Petasis alkenylboronic acids

R.A. Batey and co-workers developed a modification of the Petasis-boronic acid-Mannich reaction that occurs via N-acyliminium ions derived from A/-protected-2,3-dihydroxypyrrolidine and 2,3-dihydroxypiperidine derivatives. This method was utilized in the total synthesis of (+)-deoxycastanospermine. The formation of the A/-acyliminium ion was achieved by treating A/-Cbz-2,3-pyrrolidine with BF3-OEt2. ° Subsequent vinyl transfer from the alkenylboronic ester provided the product with excellent yield and diastereoselectivity. 

The first example of an addition reaction of an C(sp -B based organoboronic add to an iminium ion was reported by Petasis and Akritopoulou in 1993 [24]. They demonstrated the addition of ( )-alkenylboronic acids to preformed iminium ions derived from secondary amines and formaldehyde, to generate allylic amines 1 (Scheme 7.1). Typically, a two-stage process was employed for the formation of 1. Initially, a secondary amine (including, dialkyl, acyclic and cydic examples) was heated with paraformaldehyde in dioxane or toluene solvent at 90 °C for 10 min. An ( )-alkenyl-boronic acid was then added, and the solution either stirred at 90 °C for 10 min, or at room temperature for 3 h. The allylic amine product 1 was then isolated through a standard aqueous work-up (sequential treatment with aqueous HCl and NaOH). The synthetic utility of this chemistry was demonstrated in this first report by a synthesis of the oral antifungal agent naftifine (2). 

Scheme 7.1 Discovery of the Petasis borono-Mannich reaction using paraformaldehyde, amines and alkenylboronic acids.

Finn also showed the formation of 2H-chromenes under the same reaction conditions, using alkenylboronic acids and morpholine in dioxane at 90 °C. A more convenient route to the 2H-chromenes was then developed using a catalytic amount of dibenzylamine in the presence of alkenylboronic adds and salicylaldehyde (42, Scheme 7.11) [30]. Chromenes 43 were reported to arise from the initial Petasis borono-Mannich adducts 44 via an add promoted intramolecular S 2 attack of the ortho-hydroxyl group onto the protonated allylic amine of intermediate 45. A more likely mechanism involves elimination from 45 to intermediate 46, followed by 6n-electrocychzation to the product The reaction is tolerant of various functional groups and substitution patterns on the salicylaldehyde, and could also be promoted using a polymer-supported base, such as Merrifield resin-supported dibenzylamine (40-50 mol%) [30]. 

Boronic esters will also react under appropriate circumstances. Petasis used bis(isopropyl) (2B)-bromoethenylboronic ester in a reaction with glyoicyUc acid and aminodiphenylmethane [34]. Scobie and co-workers have reported the coupbng of pinacolyl aryl and alkenylboronic esters with secondary amines (38). The reaction gave good yields with alkenylboronic esters (70-82%), but worked poorly with aryl-boronic esters (0-12%). In contrast to the above results, the reaction did not proceed with primary amines under the same conditions. 

The use of chiral boronic esters in the Petasis borono-Mannich reaction has been reported to result in low levels of enantioselectivity of the adducts at room temperature (6-15% ee) [48]. Auxiliaries used in this study by Scobie and co-workers included pinanediol and tartaric acid derived alkenylboronates. Morpholine was the only secondary amine used, with the primary amine ethyl glycinate failing to react. 

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