Selective reactions using metal phenoxides. Part 1. Reactions with formaldehyde

Abstract

The reactions between formaldehyde and a series of aryloxymagnesium bromides (1 ) and their complexes with hexamethylphosphoramide (HMPA) in benzene have been investigated. In the absence of ligand 2.2'-dihydroxydiphenylmethanes (2) are obtained, while in the presence of stoicheiometric amounts of HM PA Z-hydroxybenzaldehydes (4) are produced in high yield. Both products are the result of an exceptional ortho-regioselective attack on the aromatic nucleus of the phenol. The formation of (4) has been shown to occur via an oxidationreduction process, promoted by HM PA, between the 2-hydroxybenzyl alcohol intermediate ( 5) and formaldehyde.The difference in acidity between the free and HMPA-complexed magnesium counterion is invoked to explain the two reaction pathways.IN spite of the enormous amount of work done on the reaction between phenols and formaldehyde due to its industrial importance, no great success has been achieved so far in the control of its regioselectivity and of the RESULTSThe production in high yield (Table 1) of 2,2'-dihydroxydiarylmethane derivatives (2) by means of two successive ortho-regioselective reactions on the aromatic nucleus of the TABLE 1 Reaction of aryloxymagnesium bromide, RMgBr ( l ) , with formaldehyde (0.5 equiv.) in refluxing benzene (20 h)R (la) Phenoxy (1 b) 2-Methylphenoxy (Ic) 3-Methylphenoxy (Id) 4-Methylphenoxy (le) 2-isopropylphenoxy (If) 2-t-Butylphenoxy (lg) 2,3-Dimethylphenoxy (lh) 3,5-Dimethylphenoxy (li) 2-t-Butyl-5-methylphenoxy ( l j ) 4-Methoxyphenoxy (lk) 4

ortho-Formylation of oxygenated phenols

“…164,165 In 1978 a highly selective method for the ortho-formylation of phenols was published by Casiraghi and co-workers, employing ethylmagnesium bromide, hexamethylphosphoramide (HMPA) and paraformaldehyde in refluxing benzene. 166 The authors obtained 2-hydroxybenzaldehydes as the only regioisomer in 50-90% yields from phenols substituted with alkyl, alkoxy or chloride groups.…”

“…166,167,170 The phenoxymagnesium salt (A) coordinates formaldehyde for an electrophilic aromatic substitution. After aromatization (B), the salicylalcohol reacts in an…”

Simplified synthesis of 1,1′[14C]‐methylene‐di (2‐naphthol). A radiochemical and kinetic approach

“…13 The 1,1 0 -methylene-di-(2-naphthol), whose anthelmintic activity and antinflammatory properties have been studied more than 20 years ago, [14][15][16] has been also recently employed as an intermediate compound for the preparation of heat-resistant polyesters. 17 Its synthesis is reported in literature [17][18][19] but, despite the high production yields, the experimental procedures are characterized by drastic conditions (long reaction time and high temperature) which do not match our synthetic requirements. Oliver et al 20 have also prepared 1,1 0 -methylene-di-(2-naphthol) labeled with 14 C at C-8 of both aromatic rings and, in a different synthesis, at the methylene carbon, starting from 2-[8-…”

Synthesis and anti-juvenile hormone activity of ethyl 4-[(6-substituted 2,2-dimethyl-2H-chromen-7-yl)methoxy]benzoates

“…15) Concerning its mode of action, the double bond of the chromene ring is readily oxidized by P450 in the corpora allata to the epoxide intermediate, a powerful alkylating property, which reacts with cellular macromolecular constituents to destroy the cells of the corpora allata. Therefore, in precocene II, the double bond is indispensable for anti-JH activity.…”