Pericyclic Reactions - University of Oxfordmsmith.chem.ox.ac.uk/resources/completed-handout2.pdf · It can be easier to analyse the reverse reaction. Ph O O O O Ph. ... set by pericyclic

Pericyclic Reactions 6 Lectures �Year 3

Handout 2 � Michaelmas 2017

Prof Martin Smith CRL [email protected]://msmith.chem.ox.ac.uk/

H

π6a

σ2s

Cycloadditions: oxyallyl cation P46

O OO

(4q + 2)s =(4r)a =Total =

odd ✓allowed

disrotatory

101

σ2s

ω0sO

constructive overlap ✓disrotatory

HOMO sigma

LUMO ω O

OO O

O

(4q + 2)s =(4r)a =Total =

odd ✓allowed

101

π2s

π4s

O

HOMO diene

LUMO allyl cation

constructive overlap ✓

Cycloadditions: allyl cation & allyl anion P47

Br

AgBF4π4s π2s

◼Allyl anion-alkene and reverse process

◼Allyl cation-diene

Ph

H

LDA,%45%°C

PhPh

PhPh

Ph

Ph

HPh

Ph

Ph

Ph

Ph

Ph(4q + 2)s =

(4r)a =Total =

odd ✓allowed

101

π2s

π4s

Ph

Ph

Ph

HOMO allyl anion

LUMO alkene


Cycloadditions: allyl cation & allyl anion P48

O

O Ph

H O

OPh

BuLi+ PhCO2

◼Allyl anion-alkene (reverse process)

O

O

(4q + 2)s =(4r)a =Total =

odd ✓allowed

303

σ2s

σ2sω2s HOMO ω

LUMO σ +σ


ψ3

LUMO butadiene

O

O

Ph

OO HOMO carboxylate

LUMO alkene


◼ It can be easier to analyse the reverse reaction.

PhO

O

O

OPh

1,3-dipolar cycloadditions P49

◼ sp2-hybridized central atom

π4s π2s

1,3-dipole

XY

Z XY Z X

YZ

ZY

X

◼ sp-hybridized central atom

ZY

X π4s π2s X Y Z X Y Z X Y Z

1,3-dipole

NR

NNH

RO

OO

NO

RO

OO

azomethine ylid azomethine imine carbonyl oxide carbonyl ylid nitrone ozone

nitrile ylids nitrile oxides diazoalkanes nitrile imines alkyl azides nitrous oxide

NR N OR N NHR

N NR

R

N NR

R N N NR

N N O

1,3-dipolar cycloadditions: ozonolysis P50

OO

OO

OO

OO

OOO

Oω2s σ2s σ2s

OO

O

π4s

π2s

(4q + 2)s =(4r)a =Total =

odd ✓allowed

101

OO

O

HOMO alkene

LUMO ozone


HOMO carbonyl LUMO carbonyl


OO

C

O

HOMO carbonyl ylid


LUMO carbonyl ylid

•ψ2

HOMO allyl anion

OO

C

O

1,3-dipolar cycloadditions: azomethine ylids P51

(4q + 2)s =(4r)a =Total =

odd ✓allowed

conrotatory

101

Ph

CO2EtEtO2C

H Hσ2s

ω2a

ψ2

ψ1

ψ3

•

HOMO ω

LUMO σ

constructive overlap ✓conrotatory

Ph

CO2EtEtO2C

H H

[π2s π4s] N

EtO2C CO2Et

H H

Ph

CO2Et

N CO2EtPh

CO2Et

N CO2EtPh

NEtO2C CO2Et

Ph Ph

Ph

Ph Ph

Nitrone cycloadditions in synthesis P52

◼ Nitrones are readily formed between aldehydes and substituted hydroxylamines

N

HOH

NO

NOH

N

O

Histrionicotoxin; J. Am. Chem. Soc. 2006, 128, 12656.

RNHOH

O

R' H

N

R' H

O R+ N

HR'

RO

ONR

R'

Histrionicotoxin

O

CNCN

NH2OH

NNC

OCN

NNC

OCN

NNC

OHCN

N CNNC

ON CN

NC

O

heat 180 °C

Azomethine ylids in synthesis P53

◼Total synthesis of Nominine (J. Am. Chem. Soc. 2006, 128, 8734).

