NPTEL – Chemistry – Principles of Organic Synthesis

Lecture 28

3.6.1 Introduction

Transition metals can be defined as an element whose atoms have an incomplete d-shell
or which can give rise to cations with an incomplete shell. Due to incompletely filled d-
orbitals it can exhibit a large number of oxidation states. The lower oxidation states can
act as reducing agent while the higher oxidation states act as oxidizing agents. Some
transition metals exhibit a pair of oxidation states in which the process of redox reaction
is very facile. Pd(0)/Pd(II), Cu(I)/Cu(II) and Ni(II)/Ni(IV) are examples of such oxidation
states. As such, these oxidation states may support catalytic cycles.

Transition metals can also bind to an organic ligand thus forming a metal-carbon bond.
The metal-carbon bond may have σ-character or π-character or both. In case of a bond
formation between a d-orbital of the metal with a s-containing hybrid orbital of carbon it
gives rise to a σ-organometallic compound. Similarly, if the bond is formed between a d-
orbital of a metal with π-orbitals of ligand then it gives rise to π-organometallic
compound. In the latter case, bonding is provided by both donation from a filled π-orbital
of the ligand to the empty orbital of metal and by the interaction of an unfilled π*-orbital
of the ligand with the filled metal d-orbital. Gilman‟s reagent is an example of the former
type of organometallic compounds while Zeise complex is an example of the latter
variety.

3.6.1 Titanium Catalysts

Titanium is a 3d series transition element belonging to Group IV. Thus, it has a low
valence shell electron density compared to other transition metals belonging to other
group. Since the valence shell electrons are strongly attracted by the nucleus, titanium has
a high ionization potential. However, once ionized, Ti can attain up to +IV oxidation
state. The cationic species are strong Lewis acids and, therefore, they have found
application in a wide variety of Lewis acid catalyzed reactions.

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3.6.1.1 Lewis Acid Catalysis

The Lewis acidity of TiCl4 is applied in case of aldol reaction, Micheal addition, Claisen
condensation and reductive hydrolysis among many other reactions. Some examples of
these are exemplified in Scheme 1.

Reductive Hydrolysis
NO2 O
TiCl3, H2O
O OMe O
MeO
Me Me

Claisen reaction

O O O
O pyridine O Me
Me
+ Me TiCl4 Me
O O
O O

Scheme 1

Regioselective intramolecular amination of alkynes has been accomplished using

CpTiCl3 which is key step for the total synthesis of the antifungal agent (+)-preussin
(Scheme 2).

BnO BnO
BnO
CpTiCl3

C7H15COCN N
NH2 Ph CN N
Ph H Ph Me C8H17

Preussin

Scheme 2

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3.6.1.2 Olefination
Titanium metallocenes alone do not serve much to the organic synthesis but when they
are used in conjunction with trimethyl aluminium they form interesting reagents for the
synthesis of terminal alkenes from carbonyl compounds. Tebbe‟s reagent having the
formula (η5-C5H5)2Ti CH2ClAlMe2 perform the same task as Wittig‟s reagent but the
higher reactivity of Tebbe‟s reagent allows even less reactive carbonyl compounds to be
transformed to the corresponding methylene compounds. It is prepared by the reaction of
titanocene dichloride with trimethyl aluminium in toluene (Scheme 3).

Cl Me
Ti + Al2Me6 Ti Al
Cl Cl Me

Scheme 3

Tebbe‟s reagent as shown above is not the active reagent. The active reagent, a
Schrock carbene, is formed by treating it with a mild Lewis base like pyridine. This then
reacts with the carbonyl group in a [2+2] cyclization which then undergoes ring opening
metathesis to form the alkene (Scheme 4).

O O

Me pyridine Me OEt
Ti Al Ti Me OEt
Cl Me

Scheme 4

The same transformation can also be accomplished with Petasis reagent that can
methylenate ketones, aldehydes and esters on thermolysis at 60 °C (Scheme 5).

Cl MeLi Me
Ti Ti
Cl Me

Petasis Reagent

Scheme 5

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Examples:

Me Me
O Tebee Reagent

Me Me Me Me
16%

M. Cortes, J. A. Valderrama, M. Cuellar, V. Armstrong, M. Preite, J. Nat. Prod. 2001,

64, 348.

Petasis Reagent
Me
Me Me
Me Me
Me 92%

N. A. Petasis, M. A. Patane, Tetrahedron Lett. 1990, 31, 6799.

McMurry reaction is also used to synthesize alkenes from dicarbonyl compounds using
Ti(0) generated in situ. The reduction may be carried out by a variety of reagents like Zn-
Cu couple, LiAlH4 and alkali metals Li, Na and K (Scheme 6). This reaction first
produces 1,2-diol which is then dehydrated on the surface of titanium into an alkene. The
reaction is not stereospecific since the two the carbon-oxygen bonds do not break
simultaneously.

K, TiCl3
2 Me CHO Me
Me
DME, reflux 7:3 trans:cis
C7H15
Me
Zn(Cu), TiCl3
OMe
DME, reflux C7H15
O

Scheme 6

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This methodology can be extended to ketoesters, where a cyclic enol ether is produced
which on hydrolysis gives cycloalkanone (Scheme 7).

Me Me
O O OMe O
LiAlH4, TiCl3 H+/H2O
Me 8
OMe
DME, reflux

Scheme 7

3.6.1.3 Polymerization
Perhaps the most famous titanium catalyst is a mixture of TiCl4 and AlMe3 which is
known as Zieglar-Natta catalyst. Today, a great variety of catalysts having a Ti, Zr or Hf
centre along with Mg or Al co-catalyst are known by this generic name. The
polymerization of alkenes carried out by these catalysts can be highly stereoregular by
suitable tailoring of the catalyst. This has been widely used for the polymerization of high
density polyethylene, polypropylene and polybutadiene among other alkenes. Zieglar-
Natta catalysts can be classified into 3 classes.
 Titanium chloride based catalysts. The catalysts are usually supported on silica
supports and can be used for homopolymerization as well as polymerization of
isotactic 1-alkenes.
 Metallocene based catalysts. Early transition metal metallocenes along with
methylalkoxyaluminium compounds as co-catalyst have been used for the
polymerization of alkenes. The metallocene complexes are usually bent sandwich
complexes with formula Cp2MCl2 (M= Ti, Zr, Hf).
 Coordination complexes as catalysts. A variety of coordination complexes of
different metals in conjunction with alkoxyaluminium as co-catalysts are known
to polymerize alkenes.

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1.6.1.4 Asymmetric Catalysis

The Lewis acidity of titanium has been used in asymmetric catalysis. Due to its strong
Lewis acidity, it can easily coordinate with heteroatoms like oxygen and nitrogen. Now if
the environment of the titanium centre is so modified such that the heteroatom containing
substrate can find stereoselectively, then asymmetric induction is possible. This is
achieved by attaching suitable chiral ligands to titanium centre which also tailors the
Lewis acidity of titanium. For examples, asymmetric ene and Diels-Alder reactions have
been demonstrated with excellent enantioselectivity in the presence of chiral titanium
complexes as chiral Lewis acid catalysts (Scheme 8-9).

Ti(OiPr)4
Y = Li
O Cl TiCl4 OY O OiPr
Ti Y=H
o OY Ti
O Cl -80 C to rt OiPr
O

TiCl2(OiPr)
53% ee, 31% yield 92% ee 2% yield
Y=H dry MS 4A
TiCl2(OiPr)
< 0.2% w/w H2O
Wet MS 4A

BINOL-Ti*
Wet MS 4A Active Catalyst Wet MS 4A or H2O

O
OH

Ph + H CO2nBu Ph CO2nBu Ti, Pd, Pt, Ni, Cu,

CH2Cl2, -30 oC Sc,Co, Cr, Rh

up to 98% ee 97% yield

M. Terada, Y. Matsumoto, Y. Nakamura, K. Mikami, Chem. Commun. 1997, 281.

Scheme 8

Ph Ph
O O Me H
10 mol% cat O O
H O Ph TiCl2
+ Me N O H
o Me O
-15 C O N O O
H
endo : exo 92 : 8 91% ee Ph Ph

K. Narasaka , N. Iwasawa , M. Inoue , T.Yamada , M. Nakashima , J. Sugimori,

J. Am. Chem. Soc. 1999, 111, 5340.

Scheme 9

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Chiral titanium-polymer complex has been used as recyclable catalyst for cyanohydrin
synthesis with high enantioselectivity (Scheme 10). The advantage of this protocol, the
catalyst can be recovered and recycled without loss of activity and selectivity.

R' R'

N N
1 mol % TiLn* Ti
O OH O O
2 equiv TMSCN O
R H CHCl , 0 oC, 16-48 h R CN O
3
O O
H3O+, rt, 1 h up to 98 % yield Ti
up to 88 e N N
R = aryl, benzyl, naphthyl
R' R' R' = Ph, -(CH2)4-
TiLn*
S. Sakthivel, T. Punniyamurthy, Tetrahedron: Asymmetry 2010, 21, 2834.

Scheme 10

Sharpless asymmetric epoxidation is one of the most famous examples of an

asymmetric reaction using titanium alkoxides. In this method, prochiral allylic alcohols
are stereoselectively oxidized to the corresponding epoxides using Ti(Oi-Pr)4, t-BuOOH
and (R,R) or (S,S)-diethyltartarate (Scheme 11).

Ti(O-iPr)4, t-BuOOH
O OH
OH L-(+)-DET

85% yield, 94% ee

Scheme 11

OEt
O O
E
EtO O EtO O
O O Me OH O O
Ti(Oi-Pr)4
DET i-PrO E Ti i-PrO E Ti + 2 i-PrOH
Ti Oi-Pr Ti
O O O O O
-4 i-PrOH O-iPr t-BuOOH O
O E O E Me
i-Pr i-Pr t-Bu
E = CO2Et

Scheme 12

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The reaction is believed to proceed through a dimeric complex having two titanium
centres (Scheme 12). The presence of the allylic hydroxyl group is necessary as it
coordinates with the metal thereby allowing the transfer of oxygen atom from one face
only. The absolute configuration of the epoxy alcohol can be predicted by the following
mnemonic model in which the hydroxymethylene group is positioned at the lower right.
The epoxidation takes place from the upper face of the allyl alcohol when (+)-(R,R)-DET
is used and vice versa (Scheme 13).

OH
R3 CO2Et
R1 EtO2C
"O" transfer mediated O OH
by (S,S)-DET OH
R2 D-(-)-DET

R1 R3

R2 OH
OH
R1 R3
CO2Et
O EtO2C
"O" transfer mediated OH
by (R,R)-DET OH
R2
L-(+)-DET

Scheme 13

These reaction conditions, Ti(Oi-Pr)4, t-BuOOH and (R,R) or (S,S)-diethyltartarate, have

also been extensively studied for asymmetric oxidation of aryl alkyl sulfides (Scheme
14).

