPd H LPd R
(II) (II)
R'

migratory insertion
X H R'
X H R'
LPd
R LPd
(II) H
H (II)
H H
R
C–C bond rotation

HX RX
LnPd(0)
base
X X
LPd H LPd R
(II) (II)
R'

migratory insertion
X H R'
X H R'
LPd
R LPd
(II) H
H (II)
H H
R
C–C bond rotation

HX RX
LnPd(0)
base
X X
LPd H LPd R
(II) (II)
R'

migratory insertion
X H R'
X H R'
LPd
R LPd
(II) H
H (II)
H H
R
C–C bond rotation

The Heck Reactions: Examples
The Heck Reactions: In Situ formation of Pd(0)
The Heck Reactions: Hydropalladation-Dehydropalladation
The Heck Reactions: Hydropalladation-Dehydropalladation
Mirozoki–Heck Reaction: Synthetic Applications
Danishefsky JACS 1996, 118, 2843

Me Me
Boc
MeO MeO
BocN N
BnO I O BnO O
Pd2(dba)3, (o-tol)3P
N N
Me TEA,MeCN, RF Me
OAc OAc
MsO O MsO O
Me O Me O
83% yield
Fukuyama JACS 2002, 124, 6552
Me
BocN Me
NBoc O
Me O
O
Me Pd2(dba)3, 20 mol%
O
(2-furyl)3P, 20 mol% NR
NR RN I
DMA, 90 °C NR
NBoc
O
Me NBoc
Me R=SEM O
Me
Me
66% yield
Overman JACS 2001, 123, 9468
Mirozoki–Heck Coupling: Tandem Reactions
de Meijere, A. Tetrahedron 1996, 52, 11545

The Sonogashira Reaction: Coupling to Alkynes
The Sonogashira Reaction: Coupling to Alkynes
The Sonogashira Coupling: Coupling to Alkynes
The Sonogashira Coupling: Coupling to Alkynes
Cross-Coupling of Organometallics and Halides
Cross-Coupling Reaction: The Kumada Cross-Coupling
Me MgBr Me
Et2O
Csp 3

Me MgBr Me
Et2O
Csp 3
Makoto Kumada (17 January 1920 – 28 June 2007) Professor of Chemistry first at
Osaka City University and at Kyoto University in Japan.
In 1972, Kumada's group reported nickel-catalyed cross coupling reactions nearly

concurrently with the Corriu group working in France. The Kumada coupling now
bears his name.
Me MgBr Me
Et2O
Csp 3
Makoto Kumada (17 January 1920 – 28 June 2007) Professor of Chemistry first at
Osaka City University and at Kyoto University in Japan.
In 1972, Kumada's group reported nickel-catalyed cross coupling reactions nearly

concurrently with the Corriu group working in France. The Kumada coupling now
bears his name.
What is the reaction mechanism?

Ar–R LnM(0) ArX
oxidative addtition
reductive elimination
Ar Ar
LM R LM X
(II) (II)
transmetalation
MgX2 RMgBr
Similar to:
Ar–R LnM(0) ArX
R–X
oxidative addtition
Mg/Et2O
Ar Ar
R–Mg–X
LM R LM X
(II) (II)
transmetalation
MgX2 RMgBr
Ar–R LnM(0) ArX
oxidative addtition
Ar Ar
LM R LM X
(II) (II)
transmetalation
MgX2 RMgBr
Ar–R LnM(0) ArX
oxidative addtition
Ar Ar
LM R LM X
(II) (II)
transmetalation
MgX2 RMgBr
Similar to: NaCl + AgNO3 –> NaNO3 + AgCl↓

Ar–R LnM(0) ArX
oxidative addtition
Ar Ar
LM R LM X
(II) (II)
transmetalation
MgX2 RMgBr
Cross-Coupling Reaction: Kumada Cross-Coupling
Me MgBr Me
Et2O
Csp 3
The good: no or very modest β–H elimination with when using Grignard reagents.
The bad: functional group tolerance problem-no base sensitive functional group.
Kumada Cross-Coupling: Synthetic Application
Me MgBr Me
Et2O
Csp 3

Me MgBr Me
Et2O
Csp 3
Me Me
Pd(Ph3P)4, 5 mol%
MgBr
I O PhH, 60–70 °C, 30 min O
Csp 2
Me Me Me Me
Csp2 JACS 2001, 123, 10722 88% yield
Maintain alkene configuration

S S Me
Me PdCl2(dppf), 23 mol%
Me Me OR
OR MgBr N
N Et2O, RT, 12 h
Csp 3
Me I Me
JOC 2002, 67, 7737 75% yield
Csp2
S S Me
Me PdCl2(dppf), 23 mol%
Me Me OR
OR MgBr N
N Et2O, RT, 12 h
Csp 3
Me I Me
JOC 2002, 67, 7737 75% yield
Csp2
O O
OEt OEt
P P
O OEt O OEt
OMe Ni(acac)2, 10 mol% OMe

MeMgCl
THF, 0 °C, 10 min
TESO Csp3 TESO
Me C5H11 Me C5H11
Me OMe Me OMe
Csp2 JOC 2002, 67, 8771 90% yield

