04/05/2017_Lecture:11-12

A. C-C bond forming reactions

• Kumada coupling
• Hiyama coupling
• Sonogashira coupling
• Buchwald-Hartwig cross-coupling (C-N/C-O Bond
Formation)
• Ulmann reaction (C-N/C-O Bond Formation)
• Pd catalyzed Carbonylation
• Pd catalyzed Cyanation
• Take-Home Exam Discussion
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 Suzuki Stille
R
R Negishi
Pd R
Catalyzed
Kumada
Coupling R
Chemistry
OR RSnR3
R
B
OR RZnX r Pd
o
Ni
RMgX R Hiyama

X RSiR3
+ Pd(0)
HC CR R
X= I, Br, Cl,
OTf Sonogashira
H2C R
Several
R
Coupling R

Reactions CO/ HN
Nucleophile
Zn(CN)2 R Heck
With
Different R
Substrate O N
R
CN
Nu
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Buchwald-Hartwig 2
May03-2014 Cyanation
Carbonylation
 Organosilanes
RMgX/RLi inactive but activated by a F-
very reactive and (TBAF/TASF) or base
less chemoselective (NaOH).

Organo Zinc
Organotin moisture sensitive,
compounds less reactive
toxic, less reactive

Organo Copper
Organo Boron very reactive &
expensive, less less chemoselective
reactive, of ten
not stable 

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Kumada coupling
• In 1972, Robert Corriu and Makoto Kumada reported a cross coupling
reaction between a Grignard reagent and an organic halide. Procedure
uses typically Ni or Pd, to couple combination of 2 alkyl, aryl or vinyl
groups.
• The reaction is notable for being among the first reported catalytic cross-
coupling methods. Despite the subsequent development of alternative
reactions (Suzuki, Sonogashira, Stille, Hiyama, Negishi), the Kumada
coupling continues to enjoy many synthetic applications.
- Industrial-scale production of aliskiren, a hypertension
medication.
- Polythiophenes, useful in organic electronic devices.

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History
The first catalytic coupling of Grignard reagents with
organic halides using Co catalysts in 1941 by Karasch and
Fields.

In 1971, Tamura and Kochi elaborated on this work in a series

of publications demonstrating the viability of catalysts based on
Ag, Cu and Fe. However, these early approaches produced
poor yields due to substantial formation of homocoupling
products (two identical species are coupled).

These efforts culminated in 1972, when the Corriu and Kumada

groups concurrently reported the use of Ni-containing catalysts.
With the introduction of Pd catalysts in 1975 by the Murahashi
group, the scope of the reaction was further broadened.

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Mechanism :
According to the widely accepted mechanism, the Pd-catalyzed Kumada
coupling is understood to be analogous to Pd's role in other cross coupling
reactions.
Rate-determining oxidative addition occurs more slowly than with Ni catalyst
systems.

Subsequent
transmetalation
Isomerization is with the
necessary to Grignard
bring the organic reagent forms
ligands next to a hetero-
each other into organometallic
mutually cis complex.
positions.
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 Organic halides and pseudohalides
The Kumada coupling successful w a variety of aryl or vinyl halides. In place of the
halide reagent pseudohalides can also be used, and the coupling has been shown
to be quite effective using OTs and OTf species in variety of conditions.

Despite broad success with aryl and vinyl couplings, the use of alkyl halides is less
general due to several complicating factors.

Having no π-electrons, alkyl halides require different oxidative addition

mechanisms than aryl or vinyl groups, and these processes are currently poorly
understood. Additionally, the presence of β-H makes alkyl halides susceptible to
competitive elimination processes.

These issues have been circumvented by the presence of an activating group,

such as the carbonyl in α-bromoketones, that drives the reaction forward.
However, Kumada couplings have also been performed with non-activated alkyl
chains, often through the use of additional catalysts or reagents.

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 Reaction conditions:
The reaction typically is carried out in THF or diethyl
ether as solvent under an inert environment.

Due to the high reactivity of the Grignard reagent,

Kumada couplings have limited functional group
tolerance which can be problematic in large syntheses.

Grignard reagents is sensitive to protonolysis from even

mildly acidic groups such as alcohols. Therefore,
reactions are done under non-acidic conditions. They
also add to carbonyls and other oxidative groups.

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 Stereoselectivity in Kumada Reaction
Both cis- and trans-olefin halides promote the overall retention of
geometric configuration when coupled with alkyl Grignards. This
observation is independent of other factors, including the choice of
catalyst ligands and vinylic subsituents.

Kumada coupling using vinylic Grignard reagents proceeds without

stereospecificity.

