Catalysis of 6π Electrocyclizations

Abstract

The synthetic power of pericyclic reactions has greatly increased with the emergence of catalytic variants. Indeed, catalysis in cycloadditions [1] and sigmatropic rearrangements [2] is now well established. General methods for the catalysis of electrocyclizations, however, have remained elusive, with the notable exception of the Nazarov cyclization. [3] The development of such methods would enable electrocyclizations to occur under milder conditions and create the possibility of catalytic asymmetric variants. Herein, we report the first examples of catalytic 6p electrocyclizations and provide a detailed investigation into the mechanism of these reactions.Experimental and computational studies have shown that the rate of 6p electrocyclizations can be influenced by varying the electronics of the substituents on the triene. [4][5][6][7] Electron-withdrawing groups located in the 2-position of hexatriene systems have been observed to lower their electrocyclization energy barriers, [6,7] sometimes by as much as 10 kcal mol À1 . [7,8] We envisioned exploiting this effect to catalyze 6p electrocyclizations by the coordination of a Lewis acid to a Lewis basic electron-withdrawing group located in the 2-position of a hexatriene system. This coordination should increase the electron-withdrawing effect of the substituent, thereby decreasing the electrocyclization energy barrier.We began our investigations by computationally assessing the viability of this approach in the catalysis of 6p electrocyclizations. Hexatriene systems with methyl ester substituents at all possible positions and orientations were modeled by density functional theory (Figure 1). A proton, serving as the simplest Lewis acid, was bonded to the carbonyl oxygen atom at the lone pair anti to the hexatriene. [9] As seen in Figure 1, these calculations predict a slight increase and decrease of the electrocyclization energy barrier for the (E,Z)-and (Z,Z)-1-carbomethoxy-substituted hexatriene systems (Figure 1 A and B), respectively. Calculations additionally predict a small decrease of the electrocyclization energy barrier for the 3-substituted system (Figure 1 D). However, we found that the electrocyclization energy barrier is predicted to decrease by 10 kcal mol À1 upon protonation of the 2-carbomethoxy-substituted triene system (Figure 1 C). An intrinsic reaction coordinate search in both directions from the protonated electrocyclization transition state of this system suggests that the catalyzed pathway is a concerted process, as no stationary points other than the transition state were located between the protonated triene and protonated cyclohexadiene. Figure 1. Relative electronic energies (kcal mol À1 ) of the thermal (numbers above line) and cprotonated carbonyl group (numbers below line) electrocyclization pathways computed at the B3LYP/6-31G** level of theory. 1-substituted trienes (A and B); 2-substituted triene (C); 3-substituted triene (D). [10]

Using Theory and Experiment to Discover Catalysts for Electrocyclizations

“…Recently, though, Bergman, Trauner, and co-workers have demonstrated for the first time that sixelectron electrocyclizations can be catalyzed by Lewis acids (Scheme 1). [11] Using the knowledge that 1,3,5-hexatrienes with electronwithdrawing substituents located at the 2-position cyclize with lower energy barriers than analogous systems lacking such susbtituents,…”

Asymmetric Ion Pair Catalysis of 6π Electrocyclizations: Brønsted Acid Catalyzed Enantioselective Synthesis of Optically Active 1,4‐Dihydropyridazines

“…[1,2] However, whereas other pericyclic reactions such as sigmatropic rearrangements [3,4] and cycloaddition reactions have generated much interest, electrocyclic reactions have not been fully exploited with regard to control of their absolute stereochemistry. [7] In the case of [1,6]electrocyclization reactions, [8][9][10][11] high levels of enantiocontrol were described by the groups of Toda [8] and Bach [9] in the enantioselective 6p photocyclization of acrylanilides mediated by chiral hosts. Additionally these high temperatures may also limit the use of highly functionalized substrates in targetoriented synthesis.…”

“…This is mainly because of the high temperatures needed for the initiation of the electrocyclization process. [11] In our continuous research to develop highly enantioselective metal-free procedures for the synthesis of relevant bioactive heterocycles, we became interested in the asymmetric synthesis of dihydropyridazines by using a new chiral Brønsted acid [12][13][14] catalyzed 6p-electrocyclization reaction. [2a] In particular, enantioselective 6p-electrocyclization reactions are rare and very difficult to achieve.…”

“…[2a] In particular, enantioselective 6p-electrocyclization reactions are rare and very difficult to achieve. [7] In the case of [1,6]electrocyclization reactions, [8][9][10][11] high levels of enantiocontrol were described by the groups of Toda [8] and Bach [9] in the enantioselective 6p photocyclization of acrylanilides mediated by chiral hosts. [5] In this context, Smith et al recently described an elegant protocol for the asymmetric synthesis of functionalized indolines by asymmetric 6p electrocyclization using cinchona-alkaloid-derived chiral quaternary ammonium salts as phase-transfer catalysts.…”

Organoaluminum‐Mediated Interrupted Nazarov Reaction

“…[7] For example, trialkylaluminum reagents have been used in epoxide opening, [8] S N 'type reactions, [9] and acetal cleavages. [11,12] We envisaged a new type of interrupted Nazarov reaction employing triorganoaluminum reagents, in which one of the groups on aluminum could migrate to an allyl terminus of cyclized intermediate 2, affording, after quenching of the resulting aluminum enolate, substituted cyclopentanones 3 in which R might include previously inaccessible alkyl or aryl groups (Scheme 1) by metalmediated delivery. [11,12] We envisaged a new type of interrupted Nazarov reaction employing triorganoaluminum reagents, in which one of the groups on aluminum could migrate to an allyl terminus of cyclized intermediate 2, affording, after quenching of the resulting aluminum enolate, substituted cyclopentanones 3 in which R might include previously inaccessible alkyl or aryl groups (Scheme 1) by metalmediated delivery.…”