C-C Bond Formation

C-C Bond formation
Greener way to go .
1
BITS Pilani, K K Birla Goa Campus
Background
Society
is suffering from E3
________________________________
Economic crises
Energy crises
Environment crises
>97% of all manufactured products
involve one or more chemical
processes
of the resources removed from the
Earth, only 10% are retained in the
product and 90% are waste
how do we reconcile these facts with
maintaining a healthy Environment?
3
Green & Sustainable Chemistry

How to Synthesize Any Organic Compounds
In High Yields, Efficiently,
Selectively,
Economically, Safely
YES (ES)
GREEN CHEMISTRY
C-C Bond Formation Reaction is the most Happening Reaction

in the Organic Synthesis
3
C-C Bond formation Reactions

Carbon-carbon bond formation is fundamental to all of organic chemistry
Traditional Reactions
Nucleophilic Substitution
Nucleophilic Addition
Friedel-Crafts Reaction
Grignard Reaction
Modern Reactions
Pericyclic Reaction
Diels Alder Reaction
Organometallic Reaction
Recent Development
C-H Activation Methodologies
4
7
Cross-coupling:
Catalytic C-C bond formation
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 with formation of
a new carbon-carbon bond in the product.
Cross-couplings involve reactions between two different
partners and homo- couplings couple two identical partners.
Heck reaction
Suzuki reaction Stille cross coupling
Kumada coupling
Fukuyama Reaction
Buchwald-Hartwig reaction
Negishi coupling
Hiyama coupling
Ullmann reaction
The Nobel Prize in Chemistry 2010

For palladium-catalyzed cross couplings in Organic Synthesis
Over the past four decades, organometallic coupling has been brought
6
to a level of practical importance.
Carbon-Carbon Bond-Forming Reactions

The Heck Reaction:
The Heck reaction is a Pd-catalyzed coupling of a vinyl or aryl halide with an

alkene to form a more highly substituted alkene with a new CC bond.
Palladium(II) acetate [Pd(OAc)2] in the presence of a triarylphosphine [P(otolyl)3] is the typical catalyst.
The reaction is carried out in the presence of a base such as triethylamine.
The Heck reaction is a substitution in which one H atom of the alkene starting
material is replaced by the R' group of the vinyl or aryl halide.
Carbon-Carbon Bond-Forming Reactions

The Suzuki Reaction:
The Suzuki reaction is a palladium-catalyzed coupling of a vinyl or aryl halide
(R'X) with an organoborane (RBY2) to form a product (RR') with a new CC
bond.
Pd(PPh3)4 is the typical palladium catalyst.
The reaction is carried out in the presence of a base such as NaOH or NaOMe
The halogen is usually Br or I.
The Suzuki reaction is completely stereospecific.
Aromatic C-C Bond formation

a) Transition metal catalyzed cross-coupling
cat.
M
MX salts
M = B(OR)2, Suzuki
X = halogen, N2, OTf
= ZnX, Negishi
= SnR3, Stille
= SiR3, Hiyama
= MgX, Kumada
Most popular and reliable Aromatic C-C bond formation reaction is Suzuki-
coupling reaction.
Aromatic C-C Bond formation

b) Direct arylation/ C-H activation
cat.
H
HX salts
c) Cross Dehydrogenative Coupling (CDC)/ Tandem direct arylation/

double C-H activation
cat.
H
[O]
17
General Reaction Mechanism for C-C

Bond Formation
18
General mechanism of cross-coupling
18
Suzuki Coupling Reaction in Mass

Suzuki-coupling chemistry takes hold in commercial practice, from smallscale synthesis of screening compounds to industrial production of active
ingredients
Rouhi, A. M. Chem. & Eng. News 2004, 82, 49.
O2N
B(OH)2
Cl
O2N
Pd cat.
Cl
Cl
N
Cl
O
HN
Cl
Suzuki coupling on a massive scale takes place in this BASF plant in So Paulo,
Brazil, where the fungicide Boscalid is manufactured.
19
GREEN APPROACHES
Transition-Metal-Catalyzed Cross-Coupling Reactions
---Micellar Systems
--- Water as a solvent

--- Glycerol as a Solvent
--- Microwave
--- Mechanochemical
Reactions in Micellar Systems