Kumada Cross-Coupling: Asymmetric Versions
OTf Ni(dppp), 10 mol% Me

MeMgCl
OTf MTBE, 40 °C, 10 min Me
Csp3
Csp2 Org. Proc. Res. Dev. 2003, 7, 644 82% yield,

89% ee
Kumada Cross-Coupling: Asymmetric Versions
OTf Ni(dppp), 10 mol% Me

MeMgCl
OTf MTBE, 40 °C, 10 min Me
Csp3
Csp2 Org. Proc. Res. Dev. 2003, 7, 644 82% yield,

89% ee
O
Me(or Et) O
NiCl2•glyme/L, 7 mol%
R Me(or Et)
R
Br DME,– 40 °C, 16–32 h
Ar O O
Ar–MgX
up to 95% ee N N
Fu JACS 2010, 132, 1264 Ph L Ph
The Stille Coupling
The Stille Coupling: Mechanism
The Stille Coupling: Mechanism
The Stille Coupling: Examples
The Stille Coupling: CO Insertion
The Stille Coupling: CO Insertion
Suzuki-Miyaura Cross-Coupling
Bu O Me
B Me Pd(Ph3P)4, 10 mol%
Bu
O Br Me
Me PhH, 80 °C
81% yield
Suzuki Tetrahedron Lett. 1979, 20, 3437
Bu O Me
Bu
O Br Me
Me PhH, 80 °C
81% yield
Akira Suzuki (born September 12, 1930) is a

Japanese chemist and Nobel Prize Laureate
(2010), who first published the Suzuki reaction,
the organic reaction of an aryl- or vinyl-boronic
acid with an aryl- or vinyl-halide catalyzed by a
palladium(0) complex, in 1979.
Bu O Me
Bu
O Br Me
Me PhH, 80 °C
81% yield
Akira Suzuki (born September 12, 1930) is a

Japanese chemist and Nobel Prize Laureate
(2010), who first published the Suzuki reaction,
the organic reaction of an aryl- or vinyl-boronic
acid with an aryl- or vinyl-halide catalyzed by a
palladium(0) complex, in 1979.
Which aspects made the Suzuki reaction be interesting?

Suzuki-Miyaura Reaction: Advantages and Disadvantages
Bu O Me
Bu
O Br Me
Me PhH, 80 °C
81% yield
The good: Mild condition, safe by-products, wide

functional group tolerance
The bad: need base, which cause racemization, aldol

reaction.
Prof. Akira Suzuki

Suzuki-Miyaura Cross-Coupling: Reaction Mechanism
R'–R LnM(0) RX
oxidative addtition
R R
LM R' LM X
(II) (II)
transmetalation
–BXY R'BY2, base

2Z
The Suzuki Coupling: Boronic Acids and Halides
Suzuki-Miyaura Cross-Coupling: Synthetic Applications
Me
O
Me
Me Me BocN
Me O
R O Me
B Me BocN O
O Me PdCl2(dppf)2, K2CO3 N
H
DME, 80 °C, 2 h R
O NHCbz
NHCbz N
H OMe
I
O OMe O
75% yield
Danishefsky ACIE 2002, 41, 512
Suzuki-Miyaura Cross-Coupling: Synthetic Applications
OBn BnO
OH O OH O OMOM
OMOM Pd(Ph3P)4, Cs2CO3
O O
THF/H2O, RF, 20 h
Br
BF3K 42% yield
Molander JACS 2004, 126, 10313
Suzuki-Miyaura Cross-Coupling: Fu’s Asymmetric Version
O
Ph Me O
N
Ph Cl NiCl2•diglyme/L, 10 mol% Ph ∗ Me
N
racemic
Ph
KOtBu, n–C6H13OH
(BBN-9) Et2O/Hex, RT
54% yield
Ph Ph 90% ee
L:
MeHN NHMe
Fu JACS 2011, 133, 15362

Suzuki-Miyaura Cross-Coupling: ‘Inactive’ Alkyl Halides
Me
Br NiBr2•diglyme/L, 10 mol% Me
LiOtBu, i–BuOH
(BBN-9)
PhH, 40 °C
89% yield
tBu tBu
L:
N N
Fu JACS 2013, 135, 624

Negishi Cross-Coupling
nBu
Me Br Pd(Ph3P)4, 5 mol% Me
ClZn nBu
MeO2C THF, RT MeO2C

87% yield
Negishi Chem. Comm. 1977, 683
Prof. Ei-ichi Negishi

nBu
ClZn nBu
MeO2C THF, RT MeO2C

87% yield
Ei-ichi Negishi (born July 14, 1935) is a Japanese

chemist who has spent most of his career at Purdue
University, United States. He is best known for his
discovery of the Negishi coupling.
He was awarded the 2010 Nobel Prize in Chemistry
"for palladium catalyzed cross couplings in organic
synthesis”.

nBu
ClZn nBu
MeO2C THF, RT MeO2C

87% yield
The good: high reactive reagent but safe for

stereochemistry, safe by-products, wide functional
group tolerance.
The bad: doesn’t work with secondary and tertiary

alkylzinc reagents.

