Heteroatom Formylation

Aldrich ChemFiles 2007, 7.1, 9.

Formate esters and formamides are valuable synthetic intermediates, and a variety of synthetic protocols have been devised for formylation of heteroatoms including the use of in situ-generated formic anhydride,1 mixed formic anhydrides,2or activated formate esters.3 Anhydride methodologies can often be unreliable, and if the molecule contains both hydroxyl group and amine functionalities, the reaction is often unselective, giving both O- and N-formyl adducts. Protocols using activated formate esters (or cyanomethylformate4) are often O-selective, thus precluding their use if protection at nitrogen is desired for an amino alcohol or hydroxylamine substrate.

Recently, 2,2,2-trifluoroethyl formate (TFEF, Figure 1) was shown to be a competent reagent for formylation at carbon, nitrogen, and oxygen atoms. As shown in Scheme 1, amines, alcohols, and N-hydroxylamines readily undergo reaction with TFEF in high yield.5 For optically active substrates, no loss of enantiopurity is observed. The reaction is also chemoselective as well, with N-formylation being the predominant reaction pathway for amino alcohols and hydroxylamines, provided that either formic acid or sodium formate is added to the reaction mixture. The reaction conditions are generally mild (typically between 0 and 65 °C), and common solvents are employed (MTBE, THF).

Figure 1

Scheme 1

Lastly, TFEF is also a useful reagent for the preparation of α-formyl ketones via C-formylation of kinetically-generated ketone enolates (Scheme 2). Hydroxymethylene ketones are critically important synthetic intermediates, and typically the classic Claisen formylation reaction (base-induced condensation of a ketone and a formate ester) was the only general method for their preparation. Unfortunately, the scope of the classical method is severely limited because of the equilibrating conditions required for reaction success. TFEF reacts rapidly with pre-formed ketone enolates to give the α-formylated product in good to excellent yields, often in a complementary fashion to the classical variant (Scheme 3).

Scheme 2

Scheme 3

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  1. (a) Chen, F. M. F.; Benoiton, N. L. Synthesis 1979, 709. (b) Waki, M.; Meienhofer, J. J. Org. Chem. 1977, 42, 2019. (c) Strazzolini, P. et al. Tetrahedron 1990, 46, 1081.
  2. (a) Kisfaludy, L.; Otvos, L., Jr. Synthesis 1987, 510. (b) Yamamoto, K. Bull. Chem. Soc. Jpn. 1972, 45, 1253. (c) Martinez, J.; Laur, J. Synthesis 1982, 979. (d) Yale, H. L. J. Org. Chem. 1971, 36, 3238. (e) Kitagawa, T. et al. Chem. Pharm. Bull. 1994, 42, 1931.
  3. (a) Deutch, J.; Niclas, H.-J. Synth. Commun. 1993, 23, 1561. (b) Duczek, W. et al. Synthesis 1996, 37.
  4. Hill, D. R. et al. Org. Lett. 2002, 4, 111. (5) Zayia, G. H. Org. Lett. 1999, 1, 989.

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