Distinctive Reactivity of N-benzylidene-[1,1'- biphenyl]-2-amines under Photoredox Catalysis

A simple photocatalytic method was developed for the synthesis of unsymmetrical 1,2diamines by the unprecedented reductive coupling of N-benzylidene-[1,1'-biphenyl]-2amines with an aliphatic amine. The presence of phenyl substituent in the aniline moiety of the substrate was critical for the reactivity. The reaction proceeded via radical-radical cross-coupling of -amino radicals generated by proton-coupled singleelectron transfer in the presence of an Ir-photocatalyst. On the other hand, symmetrical 1,2-diamines were selectively produced from the same starting materials by judicious choice of the reaction conditions, showcasing the distinct reactivity of Nbenzylidene-[1,1'-biphenyl]-2-amines. The developed method can be employed for the synthesis of various bulky vicinal diamines, which are potential ligands in stereoselective synthesis.


Scheme 1: Photocatalytic transformations of imines.
We planned the synthesis 1,2-diamine compounds having aliphatic amine moiety by intermolecular coupling of N-benzylidines with aliphatic amines which not only act as coupling partner but also as electron donor in photoredox cycle, the results of which we report herein. We began with the reaction of the simple N-benzylideneaniline.
However, this substrate did not furnish the desired products under several different 4 photocatalysis conditions, including those reported by Rueping. We hypothesized that the structural modification of the substrate might affect its reactivity, and to our delight, the introduction of an ortho-phenyl moiety on the N-benzylideneaniline provided the desired 1,2-amine product, wherein the N,N-dicyclohexylmethylamine (Cy2NMe) acted as both the coupling partner and an electron donor in the photoredox cycle (Scheme 1c). It is likely that the presence of the additional phenyl group in the substrate stabilizes the -amino radical intermediate, and modulates its reactivity. 46,47 In addition to the cross-coupled 1,2-diamines, we envisioned the generation of other valuable structural motifs via careful control of the reaction conditions for the reaction of the biphenyl imine derivative, N-benzylidene-[1,1'-biphenyl]-2-amine.

Results and Discussion
With the initial results in hand, we attempted the optimization of reaction conditions to improve the yield of the 1,2-diamine product (Table 1). Among the series of photocatalysts tested, ranging from the Ru/Ir polypyridyl complexes to organic dyes, the [Ir(dtbbpy)ppy)2]PF6 photocatalyst was found to be the best and afforded 2a in 60% yield, along with 11% of the homo-coupled product 3a (entries 1-9). The amount of Cy2NMe was critical for achieving selectivity, and less than two equivalents of Cy2NMe gave greater amounts of the homo-coupled product 3a (entry 10). Control experiments showed that the photocatalyst, amine base, and light source are integral aspects of the reaction (entries [11][12][13]. DMF was found to be the best solvent and yielded 2a selectively (entries [15][16][17][18][19][20][21][22]. On the other hand, the homo-coupled 3a was selectively obtained in protic solvents (entries 19 and 22), and in particular, CH3OH showed good reactivity and formed 3a in 75% yield. Unexpectedly, the cyclized product with the 5 tethered phenyl ring proposed in Scheme 1c was not generated under any of the photocatalytic conditions evaluated. With the optimized conditions in hand, the generality of the transformations was investigated using a wide variety of phenyl-substituted N-benzylideneaniline derivatives (Table 2). First, the C-C bond cross-coupling process with Cy2NMe was explored with variations of the benzylidine moiety. Reactions with both electrondonating (2b-2e) and electron-withdrawing substituents (2i-2m) proceeded well.
Several functional groups, such as benzylic (2b, 2c), ether (2e), halogens (chloro-2i, fluoro-2l), 48-50 the medicinally important CF3-group (2m), and acetal (2p) were 6 tolerated under the mild reaction conditions. The pattern of the substitutions on the aryl groups, such as ortho (2c, 2e, 2k), meta (2m, 2p), and para (2b-2d, 2g, 2i, 2l, 2o,   2p), did not have any significant impact on the reaction outcome. The heteroaryl ringbearing substrates (2n and 2o) also underwent the transformation and furnished the valuable vicinal diamine products. The modifications on the aniline moiety were also suitable, and substrates with both electron-donating (2q and 2r) and electron-withdrawing (2s) substituents underwent the cross-coupling with excellent reactivities. We also tried the transformation with aliphatic amines other than Cy2NMe, such as TMEDA, TEA, and DIPEA. However, these reactions proceeded with poor chemoselectivity and resulted in the formation of mixtures of several types of amine compounds. Table 3: Substrate scope for homo-coupling. a,b a Reaction conditions 1 (0.3 mmol) under argon atmosphere; b isolated yield; c Debrominated product was also detected and yield represents the mixture of bromo and debrominated products Next, the homo-coupling reactions of substituted (E)-N-benzylidene-[1,1'-biphenyl]-2amines were studied in CH3OH (Table 3). [51][52][53][54][55][56] It is noteworthy that the resulting symmetrical 1,2-amine compounds are potential ligands for a variety of organic transformations. The dimerization reactions proceeded well, regardless of the 8 electron-density or position of the substituent on the benzylidene moiety. The structure of the homo-coupled 1,2-diamine product 3a was unambiguously confirmed using Xray crystallography. 57 To further extend the diversity of reactivity of the imines in this process, we also attempted the use of a reducing agent in the reaction of 1a. Pleasingly, the reaction of

Conclusion
We developed a divergent synthetic approach for the valuable 1,2-diamine motifs from N-benzylidene-[1,1'-biphenyl]-2-amines, by slight alterations to the reaction conditions. The in-situ generated -amino radical intermediates successfully underwent crossand homo-coupling to yield the unsymmetrical and symmetrical 1,2-amines, respectively. It is notable that the presence of phenyl substituent at the aniline moiety was critical in the hetero-coupling with aliphatic amines. Furthermore, the reduced amine product was also obtained by employing the Hantzsch ester as an additive. The developed method can be employed for the synthesis of bulky vicinal diamines with potential applications as ligands for stereoselective synthesis.

Experimental
An oven-dried resealable tube, equipped with a magnetic stir bar, was charged with the N-benzylidene-[1,1'-biphenyl]-2-amines (0.3 mmol), [Ir(dtbbpy)(ppy)2]PF6 (0.003 mmol), and Cy2NMe (0.6 mmol). The reaction mixture was purged with argon for 20 min. Then, degassed DMF or MeOH was added to the reaction mixture under inert conditions. The reaction mixture was stirred at ambient temperature for 15 h under visible-light irradiation with blue LEDs (18 W). The progress of the reaction was monitored by using TLC. Upon reaction completion, the crude product was diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous MgSO4 and concentrated on a rotary evaporator. The desired vicinal diamine products were purified by silica-gel column chromatography using hexane/EtOAc as the eluent.