Photocatalytic reverse polarity Povarov reaction

A reverse polarity photocatalysed Povarov reaction of imines and electron deficient alkenes is described.


Introduction
Photoredox catalysis, through its ability to generate reactive radical intermediates under mild yet highly tunable reaction conditions and experimental set-ups, 1 offers great potential for new reaction discovery. 2 Pioneering developments have significantly expanded the synthetic toolbox 3 and have been applied in the construction of building blocks 4 and natural products, 5 and also in the derivatization of biologically relevant molecules 6 and macromolecular peptide structures. 7 Photocatalytic approaches to the synthesis and functionalisation of amines and their derivativeswith direct impact on medicinal chemistry programmes 8have been particularly prevalent. 9 Recent efforts have focussed on the photocatalytic generation and trapping of a-amino radicals derived from a range of starting materials. 10 Noteworthy examples include single electron transfer (SET) decarboxylation of amino acid derivatives, 11 direct hydrogen atom transfer (HAT) of aliphatic amines, 12 or via the SET reduction of imine derivatives. 13 The resulting a-amino radicals have been shown to subsequently engage in radical-radical coupling reactions, 14 partake in transition metal catalysed cross coupling processes or react with a range of electrophilic species. 15 Building on Knowles' seminal studies on proton coupled electron transfer (PCET) for the generation of a-heteroatom radicals, 13a our group recently reported the photocatalytic reductive coupling of imines with allyl sulfone electrophiles using Eosin Y as the photocatalyst, and Hantzsch ester as the stoichiometric reductant, under green LED light irradiation. 15b Contemporaneously Chen, 15a and later Ngai, 15c reported similar reactivity of in situ generated a-amino radicals from imines. Such a reversal of the natural imine polarity via the PCET manifold establishes a new umpolung approach for the synthesis of a-functionalised amines (Scheme 1a), and creates many opportunities for new reaction discovery.
Scheme 1 Previous reports in the context of this work. PC ¼ photocatalyst.
In a continuation of our programme, we sought to explore and expand the synthetic utility of photocatalytic imine umpolung chemistry. Our previous work demonstrated that the a-allylated amine product was the outcome of the reaction with Michael acceptors bearing a sulfone leaving group. 15b With prospective coupling partners not possessing a suitable leaving group it was unclear as to what the outcome of the reaction would be. Following nucleophilic addition, the intermediate g-amino radical could either gain a further electron and proton to form the Michael addition product, 15a or potentially cyclize onto the pendant electron rich aromatic ring and subsequently rearomatize (Scheme 1a). Both pathways would be synthetically useful but the latter would allow the direct construction of the biologically relevant tetrahydroquinoline scaffold, examples of which have shown to possess biological activity in g-secretase inhibitors (Scheme 1c) 16 and androgen agonists/antagonists. 17 Previous studies by Hirano and Miura on the copper catalysed redox coupling of N,N-dimethylaniline and maleimide derivatives provided some precedent for the cyclisation pathway (Scheme 1b) 18 and encouraged us to investigate along these lines of enquiry. Herein, we wish to report our ndings.
Preliminary studies were carried out using uorine tagged aldimine (1a), phenyl vinyl sulfone (2a, 3 equiv.) as the Michael acceptor, (Ir[dF(CF 3 )ppy] 2 (dtbbpy))PF 6 ([Ir], 1 mol%) as photocatalyst and the commercial Hantzsch ester (HE1, 1.2 equiv.) as a stoichiometric reductant, in DMSO, under blue LED light irradiation. Pleasingly, good reactivity was identied early and importantly cyclised product 3aa reverse polarity Povarov product 19was formed as the sole coupling product in the reaction mixture (Table 1, entry 1) as a 7 : 1 mixture of diastereomers. Despite the typical use of Hantzsch esters as a superstoichiometric reductive quencher in photoredox coupling reactions of imines, 20,21 our redoxneutral process beneted from the use of 60 mol% HE1. This was largely due to suppression of over-reduction and aza-pinacol side products (entry 2) and the use of substituted Hantzsch esters (HE4 & HE6, entries 3 & 4) further suppressed their formation. 16,22 Further reduction of the Hantzsch ester loading to 10 mol% led to lower reaction conversions (entry 5) using blue LED irradiation, however by switching to a commercial photoreactor, full conversion was achieved in 16 hours and the product was isolated in excellent yield (90%) as a 10 : 1 mixture of diastereomers. The reaction methodology was also amenable to a reduction in equivalents of vinyl sulfone coupling partner without major impact on reaction efficiency (entry 7) and reactivity was completely lost on removal of Hantzsch ester (entry 8), or iridium photocatalyst (entry 9), and in the absence of light (entry 10).