O
S Ti(O-iPr)4, t-BuOOH S
Me Me

Me L-(+)-DET/H2O Me
89% ee

Scheme 14

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Problems

A. Provide suitable catalytic system for the following transformations.

O
1.
O O
O ..
S S
Me Me
2.

OH OH
3.
O
B. Complete the following reactions.
Ti(OiPr)4, (-)-DET
1. HO
TBHP, toluene

Ti(OiPr)4, (-)-DET
2.
OH
TBHP, CH2Cl2

O
Cp2TiCl2, AlMe3
3. O

4. CH2Br2, Zn
TiCl4, THF

Ti(IV), TMSCN
5. CHO

O
OTBDMS
CO2Me Ti(IV)/HCl
6. BuO +
Me
O O
S Ti(0)
7. Ph Ph

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Text Book

M. B. Smith, Organic Synthesis, McGraw Hill, Singapore, 2004.

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Lecture 29

3.6.3 Chromium Reagents/Catalysts

Chromium can exist in a variety of oxidation states, Cr(III) and Cr(VI) being the most
common of them. These two oxidation states form a redox couple with standard reduction
potential of 1.33 V. Thus, Cr(VI) reagents are very strong oxidizing agents.
3.6.1 Oxidation of Alcohols
Chromium(VI) oxide is a very powerful oxidizing agent whose oxidizing power can be
tailored by using it in conjunction of a Lewis base like pyridine. CrO3 when dissolved in
H2SO4 forms a
F. Freeman, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Inc.,
L. A. Paquette, Ed., New York, 1995, 2, 1261.

OH O
CrO3, H2SO4
Me2CO, H2O

Scheme 1

Mechanism

O O-
H
O Cr O O Cr O
H H R H O O
O O H R
O+ O
O Cr OH
R R1 R1 H -H2O R1 R R1
H O

Scheme 2

mixture of various chromic acids (Jones Reagent). It is a very powerful oxidizing agent
capable of oxidizing primary alcohols to carboxylic acids and secondary alcohols to
ketones (Scheme 1-2).

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In the presence of pyridine, the oxidizing property of Cr(VI) is lowered and now it
can be used to selectively to oxidize primary alcohols to the corresponding aldehydes.
The chromium trioxide-pyridine complexes, CrO3·py2(Collins reagent) and pyH+CrO3Cl-
(Sarrett reagent), are also known to oxidize allylic methylene group (Scheme 3).

F. Freeman, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Inc.,
L. A. Paquette, Ed., New York, 1995, 5, 2272.

OAc O PCC (3 equiv) OAc O

Ph py, CH2Cl2, reflux Ph

OAc OAc OAc OAc
PCC = pyridinium chlorochromate

Scheme 3

Another useful application of PCC is in the conversion of allylic tertiary alcohols to

their transposed α,β-unsaturated ketones. The reaction is thought to proceed by
rearrangement of the chromate ester of the allylic alcohol to give a new allyl chromate
ester that is oxidized to the ketone (Scheme 4).

Me H Me PCC (2 equiv) Me H Me
O
Me CH2Cl2, Al2O3 Me
H OH H

Scheme 4

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Despite its wide applicability as an oxidizing agent, chromium is not environmentally

benign due to its high toxicity. Thus, the use of chromium reagents for bulk scale
productions has not attained much popularity. However, methods have been developed to
bypass this problem, one of them being the use of magnetic chromium(IV) oxide, which
can oxidize allylic and benzylic alcohols (Scheme 5). After the reaction is completed, the
CrO2 particles can be separated from the solution by a magnet.

Me Me
CrO2, CH2Cl2
Me OH Me O
H

Scheme 5

Examples:

OH Jones Oxidation
O

88%

J. Meinwald, J. Crandall, W. E. Hymans, Org. Synth. CV5, 866.

OsO4 CO2H

Jones Oxidation COOH

89%

J. R. Henry, S. M. Weinreb, J. Org. Chem. 1993, 58, 4145.

OsO4 CO2H
Ph Jones Oxidation Ph

O
75%
J. R. Henry, S. M. Weinreb, J. Org. Chem. 1993, 58, 4145.
O
Me Collins Reagent Me
Me Me
Me Me
28%

M. Harmata, G. J. Bohnert, Org. Lett. 2003, 5, 59.

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Another way to increase the E-factor is to use catalytic amount of chromium reagents
for oxidation. Thus, Cr(III)-salen complexes have been used for oxidation of alcohols.
The combination of Cr(III)-salen along with terminal oxidant PhIO is selective for allylic,
benzylic and cyclopropyl alcohols (Scheme 6).

OH O
CrIII salen (cat) N N
Ph Ph Cr
PhIO (1.5 equiv)
O Cl O
+ -
Ph N O CrIII salen
(0.3 equiv)

Scheme 6

3.6.2 Reactions of Chromium-Arene Complex

3.6.2.1 Nucleophilic Addition
Arylchromium complexes prepared by heating Cr(CO)6 with arene have found use as a
source of preparation of arene derivatives by attack of a nucleophile (Scheme 6). The
rationale for this lies in the fact that arylchromiumtricarbonyl complexes follow 18
electron complexes and as such

Cl
+ Cr(CO)6 Cl + 3CO
Cr(CO)3
Me
Cl CN
Me Me
Cl + Me - CN
-Cl
Me - CN Me
OC Cr CO
CO mild oxidation
Cr CO
OC
CO
I (18e) II (20e)

Scheme 7

they have a tendency to preserve the 18e structure. For example, (η6-chlorophenyl)tri-
carbonylchromium(0) has 18e which on addition of nucleophile generates intermediate II
with 20e that loses 2 electrons by losing chloride to regain its 18e structure.

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If there is no leaving group present on the arene, then the intermediate

cyclohexadienyl anion can be oxidized by a suitable oxidant or it may be trapped by an
electrophile (Scheme 8). In the former case it leads to re-aromatization along with
alkylation while in the latter case it leads to formation of a cyclohexadiene derivative.

H
COOEt
COOEt
+ Li COOEt
excess I2
OC Cr CO -
CO Cr CO
OC
CO
Me
CN Me
H CN
Me Me
Me
CN
+ Li Me CF3CO2H
-
OC Cr CO Cr CO
CO OC
CO

Scheme 8

N(c-C6H11)
Ph Ph CHO
a. R-Li (1 eq.),
R TMS
(OC)3Cr MeO OMe

b. TMS CH2Br
c. H2O 77% yield
91% ee

Scheme 9

Asymmetric version of the reaction has been developed for the synthesis of
functionalized cyclohexadienes form benzaldimine complexes and the conversion of
ortho-substituted anisole complexes to give cyclohexanones (Scheme 9).

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3.6.2.2 Ring Lithiation

The ring deprotonation of Cr(CO)3-complexed arene leads to the regioselective
preparation of alkylated complexes. Using chiral bases enantioselective deportonation of
prochiral substrates can be accomplished (Scheme 10).

Me Me
OMe OMe
OMe Ph N Ph
TMS BuLi, THF TMS SnBu3
Li

TMSCl Bu3SnCl Cr(CO)3

Cr(CO)3 Cr(CO)3
83% yield 82% yield
86% ee

Scheme 10

3.6.2.2 Side-Chain Activation

The Cr(CO)3 group strongly stabilizes the negative charge at the a-position of alkyl side
chains facilitating benzylic deprotonation. In case of substrates having two competing
benzylic positions the regiochemistry can be controlled by electronic effects (Scheme
11).

KOBut, CH2O

MeO MeO
Cr(CO)3 Cr(CO)3 OH
95%

Scheme 11

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3.6.2.3 As Catalysts
Arene-Cr(CO)3 complexes are a good source for the „free‟ Cr(CO)3 unit that catalyzes a
number of useful transformations. For example, the 1,4-hydrogenation of 1,3-dienes
gives Z-configurated alkenes (Scheme 12). 1,3-Dienes that can adopt a s-cisoid
conformation proceed the reaction, whereas isolated double bonds are not affected.

1 mol% (anisole)-Cr(CO)3
H2 (60 atm)
Me Me CO2Me
CO2Me
THF, 120 oC, 5 h
100%

Scheme 12

3.6.3 Chromium-Carbene Complex

Chromium forms Fischer carbene complexes that serve as reagents for various
cyclization reactions like benzannulation and cyclopropanation reactions. These reactions
are believed to take place via insertion of an alkene or alkyne to the carbene to form a
new carbene complex which undergoes further reaction (Scheme 13-14).

OLi Me3OBF4 OMe

MeLi
Cr(CO)6 (OC)5Cr (OC)5Cr
Me Me

Scheme 13

OH Me
Me Me
OMe Me -CO Me
(OC)3Cr + Me -78° C Cr(CO)3
Ph
OMe

CO2Et MeO Ph
OMe 110° C
(OC)3Cr +
Ph EtO2C CO2Et
EtO2C

Scheme 14

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3.6.4 Nozaki-Hiyama-Kishi Reaction

Much of the carbon-carbon bond forming reactions using chromium(II)-based protocols
can be summarized as involving the coupling of an organic halide (or equivalent) with a
carbonyl compound (Scheme 15).

LiAlH4 RX
2CrCl3 2"Cr(II)" "RCr(III)"
THF

Me O O
Me Me CrCl2, DMF, 25 °C Me
+
I
O MeMe OH

Scheme 15

Subsequent modification of the protocol have led to the coupling of vinyl halides and
vinyl tosylates with aldehydes. This is known as Nozaki-Hiyama-Kishi coupling where
the formation of organochromium derivatives is promoted by catalytic amount of Ni(II)
salts (Scheme 16). The stereochemistry of the vinyl group is retained in the product.

(CH2)9CH3 OH
CHO + CrCl2, cat NiCl2
Ph
THF Ph (CH2)9CH3
I 4-t-butylpyridine

Br
O Me3Si OH O
OHC CO2Et CO2Et
CrCl2, Cat. NiCl2, DMF
Me3Si

Scheme 16

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Examples

Me O
Me O
OHC CrCl2, NiCl2 O
O
I DMF HO OTBS
OTBS
OTBS
OTBS 31%

R. A. Pilli, M. M. Victor, Tetrahedron Lett. 2002, 43, 2815

CrCl2, Ni doped
Br Me Me
+ OHC
Mn, TMSCl
OTMS 81%
A. Furstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 12349.

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Problems

Predict the major product for the following reactions.

OH
PCC
1.

OTMS PCC/I2
2.

Me CrO2Cl2
3.

CrCl2
4. Br + PhCHO

CrCl2, NiCl2
5.
Br O

CrCl2, NiCl2
6.
CHO

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Reference

Transition Metals for Organic Synthesis, Vol. I, Ed., M. Beller and C. Bolm, Wiley-
VCH, New York, 1998.

