Lecture 17 - NPTEL

NPTEL – Chemistry – Principles of Organic Synthesis

Joint initiative of IITs and IISc – Funded by MHRD of 40

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

R'

OH

R H

'"R

"R

R'

R

+ H2O

Mechanism

R'

"R

"R'

OH

R H

'"R

"R

R'

RH

R'

"R

"R'

OH2

R -H2O

R'

"R

'"RR "R

'"R

R

R'

H

The driving force for the rearrangement resides in the greater stability of a tertiary

carbocation compared to that of primary carbocation.



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

Meerwein rearrangement of norbornyl systems:

Cl

classical

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.

RX

Me

Me

Me

heat

RMe

Me+ HX

Aryl groups have a greater migratory aptitude than alkyl group or hydrogen due to

the formation of lower-energy bridged phenonium ion.

MeMe

Cl MeMe

H

H

Phenonium ion

MeMe

-H

Me

Me

Rearrangements in bicyclic systems are common.

ClSnCl4

Cl

Cl

Isobornyl chloride



The rearrangement is stereosepecific

Two or more rearrangements may take place simultaneously.

OAcOAc

H H

H

Me H

MeMe

Me

Me

BF3-Ac2O

OAc

H Me

H

Me

Me

Me

Me

H

Examples:

HOHMe Me

H

Me

H Me

Me Me

Me Me

H

Me

Me Me

HO

MeMe

H

Me

H

Me

Me

H

-Amyrin enol of Freidelin

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

AcO

Me

Me OH

Me

H

MeCO2H

80%

AcO

Me

Me

MeMe

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.



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.

R

HO OHO

R

H

Mechanism

MeMe

HO OH

MeMe

H

MeMe

HO OH2

MeMe

:

Me

HO Me

MeMe

Me

O Me

MeMe

H



Examples:

HO

OHO O

+

Conc. H2SO4 0 oC

97 oCConc. H2SO4

major minor

minor major

Effect of Temeperature

Effect of Concentration

OH

HO

O O

+ +

Conc H2SO4 0 oC 0 5 95

25% Conc. H2SO430 1 690 oC

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

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

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'O

R

OH

H

CO2H

HO

R' R

R = aromatic, group without -hydrogen

Mechanism

O

R'O

R

OH H

O

R'O

R

OH OH

O

O

R

R' OH

O

HO

R

R'



Examples:

O O

Me

Me

Me

Me

OH

H

Me

Me

Me

Me

HO CO2H

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

OO

Me

OMe

NaOH

H

Me

OMe

HO CO2H

S. Deb, R. Chakraborti, U. R. Ghatak, Synth. Commun. 1993, 23, 913.

O

O

O

Me H

Me

HH

KOH, MeOH

H2O

O

Me H

Me

HH

OHCO2H

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.

R Cl

O1. CH2N2

2. Ag2O

3. H2O

HOR

O



Mechanism

R Cl

O

HOR

O

CH2-N2

R

O

CH2N2

Cl -Cl

RN2

O

H

RN2

O

H

Ag2O

-N2

R

O

H

:

carbene

RN

O

H

N..

The rearrangement of diazoketone is called the Wolff Rearrangement

Elimination of nitrogen yield a carbene followed by migration of the R group

O C

R

HH2O

H2O

R

H

O

proton

transferHO

R

H

OH

Examples:

CO2H

O

O

Cl

Cl

1.

2. CH2N2

3. Ag2O, Na2CO3, Na3S2O3

CO2H

T. Hudlicky, J. P. Sheth, Tetrahedron Lett. 1979, 29, 2667.

Cl

O

CO2Et

NHCbz 1. CH2N2

2. light, MeOH CO2Et

NHCbzMeO

O

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



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.

R Y

X: X

RNu

R

X

Nu

:

Y

XR :

no rearrangement rearrangement

X = Cl, S, O, N

Some examples follow:

Me

MeO

H

Me

Br

MeAg

-AgBr Me

MeO

H Me

Me

H2O

-HMe

OMeH

MeMeHO

Me SMe

HO H

HCl S

Me

Me

ClMeS

Me Cl

Me SMe

H2O-Cl

-H2O

N

H Me

ClOH

-H2O N

Me

Cl..

