Access to pyrrolines and fused diaziridines by selective radical addition to homoallylic diazirines

Pyrroline derivatives are common in bioactive natural products and therapeutic agents. We report here a synthesis of pyrrolines and fused diaziridines by divergent radical cyclization of homoallylic diazirines, which can serve as an internal radical trap and a nitrogen source. This reaction proceeds by selective radical addition to C 
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Created by potrace 1.16, written by Peter Selinger 2001-2019
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 C or NN bonds followed by intramolecular cyclization. Frontier molecular orbital analysis provides a deep insight into the origin of the selectivity. The reaction demonstrates a new cyclization mode, broad functional group compatibility and high product diversity, and reveals a much broader chemical space for diazirine studies.

Pyrroline and pyrrolidine structural motifs are widely encountered in bioactive natural products in plants, insects such as myrmicine ants and animals, including poison frogs. 1,2Consequently, new strategies to access pyrrolines and analogues address a long-standing interest of chemists.Notwithstanding the interest in transition-metal catalyzed synthesis of pyrroline derivatives over the past few decades, 3 radical approaches have also received remarkable attention owing to their innately attractive features which include mild reaction conditions and good tolerance of susceptible functional groups. 4The conventional radical approaches proceed through the generation of an iminyl radical by homolysis or single-electron transfer (SET) in labile precursors and the subsequent intramolecular N / C cyclization of the iminyl radical with C]C bonds.External radical acceptors are sought which can terminate the cascade reaction and furnish pyrroline products (Fig. 1a). 5We have conceived a reverse route which can access pyrrolines by C / N cyclization using external radical donors rather than acceptors (Fig. 1b).This process is intended to enrich product diversity and lead to distinct pyrrolines, such as CF 3 -substituted pyrrolines, which are difficult to produce by conventional methods.This is because there are no SOMOphiles that lead to the introduction of, for example, CF 3 groups.
Diazirines, which consist of one carbon and two nitrogen atoms in an unsaturated three-membered ring, are oen exploited in chemical biology as carbene precursors. 6They have been reported only rarely in radical reactions.The use of specic peruoroalkyl-substituted diazirines to trap carboncentered radicals was pioneered by Barton,7 and recently extended by Lopchuk et al. 8 and Liao et al. 9 Despite this elegant research, the use of diazirines as a nitrogen source for construction of valuable N-heterocycles remains underexplored.Herein, we report novel, divergent radical cyclization reactions of homoallylic diazirines (1) for the synthesis of pyrrolines and fused diaziridines (Fig. 1b).The selectivity of addition of an external radical to the C]C or N]N bond is dictated by the inherent polarity of the radical.The transformation of 1 can proceed through serial radical addition to C]C and N]N bonds, leading to diverse multi-functionalized pyrrolines (2 and 3).Alternatively, the reaction can proceed by rst adding the external radical to the N]N bond, followed by cyclization with the C]C bond, resulting in unusual fused diaziridines (4 and  5).The products may dene a much broader chemical space for diazirine studies, and in particular they can probe the reactivity and synthetic potential of diazirines.At the outset, frontier molecular orbital (FMO) analysis of the simplied model (1a ′ ) was conducted.The aim was to gain an insight into the discrepancy in the energy levels of alkenes and diazirines in the same molecule and to examine the feasibility of the hypothesis from a theoretical point of view.The results of the analysis demonstrated that the lowest unoccupied molecular orbital (LUMO) of 1a ′ is dominated by the LUMO of the diazirine moiety (Fig. 1c, le), while the highest occupied molecular orbital (HOMO) of 1a ′ is located more in the alkenyl moiety than in the diazirine (Fig. 1c, right).It was postulated that selective radical addition to the C]C or N]N bond might be controlled with an appropriate external radical.Experimental investigations began with the addition of a CF 3 radical to the dialiphatic diazirine (1a).The reactivity in radical reactions of dialiphatic diazirines without aryl or peruoroalkyl substituents has not been explored.The CF 3 radical was generated from the Ruppert-Prakash reagent (TMSCF 3 ) which was oxidized by (diacetoxyiodo)benzene (PIDA) at 0 °C (for details, see the ESI ‡).The transformation was initiated by adding a CF 3 radical to the C]C bond of 1a and ended with N]N interception, leading as expected, to the pyrroline (2a) (Scheme 1).This product is unlikely to be formed by the previously described N / C cyclization in Fig. 1b, due to the lack of a radical acceptor that can transfer the CF 3 group.The use of CsF as an additive is crucial to the reaction outcome, and other bases such as Cs 2 CO 3 or KF were ineffective in this reaction.
