Photoredox catalysed reductive aminomethylation of quaternary benzophenanthridine alkaloids

Abstract Reduction of C = N double bond is the most important phase I metabolism process of quaternary benzophenanthridine alkaloids (QBAs). Inspired by the NADPH mediated reduction in QBAs, a visible-light promoted reductive aminomethylation of QBAs for synthesis of 6-substituted benzophenanthridines was reported using QBAs and N,N-dimethylaniline as coupling partners in this study. An α-amino radical that derived from QBAs was supposed to be the key intermediate in this visible-light promoted reductive aminomethylation reaction. Graphical Abstract

CONTACT Pi Cheng picheng@hunau.edu.cn or picheng55@126.comSupplemental data for this article can be accessed online at https://doi.org/10.Previously, to get insights into the biosynthetic pathway of the above alkaloids, we proposed a biomimetic and visible-light-triggered reductive alkylation process of QBAs (Wang et al. 2021).As shown in Figure 2, nicotinamide adenine dinucleotide (NADH) and its synthetic analogue C4-alkyl-1,4-dihydropyridines (DHPs) can enable the direct single-electron reduction in QBA to give a kind of a-amino C-radical (Figure 2) under irradiation with 455 nm blue light in the absence of photocatalysts and additional additives.The a-amino C-radical can participate in a series of radical-type reaction leading to the formation of 6-SDHBs.Nevertheless, this metal-and photocatalysts-free reaction requires the formation of an electron-donor-acceptor (EDA) complex (Yang et al. 2021) to facilitate the intermolecular electron transfer.

Results and discussion
In this study, to further understand the single-electron reduction process of QBAs, a series of N,N-dimethylaniline 9 (Figure 2) were selected as electron-donor instead of C4-alkyl-1,4-dihydropyridines.Initially, we explored the reaction of sanguinarine 1 with  N,N-Dimethylaniline 9a (R 2 ¼H, Figure 2) to give 6-animomethyl substituted derivative 10a in DMSO under the irradiation of blue LED at ambient temperature.As illustrated in Table S1 in the supplementary material, the desired reductive aminomethylation process was not observed without photocatalyst (PC) (Entry 1, Table S1).But to our delight, 37% yield of compound 10a could be obtained in a DMSO solution after 24 h reaction under the irradiation of 455 nm blue light with Ru(Phen) 3 Cl 2 Á6H 2 O as photocatalyst and NaOAc as base (Entry 2, Table S1).When other inorganic salts such as Na 2 CO 3 , K 2 CO 3 , Na 2 HPO 4 , K 2 HPO 4 , CsOAC were selected as bases instead of NaOAc, the yield decreased obviously (Entries 3 À 6, Table S1).Replacing photocatalyst Ru(Phen) 3 Cl 2 Á6H 2 O with Ir (dtbby)(bby) 2 PF 6 significant increased the yield to 75% with NaOAc as base (Entry 7, Table S1), but further screen of bases was not helpful for reactivity (Entries 8 À 12).In addition, a screen of solvent showed that DMF and MeCN could not further increase the yield of compound 10a (Entries 13 À 14, Table S1).Finally, the reaction was also carried out in darkness as control experiment, but compound 10a was not detected (Entry 15, Table S1).
With the optimized conditions in hand, we first synthesised several 6-substituted dihydrosanguinarine derivatives with sanguinarine and different N,N-dimethylanilines as coupling partners.As shown in Table S2, sanguinarine 1 could be reductively aminomethylated with different N,N-Dimethylaniline derivatives as reductants, giving 10a-7f in good yields.Next, a series of 6-substituted dihydrochelerythrine derivatives were obtained based on this reductive coupling reaction, affording desired compounds (10 g-7n) in moderate to good yields.We also evaluated the reaction efficacy with electron-deficient 4-NO 2 N,N-Dimethylaniline as coupling partners, but compounds 10o were not detected.
We next turned our attention to possible reaction mechanism.To understand the role of amines in current reaction, aliphatic amine Et 3 N (11) was also chosen as reductant (Figure 3).Under the 'standard' conditions, the reductive amino alkylation reaction was not observed only with dihydrosanguinarine (13) as products (A, Figure 3).Unlike the N,N-dimethyl aniline mediated reductive aminomethylation reaction, this reduction reaction could proceeded slowly even without photocatalysts (B, Figure 3).
Based on previous literature and our experimental results, we envisioned the mechanistic scenario as shown in Figure S2 in the supplementary material.Photocatalyst Ir(dtbby)(bby) 2 PF 6 (PC) was firstly excited by 455 nm blue light to give PC Ã .PC Ã was successively reduced by N,N-dimethylaniline 9a to PC À through a single electron transfer (SET) process, and N,N-dimethylaniline 9a was oxidised to radical cation 14.Sanguinarine was then reduced by highly active reductant PC À (E 1/2 M À /M ¼ À1.51 V vs SCE) (Prier et al. 2013) to a a-amino carbon radical 15.Meanwhile, radical cation 14 was deprotonated by base NaOAc to amino methyl radical 16, which could couple with radical 15 to give target compound 10a.When Et 3 N was used as reductant as shown in Figure 3, radical 15 only abstracted a hydrogen atom from corresponding radical cation which derived from Et 3 N and gave dihydrosanguinarine 13 as main product.Without catalyst, an EDA complex could form between Et 3 N and sanguinarine and facilitate the SET process (see Figure S3, supplementary material).

Conclusion
In summary, we have demonstrated a visible-light promoted approach to 6-substituted dihydrobenzophenanthridines (6-SDHBs) through a radical coupling process with natural QBAs as starting materials.The reaction provided desired compounds in moderate to good yields under mild condition.In this radical coupling reaction, the a-amino Cradicals derived from QBAs were supposed to be the key intermediates that involved in the biosynthesis of natural 6-SDHBs.Further utilization of photoredox strategy in the synthesis of complex natural 6-substituted benzophenanthridine alkaloids is underway.