Micelles are kind of amphiphiles molecules consisting of a hydrophilic
head group and a hydrophobic lipophilic tail, and are thus able to
interact with both polar and nonpolar compounds. When the
hydrophobic tail reaches a certain chain length, the amphiphiles reduce
the unusually high surface tension of water and are referred to as
tensides (or surfactants).
Micelles are especially simple

spherical supramolecules, which are
formed by amphiphiles in water or media
similar to water. A micellar system appears
to be homogeneous since these aggregates
are of colloidal size; however, in reality the
absorbed reactants are in a microheterogeneous two-phase system.
Various Micellar Systems
Various Micellar Systems

TPGS-750-M
Synthesis of TPGS-750-M
a family of
vitamin E
Synthetic Chemistry in Micellar Systems:

Heck Coupling

SuzukiMiyaura Coupling

SuzukiMiyaura Coupling

Negishi-Like Couplings in Water
Use of TPGS-750-M, PTS

Sonogashira coupling
in PTSH2O
Lipshutz, B. H.; Chung, D. W.; Rich, B. Org. Lett. 2008, 10, 3793.
Gelman, D.; Buchwald, S. L. Angew. Chem., Int. Ed. 2003, 42, 5993.
Microwave Synthesis: Definition
Solvent free or less solvent

Faster reaction
Easy isolation and purification
Microwave Synthesis:
Heck Reaction
For review on Microwave Cross-Coupling:

Vaibhav P. Mehta and Erik V. Van der Eycken Chem. Soc. Rev., 2011, 40, 49254936
Suzuki Reaction
Negishi & Kumada Reaction
Organic mechanochemistry
Types of grinding apparatus
Advantages:
Hand-Grinding
Greener method;
Minimal to no use of solvents;
Use of ambient conditions;
Facile ways of product separation;
Ball-Milling
Mechanochemical Synthesis:
Heck Reaction
catalyst loading just 0.5 mol%
Simple thermal heating performs
poorly
Su and coworkers, Appl. Organomet. Chem., 2012, 26, 145
Reaction conducted in solid PEG

No phosphine ligand was necessary
for the catalysis
Declerck, et al. Chem. Commun., 2012, 48, 11778.
A MizorokiHeck reaction generally requires elevated temperature, unfriendly solvent

and an inert atmosphere. In this study, the use of PEG in a vibratory ball mill at a speed
of 30 Hz allowed the reaction to proceed in air under mild conditions.
For review on Mechanochemical organic synthesis:
Guan-Wu Wang Chem. Soc. Rev., 2013, 42, 7668--7700
Suzuki Reaction
First Report
Waxy reaction mixture was difficult to

mill, inert sodium chloride was added to
the reaction mixture to make it sufficiently
powdery
Nielsen et al.Synth. Commun., 2000, 30, 3501.
HMDI-CS/Pd catalyst: prepared by

cross-linking of chitosan with
hexamethylene diisocyanate with the
simultaneous incorporation of Pd(OAc)2
F. Schneider and B. Ondruschka, ChemSusChem, 2008,1, 622
KFAl2O3 was used as the base and

milling auxiliary
Cravotto et al. New J. Chem., 2012, 36, 1304.
Sonogashira Reaction
First Report
Interestingly, palladium acetate and

triphenylphosphine did not give the
coupling product
Fulmer et al. Green Chem., 2009, 11, 1821.
R. Luque and D. J. Macquarie, Org. Biomol. Chem., 2009, 7, 1627.
Glaser reaction
CuI is good as catalyst for
alkyne homocoupling product
KFAl2O3 as the milling auxiliary
Glycerol as a Solvent
MizorokiHeck reaction:
Palladium nanoparticles catalyzed diarylation
of acrylate derivatives
Palladium-catalyzed Suzuki crosscoupling reaction
Cravotto, G.; Orio, L.; Gaudino, E. C.; Martina, K. ;

Tavor, D.; Wolfson, A. ChemSusChem, 2011, 4, 1130
1134.
Delample, M.; Villandier, N.; Douliez, J.-P.; Camy, S.;

Condoret, J.-S.; Pouilloux, Y.; Barrault, J.; Jrme, F.
Green Chem., 2010, 12, 804808.
Suzuki Coupling Advances

