Switchable, Reagent‐Controlled Diastereodivergent Photocatalytic Carbocyclisation of Imine‐Derived α‐Amino Radicals

Abstract A reagent‐controlled stereodivergent carbocyclisation of aryl aldimine‐derived, photocatalytically generated, α‐amino radicals possessing adjacent conjugated alkenes, affording either bicyclic or tetracyclic products, is described. Under net reductive conditions using commercial Hantzsch ester, the α‐amino radical species underwent a single stereoselective cyclisation to give trans‐configured amino‐indane structures in good yield, whereas using a substituted Hantzsch ester as a milder reductant afforded cis‐fused tetracyclic tetrahydroquinoline frameworks, resulting from two consecutive radical cyclisations. Judicious choice of the reaction conditions allowed libraries of both single and dual cyclisation products to be synthesised with high selectivity, notable predictability, and good‐to‐excellent yields. Computational analysis employing DFT revealed the reaction pathway and mechanistic rationale behind this finely balanced yet readily controlled photocatalytic system.


Introduction
Recently,t he photocatalytic generation and downstream reactivity of a-amino radical species have attracted al ot of attention across the synthetic community. [1] These high-value reactive intermediates exhibit nucleophilic behaviour at the position alpha to the nitrogen atom, and have been shown to undergo various radical-radical coupling reactions, [2] to add to electrophilic acceptors, [3] and to intercept dual catalytic manifolds. [4] To this end, contemporary photocatalytic developments have enabled the generation of these key nucleophilic a-amino radical species from inherently electrophilic imine derivatives via single-electron reduction (often with concomitant proton transfer in aP CET mechanism). [5] This umpolung approach to amine synthesis is complementary to traditional two-electron conversions,a nd thus has expanded the range of a-branched amine architectures that can be accessed from simple and readily obtained imine precursors. [6] Previous studies from our group have revealed two distinct product-forming pathways under photocatalytic conditions,w here the outcome depended almost exclusively on the nature of the electrophilic coupling partner (Scheme 1A). Firstly,t he net reductive Giese-type products were demonstrated to be favoured when coupling with a,b-unsaturated esters (such as allyl sulfones,a nd dehydroalanine derivatives). [7] Secondly,tetrahydroquinoline products were formed through aredox-neutral reverse-polarity Povarov-type radical cascade mechanism, whose pathway was favoured by vinyl sulfone and maleimide derivatives. [8] Notably,i nt he latter cases,t he alternative Giese-type product was not obtained, even with suitable adjustment of the reaction conditions.
In ac ontinuation of our research programme into establishing new reactivity of imine-derived a-amino radical species,wesought to explore the performance of electrophiletethered imines as ameans of achieving intramolecular C À C bond formation, thereby constructing complex (poly)cyclic molecular frameworks (Scheme 1B). Whilst singly cyclised Giese-type amino-indanes or doubly cyclised tetrahydroquinoline structures could feasibly result, the predominant outcome would depend on many competing factors,s ome of which we hoped to control in order to direct the reaction towards specific valuable products. [9,10] Herein we wish to report our findings.

