NPTEL – Chemistry – Principles of Organic Synthesis

Lecture 17
8.1 Types of Rearrangements

Rearrangements are divided into intramolecular and intermolecular processes. In

intramolecular process, the group that migrates is not completely detached from the
system in which rearrangement is taking place. In contrast, in intermolecular process, the
migrating group is first detached and later re-attached at another site.

8.2 Rearrangement to Electron Deficient Carbon

These reactions are classified according to the nature of group that migrates.

8.2.1 Carbon Migration

8.2.1.1 Wagner-Meerwein Rearrangement

It is one of the simplest systems where an alkyl group migrates, with its bonding pair, to
an electron-deficient carbon atom.

"R R H "R R
R' + H2O
'"R OH '"R R'

Mechanism

"R R "R R "R R "R "R

H -H2O R H R
"R' "R' '"R H
R' OH R' OH2 R' '"R R' '"R R'

The driving force for the rearrangement resides in the greater stability of a tertiary
carbocation compared to that of primary carbocation.

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The classical and non-classical carbocation controversy concerned the Wagner-

Meerwein rearrangement of norbornyl systems:

classical
Cl

Non Classical

Cl undergoes solvolysis reaction significantly greater than the endo isomer

Cl

Features of this migration

 The carbocation may be produced by a variety of ways.
 Hydrogen can also migrate in this system.

R R
X Me
Me heat Me
+ HX
Me
Me

 Aryl groups have a greater migratory aptitude than alkyl group or hydrogen due to
the formation of lower-energy bridged phenonium ion.

-H Me
Me Me H Me
Me Cl Me H Me Me
Phenonium ion

 Rearrangements in bicyclic systems are common.

Cl
SnCl4 Cl
Cl
Isobornyl chloride

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 The rearrangement is stereosepecific

 Two or more rearrangements may take place simultaneously.

Me Me Me Me
Me
H Me Me
Me H H H
BF3-Ac2O
H H H Me

OAc Me
OAc OAc

Examples:

Me Me Me Me
H
Me H

Me Me Me H H Me

H Me Me Me
HO
H HO
Me MeH Me
Me

-Amyrin enol of Freidelin

E. J. Corey, J. J. Ursprung, J. Am. Chem. Soc. 1956, 78, 5041.

Me Me

Me OH Me
CO2H
AcO Me AcO Me Me
Me
80%
H
S. Baeurle, T. Blume, A. Mengel, C. Parchmann, W. Skuballa, S. Baesler, M. Schaefer, D. Suelzle, H.-P. Wrona-
Metzinger, Angew. Chem. Int. Ed. Engl. 2003, 42, 3961.

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8.2.1.2 Pinacol Rearrangement

Treatment of 1,2-diols (pinacol) with acid lead to rearrangement to give ketone. Although
this rearrangement fundamentally is similar to the above described Wagner-Meerwein
rearrangement, but differs in that the rearranged ion, the conjugate acid of ketone, is
relatively more stable than the rearranged carbocation formed in Wagner-Meerwein
rearrangement. Thus, the driving force for pinacol is greater compared to Wagner-
Meerwein rearrangement. However, the characteristics of the Wagner-Meerwein apply to
the pinacol rearrangement.

O
HO OH H

R R

Mechanism

HO OH HO: OH2 HO Me O Me
H H
Me Me Me Me Me
Me Me Me Me Me
Me Me Me Me

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Examples:

Effect of Temeperature
O O
OH
+
HO

Conc. H2SO4 0 oC major minor

Conc. H2SO4 97 oC minor major

B. P. Mundy, R. Srinivasa, Tetrahedron Lett. 1979, 20, 2671.

Effect of Concentration
O O
OH
+ +
HO

Conc H2SO4 0 oC 0 5 95
o 30 1 69
25% Conc. H2SO4 0 C

B. P. Mundy, R. Srinivasa, R. D. Otzenberger, A. R. DeBernardis, Tetrahedron Lett. 1979, 20, 2673.

8.2.1.3 Benzilic Acid Rearrangement

1,2-Diketones that have no -hydrogen react with hydroxide ion to give -hydroxyacid.
The best known example is the rearrangement of benzil to benzilic acid. The driving
force for the reaction lies in the removel of the product by ionization of carbonyl group.