A simple and efficient protocol for a palladium-catalyzed ligand-free Suzuki
reaction at room temperature in aqueous DMF
Liu, C.; Ni, Q.; Bao, F.; Qiu, J. Green Chem. 2011, 13, 1260.
Suzuki Coupling Advances

Reusable and Efficient Pd(OAc)2/TBAB/PEG-400 System for Suzuki-Miyaura
Cross-Coupling Reaction under Ligand-Free Conditions
(HO)2B
R
0.01-3 mol% Pd(OAc)2

0.1 eq. TBAB, 2 eq. K2CO3
R
PEG-400, 110C, 4-24 h
X
X = Cl, Br
Liu, W. -J.; Xie, Y. -X.; Liang, Y.; Li, J. -H. Synthesis 2006, 860.
Ligand free Pd/C-catalyzed Suzuki-Miyura Coupling Reaction for the synthesis

of heterobiaryl derivatives
(HO)2B
R
N
Br
10% Pd/c, Na2PO4 12 H2O

i-PrOH:H2O, 80C
Kitamura, Y.; Sako, S.; Udzu, T.; Tsutsui, A.; Maegawa, T. Chem. Commun. 2007, 5069.
20
C-C Bond formation beyond FG transformation

H
FG
FG
Cross-Dehydrogenative Coupling (CDC)

11
CH Bond Functionalization
What is CH Bond Functionalization/Activation?
(C) is sp2 or sp3 carbon atom
(C)H bond is not a traditionally reactive bond (i.e. pka > 30-35);
Selectivity is a large issue due to the ubiquitous presence of C
H bonds in all organic molecules
CH Bond Functionalization
C-H bond activation remains

as a major challenge
The metals that helps in C-H

bond activation
The number of publications on the topic of C-H functionalization (blue bars) and on
the synthesis of natural products and pharmaceuticals by CH functionalization
(red dots and line) between 1980 and 2011 (taken from Angew. Chem. Int. Ed. 2012,
51, 8960 9009)
Pioneering Work
Catalytic C-H bond activation
Electrophilic Activation Mechanism

for CH Bond Insertion
CH Activation: Arylation of CH Bonds

Reaction methodology mimicking traditional cross coupling reactions
CH bond activation strategy replaces one or two of the preactivation

requirements
General Mechanism for CDC
H
C-H bond activation
Pd(0)
R1
[PdII]
H2[O]
Oxidation
[O]
PdII
R2
Reductive elimination
H
R1
PdII
R2
C-H bond activation
Electrophilic Activation Mechanism

for CH Bond Insertion
Directed Arylations: Pd0/PdII

Pathway
Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; Wang, Y. Angew. Chem. Int. Ed. 2007, 46, 5554.
Directed Arylations: Pd0/PdII

Pathway
Shi's arylation using amides as a directing group
Yu's arylation using carboxylic acids as the directing group
yield up to 92%
Directed Arylations: PdII/PdIV

Pathway

Pathway
Daugulis has published similar reactions using a variety of directing groups
Generally high yielding (>70% yield)

Diarylation observed if no ortho or meta substituent is present
Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. and references therein

Pathway
Examples from anilide arylation
Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720.

Directed Arylations: CrossCoupling of CH Substrates

An early example using acetate protected indoles
Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.


Two recent examples
65-100 equiv
11 examples 49% to 93% yield

Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.
cosolvent
8 examples 43% to 78% yield
Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem. Int. Ed. 2008, 47, 1115.
Matt Gaunt's Meta Selective

CH Arylation
Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.

Matt Gaunt's Meta Selective

CH Arylation
Reaction and substrate scope
18 examples
11-93% yield
Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593.

Olefination Reactions via Aryl

CH Activation
Reaction methodology mimicking traditional Heck reaction
CH bond activation strategy replaces halogen functional group

CH Activation

CH Activation
Olefination via carboxylic acid directing group
Amino acid ligands enable selectivity for unsymmetrical aryl substrates
Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315.

