Boronic Mannich reaction

Related to the Mannich three-component reaction is the Petasis or boronic-Mannich reaction, which involves the reaction between an aldehyde, an amine, and a boronic acid. 

This is an example of a boronic-Mannich reaction. The mechanism is not fully established however it has been shown that an intermediate of the type ... 

A further development of the Mannich reaction is the boronic Mannich reaction, which has been described extensively by Petasis and co-workers under conventional heating methods. Gupta et al. (Personal Chemistry, Uppsala, Sweden, internal report) have performed this reaction under microwave condition in acetonitrile (Scheme 5.11). A reaction time of 4 min at 120° C afforded the products in yields ranging from 25 to 100%. Alternative amines and boronic acids could be used, but the glyoxylic acid was essential for product formation. The major drawback with this reaction under microwave conditions at present is that the outcome is highly substrate dependent. 

Nucleophilic Alkylation of Iminium Ions and other Electrophiles 9.05.3.2.1 Boron-Mannich reactions... 

Tertiary amines can serve as amine substrates for the boron-Mannich reaction, providing aromatic alkylation products of N,N-dialkyl-3-alkoxyanilines (Equation (125))573 and 1,3,5-alkoxy- or hydroxybenzenes (Equation (126)).574 The use of chiral diol esters of ( )-2-phenylethenylboronic acid for enantioselective alkylation resulted in 6-15% ee.575... 

Other reports for the boron-Mannich reaction include the synthesis of aminophenol derivatives,561 a-arylglycines,576 a growth hormone secretagogue NN703,577 a polyhydroxyindolizine alkaloid uniflorine A,578 and cyclic ct-amino acids.579 The reaction has been applied to solution-phase reactions580 and the solid-phase reaction581-585 for the synthesis of libraries of peptides, a-amino acids, and bicyclic diketopiperazines. The reactions were accelerated by the irradiation of microwave.586... 

Activated A-acyliminium ion precursors were alkylated with 1-alkenyl or aryl boronates in the presence of a Lewis acid catalyst, presumably by an analogous process to that of the boron-Mannich reaction (Equations (134) and (135)).596,597... 

Schlienger, N., Bryce, M. R., Hansen, T. K. The Boronic Mannich Reaction in a Solid-Phase Approach. Tetrahedron 2000, 56,10023-10030. 

A typical Petasis-type boronic Mannich reaction involving a styryl boronic acid, dibenzylamine, and a-hydroxypropanal has been probed mechanistieally by DFT and appears to involve intramolecular transfer of the styryl group. ... 

Y. Liu, L. Wang, Y. Sui, J. Yu, Chin. J. Chem. 2010, 28, 2039-2044. Solvent-free synthesis of alkylaminophenols via Petasis boronic Mannich reaction in one pot without catalysts. 

Ionic liquids [61], were found to accelerate the Petasis boron Mannich reaction of 2-hydroxy aryl aldehydes, secondary amines, and arylboronic acids, under mild conditions, by the group of Yadav [62]. As far as we are aware, these authors were the first (and only ) to report the use of ionic liquids in this reaction. The remarkable features of this procedure were the improvement of yields in the synthesis of the desired products, as well as enhanced reaction rates and the possibility of recycling the ionic liquid for up to five times without apparent loss in enantioselectivity. 

Primary nitroparaffins react with two moles of formaldehyde and two moles of amines to yield 2-nitro-l,3-propanediamines. With excess formaldehyde, Mannich bases from primary nitroparaffins and primary amines can react further to give nitro-substituted cycHc derivatives, such as tetrahydro-l,3-oxa2iaes or hexahydropyrimidines (38,39). Pyrolysis of salts of Mannich bases, particularly of the boron trifluoride complex (40), yields nitro olefins by loss of the amine moiety. Closely related to the Mannich reaction is the formation of sodium 2-nitrobutane-1-sulfonate [76794-27-9] by warming 1-nitropropane with formaldehyde and sodium sulfite (41). 