N

H

H

Me

H

HOH

H

HN

X

H

HH

Me

N

CNMe

OMe

O

NOMe

CNMe

O

CN

N

H

H

Me

H

O

OMe

N

CNMe

OMe

OCN

N

H

H

Me

H O

OMe

NOMe

CNMe

O 1

3.6

N

OOMe

CN

MeN

OOMe

CN

Me

Azomethine ylids in synthesis II P54

N

H

H

Me

H

N

H

H

i)#NaBH4ii)#SOCl2

i)#Bu3SnH,#AIBN

i)#DIBALii)#Ph3P=CH2

CN

N

H

H

Me

H

O

OMeCN

N

H

H

Me

H

Cl

OMeCN

N

H

H

Me

H

OMe

N

H

H

Me

H

OMe

H

N

H

H

Me

H

OMe

H

N

H

H

Me

H

O

H

N

H

H

Me

H

H

O

H

Na,$NH3,$iPrOHH+,$H2O

NH

,"MeOH

N

H

H

Me

H

H

N

H

Cheletropic reactions P55

◼A sub-class of cycloaddition/cycloreversion reactions in which the two σ – bonds are made or broken to the same atom (compare with ketenes as vinyl cations)

Oπ2a

ω0s

(4q + 2)s =(4r)a =Total =

odd ✓allowed

101

◼Addition of singlet carbenes (stereospecific) is most important: side on approach necessary:

MeMe

MeMe

Cl Cl

Cl Cl

Cl

Cl

π2s

ω0a

ω2s

(4q + 2)s =(4r)a =Total =

odd ✓allowed

213

Cl

Cl

LUMO alkene

HOMO carbene


Cl

Cl

LUMO carbene

HOMO alkene


O

CO+

Cl Cl

•

O

Cl Cl

•

OO

R

R

ClCl

R R

Cheletropic reactions: sulfur dioxide and polyenes P56

SO2 SO2

OS

O OS

O

O

S Oω2s (4q + 2)s =

(4r)a =Total =

odd ✓allowed

101

π4s

The addition of sulfur dioxide to polyenes is a reversible process

heat andpressure

heat andpressure

O

S O

O

S O

SO

O

HOMOlone pair

LUMO

LUMO diene

HOMO SO2


LUMO SO2

HOMO diene


O

S O

O

S O


◼With trienes the extrusion process dominates but considering the reverse process, the reaction must be antarafacial with respect to the triene component.

SO2

heatSO2

heat

%&SO2%&SO2

OS

Oω2s

(4q + 2)s =(4r)a =Total =

odd ✓allowed

101

π6a

OS

O

LUMO triene

HOMO SO2


LUMO SO2

HOMO triene


OS

O

O

S O

O

S O

SO

O

HOMOlone pair

LUMO

SO O

SO2too strained; ca. 104 times less reactive than


◼The cheletropic extrusion of SO2 is often used in synthesis to unmask a diene, as a prelude to a Diels-Alder or other cycloaddition

SO2

OOMeMe O

H

Me O

H

Me O

H H

Hexo

Application in the synthesis of a steroid core

Application in the synthesis of columbiasin

OOMe

MeO

Me

HHO

Me

SO2Me

H

OOMe

MeO

Me

HHO

Me

Me

O

OMe

Me

O

Me

HHO

Me

Me

H

H

HO

OMe

MeO

Me

HO

MeHMe

H

endo

MeMe

Me

Me

Electrocyclic reactions P59

Thermal electrocyclic processes will be conrotatory if the total number of electrons is 4nand disrotatory if the total number of electrons is (4n +2).

This is reversed for photochemical reactions.

