Thiyl Radicals: Versatile Reactive Intermediates for Cyclization of Unsaturated Substrates

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Review Thiyl Radicals: Versatile Reactive Intermediates for Cyclization of Unsaturated Substrates

Dylan M. Lynch and Eoin M. Scanlan *

School of Chemistry and Trinity Biomedical Sciences Institute (TBSI), Trinity College Dublin, The University of Dublin, Dublin 2, Ireland; [email protected] * Correspondence: [email protected]

Academic Editor: John C. Walton Received: 15 June 2020; Accepted: 2 July 2020; Published: 7 July 2020

Abstract: Sulfur centered radicals are widely employed in chemical synthesis, in particular for alkene and alkyne hydrothiolation towards thioether bioconjugates. The steadfast radical chain process that enables efficient hydrothiolation has been explored in the context of cascade reactions to furnish complex molecular architectures. The use of thiyl radicals offers a much cheaper and less toxic alternative to the archetypal organotin-based radical methods. This review outlines the development of thiyl radicals as reactive intermediates for initiating carbocyclization cascades. Key developments in cascade cyclization methodology are presented and applications for natural product synthesis are discussed. The review provides a chronological account of the field, beginning in the early seventies up to very recent examples; a span of almost 50 years.

Keywords: radical; cyclisation; thiyl radicals; sulfur; carbocyclization

1. Introduction Since the turn of the millennium, organosulfur compounds have garnered substantial interest in the fields of medicinal chemistry, chemical biology and material science [1–7]. Of the diverse biochemical processes involving free radicals, many are thiyl radical mediated, highlighting the chemoselectivity, efficiency and biocompatibility of these reactive intermediates [8]. Sulfur-centered radicals have been broadly utilized in a wide range of synthetic applications over the past three decades. While their general utility has been previously reviewed [9–17], this account seeks to update the reader specifically on the application of thiyl radicals (RS•), in the carbocyclizations of unsaturated moieties, and the scope and limitations of these reactions in natural product synthesis. Sulfur, in its 2 oxidation state, can act as either a nucleophile or as a radical. The S-H bond is − generally considered relatively weak, with a bond dissociation energy (BDE) of 365 kJ/mol [18], and as such, both alkyl thiols and thiocarboxylic acids (thioacids) are precursors to thiyl/acyl thiyl radicals through facile homolytic cleavage. Thiyl radicals may be generated by homolytic bond breakage, and by one-electron redox processes. In the former process, a carbon centered radical (for example, from the radical initiator azobisisobutyronitrile (AIBN)) will abstract a hydrogen atom from the thiol. 8 1 1 Rate constants for this homolytic breakdown are of the magnitude 10 M− s− , which is below the diffusion limit for this reaction [19]. In the case of redox processes, single electron oxidants such as Mn (III) complexes or other metal sources can be used to accomplish radical formation [20–22]. Both radiolysis and direct photolysis of the S-H bond under UV irradiation are also valuable pathways to thiyl radical formation [23,24]. Thiyl radicals are well known to react efficiently at sites of unsaturation, through the thiol-ene and thiol-yne reactions. A full analysis of the utility of these reactions is beyond the scope of this review, and readers are directed to the reviews already present in the literature [6,24–29]. This account will

Molecules 2020, 25, 3094; doi:10.3390/molecules25133094 www.mdpi.com/journal/molecules Molecules 20202020,, 2525,, xx FORFOR PEERPEER REVIEWREVIEW 22 ofof 4242 Molecules 2020, 25, 3094 2 of 40 will focus exclusively on the intramolecular trapping of the nascent carbon radical formed via thiyl radicalfocusradical exclusively addition,addition, andand on the howhow intramolecular thesethese radicalsradicals trapping formform ringsrings of the andand nascent productsproducts carbon inin cascadecascade radical reactions.reactions. formed via thiyl radical addition, and how these radicals form rings and products in cascade reactions. 2. Dienes and Diynes 2. Dienes and Diynes 2.1. Origin 2.1. Origin For the purpose of this review, ‘homogenous’ infersfers thethe samesame degreedegree ofof unsaturationunsaturation forfor allall reactivereactiveFor sitessites the purpose inin thethe substratesubstrate of this review, oror substrates;substrates; ‘homogenous’ i.e.,i.e., dienes, infers diynes, the same trienes, degree etc. of Possibly unsaturation the earliest for all examplereactive sitesof a incyclization the substrate cascade or substrates;on a homogenous i.e., dienes, substrate diynes, was trienes, published etc. Possiblyby Kuehne the et earliest al. in 1977.[30]example The of a account cyclization details cascade thethe cyclizationcyclization on a homogenous ofof selectedselectedsubstrate dienesdienes wiwi wasthth aa rangerange published ofof thiylthiyl by radicalradical Kuehne precursors,precursors, et al. in relying1977relying [30 ].uponupon The accountradicalradical detailsinitiationinitiation the cyclizationviavia photolysis of selected of diphen dienesyl withdisulfide a range or of thermolysis thiyl radical of precursors, benzoyl peroxide.relying upon Kuehne radical and initiation co-workers via photolysis sought ofto diphenyl compare disulfide the cyclizations or thermolysis effected of benzoyl by a range peroxide. of representativeKuehnerepresentative and co-workers thiylthiyl radicalradical sought species,species, to compare andand thusthus the cyclizationsexexperimented eff ectedwith bythe a initiator range of representativeitself, and thermal thiyl versusradical photoinitiation. species, and thus While experimented they obtained with a the nu initiatormber of itself,acyclic and adducts thermal and versus complex photoinitiation. mixtures of stereoisomers,Whilestereoisomers, they obtained aa numbernumber a number ofof cyclizedcyclized of acyclic productsproducts adducts werewere and complexalsoalso identified.identified. mixtures TheThe of stereoisomers,representativerepresentative aexampleexample number in ofin Schemecyclized 1 products shows the were cyclization also identified. of dimethyl The representativediallylmalonate example 1 under in a Schemenumber1 ofshows reaction the cyclizationconditions, theofthe dimethyl bestbest ofof whichwhich diallylmalonate employedemployed thethe1 under photolysisphotolysis a number ofof diphendiphen of reactionylsulfide conditions, in benzene the to best generate of which the employed thiyl radical the ofphotolysis ethanethiol. of diphenylsulfide These conditions in benzene resulted to in generate the formation the thiyl of radical over 90% of ethanethiol. cyclized product These conditions2,, andand sixsix minorresulted acyclic in the adducts. formation However, of over the 90% formation cyclized of product any six-membered2, and six minor cyclization acyclic products adducts. was However, ruled outthe formationsystematically. of any six-membered cyclization products was ruled out systematically.

SchemeScheme 1.1. CyclizationCyclization ofof dimethyldimethyl diallylmalonatediallylmalonate byby ethanethiylethanethiyl radical.radical. XX == H or SCH 22CHCH33.. .

Kuehne and co-workers applied these findings ﬁndings to the analogous cyclization of of αα-acoradiene-acoradiene 44,,, which proceededproceeded almostalmost quantitatively.quantitatively. Desulfurization Desulfurization with with Raney Raney nickel nickel yielded yielded dihydrocedrene dihydrocedrene6, 6the,, thethe hydrogenated hydrogenatedhydrogenated form formform of a of sesquiterpeneof aa sesquiterpenesesquiterpene found foundfound in the in essentialin thethe essentialessential oil of cedar oiloil ofof (Scheme cedarcedar 2(Scheme(Scheme). This approach 2).2). ThisThis approachwas later appliedwas later to theapplied cyclization to the ofcyclization geranyl acetate, of geranyl but the acetate, acyclic but monoadducts the acyclic ofmonoadducts geranyl acetate of geranyland the acetate thiyl radical and the source thiyl were radical mostly source obtained. were mostly obtained.

Scheme 2. CyclizationCyclization of α-Acoradiene-Acoradiene 44 byby Kuehne Kuehne et et al al.al..

These results results were were greatly greatly expanded expanded upon upon in inwork work published published by Padwa by Padwa et al. et in al. 1985.[31] in 1985 Using [31]. thioaceticUsingthioacetic thioacetic acidacid andand acid AIBN,AIBN, and PadwaPadwa AIBN, andand Padwa co-workersco-workers and co-workers werewere ableable were toto cyclizecyclize able aa to relativelyrelatively cyclizea simplesimple relatively tosylaminetosylamine simple 7tosylamine withwith twotwo allyl7allylwith substituents,substituents, two allyl substituents, inin aa 55-exo-trig-exo-trig in aprocess. 5-exo-trig Additionprocess. of Addition the thiyll of radical,radical, the thiyl formedformed radical, indirectlyindirectly formed byindirectly thermolysis by thermolysis of AIBN, and of AIBN, intramolecular and intramolecular cyclizationization cyclization ofof thethe nascentnascent of the carbon-centeredcarbon-centered nascent carbon-centered radicalradical 8 immediatelyradicalimmediately8 immediately provedproved thethe proved utilityutility the ofof utility thisthis reactionreaction of this reactionasas aa viableviable as arouteroute viable toto routeheterocyclesheterocycles to heterocycles (Scheme(Scheme (Scheme 3A).3A). ItIt may3mayA).

Molecules 2020, 25, 3094 3 of 40 Molecules 2020, 25, x FOR PEER REVIEW 3 of 42 beIt may expected be expected that the that trans the transisomerisomer would would dominate dominate in this in this process, process, whether whether for for steric steric reasons reasons or otherwise, but but in in fact fact a a general general preference preference for for the the ciscis isomerisomer isis observed. observed. Hyperconjugative Hyperconjugative mixing mixing of theof the half-filled half-filled p orbital p orbital and and the the C-H C-H σσ andand σσ* *orbitals orbitals produce produce a a semio semioccupiedccupied delocalized orbital which isis of of matching matching symmetry symmetry to theto alkenethe alkeneπ* orbital. π* orbital. Therefore Therefore in the transition in the transition state, the cisstate,-isomer the cis-exhibitsisomer a secondexhibits interaction a second interaction between the between carbon-centered the carbon-centered radical and radical remaining and remaining olefin, off settingolefin, offsettingthe nonbonded the nonbonded repulsion between repulsion the vicinalbetween substituents the vicinal of thesubstituents newly formed of the pyrrolidine newly formed [32–34]. pyrrolidine.[32–34]Simple substitution Simple at the alkene substitution terminus at the does alkene not a ffterminusect the cyclization, does not affect and thethe processcyclization, continues and the to processfollow a continues 5-exo-trig pathway.to follow a 5-exo-trig pathway.

Scheme 3. CyclizationCyclization of diene ( A)) and and diyne diyne ( B) systems via thiyl radical cascade by Padwa et al.

Padwa et al. also also reported reported the the addition of an acetylthiyl radical onto another homogenously unsaturated substrate; the corresponding N,NN,N-dipropargylsulfonamide 1111 (Scheme(Scheme 33B).B). InIn thisthis casecase however, a crystalline solid was obtained from th thee reaction as the major product, which was later identifiedidentified as the thienopyrrole 14. Following Following addition addition of of the the thiyl radical to the alkyne, the nascent carbon-centered radical cyclizes as shown in Scheme3 3.. However,However, thisthis resultsresults inin formationformation ofof aa highlyhighly unstable vinyl radical intermediate 13, which through an intramolecular homolytic substitution (S(SHi)i) extrudes an an acyl acyl radical radical to to afford afford the the observed observed product product 1414. Indeed,. Indeed, this this is isone one of ofthe the few few examples examples of aof diyne a diyne cyclization cyclization via via thiyl thiyl radicals radicals that that one one can can find find in in the the literature. literature. A A second second account account of diyne reactivity underunder thiyl thiyl radical radical addition addition appeared appeared three three decades decades later,in later, which in Agrawal which etAgrawal al. optimized et al. optimized a number of substrates with malonate-type backbones for cyclization to the respective

Molecules 2020, 25, 3094 4 of 40

a number of substrates with malonate-type backbones for cyclization to the respective thiophene [35]. This approach relies on thermolysis of AIBN in toluene with thioacetic acid as the acyl thiyl radical source, and furnished a number of the bicyclic thiophenes, in good yield.

2.2. Early Applications in Total Synthesis Shortly thereafter, a significant advancement in the application of thiyl radical initiated cascades was published by Naito et al. [36]. In a publication focused on the total synthesis of two imidazole alkaloids, Naito and co-workers employed the thiyl radical addition/cyclization cascade of an N-allyl-N-benzylcinnamamide 15 with diphenyl disulfide and thiophenol in equimolar quantities, which under photochemical irradiation cyclized to the desired 3,4-disubstituted pyrrolidinone 16, albeit as a racemic mixture. This afforded the necessary building block to complete their synthesis of isoanatine 17 and anantine 18 (Scheme4A) [ 37]. Just two years later, Naito et al. expanded upon the utility of this reaction, in part one of a series on radical cyclization in heterocycle synthesis [38]. Through application of the methodology developed for their previous alkaloid synthesis, Naito and co-workers developed a new synthetic method which furnished nitrogen-containing heterocycles from simple dienylamide starting materials. This addition generates either one or two carbon-sulfur bonds, and the desired carbon-carbon bond. The authors sought to establish the regiochemistry of thiyl radical addition, the cyclization mode (i.e., 5-exo-trig vs. 6-endo-trig) and finally, whether any stereochemical control was exerted by the process. By using a substrate with two different types of olefins, an insight Moleculesinto the 2020 chemoselectivity, 25, x FOR PEER REVIEW was also recorded. 5 of 42

Scheme 4. Dienylamide cyclizations published by Naito et al. in 1993 (A) and 1995 (B). Scheme 4. Dienylamide cyclizations published by Naito et al. in 1993 (A) and 1995 (B).

ShortlyIt was before postulated the turn that of the the millennium, cyclization anothe occurredr example through highlighting addition to the the efficacy acrylamide of the terminus,thiyl radicalfollowed addition/cyclization by cyclization ontoprocess the emerged alkene offrom the Harrowven neighboring and allyl collaborators.[42] substituent, throughIn the course a 5- exoof -trig theirpathway work in (Scheme the terpenoid4B). The field, phenylthiyl the authors radical took generated advantage in of this a sulfur reaction mediated displays radical reactivity cyclization somewhere strategybetween to a nucleophiliccomplete the and total electrophilic syntheses radical of aplysin [39], therefore and debromoaplysin. the SOMO should Through react more clever favorably retrosynthetic analysis, Harrowven et al. identified that a 5-exo-trig cyclization through a chair-like with the lower energy LUMO of an electron deﬁcient alkene—in this case the acrylamide substituent. transition state would simultaneously furnish both the sterically demanding tricyclic backbone of Furthermore, as the thiol-ene reaction is reversible [40,41] the concomitant radical formed via addition aplysin, and generate the relative stereochemical configuration for three neighboring stereogenic to the acrylamide terminus 20 would be further stabilized by its adjacent carbonyl group. In the case of centers. Employing a Raney nickel desulfurization strategy, Harrowven et al. obtained the necessary skeleton 29 in a diastereomeric ratio of 8:1 (Scheme 5). Similar to the previously discussed strategy employed by Kuehne et al., the use of thiyl radicals offers a much cheaper and less toxic alternative to the archetypal organotin based radical methods.

Scheme 5. Thiyl radical mediated cyclization and desulfurization gives 30, the precursor to all the aplysins.