CH Activation
Olefination without a directing group shows selectivity for meta functionalization
relative to EWG's
Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072.
Enantioselective CH Bond
Activation: Recent Developments
Jin-Quan Yu has published two recent examples of desymmetrizing
aryl functionalization
First example involved alkylation using boronic acids
Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 4882.
Stereochemical model for desymmetrizing alkylation reaction
Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 4882.
Another example published by Jin-Quan Yu
2nd example olefination
Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460.
Bergman and Ellman have published a few examples of enantioselective
intramolecular cyclizations
Thalji, R. K.; Ellman, J. A.; Bergman, R. G. J. Am. Chem. Soc. 2004, 126, 7192.
Harada, J.; Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772.
Enantioselective intramolecular
cyclizations
Bergman and Ellman proposition on mechanistic aspect
Harada, J.; Thalji, R. K.; Bergman, R. G.; Ellman, J. A. J. Org. Chem. 2008, 73, 6772.
Enantioselective intramolecular
cyclizations: a similar example
Bergman and Ellman proposition on mechanistic aspect
Tsai, A. S.; Wilson, R. M.; Harada, H.; Bergman, R. G.; Ellman, J. A. Chem. Commun. 2009, 3910.
Aromatic halide Aromatization

Transition metal free Arylation
ArX
Ar
H
metal free
Sun, C.-L.; Li, H.; Yu, D.-G.; Yu M.; Shi, Z.-J. Nature Chemistry 2010, 2, 1044.
1,10-phenanthroline
KOt-Bu
R
X
TC
Examples
NC
74%
36%
Ph
78%
89%
OMe
MeO
MeO
MeOC
83%
81%
73%
68%
C-C Bond; Metal free: Another example

Iodine catalyzed Reaction
MeO
MeO
H
MeO
N
MeO
MeO
H
I2 (10 mol%)
LiAlH4
MeO
N
dioxane
48%
MeO
MeO
N
THF
95%
MeO
( )-cryptophenrine
Iida, H.; Watanabe, Y.; Yanaka, M.; Kibayashi, C. J. Org. Chem. 1984, 49, 2412.
Mechanism is unknown
Natural product ()-cryptopleurine synthesis
Unactivated CH Bond
Oxidation
Oxidation of Arenes Using Molecular Oxygen
Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
Unactivated CH Bond
Oxidation
Directed Functionalization of Arenes with CF3 Groups
Nitrogen heterocycles act as directing groups
Wang, X.; Truesdale, L; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132 (11), pp 36483649
Directed Functionalization of Arenes

with CF3 Groups
Possible mechanisms
TFA is necessary for reactivity

Cu(OAc)2 is not necessary for reactivity, however it provides a 30% bump in yield
Cu(OAc)2 could be a scavenger for the dibenzothiophene byproduct as a Lewis Acid
Dibenzothiophene byproduct could also reduce PdII to Pd0 and Cu(OAc)2 could act as a
reoxidant
Wang, X.; Truesdale, L; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132 (11), pp 36483649
CDC without metal catalyst

R1
R1
DDQ
R3
R3
R2
R2
Zhang, Y., Li C. J. J. Am. Chem. Soc. 2006, 128, 4242.
Examples
78%
OMe
Br
68%
65%
Me
O
O
53%
30%
OH
40%
CH3
O
CDC without metal catalyst

Possible Mechanism
R1
R1
O
Cl
CN
Cl
SET
CN
CN
Cl
CN
O
Cl
HO
R1
CN
CN
Cl
O
H
Cl
O
H
R1
R3
O
R2
R3
R2
O
R2
O
H
R3
OH
Cl
CN
Cl
CN
OH
BITS Pilani, K K Birla Goa15
Campus
Other Cross-Coupling Reactions: Recent outcome

sp3-sp
sp -sp
Org. Lett.
2004, 6, 4997.
J. Am. Chem. Soc.

2004, 126, 11810.
R1
R2 N
CH
R3
R4
R1
NH
R3
R1
R2 N
CH
R3
R2 N
CH
R4
N
H
R2 N
CH
R4
R1
J. Am. Chem. Soc.

2005, 127, 6968.
sp3-sp2
R3
H
R6
R4
R5
R1
R2 N
CH H
R3
R1
R2 N
CH
Eur. J. Org. Chem.
R3
2006, 103, 8928.
sp3-sp2
R1
NO2
R4
NO2
H
EWG
H
R4
EWG
J. Am. Chem. Soc.

2005, 127, 3672.
J. Am. Chem. Soc.

