Formation of N-Alkylpyrroles via Intermolecular Redox Amination

Abstract

Redox isomerization reactions are of particular interest because they exhibit perfect atom economy, and they often utilize the inherent reducing power of hydrogen that is embedded in molecules to effect reduction of other functional groups. [1][2][3] In doing so, redox isomerizations are able to circumvent the requirement for exogenous reducing agents, which tend to be high energy reagents. The power of redox isomerizations is arguably increased when it is used in conjunction with C-X bond-forming reactions. The Tishchenko reaction is a classic example of such a coupling reaction that has been proposed to proceed via an intermediate redox isomerization. 2 More recently, Seidel has demonstrated several intriguing reactions where an intramolecular redox reaction is used to effect a reductive amination in concert with a second C-N bond forming reaction (eq 1). 3 Herein, we report a related, acid-catalyzed intermolecular redox amination that takes advantage of the inherent reducing power of 3-pyrroline (eq 2). Ultimately, redox isomerization can be used to form N-alkyl pyrroles via reductive amination, a reaction that cannot typically occur since pyrrole is a weak N-nucleophile. Moreover, the mild conditions, atom-economy, and operational simplicity of the redox amination reported herein make redox amination a viable alternative to more standard syntheses of N-alkyl pyyroles. 4(1) Initially, we were interested in performing an intramolecular variant of a rearrangement reaction described by Murahashi. 5 However, rather than the intended product, the alkyl pyrrole 1a was isolated in 25% yield (eq 3). Since such a reductive amination to form aromatic amines is a potentially powerful synthetic method, we chose to investigate the reaction further. Literature searches reveal that Cook discovered an analogous thermal condensation of 3-pyrroline with cyclohexanone at 140 °C in xylene to produce N-cyclohexylpyrrole in 47% yield. 6,7 Unfortunately, other ketones provided even poorer yields. Since our reaction appeared to take place under milder conditions, we set our sights on developing a catalytic reaction that would have broad utility.(To begin, reactions were performed to determine which species in the original reaction mixture was responsible for catalyzing this transformation. As can be seen from Table 1, CF 3 CO 2 H effected the reaction alone (entry 3), and Pd(PPh 3 ) 4 was somewhat detrimental to the reaction (entry 2). Moreover, performing the reaction under air was problematic due to background oxidation of 3-pyrroline to pyrrole (entry 4). Having established that the reaction was catalyzed by Brønsted acids, we turned our attention to the use of milder acids. Indeed, acetic acid and benzoic acid are both competent catalysts for the transformation and can be used interchangeably. While reactions that were run with 1:1 pyrroline/aldehyde did not completely consume the aldehyde within the allotted reaction time, the yields of the reactions were still good (entries 5, 8, and 11). Ultimately, the use of 1.5 equiv of ...

Synthesis of N-aryl-1-aminoindoles via intermolecular redox amination

“…6 Lastly, an indoline with an unprotected aniline was compatible with our redox amination, although the product 1i was formed in moderate yield. In addition, a benzo-fused indoline gave product 1g in good yield; benzoindoles are a basic skeleton found in several biologically active compounds.…”

“…Under these conditions, an 80% yield of 1-amino indole was isolated. The reaction did not proceed without catalyst or when using highly acidic Bi(OTf) 3 or TfOH catalysts (entries [4][5][6]. Weaker Brønsted acids are superior catalysts, with TFA giving just 25% yield while acetic acid provides the product in 63% yield (entries 7, 8).…”

Stronger Brønsted Acids: Recent Progress

“…142 Tunge and co-workers took advantage of the reducing power of 3-pyrroline for the formation of N-alkylpyrroles by intermolecular redox amination (Scheme 43). 143 On treatment Yu and co-workers reinvestigated Tunge's work by DFT calculation and found that the one-step direct 1,3-hydrogen shift process proposed by Tunge is not viable due to the very high activation energy, even though it has been proposed in some redox isomerization reactions. Instead, they proposed the formation of acetic-acid-assisted azomethine ylide intermediate 122 (Scheme 44).…”

tert-Amino effect: the Meth-Cohn and Reinhoudt reactions (Review)

“…Furthermore, in the case of an allylsulfanyl group it was shown that propene was eliminated in this reaction [106]. in the presence of acids led to dehydrogenation of the heterocycle and hydrogenation of the formed Schiff base resulting in the 1-substituted pyrrole 154 [108]. The reaction with indoline 155 similarly led to the indoles 156 [109,110].…”

“…The reaction with indoline 155 similarly led to the indoles 156 [109,110]. Tunge and colleagues [108] suggested that a 1,3-migration of hydrogen was the key step of this process. On the basis of quantum-chemical calculations Chinese scientists [110] proposed that the reaction took place by an intermolecular proton transfer mechanism with an activation energy of 25.6 kcal/mol in a solvent, whereas a 1,3-migration of the proton would have a barrier of 44.6 kcal/mol.…”