Molecular Rearrangements

Rearrangement is a reaction in which a group or atom moves from one position to other within the same molecule. W A

W B

A

B

Atom A in example is called migration origin and atom B as migration

terminus. These rearrangements can be of following types, i.Nucleophilic or Aninotropic : in which migrating group migrates with its electron pair. ii.Electrophilic or cationotropic : in which migrating group migrates without its electron pair. iii.Free radical : in which migrating group migrates with only one electron.

Of these most commonly found are nucleophilic one. These rearrangements can take place in two possible modes, i.Intramolecular : In these migrating group do not completely detach from migration origin and migration of group is within the molecule only. W

A

A

B

B

W

ii. Intermolecular : In these migrating group is completely detached from migration origin and migration of group can take place to different molecule.

W

A

B+ U

A

A

B

W+ A

C

U+

A

B

U+ A

C

W

C

Different pathways through which 1,2-rearrngement takes place are

given below. R

R

1.

C

R

2.

O

C

C

O

C

C

C

C R

R

3.

C

C

C

CR

4.

x

x a

b

y

a x

x

5.

a

b

+ y

b

y

a

b

+ y

Reactions 1 to 3 show first reason for 1,2-rearrangement to take place viz. formation of valence electron sextet at one of the carbon atoms of substrate i.e. either carbocation or carbenium ion. Thermodynamic driving force for potential 1,2-rearrangement will be significant if

rearrangement leads to structure with octets on all atoms [reaction 2 & 3] or generates some other more stable carbocation [reaction 1] i.e. if

newly generated carbocation is stabilized electronically by its substituents than old carbocation or angle strain is reduced due to rearrangement in cyclic carbocation or newly generated carbocation is captured in subsequent irreversible reaction. Reaction 4 & 5 show second cause for occurrence of rearrangement. In these reactions atom b is bonded to good leaving group. Heterolysis of such a bond would give a carbocation. Departure of leaving group is then assisted by neighboring group. This sometimes gives a positively charged three membered ring as in reaction 5. Rearrangement in such reactions is possible only if group x is present at new position in product than in reactant.

Broadly these reactions consists of three steps ; a)First step is generation of electron deficient centre in molecule. As the migrating group migrates with electron pair, the migration terminus must have an incomplete octet. This can be obtained in two ways ,

i.Through carbocation : Carbocations can be formed in various ways. The most common being dehydration of alcohol. This step is similar to that of SN1 or E1 reaction. R C

R C

OH

H

C

R C

OH2

-H2O

C

C

Me

Me Me

C

SN1

CH2Br

Me Me Me

C

Me

C

C

Me

CH2Me

C

Me

OH

C

CH2

Me Me

Me CH2Me +

Me

H

Rearrangement of carbocation is very important reaction in cracking of petroleum products. Me

Me Me

C

CH

CH2

H

Me

Me

Me Me

Me C

Me

C

Me

CH Me

Me C

Me

C Me

CH

CH3

ii.Through nitrenes : nitrenes can be formed by decomposition of acyl azides. R

C O

N

N

N

R

C

N + N2

O

b)Migrating group migrates to the previously formed electron deficient centre with its electron pair creating new electron deficient centre. c)In third step, newly formed electron deficient centre acquires octet either by accepting a nucleophile or excluding proton. It is observed in many cases that either two or all three steps take place simultaneously. As seen in many cases SN1 type of first step is very common followed by rearrangement to give more stable carbocation. It is proved by fact that rate of reaction increases with

ionizing power of solvent and it is unaffected by concentration of base. It has been shown that rate of migration increases with degree of electron deficiency at migration terminus.

Most of rearrangements are intramolecular. It can be shown by cross over experiments. But, one more evidence for this fact is that, if migrating group is chiral, its configuration is retained in the product. In molecules where stearic nature of migration origin and terminus can be investigated, mixed results are found i.e. either inversion or racemisation takes place. Ph

Ph

H

C

C

OH

NH2

Me

HNO2

Ph

O

Ph

C

C

Me

H

In this example inversion at migration terminus takes place.

But, it is not always possible for product to have two stearic possibilities to investigate stereochemistry at migration origin or terminus.

Eg. In Beckmann rearrangement, only group anti to hydroxyl migrates. R1

OH C

R1CONHR

N

R

This shows the concertedness of reaction. So, if, racemisation is found at migration terminus, then it is probable that first step takes place before second step, as in SN1 reaction. R A

R B

X

A

R B

A

B

product

And, if inversion occurs at migration terminus, then two steps might be concerted, as in SN2.

R

R R

A

B

X

A

B

A

B

product

In this case, neighboring group assists departure of leaving group, as in neighboring group nucleophilic substitution reaction. This

assistance increases rate of reaction. In certain cases of SN1 type process, total retention of configuration of migrating groups is seen due to conformation of carbocation.

In many reactions like Hofmann, Curtis, there is no question which group migrates but in certain cases, like Beckman reaction, there are more than one choices. But, of them, which migrates depends upon geometry of molecule. In Beckman reaction, only group anti to hydroxyl migrates, whereas in case of Wagner-Meerwein and Pinnacol rearrangement, there are many choices, as substrate contains several groups, that have equal probability of migration. Such reactions are used for direct study of relative migratory aptitude. In Pinacol rearrangement, there is one more question which hydroxyl group leaves. As it will create electron deficient centre for migration to take place. The hydroxyl group lost will be that which generates more

stable carbocation.