O R' OH HO
CO2H
R O R' R
H
R = aromatic, group without -hydrogen

Mechanism

O R' OH O R' OH O R' OH H HO R' OH

R O R O R O R O

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Examples:

O O HO CO2H
Me Me OH Me Me

Me Me Me Me
H
A. Schaltegger, P. Bigler, Helvetica Chemica Acta 1986, 69, 1666.

O CO2H
O HO
Me
NaOH Me

OMe
OMe
S. Deb, R. Chakraborti, U. R. Ghatak, Synth. Commun. 1993, 23, 913.
O
Me
O MeCO2H
OH
Me H KOH, MeOH
Me H
H H H2O
H H
O O

V. Georgian, N. Kundu, Tetrahedron 1963, 19, 1037.

8.2.1.3 Arndt-Eistert Homologation Reaction

The reaction of acid chloride with diazomethane gives a diazoketone which is in the
presence of silver oxide under heating proceeds the Wolff rearrangement to yield a
ketene that is directly converted into an acid in the presence of water.

O 1. CH2N2
2. Ag2O HO
R
R Cl 3. H2O O

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Mechanism

Elimination of nitrogen yield a carbene followed

by migration of the R group

O CH2-N2 O O O
O -Cl Ag2O
Cl N2
R Cl N2 R R :
R CH2N2 R -N2
H H H
carbene

The rearrangement of diazoketone is called

the Wolff Rearrangement O
N
.. N
R
O OH H
H H2O HO
H proton H R
O C H2O HO
R transfer O
R R

Examples:

O Cl
1.
Cl O
CO2H CO2H
2. CH2N2

3. Ag2O, Na2CO3, Na3S2O3

T. Hudlicky, J. P. Sheth, Tetrahedron Lett. 1979, 29, 2667.
O
NHCbz 1. CH2N2 MeO NHCbz
Cl
CO2Et 2. light, MeOH O CO2Et

J. M. Jimenez, R. M. Ortuno, Tetrahedron: Asymmetry, 1996, 7, 3203.

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8.2.2 Halogen, Oxygen, Sulfur, and Nitrogen Migration

In the system X-C-C-Y, an atom X with an unshared pair of electrons can assist the
heterolysis of the C-Y bond. In case of unsymmetrical system, nucleophilic attack
predominates at the less substituted carbon of the bridged ion that leads to rearranged
skeleton.

X: X R :X

R Y R Y
Nu

no rearrangement rearrangement
X:
X = Cl, S, O, N
R Nu

Some examples follow:

Me
MeO Me O H OMe
Ag H Me H2O
H Me Me
Me Me Me
Br -AgBr Me -H HO Me

Me
Me SMe MeS
HCl Me SMe -H2O S Cl

HO H Me Cl
-Cl H2O Me

Cl
OH .. Cl
Cl Cl
N -H2O N N N
H Me Me Me
Me

Rupe Rearrangement
The bridged cation may be produced via protonation of an unsaturated bond as in the
Rupe rearrangement of-acetylenic alcohols.

O
HO H R
R
R' H2O
R

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Mechanism

HO H H2O -H2O R -H R H
R R
R' R' R'
H R
OH2 O-H O
R H R
R H2O R -H

R R R
R

or
H O-H O
HO O
HO H R -H R H R
R
R
R' R R H R R

Examples:

O Me
HO
Me Me
Me Me
HCO2H
heat

W. S. Johnson, S. L. Gray, J. K. Crandall, D. M. Biley, J. Am. Chem. Soc. 1964, 86, 1966.

O Me
HO
Me Me
HCO2H
heat
AcO AcO
Me OAc Me OAc

W. S. Johnson, S. L. Gray, J. K. Crandall, D. M. Biley, J. Am. Chem. Soc. 1964, 86, 1966.
O
OH
Me
Me HCO2H Me
heat
Me Me
Me Me
K. Takeda, D. Nakane, M. Takeda, Org. Lett. 2000, 2, 1903.

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In case of a neighbouring acetoxy group, the solvolysis is assisted via a five-membered

acetoxonium ion.