With optimal conditions established, we looked to probe the scope of the photocatalytic reverse polarity Povarov reaction (Scheme 2a). Initially, the tolerance to variation on the aniline portion of the aldimine was investigated. Pleasingly, the reaction proceeded well with a number of substituents in the 4-position (3b-d). Good reaction efficiency and excellent diastereoselectivity towards the trans diastereoisomeric product was noted in all cases. 23 This is in contrast to Brønsted or Lewis acid catalysed Povarov reactions in which cis-congured stereoisomeric products oen predominate. 19 When variations to the aromatic ring of the aldehyde moiety were explored, electronics were found to play a pivotal role, with electron rich and neutral arenes giving excellent yields (3e-g, 3j-n) whereas electron poor aromatics led to longer reaction times (3h) and even complete nullication of reactivity (3i). 3-Fluoro and 2-uoro-substituted aldimines were tolerated in this chemistry however longer reaction times were required and yields diminished with proximity to the imine C]N bond (3p-r). A substituted pyridyl substrate was also shown to be effective in the reaction mixture leading to an excellent yield of product (3s).
Disappointingly, ketimines were not found to be viable substrates for this reaction (3t) even aer prolonged reaction times. 4-Chlorophenyl vinyl sulfone was found to be an excellent electrophile (3ab). Similarly, maleimide and N-phenylmaleimide electrophiles were shown to be excellent coupling partners in the new cyclisation methodology, however diastereoselectivity was respectively reduced or absent in the reaction products (3ac-ae). The chemistry was extendable to a three component one-pot process (Scheme 2b) and demonstrated the expedient construction of complex tetrahydroquinoline structures using simple building blocks, as well as its potential application to modular library synthesis. An interesting observation made throughout the optimisation studies was that aer the imine substrate 1a was consumed in the reaction vessel, product diastereomeric ratio continued to increase, suggesting that epimerization was occurring under the reaction conditions. To investigate this further, Povarov product 3a (dr 10 : 1) was resubmitted to the reaction conditions. Pleasingly an increase to 18 : 1 was observed and mass balance was maintained (Scheme 3a). As this epimerization does not take place without the iridium catalyst, or in the absence of light, a photoredox based mechanism for the formation of a planar a-amino radical is proposed. 24 Monitoring the reaction over time from initiation using 19 F NMR spectroscopy, demonstrated that the formation of 3a had an intrinsic kinetic dr of $10 : 1 in favor of the trans diastereoisomer. Then from the point of $90% conversion, the diastereoselectivity increased gradually up to 20 : 1 aer 48 hours (Scheme 3b).
Recent investigations have shown that imines (E 0 1/2 ¼ À1.90 V vs. SCE in CH 3 CN), 25 can be reduced more readily using proton-coupled electron transfer. Chen's, 15a ours, 15b and Ngai's 15c previous investigations have demonstrated that partially oxidized Hantzsch esters are acidic enough to be used as proton donors in PCET mechanisms. 26 To probe this further, the reaction was repeated using the reduced aminewhich is a by-product of the reactionas starting material (4a, Scheme 4a). Only trace amounts of product were observed, suggesting the reverse polarity Povarov reaction does not proceed via initial reduction of the imine. This reinforces the proposal of PCET construction of the key a-amino radical. As only sub stoichiometric quantities of the Hantzsch ester are needed for full conversion, its role is likely as an initiator in a self-propagating mechanism. We were intrigued to identify whether either the cyclised product 3a or an intermediate could act as a reductive quencher to propagate further product formation. To this end, we carried out a control experiment where HE4 (10 mol%) was replaced with 3a (Scheme 4b). Importantly, no product formation was observed suggesting that an intermediatenot the product of the reactionis capable of propagating this reaction mechanism. Kinetic isotope effect (KIE) studies demonstrated that the isotopic sensitivity of selectivity determining steps has a value of $1, suggesting that the substrates are kinetically committed toward product formation prior to any C-H cleavage events (Scheme 5c). 27 From these insights, we propose that PCET would enable Ir [dF(CF 3 )ppy] 2 (dtbbpy)PF 6 (E 0 1/2 ¼ À1.37 V vs. SCE in CH 3 CN) 1a to reduce the imine readily to form the key a-amino radical (Scheme 5) which can react with the phenyl vinyl sulfone in a step-wise radical cyclization to give the stabilised Povarov radical intermediate A. As this methodology only requires substoichiometric quantities of the substituted Hantzsch ester (HE4), we suggest this Povarov radical intermediate A can lose a proton (kinetically facile) to form radical anion intermediate B, in a base assisted homolytic aromatic substitution-type mechanism. 28 Using Yoon's method, we calculated the quantum yield of the reaction between 1a and 2a, to be 18. 29 This suggests that a radical chain process is in operation, with the strongly reducing radical anion intermediate able to reduce fresh imine substrate with concomitant protonation, 30 thus forming the product (3a) and regenerating the key a-amino radical.

Conclusions
In conclusion we have developed a new photocatalytic reverse polarity Povarov reaction to construct decorated tetrahydroquinolines in high yield and diastereoselectivity. This polarity reversal was postulated to stem from an a-amino radical formed via the PCET of imine derivatives. 10 mol% of a Hantzsch ester was found to be optimal as a reductive initiator, a feature which has not previously been disclosed in photoredox catalysis. Further investigations are ongoing to establish further coupling partners and scaffolds for this reverse polarity platform for the synthesis of a-functionalised amines.

Conflicts of interest
There are no conicts to declare.