Results and Discussion
Preliminary experiments were carried out using an a,bunsaturated ester tethered imine (1a), (Ir[dF(CF 3 )ppy] 2 -(dtbbpy))PF 6 as photocatalyst, the commercial Hantzsch ester (HE1)a sastoichiometric reductant, in DMSO and under blue light irradiation (Scheme 2A,l eft). Under these initial conditions,t he net reductive CÀCc oupled Giese-type amino-indane product was pleasingly observed in modest yields (2a,38%), with only the trans-configured diastereomer present. Interestingly,t he structurally complex cis-fused tetracyclic tetrahydroquinoline structure (3a)w as also isolated from the reaction mixture,albeit in low yield. Following this,p henyl-substituted Hantzsch ester (HE2,S cheme 2A, right), which our group has found to be effective in related reductive coupling methodologies, [7,11] was employed in the reaction system. In this case,t he product distribution was notably reversed, with the tetrahydroquinoline structure (3a) dominating under these conditions.The interlinked nature of these reaction products,c oupled with the absence of the opposite diastereomer for each, suggested that potentially diastereodivergent pathways leading to the net-reductive (2atrans)a nd redox-neutral products (3a-cis)w ere in operation. [12] Having uncovered this unusual redox-dependent switch in the product selectivity,w eb elieved that establishing reliable condition-controlled stereo-and redox-divergence of asingle imine starting material would be of synthetic value. [13,14] To this end, detailed optimisation studies to selectively produce either 2a or 3a were conducted (Scheme 2B;f or full optimisation details see supporting information). In an effort to maximise the yield of the Giese-type product (2a), solvent effects were found to be key to increasing selectivity,and also in avoiding direct reduction of the imine to the corresponding uncyclised amine (Entries 3-5), with DMA providing the indane framework in good yield (76 %) and selectivity (5.1:1). Initially,insitu imine formation could not be achieved under these conditions.F ortunately,asub-stoichiometric acetic acid additive eliminated the need for imine pre-formation, affording the desired product in similar yield and selectivity directly from the aldehyde and aniline precursors (Entry 6). Moving to am arginally lower-intensity,l ower-temperature light source resulted in excellent yield and selectivity (Entry 7, Conditions A). [15] Having identified that the 4-substituent of the Hantzsch ester was akey factor in switching between the two products (Entry 2), with the substituted Hantzsch ester reductant favouring the redox-neutral cyclisation product 3a,v arious Hantzsch ester derivatives were then investigated (Entries 8-12). [16] These studies identified HE6 (R = Et) as the optimal reductant, affording the fused tetrahydroquinoline product in 68 %y ield. Furthermore,a ddition of an acid co-catalyst allowed for in situ imine formation (Entry 13), and switching to the lower-intensity,lower-temperature light source resulted in a9 9% yield, with excellent selectivity (> 20:1, Entry 14,

