Sigmatropic Rearrangements

Definition: A sigmatropic rearrangement is defined as an intramolecular rearrangement of a σ bond, adjacent to one or more π systems, to a new position in a molecule, with the π systems becoming reorganized in the process.

R

R

R

R

HR HR

New position of σ bondσ bond that migrates

New position of σ bondσ bond that migrates

[1,5]

[3,3]

Pericyclic Reactions - Continued

Cope Rearrangements

Thermal rearrangement of 1,5-dienes to isomeric 1,5-dienes:

Specific value for modern organic synthesis:

- Parent Cope involves no requirement for acid or base catalysis and can thus accommodate a wide variety of functional groups.- One of the most powerful methods of synthesis of medium rings.- Due to the highly ordered cyclic TS, the reaction is extremely stereospecific. Two unsymmetrical double bonds and two asymmetric centers are translated to four new elements of stereochemistry, usually with near quantitative symmetric transmission.

The development of the oxy-Cope and anionic oxy-Cope reactions has greatly extended the utility of the Cope rearrangement by allowing easier access to diene substrates, lowering the temperature required for rearrangement, and producing carbonyl substrates irreversibly.

R R300 °C

Cope Rearrangement

- Ring strain:

60 oCJ.C.S., Chem. Commun. 1970, 1519.

H

HH

33 oCJ.C.S., Chem. Commun. 1965, 226.

Effect of Ring-Size on the Cope-Equilibrium of 1,2-Divinylcycloalkanes:

Divinylcyclopropanes

Divinylcyclobutanes

Divinylcyclopentanes

Divinylcyclohexanes

Divinylcycloheptanes

Divinyl Medium Rings

Cyclohexadienes

Cyclooctadienes

Cyclononadienes*

Cyclodecadienes*

Cycloundecadienes*

Large Ring Dienes

*The equilibrium lies in the opposite direction in the irreversible oxy-Cope reaction.

Dr. P. Wipf Page 1 of 7 10/21/2009

Characteristics of the oxy-Cope rearrangement:

- Substrate is easily prepared by Grignard addition to a carbonyl compound.

-Oxy-Cope is irreversible.

-Product has two different functional groups.

-Competing fragmentation of the substrate via a thermal retro-ene reaction:

OH

OH340 oC

(26%)O

HO

(74%) O

Characteristics of the anionic oxy-Cope rearrangement:

-Enormous rate accelerations (1010-1017).

-Sodium and, especially, potassium alkoxides are most effective.

-The primary effect of the alkoxide is to weaken the C,C-single bond, rather thanstabilizing the TS. The effect is seen in the gas phase as well as in solution.

-Both donor and acceptor groups should increase the rate (B. K. Carpenter, Tetrahedron 1978, 34, 1877):

t-Bu

-O25 oC

(73%)

t-BuO

(45%)

t-BuO

(55%)

Claisen Rearrangements

- Wipf, P. In Comprehensive Organic Synthesis; B. M. Trost, I. Fleming and L. A. Paquette, Ed.; Pergamon: Oxford, 1991; Vol. 5; pp 827-874.

propionic acid (cat.),138° C

Johnson (5)

Eschenmoser (4)xylenes, 150° C

Saucy-Marbet (3)

pTsOH (cat.), 80° C

Carroll (2)NaOAc, 100° C

6

54

32

1Claisen (1)O O

OMe

O OO

HOO O

H

OH OMe

O

OC

O

OMe

OMe

R OH

Me2N

R

O

NMe2

O

NMe2

R

R

OMe

O

OMe

O

R

MeO

OHR

OMe

OMe

-CO2

Dr. P. Wipf Page 2 of 7 10/21/2009

Cl2C=C=O

6

54

32

1X=O: Claisen RearrangementX=S: Thia-Claisen RearrangementX=N: Aza-Claisen Rearrangement

-Carbanion-AcceleratedClaisen (9)

50° CKH/HMPA

Ketene Claisen (8)room temp.

ether

benzeneReformatsky-Claisen (7)

2. H3O+

1. 85° CZn-dust

1. LDA, THF

2. TMSCl

1. 60° C

2. H3O+Ireland (6)

+

-

OH

OO

OZnBrBr

O

O

O

O OTMS

O O

OH

OO

OCl Cl

O

X

Cl ClO

OO

PhSO2

O

PhSO2 PhSO2

X

OR R

O

RR

OH

ORR

OHR R

R ≠ H

R = H

O O OH

OOH

Normal Product

Abnormal Product

The Aromatic Claisen Rearrangement

The Ireland Silyl Ester Enolate Rearrangement

Several factors contribute to the versatility of the ester enolate Claisen rearrangement. Among these are the ability to use a stoichiometric combination of the alcohol and the acid components, the relatively low temperature of the pericyclic process that allows for the assembly of complex, highly functionalized structures, and the transformation of a carbon-oxygen into a carbon-carbon bond that lends itself easily to the assembly of contiguous quaternary centers. Another particularly important aspect of the Ireland rearrangement is that, through an efficient control of ketene acetal geometry, a highly reliable and predictable transfer of stereochemistry from starting material to product can be realized Deprotonation of crotyl ester with LDA in THF leads, via the selective formation of the kinetically favored (Z)-ester enolate, upon silylation to the (E)-silyl ketene acetal. After rearrangement at 65°C and mild hydrolysis of the silyl ester, a 87 : 13 ratio of g,d-unsaturated acids is isolated in 79% yield. These two products can be obtained in a 19 : 81 ratio by using 23%HMPA/THF as a solvent system for the generation of the thermodynamically favored (Z)-silyl ketene acetal via the corresponding (E)-lithium enolate.

