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C-C Bond formation

Greener way to go .

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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?

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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
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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

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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
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The Nobel Prize in Chemistry 2010


For palladium-catalyzed cross couplings in Organic Synthesis

Over the past four decades, organometallic coupling has been brought
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to a level of practical importance.
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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.

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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.

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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.

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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]

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General Reaction Mechanism for C-C


Bond Formation

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General mechanism of cross-coupling

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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.
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GREEN APPROACHES
Transition-Metal-Catalyzed Cross-Coupling Reactions

---Micellar Systems

--- Water as a solvent


--- Glycerol as a Solvent
--- Microwave

--- Mechanochemical

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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.

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Various Micellar Systems

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Various Micellar Systems


TPGS-750-M

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Synthesis of TPGS-750-M

a family of
vitamin E

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Synthetic Chemistry in Micellar Systems:


Heck Coupling

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Synthetic Chemistry in Micellar Systems:


SuzukiMiyaura Coupling

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Synthetic Chemistry in Micellar Systems:


SuzukiMiyaura Coupling

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Synthetic Chemistry in Micellar Systems:


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

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Synthetic Chemistry in Micellar Systems:


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.

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Microwave Synthesis: Definition

Solvent free or less solvent


Faster reaction
Easy isolation and purification

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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
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Microwave Synthesis:
Suzuki Reaction

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Microwave Synthesis:
Negishi & Kumada Reaction

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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
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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
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Mechanochemical Synthesis:
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.
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Mechanochemical Synthesis:
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

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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.
BITS Pilani, K K Birla Goa Campus

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.

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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.
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C-C Bond formation beyond FG transformation


H

FG

FG

Cross-Dehydrogenative Coupling (CDC)


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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
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CH Bond Functionalization

C-H bond activation remains


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


bond activation

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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)
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Pioneering Work

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Catalytic C-H bond activation

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Electrophilic Activation Mechanism


for CH Bond Insertion

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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

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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

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Electrophilic Activation Mechanism


for CH Bond Insertion

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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.
BITS Pilani, K K Birla Goa Campus

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%

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Directed Arylations: PdII/PdIV


Pathway

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Directed Arylations: PdII/PdIV


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
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Directed Arylations: PdII/PdIV


Pathway
Examples from anilide arylation

Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720.


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Directed Arylations: CrossCoupling of CH Substrates

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Directed Arylations: CrossCoupling of CH Substrates


An early example using acetate protected indoles

Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172.


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Directed Arylations: CrossCoupling of CH Substrates


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.
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Matt Gaunt's Meta Selective


CH Arylation

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


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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.


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Olefination Reactions via Aryl


CH Activation
Reaction methodology mimicking traditional Heck reaction

CH bond activation strategy replaces halogen functional group

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Olefination Reactions via Aryl


CH Activation

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Olefination Reactions via Aryl


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.
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Olefination Reactions via Aryl


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.
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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.
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Enantioselective CH Bond
Activation: Recent Developments
Stereochemical model for desymmetrizing alkylation reaction

Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2008, 47, 4882.
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Enantioselective CH Bond
Activation: Recent Developments
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.
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Enantioselective CH Bond
Activation: Recent Developments
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.
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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.
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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.
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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%
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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

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Unactivated CH Bond
Oxidation
Oxidation of Arenes Using Molecular Oxygen

Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654.
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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
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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
BITS Pilani, K K Birla Goa Campus

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
BITS Pilani, K K Birla Goa Campus

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

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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

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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%

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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.

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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

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