From this point, Harrowven and co-workers delved deeper into the dynamics of the thiyl mediated cyclization and exploited the reaction for the cyclization of 1,6-dienes. A further account

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Molecules 2020, 25, 3094 5 of 40 thiyl radical addition to the allylic terminus 23, this stabilization is absent and as such the equilibrium of the thiol-ene reaction favors the starting amide. Naito and co-workers went on to examine the substituent effects, and found that those substrates with no additional functionality at the β-position of the acrylamide group primarily furnished lactams. The presence of a substituent α to the unsaturated amide appearedScheme to4. Dienylamide have no effect cyclizations on cyclization published dynamics. by Naito However,et al. in 1993 in (A the) and case 1995 where (B). both olefin termini are substituted, even with a methyl group, no cyclization was observed. Shortly before the turn of the millennium, anotheranother example highlighting the eefficacyfficacy of the thiyl radical additionaddition/cyclization/cyclization processprocess emergedemerged fromfrom HarrowvenHarrowven and and collaborators collaborators.[42] [42]. In the course of their work in the terpenoid field,field, the authors took advantage of a sulfur mediated radical cyclization strategy toto complete complete the totalthe synthesestotal syntheses of aplysin of andaplysin debromoaplysin. and debromoaplysin. Through clever Through retrosynthetic clever analysis,retrosynthetic Harrowven analysis, et al.Harrowven identified et that al. aidentified 5-exo-trig thatcyclization a 5-exo-trig through cyclization a chair-like through transition a chair-like state wouldtransition simultaneously state would furnish simultaneously both the sterically furnish demandingboth the sterically tricyclic demanding backbone of tricyclic aplysin, andbackbone generate of theaplysin, relative and stereochemical generate the configurationrelative stereochemical for three neighboring configuration stereogenic for three centers. neighboring Employing stereogenic a Raney nickelcenters. desulfurization Employing a Raney strategy, nickel Harrowven desulfurization et al. obtained strategy, the Harrowven necessary skeleton et al. obtained29 in a diastereomeric the necessary ratioskeleton of 8:1 29 (Scheme in a diastereomeric5). Similar to ratio the previously of 8:1 (Scheme discussed 5). Similar strategy to employed the previously by Kuehne discussed et al., strategy the use ofemployed thiyl radicals by Kuehne offers et a muchal., the cheaper use of thiyl and radica less toxicls offers alternative a much to cheaper the archetypal and less organotintoxic alternative based radicalto the archetypal methods. organotin based radical methods.

Scheme 5. ThiylThiyl radical radical mediated mediated cyclization cyclization and and desulfurization desulfurization gives gives 30, 30the, theprecursor precursor to all to the all theaplysins. aplysins.

From this point, Harrowven and co-workers delved deeper into the dynamics of the thiyl mediated cyclization and exploited the reaction for thethe cyclizationcyclization ofof 1,6-dienes.1,6-dienes. A further account published by Harrowven et al. [43] supersedes the earlier aplysin work, and a diverse library of thiabicyclo[3.3.0]octanes were synthesised through the co-cyclization of 1,6-dienes with concomitant sulfur atom transfer. The authors proposed that if the rules provided by Beckwith for ring closure [44,45] were obeyed, a second cyclization (following initial diene cyclization), of a radical intermediate predisposed to homolytic substitution at sulfur would be observed. In their screening of reaction conditions, Harrowven et al. identified that photolysis of a solution of the diene and di-tert-butyl disulfide in hexanes provided the desired tetrahydrothiophene; reactions only reached an appreciable efficiency when a quartz photochemical cell was employed (instead of a Pyrex cell), and addition of triethylborane greatly accelerated the rate. Up to 31% starting material was recovered in some cases, yet the tolerance of the thiyl radical addition/cyclization is evident in the examples shown below (Scheme6). Insert A shows some of the more exotic examples furnished by Harrowven and co-workers. In a follow up letter Harrowven et al. expanded the cyclization to a solid support [46] using a carbodiimide coupling to a Wang-type resin [47], noteworthy in that very few tin-free radical cyclizations have been conducted on solid supported substrates [48–50]. Relying instead on thermolysis of AIBN for initiation, the authors demonstrated conservation of both yield and diastereoselectivity Molecules 2020, 25, 3094 6 of 40

with respect to their preceding solution phase results. Further utility of the reaction in terpenoid synthesis by Barrero et al. [51] involved a short synthesis of ( )-dehydroiridomyrmecin, a natural ± iridoid. Again using two equivalents of thiophenol and one equivalent of AIBN in refluxing benzene afforded the backbone for this biologically interesting iridane, and comprised the first total synthesis of Moleculesthis substrate. 2020, 25, x FOR PEER REVIEW 7 of 42

R S S R t(BuS) , hν A 2 H H H H Et3B, Hexanes H H 10°C, 4-18 h S 33-55 % 31 32a-h O O O O R R 33 R 61% tBuS 5-exo-trig 2:1 t S Bu StBu S S tBu R H H H H H H O O S O O 34 H O H O H 51% 2:3 S S S H O H O H OH OH 32a* 32b 32c H CO R H CO R 55% 55% 33% 2 2 CO R CO R S 2 S 2 O H H H 35 S R=Me,52%,4:1 O S FmocN S R=Et,61%,2:1 O H H H S S 32d* 32e 32f H H 46% 45% 42% H H H H O O O O O O O O H O O O O H H H H TsN S 36 S H 50% 32g 32h 2:3 73% 33%

Scheme 6. The 1,6-diene co-cyclization by Harrowven et al. * Did not require Et3B as an additive. Scheme 6. The 1,6-diene co-cyclization by Harrowven et al. * Did not require Et3B as an additive. Insert A: Examples by Harrowven et al. Insert A: Examples by Harrowven et al.

2.3.2.3. Dienes Dienes as asPrecursors Precursors to toHeterocycles. Heterocycles. MiyataMiyata et etal. al.published published two two brief brief accounts accounts on onthe the application application of thiyl of thiyl radical radical addition/cyclization; addition/cyclization; thesethese accounts accounts comprise comprise partsparts tenten and and eleven eleven in ain series a series on heterocycle on heterocycle synthesis synthesis via radical via cyclization radical cyclizationfrom the from Naito the group Naito [52 group.[52]]. The ﬁrst The of first these of accounts these accounts employs employs a familiar a familiar cyclization cyclization strategy, strategy,but includes but includes a clever a clever elimination elimination step (Scheme step (Sch7)eme which 7) which permits permits the use the of use a catalytic of a catalytic amount amount of the of thiolthe thiol (thiophenol). (thiophenol). Miyata Miyata and co-workersand co-workers designed designed a sequential a sequential formation formation of two bondof two and bond one and bond onecleavage, bond cleavage, which furnished which furnished a trisubstitutued a trisubstitutued pyrrolidine pyrrolidine ring 39. This ring methodology 39. This methodology was implemented was implementedby the authors by inthe the authors total synthesis in the total of thesynthesis marine of product the marine ( )-α product-kainic acid (−)-α40-kainic, a potent acid neuroexcitatory 40, a potent − neuroexcitatory amino acid agonist with central nervous system activity.[53] Good yields were obtained using low loading of equimolar thiophenol and AIBN.

Molecules 2020, 25, 3094 7 of 40 amino acid agonist with central nervous system activity [53]. Good yields were obtained using low loadingMolecules 2020 of equimolar,, 25,, xx FORFOR PEERPEER thiophenol REVIEWREVIEW and AIBN. 8 of 42

SchemeScheme 7.7. StrategyStrategy employedemployed byby MiyataMiyata etet al. in the totaltotal synthesissynthesis ofof ((−)-)-αα-kainic-kainic acidacid 4040.. − A later example byby Miyata etet al.al.[52] [52] features features a a variation variation on on previous previous approaches, approaches, many of which involveinvolve backbonesbackbones composedcomposed mainlymainlymainly ofofof carboncarbcarbon (Scheme(Scheme8 8).). UsingUsing dienesdienes connectedconnected viavia hydroximates hydroximates 41,, thethe authorsauthorsauthors reportedreportedreported aaa convenientconvenientconvenient conversionconversionconversion ofof cycliccycliccyclic hydroximateshydroximateshydroximates formedformed fromfrom thiylthiylthiyl radicalradicalradical additionaddition/cyclization,/cyclization, intointo the the corresponding correspondingα,β α-disubstituted-,,β-disubstituted--disubstituted-γ-lactones.γ-lactones.-lactones. The TheThe hydrolysis hydrolysishydrolysis of the ofof cyclic thethe hydroximatescyclic hydroximates gave thegave desired the desiredcis- and cis--trans andand-lactones transtrans-lactones-lactones in excellent inin excellentexcellent yield, yield,yield, and the andand methodology thethe methodologymethodology was employedwas employed in the in synthesis the synthesis of ( )-oxo-parabenzlactone. of (±)-oxo-parabenzlactone. Interestingly, Interestingly, the unstable the unstablecis-isomer cis-isomer43 formed 43 was employed in the synthesis± of (±)-oxo-parabenzlactone. Interestingly, the unstable cis-isomer 43 viaformedformed cyclization viavia cyclization could be irreversibly could be resolvedirreversibly into theresolved synthetically intointo thethe more syntheticallysynthetically valuable trans moremore-isomer valuablevaluable42 by treatmenttranstrans-isomer-isomer with 42 sodiumby treatment ethoxide. with sodium ethoxide.

Scheme 8.8. Miyata et al. apply apply the the thiyl thiyl radical cyclization, and resolve the stereoisomers.

Miyata et al.al.[54] [54] also also published published a a wealth of cyclizable diyne systems, in their “sulfanyl“sulfanyl radicalradical addition-addition-cyclization” (SRAAC) (SRAAC) strategy. The The unbranched unbranched diynes diynes discussed herein yieldyield exoexo-oleﬁns-olefins-olefins uponuponupon completion completioncompletion of theofof cascade,thethe cascade,cascade, and thoseanand diynesthose diynes possessing possessing quaternary quaternary carbons furnished carbons cyclizedfurnishedfurnishedendo cyclizedcyclized-oleﬁns endo (Scheme-olefins-olefins9, vide (Scheme(Scheme infra). The9,9, vide authors infra applied).). TheThe authorsauthors this chemistry appliedapplied to thethisthis synthesis chemistrychemistry of atoto small thethe α fragmentsynthesis ofof 1a small,25-dihydroxy fragment vitamin of 1α,25-dihydroxy,25-dihydroxy D3. In agreement vitaminvitamin with DD results33.. InIn agreementagreement published withwith by theirresultsresults contemporaries, publishedpublished byby thetheirtheir 1,8-diyne contemporaries,contemporaries, species failed thethe 1,8-diyne1,8-diyne to cyclize speciesspecies under failfail a varietyed to cyclize of conditions. under a variety of conditions.

Molecules 2020, 25, 3094 8 of 40 Molecules 2020, 25, x FOR PEER REVIEW 9 of 42

SchemeScheme 9. Diyne 9. Diyne cyclizations cyclizations published published by Miyata by Miyata et al. Insertet al. InsertA: Synthesis A: Synthesis of Vitamin of Vitamin D3 derivative. D3 derivative. Pedrosa et al. [52] shortly thereafter reported on the carbocyclizations of perhydro-1,3-benzoxazines, furnishingPedrosa 3,4-disubtitued et al. [52] shortly pyrrolidinone thereafter derivatives reported withon the good carbocyclizations diastereoselectivity of andperhydro-1,3- complete benzoxazines,regioselectivity. furnishing A wide array 3,4-disubtitued of substituted pyrrolidino products werene derivatives synthesized, with and good substitution diastereoselectivity at both olefin andtermini complete was well regioselectivity. tolerated. The author’sA wide resultsarray furtherof substituted supported products the findings were of synthesized, Miyata et al. [and55], substitutionin that a phenyl at both thioether olefin62 terminisuitably was disposed well totole radicalrated. eliminationThe author’s can resu generatelts further secondary supported olefins the64 findingsas a result of ofMiyata the carbocyclization et al.,[55] in that process a phenyl (Scheme thioether 10 ).62 The suitably preference disposed of the to radical thiyl radical elimination SOMO can to generateinteract with secondary electron olefins deficient 64 alkenesas a result was of also the exploited,carbocyclization with the process nascent (Scheme phenythiyl 10). radical The preference attacking ofthe the acrylic thiyl olefin radical before SOMO cyclizing to interact through with the electr expectedon deficient 5-exo-trig alkenespathway was onto also the exploited, substituted with alkene. the nascent phenythiyl radical attacking the acrylic olefin before cyclizing through the expected 5-exo-trig pathway onto the substituted alkene.

Molecules 2020, 25, 3094 9 of 40 Molecules 2020, 25, x FOR PEER REVIEW 10 of 42

Scheme 10. The 3,4-disubstituted pyrrolid pyrrolidinonesinones by Pedrosa et al.

2.4. Moving Forward At thisthis juncture,juncture, the the literature literature is composedis composed of furtherof further accounts accounts on the on tolerance the tolerance of the thiylof the radical thiyl additionradical addition/cyclization/cyclization process to process varying functionalto varying groups functional (FGs), andgroups steric (FGs), demands. and Hodgson steric demands. et al. [56] demonstratedHodgson et al. the[56] utility demonstrated of this process the utility to access of this sterically process challengingto access sterically substrates, challenging and synthesized substrates, a numberand synthesized of 7-thio-substituted a number of 7-thio-substituted norbornenes from no norbornadienesrbornenes from (Scheme norbornadi 11A).enes The (Scheme diene cyclization 11A). The productdiene cyclization67 appeared product to dominate 67 appeared over to radical dominate quenching over radical from quenching solvent or from otherwise, solvent with or otherwise, a ratio of 1:6with of a66 ratio:67 obtained.of 1:6 of 66 This:67 obtained. work also This constitutes work also one constitutes of the ﬁrst on examplese of the first in thisexamples ﬁeld ofin 3-exo-trigthis field cyclization,of 3-exo-trig further cyclization, highlighting further the highlighting potential of thiylthe radicalspotential to accessof thiyl sterically radicals demanding to access substrates.sterically Ademanding communication substrates. by A James commu etnication al. [57] investigatedby James et al. the [57] tolerance investigated of the the cascadetolerance in of questionthe cascade to 3-silylheptanyldienein question to 3-silylheptanyldiene systems (Scheme systems 11B). While (Scheme sulfur-mediated 11B). While cyclizationssulfur-mediated only composedcyclizations a shortonly portioncomposed of thisa short work, portion a number of this of substitutedwork, a number dienes of were substituted successfully dienes cyclized, were providingsuccessfully the cyclized, familiar thiabicyclo[3.3.0]providing the familiar skeleton thiabicyclo[3.3.0] in one step due skeleton to the S Hini mechanismone step due previously to the SH discussed.i mechanism previously discussed.Kamimura and co-workers published an account [58] on the application of radical cascades for the synthesis of the oxa-tricyclic core of platensimycin 72, an antibiotic that inhibits two enzymes in fatty acid biosynthesis (Scheme 12). In a concise account from 2015, the authors describe a short thiyl radical triggered cyclization in their attempts to form the multicyclic core, and while their cyclization of diallymethylene-δ-lactone 73 proceeded in a highly stereoselective manner, the incorrect stereochemistry was obtained.

Molecules 2020, 25, x FOR PEER REVIEW 10 of 42

Scheme 10. The 3,4-disubstituted pyrrolidinones by Pedrosa et al.

2.4. Moving Forward At this juncture, the literature is composed of further accounts on the tolerance of the thiyl radical addition/cyclization process to varying functional groups (FGs), and steric demands. Hodgson et al. [56] demonstrated the utility of this process to access sterically challenging substrates, and synthesized a number of 7-thio-substituted norbornenes from norbornadienes (Scheme 11A). The diene cyclization product 67 appeared to dominate over radical quenching from solvent or otherwise, with a ratio of 1:6 of 66:67 obtained. This work also constitutes one of the first examples in this field of 3-exo-trig cyclization, further highlighting the potential of thiyl radicals to access sterically demanding substrates. A communication by James et al. [57] investigated the tolerance of the cascade in question to 3-silylheptanyldiene systems (Scheme 11B). While sulfur-mediated cyclizations only composed a short portion of this work, a number of substituted dienes were successfully cyclized, providingMolecules 2020 the, 25 ,familiar 3094 thiabicyclo[3.3.0] skeleton in one step due to the SHi mechanism previously10 of 40 discussed.

Molecules 2020, 25, x FOR PEER REVIEW 11 of 42

Scheme 11. (A) Work by Hodgson et al. (B) Cyclization work by James et al.

Kamimura and co-workers published an account [58] on the application of radical cascades for the synthesis of the oxa-tricyclic core of platensimycin 72, an antibiotic that inhibits two enzymes in fatty acid biosynthesis (Scheme 12). In a concise account from 2015, the authors describe a short thiyl radical triggered cyclization in their attempts to form the multicyclic core, and while their cyclization of diallymethylene-δ-lactone 73 proceeded in a highly stereoselective manner, the incorrect stereochemistry was obtained.

Scheme 11. (A) Work by Hodgson et al. (B) Cyclization work by James et al.

