Minisci reaction

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Minisci reaction
Named after Francesco Minisci
Reaction type Coupling reaction

The Minisci reaction (Italian:

Friedel-Crafts alkylation but with opposite reactivity and selectivity.[3]

The Minisci reaction often produces a mixture of

regioisomers that can complicate product purification, but modern reaction conditions are incredibly mild, allowing a wide range of alkyl groups to be introduced.[4] Depending on the radical source used, one side-reaction is acylation,[5] with the ratio between alkylation and acylation depending on the substrate and the reaction conditions. Due to the inexpensive raw materials and simple reaction conditions, the Minisci reaction has found many applications in heterocyclic chemistry.[6][7]

Reaction between pyridine and pivalic acid to 2-tert-butylpyridine

Utility of the Minisci Reaction

The reaction allows for alkylation of electron deficient heterocyclic species which is not possible with Friedel-Crafts chemistry.

arenes, nucleophilic aromatic substitution, is also unavailable to electron deficient heterocycles as the ionic nucleophilic species used will deprotonate the heterocycle over acting as a nucleophile. Again, in contrast to nucleophilic aromatic substitution, the Minisci reaction does not require functionalisation of the arene, allowing for direct C-H functionalisation.[8]

Further to this, the generated alkyl radical species will not rearrange during the reaction in the way that alkyl fragments appended by Friedel-Crafts alkylation often will; meaning groups such as n-pentyl and cyclopropyl groups can be added unchanged.[1] The alkyl radical is also a 'soft' nucleophile and so is very unlikely to interact with any 'hard' electrophiles (carbonyl species for example) already present on the heterocycle,[9] which increases the functional group tolerance of the reaction.

The reaction has been the subject of much research in recent years, with a focus placed on improved reactivity towards a greater variety of heterocycles, increasing the number of alkylating reagents that can be used, and employing milder oxidants and acids.[10][11]

Mechanism

A

free radical is formed from the carboxylic acid in an oxidative decarboxylation with silver salts and an oxidizing agent. The oxidizing agent (ammonium persulfate) oxidizes the Ag(+) to Ag(2+) under the acidic reaction conditions. This induces a hydrogen atom abstraction by the silver, followed by radical decarboxylation. The carbon-centered radical then reacts with the pyridinium aromatic compound. The ultimate product is formed by rearomatization. The acylated product is formed from the acyl radical.[4][5]

Mechanism of the Minisci-Reaction

References

  1. ^
    doi:10.1016/s0040-4020(01)97768-3
    .
  2. ISBN 978-3-642-01052-1
    .
  3. ^ Strategic applications of named reactions in organic synthesis: background and detailed mechanisms László Kürti, Barbara Czakó 2005
  4. ^
    doi:10.1021/jo00008a050
    .
  5. ^
    PMID 11405689
    .
  6. doi:10.1055/s-2007-983792
    .
  7. ISBN 978-1-4051-9365-8
    .
  8. ^
    ISSN 0022-1139
    .
  9. PMID 25310148
    .
  10. ISSN 2040-2503
    .
  11. S2CID 83463455
    .
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