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Lecture 30

3.6.4 Iron Catalysts

Iron is 3d-series transition element belonging to Group 8. It is present in haemoglobin

and myoglobin and so it is one of the most important metals in biology. It exists in +2
and +3 oxidation states mainly. In +3 oxidation state it is a strong Lewis acid while
metallic iron may behave as a single electron donor under suitable conditions.

3.6.4.1 Reduction of Nitro Group

Aromatic nitro compounds can be reduced to the corresponding aromatic amines in

presence of iron powder under acidic conditions. The reaction proceeds through single
electron transfer in similar lines to Clemensen reduction (Scheme 1).

NO2 NH2

Fe powder/ HCl

Scheme 1

3.6.4.2 C-C Bond Formation

The Lewis acidity of iron(III) has been utilized for several reactions. These reactions
mostly involve activation by co-ordination with heteroatoms or π-bonds. Bromination of
aromatic compounds can be carried out by bromine in the presence of iron powder.
Similarly, addition of catalytic amount of iron(III) salts facilitates the addition of
organometallic nucleophiles (Scheme 2).

Cationic [(allyl)Fe(CO)4] is known to react with different types of nucleophiles

regioselectively and stereoselectively. If the reaction is carried out at low temperature
then the olefin geometry can be preserved during substitution as the π-σ-π-isomerization
is slow in this case. If allyl substrates possess electron withdrawing group, then
nucleophillic substitution of the leaving group proceeds regioselectively (Scheme 3).

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Me Me
Me Me
PhMgX
cat. FeCl3 O O
O O
H+/H2O
Ph
MgCl

C7H15 Br Fe(acac)3 (0.01 equiv) C7H15

+
THF, NMP

CO2Et CO2Et
C4H9O C4H9O
Fe(acac)3 (0.01 equiv)
+ Bu
I THF, NMP
MgCl

Bu

Scheme 2

Fe(CO)4
Me SO2Ph Me SO2Ph Me SO2Ph
Fe2(CO)9/ CO
OBn OBn Fe(CO)4

Me
Me SO2Ph
Me
Me OSiMe3
(NH4)2Ce(NO3)6 Me
O

Scheme 3

3.6.4.3 Carbonylation

Iron carbonyl complexes have been used for various reactions, the most obvious of which
is carbonylation. Collman‟s reagent prepared by the reduction of pentacarbonyliron(0) by
sodium naphthalenide can be used for preparation of aldehydes and ketones. In this two
step process, Collman‟s reagent (Na2Fe(CO)4) is first treated with an alkyl halide and
subsequently with CO and an alkene to form a ketone (Scheme 4).

R. D. Pike, Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, Inc.,
L. A. Paquette, Ed., New York, 1995, 4, 2299.

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1% Na(Hg)
Fe(CO)5 Na2Fe(CO)4

-
Na2Fe(CO)4 + RX R Fe(CO)4 + NaX

- Me
CO -
R Fe(CO)4 R Fe(CO)4 - R -
R Fe(CO)4 Fe(CO)4
O O O

H+/H2O

Me
R

O
Scheme 4

An interesting fact to observe is that Collman‟s reagent causes umpolang at the carbonyl
centre. Thus, a carbonyl compound may be generated by treating alkyl-iron complex with
an electrophile (Scheme 5).

H+/ H2O R H

- O
R Fe(CO)4

O
R1X R R1

Scheme 5

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Examples:

Me

Br Collman's reagent O
1.
CH2=C=CH

J. Y. Merour, J. L. Roustan, C. Charrier, J. Benaim, J. Collin, P. Cadiot, J. Organomet.

Chem. 1979, 168, 337.

H2C-OTs O
O
Me
Me Me
Me Collman's reagent
2. Me + Me
O
O O
O
O O
Me Me
Me Me Me Me
1:1

J. E. McMurry, A. Andrejs, G. M. Ksander, J. H. Musser, M. A. Johnson, Tetrahedron

1981, 37, 319.

3.6.4.4 Hydrogenation of Alkyne

Iron phosphine catalysts, known as Bianchini catalysts, are known for selective
hydrogenation of terminal alkynes to give alkenes (Scheme 6). The selectivity is
explained by the reluctance of iron hydride complex to insert alkenes. The mechanism is
depicted below in Scheme 7.

H2/ [PP3Fe(H)(L)]BPh4 R
PP3 = P(CH2CH2PPh2)3
R

Scheme 6

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+ + +
Ph Ph Ph
Ph Ph Ph R
P H H2 P H R P
H
P Fe L -L P Fe slow H
P Fe H
PPh2 PPh2 PPh H PPh2 PPh
PPh2 2
2

+ + +
Ph Ph Ph
Ph Ph Ph
P P R P
P Fe H
P Fe P Fe H
PPh2 PPh R PPh2 PPh PPh2 PPh
2 2 2
R

R R

+
Ph
Ph
P
P Fe R
PPh2 PPh
2

Scheme 7

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3.6.4.5 Asymmetric Catalysis

3.6.4.5.1 C-C Bond Formation

Chiral iron complexes are used for asymmetric catalysis. One of the most common and
useful complex is S-aceto(carbonyl)(cyclopentadienyl)(triphenylphosphine)iron. It is a
chiral enol equivalent which when deprotonated can react with a variety of electrophiles
to generate a variety of functionalized iron compounds. Thus, it can be alkylated with a
high degree of enantioselectivity owing to the hindrance of attack by a phenyl group on
one face. A mild oxidation of this organoiron complex releases the enantiomerically pure
product (Scheme 7).

OC BuLi Ph2
PPh3 RX
Fe Fe P MeI R
Ph3P Me Fe PPh3
OC Fe Me Br2/H2O
OC
O -O R OC HO2C Me
-O R
O
CO
PPh3 HO Fe PPh3 H OH
OC BuLi
Fe Fe Et2AlCl H PTSA
Ph3P Me THF, -78° C OC O N
-O Boc NBoc Br2
O
N OH O

OC
Fe PPh3
Ph3P Me BuLi, MeI
Fe BuLi
O OC Me
Me Et Me
-O
TsO CO2Et
Ce(IV), SOCl2/EtOH
Scheme 7

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3.6.4.5.2 Sulfoxidation

The oxidation of aryl alkyl sulfides has been accomplished using in situ generated
Fe(III)-Schiff base complex in the presence of 30% H2O2 as terminal oxidant (Scheme 8).
Addition of benzoic acid as an additive enhances the enantioselectivity significantly.

O N OH

S S
Me Fe(acac)3-L* Me I OH

30% H2O2 L*
up to 94% ee

Scheme 8

3.6.4.5.3 Cycloaddition

Chiral iron(III)-bis(oxazoline) has been used for the asymmetric (4+2)-cycloaddition

reaction with good enantioselectivity (Scheme 9).

O O H O O
10 mol% cat L FeCl2I O
+ N O N N
o
CH2Cl2, -50 C O N O Ph L Ph
15 h, 85%
endo : exo 97 : 3
R : S 90 : 10

Scheme 9

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3.6.4.5.4 Oxidative Coupling

Aerobic oxidative coupling of 2-naphthols has been demonstrated using di-μ-hydroxo

iron(salan) complex (Scheme 10). The substrates having substituents at 3-position
exhibited the best enantioselectivity. Detailed kinetic and X-ray studies indicate that the
reactions take place via a radical anion mechanism.

Ph Ph

X N N
Fe
X FeLn* OH O O
2 Ph
OH
OH
Ph
X 2
JACS, 2009, 131, 6082. 93% ee O

FeLn*
Scheme 10

3.6.4.5.4 Kinetic Resolution

Aerobic oxidative kinetic resolution of secondary alcohols has been shown in the
presence of naphthoxide bound iron(salan) complex with good selectivity (krel = 7-10).
Coordination of napthoxide ion enhances the catalytic activity of the iron(salan) complex.

Ph Ph

OH N N
OH O
FeLn* Fe
Me
Me Me O O
* +
OH Ph

Ph
JACS 2011,133, 12937. 2
HO

FeLn*
Scheme 11

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Problems

A. Provide suitable reaction conditions for the following transformations.

OH OH O

Me Me Me
1. +

racemic optically active

O
2. RMgBr R
R
O

B. Complete the following reactions.

S Fe(III)/H2O2
1.

Fe(III)/PhIO
2.

Fe(III)/O2
3.
OH

Cl Fe2(CO)9
4.
Cl

Na2Fe(CO4)-PPh3
5. Br
H+

Ce(IV)
6. Fe(CO)3 + CO2Me

Na2Fe(CO4)
7. Br
H+

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Reference

Transition Metals for Organic Synthesis, Vol. I, Eds., M. Beller and C. Bolm, Wiley-
VCH, New York, 1998.

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Lecture 31

3.6.5 Cobalt Catalysts

Cobalt is present in various metalloenzymes like methylmalonyl coenzyme A mutase. It

is also a key constituent of vitamin B12 which plays an important role in normal
functioning of the central nervous system. Cobalt exists mainly in two oxidation states.
The standard electrode potential for Co(III)/Co(II) system is 1.82 V which shows that it is
a very strong oxidant. Also, the existence of cobalt based redox systems in biological
systems has intuited the exploration of similar bio-mimicking systems for redox
reactions. Some of these reactions are illustrated below.

3.6.5.1 Oxidation Reactions

Epoxidation of alkenes can be achieved by using cobalt(II)-Schiff base complex in the

presence of reducing agent such as aldehydes, -ketoester, acetal and triphenylphosphine
under molecular oxygen (Scheme 1). A series of cobalt(II) complexes have been
designed and developed for this purpose. The reactions are general, efficient and effective
at ambient temperature.

Me C7H15 OH
O2 (1 atm), Co(II)-complex Me C7H15
Me CO2Me
Me O N
O O
OH Co O
CO2Me O
CO2Me
N
MeO2C

Me C7H15 HO
O2 (1 atm), Co(II)-complex Me C7H15
Co(II)-complex
Me
CO2H Me O
CHO

Scheme 1

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In the presence of Et3SiH, hydration of alkenes can be accomplished using cobalt

catalysts with high yield (Scheme 2). The reaction is general and provides effective route
for the oxidation of alkenes to alcohols under mild conditions.

CO2Et
CO2Et
Co(tdcpp),O2-Et3Si3H, 1h Co(tdcpp) = [5,10,15,20-tetrakis(2,6-dichlorophenyl)
(Meo)3P, i-PrOH, CH2Cl2 HO porphinato]cobalt(II)
n-Pr
n-Pr
Scheme 2

Cobalt(II)-complexes with aldehyde or -ketoester have been found to be effective

method for the oxidation of alcohols to give aldehydes or ketones under molecular
oxygen (Scheme 3). The reaction conditions can be employed for the oxidation of alkanes
to give alcohols and carbonyl compounds.