SchemeScheme 12. Synthetic 12. Synthetic attempts attempts at accessing at accessing the multicyclic the multicyclic core of core platensimycin of platensimycin72, with 72 mechanism., with mechanism. Wang and colleagues have also been active in this area, and published a tandem sulfenylationWang and/cyclization colleagues of N -arylacrylamideshave also been through active a 5-inexo -thistrig mechanism,area, and whichpublished boasted a excellenttandem yieldssulfenylation/cyclization and control of regioselectivity of N-arylacrylamides for certain through substrates a 5- (Schemeexo-trig 13mechanism,)[59]. This which methodology boasted furnishedexcellent ayields number and of 3-(sulfenymethyl)oxoindolescontrol of regioselectivity 77forand certain 3-sulfenyl-3,4-dihydroquinolin-2(1H)-ones substrates (Scheme 13) [59]. This 78methodology. Up to this furnished point in the a literature,number theof vast3-(sulfenymethyl)oxoindoles majority of thiyl radical precursors77 and have3-sulfenyl-3,4- been the respectivedihydroquinolin-2(1H)-ones thiols, thioacids or78 disulfides;. Up to this this point account in the oliterature,ffers an unconventional the vast majority precursor of thiyl radical to aryl thiylprecursors radicals. have The been authors the propose respective a mechanism thiols, thioacids in which iodineor disulfides; functions asthis an account oxidant, reductant,offers an andunconventional radical initiator, precursor to generate to aryl arylthiyl thiyl radicals. radicals The from authors the correspondingpropose a mechanism sulfonyl in hydrazides which iodine76. Thisfunctions offers as an an accessible oxidant, route reductant, to thiyl and radical radical addition init/iator,cyclization to generate as sulfonyl aryl hydrazidesthiyl radicals are generallyfrom the moisture-compatiblecorresponding sulfonyl solids, hydrazides lack the expected 76. odourThis offers and are an amenable accessible to handling route byto organic thiyl chemistsradical outsideaddition/cyclization traditional ‘sulfuras sulfonyl labs’. hydrazides This methodology are generally permits moisture-compa the cyclizationtible of α ,solids,β-disubstituted lack the acrylamides,expected odour substrates and are which amenable have to previously handling beenby organic found recalcitrantchemists outside to cyclization. traditional It is ‘sulfur noteworthy labs’. thatThis themethodologyα,β-unsubstituted permits acrylamidesthe cyclization failed of toα,β cyclize,-disubstituted instead acrylamides, furnishing bisthioethers. substrates which have previously been found recalcitrant to cyclization. It is noteworthy that the α,β-unsubstituted acrylamides failed to cyclize, instead furnishing bisthioethers.

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A S O S + I2 O or N O S NHNH2 N N O O 75 76 77 78

RS SR SR SR O O N O N O N N

SR SR SR N O N O N O N O

B R

S S S 79a: R = Me, 97% O O 79b:R=H,90% N O N 79c:R=F,81% N 79d: R = Br, 83% 79 79e: R = OMe, 75% 80 81 70% 72%

H H S S S

N O N O N O

82 83 84 66% 83% 64% Scheme 13. The cyclization mechanism (A) and select examples ((B)) byby WangWang andand co-workers.co-workers.

AnAn exampleexample whichwhich highlightshighlights thethe signiﬁcantsignificant potentialpotential ofof thethe thiyl radical additionaddition/cyclization/cyclization inin dienediene cascadecascade reactionsreactions comescomes fromfrom HashimotoHashimoto etet al.al. [[60]60]. This publication from the Maruoka group detailsdetails anan organicorganic thiylthiyl radicalradical catalystcatalyst forfor enantioselectiveenantioselective cyclizationcyclization (Scheme(Scheme 1414).). ThroughThrough thethe carefulcareful designdesign ofof aa chiralchiral pocketpocket aroundaround thethe chiralchiral thiolthiol precatalyst,precatalyst, thethe authorsauthors werewere ableable toto exactexact anan enantio-enantio- andand diastereoselectivediastereoselective C-CC-C bondbond formingforming cyclizationcyclization withwith concomitantconcomitant extrusionextrusion ofof thethe thiyl radicalradical atat thethe endend ofof the cascade. With 3 mol% loading of a binaphthyl-modified binaphthyl-modiﬁed catalystcatalyst andand benzoylbenzoyl peroxideperoxide toto generategenerate thethe thiylthiyl radical,radical, aa widewide arrayarray ofof substratessubstrates werewere successfullysuccessfully cyclizedcyclized byby thisthis catalyst,catalyst, inin yields yields up up to to 99% 99% and and diastereomeric diastereomeric rations rations of up of toup 95:5. to 95:5. Indeed Indeed the catalyst the catalyst loading loading could becould scaled be asscaled low as 1low mol% as 1 at mol% larger at scales larger (1 scales mmol) (1 [61 mmol).[61]]. In their studiesIn their to studies optimize to catalystoptimize structure, catalyst Hashimotostructure, Hashimoto et al. were et able al. towere attain able yields to attain of up yields to 95%, of withup toa 95%, diastereomeric with a diastereomeric ratio (d.r.) of ratio 95:5 (d.r.) and enantiomericof 95:5 and enantiomeric excess (e.e.) excess of 86% (e.e.) using of sunlight86% using as sunlight the photolysis as the source.photolysis Hashimoto source. Hashimoto et al. continued et al. tocontinued develop to this develop methodology, this methodology, and in 2016 and published in 2016 a published communication a communication on the use of on bulky the use thiyl of radical bulky catalyststhiyl radical for [3catalysts+ 2] cyclizations, for [3 + 2] cyclizations, this time with thisN-tosylvinylaziridines time with N-tosylvinylaziridines and alkenes [and62]. alkenes.[62]

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R CO2Bn CO Bn (a) 2 CO Bn CO Bn + t t 2 R 2 BuO BuO OHHS Ar Ar 85 86 87 Si tBu (a) (R)-cat (3 mol%), benzoyl peroxide (6 mol%), hν, toluene, 0 °C, 2 h

R1 R R R RS 1 4 2 R (R)-cat R 2 3 R = 10-Bu-9-anthryl Ar = 4-CF3C6H4

RS R' RS R1 R R4 R2 R3

t CO2Me CO2 Bu Ac t CO2Me CO2 Bu Ac tBuO tBuO tBuO 88 89 90 93% yield 94% yield 99% yield 93:7 d.r. 94:6 d.r. >95:5 d.r. 88% e.e. 89% e.e. 88% e.e.

CO Bn CO2Bn CO2Bn 2 CO2H (iPr) SiO CO Bn 3 CO Bn CO2Bn COPh 2 2 i t BocHN ( Pr)3SiO BuO 91 92 93 94 95% yield 73% yield 93% yield 95% yield 34:66 d.r. 65:35 d.r. >95:5 d.r. >95:5 d.r. 51/12% e.e. 74/45% e.e. 90% e.e. 84/75% e.e. Scheme 14. Organocatalytic work published by Hashimoto et al., with a selection of substrate scope.

In a a further further example example of ofthe the application application of thiyl of thiyl radicals radicals within within organocatalytic organocatalytic systems, systems, work workanalogous analogous to that to of that Hashimoto of Hashimoto et al. et was al. was publis publishedhed by byRyss Ryss et etal. al. (Scheme (Scheme 15) 15 )[[63].63]. This This study detailed the use ofof disulfide-bridgeddisulfide-bridged peptides 95 toto mediatemediate enantioselectiveenantioselective ring-openingring-opening andand cycloaddition of vinylcyclopropanes. Using Using photolysis photolysis to to cleave cleave the the disulfide disulfide bridge of a suitablesuitable cysteine-based dimeric peptide, two equivalents of the thiyl radical per equivalent of catalyst were generated in situsitu.. The The authors authors provided provided an extensive analysis ofof potentialpotential backbonebackbone interactionsinteractions between theirtheir malonic malonic acid acid sca scaffoldffold and and the catalyst,the catalyst, and foundand found that while that the while malonic the estersmalonic provided esters mostlyprovided racemic mostly products, racemic theproducts, corresponding the corresp amide-substitutedonding amide-substitute vinylcyclopropanesd vinylcyclopropanes96 were more 96 successfulwere more insuccessful the discussed in the discussed transformation. transformation This was. This presumed was presumed by Ryss by et Ryss al. to et originateal. to originate from hydrogenfrom hydrogen bonding bonding interaction interaction between between the peptide the peptid catalyste catalyst and theand substrate. the substrate. In their In their design design of the of catalystthe catalyst the appendagethe appendage attached attached to the to proline the prolin backbonee backbone was altered; was altered; one example one example (in blue) (in is blue) shown is inshown Insert in A Insert below. A below.

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O O O O R R R R

OtBu peptide-S A Ph hν Ph H N O O O peptide-S O O O 2 N R R R R HN S O O tBuO NHBoc HN

S peptide S peptide Ph 95

tBuO

O O CF3 CF3 O O Ar Ar cat. (5 mol%) N N N N H H + hν (100W Hg lamp) H H R1 hexanes:THF 2:1 R2 Ar, rt, 16 h R1 R2 96 97a-d 98a-d

O O O O O O O O Ar Ar Ar Ar Ar Ar N N Ar Ar N N N N H H N N H H H H O H H O N O NHBoc N

98a 98b 98c 98d 53% yield 72% yield 38% yield 71% yield 73:27 d.r. (trans:cis) 88:12 d.r. (trans:cis) 91:9 d.r. (trans:cis) 96:4 d.r. (trans:cis) 86:14 e.r. (trans) 80:20 e.r. (trans) 92:8 e.r. (trans) 83:17 e.r. (trans) 71:29 e.r. (cis) 80:20 e.r. (cis) 78:22 e.r. (cis) 77:23 e.r. (cis) Scheme 15. Enantioselective workwork by by Rhyss Rhyss et et al., al., employing employing a peptide-baseda peptide-based thiyl thiyl catalyst catalyst (Insert (InsertA, 95 A)., 95). The use of thiyl radical addition/cyclization has been previously described as a useful route to thiophenes,The use through of thiyl clever radical use addition/cyclization of homolytic substitution has been reactions. previously Possibly described the most as recenta useful cyclization route to thiophenes,of a diyne substrate through wasclever reported use of by homolytic Dutta et al.,subs intitution which areactions. number ofPo pyrrolesssibly the were most prepared recent (Schemecyclization 16 )[of64 a]. diyne This accountsubstrate describes was reported the use by of Du ynamidestta et al., and in alkyneswhich a for number cyclization; of pyrroles the authors were preparedreport a ‘serendipitous (Scheme 16).[64] observation’ This account that describes the reactivity the use of of simple ynamides alkynes and was alkynes found for to cyclization; exceed the thetraditionally authors report more a reactive ‘serendipitous ynamides observation’ moieties forthat cyclization. the reactivity This of simple led to thealkynes development was found of to a exceedmethodology the traditionally in which more an alkyne reactive99 isynamides ﬁrst attacked moieties by for the cyclization. aryl sulfenyl This radical led to formedthe development from 100, whichof a methodology then cyclizes in in which a 5-exo-dig an alkynepathway 99 is ontofirst attacked the ynamides by the to aryl generate sulfenyl a number radical of formed novel 4-thioarylfrom 100, pyrroleswhich then101 cyclizes, 103–110 in .a The5-exo-dig methodology pathway onto tolerates the ynamides an array to of gene functionalrate a number groups of and novelN-protecting 4-thioaryl pyrrolesgroups, and 101 forbearance, 103–110. The to modiﬁcationmethodology of tolerates the ynamides an array and propargylicof functional terminus groups wasand alsoN-protecting recorded. groups, and forbearance to modification of the ynamides and propargylic terminus was also recorded.

Molecules 2020, 25, x FOR PEER REVIEW 15 of 42

Molecules 2020, 25, 3094 14 of 40 Molecules 2020, 25, x FOR PEER REVIEW 15 of 42

Scheme 16. Work by Dutta et al. 102 operates as a radical initiator, and scope examples are shown.

Thus far, this review has shown numerous examples that have employed the thiyl radical addition/cyclizationScheme cascade 16. WorkWork forby Dutta a variety et al. 102 ofoperates substrates. as a radical But initiator, what and are scope the examples limitations are shown. of the process? A 2017 publication[65] by Wang and colleagues poses an interesting question—is it possible that radical Thus far, this review has shownshown numerousnumerous examplesexamples that have employed the thiyl radical polycyclizationadditionaddition/cyclization could/cyclization yield cascade cascadedodecahedrane for for a a variety variety of of112 substrates. substrates., one of But But the what what top are are thesynthetic the limitations limitations targets of ofthe the process? sought process? A by organic chemists forA2017 decades?[66] 2017 publication[65] publication Woodward [by65] Wang by Wang and failedcolleagues and colleagues in synthesizingposes poses an interesting an interesting this question—is Platonic question—is ithydrocarbon,[66,67] possible it possible that radical that but the Paquette groupradicalpolycyclization succeeded polycyclization could the yield could first dodecahedrane yield synthesis dodecahedrane 112 in, oneth112e of early ,the one top of 1980s.[68] synthetic the top synthetic targets The sought targetsaccount by sought organic by by Wang et al. organicchemists chemists for decades?[66] for decades Woodward [66]? Woodward failed in failed synthesizing in synthesizing this Platonic this Platonic hydrocarbon,[66,67] hydrocarbon but [66, 67the], assesses the butPaquetteviability the Paquette group of thiyl groupsucceeded radicals succeeded the firstas the mediators synthesis ﬁrst synthesis in ofth in epolycyclizations theearly early 1980s.[68] 1980s [68 The]. Theto ac constructcount account by by Wang Wangcomplex et et al. al. molecular architecturesassesses (Scheme the viability 17). Using of thiyl density radicals as functional mediators of theory polycyclizations polycyclizations (DFT) to calculations, construct complex the molecularauthors concluded that the processarchitectures is energetically (Scheme 1717).). Using viable density in functional both a theory kinetic (DFT) and calculations, thermodynamic the authors concluded sense. While the that the process is energetically viable in both a kinetic and thermodynamic sense. While the reversibility reversibilitythat of the processthiol-ene is energetically and potential viable quenching in both a kinetic by hydrogen and thermodynamic atom transfer sense. While were the highlighted, ofreversibility the thiol-ene of the and thiol-ene potential and quenching potential by quenching hydrogen by atom hydrogen transfer atom were transfer highlighted, were thehighlighted, quantum the quantumchemicalthe chemical quantum calculations chemical calculations indicate calculations the indicate possibility indicate the thatthe possibilitypossibility one day, these that that complex one oneday, geometries theseday, complex these may becomplexgeometries obtained geometries may be obtainedusingmay be simple using obtained thiyl simple using radical simple thiyl cascades. thiylradical radical cascades. cascades.

Scheme 17. Multiple 5-exo-trig cyclizations to give dodecahedrane 112 are estimated to be possible.

exo trig Scheme3. 17.Heterogeneous SchemeMultiple 17. Multiple5- Substrates:exo-trig 5- cyclizations- Enynescyclizations and toOther to give give Mixed dodecahedrane Systems 112 are 112 estimated are estimated to be possible. to be possible. 3.1. Origin 3. Heterogeneous Substrates: Enynes and Other Mixed Systems The two earliest examples of thiyl radical cascades orchestrated on heterogeneous or ‘mixed’ systems were both reported in 1987 (Scheme 18). The first of these sulfur-triggered cyclizations, 3.1. Origin reported by Broka et al.,[69] in which nascent vinyl radicals 114 formed via thiyl addition to enynes 113, regioselectively cyclized to furnish the respective cyclohexylidine 115. The authors identified The two earliest examples of thiyl radical cascades orchestrated on heterogeneous or ‘mixed’ systems were both reported in 1987 (Scheme 18). The first of these sulfur-triggered cyclizations, reported by Broka et al.,[69] in which nascent vinyl radicals 114 formed via thiyl addition to enynes 113, regioselectively cyclized to furnish the respective cyclohexylidine 115. The authors identified

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3. Heterogeneous Substrates: Enynes and Other Mixed Systems

3.1. Origin The two earliest examples of thiyl radical cascades orchestrated on heterogeneous or ‘mixed’ systems were both reported in 1987 (Scheme 18). The first of these sulfur-triggered cyclizations, Molecules 2020, 25, x FOR PEER REVIEW 16 of 42 reported by Broka et al. [69], in which nascent vinyl radicals 114 formed via thiyl addition to enynes 113 115 that, under regioselectively ionic conditions cyclized (in to this furnish case, refluxing the respective thiophenol cyclohexylidine with the enyne. Thein benzene), authors identifiedvery little cyclizationthat under ionictakes conditions place as the (in thisrate case,of hydrogen refluxing abstraction thiophenol by with the the vinyl enyne radical in benzene), outcompetes very little the cascadecyclization reaction. takes placeBy switching as the rate to ofa procedure hydrogen abstractionwith AIBN, by and the slow vinyl ad radicaldition outcompetes of the thiol, the the authors cascade werereaction. able By to switchingfavor cyclization to a procedure over quenching with AIBN, of and the slowradical addition cascade. of theThis thiol, gave the 115 authors as the were cyclized able product,to favor cyclizationin a 75% yield over when quenching 2,2,5,5-tetramethylt of the radical cascade.etrahydrofuran This gave (TMTHF)115 as thewas cyclized used as product, the solvent. in a Broka75% yield et al. when proposed 2,2,5,5-tetramethyltetrahydrofuran that equilibration of the cyclopentylmethyl (TMTHF) was used radical, as the formed solvent. via Broka 5-exo et-trig al. proposedcyclization that of 114 equilibration, to the more of thestable cyclopentylmethyl cyclohexyl isomer radical, prior formedto hydrogen via 5- exoabstraction-trig cyclization facilitates of 114the, generationto the more of stable 115. cyclohexylA number isomer of other prior systems to hydrogen were test abstractioned to examine facilitates the thegenerality generation of ofenyne115. Acyclization, number of and other it was systems found werethat as tested the substitution to examine of the the generality olefin increased, of enyne the cyclization, success of cyclization and it was severelyfound that diminished; as the substitution for example, of the enyne olefin 119 increased, gave only the 33% success cyclized of products, cyclization and severely substrate diminished; 121 gave none.for example, enyne 119 gave only 33% cyclized products, and substrate 121 gave none.

