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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

Subject Chemistry

Paper No and Title 9; Organic Chemistry-III

Module No and Title 33: Cope, Claisen and aza-Cope rearrangements

Module Tag CHE_P9_M33

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

TABLE OF CONTENTS 1. Learning Outcomes 2. Introduction 3. Claisen rearrangements 4. Cope rearrangements 5. Summary

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

1. Learning Outcomes

After studying this module, you shall be able to

• Know what are sigmatropic rearrangements • Learn mechanism of Claisen, Cope and aza-Cope rearrangements • Identify stereochemistry of Claisen and Cope rearrangements • Evaluate variation of Cope rearrangements (aza Cope and Oxy Cope rearrangements) • Analyze and appreciate synthetic utility of [3, 3] sigmatropic shifts in synthesis

2. Introduction

Sigmatropic rearrangements are pericyclic reactions defined by the migration of a σ bond adjacent to one or more π systems, with the π systems becoming reorganized in the process. In the reaction the total number of σ or π-bonds does not change as the reactant and the product have the same number of bonds. These reactions are intra-molecular in nature and generally do not require a catalyst for their completion.

Sigmatropic rearrangements are classified based on an order which is expressed by a set of two digits in brackets: [i, j], these numbers are determined by counting the atoms over which each end of the σ bond has moved. Each of the original termini is given the number. The aliphatic Claisen Rearrangement and Cope rearrangement are [3, 3]-sigmatropic rearrangements. The common feature of all [3, 3]-sigmatropic rearrangements is a six-member transition state with a delocalized electronic structure. In Claisen rearrangement an allyl vinyl ether is converted thermally to an unsaturated carbonyl compound, while in Cope rearrangement a 1, 5-diene is rearranged or isomerizes. These rearrangements usually require high temperatures (100-350°C), although examples of catalytic syntheses are also known. For these reactions the feasibility of reactions due to stereochemical constrains is governed by the total number of π electrons present in the substrate. If the total number of π electrons is (4n+2) than suprafacial pathway is allowed and if the total number of π electrons is 4n, than antarafacial pathway is allowed.

3. Claisen rearrangement

Claisen rearrangement was discovered in 1912 and is the first known example of a [3, 3]-sigmatropic rearrangement. The reaction is an important method for carbon-carbon bond-formation and is of significant synthetic value. An example of aliphatic Claisen rearrangement where a substituted allyl vinyl ether undergoes [3, 3] sigmatropic shift to give a ketone product is shown below.

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

R1

R2

O O

R1

R2

1'1

2

2'3'

3

The rearrangements are stereo selective in nature. Stereo selectivity arises when there is a substituent on the saturated carbon atom next to the oxygen atom. The geometry of the resulting double bond strongly favors the trans (E) configuration owning to the preference of the substituent to occupy an equatorial position on the chair transition state as shown below;

OR

3, 3 O

R Trans (E)configuration

The aromatic Claisen rearrangement reaction was originally discovered by heating up a sample of allyl phenyl ether. The product has the allyl group shifted to the ortho position of the phenol. The intermediate is thought to be the keto form of the substituted phenol. This tautomerizes to phenol to restore the aromaticity of the ring.

Retro-Claisen rearrangements are known in aromatic substrates. The mechanism of retro ortho rearrangement was established based on 14C labeling of substrate, this way even without a substitution the mechanism was established unambiguously. The Claisen rearrangement usually prefers a chair-like transition state.

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

When the ortho positions have no hydrogen, a second [3, 3]-sigmatropic migration (a Cope reaction) follows whereby, the migrating group is restored to its original structure. For Claisen rearrangement, electron-donating groups increase the rate of reaction and electron withdrawing groups decrease it. For e.g. the p-amino (electron donating) compound reacts 10-20 times faster than the p-nitro (electron withdrawing) compound. Lewis acids such as AlCl3 and BF3 are known to enhance rate of reactions and lower the temperature required to bring about the transformations. The nature of solvent has also been shown to influence rate of rearrangement, where up to 300-fold change in rates were observed when same reaction was run under different solvents. With trifluoroethanol, the rearrangement goes even at room temperature. Terpenoids are among the group of important molecules that are obtained using Claisen rearrangement. Following are examples of Claisen rearrangements, where some important molecules such as fragrant compounds are obtained.

In another reaction, the isoprenoid skeleton was obtained using Claisen rearrangement.

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

Synthetic example of Claisen rearrangement

Ireland-Claisen Rearrangement This is a variant of the Claisen rearrangement where, allyl ester of a carboxylic acid undergoes the rearrangement instead of allyl vinyl ether. In the reaction the ester is first converted into silyl stabilized enolate, which further rearranges at temperatures below 100 °C. As a result of this rearrangement carboxylic acid is formed as a product. The Ireland-Claisen Rearrangement thus offers ready access to chain-extended carboxylic acids.

4. Cope and aza Cope rearrangements

Cope rearrangement: The Cope rearrangement is a well known reaction involving the [3, 3] sigmatropic rearrangement of 1, 5-dienes. These rearrangements can be performed thermally or photochemically. The Cope rearrangement of dienes has found utility in a number of regioselective and stereoselective syntheses of open ring systems.