Me

Me

Me

Me

140 °C, 5 h 140 °C, 5 h

(4q + 2)s =(4r)a =Total =

odd ✓allowed

disrotatory

101

MeMe

π6s

HMeMe

(4q + 2)s =(4r)a =Total =

odd ✓allowed

disrotatory

101

π6s

Me MeH HH

Me

H

Me

(4q + 2)s =(4r)a =Total =

odd ✓allowed

conrotatory

101X

H H

MeMeπ2a

σ2s

Symmetry allowed but geometrically constrained

Does not occur


(4q + 2)s =(4r)a =Total =

even✓allowed

conrotatory

000

π4s

PhPh

Me Meσ2a

PhPh

Me Me

HSOMOdiene

LUMO σ


Me

Me MeMe

Ph

Ph

Ph

Ph

hν

◼ Cyclopropyl cation / allyl cation interconversion

Cl Cl Clψ2

ψ1

ψ3

•

Lewis acid, low temperature

Cl

H

H

Me

Me (4q + 2)s =(4r)a =Total =

odd✓allowed

disrotatory

101

ω0s

σ2s


Cl Cl

Cl

Me

Me

H

H

HOMO σ

LUMO σconstructive overlap ✓disrotatory

Cl

Me

H

H

Me


◼ The ionisation of cyclopropyl halides and tosylates is a concerted process to give allyl cations (i.e. discrete cyclopropyl cations are not formed). The reaction can be viewed as an internal substitution in which the electrons in a σ-bond (HOMO) feed into the C-X σ* (LUMO). ◼The reaction is disrotatory and the sense of rotation (torquoselectivity) is specified – this dictates the geometry of the allyl cation and can have a large influence on reaction rate.

Cl

H

H

Me

Me


OTs

HH

HH

OTs

HH

MeH

OTs

MeH

HH

OTs

HH

MeMe

OTs

MeH

HMe

OTs

MeMe

HH

1 6 133 2 450 37000

◼Influence on rates – solvolysis in acetic acid

Cl

Electrocyclic reactions: Nazarov cyclization P62

OMe3SiFeCl3

OMe3SiFeCl3 Me3Si

OFeCl3

H H H H

H

O

H H

H

4π electrocyclicring closure

relative configurationset by pericyclic reaction

H H

O(4q + 2)s =

(4r)a =Total =

odd ✓allowed

conrotatory

011

π4a

H H

OHOMOallyl cation LUMO

alkene


◼The analogous anionic pentadienyl anion cyclization is also electrocyclic

6π electrocyclicring closure

N N

Ph

Ph Ph

H PhLiN N

Ph

Ph Ph

NN

Ph Ph

Ph

Ph PhH H

Phπ6s(4q + 2)s =

(4r)a =Total =

odd ✓allowed

disrotatory

101

Pericyclic reactions & natural products: the endiandric acids P63

HH

HHCO2Me

Ph

HH

H

PhCO2Me

HH

H

CO2MePh

HH

H

CO2Me

H

H

Ph

H

endiandric acid Amethyl ester

endiandric acid Dmethyl ester

endiandric acid Emethyl ester

endiandric acid Fmethyl ester

H

H

HCO2MeH

PhH

H

endiandric acid Cmethyl ester

endiandric acid Gmethyl ester

HH

HH CO2MePh

HH

H

H

H

Ph

H

CO2Me

endiandric acid Bmethyl ester

CO2MePh

HH

CO2MePh

HH

Ph

HH

CO2Me Ph CO2Me

CO2Me

Ph

DielsAlder

DielsAlder

DielsAlder

8πelectrocyclic

6πelectrocyclic

6πelectrocyclic

6πelectrocyclic

8πelectrocyclic

Biosynthesis: Black J. Chem. Soc., Chem. Commun. 1980, 902. Synthesis:Nicolaou,J.Am.Chem.Soc. 1982,104,5558.


HH

CO2Me

Ph

HH

H

CO2MePh

CO2Me

Ph

R

R'

HH

CO2Me

Ph

CO2Me

Ph

HH π8a

CO2MePh

HH

8π electrocyclicconrotatory

6π electrocyclicdisrotatory

HH

H

CO2Me

H

H

Ph

H

π6s

R

R'

HH

π6s6πelectrocyclicdisrotatory

exo-Diels Alderreaction

endiandric acid Amethyl ester

endiandric acid Dmethyl ester

endiandric acid Emethyl ester

H2 Lindlar

heat100 °C

HH

HHCO2Me

Ph

HH

CO2Me

Ph


HH

H

PhCO2Me

H

H

HCO2MeH

PhH

H

HH

H

H

H

Ph

H

CO2Me

Ph

HH

CO2Me

Ph CO2Me

Ph CO2MePh

CO2Me

R

R'

HH

π8a

8π electrocyclicconrotatory


π6s

R

R'

HH

π6s


exo-Diels Alderreaction

endiandric acid Bmethyl ester

endiandric acid Gmethyl ester

endiandric acid Fmethyl ester

H2 Lindlar

endo-Diels Alderreaction

endiandric acid Cmethyl ester

HH

HH CO2MePh

heat,100 °C

Sigmatropic rearrangements P66

◼ Synthetically the most important sigmatropic rearrangements are the Cope and Claisen rearrangements and variants thereof. ◼The Claisen/Cope rearrangements can proceed via chair-like or boat-like transition states – the chair-like transition state is strongly favoured unless there are steric constraints that force a boat-like transition state.