OH O OH

Me O2 (1 atm), Co(II)-complex Me
N CO2Me

Co O
O O O
CO2Me OH N
MeO2C
CO2Me

O HO
Co(II)-complex
O2 (1 atm), Co(II)-complex Me
Me

CHO CO2H

Scheme 3

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3.5.6.2 Pauson-Khand Reaction

Dicobalt octacarbonyl, the predominant cobalt carbonyl complex, has found wide
applications in organic synthesis. It is prepared by the high pressure carbonylation of
cobalt(II) salts. In solution it exists in equilibirium between two forms, both of which
obey to the 18 electron rule (Scheme 4).

O
CO CO OC C CO
OC
Co Co CO OC Co Co
CO
OC CO COCO OC C CO
O

Scheme 4

The reactions of dicobalt octacarbonyl involve insertion of CO into the substrate resulting
in carbonylation as the overall result. The reaction of an alkyne with this complex result
in the formation of stable organocobalt complex that exists as a tetrahedral cluster(I).
This cluster can react with an alkene on heating to generate a cyclopentanone derivative
via a [2+2+1] cycloaddition. This reaction is known as Pauson-Khand reaction. It is
believed to involve loss of a CO molecule from the tetrahedral complex followed by
coordination with the alkene which inserts itself in the Co-CO bond. This
intermediate(III) undergoes insertion reaction where CO insertion takes place between
the Co-alkene bond forming the intermediate(IV) which may undergo reductive
elimination to give the product (Scheme 5).

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R1 R2 R2
2 1 2 OC 1
R R R CO CO R
R Co Co Co(CO)3
OC CO
+ Co2(CO)8 Co Co CO CO CO Co(CO)3
OC -CO II
R1 CO COCO R R
I III

CO Insertion

R2
O Co(CO)3 R1
Reductive R 2
Reductive
R1 Elimination Co(CO)3 Co((CO)3
Elimination
R R1 Co(CO)3
R2 R
R O O
V
IV
Scheme 5

The reaction is completely regioselective with respect to the alkyne. The larger
substituents always occupy the position adjacent to the carbonyl group in the product.
However, the use of an unsymmetrical alkene usually leads to a mixture of regioisomers
(Scheme 6).

H H
Me Co2(CO)8 Me
O + Me O
Me C7H16 Me Me
Me 110° C
ButMe2SiO ButMe2SiO Me ButMe2SiO Me

major

Scheme 6

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Examples:

Me
Me EtO2C
EtO2C Pauson-Khand
1. O
EtO2C EtO2C
83%

M. E. Krafft, J. A. Wright, L. V. R. Bonaga, Tetrahedron Lett. 2003, 44, 3417.

MOMO H Me
MOMO Me
Pauson-Khand
Me O
2. Me
Me
64% Me
OTBS

P. Magnus, M. J. Slater, L. M. Principe, J. Org. Chem. 1989, 54, 5148.

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3.5.6.3 Cycloaddition

Dicobalt octacarbonyl can be converted into (η5-cyclopentadienyl)dicarbonylcobalt(0)

which is the catalyst for Volhardt cyclotrimerization reaction. This reaction is unique as it
brings about the formation of a benzene ring in one step by [2+2+2] cycloaddition of a
dialkyne with a monoalkyne (Scheme 7).

-2CO
+ Co Co Co
Co
OC CO Me3Si
18e 18e 16e
18e SiMe3

Me3Si Me3Si
2CO Me3Si Co

Me3Si -CpCo(CO)2 Me3Si Co

Me3Si

18e
Scheme 7

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3.5.6.4 Hydroformylation

One of the most industrially important reactions using cobalt is definitely the
hydroformylation. This reaction inserts a carbonyl group in an alkene thereby giving rise
to aldehydes (Scheme 8). It is also known as the oxo process.

Co2(CO)8 H CHO
+ 2CO + H2 Me +
Me
O Me Me

Scheme 8

Both the linear isomer (usually referred as n-product) and the branched isomer (iso-
product) are produced. The ratio of the two isomers is crucial for industry as the linear
aldehydes are usually important from their perspective. The formation of the two isomers
is outlined in the mechanism shown in Scheme 9. At a very high pressure (~ 100 bar),
dicobalt octacarbonyl reacts with hydrogen gas to form tetracarbonylhydridocobalt(I).
This complex loses one CO molecule to form a coordinatively unsaturated complex
which then undergoes alkene insertion to give n-alkyl complex (Markwonikov addition)
as well as a branched alkyl complex (anti-Markwonikov addition). Both these complexes
now undergo migratory insertion of CO to generate acyl complexes which then undergo
attack by hydrogen to yield the target aldehydes. The use of bulky ligands like PBu 3
diminishes the extent of branched aldehyde formation and improves the n/iso ratio.

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Co2(CO)8 + H2 2HCo(CO)4

H Me HCo(CO)4
+
O
Me CO -CO
H Me
Me
HCo(CO)3
H2

HCo
OC CO
CO Me
O

(CO)3Co Me
+
O
Me Me
(CO)3Co (CO)3Co
Me + Me

(CO)3Co Me

(CO)4Co Me
+
CO
Me

(CO)4Co Me
Scheme 9

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3.5.6.5 Hydrogenation
Homogeneous asymmetric hydrogenation of benzil has been accomplished using
cobalt(II) complexes in combination with quinine under 1 atm of hydrogen. The reactions
are efficient to give benzoin with good enantioselectivity (Scheme 10).
H
O O
OH
O quinine-Co N N
Co
H2 O N N
O
-10 oC 100 yield, 78% ee
O O
H
qinine-Co = quinine-quinine.HCl-NH2CH2C6H5-Co(dmg)2 (1:1:1:1) Co(dmg)2

Scheme 10

3.5.6.6 Oxidative Addition

Cobalt(II) chloride has been shown as effective catalyst for the oxidative addition of acyl
radical to electron deficient alkenes under molecular oxygen. The reactions of aliphatic
aldehydes have been explored with methyl acrylate at ambient conditions (Scheme 11).

O CoCl2 O OH
+ CO2Me CO2Me
H
O2

Scheme 11

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3.5.6.7 Kinetic Resolution

Chiral cobalt(III) salen complexes have been studied for the kinetic resolution of terminal
epoxides with nucleophiles such as water and phenols with excellent enantioselectivity.
1,2-Epoxibutane with phenol gives -aryloxy alcohol in 98% ee (Scheme 12).

N N
OH
OH M
O Co*Ln O O O
+
98% ee
97% yield
M =Co[OC(CF3)3]H2O
Co*Ln
Scheme 12

3.5.6.7 Esterification

Cobalt(II) chloride has been considerably studied as Lewis acid for the acylation of
alcohols and amines with acylating agents such as acid chloride, acetic anhydride and
acetic acid. The acylation of alcohols with acetic acid is attractive where water is
generated by-product (Scheme 13).

CoCl2 6H2O OAc

OH
AcOH
Heat

Scheme 13

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3.5.6.7 Cross-Coupling Reaction

Cobalt(II)-1,10-phenanthroline has been recently used for intramolecular cyclization of

amidines to give 2-aryl benzimidazoles in high yield (Scheme 14). The reaction is
general, efficient and operates at moderate temperature.

H
N CoLn N
N N
N Cs2CO3 N Co
Br Ph
Toluene, 100 oC (acac)2
Ph
CoLn

Scheme 14

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Problems

A. Provide suitable reaction conditions for the following transformations.

EtO2C EtO2C
1. O
EtO2C EtO2C

2. O
O

3.

OH
O OH Cl
4. Cl

B. What major product would you expect from the following?

Co2(CO)8
1.

Co2(CO)8-CO
2.

CpCo(CO)2
3. 3

Co2(CO)8
4.
CO, H2

O Co(II)/O2
5. H +
CN

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Reference

Transition Metals for Organic Synthesis, Vol. I &2, Eds., M. Beller and C. Bolm, Wiley-
VCH, New York, 1998.

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Lecture 32

11.6 Copper Catalysts

Copper catalysts find extensive applications in organic synthesis. Since lectures 8 and 22
cover the common copper-based reactions, this lecture is devoted to some of the modern
methods on the use of copper-catalysis for the synthesis of medicinally important
heterocyclic compounds.
11.6.1 Synthesis of Substituted Benzoxazoles
Benzoxazoles are important structural units present in numerous compounds that are
important in medicinal chemistry. The copper-catalyzed intramolecular cyclization of 2-
bromoanilides via intramolecular C-O cross-coupling reaction provides a straightforward
route for the construction of 2-aryl and 2-alkylbenzoxazoles (Scheme 1).
Br CuO nano N
O
Ph
N Ph K2CO3, DMSO O
H 110 °C
Scheme 1

11.6.2 Synthesis of Substituted Benzimidazoles

The above reaction conditions can be employed for the synthesis of substituted
benzimidazoles and 2-aminobenzimidazoles from 2-bromoamidines and 2-
bromoarylguanidines (Scheme 2). These processes involve intramolecular cyclization via
C-N cross-coupling reactions.
Br N
N
N 5 mol % CuO nano
N
N
HN 1.5 equiv KOH Me
DMSO, 110 °C
Me
Me
Me 5 h, yield 80%
Scheme 2

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11.6.2 Tandem Reactions

11.6.2.1 Synthesis of Substituted Indoles
Indoles are important structural motifs and found in several natural products and
biologically active compounds. The domino synthesis of polysubstituted indoles has been
shown using copper(I)-catalysis from 2-haloaniline and 1,3-dicarbonyl compounds
(Scheme 3).
O
O 10 mol % Cu2O R''
I 1 equiv Cs2CO3 R = H, Cl, Me, NO2
R + R'' R R' R' = Me, Ph, CH2-C(Me)2-
NH2 O DMSO:H2O (3:1) N R'' = Me, OMe, NHAr, CH2-C(Me)2-
R' N2, 100 °C H

O O O O O
OMe OMe OMe OEt Me
Cl Me
Me
Me Me Me Me
N N Me N N N
H H H H H
7 h, yield 81% 7 h, yield 80% 9 h, yield 78% 9 h, yield 87% 8 h, yield 85%
Scheme 3

Mechanism
This process involves condensation followed C-C cross-coupling reaction (Scheme 5).
O O
X
R' R'
I Condensation
Cu N R
N R
Reductive O
O Elimination Oxidative X
Addition R'
X O +
R' O
CuIII NH2 O R
CuIII R'
N R'
R
H X = Br, I N R
N R R = alkyl, aryl H
R" = alkyl, alkoxy, NHAr

X O Cs2CO3
CsX CuIII
R'

N R
Scheme 4

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11.6.2.2 Synthesis of Arylthioarylcyanamides and

Arylselanylarylcyanamides

The cross-coupling of 2-haloarylthiourea and 2-haloarylselenourea with aryl halides take

place in presence of copper catalysts to give 2-arylthioarylcyanamides and 2-
arylselanylarylcyanamides via intra- followed by intermolecular C-S/C-Se cross-coupling
reactions (Scheme 5). The C-S cross-coupling reactions are effective with Cu(I)/Cu(II),
while the C-Se cross-coupling reactions give the best results with the complex derived
from CuI and 1,10-phenanthroline.

