Merging gold catalysis and haloethynyl frames: emphasis on halide-shift processes

Diges pape Me ging gold ca alysis and haloe hynyl ames: Emphasis on halide-shi p ocesses Paula Fe nández-Canelas, Pablo Ba io, José M. González ⇑ Depa amen o de Química O gánica e Ino gánica and Ins i u o Uni e si a io de Química O ganome álica ‘‘En ique Moles”, Uni e sidad de O iedo, C/Julián Cla e ía 8, O iedo 33006, Spain a icle in o A icle his o y: Recei ed 2 Feb ua y 2022 Re ised 22 Ap il 2022 Accep ed 6 May 2022 A ailable online 12 May 2022 Keywo ds: Gold(I) ca alysis Haloalkyne Cycloisome iza ion Elec ophilic ac i a ion Vinylidene abs ac Haloalkynes can en e a wide a ie y o me al-ca alyzed ans o ma ion gi ing ise o he o ma ion o p oduc s wi h o wi hou showing halide-shi . This a icle o e s an o e all iew o he eac i i y o hese subs a es unde gold ca alysis. Pa icula a en ion is de o ed o in amolecula eac ions ha in ol e a concomi an halide-shi p ocess o he case o alkynyl iodides as s a ing ma e ials. Ó2022 The Au ho (s). Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). Con en s In oduc ion. . . . . ........................................................................................................ 1 Gold-ca alyzed di ec addi ion eac ions o haloalkynes. . . . . . . . .................................................................. 3 Me al inylidenes om e minal and in e nal alkynes: gene ali ies and applica ions in o ganic syn hesis. . ............................... 5 Gold inylidenes om e minal alkynes: s uc u al ea u es and syn he ic u ili y . . . . . ............................................... 5 Haloalkynes as p ecu so s o me al inylidene complexes. . . . . .................................................................. 7 Ea ly obse a ions using o he me als han gold. ........................................................................... 8 1,2-Halogen shi e en s in ca aly ic gold-ac i a ion o he e oa om-subs i u ed alkynes: gold inylidenes as likely eac ion in e media es . . 8 O he ypes o gold-ca alyzed eac ions o haloalkynes in ol ing halogen-shi ing: selec i e alkyne-alkyne and alkyne-alkene couplings . . 12 Pe spec i e. . . . . . ....................................................................................................... 14 Decla a ion o Compe ing In e es . . . . .................................................................................... 14 Acknowledgmen s . . . . . . . . . . . . . . . . . .................................................................................... 14 Re e ences . . . . ....................................................................................................... 14 Re e ences . . . . ....................................................................................................... 15 In oduc ion Haloalkynes a e unique ace ylene de i a i es [1]. They a e o signi icance o he p epa a ion o ca bon- ich ma e ials [2] and as in e media es o de eloping syn he ic me hodology, pa icula ly h ough a a ie y o halide subs i u ion p ocesses (Scheme 1)[3]. They a e aluable pa ne s in c oss-coupling eac ions [4], and a e use ul eagen s o an a ay o inno a i e ca aly ic p ocesses in ol ing selec i e CAH unc ionaliza ion eac ions (Scheme 2)[5]. Fu he mo e, ca aly ic CAC bond- o ming ans o ma ions o halogen-masked e minal alkyne de i a i es a o ding p oduc s showing halogen e en ion a e known. The dime iza ion eac ion o alkynyl halides o e s in e es ing