Conditions B).
With optimal conditions now established for both pathways,t he scope of the diastereodivergent carbocyclisation was explored (Scheme 3). Pleasingly,a lmost quantitative yield of the Giese-type amino-indane framework (2b)w as observed when unsubstituted aniline was employed in the reaction system. [17] Notably,e xcellent selectivity for the mono-cyclised product was observed consistently throughout the scope under Conditions A. When exchanging the electronwithdrawing substituent on the alkene acceptor, a,b-unsaturated nitrile (2c), tert-butyl ester (2d), and alkenyl sulfone (2e)analogues were all found to be amenable to the reaction conditions.A na rray of substituted aniline starting materials was then explored, with the reaction exhibiting tolerance to substitution in the ortho, meta,a nd para positions of the aniline fragment, including alkyl (2j), trifluoromethoxy (2l), various halogen substituents (2f-2i), and even am onoprotected diaminoarene (2k). Interestingly,amino-indole and benzoxazole heteroaromatics were demonstrated to form the desired product in good yields (2m-2n). Ortho-ethyl substituted aniline (2o)and electron-deficient anilines appended with trifluoromethyl (2p)a nd pinacolboryl (2q)s ubstituents were also tolerated using Conditions A.
Our attention then turned to probing the scope of the dual cyclisation protocol leading to the cis-fused tetrahydroquinoline products.W hilst an intermolecular reverse-polarity Povarov reaction, which is thought to operate by as imilar mechanism, has previously been reported, [8] that chemistry could not be extended to a,b-unsaturated esters,a nd therefore examining the utility of other Michael acceptors with Conditions B was of interest. Pleasingly, a,b-unsaturated nitrile (3c), tert-butyl ester (3d), and alkenyl sulfone (3e) acceptors were all effective substrates in this methodology. Ther eaction was amenable to electronic variation on the aniline ring, with alkyl (3j), trifluoromethoxy (3l), protected amine (3k), and various halogen substituents (3f-i)tolerated. Notably,t he amino-indole (3m)a nd benzoxazole (3n) heteroaromatics were demonstrated to form the desired products in good yield, constructing complex fused pentacy-Scheme 1. Reductivep hotocatalytic functionalisation of imines in the context of this work. clic architectures from simple starting materials,with absolute selectivity for the C4/C7 position of the benzenoid ring of the indole/benzoxazole heteroaromatics,respectively.Unsurprisingly,e lectron-deficient [18] and sterically demanding anilines failed to undergo the second cyclisation.
Notably,m ost of the reactions exhibiting selectivity for the product of the redox-neutral pathway (3)did not consume 1equiv.o ft he Hantzsch ester (HE6), suggesting that substoichiometric quantities of the Hantzsch ester may still be able to lead to full conversion to the tetrahydroquinoline product. With this in mind, the reaction system was studied using 20 mol %o fHE6 (Scheme 4A)o nasubset of alkenetethered imine starting materials.A lthough generally in reduced yields compared with Conditions B,t he desired products were still obtained in all cases,h ighlighting an alternative method with potential for scale-up compatibility. Furthermore,t od emonstrate gram-scale preparation of amino-indane structure 2b,acontinuous-photoflow system was devised (Scheme 4B). Using an inexpensive 3D-printed insert for the photoreactor, [19] apre-mixed solution of 1b and HE1 in DMA [0.2 M] was shown, after a45minute run and 14 minute residence time,todeliver 0.99 gof2b in a78% yield.
Following this,the homologous six-membered carbocycle was prepared quantitatively from the analogous precursor (4, Scheme 5A)u sing Conditions A. Notably,s uch 1-aminotetrahydronaphthalene ring systems form the backbone of several selective seratonin reuptake inhibitor (SSRI) drugs, including the anti-depressant Sertraline. [20] Secondly,t he precursor aldehyde 6 was subjected to the reaction conditions without the addition of the aniline, thereby forming the nucleophilic ketyl radical, which subsequently cyclised to form the substituted indanol (7)i n

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Research Articles Scheme 3. Scope of the diastereodivergent carbocyclisation. a) Product d.r.is> 20:1 unless stated otherwise. In most cases, the majority of the remaining yield was identified as the product of the opposite diastereodivergent pathway;that is, 11 %( determined by 1 HNMR analysis, see Scheme 2) of 3a was observed under ConditionsAfor the formation of 2a.S electivity ratios based on 1 HNMR analysis of the crude reaction mixture are given for each product in the SI. b) 20 mol %a cetic acid added to facilitate in situ imine formation.c )Analysis by single crystal X-ray diffraction;see SI (CIF) for details. [17] Crystal structure of 2b·HCl shown. Aromatic CH, CH 3

