Amines Petasis borono-mannich reaction

A series of functionalized 2,5-dihydrofurans was efficiently synthesized via an amine-promoted Petasis borono-Mannich reaction and a... 

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

Subsequent to this, there have been numerous reports of the use of this reaction using alkenyl, alkynyl and arylboronic adds or esters in reactions with a range of amines and aldehydes. This reaction has been variously named the boronic Acid Mannich , boronic Mannich , boro-Mannich , Petasis boronic acid-Mannich , Petasis borono-Mannich , and Petasis" reaction. The more indusive term of Petasis borono-Mannich reaction will be used throughout this chapter. 

Scheme 7.2 Petasis borono-Mannich reaction of 2-furylboronic acid, aldehydes and secondary amines.

An inherent advantage of the Petasis borono-Mannich reaction is the ability to conduct reactions in a three-component fashion, since the imine or iminium ion intermediates can be formed in situ from the condensation of either primary or secondary amines with the corresponding aldehydes or ketones. The operational advantages of such a three-component coupling approach, combined with the practical benefits outlined above, render the Petasis borono-Mannich reaction particularly desirable for parallel synthesis applications and in the generation of combinatorial libraries. In-... 

Microwave acceleration of reactions is a valuable tool for organic synthesis [39], and various specialized instruments are now commercially available. Tye and co-workers have reported the microwave-assisted Petasis borono-Mannich reaction of arylboron-ic acids and primary or secondary amines with either glyoxylic acid or salicylaldehyde [40]. Optimized reaction conditions employed didiloromethane as solvent, and microwave assisted heating at 120 °C for 10 min. Products were obtained in generally modest yields (10-83%), in part due to incomplete reaction conversion imder the reported conditions. 

Grigg and co-workers have used a sequential, one-pot Petasis borono-Mannich reaction with either Pd(0)-catalyzed carbonylative amination cyclization or Pd(0)-cat-alyzed allenylation/amination cyclization (Scheme 7.7) [46]. The overall approach results in the formation of a-amino acid derivatives of isoindolone 25 and 4-methylene-3,4 -dihydroisoquinoline 26. While this is the only reported example of a combination of a Petasis borono-Mannich reaction with a Pd(0)using other Pd(0) or transition metal catalyzed reactions is a very attractive strategy for the synthesis of complex molecules or combinatorial libraries. 

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. 

Finn and Petasis have independently shown that salicylaldehyde is a suitable aldehyde for the Petasis borono-Mannich reaction, with alkenyl, aryl and heteroaryl-boronic acids (Equation 6) [30, 31]. The reaction works best for aliphatic secondary amines, as in the formation of 41 primary amines give modest yields of adducts 41. Benzaldehydes lacking ortho hydroxyl functionality do not react, with even ortho methoxy functionality being unsuitable, which is consistent with a tethering mechanism via putative intermediate 9 (Figure 7.3). Petasis and Boral reported that reactions occurred at room temperature over 24-36 h, using EtOH, MeOH or acetonitrile. 

Microwave-assisted Petasis borono-Mannich reactions of arylboronic acids, secondary amines and salicylaldehyde have been carried out in CH2CI2 at 120 °C for 10 min [40], The main problem encountered here was incomplete conversions, resulting in modest adduct yields (23-76%). The reaction of a primary amine (p-ani-sidine) under the same conditions failed to produce the desired adducts, giving instead only the imines (cf. reactions with glyoxylic acid). 

Klopfenstein and co-workers outlined a solid-phase route to the synthesis of peptide mimetics using the Petasis borono-Mannich reaction [57]. In this study, a Wang resin supported Fmoc-protected amino acid 57 (attached via an ester linkage) was first reductively aminated to give a secondary amine 58, which was then reacted with... 

Scheme 7.13 Application of polymer-supported amines in the Petasis borono-Mannich reaction.

For Petasis borono-Mannich reactions of formaldehyde, methylation of the amine reportedly occurs as a side-reaction, presumably by iminium ion reduction [19]. The hydride source under these conditions may be formic acid, as in the Eschweiler-Clarke methylation reaction. This problem was overcome by the use of potassium trifluoroborate salts and Lewis acids in toluene at 90 °C (the reaction in highly polar solvents such as acetonitrile, DMF and DM SO gives the reduction product). 

Functionalized 2,5-dihydrofurans (21) have been prepared by a Petasis borono-Mannich reaction, using a 4-substituted l,2-oxaborol-2(5//)-ol and salicylaldehyde. ° The amine-catalysed process combines a boronic-acid-based Mannich reaction with an intramolecular Sj 2 cyclization. 

Organoboron compounds have gained special attention and importance in the last years due to their use in different processes, but one of the most important and efficient protocols is the multicomponent Petasis-borono-Mannich (PBM) reaction [17-19]. In this approach, an amine, an aldehyde, and a boronic acid react to give access to a new amine... 

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]. 

In contrast to its intermolecular counterpart, an intramolecular Borono-Mannich reaction (Petasis condensation) has been found to proceed with exclusive anti stereoselectivity. The aza-Cope/Mannich reaction has been reviewed. Unprecedented nucleophilic tribromomethylation of Al-t-butanesulfinylimines by bro-moform enables the synthesis of enantiomerically pure a-tribromomethyl amines and 2,2-dibromoaziridines. ... 

The preparation of such dihydropyrans derivatives 21-23 modified at the C-6 position by a hydrophobic substituent (zsopentyl side chain) analogous to the oseltamivir side chain is summarized in Scheme 7. It uses the borono-Mannich Petasis reaction between an amine, ot-hydro)yaldehyde 25 and boronic acid 26. This reaction proceeds with remarkably high stereocontrol, producing 1,2-aminoalcohols with an a tf-configuration. The resulting acyclic aminoalcohol 24 is the key precursor to the functionalized cyclic dihydropyrans 21-23 with the proper functionality and stereochemistry at C4. 

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