Ph

C

C

H

OH OH

Ph

Ph

H

C

C

Ph

Ph H

Ph H Ph

C

C OH

H

Ph

C

C

H

O

H

H

OH

In this example, hydroxyl group is lost from carbon bearing two phenyl

groups as it gives more stable carbocation. It is known that carbocation stability is enhanced by group in order aryl > alkyl > H. Hence, depending upon these substituents hydroxyl group is lost in

reaction. In order to study migratory aptitude in such reactions, substrate should have structure R1RC(OH)C(OH)RR1 . In this case whichever hydroxyl group leaves, it will give same carbocation and hence comparison on migratory tendencies of R and R1 can be done. Many factors are responsible in deciding migratory aptitude. One of them is conformational effect. Another factor is, relative ability of group that remains at migration origin, to stabilize positive charge. Sometimes, if group that stabilizes positive charge is present on migration origin, then group which actually is not having good migratory ability, migrates. Along with this, migratory aptitude is

related to, ability of that particular group in assisting departure of leaving group. eg. In decomposition of tosylate, only phenyl group migrates while in

acid treatment of related alkene, competitive migration of methyl

and phenyl group is seen. Me Ph

C

H C

Me

OTs

Me reflux in benzene

C

Ph * C H

C

C Me

Me Ph

Ph

Me

CH2

Me

H

Me

C

* C

Me

Me

Me

+ Me

C

C*

Me

Me

Ph

Only migration of phenyl group in first case is due to the fact that, phenyl group assists in departure of tosyl group. Whereas, no such possibility for second reaction.

All these factors costs no particular answer to migrating aptitude. Though, in most cases, aryl migrates preferentially to alkyl group, but it is not always true. Migratory aptitude of hydrogen is unpredictable. Hence, mixtures are always obtained. However, it is seen that in migration of aryl group, those having electron donating substituents at meta or para position migrates Preferentially, over those containing substituents on ortho position. While, aryl group containing electron withdrawing groups show less migratory aptitude.

A. Wagner-Meerwein rearrangement : When alcohol containing more than two alkyl or aryl group on β carbon are treated with acid, the product formed is generally a rearranged product, rather than simple substitution or elimination product. This reaction is called Wagner-Meerwein rearrangement. Newly generated carbocation is stabilized generally by loss of proton to give olefin and less often by nucleophilic substitution or loss of some other positive group. R R1 R2

H OH R3

R1

R

R2

R3

H

Mechanism of rearrangement goes through carbocation intermediate. R

R

H

R1 R2

R1

H

OH

R2

R3 H

R1

R

H

R2

R3

H R1

OH2 R3 R1

R

R2

R3

R R2

R3

Wagner-Meerwein rearrangement was first found to take place in bicyclic terpenes.

OH

Isoborneol

H

Camphene

CH3 H3C

C

CH2 Cl

H

H

H3C C

C

H3C

CH3

CH3

H OH Camphenilol

Santene

In these reactions, double bond is formed according to Zaitsev's rule. Leaving group in this reaction can be hydroxyl or any other leaving group which renders carbocationic character to carbon atom.

Direction of rearrangement is usually 30 >20 >10. Sometimes several of rearrangement occur in one system either simulataneously or in succession. Example of such a reaction is

rearrangement in triterpene, 3- β-friedelanol. This compound on treating with acid, 13(8)-oleanene is formed by seven successive 1,2 shifts. 20

20 19 12 11

H

H 1 2

10

H

14 8

22

7

4 6

3-friedelanol

18 22 13

17 1 16

15

21

11

H

9

17 14 16

2 10 5

5

3

HO

9

12

18 13

19

21

3

8

15

H 7

4 6

H 13(18)-oleanene

A positive charge is generated on C-3, followed by removal of H2O,

then hydride shift from 4 to 3; methyl shift from 5 to 4; hydride shift from 10 to 5; methyl shift from 9 to 10; hydride shift from 8 to 9; methyl shift from 14 to 8 and hydride shift from 13 to 14 takes place, generating carbocation at C-13, which is stabilized by loss of proton

from C-18 to give olefin. All these shifts are stereospecific. Alkanes in presence of Lewis acid and some suitable initiator, also

undergo Wagner-Meerwein rearrangement. Tricyclic molecules containing 10 carbon atoms on conversion give adamantane, by successive 1,2 and 1,3 shifts of hydride and alkyl

AlCl3

group. Tricyclic molecules containing more than 10 carbon atoms give alkyl substituted adamantane.

AlCl3

AlCl3

Tricyclic molecules containing 14 or more carbon atoms, give diamentane or substituted diamentane.

AlCl3 tBuBr

These reactions take place because of great thermodynamic stability of adamantane, diamentane and similar diamond like molecules. Some examples of Wagner-Meerwein rearrangement are given below. O

O

O

O

OEt HO

OEt TFA, DCM 72h

76%

Br

OH

HBr, THF 00C, 10 min

OH COOEt Ph

EtOOC 1 : 3 HSO3F, SO2ClF ~00C Ph

[ JACS, 1982, 104, 2631 ]

H O N S

S H

Ph N Ph

+ S

S

O

BF3.Et2O -780C, 5h ( 74% )

+ H O N S Ph

[ Helvetica Chemica Acta, 1999, 82, 1458 ]

S H

H O N S N Bz

+ S

O

BF3 Et2O / DCM -780C ( 75% )

S H

Bz +

H O N S

S

Bz

[ Helvetica Chemica Acta, 1999, 82, 1458 ]

H

COOMe OH Br HN O N

OMe N

O

N

O

N H

OMe OMe

COOMe Br HN O N N

OMe N

O 86%

O

N H

OMe OMe

CH3SO3H 1,2-DCE 500C

B.Pinacol rearrangement :

When vicinal diol is treated with acid, it rearranges to give aldehyde or ketone. This reaction is called as Pinacol rearrangement, reaction was originally found to take place in molecule. CH3 O

CH3 CH3 H3C

C OH

C

OH Pinacol

CH3

H

H3C

C

C

CH3

CH3 Pinacolone

The migrating group can be alkyl, aryl, hydrogen or ethoxycarbonyl etc. In case of symmetrical diols which hydroxyl is protonated and which group migrates does not have much significance, but in case of unsymmetrical diols it is important. Generally. Hydroxyl group is protonated which gives more stable carbocation.