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

12

3

1'2'

3'

CH2OH CH2OH12

3

1'2'

3'

12

3

1'

2'3'

When the diene is symmetrical the reaction gives a product identical with the starting material (as shown for 1, 5-hexatriene above). Another example is bullvalene which undergoes multiple degenerate Cope rearrangements and still retains the same structure due to fluxional nature of the molecule.

In bullvalene, the Cope rearrangement changes the position of the cyclopropane ring from 4,5,10 to 1,7,8. But the molecule could also have undergone rearrangements to put this ring at 1,2,8 or 1,2,7 position. Any of these could then undergo several different Cope rearrangements and yet do not change the fundamental structure of bullvalene. This reaction has referred as infinitely degenerate Cope rearrangement.

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

A reverse aromatic Cope rearrangement of 2-allyl-3-alkylideneindolines obtained by Horner-Wadsworth-Emmons olefination of 2-allylindolin-3-ones with diethyl cyanomethylphosphonate provided α-allyl-3-indole acetonitriles.

Following are some more examples of Cope rearrangement reactions. In the first example, an unusual Cope rearrangement leads to formation of a nine member cyclic ring.

The Cope rearrangement has been utilized to obtain sesquiterpene such as elemol, which is an essential component of galbanum oil, and many others

Aza-Cope rearrangement Similar to the Cope rearrangement, the aza-Cope rearrangements are [3, 3] sigmatropic shifts that are essentially heteroatom versions of the Cope rearrangement, where the rearrangement shifts single and double bonds between two allylic components. The thermal aza-Cope rearrangement

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

proceeds suprafacially as predicted by Woodward-Hoffman rules In aza-Cope rearrangement numbering is based on the location of the nitrogen atom in the molecule.

Due to the presence of charged nitrogen atom and thermo neutrality, cationic 2-aza-Cope rearrangements take place at temperatures 100-200 °C lower than the corresponding Cope rearrangement. This is due to the presence of the charged heteroatom in the molecule which drops the activation barrier for the reaction. Compared to cationic 2-aza Cope rearrangement, 1-aza and 3-aza-Cope rearrangements are less common.

The cationic aza Cope rearrangement has been known to proceed via catalysis, which is suggestive of ionic or even diradical mechanism in some cases. In the simplest form, the ionic nature of this reaction allows lowering of activation barrier thus promoting the reaction. Following are the transition state structure for the reaction.

The synthetic utility of cation 2-aza-Cope rearrangement arises when it is coupled with Mannich Cyclization reaction to produce acyl-substituted pyrrolidines. The pyrrolidines are important precursors for natural products like alkaloids. The aza-Cope/Mannich reaction is a synthetically useful reaction for cyclization. This coupling of cationic aza-Cope and and Mannich Cyclization leads to a thermodynamic bias towards a single rearrangement product, since the Mannich cyclization is irreversible and its product, an acyl substituted pyrrolidine ring, more stable than that of the initial rearrangement.

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

Oxy-Cope rearrangement The Oxy-Cope rearrangement involves allyl vinyl carbinols. These rearrangements also proceed via a cyclic chair conformation. In the first stage enol derivatives of aldehydes or ketones are obtained, which are unstable therefore they undergo rearrangement immediately and give the corresponding carbonyl compounds.

O

CH3 HO CHCH2

O

CH3 O CHCH2

O

O

CH3

O

CH3

H

O

H2O

O

CH3

H

O

O

O

H3C H

OH

Thermodynamically favorable anionic Oxy-Cope rearrangements have also been known, which are driven by low activation energy of the reaction. These reactions are stereospecific and takes place via a cyclic chair like conformation. For the reactions it is known that potassium ions enhance rate of reactions by many order of magnitude. One of the major applications of oxy-Cope rearrangement was found in the synthesis of Ambretone with the intensive musk odor.

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

Finally, there are reactions that involve a tendem Claisen-Cope rearrangement as shown below

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CHEMISTRY

PAPER No.9 : Organic Chemistry-III MODULE No. 33: Cope, Claisen and aza-Cope rearrangements

5. Summary

Ø Claisen rearrangement is a [3, 3] sigmatropic shift of allyl vinyl ethers in aliphatic as well as aromatic substrates.

Ø The rearrangements involve migration of a σ bond adjacent to a π bond(s) system leading to reorganization of the π bond system.

Ø Claisen rearrangements are stereoselective owning to the chair form transition state. Ø Ireland-Claisen rearrangements also involve [3, 3] sigmatropic shifts in allyl estersto give

rise to rearranged carboxylic acids. Ø Cope rearrangement is a all carbon [3, 3] sigmatropic shift in dienes. Ø Aza Cope rearrangements are heteroatom variations of Cope rearrangements that takes

place at temperature lower than that required for Cope rearrangement. Ø Cationic 2-aza Cope rearrangements are coupled with Mannich Cyclization reaction to

produce acyl substituted pyrrolidines. Ø Oxy-Cope is another variation of Cope rearrangement involving allyl vinyl carbinols

leading to formation of rearranged carbonyl compounds. Ø Claisen and Cope rearrangements along with their variants are synthetically useful

reactions to give rise to products of commercial value such as fragrant terpenoids.