Minisci reaction

The Minisci reaction (Italian: [miˈniʃi]) is a named reaction in organic chemistry. It is a nucleophilic radical substitution to an electron deficient aromatic compound, most commonly the introduction of an alkyl group to a nitrogen containing heterocycle. The reaction was published about in 1971 by F. Minisci.[1] In the case of N-Heterocycles, the conditions must be acidic to ensure protonation of said heterocycle.[2] A typical reaction is that between pyridine and pivalic acid to 2-tert-butylpyridine with silver nitrate, sulfuric acid and ammonium persulfate. The reaction resembles Friedel-Crafts alkylation but with opposite reactivity and selectivity.[3]

Minisci reaction
Named after Francesco Minisci
Reaction type Coupling reaction

The Minisci reaction proceeds regioselectively and enables the introduction of a wide range of alkyl groups.[4] A side-reaction is acylation.[5] The ratio between alkylation and acylation depends on the substrate and the reaction conditions. Due to the simple raw materials and the simple reaction conditions the reaction has many applications in heterocyclic chemistry.[6][7]

Utility of the Minisci Reaction

The reaction allows for alkylation of electron deficient heterocyclic species which is not possible with Friedel-Crafts chemistry.[8] A method for alkylating electron deficient 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 and the scope expanded to encompass a large array of alkylating agents, heterocycles and oxidants.[10]

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]

References
  1. Minisci, F.; Bernardi, R.; Bertini, F.; Galli, R.; Perchinummo, M. (1971). "Nucleophilic character of alkyl radicals—VI : A new convenient selective alkylation of heteroaromatic bases". Tetrahedron. 27: 3575–3579. doi:10.1016/s0040-4020(01)97768-3.
  2. Minisci reaction Jie Jack Li in Name Reactions 2009, 361-362, doi:10.1007/978-3-642-01053-8_163
  3. Strategic applications of named reactions in organic synthesis: background and detailed mechanisms László Kürti, Barbara Czakó 2005
  4. F. Fontana, F. Minisci, M. C. N. Barbosa, E. Vismara: Homolytic acylation of protonated pyridines and pyrazines with α-keto acids: the problem of monoacylation, in: J. Org. Chem. 1991, 56, 2866–2869; doi:10.1021/jo00008a050.
  5. M.-L. Bennasar, T. Roca, R. Griera, J. Bosch: Generation and Intermolecular Reactions of 2-Indolylacyl Radicals, in: Org. Lett. 2001, 3, 1697–1700; doi:10.1021/ol0100576.
  6. P. B. Palde, B. R. McNaughton, N. T. Ross, P. C. Gareiss, C. R. Mace, R. C. Spitale, B. L. Miller: Single-Step Synthesis of Functional Organic Receptors via a Tridirectional Minisci Reaction, in: Synthesis 2007, 15, 2287–2290; doi:10.1055/s-2007-983792.
  7. J. A. Joules, K. Mills: Heterocyclic Chemistry, 5. Auflage, S. 125–141, Blackwell Publishing, Chichester, 2010, ISBN 978-1-4051-9365-8.
  8. Antonietti, Fabrizio; Mele, Andrea; Minisci, Francesco; Punta, Carlo; Recupero, Francesco; Fontana, Francesca (February 2004). "Enthalpic and polar effects in the reactions of perfluoroalkyl radicals". Journal of Fluorine Chemistry. 125 (2): 205–211. doi:10.1016/j.jfluchem.2003.07.012. ISSN 0022-1139.
  9. Tauber, Johannes; Imbri, Dennis; Opatz, Till; Tauber, Johannes; Imbri, Dennis; Opatz, Till (2014-10-10). "Radical Addition to Iminium Ions and Cationic Heterocycles". Molecules. 19 (10): 16190–16222. doi:10.3390/molecules191016190. PMC 6270771. PMID 25310148.
  10. Duncton, Matthew A. J. (2011). "Minisci reactions: Versatile CH-functionalizations for medicinal chemists". MedChemComm. 2 (12): 1135. doi:10.1039/C1MD00134E. ISSN 2040-2503.
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