MOLECULAR

REARRANGEMENTS
(Electron Deficient Nitrogen)
VII.Rearrangement reaction of electron
deficient nitrogen

A.Hofmann rearrangement:
When an unsubstituted amide is treated with sodium hypobromite, it
gives corresponding primary amine with one carbon less. This
reaction is known as Hofmann rearrangement.
O
hydrolysis
R C NH2 + NaOBr R N C O RNH2 + CO2

R in this reaction can be alkyl or aryl.

Mechanism of reaction is as follows,
O O
O
R C NH OH Br Br OH
R C NH R C NH
H Br
O O
H2O
R C N Br R C N R N C O

O O
H
N HN OH RNH2 + CO2
OH O OH
R H R
H

In the first step, base removes proton from amide.

This conjugate base of amide then reacts with
bromine to give N-bromoamide.
Acidity of proton on nitrogen is increased by this bromine atom and
its removal becomes easy for base to give nitrene intermediate in
which nitrogen is electron deficient. 1,2-shift of alkyl group takes
place in this nitrene to give corresponding isocynate. This isocynate
on hydrolysis gives primary amine with one carbon less than starting
material.

NH2
Br2 /NaOH
H2O NH2
O

O NH2
NH2

NaOBr / H2O

NO2 NO2
If methanol is used as solvent, in place of water then
corresponding carbamate ester is obtained.
O
H
N O
NH2
NBS, DBU,
MeOH, reflux O
O O

O
H
N O
NH2 NBS, Hg(OAc)2,
CH3OH, DMF
O
N N

O O
dibromotin, Hg(OAc)2,
PhCH2OH, DMF (H3C)3C
(H3C)3C NH2 N OCH2Ph
H
 O 1. Pb(OAc)4, O R
R
O O BnOH, DMF H
1000, 15h N OB
NH2 2. TsOH, C9H19 n
C9H19
acetone, H2O, Bn O
Bn
reflux, 2.5h
75%
R :- PhMe2Si

O NH2
t BuO NH
Cl Cl
Pb(OAc)4
tBuOH
N 500 N
O O
H H
70%
 OMe
OMe OPMP OR
OPMP OR

O
O NaOMe, Br 2
MeOH, -780
1h, reflux O
O

HO NH
O
H2N O
O
93%

When optically active α-phenylpropionamide undergoes

Hofmann degradation, α-phenylethylamine of same
configuration and optical purity is obtained i.e.
rearrangement proceeds with retention of configuration.

Ph Ph
NaOH
H C CONH2 H C NH2
B.Curtius rearrangement:
In Curtius rearrangement, acyl azide are pyrolysed into
isocynate which can be hydrolyzed to corresponding amines.
O

R N C O
R N3

Curtius rearrangement is catalyzed by protic or Lewis acids.

Mechanism is similar to that of Hofmann rearrangement.
O O
-N2
R N C O
R N N N R N

However, there is no evidence of existence of free nitrene.

These two steps may be concerted.
 O

R N C O + N2
R N N N

In the similar reaction, alkyl azides give imines.

R3CN3 R2C NR

R may be alkyl, aryl or hydrogen. In case of tert.alkyl azides, there

is evidence of existence of nitrene.
Cycloalkyl azides give ring expansion.
R
R
H
N + NR
N3
80% 20%
Aryl azides also give ring expansion on heating.
NHPh
N3
PhNH2
N

If the reaction is carried out in di-tert.butyldicarbonate,

product will be Boc protected amine.
O

EtOOC EtOOC NHBoc

OH Boc2O, NaN3
Bu4NBr
Zn(OTf)2
THF, 500C
Ph Ph

[ Org. Lett. 2005, Vol.7, No.19, 4107 ]