examples based on he consid- e a ion o complemen a y s a egies Selec i e head- o- ail dime - iza ion o a yl-subs i u ed iodoalkynes can be ca aly ically accomplished using a p ope sou ce o iodonium ions h ough a ca ionic p ocess. The subs i u ion pa e n on o he a yl ing dic- h ps://doi.o g/10.1016/j. e le .2022.153857 0040-4039/Ó2022 The Au ho (s). Published by Else ie L d. This is an open access a icle unde he CC BY-NC-ND license (h p://c ea i ecommons.o g/licenses/by-nc-nd/4.0/). ⇑ Co esponding au ho . E-mail add ess: [email p o ec ed] (J.M. González). Te ahed on Le e s 99 (2022) 153857 Con en s lis s a ailable a ScienceDi ec Te ahed on Le e s jou nal homepage: www.else ie .com/loca e/ e le a es he e iciency o he o e all ans o ma ion, wi h elec on dono subs i uen s a o ding be e esul s (Scheme 3)[6]. A ela ed pho oca aly ic coupling eac ion o a yl-subs i u ed b omoalkynes was ecen ly disclosed, and yields he head- o- ail dime in an e icien and selec i e manne (Scheme 4)[7]. Mechanis ically, an ene gy ans e pa hway p omo ed by isi- ble-ligh pho oca alysis esul ing in he o ma ion o b omine and a ylace ylene adicals was p oposed. Also ecen ly, gold(I) complexes we e iden i ied as aluable ca - alys s o gi e he co esponding 1,1-diiodo-1-en-3-yne om he pa en (iodoe hynyl)a ene p ecu so . So, when di e en iodoalky- nes we e ea ed in ace oni ile wi h a ca aly ic amoun o a , p - dinuclea p opyne-gold ace ylide (dual ac i a ion ca alys ) he co - esponding head- o- ail dime iza ion p oduc s we e selec i ely assembled (Scheme 5)[8]. In e es ingly, his eac ion also allows he dime iza ion o alkyl- subs i u ed iodoalkynes, expanding he scope p e iously desc ibed o his ans o ma ion. This obse a ion is in line wi h he no iced eac i i y o his ype o ca alys o he dime iza ion o alipha ic e minal alkynes [9]. The b omoalkynyla ion o in e nal alkynes wi h b omoalkynes is ano he syn he ically use ul halogen- e en i e ans o ma ion. Jiang showed ha palladium ace a e is an e icien ca alys o accomplish his demanding ask. The CAC bond-making eac ion nicely akes place a 30 °C, in ace oni ile as sol en (Scheme 6) [10]. The eac ion can be also conduc ed using a iodoalkyne bu in lowe yield. So he iodine-con aining analogue o he enyne depic ed in Scheme 6 was p epa ed in a ela ed manne om (io- doe hynyl)benzene in 48% yield. In he con ex o he s udy o iodonium-p omo ed sel -coupling eac ions o ( e -bu yldime hylsilyl)alkynes o u nish he co e- sponding head- o- ail dime iza ion p oduc , i was also epo ed ha iodoalkynes can add ac oss he ela ed TBDMS-subs i u ed Scheme 1. Syn he ic me hodology om haloalkynes: o mal halide displacemen eac ions. Scheme 2. Some ecen c oss-coupling p ocesses in ol ing alkynyl halides. Scheme 3. Iodonium-ca alyzed iodoalkyne dime iza ion eac ion. Scheme 4. Pho oca alyzed sel -coupling o b omoalkynes. Scheme 5. Gold-ca alyzed head- o- ail coupling o iodoalkynes. Scheme 6. Palladium-ca alyzed b omoalkynyla ion o alkynes. Scheme 7. Iodonium media ed c oss-dime iza ion o a iodoalkyne and a silyl- subs i u ed alkyne. P. Fe nández-Canelas, P. Ba io and José M. González Te ahed on Le e s 99 (2022) 153857 2 ace ylenes o a o d he co esponding he e odime , a p ocess ha was no u he op imized (Scheme 7)[11]. All hose eac ions highligh some aspec s o he ich chemis y o haloakynes. This con ibu ion deals wi h he u ili y o his class o he e oa om-subs i u ed alkynes o es ablish new ans o ma- ions wi h inco po a ion o he halogen a om in