Me Me Me Me Me
OH Me OH
-Y H2O H -H
O O O O O O O O O OH O O
-H
Y OH

Problems:
A. Predict the major products in the following reactions withmechanism.
Ph Me H
1. Ph Me
HO OH

HCl
2.

H
HO
3.
H
Me
H
4. OH
OH
Me

OH
5. SOCl2
OH
Me Et3N

HO MeOH
BF3
6.
O
OH

COCl CH2N2
7.
Ag(OBz)2/MeOH

B. Solvolysis of trans-2-acetoxycyclohexyl tosylate in acetic acid about 100 times faster thatn its
cis-isomer. Explain.

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Text Books:

R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.

B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic

Synthesis, Wiley Interscience, New Jersey, 2005.

Lecture 18
8.3 Rearrangement to Electron Deficient Nitrogen

8.3.1 Hofmann Rearrangement

This rearrangement provides an effective method for the synthesis of primary aliphatic
and aromatic amines from primary amides (Scheme 1).

H2O RNH2
O
OH, H2O
R NH2 N C O
Br2 R
O
R'OH R'
O NHR

Scheme 1

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Mechanism

Treatment of amide with sodium hypobromite gives N-bromo-amide which reacts with
base to afford a conjugate base within which rearrangement takes place to give
isocyanate. The formed isocyanate may be isolated in anhydrous conditions or it can be
converted into amine by aqueous workup (Scheme 2).

O O O O H2O
OH Br-Br OH Br -Br
H Br N C O
R N R N R N R N
H H R
H

O
O
H R proton -CO2
O N H R RNH2
transfer O N
H H
Scheme 2

The workup can also be with alcohol or amine to give urethane or urea, respectively
(Scheme 3).

O O O O
R' R proton R R'NH2 R'OH R' R proton R' R
N N H N N N C O O N O N
H H transfer R' R H transfer H
Urea H
Urethane

Scheme 3

H
O
Ph O Ph Ph O N R H2O
I I I I
H2N R N C O
PhI(CF3CO2)2 F3C O O CF3 F3C O Ph O
-CF3COOH R
O O O
R.H. Boutin, G. M.
- Loudon, J. Org. Chem. 1984, 49, 4211.

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Examples:

OH OH
NH2 PhI(OAc)2
NH2
O KOH, iPrOH

J. W. Hilborn, Z.-H. Lu, A. R. Jurgens, Q. K. Fang, P. Byers, S. A. Wald, C. H. Senanayaka, Tetrahedron Lett. 2001,
42, 8919.
O
O
OH O OH C
AgOAc, NBS N
C7H15 O NH
C7H15 NH2
DMF
77% C7H15
OH
OH OH

T. Hakogi, M. Taichi, S. Katsumura, Org. Lett. 2003, 5, 2801.

8.3.2 Curtius Rearrangement

This rearrangement describes the transformation of acyl azide into isocyanate by

decomposition on heating and its application for the synthesis of primary amines,
urethanes and ureas as presented in Hofmann rearrangement.

RNH2
O H2O
O
NaN3 neat R'OH O NHR
R Cl R N3 N C O R'
-NaCl R O
R'NH2
R'HN NHR

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Mechanism

Na

O O Cl O O
NaN3 -NaCl N N -N2
R N=N=N N N N C O
R Cl R N R N
R

Examples
O
P
O N3
O
O
Ph
OH
NEtO
Et3N, EtOH H
53%
Y. Lu, R. T. Taylor, Tetrahedron Lett. 2003, 44, 9267.
O
Cl S (COCl)2, CHCl3, NaN3 Cl S NH
CO2H NH N
N N O
O N NH2
Cl Cl 34%
S. D. Larsen, C. F. Stachew, P. M. Clare, J. W. Cubbage, K. L. Biorg. Med. Chem. Lett. 2003, 13, 3491.

8.3.3 Schmidt Rearrangement

Carboxylic acid reacts with hydrazoic acid in the presence of conc. H2SO4 to give acid
azide which is present in the form of conjugate acid eliminates nitrogen to afford
isocyanate that could be converted into amine as reported in Hofmann rearrangement.

O
HN3
R OH RNH2
H2SO4

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The reaction is also effective with aldehydes, ketones, tertiary alcohols and substituted
alkenes.