 H
OH

H Boc2O, NaN3
O Bu4NBr
Zn(OTf)2
H H THF, 400C

HO H
H
NHBoc
H

H H

HO
H
 1. Et3N, DPPA H2N
HOOC BzOH
COOH NH2
2. HBr / AcOH H2N
HOOC
cis,cis-cyclohexan-1,3,5- cis,cis-1,3,5-triamino-
tricarboxylic acid cyclohexane (82%)

[ Bioorganic and Medicinal Chem. Lett., 9 April 1996, Vol.6, Issue 7,

807 ]

OH O O

O
N3 tBuOH NH
N3 reflux

O NHBoc

[ Tet. Lett., 19 Feb 2007, Vol.48, Issue 8, 1403 ]

 O
PMBO

HO O OTBS Hunigs base

iBuOCOCl
00C, NaN3
O
H2O, toluene
H H 15 min,
O TMSCH2CH2OH
3h,

O OPMB

O
O N
H

TMS

[ JACS, 2001, 123, 12426 ]

 O

O SOCl 2
Me3SiN3
reflux

HOOC
O

N
C.Lossen rearrangement:
O-acyl derivatives of hydroxamic acids on heating with base
give isocynate, this reaction is known as Losse rearrangement.
Isocynate can be further hydrolyzed to corresponding amines.
O

O R OH H2O
R N C O RNH2
R N
H
O

Mechanism is similar to that of previous reactions.

O O

O R O R
R N R N

H O O
OH

R N C O
 NHR1
CONHOC CNO
2
H NHR
H

H2O

NH2
H

R1 : Et , R2 : (CH2) 3NMe2

[ Appl. and env. Microbiology, 1997, Vol.63, No.9, 3392 ]

 O
H N C O
N COOEt
Cl EtOOC O
Et3N, H2O
Br Br

NH2
EtOH, H2O

Br
The reaction can also be carried out with hydroxamic acid.

O O

Na2CO3
CONHOH PhOSO2Cl NH

OH O O
OH OH

[ J.Braz.Chem.Soc., 1995, Vol.6, No.4, 357 ]

COOH NH2
1. NH2OH.HCl
H3PO4
2. KOH
 O
1. NH2OH.HCl NH2
H3PO4
OH 2. KOH

[ JACS, 1953, 75, 2014 ]

D.Schmidt rearrangement :
Reaction of carboxylic acid or aldehyde or ketone with
hydrazoic acid in presence of mineral or Lewis acid to give
corresponding primary amine or amide respectively is known
as Schmidt rearrangement.

H H2O
RCOOH + HN3 R N C O RNH2

O
O
H R1
+ HN3 R N
R R1 H

Cyclic ketones give lactums.

O NH
HN3 / H
O
Mechanism is similar to that of Curtius rearrangement, except
that protonated azide undergo rearrangement.

O O O
H H N N N
-H2O
R OH R R N3

O O

H
R N N N R N N N
H

H 2O
R N C O RNH2 + CO2
H
Mechanism with ketone is,
O OH H N N N
HN3 -H2O
H
1 1 R C R1
R R R R
OH

N N N
-N2 H2O
R C R1 R1 C N R

O
R1 C N R -H R1 C N R tautomerism R
1 N
R
OH2 OH H

In reaction with ketone, ketone is activated by protonation for

nucleophilic addition of azide group to it.
In case of alkyl aryl ketone, aryl group migrates preferentially
except for bulky alkyl group.
Intramolecular Schmidt reaction can be used for preparation of
bicyclic lactums.

O O

MeAlCl2 / DCM N

H Ph
N3 96%

O
N3
MeOOC TFA / 12h MeOOC
N
O
 O
O
1. SPh2 N

N3
2. LiBF4
3. TiCl4

81%

[ JACS, 1991, 113, 896 ]

O
O
TFA
N
N3

[ Org. Syn., 2007, 84, 347 ]

 MeO MeO O
Triflic acid
O dry DCM
-50-00C N
MeO MeO
H3COOC 15 min
H3COOC
N3
54%

[ JOC, 2007, 3, 949 ]

Reaction of tert. alcohol and olefins with hydrazoic acid in

acidic condition to give substituted imines is often termed as
Schmidt rearrangement.