Scheme 18. InitialInitial work by Broka et al. on on the the generality generality of enyne cyclization.

Ichinose et et al. al. reported reported an an account account of oftriethyl triethylboraneborane based based radical radical initiation initiation for foraddition addition to acetylenicto acetylenic compounds. compounds. The The authors authors explored explored addi additiontion of ofthiyl thiyl groups groups to to terminal terminal acetylene compounds,[70]compounds [70], which which proceeded proceeded regioselectively regioselectively but but not not stereoselectively (Scheme 19).19). The three examples of of interest interest to to this this review review are are that that of an of anintermolecular intermolecular dihydrothiophene dihydrothiophene synthesis synthesis 129, and129, theand vinyl the vinyl radical radical cyclization cyclization of two of twoacetylenic acetylenic olefins olefins 130 and130 and132.132 Analogous. Analogous to the to work the work carried carried out byout Broka by Broka et al. et in al. the in same the same year, year,a clear a cleartrend trend in the in substitution the substitution and steric and stericdemands demands around around the olefin the wasolefin identified. was identified.

Molecules 2020, 25, 3094 16 of 40 Molecules 2020, 25, x FOR PEER REVIEW 17 of 42

Scheme 19. WorkWork published by Ichinose et al.

3.2. Broadening Broadening the Scope Broadening the the scope scope of of the the review review to to consider consider ‘mixed’ ‘mixed’ unsaturated unsaturated systems, systems, the the inclusion inclusion of unsaturationof unsaturation at heteroatomic at heteroatomic moieties moieties must must also alsobe considered. be considered. A very A early very earlyexample example form El form Kaim El etKaim al. [71] et al. offers [71] o5-ff ersand 5- 6- andexo- 6-trigexo cyclizations-trig cyclizations of oxime of oxime ethers ethers and hydrazones. and hydrazones. By generating By generating thiyl radicalsthiyl radicals from fromthiophenol, thiophenol, a number a number of ethylenic of ethylenic and and acetylenic acetylenic hydrazones hydrazones were were cyclized cyclized under thermal initiation with AIBN in refluxingrefluxing cyclohexanecyclohexane (Scheme 2020).). Analogous Analogous to to early early work by Padwa etet al.al. previously previously discussed, discussed, the thecis isomer cis isomer predominates predominates in the cyclization,in the cyclization, despite thedespite inclusion the inclusionof heteroatoms. of heteroatoms. Furthermore, Furthe no tracermore, of uncyclized no trace productof uncyclized was detected product for thewas conditions detected reportedfor the conditionsherein. The reported methodology herein. published The methodology in this account published widened in thethis scope account for cyclizationswidened the on scope the C =forN cyclizationsbond, and general on the examplesC=N bond, from and this general work examples are detailed from below this towork show are the de rangetailed ofbelow functional to show group the rangetolerance. of functional Despite this group clear tolerance. forbearance Despite to varying this clear functionality, forbearance example to varying138 functionality,did not cyclize. example 138 didIn annot account cyclize. by Alcaide et al., an early medicinal chemistry application of the thiyl radical addition/cyclization cascade is described [72]. Highly functionalized rings fused to a common pharmacophore, a β-lactam, were synthesized via radical cascade chemistry on a number of Baylis-Hillman adducts, providing the basis for this stereocontrolled and chemoselective approach shown in Scheme 21. Several phenylthiovinyl derivatives 143a–c of the yne-ene based β-lactams 142 were obtained, and subject to further transformation. It should be noted that in the case of n = 4 i.e., the 5-hexynyl conjugated β-lactam, neither the thiyl radical addition nor classical methods such as organotin chemistry could cyclize the substrate. It is also noteworthy that it was possible for the authors to initiate thiyl-yne conjugation prior to the Michael addition, which one would expect to compete for the thiol via thia-Michael addition. With each publication that bolsters the robustness of thiyl radical utility in organic synthesis, further technologies such as flow chemistry and microwave assisted synthesis become available to the sulfur chemist. In one such paper on the use of microwave assisted radical cyclizations, Lamberto et al. [73] discuss the use of a wide variety of thiols to generate pyrrolines and pyroglutamates from alkenyl and alkynyl isocyanides (Scheme 22). This use of microwave ‘flash-heating’ technology boasts the advantage of significantly faster reaction times, and increased yields. It is worth noting that in the case of alkynyl isocyanides, protection of the alkyne terminus as a silyl ether was necessary, as unprotected substrates suffered from severely diminished cyclization yield. In a further publication [73] the authors demonstrated the applicability of this methodology to solid phase synthesis,

Scheme 20. Scope explored by El Kaim et al. Insert: Abbreviations used in the original work.

Molecules 2020, 25, x FOR PEER REVIEW 17 of 42

Scheme 19. Work published by Ichinose et al.

3.2. Broadening the Scope Broadening the scope of the review to consider ‘mixed’ unsaturated systems, the inclusion of unsaturation at heteroatomic moieties must also be considered. A very early example form El Kaim et al. [71] offers 5- and 6-exo-trig cyclizations of oxime ethers and hydrazones. By generating thiyl radicals from thiophenol, a number of ethylenic and acetylenic hydrazones were cyclized under thermal initiation with AIBN in refluxing cyclohexane (Scheme 20). Analogous to early work by Padwa et al. previously discussed, the cis isomer predominates in the cyclization, despite the Moleculesinclusion2020 of, 25 heteroatoms., 3094 Furthermore, no trace of uncyclized product was detected for17 ofthe 40 Moleculesconditions 2020 ,reported 25, x FOR PEERherein. REVIEW The methodology published in this account widened the scope18 of for 42 cyclizations on the C=N bond, and general examples from this work are detailed below to show the andrange furnishedIn of an functional account pyroglutamates bygroup Alcaide tolerance. andet al., 2-mercaptopyrrolines Despite an early this medicinal clear forbearance fromchemistry three to polymer-supportedapplication varying functionality, of the thiyl isocyanides example radical addition/cyclizationusing138 did commercially not cyclize. availablecascade resins.is described.[72] Highly functionalized rings fused to a common pharmacophore, a β-lactam, were synthesized via radical cascade chemistry on a number of Baylis-Hillman adducts, providing the basis for this stereocontrolled and chemoselective approach shown in Scheme 21. Several phenylthiovinyl derivatives 143a–c of the yne-ene based β-lactams 142 were obtained, and subject to further transformation. It should be noted that in the case of n = 4 i.e., the 5-hexynyl conjugated β-lactam, neither the thiyl radical addition nor classical methods such as organotin chemistry could cyclize the substrate. It is also noteworthy that it was possible for the authors to initiate thiyl-yne conjugation prior to the Michael addition, which one would expect to compete for the thiol via thia-Michael addition. Molecules 2020, 25, x FOR PEER REVIEW 18 of 42

In an account by Alcaide et al., an early medicinal chemistry application of the thiyl radical addition/cyclization cascade is described.[72] Highly functionalized rings fused to a common pharmacophore, a β-lactam, were synthesized via radical cascade chemistry on a number of Baylis-Hillman adducts, providing the basis for this stereocontrolled and chemoselective approach shown in Scheme 21. Several phenylthiovinyl derivatives 143a–c of the yne-ene based β-lactams 142 were obtained, and subject to further transformation. It should be noted that in the case of n = 4 i.e., the 5-hexynyl conjugated β-lactam, neither the thiyl radical addition nor classical methods such as organotin chemistry could cyclize the substrate. It is also noteworthy that it was possible for the authors to initiate thiyl-yne conjugation prior to the Michael addition, which one would expect to Scheme 21. The key radical step in an account published by Alcaide et al. competeScheme for the 20.20.thiol Scope via exploredthia-Michael by El addition. Kaim etet al.al. Insert: Abbreviations Abbreviations used in the original work. With each publication that bolsters the robustness of thiyl radical utility in organic synthesis, further technologies such as flow chemistry and microwave assisted synthesis become available to the sulfur chemist. In one such paper on the use of microwave assisted radical cyclizations, Lamberto et al. [73] discuss the use of a wide variety of thiols to generate pyrrolines and pyroglutamates from alkenyl and alkynyl isocyanides (Scheme 22). This use of microwave ‘flash-heating’ technology boasts the advantage of significantly faster reaction times, and increased yields. It is worth noting that in the case of alkynyl isocyanides, protection of the alkyne terminus as a silyl ether was necessary, as unprotected substrates suffered from severely diminished cyclization yield. In a further publication [73] the authors demonstrated the applicability of this methodology to solid phase synthesis, and furnished pyroglutamates and 2-mercaptopyrrolines from three polymer-supported isocyanides usingScheme commercially 21. The keyavailable radical resins.step in an account published by Alcaide et al.

With each publication that bolsters the robustness of thiyl radical utility in organic synthesis, further technologies such as flow chemistry and microwave assisted synthesis become available to the sulfur chemist. In one such paper on the use of microwave assisted radical cyclizations, Lamberto et al. [73] discuss the use of a wide variety of thiols to generate pyrrolines and pyroglutamates from alkenyl and alkynyl isocyanides (Scheme 22). This use of microwave ‘flash-heating’ technology boasts the advantage of significantly faster reaction times, and increased yields. It is worth noting that in the case of alkynyl isocyanides, protection of the alkyne terminus as a silyl ether was necessary, as unprotected substrates suffered from severely diminished cyclization yield. In a further publication [73] the authors demonstrated the applicability of this methodology to solid phase synthesis, and furnished pyroglutamates and 2-mercaptopyrrolines from three polymer-supported isocyanides using commercially available resins.

Scheme 22. GeneralGeneral scheme scheme of work published by Lamberto et al.

In thethe mid-2000s, mid-2000s, a relative a relative ‘renaissance’ ‘renaissance’ in the use in ofthe thiyl use radicals of thiyl as instigators radicals ofas carbocyclizations instigators of carbocyclizationswas observed. While was theobserved. present While review the is present far from revi exhaustive,ew is far from a description exhaustive, of thea description main outcomes of the main outcomes from key research groups will be discussed. Majumdar and co-workers have been particularly active in this area, publishing heterogeneous cyclizations for a range of heterocycles,

Scheme 22. General scheme of work published by Lamberto et al.

In the mid-2000s, a relative ‘renaissance’ in the use of thiyl radicals as instigators of carbocyclizations was observed. While the present review is far from exhaustive, a description of the main outcomes from key research groups will be discussed. Majumdar and co-workers have been particularly active in this area, publishing heterogeneous cyclizations for a range of heterocycles,

Molecules 2020, 25, 3094 18 of 40 from key research groups will be discussed. Majumdar and co-workers have been particularly active in this area, publishing heterogeneous cyclizations for a range of heterocycles, including cyclic ethers 157, pyrimidine-fused azocine derivatives [74], furo- and pyranocoumarin species [75], a range of pyrrolopyrimidines as 9-deazaxanthine analogs 163 [76], as well as benzoxocine 151 [77] and oxepin derivatives [78]. In several publications on the topic of heterogeneous carbocyclizations between 2007 and 2010, Majumdar et al. have reported a number of diﬃcult annulations, and broadened the role of thiyl radicals to catalyzing Claisen rearrangement, and undergoing 8-endo cyclizations for accessing sesquiterpenes. In the interest of space constraints, these accounts will not be described in full detail herein and instead a selection of key achievements is shown in Scheme 23. Molecules 2020, 25, x FOR PEER REVIEW 20 of 42

R O R O PhSH (2 eq.) SPh AIBN (2 eq.) Benzene, Δ

150 151 76-85% yield

PhS

O O O O O SPh N PhSH (2 eq.) N AIBN (2 eq.) O N O N tBuOH, Δ N N O 154 155 152 O SPh O SPh 85% O R'SH O O N N 8-endo-trig O N O N R'S N N O SPh 156 157 Ph 83% 153 92%

O Et O O O N N N N N N PhSH (2 eq.) N N AIBN (1.5 eq.) 4-exo-trig O N O N SPh O N tBuOH, Δ O N SPh SPh 164 158 159 160 62% O Et 5-endo-trig 3-exo-trig N N

O O O O N Et SPh N N N N N N 165 60% O N O N O N O H Et SPh SPh SPh Et N N 163 162 161 65% O N Et SPh 166 63% SchemeScheme 23. Selected23. Selected works works by by Majumdar Majumdar etet al.al. Inserts: :Representative Representative examples examples from from each eachpaper. paper.

Indeed, even if cyclization attempts fail and do not yield any desired product, these results are nonetheless valuable. In a follow up publication to their success with alkynyl azides, Montevecchi et al. identified several sulfanylvinyl radicals which did not undergo any 5-membered cyclization to esteric or thioesteric carbonyl moieties, nor did they obtain any evidence of successful toluenesulfanyl radicals addition to a number of alkynyl nitriles. Montevecchi and co-workers did, however, identify two radical intermediates which were successful in cyclizing onto aromatic cyano groups, which furnished a useful synthetic route to indenones.