N

Me

Cl

NMe

Cl

Rupe Rearrangement

The bridged cation may be produced via protonation of an unsaturated bond as in the

Rupe rearrangement of-acetylenic alcohols.

R'R

HO H

H2O

O

R

R



Mechanism

R'R

HO H

R

R

R'R

H2O -H2O

R'

R

H

-H H

R

R H2O

R

R

OH2

-H

R

R

O-H

R

R

O

R'R

HO H

R

R

HO

R

R

HO

H

-H

R

R

O-H

R

R

O

H

H

or

Examples:

MeHO

MeHCO2H

heat

MeMe

MeO

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

MeHO

HCO2H

heat

Me

MeO

Me OAc

AcO AcO

OAcMe

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

Me

Me

Me

OH

HCO2H

heat

Me

Me

Me

O

Me

K. Takeda, D. Nakane, M. Takeda, Org. Lett. 2000, 2, 1903.



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

acetoxonium ion.

OO

Me

Y

-YOO

Me

OO

Me

H2O

-H

OO

Me OHH

OHO

Me OH-H

OO

Me

OH

Problems:

Ph

Ph

HO

MeMe

OH

1.H

2.HCl

3.HO

H

H

4.

Me

OH

OH

Me

H

A. Predict the major products in the following reactions withmechanism.

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

5.

OH

OHMe

SOCl2

Et3N

6.

O

OH

OH

MeHO

BF3

7.

COCl CH2N2

Ag(OBz)2/MeOH



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).

R NH2

O

N C OR

OH, H2O

Br2

H2O

R'OH

RNH2

O NHR

O

R'

Scheme 1



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).

R N

O

H

HOH

R N

O

H

Br-Br

R N

O

H

Br OHR N

O

Br -BrN C O

R

O NR

O

H

H proton

transfer O NH

R

OH

-CO2RNH2

H2O

Scheme 2

The workup can also be with alcohol or amine to give urethane or urea, respectively

(Scheme 3).

N C O

R

O NR

O

H

R' proton

transferO N

H

R

OR'R'OH

Urethane

R'NH2N N

R

O

HR'H

R'NH

NH

R

O

Urea

proton

transfer

Scheme 3

PhI(CF3CO2)2

I

O O

IO PhPh

CF3F3C

OO

H2N

O

R

-

-CF3COOH

I

O Ph

IO NPh

F3C

O

R

O

H

H2O

N C O

R

R.H. Boutin, G. M. Loudon, J. Org. Chem. 1984, 49, 4211.



Examples:

NH2

OH

O

PhI(OAc)2

KOH, iPrOH

NH2

OH

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.

C7H15 NH2

OH

OH

OAgOAc, NBS

DMF77%

C7H15

N

OH

OH

C

O

NHO

C7H15 OH

O

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.

R Cl

O

NaN3

R N3

O

-NaCl

neatN C O

R

H2O

R'OH

R'NH2

RNH2

R'O NHR

R'HN NHR

O

O



Mechanism

R Cl

ONaN3

R N=N=N

O Cl

Na

-NaCl

R NN

ON

R N

ON

N-N2

N C O

R

Examples

O

OH

Et3N, EtOH

PO

N3O

Ph

EtO NH

O

53%

Cl

Cl

N

SCO2H

(COCl)2, CHCl3, NaN3

O N NH2

Cl

Cl

N

SNH

O

NHN

O

34%

Y. Lu, R. T. Taylor, Tetrahedron Lett. 2003, 44, 9267.

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.

R OH

OHN3

H2SO4

RNH2



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

alkenes.