O OH

OH H2SO4

Ph

Ph Ph

Ph

In this reaction, hydroxyl group on carbon having two phenyl groups will be protonated, as it will give more stable benzylic cation and is formed faster. When tri or tetra substituted glycol is used, different products depending upon reaction condition is obtained. It also depends upon migratory aptitude of different groups, as discussed earlier. CH3 CH3 Ph

C

C

Ph

O

cold H2SO4 Ph methyl migration

Ph

CH3

C

C

OH

OH

AcOH + trace of H C CH3 H SO 3 2 4 phenyl migration

Ph

O

C

C

CH3

Ph

When, at least one group in glycol is hydrogen, aldehyde can be prepared along with ketone. Aldehyde can be prepared in mild reaction conditions such as weak acidic conditions, low temperature. Mechanism of reaction is as follows;

R1

R1

R2

R4

C

C

OH

OH

R2

R4

C

C

R3

R1

R2

C

C R4

R1

R4

C

C

OH

OH2

R3

-H2O

R2 R3

OH O

H

R2

R3

R1

C

C

OH

R4

R3

-H

Migration of alkyl group from initially formed carbocation takes place because, carbocation containing hydroxyl group are more stable than that of 30 carbocation. Also, these carbocation can readily lose proton to give corresponding carbonyl compound. O OH OH H

OH OH H Me2C

C Ph

COOEt

Ph O Me2C

C

COOEt

O Ph Ph Ph Ph

OH OH TsOH, CDCl3

+ O

Ph Ph

[ JOC, 2004, 69, 2017 ]

O

OH Ph OH

1. MsCl, Et 3N, DCM 00C, 10 min 2. Et3Al, DCM -780C, 10 min

N

Ph

N SO2Ph

SO2Ph 90%

[ Tet. Lett., 2002, 43, 6937 ]

Synthetically useful Pinacol rearrangement reaction is syntheses of bridged bicyclic compound from a diol in following way. OH

OH

O

OH H

LiAlH4

H

OH2 -H2O

-H

H

Similar type of reaction is also shown by compounds containing different group than hydroxyl on adjacent carbon of that containing hydroxyl group on it. This reaction is known as Semipinacol rearrangement and involves 1,2 shift of H or alkyl from oxygenated carbon atom to neighboring C atom i.e. carbocation to carboxonium ion rearrangement.

-BF3

BF3.Et2O O

O BF3

O

H H

H

OTs LiClO4 in THF, CaCO3

HO O

-H

HO

O

O

O O

O

AgNO3 I OH

O

O

C.Expansion and contraction of rings : When a positive charge is placed on alicyclic carbon, migration of alkyl group can take place, giving ring smaller than original one. In this transformation secondary carbocation is converted to primary carbocation. CH2

Similarly, when positive charge is present on carbon α to alicyclic ring, then migration of alkyl group can give ring larger than original one. CH2

This newly formed carbocation can then be stabilized by either elimination or substitution.

This reaction represents special case of Wagner-Meerwein rearrangement. Generally, a mixture of rearranged and non rearranged products is formed. OH

NH2 HNO2

+

CH2OH

HNO2

CH2NH2

Reaction in which carbocation is formed by diazotization of amide is called Demjanov reaction. HNO2 NH2

OH + OH

Mechanism is as follows. H N

N O

H

HO

O

O

-H2O

O N

N H2O

+O NH2

O

O N

O

O N

O -HNO2

H

N

HN

N

O

-H2O N

N

OH

N

N

OH2

H NO2 -N2 N

N

H2O

OH

NH2 HNO2

O

O LAH / Et2O 00C

OH

OH +

NaNO2 0.25M H2SO4 / H2O 0-40C

CN NH2

O

O

+

HO

HO

O

O OAc

LiAlH4 / Et2O 00C

CN

OAc

NH2

O

O + O O 12 : 1

[ Tetrahedron, 1993, 49, 1649 ]

NaNO2 0.25M H2SO4 / H2O, 0-40C 100%

It is found that, expansion reaction give good yields in smaller rings where expansion gives relief from angle strain and contraction reaction give otherwise good yields except for cyclopentyl cation. An example of such ring expansion is; treatment of 16-methylpentaspiro[2.0.2.0.2.0.2.0.2.1]hexadecan-16-ol with p-toluenesulfonic acid in acetone-water to give 2-methylhexacyclo[12.2.0.02,5.05,8.08,11.011,14]hexadecan-1-ol. H3C

CH3

OH H

.

OH

OH H

H

H

OH

40%H2SO4

H

H

Reaction of certain amino alcohols give analogous reaction to semipinacol rearrangement. This reaction is known as Tiffeneau-Demjanov rearrangement.

O

CH2NH2 HNO2 OH

These reactions carried out on four to eight membered ring, give better results as compared to analogous Demjanov rearrangement.

OH

NaNO2, AcOH, H2O, 00C, 1h then reflux 1h O 98%

NH2

SnBu3 SnBu3 HO

CH2NH2

NaNO2 AcOH

64%

O +

SnBu3 O

36%

[ Org. Biomol. Chem., 2004, 2, 648 ]

H2N CONEt2

CONEt2

O

OH NaNO2, AcOH, H2O, 0-50C

O

N

60%

D.Acid catalyzed rearrangement of aldehyde or ketone : Aldehyde or ketone on acid treatment give another ketone by rearrangement.