Molecules 2020, 25, 3094 19 of 40

Montevecchi et al. detailed the addition of thiyl radicals to alkynyl azides [79] as well as attempted cyclizations onto carbonyls and cyano groups [80]. The group continued to explore these processes, and also published on the relative reaction rates of thiyl radical addition and hydrogen atom abstraction [81]. In their investigation of alkynyl azides as suitable substrates for thiyl radical mediated cyclization, the authors identiﬁed two suitable 2-sulfanylvinyl radicals which underwent 5-exo cyclization onto the azido moiety, preventing intramolecular addition to the sulfanyl aromatic ring (Scheme 24). In the course of this project, Montevecchi and co-workers rationalized the ability of these two radicals to cyclize by considering the resonance stabilization of the nascent triazenyl radicals, caused by delocalization into the indole ring. They also reasoned that the failure of other radicals to undergo cyclization may be explained by unfavorable polar eﬀects in the transitions state between the more electrophilic vinyl radicals and the aliphatic azido moiety. Note that while benzyl mercaptan is shown as the thiol agent in Scheme 24, similar success was observed with thiophenol as the thiyl radicalMolecules precursor.2020, 25, x FOR PEER REVIEW 21 of 42

SchemeScheme 24. Alkynyl 24. Alkynyl azide azide cyclizations cyclizations reported reported by Montevecchi by Montevecchi et al. et Insert al. InsertA: Uncyclizable A: Uncyclizable radicals. radicals. Indeed, even if cyclization attempts fail and do not yield any desired product, these results are nonetheless3.3. Cyclizations valuable. onto Nitrog In a followenous Moieties, up publication and Further to their SH successi Chemistry with alkynyl azides, Montevecchi et al. identified several sulfanylvinyl radicals which did not undergo any 5-membered cyclization to esteric An excellent example of the convenience of thiyl radical addition/cyclization cascades with or thioesteric carbonyl moieties, nor did they obtain any evidence of successful toluenesulfanyl radicals heterogeneous substrates comes from Keck et al. who employed 6-exo cyclizations of substituted addition to a number of alkynyl nitriles. Montevecchi and co-workers did, however, identify two thiovinyl radicals with oxime ethers for the synthesis of high value alkaloids. In their total synthesis radical intermediates which were successful in cyclizing onto aromatic cyano groups, which furnished of (+)-lycoricidine 176 and (+)-narciclasine 179, a nascent vinyl radical is generated via addition of a a useful synthetic route to indenones. phenylthiyl radical to a disubstituted alkyne. Thiyl addition to the alkyne, and subsequent addition to an oxime ether furnishes the corresponding ring system 175 or 178, which was then further 3.3. Cyclizations onto Nitrogenous Moieties, and Further SHi Chemistry transformed to the target alkaloid. In the course of these studies, the authors noted that no formal synthesisAn excellent of narciclasine example had of been the accomplished, convenienceof and thiyl thus radical applied addition the same/cyclization methodology cascades with some with heterogeneousmodification to substratesthe substrate comes backbone from Keck(Scheme et al.25). who Keck employed and co-workers 6-exo cyclizations also identified of substitutedthe reverse thiovinylregiochemistry radicals of withstannyl oxime and ethersphenylthiyl for the radicals synthesis to ofthe high same value alkyne alkaloids. in this account. In their total synthesis of (+)-lycoricidine 176 and (+)-narciclasine 179, a nascent vinyl radical is generated via addition of a phenylthiyl radical to a disubstituted alkyne. Thiyl addition to the alkyne, and subsequent addition to an oxime ether furnishes the corresponding ring system 175 or 178, which was then further transformed to the target alkaloid. In the course of these studies, the authors noted that no formal synthesis of narciclasine had been accomplished, and thus applied the same methodology with some modification to the substrate backbone (Scheme 25). Keck and co-workers also identified the reverse regiochemistry of stannyl and phenylthiyl radicals to the same alkyne in this account.

Scheme 25. Total syntheses of lycoricidine and narciclasine by Keck et al., involving radical cyclization.

Fernández et al. published a one-step cyclization of ketimines into cyclized allylamine derivatives in the mid-2000s, which again relies upon a tandem radical addition/cyclization strategy (Scheme 26).[82] Using a substrate inspired by the research group’s interest in tetrodotoxin, a number of thiyl radical mediated cyclizations were attempted. The authors sought to exert control over

Molecules 2020, 25, x FOR PEER REVIEW 21 of 42

Scheme 24. Alkynyl azide cyclizations reported by Montevecchi et al. Insert A: Uncyclizable radicals.

3.3. Cyclizations onto Nitrogenous Moieties, and Further SHi Chemistry An excellent example of the convenience of thiyl radical addition/cyclization cascades with heterogeneous substrates comes from Keck et al. who employed 6-exo cyclizations of substituted thiovinyl radicals with oxime ethers for the synthesis of high value alkaloids. In their total synthesis of (+)-lycoricidine 176 and (+)-narciclasine 179, a nascent vinyl radical is generated via addition of a phenylthiyl radical to a disubstituted alkyne. Thiyl addition to the alkyne, and subsequent addition to an oxime ether furnishes the corresponding ring system 175 or 178, which was then further transformed to the target alkaloid. In the course of these studies, the authors noted that no formal synthesis of narciclasine had been accomplished, and thus applied the same methodology with some modificationMolecules 2020, 25 to, 3094 the substrate backbone (Scheme 25). Keck and co-workers also identified the reverse20 of 40 regiochemistry of stannyl and phenylthiyl radicals to the same alkyne in this account.

Scheme 25.25. TotalTotal syntheses syntheses of lycoricidineof lycoricidine and narciclasineand narciclasine by Keck by et al.,Keck involving et al., radicalinvolving cyclization. radical cyclization. Fernández et al. published a one-step cyclization of ketimines into cyclized allylamine derivatives in theFernández mid-2000s, whichet al. againpublished relies upona one-step a tandem cyclization radical addition of ketimines/cyclization into strategy cyclized (Scheme allylamine 26)[82]. derivativesUsingMolecules a 2020 substrate ,in 25 the, x FOR mid-2000s, inspired PEER REVIEW by which the research again relies group’s upon interest a tandem in tetrodotoxin, radical addition/cyclization a number of thiyl strategy radical22 of 42 (Schememediated 26).[82] cyclizations Usingwere a substrate attempted. inspired The by authors the research sought group’s to exert interest control in over tetrodotoxin, cyclization a throughnumber ofthecyclization thiyl 6-endo radicalversus through mediated the the5-exo 6- endocyclizationsmode. versus Indeed thewere by5-exo atte substitution mode.mpted. Indeed The the alkyneauthors by substitu terminussoughttion to withthe exert alkyne a phenylcontrol terminus group over 185 withrestored a phenyl some group control 185 restored over the cyclizationsome control mode, over and the throughcyclization using mode, the traditionaland through PhSH using/AIBN the couple,traditional a number PhSH/AIBN of conditions couple, werea number explored. of conditions Interestingly, were the explored. use of a mediumInterestingly, pressure the mercuryuse of a lampmedium as thepressure irradiation mercury source lamp permitted as the irradiation the use of so justurce 1.05 permitted equivalents the ofuse thiophenol of just 1.05 and equivalents no AIBN wasof thiophenol required; and these no conditions AIBN was gave required; the highest these cond cyclizationitions gave yield the of highest 75%. However cyclization this yield success of 75%. was reliantHowever on thethis alkynyl success substituent was reliant being on the a phenyl alkynyl group, substituent as esters being and ethers a phenyl did not group, promote as esters formation and ofethers the desireddid not cyclohexeynlaminepromote formation 186of the. desired cyclohexeynlamine 186.

Scheme 26. Possible ketimineketimine cyclizationcyclization pathways. pathways. Insert InsertA A: Optimized: Optimized cyclization cyclization by by Fern Fernándezández et al.et al. Friestad et al. published an account of chiral hydrazone cyclization, using silicon tethered alkynes (SchemeFriestad 27)[83 et]. al. A onepublished pot process an account involving of thiyl chiral addition hydrazone to the cyclization, ethynyl terminus using and silicon a desilylation tethered withalkynes standard (Scheme ﬂuoride 27).[83] sources A one furnished pot process (E)-vinylsulﬁdes involving thiyl189a addition–e. The to authors the ethynyl report terminus this cascade and as a thedesilylation synthetic with equivalent standard of an fluoride acetaldehyde sources Mannich furnished reaction. (E)-vinylsulfides While the intermediate 189a–e. The heterocycle authors report was this cascade as the synthetic equivalent of an acetaldehyde Mannich reaction. While the intermediate heterocycle was not isolated or explicitly discussed in this publication, it is implied that the 5-exo mode of cyclization predominates with the nascent thiovinyl radical. Collapse of the intermediate cyclized product following fluoride-mediated cleave provides the desired product in good yield. Friestad and Messari had also developed a diastereoselective vinyl addition to chiral hydrazones in an earlier account,[84] and proceeded to develop a similar chiral hydrazone cyclization with silicon-tethered alkenes analogous to 187a–e.[85] In the first of these accounts, vinyl addition to α,β-dihydroxyhydrazones was also investigated, with excellent extension of the scope of their methodology and without extensive protection strategies or hydroxyl group differentiation. The methodology employed by Friestad et al. hinges on the exploitation of temporary silicon-tethers, which permits facile and stereocontrolled vinyl addition to C=N bonds to furnish valuable synthetic scaffolds, such as acyclic amino alcohols.[84]

Scheme 27. (E)-vinylsulfide work by Friestad et al.

Previously discussed work by Padwa et al. has shown that a sulfur atom suitably disposed to undergo SHi can extrude an acyl radical under the appropriate conditions. Almost twenty years after this account, Benati and co-workers exploited this methodology for the production of aldehydes under tin and silicon free conditions (Scheme 28).[86] Benati’s radical cascade reaction between

Molecules 2020, 25, x FOR PEER REVIEW 22 of 42 cyclization through the 6-endo versus the 5-exo mode. Indeed by substitution the alkyne terminus with a phenyl group 185 restored some control over the cyclization mode, and through using the traditional PhSH/AIBN couple, a number of conditions were explored. Interestingly, the use of a medium pressure mercury lamp as the irradiation source permitted the use of just 1.05 equivalents of thiophenol and no AIBN was required; these conditions gave the highest cyclization yield of 75%. However this success was reliant on the alkynyl substituent being a phenyl group, as esters and ethers did not promote formation of the desired cyclohexeynlamine 186.

Scheme 26. Possible ketimine cyclization pathways. Insert A: Optimized cyclization by Fernández et al.

Friestad et al. published an account of chiral hydrazone cyclization, using silicon tethered alkynes (Scheme 27).[83] A one pot process involving thiyl addition to the ethynyl terminus and a Moleculesdesilylation2020, 25with, 3094 standard fluoride sources furnished (E)-vinylsulfides 189a–e. The authors report21 of 40 this cascade as the synthetic equivalent of an acetaldehyde Mannich reaction. While the intermediate heterocycle was not isolated or explicitly discussed in this publication, it is implied that the 5-exo notmode isolated of cyclization or explicitly predominates discussed inwith this the publication, nascent thiovinyl it is implied radical. that Collapse the 5-exo modeof the ofintermediate cyclization predominatescyclized product with following the nascent fluoride-mediated thiovinyl radical. cleave Collapse provides of the the desired intermediate product cyclized in good product yield. followingFriestad and fluoride-mediated Messari had also cleave developed provides a diastereoselective the desired product vinyl in goodaddition yield. to Friestadchiral hydrazones and Messari in hadan earlier also developed account,[84] a diastereoselective and proceeded vinyl to develop addition a to similar chiral hydrazones chiral hydrazone in an earlier cyclization account with [84], andsilicon-tethered proceeded to alkenes develop analogous a similar chiral to 187a hydrazone–e.[85] cyclizationIn the first with of these silicon-tethered accounts, alkenesvinyl addition analogous to toα,β187a-dihydroxyhydrazones–e [85]. In the first ofwas these also accounts, investigated, vinyl with addition excellent to α,β -dihydroxyhydrazonesextension of the scope wasof their also investigated,methodology withand without excellent ex extensiontensive protection of the scope strategies of their or methodologyhydroxyl group and differentiation. without extensive The protectionmethodology strategies employed or hydroxyl by Friestad group et dial.ff erentiation.hinges on the The exploitation methodology of employedtemporary by silicon-tethers, Friestad et al. hingeswhich permits on the exploitation facile and stereocontrolled of temporary silicon-tethers, vinyl addition which to C=N permits bonds facile to furnish and stereocontrolled valuable synthetic vinyl additionscaffolds, to such C= Nas bondsacyclic to amino furnish alcohols.[84] valuable synthetic scaffolds, such as acyclic amino alcohols [84].

Scheme 27. (E)-vinylsulfide)-vinylsulﬁde work by Friestad et al.

Previously discussed work by Padwa et al. has sh shownown that a sulfur atom suitably disposed to undergo SHii can can extrude extrude an an acyl acyl radical radical under under the the approp appropriateriate conditions. Almost twenty years after this account, Benati and co-workers exploited this methodology for the production of aldehydes under Moleculesthis account, 2020, 25 ,Benati x FOR PEERand REVIEWco-workers exploited this methodology for the production of aldehydes23 of 42 tinunder and tin silicon and freesilicon conditions free conditions (Scheme 28(Scheme)[86]. Benati’s28).[86] radicalBenati’s cascade radical reaction cascade between reaction thiophenol between and pentynylthiol esters 190 provides both aromatic and aliphatic aldehydes, and permits a formal thiophenol and pentynylthiol esters 190 provides both aromatic and aliphatic aldehydes, and permits areduction formal reduction of esters toof aldehydesesters to aldehydes even with even substituents with substituents which would which normally would be normally very sensitive be very to sensitiveany reducing to any conditions. reducing Theconditions. formation The of formation concomitant of concomitant dihydrothiophenes dihydrothiophenes191 frames this191 accountframes thisas relevant accountto as the relevant present to review,the present and review, oﬀers a and useful offers synthetic a useful route synthetic to this ro sulfur-basedute to this sulfur-based heterocycle; heterocycle;albeit with a albeit lack ofwith diastereoselectivity. a lack of diastereoselectivity.

SchemeScheme 28. 28. RadicalRadical production production of of aldehydes, aldehydes, by by Benati Benati et et al. al.

InIn aa moremore exotic exotic example example of radicalof radical annulation, annulati aon, powerful a powerful method method to access to lactams access waslactams described was describedby Tojino by et al.,Tojino which et al., proceeded which proceeded with incorporation with incorporation of carbon of monoxide carbon monoxide195 into the195 incipientinto the incipientheterocycle heterocycle (Scheme 29 (Scheme)[87]. This 29).[87] cyclizative This cyclizative radical carbonylation radical carbonylation of suitable azaenyne of suitable substrates azaenyne194 substratesgenerated 194 a number generated of nitrogenous a number of heterocycles, nitrogenous with heterocycles, a comparison with between a comparison silicon between and thiol silicon based andradical thiol precursors. based radicalE/Z selectivity precursors. was E/Z observed selectivity for thewas thiol observed and silane for the mediated thiol and cyclizations silane mediated in which cyclizations100% E-selectivity in which was 100% observed E-selectivity in many was cases observed (e.g., 198ain manyand cases198b );(e.g., this 198a is in and contrast 198b to); this classical is in contrasttin-based to methods, classical tin-based which mostly methods, initiate which a Z-selective mostly initiate process a [Z88-selective]. process.[88]

Scheme 29. Work by Tojino et al., displaying excellent E/Z selectivity. The proposed mechanism is shown.

Okiko Miyata and co-workers published an account in their series of radical cyclizations for heterocycle synthesis, in which selectivity for cyclization onto oxime ethers was reported (Scheme

Molecules 2020, 25, x FOR PEER REVIEW 23 of 42 thiophenol and pentynylthiol esters 190 provides both aromatic and aliphatic aldehydes, and permits a formal reduction of esters to aldehydes even with substituents which would normally be very sensitive to any reducing conditions. The formation of concomitant dihydrothiophenes 191 frames this account as relevant to the present review, and offers a useful synthetic route to this sulfur-based heterocycle; albeit with a lack of diastereoselectivity.

Scheme 28. Radical production of aldehydes, by Benati et al.

In a more exotic example of radical annulation, a powerful method to access lactams was described by Tojino et al., which proceeded with incorporation of carbon monoxide 195 into the incipient heterocycle (Scheme 29).[87] This cyclizative radical carbonylation of suitable azaenyne substrates 194 generated a number of nitrogenous heterocycles, with a comparison between silicon and thiol based radical precursors. E/Z selectivity was observed for the thiol and silane mediated Moleculescyclizations2020, 25in, 3094which 100% E-selectivity was observed in many cases (e.g., 198a and 198b); this22 is of in 40 contrast to classical tin-based methods, which mostly initiate a Z-selective process.[88]

Scheme 29. WorkWork by by Tojino Tojino et et al., al., displaying displaying excellent excellent EE/Z/Z selectivity.selectivity. The The proposed proposed mechanism mechanism is isshown. shown.

MoleculesOkiko 2020 , Miyata25, x FOR and PEER co-workers REVIEW published an account in their series of radical cyclizations24 of for 42 heterocycle synthesis,synthesis, inin whichwhich selectivity selectivity for for cyclization cyclization onto onto oxime oxime ethers ethers was was reported reported (Scheme (Scheme 30). This account details some of the previously discussed selectivity for radical addition to electron 30). This account details some of the previously discussed selectivity for radical addition to electron deficientdeﬁcient alkenes,alkenes, andand thethe key key advancement advancement of of this this work work is theis the generation generation of 5-membered of 5-membered lactams lactams with withalkyloxyamino alkyloxyamino moieties moieties200, which 200, which is the is result the result of preferential of preferential addition addition of an αof-carbonyl an α-carbonyl radical radical to the tooxime the oxime ether 199ether. Analogous 199. Analogous to the to explanation the explanation in Section in Section 2.2., the 2.2., regioselectivity the regioselectivity of this of process this process can be canexplained be explained by SOMO by SOMO/HOMO/HOMO interactions, interactions, and the and stability the stability of theradical of the radical intermediate intermediate.[89] [89].