With the optimized reaction conditions established, the scope of aliphatic diazirines was explored (Fig. 2).An array of diazirines bearing diverse skeletons were tested and easily converted into the corresponding pyrrolines in synthetically useful yields.The benzyl-substituted diazirine (1h) gave rise to a mixture of a product (2h) with an over-oxidized product (2h ′ ), resulting from the spontaneous oxidation of the methylene between the phenyl and the pyrroline in air during the work-up procedure.3f,10 Diazirines bearing 1,1-disubstituted alkenes tended to construct pyrrolines containing quaternary centers regardless of steric hindrance.The substituents could contain alkyl, alkenyl, aryl, or heteroaryl groups (2i-2t).The electronic properties of aryl substituents had only a modest impact on the reaction outcomes (2m-2r).In those cases, the undesired oxidation of the tertiary benzylic radical intermediates to cations, which can occur under oxidative conditions, was not observed, indicating the priority of the intramolecular trapping of the benzylic radical by the N]N bond.The reaction of a diazirine (1u) bearing an internal alkene also proceeded Scheme 1 Optimal conditions for the formation of pyrroline by radical trifluoromethylation. smoothly, leading to an aza-spiro product (2u) with exclusive diastereoselectivity (dr > 20 : 1).Aryl-substituted diazirines (2v) are also suitable substrates for the reaction.In addition to pyrrolines, tetrahydropyridine as a six-membered analogue could also be produced under the same conditions (2w, 2x and 2y), enriching the product library.Construction of other sixmembered N-containing heterocycles could also be anticipated by placing various heteroatoms on the aliphatic chain.Attempts to construct seven-or eight-membered or even larger N-containing heterocycles by extending the aliphatic chain were unsuccessful.Remarkably, it was found however that this protocol can be applied to the dearomative 2,3-difunctionalization of indoles, providing spiro-indoline products (2z-2ab) with excellent stereo-selectivity.These three-dimensional indolines are widely distributed in various bioactive molecules. 11 Using electrophilic radicals other than the CF 3 radical further enriched the diversity of products from the reaction.As shown in Fig. 3, a portfolio of external radicals, such as di-or peruoroalkyl radicals, electron-decient alkyl radicals and sulfonyl radicals proved to be amenable to photoredox catalytic conditions, leading to the corresponding pyrrolines (3a-3m) in acceptable yields.The formation of 3e and 3f from the enynesubstituted diazirine precursors, is noteworthy, as the nascent propargyl radical was retained and engaged in the cyclization without conversion to the tautomeric allenyl radical. 12A set of (hetero)aryl, alkyl and styryl substituted sulfonyl radicals were added readily to the substrates, but the strong electron-decient radicals delivered a lower yield (3k).A sulfonyl radical could also be generated under thermal conditions using copper(II) acetate as the oxidant and sodium p-toluenesulnate as the radical source (3g).Combining this process with a metal-hydride hydrogen atom transfer (MHAT) led to the products containing incorporated hydrogen or deuterium (3n, 3o) in good yields, demonstrating the breadth of the method.