R2

R1

O

C

C

R3

R4

H

R2

R4

O

C

C

R1

R3

Certain aldehyde or ketone are converted in this way to other ketones. But, conversion of ketone to aldehyde is not seen in any case. Mechanism of the reaction goes through protonation of carbonyl oxygen. Two pathways are possible. One in which migration of two groups is in opposite direction and other in which migration is in same direction.

Actual pathway is not certain. But, it is found that in certain cases only one operates while in others both operate at same time. This can be demonstrated by labeling carbonyl carbon. In first case, labeled

carbon is carbonyl carbon while in second case labeled carbon is carbon α to carbonyl group. Pathway 1: R2

R1

O

C

C

H

R4

R2

R4 C

C

R3

OH

R1

OH

C

C

R4

R3

R3

R2

R1

R2

R4

OH

C

C

R3

R1

-H

R2

R4

O

C

C

R3

R 1

Pathway 2:

R2

R1

O

C

C

R1 H

R4

R2

R3

C

C

R3

OH

R4

R2

R3

R1

C

C

R4

O H

R3 R2

C

C

OH

R4

R3 R1

-H

R2

C

C

O

R4

R1

In case of α hydroxy aldehyde or ketone process may stop after one migration. This is called α ketol rearrangement.

R2

R1

O

C

C

R3

H

R3

OH

O

R1

O

C

C

R2

OH

Benzene : conc.H2SO4 7:5 24h

O

85% O

Benzene : conc.H2SO4 7:5 24h

O

80%

[ J. Chem. Soc., 1956, 2483 ]

E.Dienone-phenol rearrangement : Cyclohexadienone containing two alkyl groups at position two or four,

on acid treatment undergoes 1,2-shift of one of these alkyl group, to Give disubstituted phenol. Driving force of reaction is aromatization of ring. O

OH H R

R

R

R

Mechanism is as follows; O

OH

OH

H

R H

R

R

R

OH

R R

R

R

Particularly useful example is in syntheses of steroidal compound.

OH

OH H

H H2SO4 H O

H

H

H

HO 1-methyloestradiol

F.Wolff rearrangement : Wolff rearrangement is rearrangement reaction, in which a diazo ketone is converted into ketene. R' R

R' N2

O

-N2

R' R

C

C

O

R O

The rearrangement reaction takes place in presence of light, heat or transition metal catalyst such as Ag2O.

The mechanism is supposed to proceed through formation of carbene in presence of heat or light. It may also proceed through concerted pathway in which no carbene is formed in presence of Ag2O.

Thermally reaction is possible in range of room temperature to 7500C. Generated ketene is highly reactive species, hence is more isolated. It either adds nucleophile or undergoes (2+2) cycloaddition. If the added nucleophile is water, then it forms carboxylic acid with one carbon more. This reaction is known as Arndt-Eistert syntheses. This reaction is of particular use in preparation of carboxylic acids with one carbon more than starting one. COOH

O

H N2 H HO

H

h,dioxane Et2O, H2O

H

HO

[ Org. Syn. Coll. 1988, 6, 840;1972, 52, 53]

H

Migratory aptitude of particular group is determined by whether reaction is proceeding by thermal or photochemical pathway. In photochemical pathway methyl is migrated preferentially while in thermal pathway phenyl group migrates. O Ph Ph

-N2

Ph C

O

C

Ph

N2

[ Org. Syn. Coll.1955, 3, 356; 1940, 20, 47 ] O

O

O H

N2

h / EtOH : dioxane 1:1

O

O

O

COOMe N2 h / MeOH

O N

O

N

90%

Other 1,2 migrations to carbene are also known.

CH3

CH3 H3C

C

CHN2

h

H3C H 3C

C

CH

C H3C

CH3

CH3

CHCH3

52% +

47%

G.Homologation of aldehyde or ketone : Aldehyde or ketone can be converted to their higher analogs on treatment with diazomethane. O

O CH2N2

R

R'

R' R

O

O CH2N2

R

H

R

Though, it appears to be an insertion reaction, it is purely rearrangement reaction. Carbene is not formed in the reaction.

Mechanism is as follows, O R

C

N

CH2 R' + H2C

N

N

R

C

R'

N -N2

O O

CH2 R

C

R'

R

C

H2 C

R'

O

In case of aldehyde, hydrogen migrates preferentially which is evident from good yields of methyl ketone.

An interesting example of this reaction is, preparation of bicyclic ring compound using alicyclic compound containing diazo group in side chain.

O

O

O

CHN2

+

H.Neighboring group participation: Rearrangement is seen in reaction of NGP type, when the group showing anchimeric assistance is detached at one point in substrate and is attached to other point in final product. R2 N

NR2 Ph

CH

CH

COPh

NR2 CH

CH

COPh

OH NR2 :-

N

CH H 2O

Br

Ph

Ph

O

CH

COPh

-H

In this reaction, due to anchimeric assistance of morpholino group,

rearrangement is seen. Cl H3C

CH

ONs :- RO2SO

OOCCF3 CH2

ONs

CF3COOH

NO2

H3C

CH

CH2

Cl

I.Migration of boron to electron deficient carbon: On heating non terminal boron at about 100-2000C, boron moves towards end of chain.

C

C

C

C

C

C

C

C

C

C

C

C

C

Boron can move past a branch.

C

C

B

C

C

C

C B

B

B

C

C

C C

C

C B

But, boron can not move past double branch. C

C C

C

B

C

C

C

C

C

C

C

C

B

C

CH

CH3 B

CH

C

C

C

C

H3C

C CH3

C B

CH3

CH3 CH3

C

C

CH3

CH3 H3C

C

C

CH2

CH

CH2 B

If boron is present on ring, then it moves across ring and if an alkyl side chain is present on ring, it ends on terminal carbon of side chain.

1500 diglyme

B

B

The reaction is useful in migration of double bond in controlled way.