O O
HN3 HN3 R
R R OH N
R H H N
H2SO4 H R R H2SO4 R R
O O R HN3 R
HN3 R
R N
R R R N R H2SO4 R R
H2SO4 H R

Mechanism

H
O :O: O N N N O
H -H2O .. N N -N2
R OH R O R N N C O
R OH2 R H R
H2O
RNH2
-CO2

H OH2 R
:O: N N N OH N
:OH N H R .. N N -H2O N
H R N N
N R N R
R R R R R H
H H

R OH2 OH O
N -N2 H2O R -H
-H N R N-R N R R
N R R N R N
R H

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Examples:

O H
NaN3 Me N CO2Et
CO2Et
Me
MeSO3H
Et C4H7 O Et C4H7
55%
M. Tanaka, M. Oba, K. Tamai, H. Suemune, J. Org. Chem. 2001, 66, 2667.

CO2Et CO2Et CO2Et

N N Ph Ph N
Ph H H O H
HN3 HN
+
H2SO4 N
O O 66% H
36%
G. R. Krow, S. W. Szczepanski, J. Y. Kim, N. Liu, A. Sheikh, Y. Xiao, J. Yuan, J. Org. Chem. 1999, 64, 1254.

8.3.4 Lossen Rearrangement

Ester of hydroxamic acid reacts with base to give isocyanate that could be converted into
amine as shown in Hofmann rearrangement.

O
Base
O R' RNH2 + R'COO + CO2
R N H2O
H
O
H -CO2
N OH RNH2
R
H2O O
O
TsOH
OH N C O
R N R H
H Base N NR'2
R'2NH R
O

Mechanism

O O
Base .. O -R'CO2 H2O
O R' R' RNH2
R N R N N C O
H O O R

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Examples:

O O O
S Ph OH NH2
N O OH

O O

L. Baue, S. V. Miarha, J. Org. Chem. 1959, 24, 1293.

O
O NHOH O
N
N O
O N
N H H N

N Me N Me

J. Bergman, J.-O. Lindstriim, Tetrahedron Lett. 1976, 17, 3615.

All these four rearrangements have common intermediate isocyanate forming from
different substrate precursors. Among the all, the Hofmann rearrangement is more
convenient providing that other functional group do not react under the conditions.

8.3.4 Beckmann Rearrangement

Oximes rearranges in acidic conditions to give amides. The reaction is intramolecular and
stereospecific: the substituent trans to the leaving groups migrates.

R NH2OH R OH H R R'
O NH The reaction can also be carried out
N with PCl5, PPA, P2O5 or TsCl.
R' -H2O R' H2O O

An interesting application of this method is the synthesis caprolactam from

cyclohexanone oxime. Caprolactam is the substrate precursor for nylon preparation.

OH O
N
HN H
Cocn. H2SO4 heat N
*
O n
caprolactam

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Mechanism

R OH H R OH2 -H2O R R R'

H2O
N N N: R N R' N
R' R' R' H2O

-H R R' proton R R'

N N
H-O H transfer O H

Examples:

HO
N
PCl5
NH
H2O
O
J. A. Robi, E. Dieber-McMaster, R. Sulsky, Tetrahedron Lett. 1996, 37, 8985.

Me Me
Me
PPA Me
OH + NH
N N
Me H O Me
O
Me Me Me
N. Komatsu, S. Simizu, T. Sugita, Synth. Commun. 1992, 22, 277.

Ph Ph
P2O5
HN
MeSO3H
HO N H O H
P. W. Jeffs, G. Molina, N. A. Cortese, P. R. Hauck, J. Wolfram, J. Org. Chem. 1982, 47, 3876.
The rearrangement of amidoximes lead to the formation of urea derivatives which is
called the Tiemann Rearrangement

OH O SO Ph
N N 2 O
PhSO2Cl H2O R R'
R' R' N N
R N R N H H
H H

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Problems:
What products would you expect from the following reactions?
Explain with mechanisms.

NH2 Br2-KOH
1.
N
O
Br2-KOH
2. NH

O
OH
N
H
Me
3.

N
OH H2SO4
4.

N3 HCl-EtOH
5. CO2H
O

OH PhSO2Cl/H2O
N
6.
Me NHMe

Me3Al
7.
N
OMs

Text Books:
R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.
J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew York, 1992.