I CN
H
N NH2 2.5 mol % CuSO4·5H2O NH
R + R' R R'
W 1.5 equiv Cs2CO3
I S
DMSO, 90 °C, 5-8 h
R = H, Cl, Me Yield 83-98%
R' = H, Cl, Me, OMe, NO2, NH2
CN CN CN
NH NH NH

Me W Me W Me W
OMe

Scheme 5

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Mechanism
The proposed catalytic cycle involves intra- followed by intermolecular cross-coupling
reactions (Scheme 6).
H:B + X- CuII
:B X +e NCN
CuI + BH
W = S, Se Me W
H
N NH2 X = I, Br N NH2 Intermolecular
M = Cs Cross-Coupling
R W Me
W Me Cu
Cu CuX
X Intramolecular Cu
Cross-Coupling W :B
N
N C
CuI NH2
H N
N NH2 +e Me W :B
H
R
W CuII
X
H:B + X-
Scheme 6

11.6.2.3 Synthesis of 1,3,5-Trisubstituated 1,2,4-Triazoles

Bisarylhydrazones undergo reaction in the presence of DABCO and Cu(OAc)2 to afford

1,3,5-trisubstituated 1,2,4-triazoles (Scheme 7). This is the first example for room
temperature copper-catalyzed C-H functionalization process.

R'
i. DABCO (1 equv)
R' R" Toluene, 60 C
30 h, Air N
N ii Cu(OAc)2.H2O (10 mol %) N C-N
N N
H r.t, Air
R'
R', R" = EWG, EDG

R"

Scheme 7

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Mechanism

The detailed investigation suggests that DABCO acts as base as well as ligand for the
copper-catalysis (Scheme 8).

Ar1 H H
Ar1 Ar1 N Ar1 N
HN Ar2 N Ar2
N Base(B) 1a-l, 1o-r Oxidation
NH N N N
N BH N Ar1 N Ar1
Ar2 Ar2 B Ar2 Ar2
1a-l, 1o-r P Q

CuIIX2
H2O Ln H
air + HX
Q Ar1 N
LnCu X I II
LnCu X2 N Ar2
2
Ar NO LnCuIX+ X-+ N
N Ar1
X = OAc
Ln = DABCO Ar2
Ar1 O
NH
HN HX
N Ar1
LnXCuII Ar2 CuIIXLn
O
Ar1 N
Ar1 O N 1 N Ar2
N Ar 2 Ar
CuIIX2Ln N N
HN 1
N Ar1
N Ar N 1
N Ar Ar2
Ar2 S
CuIIX2Ln Ar2 O2

Ar1 O
NH
HN CuIIX2Ln + H2O
N Ar1
Ar2 O
CuIIXLn CuIIXLn O

O O Ar2 CuIIIXLn
H O O
Ar2 N
Ar1 N N N Ar2
N Ar1 N N
N N Ar1 N
Ar 2
N N Ar1
Ar1 Ar2 Ar2
Ar1
Scheme 8

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11.6.2.3 Synthesis of 2,4,5-Trisubstituated 1,2,3-Triazoles

The above process, in the absence DABCO, affords 2,4,5-trisubstituted 1,2,3-triazoles
(Scheme 9).

R' C-C
R'
R'
R"
Cu(OAc)2.H2O (20 mol %)
N N
2 N Toluene, 60 C
N Air N
H N-N
R', R" = EWG, EDG
R"
Scheme 9

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Mechanism
The reaction intermediates have been isolated and the proposed mechanism is shown in
Scheme 10.
Dimerization Ar1
HN Ar2 Oxidation
N
N Ar2 NH
Ar2 N
Ar2
H2O
Cu(0)+ 2XH + air
CuIIX2

Ar1 Ar1
Ar1 Ar 2
Ar1 CuIX + X- + N
N NH Ar1 NH
N N
N Ar2
Ar2 N N
XH
Ar2

XH
1
Ar1 Ar1 Ar
H CuIX + CuIX
Ar1 N 2 N
N Ar N N
N N
NH + X -
Ar2 Ar2
Ar2

Dimerization
Cu(0)
Ar1
1
Ar Ar1 N
H
Ar 1
N N Ar2
2
N Ar N I
N I N Cu X
NH Cu X F Ar2
Ar2 Isomerization

Scheme 10

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11.6.2.4 Synthesis of Substituted Benzimidazoles and Benzoxazoles

Using Cu(OTf)2, N-protected bisarylhydrazones and bisaryloxime ethers can be
converted into 2-arylbenzimidazoles and 2-arylbenzoxazoles under neutral conditions at
moderate temperature (Scheme 11). The cross-over experiments with two different
bisaryloxime ethers show that the protocol involves intramolecular process (Scheme 12).

Cu(OTf)2 N

N Toluene, 110 oC N
N
3 - 5 h, N2 Bn
Bn
20 mol % Cu(OTf)2 N

toluene, O2 balloon O
N 80 oC, 1.5 - 4 h
O 2.5 h, yield 80%
Scheme 11

Br N N
Br Me
+
O O
N Me 20 mol % Cu(OTf)2
O products formed
+ Toluene, O2 balloon Br N N
80 C, 4 h Me +
N
O O O
Crossover products (Not obtained)
Scheme 12

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Mechanism
Observed results suggest that the process involves a tandem C-H functionalization, C-O
or C-N bonds formation (Scheme 13).
R1 R1

H H
L
N N
X X H Cu
CuL2 L2Cu -LH N
R2 X
R2 R1
R2
a b
X = O, NBn R1, R2 = EWG, EDG
-LH
L = OTf
N Cu
N
R2 + Cu(0) R2
X R1 X
R1
c
Scheme 13

Three component syntheses of 2-aminobenzimidazoles and analogues can be

accomplished from 2-haloaniline, sodium azide and isothiocyanate using copper-based
systems (Scheme 14).

N N
NH2 N
R'NCS, [Cu] N
R
[C 90

NaN3, Et3N R
u]

HN
,b oC

Br
DMF, RT R'
as

Br
e

Ligand N
R = EDG, EWG
Base RT R NH2
R' = alkyl, aryl, naphthyl N
Ar
N u] R'
Ar
N [C o C
R N N3
N
N
[Cu], RT
R 90
N N
R' R'

Scheme 14

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Mechanism

This reaction involves a tandem addition/substitution/electrocyclization/N-

arylation/tautomerism processes (Scheme 15)

H H H
NH2 N N
R' Et3N N N
R R'NCS R'
R R
Br S S
Br [Cu]
Br [Cu]
NaN3 substitution
N N H
R N N N N
R' + CuS +sulphide
:B R
III HN N
Cu R' Br 3
- N
H:B + X +N X
electrocyclization
- oxidative N N
N N N
addition N
R
III N X = I, Br
R' HN
Cu reductive Br R'
[Cu] R
elimination

R'' C H
[Cu]
R
N
R'' C [Cu] N3 [Cu]
N N
R' +N
+ R R
N - N N N N
- +
R N N [Cu] +H NH2
N N N
Cu C R" f
R' R' N2 R'

N N N +H+ N N N
R N R N
N -[Cu]
R" N R"
R' [Cu] R'

Scheme 15

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Problems

Predict the major products for the following reactions.

Me

Cu(OTf)2/toluene
1.
N
N

Ph

H H
N N
Cu(OAc)2, TEA
2.
S
NaN3

CuI, Et3N, THF

3. N3 +

Cu(OAc)2
4. N3
DMF., 90 oC

O
I CuI, Bu4NBr
NH2
5. +
Br

Me

Cu(OAc)2, air
6.
N
N
H
Me

DABCO
7. N Cu(OAc)2, air
N
H

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Reference

Transition Metals for Organic Synthesis, Vol. I, Ed., M. Beller and C. Bolm, Wiley-
VCH, New York, 1998.

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Lecture 33

3.6.5 Rhodium Catalysts

Rhodium is a silvery white monoisotopic metal of platinum group metals belonging to

the 4d series. Rhodium is used mainly in the three way catalytic convertors of
automobiles for oxidation of incompletely burnt hydrocarbons. It is also alloyed with
platinum and palladium for use in high temperature surroundings. The most stable
oxidation state of rhodium is +3 but it can show oxidation states ranging from 0 to +6.

3.6.5.1 Hydrogenation

Transition metal catalyzed hydrogenation of alkenes and carbonyl compounds occupies

an important position in organic synthesis. Wilkinson‟s complex, [RhCl(PPh3)3], is one of
the most versatile catalysts for the homogeneous hydrogenation process. It is obtained in
the form of a red-violet crystalline solid from the reaction of RhCl3 with excess of PPh3
in boiling EtOH (Scheme 1).

EtOH
RhCl3 3H2O + PPh3 (PPh3)3RhCl
Boiling

Scheme 1

K. Burgess, W. A. van derDonk, Encyclopedia of Reagents for Organic Synthesis, John

Wiley and Sons, Inc., L. A. Paquette, Ed., New York, 1995, 2, 1253.

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Rhodium-catalyzed hydrogenation is compatible with the substrates having functional

groups such as oxo, cyano, nitro, choro and azo, and selectively reacts with the double
bond (Scheme 2). Chelation of the functional group on the catalytically active Rh may
lead to high degree of selectivity. The reduction takes place from the less-hindered face
with a cis-stereochemistry.
OH OH

Wilkinson's Catalyst
H2, C6H6

Scheme 2

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Mechanism
The initial dissociation of a triphenylphosphine ligand leads to the formation of a 14-
electron Rh complex that undergoes oxidative addition with H2 followed by π-
complexation with alkene, intramolecular hydride transfer and reductive elimination of
the target product (Scheme 3).

PPh3
Ph3P Rh Cl
Ph3P 16e

-PPh3
R'CH2CH3
Ph3P H2
Rh Cl
reductive elimination Ph3P oxidative addition
14e

H R'
Ph3P
Rh H
Ph3P Ph3P
Cl Rh H
Ph3P
16e Cl
16e

R'
insertion Ph3P H H
Rh
Ph3P
Cl
'
18e R

Scheme 3

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Examples:

OAc OAc
AcO AcO

Wilkinson's Catalyst
AcO AcO
1. AcO AcO
H2 S
S O
O

O N CO2Me O N CO2Me
H H
Yield: 18%

L. J. Whalen, R. L. Org. Lett. 2004, 6, 3221.

O
O O
O
Et
Et Wilkinson's Catalyst
2.
O
O H2
Yield: 95%

H. M. L. Davies, E. Saikali, N. J. S. Huby, V. J. Gilliatt, J. J. Matasi, T. Sexton, S. R.

Childers, J. Med. Chem. 1994, 37, 1262.