2006, 128, 14010.
sp3-sp3
R4
R6
R5
R4
R2 N
CH
EWG
R3
EWG
sp -sp
CDC Reaction Simple Dream

[cat.]
R1
R2 C H
R3
R6
H C R
5
R4
1/2 O2
HOH
R1
R6
R2 C C
R5
R3
R4
HOH
No protection of any functional Groups

Water as a solvent
Oxygen as a oxidant
[cat.] = [Fe], [Cu], or no catalyst
CDC with O2 in water

R4
H
R1
R2
N
NO2
R1
R2
N
O2 (1 atm.)
H2O
R3
H2O
NO2
R3
CuBr (cat.)
R4
R1
CO2R5
R2
N
CO2R5
H2O
CO2R5
R3
CO2R5
Basle, O.; Li, C. -J. Green Chem. 2007, 9, 1047.
Examples
N
Ph
NO2
90%
Me
90%
Ph
NO2
Me
NO2
95%
Ph
MeO
O
O
82%
Ph
OMe
N
EtO
O
Ph
OEt
O
80%
42
Disadvantages with CDC

Needed
Presence of heteroatom (usually O or N) C to be coupled as a
electrophilic partner.
Directing group activating the electrophilic position.
Take Home message

We expect that C-C bond formations based on Cross
Dehydrogenative Coupling will have a positive economic
and ecological impact on the next generation of Chemical
Synthesis.
- C. -J. Li

C-C Bond Formation

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C-C Bond Formation

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C-C Bond formation

Green & Sustainable Chemistry

C-C Bond Formation Reaction is the most Happening Reaction

C-C Bond formation Reactions

Suzuki reaction Stille cross coupling

The Nobel Prize in Chemistry 2010

Carbon-Carbon Bond-Forming Reactions

The Heck reaction is a Pd-catalyzed coupling of a vinyl or aryl halide with an

BITS Pilani, K K Birla Goa Campus

Carbon-Carbon Bond-Forming Reactions

BITS Pilani, K K Birla Goa Campus

Aromatic C-C Bond formation

X = halogen, N2, OTf

BITS Pilani, K K Birla Goa Campus

Aromatic C-C Bond formation

c) Cross Dehydrogenative Coupling (CDC)/ Tandem direct arylation/

General Reaction Mechanism for C-C

BITS Pilani, K K Birla Goa Campus

General mechanism of cross-coupling

BITS Pilani, K K Birla Goa Campus

Suzuki Coupling Reaction in Mass

--- Water as a solvent

BITS Pilani, K K Birla Goa Campus

Reactions in Micellar Systems

Micelles are especially simple

BITS Pilani, K K Birla Goa Campus

Various Micellar Systems

BITS Pilani, K K Birla Goa Campus

Various Micellar Systems

BITS Pilani, K K Birla Goa Campus

BITS Pilani, K K Birla Goa Campus

Synthetic Chemistry in Micellar Systems:

BITS Pilani, K K Birla Goa Campus

Synthetic Chemistry in Micellar Systems:

BITS Pilani, K K Birla Goa Campus

Synthetic Chemistry in Micellar Systems:

BITS Pilani, K K Birla Goa Campus

Synthetic Chemistry in Micellar Systems:

BITS Pilani, K K Birla Goa Campus

Synthetic Chemistry in Micellar Systems:

BITS Pilani, K K Birla Goa Campus

Microwave Synthesis: Definition

Solvent free or less solvent

BITS Pilani, K K Birla Goa Campus

For review on Microwave Cross-Coupling:

BITS Pilani, K K Birla Goa Campus

BITS Pilani, K K Birla Goa Campus

Reaction conducted in solid PEG

A MizorokiHeck reaction generally requires elevated temperature, unfriendly solvent

Waxy reaction mixture was difficult to

Nielsen et al.Synth. Commun., 2000, 30, 3501.

HMDI-CS/Pd catalyst: prepared by

KFAl2O3 was used as the base and

Interestingly, palladium acetate and

Fulmer et al. Green Chem., 2009, 11, 1821.

R. Luque and D. J. Macquarie, Org. Biomol. Chem., 2009, 7, 1627.

BITS Pilani, K K Birla Goa Campus

Palladium-catalyzed Suzuki crosscoupling reaction

Cravotto, G.; Orio, L.; Gaudino, E. C.; Martina, K. ;

Delample, M.; Villandier, N.; Douliez, J.-P.; Camy, S.;

Suzuki Coupling Advances

BITS Pilani, K K Birla Goa Campus

Suzuki Coupling Advances