The Petasis-Akritopoulou Reaction

An interesting mechanistic proposal (not considered here) was proffered by this group. 

R = Ts, COjMe Ar = indol-3-yl, 5-acetylpyirol-3-yl, furan-2-yl, thiophen-2-yl, 4-(Me2N)CgH4 and derivatives 

Petasis and Zavialov [52a] have developed a three-component variant of the Mannich reaction for the synthesis of a-amino acids and their M-substituted derivatives. The same group reported a 

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. 

So far, all of the reported Petasis-Akritopoulou reactions were carried out in organic solvents such as methanol, ethanol, dichlorometane, toluene, dioxane, and acetonitrile. Even HFIP was applied with success in some cases [ 58,59]. However, these procedures required either a long reaction time or MW activation. Gois and coworkers [60] reported an interesting study where water was successfully used as solvent for this reaction, using different aldehydes such as salicylaldehyde, glyoxalic acid, and gly-coaldehyde. Density functional theory (DFT) studies were performed to understand the mechanistic 

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Scheme 6.40 The use of the Petasis-Akritopoulou reaction for the synthesis of a-arylglycines from aryl...

Scheme 6.41 Synthesis of pyrimidinyl arylglydnes using the Petasis-Akritopoulou reaction, as described by the Villalgordo group [55].

Boronic acids bearing strong electron-poor aromatic groups (such as pyridinyl) were reported to lack reactivity in the Petasis-Akritopoulou reaction, using standard conditions (dichloromethane, room temperature) [54]. Boronic esters were also studied [57] and the authors reported that the mechanism of formation of the boronate species was different from that with phenylboronic acid derivatives. Piettre and coworkers considered the use of hexafluoro-iso-propyl alcohol (HFIP), which is an alcohol with higher ionizing power, as the solvent in the Petasis-Akritopoulou reaction with boronic esters (Scheme 6.43). Compared to the use of methanol as solvent and microwave-assisted irradiation (MW), the yields were much higher (a maximum of 99% yield was obtained ) [58]. 

In the course of an attempt to synthesize pyrrolidine-derived arylglycines, in 2005, Nanda and Trotter reported a diastereoselective synthesis of such compounds, applying the Petasis-Akritopoulou reaction, where the use of HFIP as cosolvent dramatically reduces the reaction times from several days to less than 24h. High diastereoselectivities were achieved (Figure 6.3) [59]. 

Figure 6.4 Products derived from the catalytic enantioselective Petasis-Akritopoulou reaction of quinolones catalyzed by a thiourea catalyst, as described by Takemoto s group [65].

As mentioned previously in this book, the quest for sustainable, atom-economical, and environmentally friendly chemical processes is a big current issue. Besides one-pot, sequential reaction processes (generally catalyzed by either metals or enzymes), multicomponent reactions have become very important [51]. The Petasis reaction, alternatively called Petasis horono Mannich reaction, is a mUd multicomponent reaction, which was reported first by Petasis and Akritopoulou in 1993 [52]. This reaction allows the one-pot three-component condensation of an aryl- or alkylboronic acid, an amine, and an aldehyde (or generally a carbonylic compound) to generate substituted amines at room temperature (Scheme 6.38). 

Eor pioneering examples, see (a) N. A. Petasis, I. Akritopoulou, Tetrahedron Lett. 1993, 34, 583-586. The boronic acid Mannich reaction a new method for the synthesis of geomet-ricaUy pure aUylamines. (b) N. A. Petasis, I. A. Zavialov, J. Am. Chem. Soc. 1997, 119, 445-446. A new and practical synthesis of a-amino acids from alkenyl boronic acids, (c) N. A. Petasis, A. Goodman, I. A. Zavialov, Tetrahedron 1997, 53, 16463-16470. A new synthesis of a-arylglycines from aryl horonic acids. 

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). 

In 1993, Petasis and Akritopoulou described the addition of vinyl boronic acids to formaldimine, leading to tertiary allylic amines [78]. Owing to the rruld reaction... 

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