B B RCH CH2

B

OH

B H2O2 /OH

BH3, THF

1100C

H BH2

H2O2 / OH

H H

CH2BH2 H H CH2OH

J.Neber rearrangement: Neber rearrangement is a reaction in which a ketoxime tosylate is converted to α-amino ketone upon treatment with base. NH2 R' R

R'

base

R

NOTs

O

R'

R' R

base NOTs

R

R N

N OTs

NH2 R' R O

R'

H 2O

Base first abstracts proton α to ketoxime group. This carbanion then displace tosylate group in nucleophilic displacement and forms azirine which on hydrolysis gives α-aminoketone. The reaction is sometimes assisted by Beckmann rearrangement though it generally occurs in acidic conditions. F

F NHBz 1. 50% Toluene / KOH 2. BzCl, Py / DCM, 6N HCl

Ph

Ph O

NOTs

[ JACS, 2002, 124(26), 7640 ]

NO2

NO2

O2N

CH2

C

H2O, NaHCO3

O2N

CH

NOTs

C

NH2

[ JACS, 1953, 75(1), 38 ]

Cl

CH2

C

Cl

NOTs NH2 Cl

CH

C O

Cl

H2O , NaHCO3

O

Ph

Ph

Ph

N

Ph

N

K2CO3 THF , rt ,18h H2N N

O OTs

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 R

C

NH2 + NaOBr

R

N

R in this reaction can be alkyl or aryl.

C

O

hydrolysis

RNH2 + CO2

Mechanism of reaction is as follows, O R

C

O

O NH

OH

R

C

Br

NH

Br

R

C

H

Br

O R

C

O N

Br

R

O N R

C

R

N

N

C

O

H2O

O OH

H

OH

NH

HN R

H O

OH OH

RNH2 + CO2

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 NH2

NBS, DBU, MeOH, reflux

O O

O

O

O NH2

H N

NBS, Hg(OAc)2, CH3OH, DMF

O O

N

N

O

O (H3C)3C

NH2

dibromotin, Hg(OAc)2, PhCH2OH, DMF

(H3C)3C N H

OCH2Ph

O

R O

O

C9H19 Bn

1. Pb(OAc)4, BnOH, DMF 1000, 15h NH2 2. TsOH, C9H19 acetone, H2O, reflux, 2.5h

O

R H N Bn 75%

OB n O

R :- PhMe2Si

O O

NH2 Cl N

O

H

t BuO

NH

Pb(OAc)4 tBuOH 500

Cl N

O 70%

H

OPMP OR

OMe

OPMP OR O

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

O O

O

HO

O H2N

OMe

NH

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 H

C

CONH2

NaOH

H

C

NH2

B.Curtius rearrangement: In Curtius rearrangement, acyl azide are pyrolysed into isocynate which can be hydrolyzed to corresponding amines. O R R

N

C

O

N3

Curtius rearrangement is catalyzed by protic or Lewis acids.

Mechanism is similar to that of Hofmann rearrangement. O

O -N2 R

N

N

N

R R

N

C

O

N

However, there is no evidence of existence of free nitrene. These two steps may be concerted.

O R R

N

N

N

C

O + N2

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 OH

Ph

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

EtOOC

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

NHBoc

Ph

H OH H H

O H

HO

H

H

NHBoc H H HO H

H

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

HOOC

COOH

HOOC

1. Et3N, DPPA BzOH 2. HBr / AcOH

cis,cis-cyclohexan-1,3,5tricarboxylic acid

H2N

NH2

H2N cis,cis-1,3,5-triaminocyclohexane (82%)

[ Bioorganic and Medicinal Chem. Lett., 9 April 1996, Vol.6, Issue 7, 807 ] OH

O

O O N3 N3

O

tBuOH reflux

NH

NHBoc

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

O PMBO HO

OTBS

O O H

H O

O

OPMB O

O

N H

TMS

[ JACS, 2001, 123, 12426 ]

Hunigs base iBuOCOCl 00C, NaN3 H2O, toluene 15 min, TMSCH2CH2OH 3h,

O

O

HOOC O

N

SOCl 2 Me3SiN3 reflux

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

O R

N H

OH

R

C

N

O

H2O

O

Mechanism is similar to that of previous reactions. O

O R

O R

H

OH R

R

N

N

O C

O

R

O N O

RNH2

NHR1 CONHOC H

NHR

2

CNO H H2O

NH2 H

R1 : Et , R2 : (CH2) 3NMe2

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

O Cl EtOOC

H N

N

COOEt O

Et3N, H2O Br

Br NH2 EtOH, H2O Br

C

O

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

O

CONHOH

Na2CO3 PhOSO2Cl

NH

OH

O

OH

OH

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

NH2 1. NH2OH.HCl H3PO4 2. KOH

O

O 1. NH2OH.HCl H3PO4 OH 2. KOH

[ JACS, 1953, 75, 2014 ]

NH2

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

RCOOH + HN3

R N

C

H2O

RNH2

O

O R

O

1

+ HN3

R1

H R

R

N H

Cyclic ketones give lactums. NH

O HN3 / H

O

Mechanism is similar to that of Curtius rearrangement, except that protonated azide undergo rearrangement. O

O

R

OH

H -H2O

O H

N

N

N

R

R

O

O H

R

R

N

N H

C

N

O

N

R H 2O

N H

RNH2 + CO2

N

N

N3

Mechanism with ketone is, OH

O H 1

R

R

R

H

N

N

R

C

R1

N

-H2O

HN3 R

1

OH N R

C

N

N -N2

1

R

R1

N

C

R

H2O

O R1

C OH2

N

R

-H

R1

C OH

N

R tautomerism R1

In reaction with ketone, ketone is activated by protonation for nucleophilic addition of azide group to it.