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Lecture 19
8.4 Rearrangement to Electron Deficient Oxygen

8.4.1 Baeyer Villiger Reaction

Treatment of ketones with peroxyacid gives ester. The reaction is effective with acid or
base and the mechanism is closely related to pinacol rearrangement: nucleophilic attack
by the peroxyacid on the carbonyl group gives an intermediate that rearranges with the
expulsion of the anion of the acid.

RCOOOH
O O
H
HOOH O

OH
Mechanisms
Acid Catalysed Reaction

O R O
HO O
O H OH OH OHH OH
O O -H O
O R O R

OH OH OH O
H : OH : OH -RCO2H
O O -H
O R O R O O

Base Catalysed Reaction

OH
HOOH HOO + H2O

O O
O OOH O H -OH
O O

Migratory Aptitude: 3◦ > 2◦ > PhCH2 > Ph > 1◦ > Me > H.

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Examples:

O O
MCPBA
O
75%

Y. Chen, J. K. Snyder, Tetrahedron Lett. 1997, 38, 1477.

O MCPBA
O
75% O

A. E. Greene, C. Le Drian, P. Crabbe, J. Am. Chem. Soc. 1980, 102, 7584.

8.4.2 Hydroperoxide Rearrangement

Tertiary hydroperoxide with acid undergoes rearrangement to give ketone and alcohol or
phenol. The mechanism is similar to that of Baeyer-Villiger reaction. For example,
cumene forms hydroperoxide by autoxidation which rearranges in the presence of an acid
to give phenol and acetone.

.. Me Me Me
Me Me
Me Me O H O H
Me O Me O O Me O OH2
H
O2 H -H2O H2O

Me Me
HO O-H OH
proton O

transfer + Me Me

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8.4.2 Dakin Reaction

Benzaldehyde or acetophenone bearing hydroxyl substituent in the ortho or para position
proceed rearrangement to give catechol or quinol, respectively. The reaction is
performed in the presence of alkaline hydrogen peroxide and the mechanism is similar to
that of Baeyer-Villiger reaction.

O R
OH
OH
H2O2, OH OH
R = H, Me
H

Proposed Mechanism

O O
R OH
O R O O H O R OH
O R
O
OH OH OH
OH OOH OH -RCO2H
-OH OH

Examples:

OH OH
Na2CO3, H2O2
Me THF, DMF, H2O OH
O 90%

G. W. Kabalka, N. K. Reddy, C. Narayana, Tetrahedron Lett. 1992, 33, 865.

O
CHO OH
H2N NH2

HO H2O2 HO
83%
R. S. Varma, K. P. Naiker, Org. Lett. 1999, 1, 189.

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8.5 Rearrangement to Electron-Rich Carbon

This group of reaction has been less explored, and is less of synthetic importance
compared to the rearrangements to electron deficient carbons. The rearrangements to
electron deficient hetero atom may be generally explained as:

R
R C C X = N, S, O
X X

8.5.1 Stevens Rearrangement

Quaternary ammonium salt which has -hydrogen proceeds E2 (Hofmann) elimination
with base.

H OH
NMe3 H2O + H2C=CH2 + Me3N

In case of quaternary ammonium salts containing -ketone or ester or aryl group, an -

hydrogen is removed by base to give an ylide and then the rearrangement occurs.

R H R' R
H base H
R' N N Z = ketone, ester
"R Z "R Z

Migratory Aptitude R = propargyl > allyl > benzyl > alkyl

Mechanism

R H base R H R' R H R' R

R' N H R' N N H
N
"R Z "R Z "R Z "R Z
Solvent Cage

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Examples:

MeO OMe MeO OMe

MeO MeO
t-BuO
MeO MeO
77%
N N Me
I Me
Me Me

S. Hanessian, M. Mauduit, Angew. Chem. Int. Ed. Engl. 2001, 40, 3810.

O O
N2 Cu O
O OMe copper O OMe
O
catalysis OMe
H H H
89%

F. P. Marmsaeter, G. K. Murphy, F. G. West, J. Am. Chem. Soc. 2003, 125, 14724.

8.5.2 Sommelet-Hauser Rearrangement

In the absence of -carbonyl group, the -hydrogen is too weakly acidic for hydroxide
ion induced rearrangement. Thus, a strong base, such as amide ion in liquid ammonia, is
to be used, when the rearrangement takes a different course: instead of [1,2] shift
(Steven’s rearrangement), a [3,2]-sigmatropic rearrangement takes place which is called
Sommelet-Hauser rearrangement.