OH R R
HN3 / H2SO4
N
R R
R R
 R R R R
HN3 / H2SO4

R R R N R

Mechanism of the reaction is as follows.

OH
OH2
H -H2O HN3
R R
R R R
R R R
R

N N N
-N2 R
C N R
R R
R
R
R R RH R RH R H
H HN3 -N2
N N N
R R R R R R

RH R
R R
-H
R N R
R N R
H
 O O O
H
H3C N
H3C OEt OEt
CH3 CH3
O
NaN3, CH3SO3H

CHCl3, 0.5-1 h

89%

[ Tet. Lett., 1988, 29, 403 ]

 O O O
H
N
NaN3, CH3SO3H
DME, -300C-rt
ADA O ADA

O
N

ADA

ADA :
E.Beckmann rearrangement :

Oximes on treatment with Lewis acid or protic acid rearrange to

give substituted amides. This reaction is called as Beckmann
rearrangement.
R R' O
PCl3
R
N R' N
OH H

Generally group anti to hydroxyl migrates. However this is no

hard and fast rule. R and R’ can be alkyl, aryl or hydrogen.
Hydrogen does not migrate under conditions of reaction but it
migrates when reaction is carried out with nickel acetate under
neutral conditions.
Like Schmidt rearrangement, oximes of cyclic ketones give ring
enlargement.

NOH NH
O

Mechanism of reaction usually goes through alkyl migration

with expulsion of hydroxyl group followed by reaction similar to
Schmidt rearrangement.
 OH OH2
N N -H2O
H R1 C N R

R R1 R R1

R1 C N R
R1 C N R
R1 C N R -H

H2O OH2

R1 C O
N R
R
1
R N
OH H

Other reagents convert hydroxyl to an ester leaving group.

Course of mechanism is supported by detection of nitrillium
ion by NMR and UV spectroscopy.
 OH
N H
N
H3PO4
microwave O
MeO
MeO 82%

[ Indian journal of chemistry, 2005, 44B, 18 ]

H
N
OH
N
O
MeCN, 10% Ga(OTf)3
+
850C, 16h O

N
H

[ Catalysis Lett., 2005, 103, 165 ]

 SOCl2, 100C, 1%KOH

HO
N

O
HN

[ Chemistry of natural compounds, 2009, 45, 519 ]

 N
N H2SO4
O
OH microwave
N
1800C N

[ SynComm., 2006, 36, 321 ]

Cl H O
N
N N
N
OH Cl N Cl
DMF, rt, 8h
100%

[ JOC, 2002, 67, 6272 ]

 OH
I N I
H
12% HgCl2, N
MeCN , 8h

[ JOC, 2007, 72, 4536 ]

F.Stieglitz rearrangement :

Stieglitz rearrangement is a general term applied for rearrangement

reaction of trityl-N-haloamines and hydroxylamines to trityl imine.

PCl5
Ar3C NHOH Ar2C NAr
base
Ar 3C NHX Ar2C NAr

Mechanism is as follows,

Cl
Ph OH Cl Cl Ph O Cl
NH + P NH P
Cl Cl Cl
Ph Ph
Ph Cl Ph Cl

Ph
NPh
Ph
Reaction can also be facilited by treatment with lead tetraacetate.

Pb(OAc)4
Ar3CNH2 Ar2C NAr

NH2
Pb(OAc)4 Ph2C N OCH3
Ph2 C OCH3
~98%
+

PhN C OCH3
Ph
~2%

[ JOC, 1974, 39, 3932 ]

When methanolic solution of N-chloroisoquinudine was
refluxed for 2h with AgNO3, AgCl was precipitated and 60%
of 2-methoxy-1-azabicyclo[3.2.1]octane was obtained.

AgNO3
MeOH
N
N
Cl MeO