When the triphenylphosphine ligands are replaced by chiral phosphines, the complex
becomes chiral and converts prochiral alkenes into chiral alkanes with excellent
enantioselectivity. For example, itaconic acid undergoes hydrogenation to give (S)-
methylsuccinic acid with 95% ee in the presence of chiral CAPP-Rh(I) complex (Scheme
4).

Ph2P NH
CO2H Rh-L, 1 atm H2 CO2H

C6H6-MeOH, RT N PPh2 R =
CO2H CO2H
95%ee R O Br
CAPP

Scheme 4

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Likewise, 1-naphthyl methyl ketone enol acetate can be hydrogenated using Rh-
diphospholane with 94% ee (Scheme 5).

OAc Rh(I)-L*, 2 atm H2 OAc

P P
MeOH, RT
L*
94% ee

Scheme 5

A similar result is obtained with the hydrogenation of N-acylaminoacrylic acids utilizing

Rh-BINAP complex (Scheme 6).

CO2Me [Rh((R)-BINAP)MeOH)2]ClO4 CO2Me PPh2

NHAc PPh2
NHAc
99-100% ee

(R)-BINAP
Scheme 6

Likewise, the hydrogenation of ketopantolactone using Rh-(2S,4S)-BPPM can be

accomplished with good enantioselectivity (Scheme 7).

Ph2P
O OH
[(RhCl(COD)]2 PPh2
N
O O (2S,4S)-BPPM O O
CO2C(Me)3
H2
87 ee
(2S,4S)-BPPM

Scheme 7

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3.6.5.2 Hydroboration
Wilkinson‟s complex serves as an effective catalyst for the addition of catecholborane
(CB) to alkenes and alkynes. The Rh-catalyzed reaction is sensitive to steric effects, and
can be diastereoselective which is complementary to uncatalyzed hydroborations
(Scheme 8). This has been employed for the diastereoselective synthesis of several
natural products. Scheme 9 presents some examples.

OR' OR' OR' O

R2BH CB BH
HO R" R" HO R"
Rh(I) O
R"' R"' R"'
CB

Scheme 8

Rh(PPh3)3Cl HO
PhH2CO OEt PhH2CO OEt S. Hatakeyama et al., Tetrahedron
O CB O Lett. 1994, 35, 7993.
O O
(+)-Luffariolide E

OH
Me Me
MeO MeO
-do-
A. N. Hulme, et al., J. Org. Chem. 1995, 60, 1265.

(-)-Eptazocine

O O
O -do- O
OH OH J. Cossy, S. BouzBouz, Tetraheron Lett. 1996,
Me Me
37, 5091.

OH
(+)-Paeonilactone C

Scheme 9

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Asymmetric hydroboration of prochiral alkenes can be demonstrated using chiral Rh(I)

complex with catecholborane with excellent enantioselectivity. For example,
hydroboration of styrene with CB in the presence of Rh(I)-(R)-BINAP takes places with
94% ee (Scheme 10)

OH
[Rh(COD)2]BF4 PPh2
(R)-BINAP PPh2
CB, -78 oC Me
Me 94% ee
(R)-BINAP

Scheme 10

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Mechanism
The reaction takes place via oxidative addition, alkene complexation, hydride migration
and reductive elimination (Scheme 11).

L
L Rh Cl
L
H -PPh3
B(OR)2
L (OR)2BH
Rh Cl
reductive elimination L oxidative addition

H
L L
Rh B(OR)2 Rh B(OR)2
L L
Cl Cl

hydride migration
LH
Rh alkene complexation
L
Cl B(OR)2

Scheme 11

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3.6.5.3 Hydrosilylation
Rhodium catalyzed hydrosilylation of ketones, imines and alkenes provides an effective
route to alcohols, amines and alkanes. Subsequently, a number of chiral rhodium
complexes are developed for asymmetric hydrosilylation. Scheme 12-13 shows some
examples for chiral rhodium-phosphine catalyzed hydrosilylations.

1 mol% RhCl3(Pybox-i-Pr)
4 mol% Pybox-i-Pr
2 mol% AgBF4
Me
Me 1.6 equiv Ph2SiH2
HO H O
O O N RhCl3 O O
N
94% y, 95% ee N N N Rh N
Cl3
-do-
(R,R)-Pybox i-Pr
O HO H
92% y, 99% ee

Scheme 12

H
Ph O PPh2
Ph (R,R)-DIOP/Rh NHBn
N PPh2
H O
Me Bn PhSiH 2 Me H
H3O+
97% y, 65% e (R,R)-DIOP/Rh

Me Me Me Me Me Me
(R,R)-DIOP/Rh [O]

O O SiR2 OH OH
SiR2H
(R = 3,5-Me2C5H3) 66% y, 93%

Scheme 13

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Mechanism
The reaction takes place via oxidative addition, insertion and reductive elimination
(Scheme 14).

Rh(I)Ln
R3Si-H
XSiR3 low oxidation state
oxidative addition
H
X = NR, O, CH2
reductive elimination
insertion
X
H Rh(I)Ln

SiR3
high oxidation state

Scheme 14

3.6.5.4 Cycloaddition
The cycloaddition reaction using chiral rhodium complexes finds wide applications in
organic synthesis. Scheme 14 presents an example for chiral rhodium-catalyzed
intramolecular [4+2]-cycloaddition reaction.

OMe Et

P
Ph
Ph 5 mol% [RhCl(L*)]2 Et Et
Me
O 20 mol% AgSbF6
O P
CH2Cl2, r.t
H
L* Et
- 26% ee, 91% yield
Chiral Diene (R,R)-Et-Duphos
PPh3 26% ee, 85% yield
(R,R)-Et-Duphos 95% ee, 99% yield Effect of the combination of
C1-symmetric chiral diene (L*) and
(R,R)-Et Duphos

Scheme 15

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Mechanism

The reaction takes place via oxidative cyclization (Scheme 16).

Ph Ph
Me O
O
+ P
H Rh *
P
*
Ph
* Ph
Rh Me + P
O H Rh *
O P
H Ph
* oxidative
O Rh
cyclization
H

Scheme 16

3.6.5.5 Hydroformylation

Transition metal catalyzed hydroformylation of alkenes with carbon monoxide and

hydrogen is an important tool for organic synthesis. The reaction is generally carried out
at temperature between 40 and 120 oC and total pressure between 10 and 100 atm, in the
presence of catalytic amount of rhodium, cobalt or palladium catalysts (Scheme 17).

N
CHO
Rh/P(OPh)3
+ CO + H2 N
H
Milverine

Scheme 17

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3.6.5.5 Cyclopropanation and C-H Insertion

Rhodium(II) complexes are highly efficient and versatile catalysts for the extrusion of
dinitrogen from diazo compound. Dirhodium(II) carboxylates, especially, Rh2(OAc)2, are
extensively used for cyclopropanation and C-H insertion. The nature of ligand plays a
crucial role in the selectivity of the products (Scheme 18-19).

Rh2L4
CHN2 +
CH2Cl2
O O O
Rh2(OAc)4 97% y 44 56
Rh(pfb)4 56% y 0 100
Rh2(cap)4 76% y 100 0
pfb = perfluorobutyrate cap = caprolactam
Scheme 18

O
O
O O
Rh(II) C-H insertion
O .. CO2Me
Me OMe Me
H
Me N2 OMe
H

Scheme 19

Examples:

N2CHCO2Me
CO2Me
Rh(CF3CO2)2

A. J. Anciaux, et al., J. Org. Chem. 1981, 46, 873.

Rh(II)

O O
N2
J.L. Kane et al., Org. Lett. 2001, 3, 1081.

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Problems

A. Predict the major product of the following compounds with hydrogenation using
Wilkinson-type complexes.

OAc

H
O
OBz
H
O
O

B. Complete the following reactions.

Ar
RhLn, H2
1.
AcHN CO2Me

CO2H RhLn, H2
2. Ph
NHAc

RhLn
3. NEt2

H2O
4. NEt2

O O
Rh2+
5. OMe
N2

OH
6. Rh, H2

CN

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Reference

Transition Metals for Organic Synthesis, Vol. I, Ed., M. Beller and C. Bolm, Wiley-
VCH, New York, 1998.

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Lecture 34

11.8 Palladium Catalysts

There are several features which make reactions involving Pd catalysts particularly useful
and versatile among many transition metals used for organic synthesis. Most importantly,
Pd catalysts offer an abundance of possibilities for carbon-carbon and carbon-heteroatom
bonds formation in organic synthesis. The tolerance of Pd catalysts towards many
functional groups such as carbonyl and hydroxyl groups is an important feature.

11.8.1 Oxidative Addition

The “oxidative” addition is addition of a molecule X-Y to Pd(0) with cleavage of its
covalent bond, forming two new bonds (Scheme 1). This process is similar to the
formation of Grignard reagent from alkyl/aryl halide and Mg(0).

oxidadtive addtion
Pd(0) + X Y X-Pd(II)-Y

Scheme 1

The oxidative addition occurs with coordinative unsaturated complexes. As a typical

example, the saturated Pd(0) complex undergoes reversible dissociation in situ in a
solution to give the unsaturated 16-electrons species which is capable to undergo
oxidative addition (Scheme 2).

Ph-I
Pd(PPh3)4 Pd(PPh3)2 Ph-Pd-I(PPh3)2
18-electrons 16-electrons 14-electrons
2PPh3

Scheme 2

Oxidative addition is facilitated by higher electron density of Pd, and in general, σ donar
ligands such as R3P attached to Pd facilitate the reaction. On the other hand,  acceptor
ligands such as CO and alkenes tend to suppress oxidative addition.

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11.8.2 Suzuki-Coupling
The Suzuki coupling of a boronic acid with a halide or triflate has emerged into one of
the most important cross-coupling reactions, covering about a quarter of all palladium-
catalyzed coupling reactions (Scheme 3).

O Heat O
+ H B B
O O
(PPh3)2PdCl2 Br
KOH
Toluene

Scheme 3

General source of common boron reagents:

OR' Hydrolysis OH
R-Li + B(OR')3 R B R B
OR' OH

O
HB + R- O
O R B O

BCl3 + R3SiH

R R'OH R
HBCl2
R H
H BCl2 H B(OR')2

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Mechanism

Oxidative addition of the Pd(0) with vinyl halide leads to the formation of the
intermediate A that with base gives organopalladium alkoxide B. Due to low
nucleophilicity of the organoboron, the transmetallation takes place faster with B
compared to A to afford the intermediate C that can complete the catalytic cycle by
reductive elimination of the target product (Scheme 4).