o he s uc u e o he p oduc , in pa icula h ough ans o ma ions ha , eason- ably, migh be a ionalize assuming he in e mediacy o me al inylidene species. Main a en ion will be de o ed o he g owing numbe o gold-ca alyzed p ocesses ul illing his condi ion. Acco dingly, his b ie accoun will be a anged acco ding o he discussion o he main ollowing opics: – Gold-ca alyzed di ec addi ion eac ions o haloakynes. – Me al- inylidenes in o ganic syn hesis. – Gold inylidenes: s uc u e and syn he ic u ili y. – Haloakynes as a po en ial sou ce o gold inylidenes. – Gold-ca alyzed eac ions o haloalkynes in ol ing halogen shi ing: selec i e alkyne-alkyne and alkyne-alkene couplings. In his con ex we will b ie ly ou line ou wo k in his ield, as well as ecen con ibu ions om o he au ho s ha , hough e ol - ing hough di e en ia e eac ion mechanisms, con ibu e o shape and de elop ano he g owing ho a ea o gold ca alysis. Gold-ca alyzed di ec addi ion eac ions o haloalkynes. The abo e p esen ed ans o ma ions a e a pe sonal selec ion o ep esen a i e eac ions ha con ibu e o highligh some signi i- can aspec s o he chemis y o haloalkynes. In e es ingly, along he wo pas decades a ple ho a o gold-ca alyzed new syn he ic p ocesses and a numbe o dis inc i e s uc u al ea u es we e doc- umen ed [12], wi h alkynes p o ing o be unique pa ne s o gold [13]. In his scena io, gold-ca alyzed hyd o unc ionaliza ion eac- ions o unsa u a ed CAC mul iple bonds we e apidly de eloped [14]. These p ocesses ha e an impac on o haloalkyne chemis y, which was pu in o con ex in ano he ecen e iew [15]. The sea ch o e icien al e na i es o he use o me cu y sal s as ca alys s in he addi ion eac ion o wa e o alkynes o e ed a use ul ans o ma ion o ca alys s de elopmen . I has been an ac i e esea ch a ena om he ea ly days o he s udy o he syn he ic u ili y o di e en gold species [16]. The me i o gold ca alysis o access a -halome hylke ones upon eac ion o haloaky- nes wi h wa e was p o ed (Scheme 8,eqa)[17]. A ela ed egioselec i e hyd a ion eac ion o halo-subs i u ed p opa agyl ca boxyla es unde gold(I) ca alysis was epo ed o p oduce aluable syn he ic in e media es ha ing he s uc u e o a -acyloxy a ’-halo ke ones [18]. In e es ingly, he gold-ca alyzed alkyne hyd a ion can be also coupled wi h a u henium-ca alyzed asymme ic ans e hyd ogena ion eac ion o u nish chi al b- ad ene gic ecep o blocke s, in a new one-po cascade, as shown in Scheme 8, eq b o a selec i e syn hesis o (R)-Ni elanol [19]. Fu he mo e, a -halome hyl ke ones can be di ec ly accessed om e minal alkynes conduc ing he gold-ca alyzed hyd a ion eac ion in he p esence o N-halosuccinimides [20]. In connec ion wi h he iodina ion eac ion o e minal alkynes, Gagosz was he i s o demons a e he nice s e eochemical com- plemen a i y o gold(I)-ca alyzed cycliza ion eac ions o e minal p opa gyl e -bu ylca bona es o p epa e cyclic ca bona es. To his end, bo h, he ac i a ion o a e minal alkyne unde iodina ion con- di ions and, al e na i ely, he ela ed hyd o- unc ionaliza ion p o- cess s a ing om he pa en iodoalkyne we e de eloped (Scheme 9)[21]. Scheme 8. Gold-ca alyzed addi ion o wa e o b omoalkynes and i s subsequen syn he ic applica ion. Scheme 9. S e eoselec i e syn hesis o inyl iodides om gold(I)-ca alyzed cycliza ion eac ion o p opa gyl ca bona es. Scheme 10. (Z)-b-iodoenol es e s by ca aly ic in e molecula addi ion eac ion o ca boxylic acids o iodoalkynes. Scheme 11. Ca aly ic hyd ochlo ina ions o b omoalkynes. P. Fe