R N H

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 N

MeAlCl2 / DCM

Ph 96%

H N3

N3 MeOOC O

O TFA / 12h

MeOOC N

O O 1. N3

SPh2

N

2. LiBF4 3. TiCl4

81%

[ JACS, 1991, 113, 896 ] O O TFA

N3

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

N

MeO

MeO Triflic acid dry DCM -50-00C 15 min

O MeO H3COOC

O N

MeO 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 HN3 / H2SO4

R

R

R

R N

R

R

R

R

R

R

N

HN3 / H2SO4 R

R

R

Mechanism of the reaction is as follows.

OH

OH2

H R

R

R

N R

R

N R

R

N

-N2

-H2O R

R

R C R

N

R

R

HN3 R

R

R

RH

R

HN3

H R

R

R

RH

RH

R

R

N

R

R

R

R

R

N

-H R

N H

R

R H

R

R

N

N

-N2

O

O

O H N

H3C H3C

OEt CH3

O

NaN3, CH3SO3H CHCl3, 0.5-1 h 89%

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

OEt CH3

O

O

O H N

ADA O N ADA

ADA :

NaN3, CH3SO3H DME, -300C-rt

O

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

N

R R'

OH

N 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 R R1

N

H R1 C

R N

-H2O

C

N

N

R

R C

N

R -H

R OH2

H2O R1

C

R1

R1 R1

R1

C OH

N

O

R R

1

R N 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 ]

H2SO4 microwave 1800C

N OH

N

N O N

[ SynComm., 2006, 36, 321 ] H N

Cl N

N OH

Cl

N N

Cl

DMF, rt, 8h 100%

[ JOC, 2002, 67, 6272 ]

O

OH I

I

N 12% HgCl2, MeCN , 8h

H N O

[ 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. Ar3C

NHOH

Ar 3C

NHX

PCl5 base

Ar2C Ar2C

NAr NAr

Mechanism is as follows, Ph NH Ph Ph

+

Cl

P Cl

Ph Ph

Cl

Cl

OH

NPh

Cl

Ph

O NH

Cl P

Ph Ph

Cl

Cl Cl

Reaction can also be facilited by treatment with lead tetraacetate.

Ar3CNH2

NH2 Ph2

C

OCH3

Pb(OAc)4

Pb(OAc)4

Ar2C

Ph2C

NAr

N

OCH3 ~98% +

PhN

[ JOC, 1974, 39, 3932 ]

C Ph

OCH3 ~2%

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

A.Baeyer-Villiger rearrangement : In Baeyer-Villiger rearrangement, ketone on treatment with peracid gives ester by oxyinsertion. Reaction is catalyzed by presence of acid catalyst.

O

O PhCO3H

R

R1

R

OR1

Reaction is particularly useful for synthesis of lactones. O

O O CF3CO3H

H

H R

R : H, OAc, OCOPh etc.

R

Mechanism is as follows, OH

OH

O

R2CO3H

H R

RO

R1

C OH

R

R

1

R

C

R1

O

O

R1

R2 O

O -H RO

R1

First step is addition of peroxy acid to carbonyl forming tetrahedral intermediate. In next step concerted migration of migrating group and loss of carboxylic acid to give product. The mechanism is supported by fact that oxidation of Ph2C18O yields

only PhC18OOPh i.e. there is no scrambling of 18O label in product ester. Loss of carboxylates and migration of R is concerted is by fact that reaction is speeded up by electron withdrawing substituent in leaving group and electron donating substituent in migrating group. Carboxylates are as such not very good leaving group. But, O-O bond is very weak and monovalent O can not carry positive charge. So that once peracid is added loss of carboxylate is concerted with rearrangement driven. Synthetic usefulness is syntheses of L-Dopa drug used to treat Parkinson's disease.

O COOH NH2

COOH

HO

NH2 HO

L-tyrosine O

H2O2, NaOH

AlCl 3, AcCl

COOH

HO

COOH

H3O O

NH2 HO

NH2 HO L-Dopa

If the migrating group is chiral then its stereochemistry is retained. By looking at orbitals involved in reaction, this can be explained. The sp3 orbital of migrating carbon just slips from one orbital to next with minimum amount of structural reorganization.

new sigma bond forms on same face

of migrating groupstereochemistry retained.

Migratory aptitude in unsymmetrical ketones is as, H>30>cyclohexyl>20>benzyl>aryl>10>methyl. In case of aryl group, migrating ability is increased by electron donating groups present on ring. F

F mCPBA / CHCl3 Ph NaHCO 3

Ph O

F O

Ph O 71%

Ph

+ Ph

O Ph O 29%

Migration is favored when migrating group is antiperiplanar to the O-O bond of leaving group. This is known as primary stereoelectronic

effect. Antiperiplanar alignment of lone pair of electrons on O2 with migrating group is termed as secondary stereoelectronic effect.

OCOR' O primary

H R

R

secondary

In case of unsaturated ketones epoxidation is likely a competitive reaction. But, Baeyer-Villiger rearrangement is favored because ring

strain can be relieved by oxyinsertion and ring expansion. BnO BnO mCPBA O O O

H

H

O

O H2O2, AcOH

O H

H

Chemoselective oxidation of β-lactum aldehyde has been achieved with mCPBA in DCM where only formates are formed in better yields. H

C

H

H CHO

C

H

mCPBA, DCM rt, 20h

OCHO O

O

OMe

OMe 70%

[ Tet. Lett., 1995, 36, 3401 ]

Aldehyde can be oxidized to carboxylic acid due to preferential migration of hydride. Group that can stabilize positive charge on oxygen migrates. O

O H

OH

mCPBA, DCM

Br

Br Cl

Cl

Other reactions are given below. O

O H2O2 BF3 ether O

[ JOC,1962, 27, 24 ]