Me NaNH2 Me
Me N
N
Me [2,3] Me
Me

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Mechanism

H
H 2 Me Me
NH2 3 [2,3] N N
Me Me
N N Me Me
Me 2 1 Me CH2 Me
1

There can be competition between Stevens and Sommelet-Hauser rearrangement

mechanisms.

R
sommelet-Hauser
NMe
R [2,3]
Me
N Me
Me
Stevens Rearrangement
R
[1,2]
NMe2

Examples:

Me
OMe
S Me
Me
Cl MeO Cl
SMe MeS
+
MeOH
Cl Cl
Cl
58% 7%
T.-J. Lee, W. J. Holtz, Tetrahedron Lett. 1983, 24, 2071.

NC CN
CN CN NMe2
NaOH CN
N
Me Me benzene + NMe2
Cl HCl
Cl 87% 92 8 CN
A. Jonczyk, D. Lipiak, J. Org. Chem. 1991, 56, 6933.

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8.5.3 Wittig Rearrangement

Ethers undergo [1,2]-sigmatropic rearrangement in the presence of strong base such as
amide ion or phenyllithium to give more stable oxyanion. The mechanism is analogous to
that of Stevens rearrangement.

H R'
R"Li H R = H, alkyl, aryl, alkenyl, alkynyl, -CO2R
R'
R O R O R' = alkyl, allyll, benzyl, aryl

Mechanism

Li Li
H . R' R'
R"Li . R' .
R' R'
R O R O R O. R O Li R O Li
-R"H
Solvent Cage
H2O R'
H
-LiOH R O

Examples:

TIPS
H
OH
O
TIPS n-BuLi, TMEDA
Me Me

O Me THF O Me
H H
78%
P. Wipf, T. H. Graham, J. Org. Chem. 2003, 68, 8798.

Me
Me Me
Me OH O
O n-BuLi O
O O
Me
Me
30%
R. E. Maleczka, Jr., F. Geng, J. Am. Chem. Soc. 1998, 120, 8551.

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NPTEL – Chemistry – Principles of Organic Synthesis

8.5.4 Favorskii Rearrangement

-Haloketones with base afford enolates which rearrange to give esters via
cyclopropanones.

O
R"OH, OR" R
R R' R'
CO2R"
Cl

Mechanism

O O O O O OR"
OR" R R' R R' -Cl OR"
R R'
R R' R R'
Cl H Cl Cl

O O
OR" R"O-H OR"
R R
H
R' R'
The direction of ring opening of cyclopropanone is determined by the more stable
carbanion, formed in the reaction.

CH2 CH3
MeOH
Ph CO2Me Ph CO2Me
less stable
not favoured
Ph Cl Ph H
Ph MeO MeOH
O MeO CO2Me
CO2Me Ph
O HCl O Ph
MeO
Ph O more stable
favoured
Cl

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NPTEL – Chemistry – Principles of Organic Synthesis

Examples:

Br
Me Et2N, CF3CH2OH O

O O
OMe O
OMe OMe
O 73%
M. W. Finch, J. Mann, P. D. Wilde, Tetrahedron 1987, 43, 5431.
CO2Et CO2Et
N N
MeO
Br
CO2Me
DME 56%
O
R. Xu, G. Chu, D. Bai, Tetrahedron Lett. 1996, 37, 1463.

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NPTEL – Chemistry – Principles of Organic Synthesis

Problems:
A. Formulate mechanisms for the following reactions.
O
Br CO2Me
MeO, MeOH MeO2C
1. Br Et
MeO2C
Br
Bu3Sn Me OH
n-BuLi, THF
2. Me Me Ph
O Ph
Me
OH OH
CHO OH
Sodium percarbonate
3.
THF, DMF, H2O
Cl Cl

B. Complete the following reactions.

O

mCPBA
1.

O
Br OH
2.