S.3.2 Via Mannich-Type Reaction. Hattori et al.42 used a Mannich-type reaction for constructing the taxol side chain. In the presence of a BINOL-containing boron compound, the asymmetric Mannich reaction proceeded smoothly, providing the product with good yield (Scheme 7-86). 

Allylic amine from the three-component reaction of a vinyl boronic acid, a carbonyl and an amine. Also known as boronic acid-Mannich or Petasis boronic acid-Mannich reaction. Cf. Mannich reaction. 

Nucleophiles other than hydride can be added to support-bound imines to yield amines. These include C,H-acidic compounds, alkynes, electron-rich heterocycles, organometallic compounds, boronic acids, and ketene acetals (Table 10.9). When basic reaction conditions are used, stoichiometric amounts of the imine must be prepared on the support (Entries 1-3, Table 10.9). Alternatively, if the carbon nucleophile is stable under acidic conditions, imines or iminium salts might be generated in situ, as, for instance, in the Mannich reaction. Few examples have been reported of Mannich reactions on insoluble supports, and most of these have been based on alkynes as C-nucleophiles. 

Asymmetric Mannich reactions provide useful routes for the synthesis of optically active p-amino ketones or esters, which are versatile chiral building blocks for the preparation of many nitrogen-containing biologically important compounds [1-6]. While several diastereoselective Mannich reactions with chiral auxiliaries have been reported, very little is known about enantioselective versions. In 1991, Corey et al. reported the first example of the enantioselective synthesis of p-amino acid esters using chiral boron enolates [7]. Yamamoto et al. disclosed enantioselective reactions of imines with ketene silyl acetals using a Bronsted acid-assisted chiral Lewis acid [8]. In all cases, however, stoichiometric amounts of chiral sources were needed. Asymmetric Mannich reactions using small amounts of chiral sources were not reported before 1997. This chapter presents an overview of catalytic asymmetric Mannich reactions. 

The reaction is also referred to as the Boronic Acid Mannich Reaction, since it proceeds via an imine with the organic ligand of the boronic acid acting as the nucleophile, similar to the role of the enolizable ketone component in the original Mannich Reaction. 

Regardless of how it does take place, the fact that this addition is irreversible certainly imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits the number of cases where the yields are synthetically useful. By comparison, the Boronic Acid Mannich Reaction permits a much broader scope of conversions to be carried out. 

Multi-component procedures based upon the Mannich reaction and boron reagents were reported in 1993 as a reaction between vinylboronic acids and the adducts of secondary amines and paraformaldehyde (Table 5, entries 1 and 2).558... 

Other Uses. Reagent 1 has been used for enantioselec-tive enolborination, albeit with poor (1.1 1) selectivity. Similar bis-sulfonamide-derived boron Lewis acids have been used for aldol additions, "" ester-Mannich reactions, Diels-Alder reactions, Ireland-Claisen reactions, and [2,3]-Wittig rearrangements. Similar bis-sulfonamide-derived aluminum Lewis acids have been used for aldol additions, Ehels-Alder... 

The mechanism of the Petasis boronic acid-Mannich reaction is not fully understood. In the first step of the reaction, upon mixing the carbonyl and the amine components, three possible products can form iminium salt A, diamine B, and a-hydroxy amine C. It was shown that preformed iminium salts do not react with boronic acids. This observation suggests that the reaction does not go through intermediate A. Both intermediate B and C can promote the formation of the product. Most likely, the reaction proceeds through intermediate C, where the hydroxyl group attacks the electrophilic boron leading to an ate -complex. Subsequent vinyl transfer provides the allylic amine along with the boronic acid sideproduct. 

Cytoxazone is a novel cytokine modulator. The total synthesis of this natural product and its enantiomer was accomplished by S. Sugiyama. The 3-amino-1,2-propanediol moiety was synthesized by a Petasis boronic acid-Mannich reaction between DL-glyceraldehyde, (R)-1-(1-naphthyl)ethylamine and 4-methoxyphenylboronic acid to provide a 1 1 mixture of the diastereomeric products. The diastereomers could be separated at a later stage in the synthesis and transformed into (-)- and (+)-cytoxazone. 

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