Mechanism and Synthetic Applications of the Wolff Rearrangement
Dr. Aniello Palma
Email: [Link]@[Link] : @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 [Link]@[Link]
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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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