Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolecular [1,5]-hydride shift/isomerization reaction

Summary Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes via intramolcular [1,5]-hydride shift/isomerization reaction has been realized, using the inherent reducing power of 3-pyrrolines. A series of N-arylpyrrole containing amines are obtained in high yields.

report herein the Lewis acid-catalyzed redox-neutral amination of 2-(3-pyrroline-1-yl)benzaldehydes using the iminium group as the H-shift acceptor (Scheme 1, reaction 3). Notably, this reaction should meet the requirement that the iminium formation reaction should be faster than the aldehyde redox reaction.

Results and Discussion
In our initial investigation, aldehyde 1a and dibenzylamine (2a) were chosen as the model reaction substrates. In the presence of 10 mol % PhCOOH, the reaction of 1a with 2a in DCE at rt for 24 h gave the trisubstituted amine 3a in 50% yield (entry 1, Table 1). Encouraged by this result, we screened readily available Brønsted and Lewis acids ( Table 1). Except the Lewis acid AlCl 3 , other strong Brønsted acids and common Lewis acids could be used as the catalyst in this reaction, affording the desired products in excellent yields (entries 2-8, Table 1). Considering that ZnCl 2 is cheaper and easy to handle, it was chosen as the catalyst for further optimization reactions. Furthermore, various solvents such as DCE, CH 2 Cl 2 , CHCl 3 , toluene, CH 3 CN and THF were examined. All the solvents afforded the desired product in satisfactory yields (entries 8-13, Table 1). Subsequently, the loading of dibenzylamine (2a) and the catalyst was examined. The results show that decreasing the amount of 2a to 1.2 equiv and ZnCl 2 to 5 mol % did not affect the yield (entry 16, Table 1).
Finally, we established the optimized reaction conditions using ZnCl 2 (5 mol %) as the catalyst and CH 2 Cl 2 as the solvent, and running the reaction at room temperature or under reflux.
Under the optimized conditions, the results of the amination reaction of 2a with various 2-(3-pyrroline-1-yl)benzaldehydes 1 are shown in Scheme 2. The reactions proceeded smoothly to give the corresponding N-arylpyrrole amines 3 in good to excellent yields (71-97% yields). Notably, the substitution of the benzene ring had little effect on the reaction since both electrondonating (3b, 3c) and electron-withdrawing groups (3d-i) were tolerated in the reaction.
Next, the scope of amines 2 was explored. The results are summarized in Scheme 3. Reaction of secondary amines possessing aryl-aryl, alkyl-alkyl and aryl-alkyl moieties yield the corresponding N-arylpyrrole amines 3j-p in high yields (81-94% yields). Various cyclic secondary amines were also good substrates for this reaction, affording the desired products (3q, 3r, 3s) in good to high yields (77-98% yields) with DCE as the solvent under reflux conditions. The reaction with indoline, tetrahydroquinoline, and tetrahydroisoquinoline could also be realized to give products 3t, 3u, and 3v in good yields (76-88% yields), respectively. Finally, primary amines were examined. The reaction with excess benzylamine (5.0 equiv) in the presence of Zn(OTf) 2 as the catalyst afforded the desired product  3w in 98% yield. However, when n-BuNH 2 was used as the substrate, the yield was reduced to 33% even under high temperature. Notably, according to the 1 H NMR spectrum of the crude product, the reaction with phenylamine using Zn(OTf) 2 as the catalyst afforded only the corresponding imine product, indicating that the [1,5]-hydride shift/isomerization reaction did not occur. To our delight, this reaction proceeded smoothly at room temperature to give the desired N-arylpyrrole amine 3y in high yield (99% yield) when p-TsOH·H 2 O was used as the catalyst instead of Zn(OTf) 2 .

Experimental
General procedure for the preparation of N-arylpyrroles 3: A mixture of benzaldehyde 1 (0.3-0.5 mmol), amine 2 (1.2 equiv) and ZnCl 2 (5 mol %) were stirred in dichloromethane or DCE (5.0 mL) at room temperature or reflux and monitored by TLC. After completion of the reaction (about 24 h), the solvent was removed by evaporation and the residue was purified by flash column chromatography on silica gel to give N-arylpyrrole 3.

Supporting Information
Supporting Information File 1 Experimental details, analytical data, and copies of the 1 H and 13 C NMR spectra of the final products.