This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
Article Cite This: ACS Omega 2019, 4, 870−879
http://pubs.acs.org/journal/acsodf
Synthesis of Selenoaziridines: A Study on Stereochemical Outcomes of the Reaction of Aziridine Radicals and Anions Generated from Iodoaziridines Tom Boultwood‡,† and James A. Bull*,‡ ‡
Department of Chemistry, Imperial College London, Molecular Sciences Research Hub, White City Campus, Wood Lane, London W12 0BZ, U.K.
Downloaded via 5.62.155.126 on January 19, 2019 at 05:44:15 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: The synthesis of a new functional group in the form of selenyl-substituted aziridines is described. Selenoaziridines are stereoselectively prepared by functionalization of intact aziridine precursors involving radical and anionic intermediates. Radicals are generated from cis-N-Ts iodoaziridines by activation of the C−I bond using alkoxides as a source of single electrons. These form predominantly trans-substituted selenoaziridines dependent on the size of the diselenide. cis-Aziridinyllithiums generated by Li−I exchange also react with diselenides stereospecifically to form a range of cis-selenoaziridines. Proposals for the stereochemical outcome are presented.
■
idines.12,13 The generation of aziridinyl metal species via functional group exchange has enabled the development of aziridinyl palladium-catalyzed cross-coupling, as reported recently by ourselves14 and Vedejs.15 On the other hand, the functionalization of aziridines via formation of aziridinyl radical species has received far less attention. Most notable approaches to C-centered aziridinyl radical species have been demonstrated by Ziegler (Scheme 1b), forming bromoaziridines (4:1 cis/trans) via a Barton decarboxylation bromination sequence from aziridine carboxylates, in the synthesis of mitomycin-like antitumor agents.16 Yamanaka has also demonstrated the formation of halogenated aziridines via aziridinyl radical intermediates.17 Selective reduction of 2,2-dihalogenated aziridines with H-SnBu3 through a radical chain reaction affords the dehalogenated aziridine via a carbon-centered radical species. We were interested in the generation of aziridinyl radicals from iodoaziridines to investigate the formation and reactivity of these radical species. We chose to investigate this through the formation of C-selenoaziridines, a novel functional group, which we also expected to allow facile interpretation of the stereochemical outcome. In particular, we envisaged the use of KOtBu as a source of electrons to reduce the iodoaziridine and form the intermediate aziridinyl radical. Alkoxide bases in combination with simple alcohols/amine ligands have been used for the generation of radical species in metal-free crosscoupling reaction.18−20 KOtBu, in particular, has been shown to provide weakly solvated electrons and be sufficient to
INTRODUCTION Aziridines are widely regarded as valuable synthetic intermediates in organic synthesis.1 The ring strain inherent in the three-membered ring makes them reactive as electrophiles in stereocontrolled ring opening processes to generate Ncontaining compounds.2,3 In addition, the small ring structure confers a structural fascination, which has led to numerous studies into new aziridine derivatives and their reactivity in a wide variety of chemistry. A variety of heteroatom-substituted aziridines have been developed, which have afforded further diverse reactivity.4 There has been a considerable interest in the functionalization of intact aziridines as a divergent strategy to prepare aziridine derivatives.5−15 Predominantly, this has been achieved via the generation of aziridinyl anions and trapping with highly reactive electrophiles.5 Early studies from Beak demonstrated the viability to deprotonate N-Boc aziridines.6 More recently, Hodgson developed stereoselective reaction of terminal aziridines with strong lithium amide bases in a regioand stereoselective fashion using N-Bus aziridines and a range of electrophiles at low temperature.7 Installation of the electrophilic moiety occurs trans to the alkyl group on the ring. In contrast, Florio and co-workers have demonstrated that aromatic substituted N-Bus aziridines undergo benzylic deprotonation, resulting in the formation of terminal disubstituted aziridines, after trapping with suitable electrophiles.8 Functional group exchange leading to unstabilized aziridinyl metal species, as well as trapping with electrophiles, has also been effective as an approach to intact aziridine functionalization, with leading works from Satoh,9 Vedejs,10 and Aggarwal.11 We recently disclosed a route to cissubstituted N-Ts aziridines via a stereospecific Li−I exchange/electrophilic trapping protocol using N-Ts iodoazir© 2019 American Chemical Society
Received: October 30, 2018 Accepted: December 26, 2018 Published: January 10, 2019 870
DOI: 10.1021/acsomega.8b03019 ACS Omega 2019, 4, 870−879
ACS Omega
Article
the synthesis of cis-substituted selenoaziridines.12 Pleasingly, this could be achieved for selenides through treatment of iodoaziridine 1 with nBuLi and reaction with diphenyldiselenide. Low temperatures were required for the stability of the intermediate aziridinyl lithium species, which is formed and reacts very rapidly. Re-evaluation of the reaction conditions allowed a reduction of the amount of diselenide used to 1 equiv (Scheme 3) to afford selenoaziridine cis-5a in high yield
Scheme 1. (a−c) Approaches to the Functionalization of Intact Aziridines Involving (a) Aziridinyllithium and (b) Aziridinyl Radical Intermediates and (c) This Work
Scheme 3. Formation of cis-Selenoaziridine 5a by Stereospecific Lithiation/Trapping of Aziridinyl Lithiums with Diphenyl Diselenide
as a single cis-diastereoisomer. Interestingly, the lithium phenylselenide generated as the by-product of Ph2Se2 reacts preferentially with the nBuI generated through the exchange process. This protects the aziridine products from potential further ring opening reactions or from undesired alkylation reactions. The scope of this reaction was then explored varying both the diselenide and iodoaziridine (Scheme 4), with cispromote biaryl cross-coupling reactions in the presence of an aryl halide and benzene.21 Here, we report studies into the synthesis of seleniumsubstituted aziridine derivatives. Selenoaziridine derivatives with cis- and trans-substitution are accessed stereoselectively via aziridinyllithium species and aziridinyl radicals, both generated from iodoaziridines. This involves a new approach to the preparation of aziridinyl radicals, generating the radical species from iodoaziridines by a single electron transfer from KOtBu to functionalize the intact aziridine.