Scheme 30. OximeOxime ether ether work work by by Miyata Miyata et al.

A short communication from Nanni et al. on on the regioselectivity of imidoyl radical cyclizations featuresfeatures aryl aryl thiyl thiyl radicals, radicals, generated generated from from photolyt photolyticic cleavage cleavage of a of disulfide a disulﬁde (Scheme (Scheme 31).[90] 31)[ This90]. paper,This paper, published published in the in2000s, the 2000s,expands expands upon original upon original work conducted work conducted in the late in the90s lateby the 90s authors by the whoauthors could who not could unambiguously not unambiguously assign assign the identity the identity of the of theproducts products at atthe the time.[91] time [91]. This This reaction reaction between thiyl radicals and isocyanides comprises a a cascade reaction reaction in which radical 204 attacks the isocyanideisocyanide group group of 205. Concomitant Concomitant nitrogen-centered nitrogen-centered radical radical formation formation allows allows the the cascade cascade to to continue through through cyclization cyclization into into the the aromatic backbone 207.. The The authors authors postulated postulated that that the the fast, fast, reversiblereversible cyclization of the the imidoyl imidoyl radical radical onto onto the the sulfur sulfur center center is is offset oﬀset by by the the slow slow but but essentially essentially irreversible radical addition to the cyano group. Two reaction pathways are proposed to explain the products observed, and the one to yield the major product 208 is shown below in Scheme 31.

Scheme 31. Reaction pathway to major product isolated by Nanni et al.

In the same year, Rainer and Kennedy reported a cascade to dithioindoles 212a–f from arylisonitriles bearing alkynes as ortho substituents 209.[92] A number of indoles were successfully synthesized, with the 5-exo-dig process appearing to outcompete other cyclization pathways (Scheme 32). A number of thiyl radical precursors were tested using a model substrate, and successful cyclization yields ranged from ca. 50 to 95%

Molecules 2020, 25, x FOR PEER REVIEW 24 of 42

30). This account details some of the previously discussed selectivity for radical addition to electron deficient alkenes, and the key advancement of this work is the generation of 5-membered lactams with alkyloxyamino moieties 200, which is the result of preferential addition of an α-carbonyl radical to the oxime ether 199. Analogous to the explanation in Section 2.2., the regioselectivity of this process can be explained by SOMO/HOMO interactions, and the stability of the radical intermediate.[89]

Scheme 30. Oxime ether work by Miyata et al.

A short communication from Nanni et al. on the regioselectivity of imidoyl radical cyclizations features aryl thiyl radicals, generated from photolytic cleavage of a disulfide (Scheme 31).[90] This paper, published in the 2000s, expands upon original work conducted in the late 90s by the authors who could not unambiguously assign the identity of the products at the time.[91] This reaction between thiyl radicals and isocyanides comprises a cascade reaction in which radical 204 attacks the isocyanide group of 205. Concomitant nitrogen-centered radical formation allows the cascade to Molecules 2020, 25, 3094 23 of 40 continue through cyclization into the aromatic backbone 207. The authors postulated that the fast, reversible cyclization of the imidoyl radical onto the sulfur center is offset by the slow but essentially irreversibleirreversible radicalradical additionaddition toto thethe cyanocyano group.group. Two reaction pathways are proposed to explain the productsproducts observed,observed, andand thethe oneone toto yieldyield thethe majormajor productproduct 208208 isis shownshown belowbelow inin SchemeScheme 31 31..

Scheme 31. Reaction pathway to major product isolated by Nanni et al.al.

InIn thethe same same year, year, Rainer Rainer and Kennedyand Kennedy reported reported a cascade a to cascade dithioindoles to dithioindoles212a–f from arylisonitriles212a–f from bearingarylisonitriles alkynes bearing as ortho alkynessubstituents as ortho209 substituents [92]. A number 209.[92] of A indoles number were of indoles successfully were synthesized,successfully withsynthesized, the 5-exo with-dig process the 5-exo appearing-dig process to outcompete appearing to other outcompete cyclization other pathways cyclization (Scheme pathways 32). A (Scheme number of32). thiyl A radicalnumber precursors of thiyl wereradical tested precursors using a modelwere tested substrate, using and a successful model substrate, cyclization and yields successful ranged fromcyclizationMolecules ca. 2020 50 yields, to 25 95%, x FOR ranged PEER REVIEWfrom ca. 50 to 95% 25 of 42

Scheme 32. Results published by Rainer et al. on arylisonitrile cyclization methodology.

A similarsimilar approachapproach waswas publishedpublished byby MitamuraMitamura etet al.,al., relyingrelying onon cyclizationcyclization ofof thethe thioimidoylthioimidoyl radicalradical ontoonto anan orthoortho alkenealkene.[93] [93]. Radical Radical cyclization of ortho-vinyl and orthoortho-allyl-allyl phenylisocyanidesphenylisocyanides furnishedfurnished bisthiolatedbisthiolated indoleindole and and quinoline quinoline derivatives derivatives in in moderate moderate yields. yields. This This approach approach employed employed a photoinduceda photoinduced thiotelluration, thiotelluration, and and while while tellurium tellurium is absent is absent from thefrom bisthiolated the bisthiolated product, product, it appears it toappears play a to crucial play a role crucial in the role reaction in the mechanism;reaction mech thisanism; is analogous this is analogous to systems to employing systems employing the diphenyl the disulﬁdediphenyl anddisulfide diphenyl and diphenyl diselenide diselenide pair. It is pair. probable It is probable that the telluriumthat the tellurium/sulfur/sulfur combination combination aﬀords regioselectivityaffords regioselectivity due to the due high to the reactivity high reactivity of the phenylthiyl of the phenylthiyl radical [radical,[94]94], and the and high the carbon high radicalcarbon capturingradical capturing ability ofability the phenyltellurideof the phenyltelluride species. species. It is noteworthy It is noteworthy to consider to consider that thethat relative the relative rate ofrate dichalcogenides of dichalcogenides for capturing for capturing carbon-entered carbon-entered radicals radicals is of is the of order the orderkPhSSPh kPhSSPh:kPhSeSePh:kPhSeSePh:kPhTeTePh:kPhTeTePh == 1:160:6301:160:630.[95–97] [95–97]. Analogous toto thosethose resultsresults byby RainerRainer andand co-workers,co-workers, MinozziMinozzi etet al.al. published a similar radical cyclizationcyclization ofof anan alkynylalkynyl arylisonitrilearylisonitrile 213213.[98][98]. Interestingly, Interestingly, this proceeded as aa multi-stepmulti-step cascadecascade whichwhich resultedresulted inin thethe formationformation ofof quinolinequinoline 220220 (Scheme(Scheme 3333,, InsertInsert A),A), asas wellwell asas formationformation ofof spirocyclesspirocycles 218 andand 219219.. The authors propose that the thioimidoylthioimidoyl radical 214 formedformed fromfrom thiylthiyl addition toto the the isonitrile isonitrile can can cyclize cyclize onto onto the alkyne the alkyne as previously as previously shown, butshown, a 1,5-hydorgen but a 1,5-hydorgen migration migration and cyclization then furnishes the observed spirocyclic compounds. A proposed mechanism is detailed in Scheme 33.

Scheme 33. Spirocycle formation by Minozzi et al. Major product 220 formed through separate pathway.

Molecules 2020, 25, x FOR PEER REVIEW 25 of 42

Scheme 32. Results published by Rainer et al. on arylisonitrile cyclization methodology.

A similar approach was published by Mitamura et al., relying on cyclization of the thioimidoyl radical onto an ortho alkene.[93] Radical cyclization of ortho-vinyl and ortho-allyl phenylisocyanides furnished bisthiolated indole and quinoline derivatives in moderate yields. This approach employed a photoinduced thiotelluration, and while tellurium is absent from the bisthiolated product, it appears to play a crucial role in the reaction mechanism; this is analogous to systems employing the diphenyl disulfide and diphenyl diselenide pair. It is probable that the tellurium/sulfur combination affords regioselectivity due to the high reactivity of the phenylthiyl radical,[94] and the high carbon radical capturing ability of the phenyltelluride species. It is noteworthy to consider that the relative rate of dichalcogenides for capturing carbon-entered radicals is of the order kPhSSPh:kPhSeSePh:kPhTeTePh = 1:160:630.[95–97] Analogous to those results by Rainer and co-workers, Minozzi et al. published a similar radical cyclization of an alkynyl arylisonitrile 213.[98] Interestingly, this proceeded as a multi-step cascade which resulted in the formation of quinoline 220 (Scheme 33, Insert A), as well as formation of Molecules 2020, 25, 3094 24 of 40 spirocycles 218 and 219. The authors propose that the thioimidoyl radical 214 formed from thiyl addition to the isonitrile can cyclize onto the alkyne as previously shown, but a 1,5-hydorgen andmigration cyclization and thencyclization furnishes then the observed furnishes spirocyclic the observed compounds. spirocyclic A proposed compounds. mechanism A isproposed detailed inmechanism Scheme 33 is. detailed in Scheme 33.

Scheme 33.33.Spirocycle Spirocycle formation formation by Minozziby Minozzi et al. et Major al. Major product product220 formed 220 throughformed separatethrough pathway.separate pathway. 3.4. Modern Approaches Each new report that demonstrates the usefulness of thiyl radicals for cascade chemistry further broadens the array of substrates that can be successfully cyclized. In the following subsection, recent results from the last decade are discussed, with the intent of outlining the current state-of-the-art for heterogeneous cyclizations. An excellent account of enyne cyclization by Taniguchi et al. builds upon work published forty years previous by Wang [99], in which the disulfide bond of diphenyl disulfide was cleaved by dimethylaniline to yield polymers via reaction with a suitable nitrile species. This original reaction was postulated to initiate by single-electron transfer (SET) from the amine. Taniguchi and co-workers then published a hydrothiolation of alkynes and subsequent cascade cyclization, with initiation of the process by tripropylamine (Scheme 34)[100]. This methodology offers an inexpensive approach to cyclization, and the annulated products can be separated by evaporation of the alkyl amine and standard chromatography. A mixture of 5-exo and 6-endo products were obtained, and the account provides an interesting example of aqueous thiyl radical addition, and non-classical initiation. A number of examples, with a range of olefinic substituents and varying heteroatoms bridging the alkyne and alkene were reported. Access to the pentacyclic core of the fungal-derived asperparalines was explored by Crick et al., who designed a clever radical cascade sequence comprised of 1,6-hydrogen atom transfer, followed by two cyclization steps (Scheme 35)[101]. These valuable alkaloids have been shown to act as strong selective antagonists of nicotinic acetylcholine receptors [102] and possess a bridged bicyclic core which is the backbone of many natural products. While this account describes multiple cyclized products generated during the optimization of cyclization methodology, Crick and co-workers were able use diketopiperazine 230 to isolate a single diastereomer product 231 with the desired configuration for the asperparaline core, albeit in modest yield. Molecules 2020, 25, x FOR PEER REVIEW 26 of 42

3.4. Modern Approaches Each new report that demonstrates the usefulness of thiyl radicals for cascade chemistry further broadens the array of substrates that can be successfully cyclized. In the following subsection, recent results from the last decade are discussed, with the intent of outlining the current state-of-the-art for heterogeneous cyclizations. An excellent account of enyne cyclization by Taniguchi et al. builds upon work published forty years previous by Wang,[99] in which the disulfide bond of diphenyl disulfide was cleaved by dimethylaniline to yield polymers via reaction with a suitable nitrile species. This original reaction was postulated to initiate by single-electron transfer (SET) from the amine. Taniguchi and co-workers then published a hydrothiolation of alkynes and subsequent cascade cyclization, with initiation of the process by tripropylamine (Scheme 34).[100] This methodology offers an inexpensive approach to cyclization, and the annulated products can be separated by evaporation of the alkyl amine and standard chromatography. A mixture of 5-exo and 6-endo products were obtained, and the account provides an interesting example of aqueous thiyl radical addition, and non-classical initiation. A

numberMolecules of 2020examples,, 25, 3094 with a range of olefinic substituents and varying heteroatoms bridging25 of 40 the alkyne and alkene were reported.

Molecules 2020, 25, x FOR PEER REVIEW 27 of 42 SchemeScheme 34. Cyclization 34. Cyclization reaction reaction by by Taniguchi Taniguchi et et al. Insert A A:: Examples Examples of of scope scope by by Taniguchi Taniguchi et al. et al.

O Access to the pentacyclic core of the fungal-derived asperparalinesN SPhwas explored by Crick et al., O who designed a clever radical cascadeO sequence comprised ofO 1,6-hydrogenH atom transfer, followed by two cyclization steps (SchemeNH 35).[101] These valuablePhSH alkaloids have been shown to act as strong N AIBN selective antagonists of Nnicotinic acetylcholine receptors[102] and possessHN a bridged bicyclic core t which is the backbone of many natural products.BuOH/Toluene While this account describesN multiple cyclized O O O O products generated during the optimization of cyclization methodology, Crick and co-workers were 230 231 able use diketopiperazine 230 to isolate a single diastereomer product 231 with the desired 30% configuration for the asperparaline core, albeit in modest yield. SchemeScheme 35. Key 35. Keycyclization cyclization step step employed employed by by Crick Crick and and co-workers. co-workers.

Shortly thereafter, Zhou and colleagues published a manganese (III) mediated addition of thiyl Shortlyradicals thereafter, to 1,3-diarylpropynones Zhou and colle to yieldagues thiolated published indenones a manganese (Scheme 36 ).(III) The mediated account describes addition the of thiyl radicals touse 1,3-diarylpropynones of Mn(OAc)3-induced formation to yield of thiolated thiophenoxyl indenones radical which (Scheme undergo 36). regioselective The account addition describes the use of Mn(OAc)to an array3-induced of substrates, formation which can of bethiophenoxyl further functionalized. radical which The authors undergo note thatregioselective this oﬀers an addition to an arrayalternative of substrates, to the heavy-metal which can catalysis be further (e.g., Pd orfunc Rhtionalized. complexes) employed The authors to form note 2,3-disubstituted that this offers an alternativeindenones to the heavy-metal234 from alkynes catalysis232, and (e.g., permits Pd mild or Rh conditions complexes) and moderate employed scope. to form 2,3-disubstituted indenones 234 from alkynes 232, and permits mild conditions and moderate scope.

Scheme 36. Indenone synthesis by Zhou et al.

Previously we have seen the use of SHi chemistry to synthesize thiophenes from suitable diyne precursors. These are limited to substrates bearing homogenous unsaturation, and thus Kamimura et al. published a detail account [103] on the use of radical cascades to prepare bicyclic dihydrothiophenes (Scheme 37). Once again, the translocated radical 243 undergoes intermolecular addition at the sulfur atom, resulting in extrusion of an alkyl radical. A reaction pathway proceeding through 5-exo-dig cyclization and either stepwise or direct homolytic substitution was proposed. Overall, chiral enynes were converted to bicyclic pyrolidinodihydrothiophenes 244 in a process where a thiyl radical serves as a sulfur biradical surrogate. Improvements in stereoselectively were observed by Kamimura et al. when large excesses of the thiyl radical precursor were employed in a photoinitiated reaction. An assortment of alkyl disulfides were tested as thiyl radical precursors, and dimethyl disulfide was determined as the best precursor, with 78% yield and a 90:10 trans:cis ratio attained with 20 equivalents of disulfide. The authors also varied the substitution of the tertiary amine backbone, and furnished a number of novel compounds, with fair to good stereoselectivity.

Molecules 2020, 25, x FOR PEER REVIEW 27 of 42

O N SPh O O O H NH PhSH N AIBN N HN tBuOH/Toluene N O O O O 230 231 30% Scheme 35. Key cyclization step employed by Crick and co-workers.

Shortly thereafter, Zhou and colleagues published a manganese (III) mediated addition of thiyl radicals to 1,3-diarylpropynones to yield thiolated indenones (Scheme 36). The account describes the use of Mn(OAc)3-induced formation of thiophenoxyl radical which undergo regioselective addition to an array of substrates, which can be further functionalized. The authors note that this offers an alternativeMolecules 2020 to, 25 the, 3094 heavy-metal catalysis (e.g., Pd or Rh complexes) employed to form 2,3-disubstituted26 of 40 indenones 234 from alkynes 232, and permits mild conditions and moderate scope.

