O-H insertion and tandem N-H insertion/cyclization reactions using an iron porphyrin as catalyst with diazo compounds as carbene sources

Abstract

Iron(III) tetraphenylporphyrin chloride, Fe(TPP)Cl , efficiently catalyzed the insertion of carbenes derived from methyl 2-phenyldiazoacetates into O-H bonds of aliphatic and aromatic alcohols, with yields generally above 80%. Although the analogous N-H insertions are rapid at room temperature, the O-H insertion reactions are slower and required heating in refluxing methylene chloride for about 8 hours using 1.0 mol.% catalyst. Fe(TPP)Cl was also found to be effective for tandem N-H insertion/cyclization reactions when 1,2-diamines and 1,2-alcoholamines were treated with diazo reagents to give piperazinones and morpholinones and related analogs such as quinoxalinones and benzoxazin-2-ones. This approach provides a new one-pot route for synthesizing these classes of heterocyclic compounds.

Cytochrome P450-catalyzed insertion of carbenoids into N–H bonds

“…This product distribution is consistent with what has been observed with other metalloporphyrins such as iron tetraphenylporphyrin (FeTPP). 10 The ability of P450 variants to make the single insertion product exclusively agrees with our hypothesis that the protein binding pocket can control reaction selectivity and constitutes a major advantage of protein-mediated catalysis over catalysis by isolated metalloporphyrins.…”

“…N-H insertion with metal porphyrins has been reported in organic solvents, but these reactions often form a mixture of the single and double N-H insertion products when primary amines are used. 10 An enzyme, on the other hand, should be able to sterically select for one product compatible with the binding pocket.…”

Myoglobin-catalyzed intermolecular carbene N–H insertion with arylamine substrates

“…As a comparison, 10- to 25-fold higher catalyst loadings have been reported in association with similar transformations and yields using transition metal complexes. 2b,3h Relatively high turnover numbers (200 TON) were obtained also in the presence of stoichiometric amounts of dithionite relative to the Mb catalyst ( Table 1 ), indicating that an excess of reductant is beneficial but not essential for the transformation. Importantly, Mb(H64V,V68A) was found to remain active in the presence of the amine substrate and EDA at a concentration as high as 0.16 M, which corresponds to ~15 g aniline/L ( Table 1 ).…”

“…2 In the context of this reaction, a variety of transition metal catalysts have been investigated over the past years, including Cu−, Rh−, Ru−, Ag−, and Fe-complexes. 3 Since this transformation has no counterpart among those catalyzed by naturally occurring enzymes, the development of biocatalysts capable of supporting these transformations has direct relevance toward expanding the toolbox of environmentally friendly and sustainable processes for the synthesis of organic molecules.…”

Computation Sheds Insight into Iron Porphyrin Carbenes’ Electronic Structure, Formation, and N–H Insertion Reactivity

“…Metallocarbenes in general have the potential to play significant roles in the synthesis of a dazzling myriad of compounds, including pharmaceutically promising drugs, such as Thienamycin, Indatraline, and Maoecrystal V, accomplishing reactions such as N-H insertion, C-H insertion, and O-H insertion. 23 In addition to accomplishing many reactions, iron porphyrin carbenes can accomplish reactions under many different conditions: for instance, water-soluble iron porphyrins mediate cyclopropanation 13 and N-H insertion. 1 Among iron carbenes, the structure and reactivity of iron porphyrin carbenes have captured chemists' interest.…”