Scheme 4. Formation of cis-Selenoaziridines via Stereospecific Lithiation/Trapping of Aziridinyl Lithiums with Diselenidesa
■
RESULTS AND DISCUSSION N-Ts iodoaziridines 1−4 were prepared in gram quantities from simple imines according to our previously reported protocols and formed exclusively as their cis-diastereoisomers (Scheme 2).13 For alkyl-substituted N-Ts imines, the diiodomethylmagnesium reagent was used, formed by exchange of ethylmagnesium chloride with iodoform.13d For the phenyl imine, LiCHI2 was suitable, formed by the deprotonation of diiodomethyllithium with LiHMDS.22 To establish the viability of the selenoaziridine functional group, we first applied our lithiation and trapping protocol to
Reaction conditions: nBuLi (1.5 equiv), THF (0.065 M), −100 °C, addition of aziridine (0.27 mmol) in THF, 5 s; then, diselenide (1.0 equiv), THF, −100 °C, 5 min. bContained 2-phenyl-1-(tosyl)aziridine as an inseparable impurity (7% yield). cContained 2-phenyl1-(tosyl)aziridine as an inseparable impurity (6% yield). dYield calculated on the basis of desired product only. a
Scheme 2. Diastereoselective Synthesis of N-Ts Iodoaziridines via Addition of Diiodomethylmagnesium Chloride or Diiodomethyllithium to N-Ts Imines
selenoaziridines being formed exclusively in all cases, as supported by coupling constants, on the analysis of the 1H NMR spectra of the crude product (e.g., for selenoaziridine cis5a, δ 4.26 ppm, J = 6.8 Hz for CHSePh; cf. J = 4−5 Hz for typical trans-substitution). Employing (1) diphenyl diselenide or (2) dibenzyl diselenide as the electrophile gave similar results with each of the iodoaziridines. Trapping the corresponding aziridinyllithium species afforded cis-selenoaziridines 5−8 in high yields. Both secondary alkyl and phenyl 871
DOI: 10.1021/acsomega.8b03019 ACS Omega 2019, 4, 870−879
ACS Omega
Article
and led to almost quantitative return of starting iodoaziridine 1 under the reaction conditions. Kappe has shown that LiHMDS can be used in place of KOtBu to affect the direct arylation of benzene with aryl bromides in the presence of 1,10phenanthroline.23 Iodoaziridine 1 was subjected to the reaction conditions in the presence of NaHMDS, which led to the desired formation of selenoaziridine 5a but in reduced yields to KOtBu/iPrOH (entry 6). Chan has demonstrated that cesium alkoxides can be employed in transition metal-free crosscoupling of benzene with aryl halides.24 However, cesium carbonate in combination with iPrOH also led to reduced yields of selenoaziridine 5a, although an increased dr (8.7:1) was observed (entry 7). After extensive further study, conditions using KOtBu (1.6 equiv) and iPrOH at 0.1 M substrate concentration were chosen as optimal to generate the desired reactive aziridinyl radical species from iodoaziridine 1 and trap with diphenyl diselenide in good yield and dr for 5a (Table 2, entry 1). A full
iodoaziridines were tolerated, affording the corresponding selenoaziridines, which were stable to silica gel chromatography. The sterically hindered tert-butyl-substituted iodoaziridine also gave rise to exclusively the cis-substituted selenoaziridines 7, implying very high stereochemical fidelity in the exchange process. Competing dehalogenation of iodoaziridine 4, arising from protonation of the highly reactive aziridinyllithium intermediate to give 2-phenyl-1-tosylaziridine, led to slightly reduced yields for selenoaziridines 8a and 8b. Attempts at trapping the highly reactive aziridinyllithium species arising from Li−I exchange on iodoaziridine 1 with Se2Me2 resulted in poor conversion to the desired cisselenoaziridine (