◼Where possible, substituents generally adopt equatorial sites in the chair-like transition state.

OR

R'

OR

R'

ROH

OHR

R'

OR

R'H

[3,3]-sigmatropicrearrangement

[3,3]-sigmatropicrearrangement

R’ = H,tautomerism

tautomerism

Claisen rearrangements P67

heat +

(4q + 2)s = 3(4r)a = 0Total = 3

odd ✓allowed

π2s

π2s

σ2s

major minor

diequatorialH

Me

MeH

H

Me

MeH

Me

HMe

H

Me

HMe

H

cis, cis - minortrans, trans - major diaxial

heat

H

H

MeMe

H

H

MeMe

cis, trans

Claisen and Cope variants P68

OH

OEt

OEtOEt

cat.Hheat

O

OEtO

OEt

◼ Johnson-Claisen rearrangement - synthesis of γ,δ-unsaturated esters.

O

OEt

Me

H

O

OEt

Me

H

◼ Eschenmoser-Claisen rearrangement

HO

MeO

OMeNMe2

O

NMe2

O

NMe2

OHO

O

Othen%heat

◼ Carroll rearrangement

◼ Ireland-Claisen rearrangement

O

O LDAthenMe3SiCl O

OSiMe3[3,3]

O

OSiMe3

O

OHH3O+

Cope and Oxy-Cope rearrangement P69

R

heat

R b

aa

ab

c

c

d a

a

a

b

c

c

c d

b b

◼ Bullvalene - valence isomers interconvert by degenerate Cope rearrangements.

◼ Cope rearrangement: high temperatures usually required (>200˚C)

◼The anionic oxy-Cope can be conducted at low temperature (0 °C).

OH OH O

oxy-Cope

O O OK

anionic oxy-Cope

k1 k2

k2/k1 ∼1010 – 1017

MeO

O

MeO

O

HH H

H

MeO

O

H

H

MeO

O1

23

4

51

23

4

5

◼A useful method for the synthesis of cis-decalins

1,n-hydride shifts P70

◼A suprafacial 1,n-hydride shift involves the hydrogen moving from one end of the conjugated system to the other across one face of the conjugated system.

◼An antarafacial 1,n-hydride shift involves the hydrogen moving from one end of the conjugated system to the other and moving from one face of the conjugated system to the opposite face.

HH

[1, 5]1

1

2 34

5

H

(4q + 2)s =(4r)a =Total =

odd✓allowed

101

π4sσ2s

(4q + 2)s =(4r)a =Total =

odd✓allowed

011

π4a

Hσ2a

H H

[1, 7]

1

1

2

3

4

5 6

7

H

π6a

σ2s

(4q + 2)s =(4r)a =Total =

odd✓allowed

101

1,n-hydride shifts P71

◼ 1,5-Hydride shifts occur readily when the two ends of the diene are held close.

Me H MeH

H

Me

HH

Me

HH

MeH

H0°C

◼ In acyclic systems, 1,5-hydride shifts can be much slower.

Chiralacetic acid

DPh

T

tBu

Me H

DPh

T

tBu

Me

HDPh

T

Me

H tBuO

HOT

DH

allylic strain

H

Me tBuDT

Ph

H

MetBu

DT

Ph

H

DT Me tBu

disfavoured conformation

200 °C[1,5]

1,2-shifts P72

◼ 1,2-Shifts of alkyl groups can also be pericyclic.

R

RR

R

RR

(4q + 2)s =(4r)a =Total =

odd✓allowed

101

σ2s ω0s

R

R

R

◼Allowed, concerted 1,2-shifts of carbanions are geometrically impossible.

R

RR

R

RRX

R

R

R(4q + 2)s =

(4r)a =Total =

even✗forbidden

202

ω2sσ2s

◼ 1,2-Shifts of carbanions occur by a radical mechanism – 1,2-Wittig & 1,2-Stevens rearrangements

OMe

OMe

BuLi OMe•

• O

Me•

•OH

Me

O

Me

X

DHAcO H

HD

AcO H D

AcO

1,3 & 1,4-shifts P73

◼Thermal [1,3]-alkyl shifts occur with inversion of configuration in the migrating group.