R H

OHN3

H2SO4

H NH

O

R

R R

OHN3

H2SO4

R NH

O

R

R OH

R R

HN3

H2SO4

N

R

R

R

R

R

R

R

HN3

H2SO4

N

R

R

R

Mechanism

R OH

OH

R OH2

O::

-H2OOR

R

O N N N

H

R NH

N

ON.. -N2

N C O

R

H2ORNH2

-CO2

R R

OH

R R

OH:

-H

:: N NNH

R NH

NR

OHN H

R NH

NR

OH2N.. -H2O

R NN

RN

H

R NN

RN -N2

R N-RH2O

R NR

OH2

-HR N

R

OH

R NH

R

O



Examples:

MeCO2Et

O

Et C4H7

NaN3

MeSO3H

HN CO2Et

Et C4H7O

Me

55%

M. Tanaka, M. Oba, K. Tamai, H. Suemune, J. Org. Chem. 2001, 66, 2667.

N

O

Ph H

CO2Et

HN3

H2SO4

+

CO2EtN

HN

PhH

ONH

CO2EtNPh

HO

66% 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.

R NH

O R'

O

O

Base

H2ORNH2

R'COO+ + CO2

R NH

OH

OTsOH

Base

N C O

R

H2O

R

HN NR'2

O

R

HN OH

O

-CO2RNH2

R'2NH

Mechanism

R NO R'

O

O

Base

H

R NO R'

O

O

.. -R'CO2N C O

R

H2ORNH2



Examples:

N

O

O

O

S PhO O

OHOH

O

NH2

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

N

N

Me

O

O NHOH

NH

NH

O

N

N

Me

ON

O

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.

H

H2ONH

R

O

R'The reaction can also be carried out with PCl5, PPA, P2O5 or TsCl.N

OHR

R'

O

R

R'

NH2OH

-H2O

An interesting application of this method is the synthesis caprolactam from

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

Cocn. H2SO4

NOH

HN

O

caprolactam

heatHN

O

*

n



Mechanism

N

OHR

R'

HN

OH2R

R'

-H2ON

R

R'

R N R'H2O

: N

R'R

H2O

proton

transferN

R'R

H-O H

-H

N

R'R

O H

Examples:

NHO

PCl5

H2ONH

OJ. A. Robi, E. Dieber-McMaster, R. Sulsky, Tetrahedron Lett. 1996, 37, 8985.

N

Me

Me Me

OHPPA

NH

NH+Me

Me O

Me

Me

MeO

Me

N. Komatsu, S. Simizu, T. Sugita, Synth. Commun. 1992, 22, 277.

H

Ph

NHOH

Ph

HN

O

P2O5

MeSO3H

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

R NH

R'

NOH

R NH

R'

NO SO2Ph

H2ONH

NH

R'

O

RPhSO2Cl



Problems:

N

NH2

O

Br2-KOH1.

2. NH

O

O

Br2-KOH

3.Me

NOH

H

4.

NOH H2SO4

5. N3CO2H

O

HCl-EtOH

What products would you expect from the following reactions?

Explain with mechanisms.

6.Me NHMe

NOH PhSO2Cl/H2O

7.

NOMs

Me3Al

Text Books:


York, 2009.

J. March, Advanced Organic Chemistry, 4th

ed, Wiley Interscience, Yew York, 1992.



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.

ORCOOOH

H

HOOH

OH

O

O

Mechanisms

O H OH OHHO

O R

OOHH

OO

O

R-H

OHO

O

O

R

H OHO

O

OH

R

: OHO

O

OH

R

:

O

OH-RCO2H -H

O

O

Acid Catalysed Reaction

O OOH

Base Catalysed Reaction

HOOHOH

HOO + H2O

O

OO H -OH

O

O

Migratory Aptitude: 3◦ > 2

◦ > PhCH2 > Ph > 1

◦ > Me > H.



Examples:

OMCPBA

O

O75%

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

O MCPBA

75%

O

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

O2

Me

MeO

OH

H

Me

MeO

OH

H

..

-H2O

O

Me

Me

H2O

O

Me Me

OH2

HO

Me Me

O-Hproton

transfer

OH

+ Me Me

O



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.

RO

R = H, MeH2O2, OH

H

OHOH

OH

Proposed Mechanism

RO

H

OH

O

OHOOH

RO

OHO

O H

-OH

O

R

OHOH

O

OOH

R

-RCO2H

OH

OH

Examples:

OH

Me

O

Na2CO3, H2O2

THF, DMF, H2O

OH

OH

90%

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

CHO

HO

H2N NH2

O

H2O2

OH

HO83%

R. S. Varma, K. P. Naiker, Org. Lett. 1999, 1, 189.



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:

RX

CX

C

R

X = N, S, O

8.5.1 Stevens Rearrangement

Quaternary ammonium salt which has -hydrogen proceeds E2 (Hofmann) elimination

with base.