Negishi Cross-Coupling: Proposed Reaction Mechanism
R'–R LnM(0) RX
oxidative addtition
R R
LM R' LM X
(II) (II)
transmetalation
ZnX2 R'ZnX
Negishi Cross-Coupling: Synthetic Applications
OMe OMe
MeO Pd2(dba)3, Ph3P MeO
O ZnCl2,THF, RT O
Br N N Li N
NiPr2 N NiPr2
80% yield
OL 2002, 4, 2835
OMe OMe
MeO Pd2(dba)3, Ph3P MeO
O ZnCl2,THF, RT O
Br N N Li N
NiPr2 N NiPr2
80% yield
OL 2002, 4, 2835
Me
SEMO Me SEMO OTBDPS
OTBDPS
Pd(Ph3P)4, 5 mol%
I
THF, RT, 20 min
ZnCl
Me OTHP
Me OTHP 84% yield
JACS 1998, 120, 11198

OTBDPS
OTBDPS
I Me Me
Me
HN O Me
Pd(Ph3P)4, 5 mol% OMe HN O
iPr NHBoc
THF, RT, 20 min iPr NHBoc
Me Me
ZnCl 81% yield

OMe
JOC 1999, 64, 3000

Negishi Cross-Coupling: Fu’s Asymmetric Version
Br
NiBr2•diglyme/L, 10 mol%
R ∗ R
ZnI CsI, DCM/dioxane, –30 °C
racemic up to 91% yield

up to 95% ee
N O
L:
N
tBu
Fu JACS 2012, 134, 17003
Do we really need organometallic reagents in cross-coupling reactions?

Metal-Catalyzed C–C Bond Formation: Allylic Substitution
Metal-Catalyzed C–C Bond Formation: Cycloaddition
Metal-Catalyzed X–C Bond Formation
Metal-Catalyzed X–C Bond Formation
Metal-Catalyzed X–C Bond Formation: Nucleophilic Attach
Metal-Catalyzed X–C Bond Formation: Cobalt
Olefin Metathesis
Olefin Metathesis
Olefin Metathesis: Mechanism
Cross Metathesis
Ring-Opening Metathesis: Schrock’s Catalyst
Ring-Closing Metathesis: Grubb’s Catalyst
Metal-Catalyzed C–C Bond Formation: Olefin Metathesis
Ring-Opening Metathesis: Natural Product Synthesis

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General Method to Make a Bond in Organic Synthesis

R R' Rδ+ + R'δ–

R R' Rδ+ + R'δ–

Corey-Posner, Whitesides-House reaction

R R' Rδ+ + R'δ–

δ– MgBr δ+ Br Csp2 – Csp2

R R' Rδ+ + R'δ–

δ– MgBr δ+ Br Csp2 – Csp2

How to make this transformation occur?

“A coupling reaction in organic chemistry is a catch-all term for a variety of

“A coupling reaction in organic chemistry is a catch-all term for a variety of

How many cross-coupling reactions have been known?

1850 1900 1950 2000

1850 1900 1950 2000

1850 1900 1950 2000

1850 1900 1950 2000

1850 1900 1950 2000

1850 1900 1950 2000

1850 1900 1950 2000

This talk briefly mentions some cross-coupling reactions including Kumada,

Csp2 Kumada JACS 1972, 94, 4374 98% yield

What is the reaction mechanism?

120 °C, 2 hrs 100 °C, 2 hrs

Tsutomu Mizoroki succumbed to Richard Fred Heck (born August 15,

120 °C, 2 hrs 100 °C, 2 hrs

“Unfortunately, Mizoroki died quite young, before he could do much

120 °C, 2 hrs 100 °C, 2 hrs

The bad: β–H elimination.

How the reaction works?

R syn β–H elimination R'

How the reaction works?

R syn β–H elimination R'

How the reaction works?

R syn β–H elimination R'

How the reaction works?

R syn β–H elimination R'

How the reaction works?

R syn β–H elimination R'

How the reaction works?

Danishefsky JACS 1996, 118, 2843

de Meijere, A. Tetrahedron 1996, 52, 11545

Csp2 Kumada JACS 1972, 94, 4374 98% yield

Csp2 Kumada JACS 1972, 94, 4374 98% yield

In 1972, Kumada's group reported nickel-catalyed cross coupling reactions nearly

Csp2 Kumada JACS 1972, 94, 4374 98% yield

In 1972, Kumada's group reported nickel-catalyed cross coupling reactions nearly

What is the reaction mechanism?

Ar–R LnM(0) ArX

Ar–R LnM(0) ArX

Ar–R LnM(0) ArX

Similar to: NaCl + AgNO3 –> NaNO3 + AgCl↓

Ar–R LnM(0) ArX

Csp2 Kumada JACS 1972, 94, 4374 98% yield

Csp2 Kumada JACS 1972, 94, 4374 98% yield

Csp2 Kumada JACS 1972, 94, 4374 98% yield

Maintain alkene configuration

OMe Ni(acac)2, 10 mol% OMe

Csp2 JOC 2002, 67, 8771 90% yield