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 Chemoselectivity in Kumada Reaction
Grignard reagents do not typically couple with chlorinated
arenes. This low reactivity is the basis for chemoselectivity for
nickel insertion into the C-Br bond of bromochlorobenzene
using a NiCl2-based catalyst.

NiCl2 catalyzed Kumada coupling shows haloselectivity on bromochlorobenzene.

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•
Hiyama Reaction:
Reaction of organosilanes with alkyl/aryl halides or triflates
• History:
• It was discovered by Tamejiro Hiyama and Yasuo Hatanaka in 1988
• Reaction of organosilanes with alkyl/aryl halides or triflates

Tamejiro Hiyama

New bond
3 mol % Pd(OAc)2 formed
6 mol % DABCO
F Si(OMe)3 + Br F
2 eq TBAF, dioxane,
80 oC, 4 hr, 85 %

J.-H. Li, C.-L. Deng, W.-J. Liu, Y.-X.

Xie, Synthesis, 2005, 3039-3044.

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Mechanism:
F Br

Pd0L2
Oxidative
Reductive Addition
elimination

L
L
PdII L Hiyama Reaction PdII Br
L

F
F F
NBu4+ F-

Si(OMe)3
trans-cis F Si(OMe)3
isomrization L Transmetallation NBu4+

PdII F
L Br
Si(OMe)3
F NBu +
4

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Synthetic Application
Hiyama Reaction is applied to the synthesis of many
natural products including Papulacadin D, an anti-
fungal agent.

Tris(dibenzylideneacetone)dipalladium(0)

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Sonogashira cross coupling:
• The direct palladium-catalyzed C-C bond formation
• Reaction of alkyne with vinyl/aryl halides or triflates using
Cu as co-catalyst New bond
formed
Pd(PPh3)4, CuI
Ph H + Br Ph
NEt3, reflux

Ph Ph
Ph Ph Pd(PPh3)4, CuI
Ph H +
I NEt2H, reflux,
90 % Ph
New bond
formed
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History:
• It was first published by K. Sonogashira, Y. Tohda, and N.
Hagihara in 1975
• Reaction of alkyne with alkyl/aryl halides or triflates in the
presence of Cu as co-catalyst and base
General Features: Kenkichi
•mild conditions such as room temperature, aq. media, and Sonogashira
mild base.
•Terminal alkynes are used.
•stereospecific .
• The catalyst can be Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppe)Cl, Pd(dppp)Cl2, and
Pd(dppf)Cl2
•Base used are NEt3, NHEt2
•Copper (I) is used as catalyst to accelerate the reaction.
•Rate of aryl/vinyl halides/triflates

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Mechanism: Ph
Br

Pd0L2

Reductive
elimination Oxidative
Addition

L
L
PdII L
Sonogashira PdII Br

Ph
coupling L

Cu Ph
Transmetallation
NHEt3+ I-

trans-cis
isomrization L
PdII Ph
CuII NEt3
L

H Ph

CuII

H Ph
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The geometry of the alkene is preserved!!!
cis (Z) and trans (E) dichloroethylene give the two different
geometrical isomers in >99% stereochemical purity.

Ph
Cl Pd(PPh3)4, CuI
(Z)
+ H Ph (Z)
Cl BuNH2, rt, Cl
5 hr, 95 %
Ph
Cl Pd(PPh3)4, CuI
(E)
+ H Ph (E)
Cl BuNH2, rt, Cl
5 hr, 98 %

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Synthetic Application
Sonogashira reaction is versitile reaction for the synthesis of a
variety of compounds including Altinicline. Altinicline is
a nicotinic acetylcholine receptor agonist that has shown
potential in the treatment of Parkinson’s disease, Alzheimer’s
disease, and Schizophrenia.

Altinicline

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Buchwald-Hartwig cross-coupling
• It was discovered by Stephen L. Buchwald and
John F. Hartwig (1994)
• Reaction of alkyl or aryl amines/alcohols with aryl
halides or triflates in the presence of base and Pd
catalyst Stephen L. Buchwald

General Features.