SchemeScheme 36. IndenoneIndenone synthesis synthesis by by Zhou Zhou et et al. al.

PreviouslyPreviously we we have seen the use of SHii chemistry chemistry to to synthesize synthesize thiophenes thiophenes from from suitable suitable diyne diyne precursors. These areare limitedlimited to to substrates substrates bearing bearing homogenous homogenous unsaturation, unsaturation, and and thus thus Kamimura Kamimura et al. etpublished al. published a detail a account detail [103account] on the [103] use ofon radical the use cascades of radical to prepare cascades bicyclic to dihydrothiophenes prepare bicyclic dihydrothiophenes(Scheme 37). Once again,(Scheme the 37). translocated Once again, radical the 243translocatedundergoes radical intermolecular 243 undergoes addition intermolecular at the sulfur additionatom, resulting at the sulfur in extrusion atom, resulting of an alkyl in extrusion radical. of A an reaction alkyl radical. pathway A proceedingreaction pathway through proceeding 5-exo-dig throughcyclization 5-exo and-dig either cyclization stepwise and or directeither homolytic stepwise substitutionor direct homolytic was proposed. substitution Overall, was chiral proposed. enynes Overall,were converted chiral enynes to bicyclic were pyrolidinodihydrothiophenes converted to bicyclic pyrolidinodihydrothiophenes244 in a process where a thiyl 244 radical in a servesprocess as wherea sulfur a biradicalthiyl radical surrogate. serves Improvementsas a sulfur biradical in stereoselectively surrogate. Improvements were observed in by stereoselectively Kamimura et al. whenwere observedlarge excesses by Kamimura of the thiyl et radical al. when precursor large excesses were employed of the thiyl in a radical photoinitiated precursor reaction. were employed An assortment in a photoinitiatedof alkyl disulfides reaction. were An tested assortment as thiyl radicalof alkyl precursors, disulfides were and dimethyltested as thiyl disulfide radical was precursors, determined and as dimethylthe best precursor, disulfide withwas determined 78% yield and as athe 90:10 besttrans precursor,:cis ratio with attained 78% withyield 20and equivalents a 90:10 trans of disulfide.:cis ratio attainedThe authors with also 20 variedequivalents the substitution of disulfide. of The the tertiaryauthors amine also varied backbone, the substitution and furnished of athe number tertiary of amineMoleculesnovel compounds,backbone, 2020, 25, x FOR and with PEER furnished fair REVIEW to good a number stereoselectivity. of novel compounds, with fair to good stereoselectivity.28 of 42

Scheme 37. CyclizationCyclization by by Kamimura Kamimura et al., with proposed mechanism.

Patel and co-workers published an extensive me methodologythodology for the synthesis of tricyclic and spirocyclic heterocycles based onon aa thiylthiyl radicalradical/is/isocyanideocyanide couplecouple (Scheme(Scheme 3838).[104])[104]. This This alternative alternative to tin-based methods provides access to pyrroloquinolines 246, and spirocycles 247 and 248 from a common precursor, aiding the investigation of different heterocyclic motifs. Interestingly, the authors were able to select for 6-endo or 5-exo cyclization by altering the equivalents of radical initiator. Generally, one observes a trend of 5-exo favoured cyclization when concentration is low (ca 0.05 M) and the number of equivalents of AIBN is high (ca. 1.5 equivalents). In contrast, high concentration (0.1 to 0.2 M) and low loadings of initiator (ca. 0.3 equivalents) seem to favour 6-endo cyclization. As discussed by the authors, the kinetic 5-exo spirocycle predominates with increased quantities of initiator, indicating the nascent heterocycle is trapped and that the reaction is reversible. It follows that the thermodynamic 6-membered heterocycle predominates when the cyclization is slow, such as in the case where AIBN loading is reduced.

BocN

MeO2C

(a) N SPh

BocN 246 62% MeO2C

NC 245 BocN BocN MeO2C MeO2C (b) SPh + SPh N N 247 248 47% 18%

(a) PhSH (5 eq.), AIBN (0.1 eq.), Toluene (0.03 M), Δ (b) PhSH (5 eq.), AIBN (0.3 eq.), Toluene (0.03 M), Δ Scheme 38. Cyclizations by Patel et al., in which control over cyclization mode can be tuned.

Many of the cyclization reactions of enynes discussed herein utilize thiophenol as the thiyl radical precursor; while this reagent has enjoyed a special place in sulfur radical addition/cyclizations, a number of diverse thiyl precursors have demonstrated utility in this area. One such example that boasts desirable biological properties such as lipophilicity and resistance to metabolic processes is the trifluoromethylthio group (SCF3). Qiu et al. recently published a trifluoromethylthiolation cyclization between 1,6-enynes and an aromatic substituent,[105] which

Molecules 2020, 25, x FOR PEER REVIEW 28 of 42

Scheme 37. Cyclization by Kamimura et al., with proposed mechanism. Molecules 2020, 25, 3094 27 of 40 Patel and co-workers published an extensive methodology for the synthesis of tricyclic and spirocyclic heterocycles based on a thiyl radical/isocyanide couple (Scheme 38).[104] This alternative to tin-based methods provides access access to to pyrroloquinolines pyrroloquinolines 246,246, andand spirocycles spirocycles 247247 and 248 from a common precursor, aiding the investigation of differ diﬀerentent heterocyclic motifs. Interestingly, Interestingly, the authors were ableable to to select select for for 6-endo 6-endoor 5- orexo 5-cyclizationexo cyclization by altering by altering the equivalents the equivalents of radical of initiator. radical Generally,initiator. Generally,one observes one a trendobserves of 5- exoa trendfavoured of 5-exo cyclization favoured when cyclization concentration when isconcentration low (ca 0.05 M) is low and the(ca number0.05 M) andof equivalents the number of of AIBN equivalents is high (ca. of AIBN 1.5 equivalents). is high (ca. In1.5 contrast, equivalents). high concentrationIn contrast, high (0.1 concentration to 0.2 M) and (0.1low to loadings 0.2 M) and of initiator low loadings (ca. 0.3 of equivalents) initiator (ca. seem 0.3 equivalents) to favour 6- endoseemcyclization. to favour 6- Asendo discussed cyclization. by theAs discussedauthors, the by kinetic the authors, 5-exo spirocycle the kinetic predominates 5-exo spirocycle with increased predominates quantities with of increased initiator, indicatingquantities theof initiator,nascent heterocycle indicating the is trapped nascent and heterocycle that the reactionis trapped is reversible.and that the It followsreaction that is reversible. the thermodynamic It follows that6-membered the thermodynamic heterocycle 6-membered predominates heterocycle when the cyclizationpredominates is slow, when such the cyclization as in the case is slow, where such AIBN as inloading the case is reduced.where AIBN loading is reduced.

BocN

MeO2C

(a) N SPh

BocN 246 62% MeO2C

NC 245 BocN BocN MeO2C MeO2C (b) SPh + SPh N N 247 248 47% 18%

(a) PhSH (5 eq.), AIBN (0.1 eq.), Toluene (0.03 M), Δ (b) PhSH (5 eq.), AIBN (0.3 eq.), Toluene (0.03 M), Δ Scheme 38. CyclizationsCyclizations by by Patel Patel et et al., al., in which control over cyclization mode can be tuned.

Many of the cyclization reaction reactionss of enynes discussed herein utilize thiophenol as the thiyl radical precursor;precursor; while while this reagentthis reagent has enjoyed has a specialenjoyed place a inspecial sulfur radicalplace additionin sulfur/cyclizations, radical addition/cyclizations,a number of diverse thiyl a number precursors of diverse have demonstratedthiyl precursors utility have in demonstrated this area. One utility such example in this area. that Oneboasts such desirable example biological that boasts properties desirable such biological as lipophilicity properti andes resistancesuch as lipophilicity to metabolic and processes resistance is the to metabolictrifluoromethylthio processes group is the (SCF trifluoromethylthio3). Qiu et al. recently group published (SCF a3). trifluoromethylthiolation Qiu et al. recently published cyclization a trifluoromethylthiolationbetween 1,6-enynes and an cyclization aromatic substituent between 1,6-enynes [105], which and permits an aromatic the construction substituent,[105] of a number which of polycyclic fluorene systems (Scheme 39). Improved yield and reaction control necessitated the addition of a terpyridine ligand Ligand-1, which was postulated to coordinate to the HMPA additive and reduce the redox potential of the silver trifluoromethylthiol; this likely reduces oxidative decomposition. A number of annulated products were synthesized, and representative examples of this methodology are shown in Scheme 39. One account of particular interest was published by Chen and co-workers in early 2019, in which the authors used visible light (in the form of a green LED) and Eosin Y to synthesize 2-sulfenylindenones from the corresponding 1,3-diarylpropynones (Scheme 40)[106]. While this approach boasts environmental compatibility and cheap reagents, admittedly the reaction time is quite long (up to 36 h) and yields varied widely based on reaction solvent. However, a number of indenone species 259a–j were prepared and a wide substrate scope was explored, showing the forbearance of the methodology to differing functional groups on both the aromatic backbone and phenylthiyl species. Molecules 2020, 25, x FOR PEER REVIEW 29 of 42 permits the construction of a number of polycyclic fluorene systems (Scheme 39). Improved yield and reaction control necessitated the addition of a terpyridine ligand Ligand-1, which was postulated to coordinate to the HMPA additive and reduce the redox potential of the silver trifluoromethylthiol; this likely reduces oxidative decomposition. A number of annulated products were synthesized, and Moleculesrepresentative2020, 25, examples 3094 of this methodology are shown in Scheme 39. 28 of 40

MoleculesScheme 2020, 25 39.39., x Triﬂuoromethylthiolation FORTrifluoromethylthiolation PEER REVIEW work work by Qiuby Qiu et al. et Substitution al. Substitution on the on aryl the ring aryl was ring well tolerated.was well30 of 42 tolerated.

One account of particular interest was published by Chen and co-workers in early 2019, in which the authors used visible light (in the form of a green LED) and Eosin Y to synthesize 2-sulfenylindenones from the corresponding 1,3-diarylpropynones (Scheme 40).[106] While this approach boasts environmental compatibility and cheap reagents, admittedly the reaction time is quite long (up to 36 h) and yields varied widely based on reaction solvent. However, a number of indenone species 259a–j were prepared and a wide substrate scope was explored, showing the forbearance of the methodology to differing functional groups on both the aromatic backbone and phenylthiyl species.

Scheme 40. SubstrateSubstrate scope scope examined examined by Chen and co-workers.

3.5. State of the Art Thiyl radical mediated cyclization has been employed in the synthesis of a number of privileged scaffolds and complex substrates. One such example by Gharpure et al.,[107] reports the synthesis of pyrrolo[1,2-a]indole derivatives. This motif appears in a number of important pharmaceutical compounds such as those possessing antimalarial properties like Flinderole C,[108] and mitomycins which act as antitumor agents that can cross-link DNA.[109] This account by Gharpure and co- workers describes the use of enyne cyclization through a 5-exo-trig mechanism to generate a number of N-fused indolines 262a–c and indoles 260a–c from the corresponding N-propargylindones 261 (Scheme 41). The preference for indole vs. indolines was dictated by the identity of the propargylic substituents; indoline derivatives were furnished when R2 = Ph and R3 = H, and indoles were generated when these substituents were replaced by alkyl moieties such as a gem-dimethyl group. The authors propose that the bulkier aryl ring prefers to occupy the less sterically crowded face of the transition state. As the reduction of the radical (formed via 5-exo-trig cyclization onto the heterocyclic backbone) proceeds through a late transition state, the R1 substituent also prefers to occupy the less sterically incumbent face of the transition state, which permits delivery of a hydrogen atom to furnish the stereochemistry observed in 262a–c. To explain the generation of 260a–c, Gharpure et al. propose that the presence of an alkyl substituent on both faces of the transition state significantly slows down this hydrogen atom delivery, and thus when R2 and R3 = alkyl, a competing hydrogen abstraction provides the indole structures observed in 260a–c with concomitant aromatization as the driving force. The products obtained through this methodology were elaborated to the multicyclic core of yuremamine, a natural product featuring five contiguous stereocenters.[110] Shortly thereafter, Shibata and co-workers described the thiyl radical mediated cyclization of ω-alkynyl O-silyloximes with an odourless thiyl precursor, 4-tert-butylbenzenethiol.[111] This approach furnished a number of cyclic O-silylhydroxylamines in good yields. Removal of the silyl group yielded a number of

Molecules 2020, 25, 3094 29 of 40

3.5. State of the Art Thiyl radical mediated cyclization has been employed in the synthesis of a number of privileged scaﬀolds and complex substrates. One such example by Gharpure et al. [107], reports the synthesis of pyrrolo[1,2-a]indole derivatives. This motif appears in a number of important pharmaceutical compounds such as those possessing antimalarial properties like Flinderole C [108], and mitomycins which act as antitumor agents that can cross-link DNA [109]. This account by Gharpure and co-workers describes the use of enyne cyclization through a 5-exo-trig mechanism to generate a number of N-fused indolines 262a–c and indoles 260a–c from the corresponding N-propargylindones 261 (Scheme 41). The preference for indole vs. indolines was dictated by the identity of the propargylic substituents; indoline derivatives were furnished when R2 = Ph and R3 = H, and indoles were generated when these substituents were replaced by alkyl moieties such as a gem-dimethyl group. The authors propose that the bulkier aryl ring prefers to occupy the less sterically crowded face of the transition state. As the reduction of the radical (formed via 5-exo-trig cyclization onto the heterocyclic backbone) proceeds through a late transition state, the R1 substituent also prefers to occupy the less sterically incumbent face of the transition state, which permits delivery of a hydrogen atom to furnish the stereochemistry Molecules 2020, 25, x FOR PEER REVIEW 31 of 42 observed in 262a–c. To explain the generation of 260a–c, Gharpure et al. propose that the presence of hydroxylaminesan alkyl substituent which on bothcould faces be further of the transition transforme stated to signiﬁcantly nitrones, a slowsmotif downwhich this has hydrogen demonstrated atom potentialdelivery, in and neuroprotective thus when R2 and antiaging R3 = alkyl, drugs.[112] a competing hydrogen abstraction provides the indole structures observed in 260a–c with concomitant aromatization as the driving force.

SchemeScheme 41. 41. RepresentativeRepresentative indole indole and and indolines indolines examples examples published by Gharpure et al.

WhileThe products many of obtained the examples through discussed this methodology herein have were employed elaborated thermal to the initiation multicyclic in boiling core of benzene,yuremamine, or photolysis a natural with product high featuring intensity ﬁveultrav contiguousiolet lamps, stereocenters there are a [ 110number]. Shortly of visible-light thereafter, inducedShibata andcascades co-workers reported described in the literature. the thiyl radicalXie et al. mediated developed cyclization a reliable of routeω-alkynyl to benzothiophenesO-silyloximes (Schemewith an odourless42A) through thiylprecursor, the visible-light 4-tert-butylbenzenethiol induced cyclization [111]. of This 2-alkynylanilines approach furnished 263 aat number room temperature.[113]of cyclic O-silylhydroxylamines Good yields an ind goodoverall yields. forbearance Removal to substitution of the silyl groupon the yieldedalkyne terminus a number are of reported,hydroxylamines and a mechanism which could in which be further hydrogen transformed peroxide to oxidizes nitrones, cyclized a motif intermediate which has demonstrated 270 to reform aromaticitypotential in is neuroprotective proposed. Analogou and antiagings to the control drugs [ 112experiments]. by their contemporaries, the authors employed a ‘TEMPO test’, in which one equivalent of TEMPO is added to the reaction, and the quenched radical intermediates identified by mass spectrometry. A similar approach was published by Ye et al.,[114] which again relied on visible light to cyclize alkynes 273 and aryldisulfides 266 to benzothiophenes 274 (Scheme 42B). Interestingly, the authors found that oxygen could be used as the sole oxidant, and irradiation with sunlight could initiate the reaction efficiently. Ye and co-workers identified the optimal concentration of O2 to be around 15% and explained that although the reaction also occurs under argon, this is likely due to oxygen seeping through the septum. Yuan et al. achieved similar findings (Scheme 42C) to Ye et al. and Xie et al., while exploring the use of N-methacryloylbenzamides 275 as substrates to generate isoquinoline-type compounds 277.[115] The contributions from the three aforementioned authors are summarized in below, and the putative mechanism proposed by Xie et al. is included.