Bu3Sn Me n-BuLi
3. O Ph

Me O n-BuLi
4. O O

I SnMe3

N MeLi
5. Me
Me

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NPTEL – Chemistry – Principles of Organic Synthesis

Text Books:

R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.

B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic

Synthesis, Wiley Interscience, New Jersey, 2005.

J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew York, 1992.

Lecture 20
8.6 Aromatic Rearrangements

A number of rearrangements occur in aromatic compounds of the type:

Y
X XH XH
Y
+

X is usually nitrogen or oxygen. Both intermolecular and intramolecular migrations are

known.

8.6.1 Intermolecular Migration from Nitrogen to Carbon

Aniline derivatives readily proceed rearrangement on treatment with acid. First, the
formation of conjugate acid of the amine takes place which then eliminates the
electrophilic species that reacts at the activated ortho or para position of the aromatic
ring.

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NPTEL – Chemistry – Principles of Organic Synthesis

8.6.1.1 N-Haloanilides (Orton Rearrangement)

Treatment of N-chloroacetanilide with hydrochloric acid affords a mixture of ortho and
para-chloracetanilides in the same proportions as in the direct chlorination of
acetanilide.

Ac H Ac H
Ac Cl N N
N
Cl
HCl +

Cl

Mechanism

H H
O OH O O O
Cl ..
Cl Me N Me N Me NH Me NH
Me N
H Cl -H Cl-Cl
H
-Cl2

O O
H H
Me N Me N
Cl
+ HCl

H Cl Cl

8.6.1.2 N-Alkyl-N-nitrosoanilines (Fisher-Hepp Rearrangement)

The conjugate acid of the amine releases nitrosonium ion which reacts at para-position
to give the p-nitroso product.

H
Me N Me N Me H Me H
N O N O N N

H -NO NO
-H
N=O

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NPTEL – Chemistry – Principles of Organic Synthesis

Mechanism

R R R
H
N: N intramolecular
..N
NO H NO transfer of NO H
+ NO

R
N H
-H NHR
ON
H ON

8.6.1.3 N-Arylazoanilines
N-Arylazoanilines undergo rearrangement in presence of an acid to produce 4-(2-
aryldiazenyl)aniline. On treatment with acid, aryldiazonium ion is formed from the
conjugate acid of amine, which migrates to the para position almost selectively.

H
H N Ar H N H .. H H H
N N N N Ar
.. N N

H -ArN2 ArN2

-H
N
N
Ar

8.6.1.4 N-Alkylanilines (Hofmann-Martius Rearrangement)

The mechanism of this rearrangement is same as described above, except the requirement
of higher temperature (250-300 oC).

Me H H H H H
N N N
HCl Me
+
heat
Me

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NPTEL – Chemistry – Principles of Organic Synthesis

Mechanism

H H .. H H
Me .. H H N Me
H
N NH2
N N
H Me
Cl
H Cl Me
+ Me-Cl

H .. H H H
N N NH2
Cl
+ Me-Cl

Me H CH3

8.6.1.5 N-Arylhydroxylamines (Bamberger Rearrangement)

Arylhydroxyamines with acid undergoes rearrangement to give aminophenols.
Mechanism of this reaction is different from those described above. In this
rearrangement, the conjugate acid of the hydroxylamine undergoes nucleophilic attack by
the solvent.

H OH H OH2 NH2
N N NH

H -H

H2O H OH OH

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NPTEL – Chemistry – Principles of Organic Synthesis

Examples:

Cl HOAc, H2SO4 HO Cl

H2O, Et2O NHOH

NHOH

R. E. Harman, Org. Synth. CV4, 148.

OEt
NOH O
O O
HCl, EtOH

H2O

J. C. Jardy, M. Venet, Tetrahedron Lett. 1982, 23, 1255.

8.6.2 Fries Rearrangement

Aryl esters with Lewis acid undergo rearrangement to give phenols having keto
substituent at ortho and para positions. The complex between the ester and Lewis acid
gives an acylium ion which reacts at the ortho and para positions as in Friedel-Crafts
acylation.

OH OH
O R Lewis acid or
O R
O Protic workup
R O

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NPTEL – Chemistry – Principles of Organic Synthesis

Mechanism
In general, low temperature favors the formation of para-product (kinetic control) and
high temperature lead to the formation ortho-product (thermodynamic control).