• milder conditions
• Amines may be Prim., Sec., aliphatic or aromatic
amines, imides, sulfonamides, sulfoximines.
• Best results with electron poor aryl halides John F. Hartwig
•  bulky base are used (KOtBu and LiHMDS)

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 Buchwald-Hartwig cross-coupling
• The direct palladium-catalyzed C-N and C-O bond
formation
• Reaction of amines/alcohols with aryl halides or
triflates Br
N Ph
Pd(dba)2 New bond
formed
+ HN Ph
P(o-tolyl)3, NaOt Bu

65 oC, 88 %
I
PdCl2[P(o-tolyl)3]2
+ N New bond
N LiHMDS, 100 C o
formed
H
94%

Br
HO Pd(OAc)2, PPh3 O
+
K3PO4, 100 oC
CO2Me CO2Me
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Mechanism:
N Br

Pd0L2
Oxidative
Reductive Addition
elimination

L
N
PdII L Buchwald-Hartwig L
H
PdII Br t
N
Cross Coupling L
OBu
Coordination

NaBr
Ht OBu L N
H
Base mediated PdII Br t
OBu
Pd-amine bond
formation L
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 Ullmann reaction
The copper-catalyzed C-C, C-N and C-O bond formation
• “Classic” Ullmann Reaction--synthesis of symmetric biaryls via
aryl halides.
•“Ullmann type” Reaction—reaction between amines/alcohols
with aryl halides

“Classic” Ullmann
Reaction-

“Ullmann type”
Reaction

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Reaction mechanism
“Classic” Ullmann Reaction.
Biaryls are available through coupling of the Ar-X with an excess of Cu at elevated
temp (200 oC). The active species is a Cu(I)-compd which undergoes oxidative
addition with the 2nd eq of halide, followed by reductive elimination and the formation
of the aryl-aryl carbon bond.

Ullmann type Reaction.

Ullmann-type reactions proceed through a catalytic cycle, and in one mechanism
Cu is postulated to undergo oxidation to Cu(III). As some Cu(III) salts have been
prepared, the suggestion for the mechanism is intriguing.

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Aryl Amines before Buchwaid-Hartwig

1. Scope has been expanded to include many Nu

2. Limited by Harsh reaction conditions
3. Multiple Mechanisms thought to be operating, catalyic
species poorly defined
Aryne Chemistry allows for amination of an expanded scope
of aryl halides

•Low Functional group compatibility

•Regiocontrol is a problem
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Palladium-Catalyzed Carbonylation—A Reaction
Come of Age

The Pd-catalyzed carbonylation of aryl and vinyl halides was first described more than
30 years ago by Richard Heck. Due to limitations the reaction has achieved less
prominence than the coupling reaction that also bears his name. Nevertheless, the
attractiveness of this chemistry for forming carbonyl derivatives has led many
researchers over the intervening years to attempt to increase the scope of the reaction
beyond the originally described bromide, iodide, and triflate substrates, with conditions
suited to large-scale application (particularly low pressure). To a large degree, this has
now been achieved. This review describes the progress made regarding the selection of
catalysts and conditions for this set of reactions, including illustrations from our own
research. Reactions can now be carried out with aryl chlorides and tosylates bearing a
range of substituents affecting both the electronic and steric properties of the substrate.
The complexities of the reaction, represented by the interplay of catalyst, CO pressure,
temperature, base, and solvent, make parallel screening desirable for optimization
studies.
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A General, Practical Palladium-Catalyzed Cyanation of (Hetero)Aryl
Chlorides and Bromides
Traditionally, benzonitriles are synthesized by diazotization of anilines followed by
a Sandmeyer reaction with superstoichiometric amounts of copper(I) cyanide.

Another common route to benzonitriles is the Rosenmund–von Braun reaction,

which typically entails heating superstoichiometric amounts of copper(I) cyanide
with an aryl iodide at elevated temperature.

Recent advances have allowed for the use of catalytic quantities of copper;
however, these approaches still have limitations.

The first Pd catalyzed cyanation method was reported by Takagi et al. 40 years
ago. Despite great advances cross-coupling procedures to form aryl nitriles have
obtained a reputation as being highly irreproducible.

The nontoxic cyanide source K4[Fe(CN)6]⋅3 H2O can be used for the cyanation of
(hetero)aryl halides. The application of palladacycle catalysts prevents poisoning
during catalyst formation, thereby allowing for low catalyst loadings, fast reaction
times, and wide heterocyclic substrate scope.

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 Palladium-Catalyzed Cyanation

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Importance of Nitriles
Aromatic nitriles have application in a variety of fields as both synthetic
intermediates and final targets.

Antineoplastic Letrozole, antidepressant Citalopram, and anti-HIV drug

Etravirine all possess an aryl nitrile moiety.

Letrozole 
non-steroidal aromatase inhibitor for the
treatment of hormonally-responsive breast
cancer after surgery.
Etravirine (anti-HIV drug) 
non-nucleoside reverse
transcriptase inhibitor (NNRTI).