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Research Articles excellent yield (Scheme 5B), with a9:1 dr in preference of the trans diastereomer. Finally,s ubstrates with linear aliphatic backbones (8a & 8b)w ere successfully cyclised under photocatalytic Conditions A,affording the corresponding aminocyclopentanes (9a & 9b)i ne xcellent yield. Interestingly,h owever,u nder Conditions B or any variant thereof,n oe vidence of an operational dual cyclisation pathway was detected and only diastereomeric products of asingle cyclisation pathway were isolated. [21] From am echanistic standpoint, and in order to elucidate the origin of the reagent-controlled diastereodivergent photocatalytic cyclisation, in-depth DFT (density functional theory) analysis (see Supporting Information for full computational details) was performed (Scheme 6). The a-amino radical 1,g enerated by the well-established iridium photocatalyst mediated proton-coupled electron transfer (PCET) of imine 1b, [1a, 5a, 7, 8] undergoes the first cyclisation through Giese addition to the tethered a,b-unsaturated ester (Scheme 6A). [5c, 22] Studies on the first cyclisation revealed that the formation of trans intermediate 2-trans through the transition structure (TS) TS2 is kinetically favoured in comparison to TS1 that forms 2-cis. Following this,the second cyclisation for the cis isomer from 2-cis proceeds through TS3 with al ower energy barrier than TS1,w hereas the second cyclisation for the trans isomer from 2-trans proceeds through TS4 with ah igher energy barrier than TS2 to form the energetically unfavourable intermediate 3-trans. In each case,t he preferred TS (TS2 and TS3)a dopts as taggered conformation with ad ihedral angle (]HCCH) around the newly forming CÀCb ond of nearly 1808 8 (Scheme 6B and C). Taken altogether, our computational investigations suggest that product 2b results from facile termination of 2-trans by aH antzsch ester-derived species,a nd product 3b is formed from doubly cyclised 3-cis as aresult of milder reducing conditions. [8,23] Deuterium incorporation studies revealed that 2-trans could reasonably be reductively quenched via HAT, or by sequential electron transfer/proton transfer (ET/PT) from an oxidised Hantzsch species,w ith both pathways competing (see Supporting Information). However,t his finding does not explain the origin of the different reaction outcomes when employing substituted vs. unsubstituted Hantzsch esters.I ndeed, bond dissociation energy calculations reveal that oxidised forms of both HE1 and HE6 can feasibly act as HATd onors,a nd both can also feasibly reduce 2-trans by an ET/PT pathway (see Supporting Information for details). Instead, apossible explanation lies in the difference in oxidation potentials between HE1 and HE6 (+ 0.97 Vand + 1.10 Vv s. SCE respectively;s ee Supporting Information for electrochemical measurements). With the unsubstituted Hantzsch ester being more readily oxidised, there is likely ah igher concentration of oxidised Hantzsch species,c apable of terminating the intermediate radical 2trans. This concurs with the observed difference in reaction rates between Conditions A and B,w ith the former being around five times faster in time-course studies. [24] To further validate the hypothesis that ah igher concentration of active HATagent favours termination of 2-trans, and therefore formation of addition product (2b)o ver the tetrahydroquinoline product (3b), doping experiments with 1,4-cyclohexadiene (1,4-CHD,ac ommonplace hydrogen atom transfer donor) were conducted (Table 1).
Starting with ar eaction system that afforded significant quantities of both products (2b:3b= 1:3.8, Table 1e ntry 1), the addition of 1equivalent of 1,4-CHD caused adistinct shift towards the single-cyclisation product (2b:3b= 1:1.5, Table 1 entry 2). Addition of af urther 2equivalents of the HAT donor increased this further, and addition of 5equivalents was sufficient to cause the single-cyclisation product to dominate (2b:3b= 1.9:1, Table 1e ntry 4). These experimental results are consistent with the existence of an HAT termination leading to the generation of 2b,w hich can be switchably controlled to allow either product of the diastereodivergent pathways to be selectively obtained.

Conclusion
Aswitchable photocatalytic diastereodivergent carbocyclisation of imine-derived a-amino radicals has been developed. Tw os ets of reaction conditions,w herein both the stereochemical and reactivity outcomes are predictably determined by the judicious choice of Hantzsch ester and solvent, lead selectively to either aGiese-type bicyclicaminoindane structure or af used tetracyclic tetrahydroquinoline architecture.T he robust strategy for single cyclisation was also shown to be applicable to larger ring systems,k etyl radicals,u nbiased aliphatic substrates,a nd to ac ontinuous flow regime.D FT analysis,d euterium incorporation studies, electrochemical measurements,a nd HAT-agent doping experiments aided in rationalising the diastereodivergent reaction pathways responsible for the reagent-controlled switchability of the product outcome.W ork is currently ongoing to uncover and develop further cascade cyclisations for the synthesis of complex amine frameworks.

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