O

O cyclohexanone oxygenase O O

O

[ JACS, 1988, 110, 6892 ] O

O CF3CO3H in H2O2 (CF3CO) 2O in DCM Na2HPO4 in DCM

[ JACS, 1955, 77, 2287 ]

O

Cl

Cl O

O BnO

Cl

BnO

O

mCPBA NaHCO3 DCM

O

O

O

BnO OBn

OBn

HO

Cl

BnO

O

O

HO

O O

mCPBA, DCM HO

HO H O

O H

Caro's reagent

O

O

O

O

KHSO5, rt, 24h O

O

O

O O

KHSO5, rt, 24h

O

O cyclopentanone monooxygenase

O

98% ee

[ Chem.Comm., 1996, 2333 ]

O

O

H

H N

mCPBA, NaHCO3 DCM, rt, 30 min

H

Cbz

O

H

H

N Cl

H

Cl

Cbz 85%

[ JOC, 2002, 67, 3651 ] CbzHN

COOMe

CbzHN

H

H

0

TFPAA, 0 C, DCM, >5h

Ph

COOMe

PhO

O

O

[ JOC, 2008, 73, 2633 ]

75%

O

O O

mCPBA NaHCO3 DCM, 00C, 30min

60%

[ Tet. Lett., 2009, 50,4519 ]

H3CO

O H3CO H2O2, supported MTO, tBuOH, 800C O

O

O O

MTO : Methyltrioxorhenium [ Tet. Lett., 2001, 42, 5401 ]

HO

HO

H

H 4 eq mCPBA 1,2-DCE, rt then 800C 48h

O H

O OAc

H O

65%

[ JACS, 2010, 132, 8219 ] O

O 1. Fe2O3, O2 C6H5CHO benzene 2. NaHCO3

O O O

+

97 : 3

[ Tet. Lett., 1992, 33, 7557 ]

Bu O

O

P

O

Bu2BOTi Pr2NEt DCM, -100C

N O

O

P

O N

O

P

O N

O

75%

[ JOC, 1993, 58, 4516 ]

B O

Bu 1. PhCHO, -780C 2. 30% H2O2

O Ph

Ph

O

mCPBA, DCM -400C, 60 min

O N

N O

CH2Ph

CH2Ph O

[ JOC, 1994, 59, 3123 ]

B.Rearrangement of hydroperoxide : Hydroperoxides can be cleaved in presence of protic or Lewis acid. Reaction goes through rearrangement. R R

O

C

O

O

H

H

+ ROH R

R

R

Mechanism is as follows. R

R R

C

O

O

H

H

R

C

R C OH2

O

O

H

R

R

R

H

O + ROH

OR R

R

R

-H2O R

C

H2O OR

Acid converts peroxide to protonated peroxide which loses water molecule. Simultaneously, shift of alkyl group to electron deficient oxygen gives rearranged carbocation, which reacts with water to give hemiketal which breaks down to give alcohol and ketone. Ph

OH

O

OOH AcOH

+

Alkyl group must be showing some sort of anchimeric assistance and the rearrangement must be going through benzonium ion.

OH H2O / H

+

OOH

Benzonium ion : S

T

O

1,2-free radical rearrangements though less common are observed in some cases. The mechanism is similar. First a free radical is generated, which rearranges itself by one electron transfer. This is followed by stabilization of newly formed radical. R

R A

B

A

product

B

As in carbocation rearrangement reactions, radical rearrangements also show pattern as primary to secondary to tertiary.

Reaction of 3-methyl-3-phenylbutanal with di-tert.butylperoxide gave product with and without rearrangement.

Me

C

Ph

Ph

Ph H2 C

Me

CHO

H CH2 abstraction Me

C

C Me 50%

Me

Me

CH3

rearrangement

Me

C Me

H2 C

Ph

H abstraction

Me

H C

H2 C

Ph

Me 50%

In this reaction no migration of methyl group is seen. Also, migration of hydrogen is not seen (seen to lesser extent ) in free radical

rearrangement. As phenyl group, groups like vinyl, acetoxy can also migrate. Also, migration for chloro group has been observed. Cl

Cl Cl

C

CH

CH2

Br

Cl

C Cl

CH

CH2

Cl

Cl

Cl

C

Br

Cl

Br

C H

CH2

Br2

Cl

Br

Cl

Br

C

C H

CH2

Cl

It is shown that migration of Cl takes place easily if migration origin is tertiary and migration terminus is primary.

Migration of chlorine and bromine might be taking place because they can accommodate an odd electron in vacant d-orbital. In summary, 1,2-free radical rearrangements are less common as compared to analogous carbocation process and direction of migration is usually towards more stable radical. Apart from usual 1,2 shifts, 1,3 and longer distance shifts are also known. 1,5 being most common. Transannular H shifts are also known.

Stevens rearrangement : In Stevens rearrangement, quaternary ammonium salt containing

electron withdrawing group on α carbon atom when treated with strong base rearrange to give tertiary amine. Z

R3 N R1

R2

R3

Z

NaNH2

N R1

R2

Rearrangement is intramolecular is shown by cross over experiment. Also, retention of configuration was seen in product. Two mechanistic pathways are possible. One involving radical pair trapped in solvent cage. Presence of solvent cage is important in order to explain retention of configuration.

R3

Z

Z R2

N

base

R3 N

R3

Z R2

R2

N

R1

R1

Z

R3 N

R2

R1

R1

R3

Z N R1

R2

Other is involving ion pair in solvent cage. Z

R3 N R1

Z R2

base

R3 N R1

Z R2

R3 N R1

R3

Z R2

N R1

R2

Concerted reaction mechanism can also operate. But, it can not be accounted as it requires antarafacial mode but migrating group retains its configuration. Reaction is used for ring enlargement. Ph N

Bz

N

NaNH2 / NH3

90%

When Z group is an aryl group, the rearrangement is known as Sommelet-Hauser rearrangement, in which reaction of tert.alkyl ammonium salt with NaNH2 gives N-dialkylbenzylamine with ortho substituted aromatic ring.

