Petasis Borono-Mannich Condensation

Careful optimization of the reaction conditions has been undertaken, thus showing the need to pre-form the intermediate iminium ion in dry THE for 2 h before adding the supported boronic acid and the appropriate volume of THE/EtOH 8 3 (v/v). The process is driven by the large excess of ethanol and by the consumption of the boronic ester, which adds to the iminium ion intermediate. Solid-supported acyclic amines were equally successful, while the main limitation of the process stems from the fact that only electron-rich arylboronic acids gave good conversions. 

The resin was subjected to CH2CI2/TFA 95 5 (v/v) (3 mL) for 1 h. The cleavage solution was collected by filtration and the resin was rinsed as follow  

The combined filtrates were concentrated and dried in vacuo for 12 h to afford the crude product. 

TsOH (0.32 g, 1.8 mmol) were mixed in CHCls/MeOH/TMOF 1 1 1 (v/v/v) for 2 h. The mixture was then added to the Rink-isonitrile resin (2.0 g, 1.8 mmol). The suspension was agitated overnight at ambient temperature. The resin was washed with N,N-dimethylformamide (DMF), MeOH, 10% DIPEA/CH2CI2, CH2CI2, MeOH, and then dried to afford the intermediate resin. 

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Petasis (borono-Mannich) condensation (Scheme 91) [353] To piperazinetrityl resin (32 mg, 0.030 mmol, loading 0.95 mmol g ) weighed out in a 10-mL Teflon fritted vessel was added a solution of glyoxylic acid monohydrate (0.032 mmol) in dry THE (2 mE). The suspension was allowed to mix under N2 at r. t. for 2 h. An excess of DEAM-PS boronic ester (120 mmol) was then added, followed by THP/EtOH 8 3 (v/v) (1.5 mE). The suspension was mixed under N2 at 55 °C for 48 h and then cooled at r.t. The resin mixture was filtered and washed as follows ... 

In 2003, Portlock and coworkers [53a] demonstrated that the Petasis borono Mannich (three-component) condensation can be performed in tandem with the Ugi (four-component) condensation to provide access to six-dimensional libraries of compounds with application in the drug discovery area. 

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-... 

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. ... 

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