Casiraghi formylation

In organic synthesis, the Casiraghi formylation is the formation of a salicylaldehyde from a phenol and paraformaldehyde. The reaction requires a strong Brønsted base and a weak Lewis acid, and gives a methanol coproduct:^[1]

(H₂CO)_2n + nB + nLA + nHArOH → nHC(=O)ArOH + n[HB][LA:OMe]

Formally, it combines the Cannizzaro disproportionation with a directed Friedel-Crafts acylation.

In Casiraghi's original 1978 formulation, Grignard reagents served as both the hindered base and Lewis acid.^[2]^[3]

Applications include the synthesis of tocopherol derivatives.^[4]

References

^ Hofsløkken, Nini U.; Skattebøl, Lars; Johansson, Fredrik; Bertilsson, Sophie K.; Andersson, Pher G.; Møller, Jørgen; Senning, Alexander; Yao, Xin-Kan; Wang, Hong-Gen; Tuchagues, J. -P.; Ögren, Mattias (1999). "Convenient Method for the ortho-Formylation of Phenols". Acta Chemica Scandinavica. 53 (53): 258–262. doi:10.3891/acta.chem.scand.53-0258. ISSN 0904-213X. Archived (PDF) from the original on 13 May 2019. Retrieved 4 Nov 2023.
^ Casiraghi, Giovanni; Casnati, Giuseppe; Puglia, Giuseppe; Sartori, Giovanni; Terenghi, Giuliana (1980). "Selective reactions between phenols and formaldehyde. A novel route to salicylaldehydes". Journal of the Chemical Society, Perkin Transactions 1: 1862. doi:10.1039/p19800001862. ISSN 0300-922X.
^ Aldred, Robert; Johnston, Robert; Levin, Daniel; Neilan, James (28 Feb 1994) [13 Jan 1994]. "Magnesium-mediated ortho-specific formylation and formaldoximation of phenols" (PDF). Journal of the Chemical Society, Perkin Transactions. 1: 1823–1831. doi:10.1039/p19940001823. Archived (PDF) from the original on 5 Nov 2023. Retrieved 4 Nov 2023 – via The Vespiary.
^ Alsabil, Khaled; Viault, Guillaume; Suor-Cherer, Sorphon; Helesbeux, Jean-Jacques; Merza, Joumaa; Dumontet, Vincent; Peña-Rodriguez, Luis Manuel; Richomme, Pascal; Séraphin, Denis (2017-12-07). "Efficient ortho-formylation in vitamin E series, application to the semi-synthesis of natural 5- and 7-formyl-δ-tocotrienols revealing an unprecedented 5-bromo-7-formyl exchange". Tetrahedron. 73 (49): 6863–6870. doi:10.1016/j.tet.2017.10.039. ISSN 0040-4020.

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[Modern-1] Hofsløkken, Nini U.; Skattebøl, Lars; Johansson, Fredrik; Bertilsson, Sophie K.; Andersson, Pher G.; Møller, Jørgen; Senning, Alexander; Yao, Xin-Kan; Wang, Hong-Gen; Tuchagues, J. -P.; Ögren, Mattias (1999). "Convenient Method for the ortho-Formylation of Phenols". Acta Chemica Scandinavica. 53 (53): 258–262. doi:10.3891/acta.chem.scand.53-0258. ISSN 0904-213X. Archived (PDF) from the original on 13 May 2019. Retrieved 4 Nov 2023.

[OrigFollowUp-2] Casiraghi, Giovanni; Casnati, Giuseppe; Puglia, Giuseppe; Sartori, Giovanni; Terenghi, Giuliana (1980). "Selective reactions between phenols and formaldehyde. A novel route to salicylaldehydes". Journal of the Chemical Society, Perkin Transactions 1: 1862. doi:10.1039/p19800001862. ISSN 0300-922X.

[Oximes-3] Aldred, Robert; Johnston, Robert; Levin, Daniel; Neilan, James (28 Feb 1994) [13 Jan 1994]. "Magnesium-mediated ortho-specific formylation and formaldoximation of phenols" (PDF). Journal of the Chemical Society, Perkin Transactions. 1: 1823–1831. doi:10.1039/p19940001823. Archived (PDF) from the original on 5 Nov 2023. Retrieved 4 Nov 2023 – via The Vespiary.

[Apps-4] Alsabil, Khaled; Viault, Guillaume; Suor-Cherer, Sorphon; Helesbeux, Jean-Jacques; Merza, Joumaa; Dumontet, Vincent; Peña-Rodriguez, Luis Manuel; Richomme, Pascal; Séraphin, Denis (2017-12-07). "Efficient ortho-formylation in vitamin E series, application to the semi-synthesis of natural 5- and 7-formyl-δ-tocotrienols revealing an unprecedented 5-bromo-7-formyl exchange". Tetrahedron. 73 (49): 6863–6870. doi:10.1016/j.tet.2017.10.039. ISSN 0040-4020.

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