1,3-alkyl shift

AcO HH

D

DHAcO

H

(4q + 2)s =(4r)a =Total =

odd✓allowed

101

π2s

σ2a

◼Thermal 1,3-shift of hydrogen is only geometrically reasonable in a suprafacial (thermally disallowed).

◼ In the following [1,4]-shift, migration occurs with inversion of configuration with D always on the concave face of the bicyclic structure.

H(4q + 2)s =

(4r)a =Total =

even✗forbidden

200

π2s

σ2s

HHOMO σLUMO π

constructive overlap ✓antarafacial shift allowed

but geometrically unreasonable

1

1 2

3

H H

H H

HD

D HD H D H(4q + 2)s =

(4r)a =Total =

odd✓allowed

101 σ2a

π2s

12

3 4 1

BuLiO

ArO

ArO

Ar

1,n-shifts P74

O

Ar

◼ [2,3]-Wittig rearrangement – most likely proceeds via an envelope transition state; large groups at the allylic position will tend to occupy a pseudo-equatorial position.

(4q + 2)s =(4r)a =Total =

odd✓allowed

303

ω2s

σ2sπ2s

NNMe2 Me NMe2

[2,3]

[2,3]

tautomerism

◼ Sommelet-Hauser rearrangement.

◼ 1,5-Alkyl shift with retention of configuration in the migrating group.

HHheat

[1,5] [1,5]

H(4q + 2)s =

(4r)a =Total =

odd✓allowed

101

π4s σ2s

2,3-rearrangements P75

◼ Meisenheimer Rearrangement. ◼ Rearrangement of allyl sulfoxides, sulfinimines and sulfonium ylids.

R

NO

R

ONMe2[2,3]

SX Ph

XSPh

[2,3]X = O, NTs, CH2

◼A [9,9]-sigmatropic shift.

H2N NH2 NH2 NH2

H H

NH2H2N

H2N

H2N

1

2 3

4

1

56

7

8

9 9

[9,9]

H2N

H2N

(4q + 2)s =(4r)a =Total =

odd✓allowed

101

π8s

π8s

σ2s

Group transfer reactions P76

◼ Group transfer – appear to be a mix of a sigmatropic rearrangement and a cycloaddition. They are bimolecular and so are not sigmatropic rearrangements, and no ring is formed so they are not cycloadditions.

H

HO

OMe OMe

O

230 °C

(4q + 2)s =(4r)a =Total =

odd✓allowed

303

H

π2s

π2sσ2sH

HOMOσ + π

LUMO π


HO

OMe OMe

O

AlCl3

◼ Conia-ene reaction.

O 350$°C OH

O CH3ene

tautomerise

Group transfer reactions P77

◼ Carbonyl-ene reaction - frequently catalysed by Lewis acids.

180 °C, 48 hSnCl4, 0 °C

CO2Me

CO2MeOOH

CO2MeCO2Me OHMeO2C CO2Me

922.5

897.5

CO2Me

CO2Me

O

H

◼Thermal carbonyl ene reaction: sterics are important.

OHMeO2C CO2Me

CO2Me

CO2Me

OH

SnCl4

◼ In the Lewis acid-catalysed reaction significant positive charge develops in the “eneophile”.

◼ Retro-ene and retro group transfer reactions are common.

X HOR heat

+ RX

OHO H heat

+

SMeS

O HS

MeS

retro-ene

retro group transfer: X = S, Se, or NR (Cope elimination)

OH

CO2MeCO2Me

Summary of pericyclic reactions P78

Four classes: Cycloadditions (chelotropic reactions); Electrocyclic reactions; Sigmatropic rearrangements; Group transfer.

A ground state pericyclic reaction is symmetry allowed when the total number of (4q + 2)s

and (4r)a components is odd (q and r must be integers).

A pericyclic change in the first electronically excited state (i.e. a photochemical reaction) is symmetry allowed when the total number of (4q + 2)s and (4r)a components is even.

For thermal cycloadditions and group transfers:

1. If the total number of electrons is (4n + 2),both components can be used in a suprafacial manner.

2. If the total number of electrons is (4n),one of the components is suprafacial and the other antarafacial.

For electrocyclic reactions:3. Thermal electrocyclic processes will be conrotatory if the total number of electrons is 4n

and disrotatory if the total number of electrons is (4n +2).

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Pericyclic Reactions - University of Oxfordmsmith.chem.ox.ac.uk/resources/completed-handout2.pdf · It can be easier to analyse the reverse reaction. Ph O O O O Ph. ... set by pericyclic