nández-Canelas, P. Ba io and José M. González Te ahed on Le e s 99 (2022) 153857 3 In e es ingly, Cadie no, Ga cía-Ga ido and hei eam epo ed a syn he ically aluable in e molecula addi ion eac ion o ca - boxylic acids o iodoalkynes, which esul ed in he selec i e o ma- ion o (Z)-b-iodoenol es e s, which we e hen elabo a ed in o (Z)- enynyl es e s by palladium-ca alyzed Sonogashi a c oss-coupling eac ion wi h e minal ace ylenes (Scheme 10)[22]. Besides oxygen-based nucleophiles, o he he e oa oms add ac oss haloalkynes unde gold ca alysis. S e eoselec i e hyd ochlo- ina ion eac ions o haloalkynes a e known. Ca alysis based on bo h hyd ogen-bonding-assis ed B øns ed acid and on gold species we e applied o his pu pose. Fo ins ance, 4-(b omoe hynyl)phe- nyl ace a e can be selec i ely di e si ied in o he (Z) and (E) iso- me s o 4-(2-b omo-1-chlo o inyl)phenyl ace a e applying al e na i e ca aly ic condi ions (Scheme 11)[23]. A gold(I) ca alyzed Ri e - ype p ocess gi ing (Z)-b-halogena ed enamides om he eac ion o ni iles and wa e wi h b omo- o chlo oalkynes was ecen ly disclosed (Scheme 12)[24]. Mo eo e , new ca bon–ca bon bond- o ming e en s esul ing om di ec addi ion o C-based nucleophiles o haloalkynes a e also known. Thus, he iodoalkyne ca bocycliza ion eac ion depic ed in Scheme 13 ep esen s an ea ly example, which esul s in a syn he ically aluable gold-ca alyzed 5-endo-dig cycliza ion o in e nal alkynes, including bo h C- and halo-subs i u ed p ecu so s [25]. In some cases, In(III) demons a ed capabili y o complemen Au(I) ca alysis p omo ing addi ion eac ions o C-based nucle- ophiles o CAC mul iple bonds. Thus, Nakamu a documen ed a aluable syn-addi ion o 1,3-dica bonyl compounds o iodoalkynes. The esul ing E-alkenyl iodides a e pa ne s o u he de i a iza- ion o assemble isubs i u ed alkenes wi h de ined s e eochem- is y as depic ed in Scheme 14 [26]. The ca aly ic eac ion o phenols wi h 1-b omo-1,5-enynes gi es 2-(halocyclopen -2-en-1-yl)phenols h ough a domino p o- cess (Scheme 15)[27]. The eac ion also wo ks o chlo o enynes bu ails o he ela ed iodine-modi ied enynes. A chemo- and egioselec i e CAH bond- unc ionaliza ion o phenols by eac ion wi h haloalkynes unde gold ca alysis was documen ed, and ga e a yl-subs i u ed alkenes bea ing a phenol subs i uen (Scheme 16). [28]. Mo eo e , 1-iodoalkynes a e pa icula ly eac i e subs a es owa ds o ganic azides in he coppe -ca alyzed azide-alkyne cycloaddi ion chemis y (CuCAAC), a o ding 5-iodo-1,2,3- iazoles Scheme 12. Gold(I)-ca alyzed Ri e eac ion o haloalkynes. Scheme 13. Ca aly ic Conia-ene cycliza ion o a iodoalkyne. Scheme 14. Indium-ca alyzed C-addi ion o iodoalkynes. Scheme 15. Ca aly ic eac ion: 1-halo-1,5-enyne and phenols. Scheme 16. Selec i e addi ion o phenols o haloalkynes. Scheme 17. Iodoalkynes in he CuAAC eac ion. Scheme 18. Ca alysis by in-si u gene a ed inylidene species. P. Fe nández-Canelas, P. Ba io and José M. González Te ahed on Le e s 99 (2022) 153857 4 in a selec i e manne , unde mild ca aly ic eac ion condi ions (Scheme 17)[29]. In his syn he ic scena io, he eac i i y o his ype o in e nal alkynes exceeds ha o e minal alkynes. Me al inylidenes om e minal and in e nal alkynes: gene ali ies and applica ions in o ganic syn hesis Di e en eac ion pa hways and p ecu so s a e a ailable o access alkenylidene ca bene ( o sho inylidene) in e media e species [30]. The gene a ion o inylidene eac i e species by iso- me iza ion o e minal alkynes a ac ed much in