HNMe3

OHH2O + 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.

N

Z

HH

R

R'

"R

baseN

Z

RH

R'

"R

Z = ketone, ester

Migratory Aptitude R = propargyl > allyl > benzyl > alkyl

Mechanism

N

Z

HH

R

R'

"R

baseN

Z

HR

R'

"RN

Z

HR'

"R

R

Solvent Cage

N

Z

RH

R'

"R



Examples:

MeO

MeO

N

MeMeI

MeO OMe

MeO

MeO

N

MeMe

MeO OMe

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

O

H

N2

O

OMe copper

catalysis

O

H

OMe

OCu

O

O

OMeH

89%

77%

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

t-BuO

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.

NMe

MeMe

NaNH2

Me

NMe

Me[2,3]



Mechanism

NMe

Me

HNH2

NMe

MeN

Me

MeCH2

H

[2,3]

12

3

1

2

Me

NMe

Me

There can be competition between Stevens and Sommelet-Hauser rearrangement

mechanisms.

NMeMe

sommelet-Hauser

Stevens Rearrangement

NMe2

R

R

Me

NMe

R

[2,3]

[1,2]

Examples:

Cl

Cl

S

Me

Me

MeOH

Cl

Cl

Me

+SMe

Cl

OMe

MeS

58% 7%

T.-J. Lee, W. J. Holtz, Tetrahedron Lett. 1983, 24, 2071.

Cl

CN

N

CN

Me Me

NaOH

benzeneCl

NC

CNNMe2

+HCl

CN

NMe2

CN92 887%

A. Jonczyk, D. Lipiak, J. Org. Chem. 1991, 56, 6933.

MeO



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.

R OR'

H

R"LiR O

H

R'R = H, alkyl, aryl, alkenyl, alkynyl, -CO2R

R' = alkyl, allyll, benzyl, aryl

Mechanism

R OR'

HR"Li

R OR'

Li

-R"HR O

Li

R'.

.

R O Li

R'..

Solvent Cage

R O

R'

Li

H2O

-LiOH R OH

R'

Examples:

O

O

TIPS

Me

Me

H

n-BuLi, TMEDA

THF O Me

Me

H

OHH

TIPS

78%

P. Wipf, T. H. Graham, J. Org. Chem. 2003, 68, 8798.

O

Me

O

O

MeMe

n-BuLi

Me

O

O

MeMe

OH

30%

R. E. Maleczka, Jr., F. Geng, J. Am. Chem. Soc. 1998, 120, 8551.



8.5.4 Favorskii Rearrangement

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

cyclopropanones.

R R'

O

Cl

R"OH, OR" RR'

CO2R"

Mechanism

R R'

O

HCl

OR"R R'

O

Cl R R'

O

R R'

O

Cl

OR"

R R'

O OR"

R'

OR"

O

RR"O-H

-Cl

R'

OR"

O

R

H

The direction of ring opening of cyclopropanone is determined by the more stable

carbanion, formed in the reaction.

Ph Cl

O

Ph

O

Cl

HCl

O

PhPh

MeO O PhCO2Me Ph

CO2MeMeOHH

more stable

favoured

Ph CO2Me

CH2

less stable not favoured

MeOHPh CO2Me

CH3

MeO MeO



Examples:

Me

Br

OOMe

Et2N, CF3CH2OH

O

OMeO

OMeO

O

73%M. W. Finch, J. Mann, P. D. Wilde, Tetrahedron 1987, 43, 5431.

NCO2Et

Br

O

DME

NCO2Et

CO2Me

56%

R. Xu, G. Chu, D. Bai, Tetrahedron Lett. 1996, 37, 1463.

MeO



Problems:

O

Br

Br

CO2Me

BrMeO, MeOH

1.

2. MeO Ph

Bu3Sn Men-BuLi, THF

3.