It was found that the addition of P-centered radicals to diazirine (1) proceeded through a distinct pathway and resulted in fused diaziridine products (Fig. 4).Diarylphosphinoyl radicals were generated from diarylphosphine oxides in the presence of silver nitrate as a catalyst, and were selectively added to the N]N rather than the C]C bond.The N / C cyclization generated an alkyl radical reaction which was terminated by HAT from diarylphosphine oxide.Meanwhile, the diarylphosphinoyl radical was regenerated, perpetuating the radical chain process.Compared to the diazirines (4a, 4b) which bear a 1,2-dialkyl alkene, the diazirine bearing a trisubstituted alkene delivered a lower yield (4c), probably because of the weak H-atom transfer (HAT) ability of the tertiary alkyl radical and the steric congestion that impeded the  HAT.The engagement of the highly reactive primary alkyl radicals from HAT was less controllable, and also led to a decreased yield (4d). Skeletal complex polycyclic diaziridines (4e, 4f) are otherwise difficult to prepare, but were furnished in useful yields by this method.A quaternary carbon center can be readily constructed in this reaction.
The reductive cyclization of 1 was accomplished to generate a new type of fused diaziridine (5) under photochemical conditions using a Hantzsch ester (HE) as a reducing agent (Fig. 5).These fused diaziridines might serve as versatile precursors for various N-heterocycles according to published approaches. 13The reaction leading to fused diaziridines was initiated by the reductive quenching of excited fac-Ir(ppy) A scaled-up preparation of pyrroline (2m) from 2 mmol of 1m was achieved with 82% isolated yield, illustrating the practicality of the protocol.The products could be further converted to other valuable molecules (Fig. 6).For example, in the presence of diisobutyl aluminum-hydride (DIBAL-H), 2m was readily reduced to a pyrrolidine (6).The treatment of 2m with m-CPBA gave rise to a fused oxaziridine (7).The [3 + 2] cycloaddition of 2a with N-hydroxybenzimidoyl chloride generated the biologically relevant, CF 3 -substituted 1,2,4-oxadiazoline (8). 14Addition of an allyl Grignard reagent to the C]N bond of 2m in the presence of BF 3 $Et 2 O afforded 2,2,5,5-tetrasubstituted pyrrolidine (9).Simple treatment of 5a with acetyl chloride resulted in N-acetyl-tetrahydropyridazine (10) by a ring-opening process.
Based on the above experimental and computational results, a plausible mechanism is depicted in Fig. 7.For electrophilic radicals such as the uoroalkyl and sulfonyl radicals, the selective addition to the C]C bond of 1, followed by intramolecular trapping of a radical (a) by the N]N bond gives rise to an N-centered radical (b), which can form a dimer (c).Intermediate c is unstable, and simultaneously undergoes N 2 extrusion to afford two molecules of the pyrroline product. 7,15e formation of radical b was conrmed by the detection by HRMS of the fused diaziridine (d) which is gained from competitive HAT.In contrast, the relatively nucleophilic phosphinoyl radical prefers addition to the N]N bond of 1, resulting in radical e.The subsequent intramolecular cyclization to the C]C bond and HAT affords the fused diaziridine products.The formation of intermediate e was conrmed by the isolation of byproduct g derived from HAT.

Conclusions
In summary, a novel radical-mediated divergent synthesis of pyrrolines and fused diaziridines from rationally designed alkene-substituted diazirines is described.The key to the success of the reaction is the selective addition of an external radical to the C]C or N]N bond, which is controlled by the inherent electronic characteristics of the external radical.FMO sheds light on the underlying reason for the chemoselectivity.The protocol features good functional group tolerance and high product diversity, and creates a much broader chemical space for diazirine studies.
3 with Hantzsch ester to form an Ir(II) species.Its strong reduction potential (E III/II 1/2 = −2.19V vs. SCE) enables single-electron reduction of the N]N bond of diazirine (E RE 1/2 = −2.06V vs. SCE) to an N-centered radical anion (for details, see the ESI ‡), and this is followed by a sequence of intramolecular cyclization, HAT and protonation.It should be noted that excited fac-Ir(ppy) 3 ðE III*=IV 1=2 ¼ À1:73 V vs: SCEÞ is not sufficient to reduce diazirines to trigger the reaction.