e es o e he yea s [31]. T ansi ion me al inylidene compounds allow o a ine uning o he eac i i y o hese ypes o eac ion in e media es, enabling unique ca aly ic applica ions in o ganic syn hesis [32]. Seminal disco e ies o m Dixneu esul ed in he assembly o inyl ca bama es om u henium-ca alyzed eac ions o e minal alky- nes, CO 2 and die hylamine (Scheme 18)[33]. Fi s , polynuclea u henium complexes we e used as he ca a- lys sou ce [33s]. Condi ions we e hen iden i ied using mononu- clea complexes [33b]. Ru henium- inylidene in e media es esul ing om he ini ial in e ac ion o e minal alkynes wi h he me al we e p oposed as he ca aly ic ac i e species [33c]. Also e y ea ly, T os disclosed a u henium-ca alyzed addi ion o allylic alcohols o e minal alkynes a o ding b, c -unsa u a ed ke ones. Mechanis ic s udies suppo he pa icipa ion o a u henium iny- lidine complex as he eac ion in e media e (Scheme 19)[34]. Me lic p esen ed a u henium-ca alyzed cycliza ion eac ion o dienylalkynes based on his p inciple. A a ie y o used ca bo- and he e ocyclic s uc u es we e p epa ed in a ca aly ic manne [35]. Ru henium ca alysis g ea ly con ibu ed o de elop he syn he ic po en ial associa ed wi h he e minal alkyne o me al inylidene equilib ia [36]. None heless ca aly ic sys ems based on o he me - als we e also documen ed [37–40]. The e minal alkyne o inyli- dene isome iza ion a a me al cen e keeps on d awing much a en ion om he chemical communi y [41]. In addi ion o he po en ial associa ed wi h he use o e minal alkynes as subs a es o access eac i e me al inylidene species, s uc u al s udies p o ing ha in e nal alkynes can also gene a e me al inylidine a e known. Thus, he he mal eac ion o a cyclo - iphospha o u henium complex wi h an in e nal alkyne ga e ise o he isola ion and cha ac e iza ion, bo h in solu ion and in he solid s a e, o u henium- inylidine complexes [42]. Besides disclosing he syn hesis o addi ional ca ionic i on and u henium inylidene complexes om isome iza ion eac ions o dia ylace ylene de i a i es [43], as well as compu a ional s udies on his ea angemen p ocess [44], Mu oh and Ishii epo ed ca - aly ic applica ions o his elusi e en y o inylidene complexes [45–47]. Thus, based on he 1,2-ca bon mig a ion, a u henium- ca alyzed N-[2-(a yle hynyl)a yl]ace amide cycloisome iza ion leading o N-acyl-3-a ylindoles was p esen ed (Scheme 20)[48]. Me oxyca bonyl [49] and acyl [50] subs i u ed alkynes a e also p ope sou ces o ca bon-based g oups ha en e his alkyne o inylidene isome iza ion s ep, a a ansi ion me al cen e . Fa om he abo e discussed C-subs i u ed in e nal ace ylene de i a i es, he e oa om-subs i u ed ones encode a wide se o di - e en ia e classes o p ecu so s. They ound u ili y o assemble me al inylidine complexes a ansi ion me al cen e s, which keeps on expanding he bo de s o his ield. Among hem, s uc- u al s udies on he complexes esul ing om he 1,2-mig a ion o elemen s belonging o g oup 14 o he han ca bon, as silicon [51] and in [52], and g oup 16, as sul u [53] and selenium [54], we e ea ly epo ed and conque ed a en ion. Mo e ecen ly, he use o phospho ous-subs i u ed alkynyl de i a i es o access inylidene species was also p o ed. [55]. Gold inylidenes om e minal alkynes: s uc u al ea u es and syn he ic u ili y Along he pas wo decades, esea ch e o s aimed o p omo e he ca aly ic ac i a ion o alkynes by means o gold complexes unde wen eno mous ad ances [13,56]. Compa ed wi h signi ican disco e ies o complex eac ion