Wipf, P., "Claisen rearrangements." In B. M. Trost, I. Fleming and L. A. Paquette, editors. Comprehensive organic synthesis. Vol 5. Oxford: Pergamon; 1991. p. 827-874.

Dr. P. Wipf Page 3 of 7 10/21/2009

O

OSiR3

O

OSiR3

HO2C

HO2C

O

O

LDA, THF;TMSCl; Δ; NaOH/H2O; 79%

LDA,THF/23%HMPA;TMSCl; Δ; NaOH/H2O; 73%

19 : 81

87 : 13

(Z)-silyl ketene acetal

(E)-silyl ketene acetal

A : B

A

B

O

R

O

R

ROC

ROC

via chair TS‡

via boat TS‡

via chair TS‡

O

PhO

1. LDA, THF, 23% HMPA; -78 °C2. TBS-Cl; -78 °C to 50 °C O

Ph

Δ

OTBS

O

OTBS

‡Ph

TBSO Ph

O

Dr. P. Wipf Page 4 of 7 10/21/2009

Woodward-Hoffmann RulesAmong the theories that are commonly used to analyze pericyclic reactions, three are generally considered to be the most useful:

1. Fukui’s Frontier MO interactions. This analysis applies HOMO-LUMO interactions as well as orbitals close to HOMO & LUMO, and it is more intuitive that the original orbital symmetry arguments.

Closed-Shell Repulsion Coulomb Interaction Frontier Orbital Interaction

-unocc.unocc. occ.occ.

ss r Er - Es

2(Σabcracsbβab)2+

k<lεRkl

QkQl

ab

(qa + qb)βabSab +ΔE = -r

ΣΣΣΣΣΣ

- Coulson, C. A.; Longuet-Higgins, H. C. Proc. Roy. Soc. A 1947, 192, 16.- Klopman & Salem (JACS 1968, 90, 223, 543, 553).- Fukui, K. Acc. Chem. Res. 1971, 4, 57.

qa and qb Electron densities in orbitals a and b.β and S Resonance and overlap integral.Qk and Ql Total charges at atoms k and l.ε Local dielectric constant.Rkl Distance between atoms k and l.cra Coefficient of atomic orbital a at the molecular orbital r.Er Energy of molecular orbital r.

Rather than considering the relative phases, i.e. symmetry, of all orbitals involved during the transformation of reactants into products, the frontier orbital approach makes predictions for the outcome of pericyclic reactions based on the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO). In this, the electrons in the HOMO of one reactant are looked upon as analogous to the outer (valence) electrons of an atom, and reaction is then envisaged as involving the overlap of this (HOMO) orbital with the LUMO of the other reactant. Where, as in electrocyclic reactions, only one species is involved only the HOMO needs be considered.

OIf, upon examination of the interactions that occur in the frontier orbitals (HOMO, LUMO if applicable, otherwise only HOMO) the interactions are constructive (of the same phase, the reaction is considered “allowed”.If the orbital overlap is destructive (i.e. of different phase), then the reaction is “forbidden”.

Dr. P. Wipf Page 5 of 7 10/21/2009

+ O

OMe

Δ

‡

O

MeO

CO2Me

2. The Dewar-Zimmerman Theory of Aromatic Transition States. This analysis is possibly the most general and easiest to apply to a broad range of pericyclic reactions, but it is also the least anchored in fundamental physical principles.

For applying this model, choose a basis set of 2p atomic orbitals for all atoms involved (1s for hydrogens). After assigning any phases to these orbitals (no relationship to MO’s is required!), connect the orbitals that interact in the starting materials, before the reaction begins. Allow the reaction to proceed according to the postulated geometry; connect the lobes that begin to interact and were not connected in the starting materials.Count the number of phase inversions that occur - a phase inversion within an orbital is not counted.Based on the number of phase inversion of the orbital perimeter, identify the topology of the system: Odd # of phase inversions: Möbius topologyEven # of phase inversions: Hückel topology

The transition state can now be assigned as antiaromatic or aromatic, based on the number of electrons in the system:Möbius topology: Aromatic for 4n, Antiaromatic for 4n+2Hückel topology: Aromatic for 4n+2, Antiaromatic for 4nif the transition state is aromatic, then the reaction is thermally allowed. If the transition state is antiaromatic, a photochemical process is required. connect

orbitals

disrotatory closure conrotatory closure

zero phase inversions - Hückel topology 4 electrons in system - antiaromatic and forbidden

one phase inversion - Möbius topology 4 electrons in system - aromatic and allowed

Dr. P. Wipf Page 6 of 7 10/21/2009

Thermal processes involving 4n+2 electrons will be suprafacial/disrotatory and involve a Hückel-type TS‡, whereas thoseinvolving 4n electrons will be antarafacial/conrotatory and the orbital array will be of the Möbius type.

Dr. P. Wipf Page 7 of 7 10/21/2009