O R O R O
LA
+ LA + R C O R C O
O O
LA
LA OH
low temperatue O O
protic O
H
O workup
R
R C O R
or

R
R C O LA O
H
O O protic OH
high temperature
workup R

O
Examples:

OAc OH O

Cu(OTf)2 Me

MeSO3H
90%
O. Mouhtady, H. Gaspard-Iloughmane, N. Roques, C. LeRoux, Tetrahedron Lett. 2003, 44, 6379.

OH
OAc OH O
Me
Me ZrCl4 Me
Me +
CH2Cl2
47% Me O
32%
D. C. Harrowven, R. F. Dainty, Tetrahedron Lett. 1996, 37, 7659.

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NPTEL – Chemistry – Principles of Organic Synthesis

8.6.3 Intramolecular Migration from Nitrogen to Carbon

The mechanisms of these reactions are not fully understood.
8.6.3.1 Phenylnitramines
These compounds on heating with acid rearrange to give mainly the o-nitro-derivative.
For example,

H
H NO2 H NO2 NH2
N N NH2 NH2
H NO2
H -H
NO2 +

NO2
major minor

8.6.3.2 Phenylsulfamic Acids

These compounds rearrange on heating to give o-sulfonic acid derivative that further
rearranges at high temperature to afford p-sulfonic acid derivatives. For example,

H SO3H NH2
N NH2 NH2
H SO3H 180 oC
SO3

SO3H

8.6.3.3 Hydrazobenzenes
These compounds undergo [5,5]-sigmatropic rearrangement in the presence of acid to
give benzidines.

H
N H
N H2N NH2
H

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NPTEL – Chemistry – Principles of Organic Synthesis

Mechanism

H2
.. H
N
2H
N H2N NH2
N .. N
H H2

NH2 H N
2 H -2H
H2N NH2 H2N NH2
H

Examples:

Me Me
N N
SO2
MeHN NHMe
20 oC, 48 h
75%

M. Nojima, T. Ando, N. Tokura, J. Chem. Soc., Perkin Trans I 1976, 14, 1504.

Br
Br Br
HN HCl
NH H2N NH2
75%
Br
H. R. Snyder, C. Weaver, C. D. Marshall, J. Am. Chem. Soc. 1949, 71, 289.

8.6.4 Claisen Rearrangement

Aryl allyl ethers undergo [3,3]-sigmatropic rearrangement on being heating to
allylphenols.

O OH

heat

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NPTEL – Chemistry – Principles of Organic Synthesis

Mechanism

1
3 OH
1O O
2
3 [3,3]
2 H

If the ortho position is blocked, rearrangement continues to give para-product.

O OH
O O R
R R
[3,3]
R
H

Examples:

O O O OH

Florisil
O O
OMe OMe
Me Me
F. X. Talams, D. B. Smith, A. Cervantes, F. Franco, S. T. Cutler, D. G. Loughead, D. J. Morgans, Jr.,
R. J. Weikert, Tetrahedron Lett. 1997, 38, 4725.

MeO OMe MeO OMe

xylene

O heat
OH
OMe OMe
S. Lambrecht, H. J. Schaefer, R. Froehlich, M. Grehl, Synlett 1996, 283.

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NPTEL – Chemistry – Principles of Organic Synthesis

Problems:
A. Complete the following reactions with major products and mechanism.
O
Me
O
K-10 clay
1.
microwave
Me
O

O Me
Me heat
2.

Me O
heat
3.

NHOH
H
4.
H2O

NH2
O
H
5.

B. Write mechanism for the following conversion.

NH2
H
N H
N NH2
H

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NPTEL – Chemistry – Principles of Organic Synthesis

Text Books:

R.O.C. Norman and C. M. Coxon, Principles of Organic Synthesis, CRC Press, New
York, 2009.

B. P. Mundy, M. G. Ellerd, F. G. Favaloro Jr, Name Reactions and Reagents in Organic

Synthesis, Wiley Interscience, New Jersey, 2005.

J. March, Advanced Organic Chemistry, 4th ed, Wiley Interscience, Yew York, 1992.

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