Citalopram
 antidepressant drug of
the selective serotonin reuptake
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inhibitor (SSRI)  28
 FZB Chem 706-Take Home_Exam, April 01, 2017
Total marks = 15

Q4 (iv). Mukiyama Aldol reaction follows______________

Model. (0.5 mark)

Correct Q4 (iv).
Mukiyama Aldol reaction does not follow
_______________ Model. (0.5 mark)

A4 (iv). Mukiyama Aldol reaction does not follow

Zimermann Traxler Model. (0.5 mark)

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Q13. Give the name of the reactions and draw the product/ products for
Q11-Q13. (0.5 mark each)

BnO OBn
OH BnO OBn 5mol% Pd2(dba)3
CHCl3
t-Bu O Si
Si t-BuONa (2 eq) t-Bu O
I Si
t-Bu O Toulnene, 50oC, 5hr t-Bu O
OPiv
OPiv

A13. Name of the transformation: Hiyama coupling

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Q17. Write a plausible mechanism for the following
transformation. (0.5 mark)

Li, NH3
O O

O O O

Li
Li

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Q18. Identify Aldol motif in following cytotoxic macrolide A.
(1 mark)

OH Me Me
HO O 5
9 7
O
MeO 11 Me 3

Me O
Me 13 OH Me 1
17 19 O
15 H OH H
MeO O 27
HO 21 25 OMe
A OP
Me 23 Me
OH

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A18. Identify 1,3- OH Me Me
hydroxy ketone moiety. HO O 5
9 7
O
MeO 11 Me 3

Me O
Me 13 OH Me 1

20 PO 28 17 19 O
O 15
Me OMe H 20OH O
H
H2PO MeO 27
22 HO 21 25 OMe
A OP
Me 23 Me Me
Aldol 23
OH OH OH

C20-C28 (7)

28
PO 28 PO
O Me
Me OMe OMe

+ H 23
H 23 +
H
HO Me
OH O O
O
20-22 (8) 23-28 (9) 23-28 (9)
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 O H 28
A18. Identify 1,3- OH Me Me HO
OMe
25
hydroxy ketone moiety. HO O
9
5 22 OP
7 Me
O 23
MeO 11 Me 3 OH
Me O
20 PO 28 Me 13 OH Me 1
21 O
Me OMe 19 O
PO 17
22 15 H 20OH O H 28
MeO
Me 23 HO 21 25 OMe
A 22
OH OH OP
Aldol Me 23 Me
OH
C20-C28 (7)

O PO 28
Me OMe
22
21
+ H 23
HO Me 28 28
OH PO PO
O OMe Me
Me OMe
20-22 (8) 23-28 (9)
R 23
R 23 25
25 +
H
OH O
O O
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23-28 (9) 34
Q19. Fill in the boxes as indicated. Product will be enantiopure, so carefully assess
your stereochemical assignment and the syn or anti orientation of the two chiral
centres.
(1 mark) O O
O O
N N
H
O TiCln OTiCln
H
O
CH3 CH3 State the geometry of
the double bond
TS-A

O
O
N
H
H O TiCln
O
CH3 Draw the product from TS-B, but with the
TS-B same configration as in the TS

State the conincing reason

why TS-A would be expected
to be much higher in energy
than TS-B O O

O N

FIll in the missing substituents with the

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35
A19.

O O
O O
N N
H H
H O TiCln H O TiCln
O O
CH3 CH3
TS-A TS-B
State the convincing reason why TS-A would be expected to
be much higher in energy than TS-B

Reason:
Because both i-Pr group of akdehyde and oxazolidone are at
the back and will experience steric repulsion. Therefore, TS-A
is unfavoured.

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Q19. State the geometry of the double bond.

O 1 1
O TiClnO CH3
N2 1 O
OTiCln N2 H2
H O
2
CH3
1
Z-enolate

Cahn–Ingold–Prelog priority rules 

Double bonds: E/Z

If both high priority substituents are on the same side of the double bond, i.e. in
the cis configuration, then the stereoisomer is assigned a Z or Zusammen
configuration.

If, by contrast they are in a trans configuration, then the stereoisomer is

assigned an E or Entgegen configuration.
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37
Q19. Fill in the boxes as indicated. Product will be enantiopure, so carefully assess
your stereochemical assignment and the syn or anti orientation of the two chiral
centres.
(1 mark)

O
O
O N
O H
N O
H H
OH
H O TiCln CH3
O
CH3 Draw the product from TS-B, but with the
TS-B same configration as in the TS

State the conincing reason

why TS-A would be expected
to be much higher in energy
than TS-B O O OH

O N
CH3

FIll in the missing substituents with the

proper stereochemistry

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38
 O O O
O O O
N N N
H H H
H O TiCln H O TiCln H O
O O OH
CH3 CH3 CH3 Below the
TS-B plane

O O OH

O N
CH3

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