PdL4
R'
-2L
"R R'-X
reductive Pd(0)L2 oxidative addition
elimination

L L
Pd L Pd X
R' R' L
"R
NaOR

c-s-trans
isomerism
NaX
L Pd R' L Pd OR
L R' L
"R
R'' O
B
RO B O O
O transmetallation

Scheme 4

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Examples:

Me Me
B(OH)2
MeO2C MeO2C
Pd(Pt-Bu3)2, CsF
76%

M. Rubina, M. Rubin, V. Geforgyan, J. Am. Chem. Soc. 2003, 125, 7198.

Me Me
Pd2(dba)3, P(t-Bu)3
MeO Cl + (HO)2B MeO
KF, THF, rt
88%

A. F. Littke, C. Dai, G. C. Fu, J. Am. Chem. Soc. 2000, 127, 4020.

OMe

I B(OH)2
Pd(OAc)2, P(o-tol)3
I + OMe
N K2CO3, aq. acetone N
SO2Ph SO2Ph
OMe
98%

Y. Liu, G. W. Gribble, Tetrahedron Lett. 2000, 41, 8717.

OC8H17 CHO HO H17C18O
B(OH)2 OH Pd(PPh3)2Cl2 / PPh3 / K2CO3 O
+
(HO)2B THF, Reflux, 24 h, 80 % O
OC8H17 OTf OC18H17 OH
S. Sakthivel, T. Punniyamurthy, Tetrahedron: Asymmetry 2012, 23, 101.

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11.8.3 Heck Reaction

The Heck reaction, is one of the most synthetically important Pd-catalyzed C-C cross-
coupling reactions, couples an alkene with a halide or triflate to form a new alkene
(Scheme 6). The alkene can be mono- or disubstituted and can be electron-rich, poor or-
neutral.

Pd(0)
R-X + R' R
R'
base

Scheme 6

Asymmetric version of this coupling reaction has also been explored. For example, the
chiral palladium complex having amino acid-derived phosphine ligand catalyzes the
reaction of phenyl triflate with dihydrofuran with excellent enantioselectivity (Scheme 7).

TfO Pd(dba)2, L*
+ O
O THF, i-Pr2NEt O
PPh2 N
87% yield L*
97% ee

Scheme 7

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Likewise, the intramolecular Heck reaction using (R)-BINAP affords decalin derivative
with 80% ee (Scheme 8).

TBSO
TBSO Pd(OAc)2 TBSO
carbometallation
(R)-BINAP
I PdOAc
Ag3PO4 -elimination
L*
H
67% yield
80% ee
Scheme 8

Mechanism

The mechanism involves the oxidative addition, carbometallation,-hydride

elimination and elimination of the target product (Scheme 9).

PdL4
-2L
base.HX R'-X
reductive Pd(0)L2 oxidative addition
elimination
base

L X
Pd L Pd X
H L R' L

R"
X
"R R' L Pd
L
H
R'
"R
syn--hydride elimination

Scheme 9

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Examples:

PdL2
I
Pd(OAc)2, PPh3

Ag2CO3
85%

M. M. Abelman, L. E. J. Am. Chem. Soc. 1988, 110, 2338.

I TMS TMS

Pd(OAc)2, AgNO3
Et2N, DMSO 64%

K. Karabelas, A. Hallber, J. Org. Chem. 1988, 53, 4909.

O
O

I PdCl2(MeCN)2

O
O Et3N
Me O
Me O
55%

F. E. Ziegler, U. R. Chakroborty, R. B. Weisenfield, Tetrahedron 1981, 37, 4035.

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11.8.4 Stille Coupling

The coupling of vinyl stannanes with vinyl halides or triflates using palladium catalysis is
one of the powerful methods for the carbon-carbon bond formation (Scheme 10). It is
effective under relatively neutral conditions and compatible with many functional groups.
Please see section 10.5.1 for mechanism

SnBu3 Pd2(dba)3
AsPh3, CuI
+ I
Me O DMF Me
O O O
46%
Scheme 10

11.8.5 Stille Carbonylative Coupling

The coupling reaction of aryl or vinyl triflate with organostannane using palladium-
catalysis in the presence of carbon monoxide and lithium chloride takes place under
relatively mild conditions to give good yields of ketones (Scheme 11).

O
OTf NMP, Pd2(dba)3
+ SnBu3
CO2Me AsPPh3, LiCl, CO CO2Me

Scheme 11

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Mechanism

The reaction occurs via oxidative addition, carbonyl insertion, transmetallation and
reductive elimination processes (Scheme 12).

PdL4

O -2L

R' R" R'-X

reductive Pd(0)L2 oxidative addition
elimination
L L
Pd
O R"
L Pd X
R' R' L
cis-trans
isomerism
CO
L R" insertion
Pd
O L
L Pd X
R' O L
R'
XSn(R")3
R"Sn(R")3
transmetallation

Scheme 12

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Examples:

O O
I
PdCl2(CH3CN)2, AsPh3, Cu(I)
+ SnBu3
Me NMP Me

S. T. Handy, X. Zhang, Org. Lett. 2001, 3, 233.

O O

O Pd2(dba)3, AsPh3 O

Cl
Bu3Sn

C. Boden, G. Pattenden, Synett 1994, 181.

Bu3Sn O
OTf Pd(PPh3)4
+
LiCl, CO
TMS
TMS

R. D. Mazzola, Jr., et al., J. Org. Chem. 2004, 69, 220.

11.8.5 Sonogashira Coupling

The reaction involves the coupling aryl halides with alkynes using the combination of
palladium and copper catalysts in the presence of base at moderate temperature (Scheme
13). It is compatible with functional groups such as hydroxo, carbonyl, amino, acyloxy,
acetal, esters and amides, and finds extensive applications in organic synthesis.

PdCl2(PhCN)2, P(t-Bu)3
Br + H R R
CuI, i-Pr2NH, dioxane

Scheme 13

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Mechanism

Oxidative addition of Pd(0) with aryl halide gives Pd(II) intermediate A that undergoes
reaction with in situ generated alkynyl copper to give intermediate B. The latter complete
the catalytic cycle by the reductive elimination of the substituted alkyne (Scheme 14).

PdL2 R-X
R R' oxidative
addition
reductie X = halogen
eliminatioon R =aryl, vinyl
R L
Pd
L XA L
R
Pd
L
B
R'
CuX R' Cu
transmetallation

Scheme 14

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Examples:

Br 3 mol % Pd(PPh3)2Cl2 O
O 2 mol % PPh
3
4 mol % CuI Me3Si OH
OH
1.5 equiv Et3N
t-Bu t-Bu
THF, RT, 12 h
SiMe3
80%
S. Jammi, L. Rlout, T. Punniyamurthy, Tetrahedron: Asymmetry 2007, 17, 2016.

Br 3 mol % Pd(PPh3)2Cl2 O OC8H17

C8H17O 2 mol % PPh3 O
4 mol % CuI
HO OH
Br OC8H17 2 equiv (C3H7)2NH
0.5 equiv
THF, 80 oC,12 h t-Bu OC8H17 t-Bu
20%
S. Jammi, L. Rlout, T. Punniyamurthy, Tetrahedron: Asymmetry 2007, 17, 2016.

Me Pd(0), CuI Me
I +
O OH base O OH

M. Feuerstein, H. Doucet, M. Santelli, Tetrahedron Lett. 2004, 45, 1603.

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11.8.6 Nigishi Coupling

The coupling of organozinc compounds with alkenyl, akynyl, aryl, allylic and benzyl halides
using Pd(0) provides another powerful method for carbon-carbon bond formation (Scheme 15).
Section 3.3.3 presents the mechanism.

Br Pd(0), THF Me Br
Zn
TBSO + TBSO
Br

SiMe3
SiMe3

Scheme 15

Examples:

Me Me Me Me Me Me
ZnCl2, t-BuLi
I Me OTBDMS
Me Me
OTBDPS
Me
I
Pd(PPh3)4
G. D. McAllister, R. J. K. Taylor, Tetrahedron Lett. 2004, 45, 2551.

OLi OH
ZnBr2, PhBr
Li
Pd(PPh3)2(OAc)2

M. Yus, J. Comis, Tetrahedron Lett. 2001, 42, 5721.

Me Me Me Me
Pd(P(t-Bu)3)2(OAc)2
Cl + ClZn
THF/NMP, 100 oC
Me Me

C. Dai, C. Fu, J. Am. Chem. Soc. 2001, 123, 2719.

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11.8.7 C-H Activation

Palladium-based catalysts have been explored for carbon-heteroatom bond formation via
cross-coupling as well as C-H activation. For example, the synthesis of 1-aryl-1H-
benzotrizole can be accomplished from triazene via C-H activation using Pd(OAc)2 under
aerobic conditions (Scheme 16).

R"
"
R
N Pd(II) N
R' X
X N
N
H

Scheme 16

Mechanism

Molecular oxygen reoxidizes the reduced palladium (0) to palladium (II) to complete the catalytic
cycle (Scheme 15).

R''
R''
N
R'
O2 X
N N
R' X H
N Pd(0) Pd(II)L2
R', R'' = alkyl, Cl
:B = base
R" L
Pd
N L Pd R"
R'
X N
N R'
X
N
H
L
R" :B
Pd
LH N
R'
X
N H:B + -L

Scheme 15

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Examples:

Pd(0), base
Ar-NH2 + R'NH2 ArNHR'
R' = alkyl, aryl

J. P. Wolfe, S. Wagaw, S. L. Buchwald, Acc. Chem. Res. 1998, 31, 805.

R"
R"
N Pd(OAc)2 (10 mol %) N
'
R N
N Cs2CO3 (2 equiv)
N N
H DMF, 110 oC, O2
Yield 70-88%
4A MS
R', R" = H, Cl, Et, Me

R. K. Kumar, M. A. Ali, T. Punniyamurthy, Org. Lett. 2011, 13, 2102; Synfacts

2011, 596.

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Problems

A. How will you synthesize the following compounds using the Heck and Suzuki
couplings?

t-Bu Me O

Me

B. Complete the following.

Pd(OAc)2
1. Br + HN O
NaOt-Bu

Br
Et2Zn, Pd(dppe)Cl2
2.
EtO2C

O
Si PdI2, CuI
3. +
N I N PPh3
CO2Ph CO2Ph

Bu3SnH, Pd(0)
4. + Br
Ph
OH

Si(OR)3 OTf
Pd(dba)2
5. +
TBAF

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Text Book

J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University Press,

New York, 2001.

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Lecture 35

11.9 Nickel Catalysts

Nickel-based catalytic systems are used in the production of many industrial and
consumer products, and play a key role in organic synthesis.

11.9.1 Hydrogenation

Raney Ni (Ni-Al) is produced when a block of Ni-Al alloy is treated with concentrated
NaOH. This treatment, called "activation", dissolves most of the Al out of the alloy. The
porous structure left behind has a large surface area, which gives high catalytic activity.
The ratio of Ni to Al is around 1 for the original material used by Raney, and may vary
from about 1 to 4.

T. K. Yang, D. S. Lee, Encyclopedia of Reagents for Organic Synthesis, John Wiley and
Sons, Inc., L. A. Paquette, Ed., New York, 1995, 6, 4401.

It is one of the common catalysts used for the hydrogenation of aromatic compounds. A
practical example is shown in Scheme 1, where benzene is reduced to cyclohexane.