OH

Cl

CHOSodium percarbonate

THF, DMF, H2O

OH

Cl

OH

MeO2C

MeO2C

Et

Me Ph

OH

Me

A. Formulate mechanisms for the following reactions.

B. Complete the following reactions.

O

1.mCPBA

2.

O

Br OH

3.O Ph

Bu3Sn Me

4. O

Me

O

O

n-BuLi

n-BuLi

5.N

SnMe3

Me Me

I

MeLi



Text Books:


York, 2009.





Lecture 20

8.6 Aromatic Rearrangements

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

XY

XH

Y

+

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.



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.

NAc Cl

HCl

NAc H

+

NAc H

Cl

Cl

Mechanism

NMeCl

O

H

NMeCl

OH

Cl

-Cl2

NMe

OH

H

NHMe

OH

-H

NHMe

O

Cl-Cl

..

H Cl

NMe H

O

ClHCl

NMeH

O

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.

NMe N

NMe N

H

NMe H

-H

NMe H

O

H

O

-NO NO

N=O



Mechanism

N

R

NO H: N

R

NO

Hintramolecular transfer of NO

N

R

H+ NO

..

N

H

ON

R

H-H NHR

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.

NH N

NH N

H

N

H

NAr Ar

-ArN2

NH H

ArN2

-H

NH H

NN

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).

NMe H

HCl

heat

NH H

Me

NH H

+Me



Mechanism

NMe H..

H

NMeH

H

Cl

NH H

+ Me-Cl

..N

H

Me

HH

Cl Me

NH2

NH H

+ Me-Cl

..N

HH

Cl

NH2

HMe 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.

NH OH

NH OH2 NH

H

H OH

-H

H2O

NH2

OH



Examples:

Cl

NHOH

HOAc, H2SO4

H2O, Et2O

Cl

NHOH

HO

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

ONOH

HCl, EtOH

H2O

OO

OEt

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.

O

O

R Lewis acid

Protic workup

OH

R

Oor

OH

O

R



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

O

RLA O

O

R

LA

O

+ LA + C OR CR O

low temperatue

high temperature

O

LA

CR O

O

H

R

O

protic

workup

O

LACR O

O protic

workup

H

RO

OH

R

O

OH

O

R

or

Examples:

OAc

Cu(OTf)2

MeSO3H

OH

Me

O

90%

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

Me

OAc

ZrCl4

CH2Cl2

Me

OH

Me

O

+

Me

OH

O Me47%

32%

D. C. Harrowven, R. F. Dainty, Tetrahedron Lett. 1996, 37, 7659.



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,

NNO2H

H

NNO2H

H

NH2

H

NO2

-H

NH2

NO2

+

major

NH2

NO2

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,

NSO3HH NH2

SO3H

NH2

H

SO3

NH2

SO3H180 oC

8.6.3.3 Hydrazobenzenes

These compounds undergo [5,5]-sigmatropic rearrangement in the presence of acid to

give benzidines.

NH

HN H

NH2H2N



Mechanism

NH

HN

NH2H2N

.... 2H

NH2

H2N H2N NH2

NH2 H2NH

H

NH2H2N-2H

Examples:

N N

MeMe

SO2

20 oC, 48 hNHMeMeHN

75%

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

HN

NH

Br

Br

HClNH2H2N

75%

BrBr

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.

heat

OHO



Mechanism

O

1

2

31

2 3 [3,3]

O

H

OH

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

O

[3,3]O

R

O

R

H

R

OH

R

Examples:

O

O O

Me

OMe

FlorisilO

O OH

Me

OMe

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.

O

OMe

MeO OMe

xylene

heatOH

OMe

MeO OMe

S. Lambrecht, H. J. Schaefer, R. Froehlich, M. Grehl, Synlett 1996, 283.



Problems:

Me

O

O

Me

1.K-10 clay

microwave

2.

Me

O

O

Me

3.

OMeheat

NHOH

4.

A. Complete the following reactions with major products and mechanism.

heat

5.

ONH2

H

H

H2O

B. Write mechanism for the following conversion.

HN

NH

H

NH2

NH2



Text Books:


York, 2009.





Lecture 17 - NPTEL

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