se ings based on gold-ca alyzed ac i a ion o alkynes h ough an in e media e gold ca bene, he numbe o s udies and he p og esses accomplished dealing wi h ela ed inylidene in e media es a e scan and mo e ecen [57]. F om he s uc u al poin o iew Widenhoe e e ealed use ul insigh s in o he na u e o his elusi e in e media e species, cha - ac e izing he i s gold inylidene complex (Scheme 21)[58]. A p esen , he mos ad anced and p ac iced app oach ha exploi s he po en ial o gold inylidenes o mo e o wa d he ield o o ganic syn hesis elies on he no ion o dual ac i a ion ca aly- sis. Rema ks on gold ace ylides [59], and key indings in la e 2011 independen ly accomplished by he g oups o Zhang and Hashmi con ibu ed o de elop his no ion (Scheme 22). Zhang documen ed a B e PhosAuNT 2 -ca alyzed isome iza ion o (2-e hynylphenyl)alkynes o icyclic indenes (Scheme 22,eqa) [60]. Mechanis ic and compu a ional s udies suppo he in ol e- men o gold inylidenes as key in e media es. Almos simul ane- Scheme 19. Ru henium-ca alyzed econs uc i e condensa ion o e minal ace yle- nes and allylic alcohols. Scheme 20. Indoles upon Ru-ca alyzed 1,2-ca bon shi . Scheme 21. Gold inylidene syn hesis and cha ac e iza ion. P. Fe nández-Canelas, P. Ba io and José M. González Te ahed on Le e s 99 (2022) 153857 5 ously, s udies by Hashmi p oposed a key ole o gold inylidine in e media es o explain he unexpec ed o ma ion o b-a yla ed naph halene egioisome s in cycliza ion-hyd oa yla ion eac ions o 1,2-dialkynyla enes wi h benzene, using IP AuNT 2 as ca alys (Scheme 22,eqb)[61]. Hashmi also epo ed he syn hesis o dibenzopen alenes om a ene-1,2-diynes ea u ing an a yl-subs i- u ed and a e minal ace ylene agmen s (Scheme 22,eqc)[62– 64]. A dual ac i a ion mode o he wo alkyne agmen s was in oked. The in ol emen o gold inylidene in e media e was c u- cial o a ionalize his esul . A de ailed mechanis ic pic u e o he e en s in ol ed in he ca - aly ic dual-ac i a ion mode was disclosed by Hashmi and his eam (Scheme 23)[65], including he e en ual ca alys ans e -s ep and he equilib ium be ween he ac i e monogold species in ol ed in such ope a ion and he gem-diau a ed species. The no ion o dual gold ca alysis apidly ma u ed and he esul ing syn he ic me hodology was soon pu in o con ex and e iewed [66]. Besides, Hashmi and his g oup u he epo ed el- e an new ans o ma ions [67] and ca e ul s udies on he de ec- ion o in e media e species ope a ing in he dual-gold-ca alyzed ac i a ion o 1,5-diynes owa ds benzene, p o iding suppo o he concep ual basis behind he s a egy [68]. Ea ly, his g oup also ecognized he me i o he dual gold- ca alysis o ge iodo ul enes om ca aly ic cycloisome iza ion eac ions o 1-(3,3-dime hylbu -1-yn-1-yl)-2-(iodoe hynyl)a enes (Scheme 24)[69]. The ca aly ic cycle comp ises he gene a ion o a gold ace ylide. Subsequen ly a gold inylide esul s ou o he dual ac i a ion mode and e ol es h ough di e en species o en- de a inyl gold in e media e, which yields he iodo-con aining ul- ene ia an unp eceden ed iodine/gold exchange. Nowadays, he dual gold-ca alysis ac i a ion mode is a ai ly ac i e esea ch a ena and se e al g oups a e con ibu ing o i s u - he de elopmen . Addi ional in amolecula elabo a ion o diyne ames in o syn he ically use ul p oduc s we e epo ed [70–72]. Apa om dual gold-ca alysis, Hashmi and his g oup epo ed a ca aly ic s a egy o he cycliza ion o a , x -alkynyl osyla es o cycloalkylideneme hyl osyla es, which is p oposed o in ol e as in e media e