O
Raney Ni oxidation OH
HO
H2 O

Scheme 1

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Raney Ni is also used for the reduction of a series of functional groups. For example,
Raney Ni is particularly useful for the cleavage of C-S bond (Scheme 2).

S Raney Ni R
R
+ CH3CH3 + 2NiS
R S H2 R

Scheme 2

The Raney Ni modified by tartaric acid and NaBr is an excellent catalyst for asymmetric
hydrogenation of -keto esters,-ketones and -keto sulfones (Scheme 3). Appropriate
pH, temperature and concentration of NaBr should be carefully chosen.

O O OH O
Raney Ni-U-(R,R)-DET
Me OMe + H2 Me OMe
o
NaBr, THF-AcOH, 60 C
100 atm up to 90% ee

O O OH OH
Raney Ni-U-(R,R)-DET
Me Me + H2 Me Me
THF, 100 oC
99 atm NaBr, 91% ee

O O2 OH O
Raney Ni-U-(S,S)-DET 2
Me S + H2 Me S
Me o Me
NaBr, THF-AcOH, 100 C
97 atm up to 71% ee

Scheme 3

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Examples:

Raney-Ni Me
Me
S CO2Me
CO2Me CO2M2
CO2M2
81%

S.-M. Yang, S. K. Nandy, A. R. Selvakumar, J.-M. Fang, Org. Lett. 2000, 2, 3719.

Raney-Ni
CO2t-Bu CO2t-Bu
N N
H BH3
H
96%

M. Couturier, J. L. Tucker, B. M. Andresen, P. Dube, J. T. Negri, Org. Lett. 2001, 3, 465.

NC CN CH2NH2
H2NH2C
Raney-Ni
N (CH2)n NH N (CH2)n NH
H H

B. Klenke, I. H. Gilbert, J. Org. Chem. 2001, 66, 2480.

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11.9.2 Hydrocyanation
Organonitriles are key intermediates for the synthesis numerous compounds including
polymers, fibers, agrochemicals, cosmetics and pharmaceuticals. Nickel complexes find
wide applications for the hydrocyanation of alkenes and alkynes. For example,
triarylphosphite nickel complex catalyzes the reaction of 1,3-butadiene with HCN to
afford nylon 6,6-precursor AND (adiponitrile) by anti-Markovnikov fashion (Scheme 4).
Using this process annually 1 billion pounds of AND is produced.

Ni[P(OAr)3]4
Ni[P(OAr)3]4 Lewis Acid
+ HCN NC
CN CN
HCN
ADN

NiL4CN

Scheme 4

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11.9.3 Cross-Coupling Reactions

11.9.3.1 Negishi Coupling
Unsaturated alkyl bromide proceeds C-C cross-coupling with Et2Zn in the presence of
Ni(acac)2 (Scheme 5). Under this condition, saturated alkyl bromide produces the
bromide-zinc exchange product.

20 mol% LiI, THF

7.5 mol% Ni(acac)2
Br + Et2N Et
-35 oC, 4-18 h
82%

20 mol% LiI, THF

7.5 mol% Ni(acac)2
XZn + Et2N BrZn
-35 oC, 4-18 h
85%
alkyl-alkyl Negishi coupling

Scheme 5

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Mechanism
The coordination of the remote double bond to the nickel center is crucial for the cross-
coupling reaction (Scheme 6).

R R R
R'2Zn Reductive elimination

Ni L Ni L R'
L X L R'

[NiL2] [Ni(acac)2]

R
R
R transmetallation
L ZnX
X Ni
L R'

Scheme 6

The presence of a remote carbonyl and cyano groups in the alkyl halides also facilitates
their cross-coupling with diorganozincs. For example, functionalized diorganozincs and
alkyl iodides can be cross-coupled using m- or p-trifluoromethyl styrene as a promotor
and Ni(acac)2 as a catalyst (Scheme 7).

10 ml% Ni(acac)2
NC I + (C5H11)2Zn NC

O O
10 ml% Ni(acac)2
I + (C5H11)2Zn Ph
Ph

Giovannini et al., J. Org. Chem. 1999, 64, 3544.

Scheme 7

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11.9.3.2 Kumuda Coupling

The coupling of Grignard reagents with alkyl, vinyl or aryl halides under Ni-catalysis provides an
effective route for carbon-carbon bond formation. For example, the synthesis of unsymmetrical
biaryls can be accomplished from phenylmagnesium bromide and 1-chloro-4-methoxybenzene
using Ni(COD)2 which is an example for low cost production of biaryl compounds (Scheme 8).

Ni(COD)2
MeO Cl + MgBr MeO
O
P t-Bu
H
t-Bu

Scheme 8

RX
R-R' Ni(0)L2 oxidative
reductive addition
elimination

X
R' L
L Ni
Ni R L
L R
R'MgX

cis-trans transmetallation
isomerization R'
L
Ni MgX2
R L
Scheme 9

Mechanism
The reactions involve the oxidative addition followed by reductive elimination via
transmetllation and cis-trans isomerization (Scheme 9).
In case of alkyl halide, an influence of 1,3-butadiene on the reaction has been noted
(Scheme 10).
Br Br
NiCl2
+ MgCl
Br
100%
Scheme 10

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Mechanism
The acceleration of the reaction with butadiene is described in Scheme 11.

2
Ni(0)L2 oxidative
R-R' addition
reductive
elimination

Ni
Ni
R R' MgX
RMgX

Ni
R'X R MgX

Scheme 11

Examples:

NiCl2
MgBr
Br +
100%

J. Terao, H. Watanabe, A. Ikumi, H. Kuniysu, N. Kambe, J. Am. Chem. Soc. 2002, 124,
4222.
Ni(dppb)Cl2
BrMg S
+ S
N PPh2 PPh2
N Br
dppb

G. Y. Li, W. J. Marshall, Organometallics 2002, 21, 590.

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11.9.3.3 Suzuki Coupling

Nickel complexes having nitrogen based ligands catalyze the Suzuki coupling with
secondary halides (Scheme 12).

6 mol% NiCl2
Br 8 mol% L
+ Ph 9-BBN
1.2 equiv KOtBu NHMe
Ph MeHN L
RT

4 mol% Ni(COD)2
Br + 8 mol% L1
(HO)2B
1.6 equiv KOtBu
CN 60 oC CN N L1 N

Scheme 12

11.9.3.4 Hiyama Coupling

Hiyama coupling can be successfully carried out using nickel catalysts at moderate
temperature (Scheme 13).

6.5 mol% NiBr2

7.7 mol% L1
Br + F3Si
3.8 equiv CsF
60 oC
6.5 mol% NiBr2 N L1 N
7.7 mol% L1
Br + (HO)2B OMe OMe
3.8 equiv CsF

Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788.

Scheme 13

11.9.3.5 Stille Coupling

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Stille coupling is also effective with nickel complexes at moderate temperature (Scheme
14).

Me Me
10 mol% NiCl2
15 mol% L2
Br + Cl3Sn
7equivKOtBu
60 oC N N
L2
-do-
Br + Cl3Sn F F

Powell, D. A.; Maki, T.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 510.

Scheme 14

11.9.3.6 Reductive Aldehyde and Diene Coupling

Addition of dienes to aldehydes has emerged as a useful reaction to yield
unsaturatedor -unsaturated alcohols (Scheme 15). The reaction is initiated either
by formation of an oxametallocycle or by hydrometallation of the diene.
OH
Cat. Ni(acac)2
CO2Me + PhCHO Ph
Et3B CO2Me
OBn
Cat. Ni(acac)2
BnO

CHO Et2Zn or Et3B OH

Scheme 15

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Examples:

MeO2C Ni(acac)2 MeO2C

Me Et2Zn
CHO THF OH
72%

K. Shibata, M. Kimura, M. Shimizu, Y. Tamaru, Org. Lett. 2001, 3, 2181.

Ph

O SnBu3 Ph OHC
H H Ni(acac)2, DIBAL

TMSCl
74%
M. Lozanov, J. Montgomery, J. Am. Chem. Soc. 2002, 124, 2106.

O O
Me Zn
2 Me
Me Me
Ni(acac)2, Et2O
Me Me Me Me
67%
A. E. Greene, J. P. Lansard, J. L. Luche, C. Petrier, J. Org. Chem. 1984, 49, 931.

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11.9.3.7 Cycloaddition
The most widely used application of the nickel-diene complex is the different mode of
coupling of 1,3-dienes, including dimerization, trimerization and oligomerization
(Scheme 16).

NiLn

NiLn

LnNi

Ln
Ni

LnNi

Scheme 16

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For example, the structurally complex eight membered rings can be constructed via
[4+4]-cycloaddition (Scheme 17).

OTBDMS OTBDMS
OTBDMS 20 mol% Ni(COD)2
60% mol% P(OC6H4-2-Ph)3
COD =
+
o
Toluene, 85 C

7:1
Scheme 17

Compared to the [4+4]-cycloaddition, the [4+2] is stereospecific and effective at low

temperature (Scheme 18).

OMOM
10 mol% Ni(COD)2
20 mol% P[OCH(CF3)2]3 MeO

TMSO Cyclohexane, RT
MeO OMOM

Scheme 18

11.9.4 Carbonylation

Ni catalyzes the addition of carbon monoxide to alkenes and alkynes in presence of water
or MeOH to give carboxylic acid or ester, respectively, which are very useful processes
in organic synthesis (Scheme 19).

CO2Me
Ni(COD)2
BnN BnN
Br
MeOH, CO

Scheme 19

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11.9.5 Alkene/Alkyne Oligomerization Reactions

In the presence of catalysts, alkynes and alkenes can react itself or with many other
organic and inorganic compounds. Nickel catalysts are found wide applications for this
purpose. For example, Reppe synthesis of cyclic polymerization of acetylene gives
cyclooctatetraene, which represents a true milestone in transition-metal-catalysis
(Scheme 20).

Ni(CN)2, CaC2, THF

60 oC, 15 bar
90%
Scheme 20

The formation of organonickel compounds have been revealed by a carefully designed

experiment (Scheme 21).

Ph Ph Ph Ph
Ph
SO2Ph Ni(COD)2 Ph Ph Ph Ph Ph 100 oC Ph Ph
N PCy3 N SO2Ph
N Ni Ph N Ph
Ph Ph Ni SO2Ph rt Ph
PhH, rt PCy3
PCy3 Ph SO2Ph

Scheme 21

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Problems

Complete the following with major products.

Ni(acac)2, Et2Zn
1.
CHO

MeOH, CO, Ni(COD)2

2. N Br
Ph Et3N, CH3CN

I Ni(COD)2
3.
I DMF

Br Ni, Zn
Br
4.

O
Ni(COD)2, MeMgBr
Me
5.
OMe
Me

Text Book:

M. B. Smith, Organic Synthesis, 2nd Ed., McGraw Hill, New York, 2004.

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