Molecules 2020, 25, 3094 30 of 40

While many of the examples discussed herein have employed thermal initiation in boiling benzene, or photolysis with high intensity ultraviolet lamps, there are a number of visible-light induced cascades reported in the literature. Xie et al. developed a reliable route to benzothiophenes (Scheme 42A) through the visible-light induced cyclization of 2-alkynylanilines 263 at room temperature [113]. Good yields and overall forbearance to substitution on the alkyne terminus are reported, and a mechanism in which hydrogen peroxide oxidizes cyclized intermediate 270 to reform aromaticity is proposed. Analogous to the control experiments by their contemporaries, the authors employed a ‘TEMPO test’, in which one equivalent of TEMPO is added to the reaction, and the quenched radical intermediates identified by mass spectrometry. A similar approach was published by Ye et al. [114], which again relied on visible light to cyclize alkynes 273 and aryldisulfides 266 to benzothiophenes 274 (Scheme 42B). Interestingly, the authors found that oxygen could be used as the sole oxidant, and irradiation with sunlight could initiate the reaction efficiently. Ye and co-workers identified the optimal concentration of O2 to be around 15% and explained that although the reaction also occurs under argon, this is likely due to oxygen seeping through the septum. Yuan et al. achieved similar findings (Scheme 42C) to Ye et al. and Xie et al., while exploring the use of N-methacryloylbenzamides 275 as substrates to generate isoquinoline-type compounds 277 [115]. The contributions from the three aforementioned authors are summarized in below, and the putative mechanism proposed by Xie et al. is included. Molecules 2020, 25, x FOR PEER REVIEW 32 of 42

Ar A Ar S R S H2O2 (2 eq.) + S R PhCl, Blue LED R R1 R1 263 264 265

Ph Ph S S

hν H S N S NH O O 266 267268 269

Ph Ph Ph S OH S S

+ H H NH NH NH OH H2O O OH O O

270hν 271 272

H2O2

B R1 R2 S S Visible light + Air R1 R2 S 266 273 274

C O O O R N 2 O2 R1 N + TsOH (20 mol%) R1 O R R SH 2 3 SR3 275 276 277 SchemeScheme 42. Cyclizations42. Cyclizations reported reported by by Xie Xie etet al.al. ( AA),), Ye Ye et et al. al. (B (),B and), and Yuan Yuan et al. et ( al.C) respectively. (C) respectively.

Shortly thereafter, Nair et al. described a diastereoselective visible-light mediated cascade of cyclohexadienones 278 with alkyne tethers (Scheme 43).[116] Good yields were reported, as was good functional group tolerance. This account relies on Eosin Y as the organic photocatalyst, and boasts an array of thiophenols/thiols as radical precursors, with electron donating and electron withdrawing groups in para- and ortho- positions tolerated for the aromatic thiols. The authors were also able to demonstrate the applicability to gram scale synthesis, and reported favourable green chemistry metrics (atom economy, and efficiency). A publication [117] by Mallick et al. reported comparable results, employing the same reactions conditions previously developed in the Sahoo group (Section 2.4, Dutta et al.). Mallick and co-worker’s approach employed a N-hydroxyphthalimide-mediated radical cyclization of yne-dienones, yielding 3-thioaryl-[6,6]-dihydrochromenone derivatives. Altering the substituents of the aryl thiol, or the functional groups presented by the yne-dienone were again well tolerated in the cascade.

Molecules 2020, 25, 3094 31 of 40

Shortly thereafter, Nair et al. described a diastereoselective visible-light mediated cascade of cyclohexadienones 278 with alkyne tethers (Scheme 43)[116]. Good yields were reported, as was good functional group tolerance. This account relies on Eosin Y as the organic photocatalyst, and boasts an array of thiophenols/thiols as radical precursors, with electron donating and electron withdrawing groups in para- and ortho- positions tolerated for the aromatic thiols. The authors were also able to demonstrate the applicability to gram scale synthesis, and reported favourable green chemistry metrics (atom economy, and eﬃciency). A publication [117] by Mallick et al. reported comparable results, employing the same reactions conditions previously developed in the Sahoo group (Section 2.4, Dutta et al.). Mallick and co-worker’s approach employed a N-hydroxyphthalimide-mediated radical cyclization of yne-dienones, yielding 3-thioaryl-[6,6]-dihydrochromenone derivatives. Altering the substituents of the aryl thiol, or the functional groups presented by the yne-dienone were again well Moleculestolerated 2020 in, the25, x cascade.FOR PEER REVIEW 33 of 42

SchemeScheme 43. 43. CyclizationCyclization reported reported by by Nair Nair et etal. al.Select Select examples examples that that demonstrate demonstrate FG tolerance FG tolerance are shown.are shown.

FurtherFurther examples examples of of the the use use of of isocyano isocyano groups groups as as radical radical acceptors acceptors was was pub publishedlished by byLi et Li al. et in al. 2019,in 2019, in inwhich which a denitrogenative a denitrogenative annu annulationlation of of 1-azido-2-isocyanarenes 1-azido-2-isocyanarenes 289289 furnishedfurnished an an array array of of 2-thiolated2-thiolated benzimidazoles benzimidazoles 291 (Scheme 44).[118]44)[118]. The The authors authors report report both both a a ‘promoter-free’ ‘promoter-free’ pathway pathway andand one one involving involving AIBN, AIBN, both both of ofwhich which are are heated heated in toluene in toluene in an in inert an inertatmosphere. atmosphere. While Whilethe AIBN the pathwayAIBN pathway offers ohigherﬀers higher yields yields in almost in almost every every example, example, a catalyst-free a catalyst-free pathway pathway in in which which the the only only by-productby-product is is the the extruded extruded nitrogen nitrogen gas gas from from cyclization cyclization onto onto the the orthoortho-azide-azide is is appealing. appealing. Li Li et et al. al. argueargue that that that that the the thiyl thiyl radicals radicals could could be be initiated initiated by by trace trace oxygen oxygen in in the the reaction reaction vessel, vessel, although although it it hashas previouslypreviously beenbeen reported reported that that certain certain thiols thiols can reactcan react successfully successfully via a radicalvia a radical mechanism mechanism without withoutcatalysts orcatalysts initiators or [119initiators,[119]], and indeed and thiols indeed may react thiols with may isocyanides react with at elevated isocyanides temperatures at elevated [120]. temperatures.[120]The authors report The this authors one pot report method this as one having pot me highthod functional as having group high func tolerance,tional andgroup a numbertolerance, of andprepared a number examples of prepared are shown examples in Scheme are shown 44. in Scheme 44.

Scheme 44. AIBN-initiated pathway to benzimidazoles described by Li et al.

Molecules 2020, 25, x FOR PEER REVIEW 33 of 42

Scheme 43. Cyclization reported by Nair et al. Select examples that demonstrate FG tolerance are shown.

Further examples of the use of isocyano groups as radical acceptors was published by Li et al. in 2019, in which a denitrogenative annulation of 1-azido-2-isocyanarenes 289 furnished an array of 2-thiolated benzimidazoles 291 (Scheme 44).[118] The authors report both a ‘promoter-free’ pathway and one involving AIBN, both of which are heated in toluene in an inert atmosphere. While the AIBN pathway offers higher yields in almost every example, a catalyst-free pathway in which the only by-product is the extruded nitrogen gas from cyclization onto the ortho-azide is appealing. Li et al. argue that that the thiyl radicals could be initiated by trace oxygen in the reaction vessel, although it has previously been reported that certain thiols can react successfully via a radical mechanism without catalysts or initiators,[119] and indeed thiols may react with isocyanides at elevated Moleculestemperatures.[120]2020, 25, 3094 The authors report this one pot method as having high functional group tolerance,32 of 40 and a number of prepared examples are shown in Scheme 44.

SchemeScheme 44. 44.AIBN-initiated AIBN-initiated pathway pathway to benzimidazoles benzimidazoles described described by Li by et Li al. et al.

Molecules 2020, 25, x FOR PEER REVIEW 34 of 42 Research from Gharpure et al. elaborates on the pyrrole synthesis previously developed by Dutta et al.,Research but insteadfrom Gharpure offers tetrasubstituted et al. elaborates furanson the pyrrole297a–c synthesisfrom alkynyl previously vinylogous developed carbonates by 296 (SchemeDutta et al.,45 )[but121 instead]. The offers authors tetrasubstituted note that substitution furans 297a– atc from the αalkynyl-position vinylogous of the alkynyl carbonates vinylogous 296 carbonate(Scheme aff 45)ects [121]. diastereoselectivity The authors note ofthat the substitution cascade,and at the propose α-position a mechanism of the alkynyl in whichvinylogous the thiyl radicalcarbonate attacks affects the alkyne diastereoselectivity first. The nascent of the carbon-centered cascade, and propose radical a mechanism then cyclizes in which onto the the remainingthiyl olefin,radical and theattacks cascade the alkyne continues first. The with nascent propagation carbon-centered of the radical radical then chain. cyclizes It is noteworthy onto the remaining that in this account,olefin, thiophenol and the cascade can actcontinues not only with as propagation a source of of thiylthe radical radicals chain. but It asis noteworthy an oxidant that with in AIBNthis to transformaccount, dihydrofurans thiophenol can to act furans. not only as a source of thiyl radicals but as an oxidant with AIBN to transform dihydrofurans to furans.

SchemeScheme 45. 45.Cyclizations Cyclizations and and polyheterocycle polyheterocycle syntheses syntheses reported reported by byGharpure Gharpure et al. et al.

The Hong group reported a breakthrough in mid-2019, in which the substrate and photosensitizer were combined in a single molecule (Scheme 46). This account by Kim et al. examined the photochemical activity of quinolinone-based substrates 304 which could reach an excited state and initiate thiyl radical formation, while the ground state acted as a radical accepting substrate. The products of this ground state substrate are dictated by whether a hydrogen atom transfer (HAT) or single electron transfer (SET) step occurs, which is determined by the coupling reagents used.[122] The authors report a diverse assemblage of dihydro- and tetrahydrophenanthridin-6(5H)-ones prepared in a metal-free and essentially photocatalyst-free cascade. A number of bioactive thiols such as cysteine, captopril and gemfibrozil were successfully applied in this methodology, which exerts a 6-endo-trig cyclization following thiyl radical addition. The tolerance of this methodology to bioactive thiols indicates that this method may be applied to generating compound libraries for combinatorial chemistry (or otherwise), or modifying existing bioactive thiols. A selection of examples from both the disulfide and thiol pathways are shown in Scheme 46.

Molecules 2020, 25, 3094 33 of 40

The Hong group reported a breakthrough in mid-2019, in which the substrate and photosensitizer were combined in a single molecule (Scheme 46). This account by Kim et al. examined the photochemical activity of quinolinone-based substrates 304 which could reach an excited state and initiate thiyl radical formation, while the ground state acted as a radical accepting substrate. The products of this ground state substrate are dictated by whether a hydrogen atom transfer (HAT) or single electron transfer (SET) step occurs, which is determined by the coupling reagents used [122]. The authors report a diverse assemblage of dihydro- and tetrahydrophenanthridin-6(5H)-ones prepared in a metal-free and essentially photocatalyst-free cascade. A number of bioactive thiols such as cysteine, captopril and gemﬁbrozil were successfully applied in this methodology, which exerts a 6-endo-trig cyclization following thiyl radical addition. The tolerance of this methodology to bioactive thiols indicates that this method may be applied to generating compound libraries for combinatorial chemistry (or otherwise), or modifying existing bioactive thiols. A selection of examples from both the disulﬁde and thiol pathways are shown in Scheme 46. Molecules 2020, 25, x FOR PEER REVIEW 35 of 42

Scheme 46.SchemeSelected 46. Selected examples examples from from Kim Kim et et al. al. Insert:Insert: 306306 servesserves as an as additive an additive in the thiol in thepathway. thiol pathway.

Somewhat analogous to the work reported by the Hong group, a recent report by Ho et al. describes an electron-donor-acceptor (EDA) complex which undergoes visible light-induced charge transfer, and facilitates the radical spirocyclization of a number of indole-tethered ynones 307a–j (Scheme 47) [123]. The EDA complex promotes thiyl radical generation and initiates a cascade that features a dearomatizing spirocyclization with concomitant carbon-sulfur bond formation, to yield a number of indolines 308a–j. The authors highlight that this is only the second reported use of intramolecular EDA complexes in the literature,[124] and admit that this rare form of radical activation was uncovered serendipitously. Regioselective addition of the somewhat electrophilic

Molecules 2020, 25, 3094 34 of 40

Somewhat analogous to the work reported by the Hong group, a recent report by Ho et al. describes an electron-donor-acceptor (EDA) complex which undergoes visible light-induced charge transfer, and facilitates the radical spirocyclization of a number of indole-tethered ynones 307a–j (Scheme 47)[123]. The EDA complex promotes thiyl radical generation and initiates a cascade that features a dearomatizing spirocyclization with concomitant carbon-sulfur bond formation, to yield a number of indolines 308a–j. The authors highlight that this is only the second reported use of intramolecular EDA complexes in the literature [124], and admit that this rare form of radical activation Molecules 2020, 25, x FOR PEER REVIEW 36 of 42 was uncovered serendipitously. Regioselective addition of the somewhat electrophilic thiyl radicals to thiylynones radicals initiates to ynones the process, initiates followed the process, by attack foll ofowed incipient by attack carbon-centered of incipient radicalcarbon-centered on the tethered radical onaromatic the tethered group. aromatic group.

R4S O O

R3 R4-SH R R Blue LED 2 2 R3 N DCE N H

R1 R1 307a-j 308a-j

PhS PhS PhS PhS C3H7S O O O O O Ph Ph Ph Ph

N N N N N H H 308a 308b 308c 308d 308e 69% 68% 99% 85% 90%

O2N HO Ph S S S S S O O O O O Ph Ph Ph Ph Ph

N N N N N

308f 308g 308h 308i 308j 74% 42% 85% 99% 86% SchemeScheme 47. 47. CascadeCascade developed developed by by Ho Ho et etal., al., with with sele selectedcted examples. examples. Ynone/thiol Ynone/thiol scope scope was was well tolerated.well tolerated. 4. Conclusions 4. Conclusions Thiyl and acyl thiyl radicals have found broad application in organic synthesis, from heterocycle Thiyl and acyl thiyl radicals have found broad application in organic synthesis, from heterocycle formation to sterically recalcitrant carbocyclizations. They boast mild generation and remarkable formation to sterically recalcitrant carbocyclizations. They boast mild generation and remarkable reactivity; their utility provides access to radical chemistry to those chemists beyond the archetypal reactivity; their utility provides access to radical chemistry to those chemists beyond the archetypal sulfur laboratory. The addition of these radicals to homogenous systems facilitates the synthesis sulfur laboratory. The addition of these radicals to homogenous systems facilitates the synthesis of of alicycles and thiophenes, while their addition to heterogeneous systems gives rise to numerous alicycles and thiophenes, while their addition to heterogeneous systems gives rise to numerous heterocycles and fused ring systems. Their application to intramolecular cascade reactions has been heterocycleswidely explored, and fused and continues ring systems. to be developedTheir application for organocatalytic to intramolecular and enantioselective cascade reactions systems. has This been widelyreview explored, highlights and the continues vast array to of be complex developed architectures for organocatalytic rendered accessible and enantioselective by the thiol-ene systems. and Thisthiol-yne review reactions highlights in particular, the vast andarray hopes of complex to demonstrate architectures the versatility rendered of thiylaccessible and acyl by thiyl the radicalsthiol-ene andas athiol-yne whole. reactions in particular, and hopes to demonstrate the versatility of thiyl and acyl thiyl radicals as a whole.

Funding: This research was funded by Science Foundation Ireland, grant number 15/CDA/3310.

Acknowledgments: In this section you can acknowledge any support given which is not covered by the author contribution or funding sections. This may include administrative and technical support, or donations in kind (e.g., materials used for experiments).

Conflicts of Interest: The authors declare no conflict of interest.

References

Molecules 2020, 25, 3094 35 of 40

Author Contributions: Writing—original draft preparation, D.M.L.; writing—review and editing, E.M.S.; funding acquisition, E.M.S. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Science Foundation Ireland, grant number 15/CDA/3310. Acknowledgments: In this section you can acknowledge any support given which is not covered by the author contribution or funding sections. This may include administrative and technical support, or donations in kind (e.g., materials used for experiments). Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

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