Mechanism and Synthetic Applications of the Wolff Rearrangement

Dr. Aniello Palma

Email: a.palma@imperial.ac.uk : @palmaniello #WolffRearrangement

Friedrich Schiller University Jena

31/03/2014

Objectives

Reaction mechanisms Synthetic importance of this rearrangement

(homologation reactions, b -aminoacids synthesis, ring-contraction reactions)

The Wolff Rearrangement

O N2(g) R2 N2 s-E O
or h or Ag+

HNu R2 R1 Ketene A B

Nu

O R1

N2 R2

O R1

H R2 R1 O

s-Z

B A

R1

R2

N2(g) extrusion and 1,2 shift Mechanism?

Wolff, L., Justus Liebigs Ann. Chem. 1902, 325, 129.
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If R2 = H, [s[s-Z] >> [s[s-E] (Assuming R1 H)

O R1 N2 R1

If R2 = large group, group, [s[s-E] >> [s[s-Z] (Assuming R1 H)

O R2 N2 s-E

R2 s-Z

Steric interactions between R1 and R2 govern equilibrium

O Nu

R2 H R1

Ketene can be detected by React IR

R2 R1 R1

HNu R2
4 e-

O Nu

R2 H R1

Ketene HNu R2 Nu H R1 O

4 e-

R1

R2 O

a carbene carbonyl can be detected by React IR and in some cases ESR

Homologation Reactions
Arndt-Eistert Synthesis
O OH SOCl 2 O Cl CH2N2 ether O H N2 -N2(g) Ag+ cat. H O H2O O OH

O HN O OO N HN O N H O

N O

OBzl O

Seebach, D. Ang. Chem. Int. Ed. Engl., 1995, 34, 471-472

Ring Contraction Reactions

O R1 O R2 O h N2 -N2(g) O R1 R2 O R3OH O O R1 R2 O OR3 O

H H HO O 1233A O COOH O O

NH O O O

C5H11 Lipstatin C6H13

: h :

Migratory Trends
H > Aryl > Alkyl (heteroatoms do not migrate) H > Alkyl > Aryl >> SR > OR > NR2 Schobert, R., Synthesis, 2013, 45, 773-776
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Ring Contraction Reactions

Hydrophilic
Sugar based polymer HN O S O Sugar based polymer HN O S O h - N2(g) O HO Hydrophilic

Hydrophobic
O Amphiphilic N2

N2(g)
Drug delivery

= Drug

Dong, C. Polym. Chem., 2014, 5, 1605-1613 Ji, J. J. Mater. Chem., 2012, 22, 16865-16871

Pericyclic Reactions
O N2 R3 Z R5 ynamide N R4 h or - N2( g) OH R1 R2 R3 R4 N Z R5

R1 R2

a -diazo ketone

W olf f Rearr angement

6 electr ons electrocyclic closur e and taut omer ization

O R1 R2 R3 R4 N

R5 Z O R1 R2

R4 R5 N R3 Z 4 electr ons R2 R1

R4 R3 N Z R5

[ 2+2] cycloaddit ion

electrocyclic cleavage

Danheiser R. L. J. Org. Chem., 2013, 74, 11450-11469

Objective Test

Self assessment : Evaluate your comprehension of the key concepts to ensure the objectives of the lecture are met. Instructions: Complete the Objective Test. Check the answers at the following twitter account: @palmaniello and in the search bar of this account type: @palmaniello #WolffAnswers You do not have to be a twitter user to access this file. If you experience any difficulties please request the answers via email a.palma@imperial.ac.uk
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Mechanism Recap
Two competing mechanisms; Concerted and Stepwise Chiral groups (*R1) migrate with retention of configuration s-Z conformers typically undergo a Concerted mechanism (R1 and N2 in an ideal antipleriplanar geometry) s-E conformers typically undergo a Stepwise mechanism (R1 and N2 are not antiperiplanar and a carbene intermediate has been proposed) The reactive nature of carbene intermediates could lead to undesired by-products (insertion type reactions)

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Synthetic Applications Recap

1. Homologation reactions
N2(g) O R H N2 R O HNu H R O Nu

Carbonyl compounds with n carbons are rearranged into carbonyl compounds witn n+1 carbons

2. Ring contraction reactions

O N2 N2(g) O HNu H O Nu

Cyclic a diazo carbonyl compounds with n carbons are rearranged into cyclic carbonyl compounds with n-1 carbons

3. Pericyclic reactions
O R1 N2(g) N2 R1 O AB AB R1 O H The ketene generated during the rearrangement undergoes pericyclic reactions

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 Neutral species 6 valence electrons There are two different type of carbenes:

Carbene

Triplet & Extremely Reactive species

A B

Singlet
A B C R R1 R3 O R H C R1 H C R1

C R R1 Carbene

RO H

R 3CH2 H

R 3H 2C R

Reading: Organic Chemistry, Clayden, Greeves, Warren, Wothers, Chapter 40.

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