N N

NaNH2 / NH3

Another competing reaction is Hofmann elimination, when one of the alkyl group contains β hydrogen atom. Sulfur yields in place of nitrogen yields also give similar reaction. R1 Z

H C

Z

H C

S R

2

R1

SR2

Some examples of Steven rearrangement are given below. O O NaOH N

Ph

N Ph

Ph Ph

Et N

Et2N KOtBu / MeCN

Et

N

PhLi N

tBuOK 1,4-dioxane 800C N

N 88%

BnOOC

O H

N

COOBn

base N

O

84%

N

PhHCN

nBuLi in hexane

N

N

Ph

[ JOC, 1974, 39, 130 ] Br EtOOC N

EtOOC

COOEt

K2CO3 DMF 00C-rt

EtOOC N

COOEt N

[ Tet. Lett., 2002, 43, 899 ]

COOEt

O NC

N HN base N

N

N

NC

O

O

HN

NC

HN

N

+

N N

N

N N

N

N

R1

Ph Ph base N

R

Ph Ph

1

N

THF, PhLi / KHMDS -780C N OTf

[ Tet. Lett., 2004, 45, 7525 ]

N

Wittig rearrangement : Ethers on reaction with alkyl lithium rearrange in similar manner to that of Stevens rearrangement to give alkoxy lithium. This reaction is called Wittig rearrangement. R3

H 1

R

C

OR

3

R4Li

R1

R2

C

OLi + R4H

R2

This alkoxy lithium can then be converted to alcohol. R3 R1

C R2

R3 OLi

H

R1

C R2

OH

R may be alkyl, aryl or vinyl group. Migratory aptitude are allylic, benzyl>ethyl>methyl>phenyl. Mechanism follows radical pair pathway.

H R1

C

OR3

R4Li

R1

C R2

R2 R3 R1

C R2

OLi

OR3

R1

C R2

O R3

R1

C

O

R2 R3

Li

i.Reaction is largely intramolecular ii.Migratory aptitude of group is analogs to free radical mechanism.

iii.Product obtained is with retention of configuration.

H

BuLi Ph

O Ph

OLi

Ph

OH

OH O

O H OTBDPS

TMS nBuLi, THF, ether, 00C

O TMS H OTBDPS 60%

O O

tBuLi

OH

O

58%

NOMe

NOMe O MeO

2eq. LDA THF, -780C

OH MeO

CH2Ph

Li

O Naphthyllithium THF, -780C, 20 min

tBu

tBu

SePh CH2Ph

OH + tBu

tBu OCH2Ph

OH

[ Tet. Lett., 1993, 34, 297 ]

DMSO / H2O / K2CO3 4h, OCH2Ph

HO O

O

O

tBuLi THF -780C

OMe OMe

[ Tetrahedron, 2005, 61, 1095 ]

When R2 is a good leaving group and electron withdrawing functional group like CN, then this group is eliminated and ketone is formed. H R1

C

O

R2Li

OR

+ R2H + LiCN R1

CN

R

C

OR

R2Li

1

R

C CN

CN O R1

R

Li

H 1

R

R

O R

1

R

R C OLi CN

R1

C CN

OLi

Bt

Ph

OCH3

LDA Ph

OCH3

O

O 61%

Bt : benzotriazol-1-yl HO O

O

TBSO

Ph

O nBuLi, THF -780C-00C

TBSO

OTBS

Ph

HO

TBSO

[ JACS, 1996, 118, 3317 ]

OTBS

F 3C

Ph

O N

Ph

Ph N

Ph F 3C

OH

O LiHMDS THF / ether -780C-rt

+ OH

O

F3C

Ph

N O

[ Org. Lett., 2001, 3, 2529 ]

PhH2C

OH

H2 C

O

MeLi Ph

C H

H2 C

[ JACS, 1962, 84, 4295 ] OH Ph

O

Ph

Ph

nBuLi

Ph

OH O

Ph

Ph

nBuLi Ph

Ph + Ph

Li

[ JACS, 1966, 88, 78 ]

Ph OH

Et2O BuLi rt, 1.3h

O O

O

O N

29%

[ Tet. Lett., 2000, 11, 1003 ]

N

The purpose of crossover experiment is to determine whether reaction takes place intermolecularly or intramolecularly i.e. whether reactant

break apart to form intermediate which are released into solution before they combine to give product. In this experiment two substrate differing in substituent are mixed

together and are reacted in same reaction condition and the product obtained is analyzed. Consider, a simple reaction in which A-B reacts to give C-D. A A

B + A*

B*

C

D + C*

B + A*

B*

C

D + C*

D* D* + C*

D + C

D*

There are two possibilities of outcome of reaction. One in which no crossover of substituent is seen. This is possible if reaction is intramolecular. And other possibility is that mixture of products obtained is by crossover reaction. This is possible in case of intermolecular reaction.

Thus crossover experiment gives useful information about course of reaction.

The experiment can be illustrated by considering Fries rearrangement.

p-Tolylbenzoate (I) on rearrangement gives 2-hydroxy-5-methylbenzophenone (II). OH O

Ph AlCl3

Ph

O I

II

O

In the similar reaction, o-chloro-p-tolylacetate (III) give 2-hydroxy-3-chloro-5-methylacetophenone (IV). Cl Cl

OH O

AlCl3 O

III

IV

O

When I and II are mixed together and product is analyzed, V and VI, along with II and IV are obtained. Cl OH

OH Ph

O V

O VI

This shows that the reaction proceeds intermolecularly and fragments

are formed in solution.