a gold- inylidene (Scheme 25)[73]. The yield was op imized by ine uning he NHC ligand. Replacing he 2,6-diiso- p opylphenyl uni a ached o one o he ni ogens by a cyclopen- adecyl g oup, inc eases he yield om 69% up 92%. Gold(I) ace ylides o e ed addi ional al e na i e en ies o gold inylidenes. Zhang showed ha he ca aly ic eac ion o conju- ga ed enynones wi h gold(I) in he p esence o a b omonium dono ende s cyclopen enone ames (Scheme 26)[74]. Fü s ne also ecognized a gold inylidene as in e media e in he eac ion o TBSOT wi h he 2’-subs i u ed IP -gold ace ylide de i ed om [1,1’-biphenyl]-2-ca baldehyde (Scheme 27)[75]. As shown in he p e ious sec ion, se e al me als eac wi h e minal alkynes o gi e inylidene complexes ia 1,2-hyd ogen shi . Using gold ca alysis, Ge o gyan and his g oup epo ed Scheme 22. Bases o he dual gold ca alysis app oach o ca aly ic gold inylidene gene a ion and syn he ic applica ions. [IP : 1,3-bis(2,6-diisop opylphenyl)imida- zol-2-ylidene]. Scheme 23. Dual gold-ca alyzed app oach o benzo ul enes. Scheme 24. Dual gold-ca alysis in ol ing a iodoalkyne. Scheme 25. Lea ing g oup app oach o gold inylidenes. P. Fe nández-Canelas, P. Ba io and José M. González Te ahed on Le e s 99 (2022) 153857 6 gold(III)-ca alyzed cycloisome iza ion eac ions o p opa gylic de i a i es om N-con aining he e ocycles (Scheme 28)[76]. I ea u es a 1,2-H shi om a e minal alkyne, as well as 1,2- mig a ions o silyl, s annyl and ge myl g oups om he co e- sponding he e oa om-masked ace ylene p ecu so s. Based on he s uc u e o he p oduc s and some con ol expe imen s, i was ini- ially assumed ha he eac ion in ol es a gold inylidene as in e - media e. Subsequen , heo e ical calcula ions ully suppo ed an al e na i e mechanism (Scheme 29)[77]. Haloalkynes as p ecu so s o me al inylidene complexes Se e al ansi ion me al complexes unde go oxida i e addi ion p ocesses in he p esence o alkynyl halides, hus limi ing he Scheme 26. Gold inylidenes by in e molecula elec ophilic ac i a ion o ace ylides. Scheme 27. Gold inylidenes by in amolecula elec ophilic ac i a ion o ace ylides. Scheme 28. Gold(III)-ca alyzed cycloisome iza ion in ol ing 1,2-hyd ogen shi . Scheme 29. Ca aly ic isome iza ion o p opa gylpy idines. Scheme 30. 1,2-I shi o gi e b-iodo Mn- inylidene complex. Scheme 31. Me al- inylidene complex upon eac ion o me al-ace ylides wi h iodonium dono s. Scheme 32. Ca aly ic elabo a ion and eac i i y o an iodo-subs i u ed ungs en inylidene complex. Scheme 33. Pionee ing wo k on 1,2-halogen mig a ion om gold-ca alyzed haloalkyne ac i a ion eac ions. P. Fe nández-Canelas, P. Ba io and José M. González Te ahed on Le e s 99 (2022) 153857 7 applicabili y o hese he e oa om-subs i u ed alkynes o u nish inylidene complexes. E en hough, some examples a e known, i ually in ol ing iodo-subs i u ed ace ylene de i a i es. Ea ly obse a ions using o he me als han gold. Be ke p epa ed and cha ac e ized by X- ay di ac ion a man- ganese inylidene complex upon i adia ion o a iodoalkyne and cyclopen adienyl manganese ica bonyl (Scheme 30)[78]. An opposi e en y o o ge inylidene complexes a ansi ion me al cen e s is based on he eac ion o ansi ion me al ace y- lides wi h a p ope halogen sou ce o he elec ophile, a p ocess ha selec i ely akes place a he b-ca bon o he pa en alkynyl complex (Scheme 31,eqa[79] and b [80]). The numbe o syn he ic epo s based on a ca aly ic 1,2-halo- gen ea angemen is limi ed. Iwasawa documen ed a ca aly ic iso- me iza ion o o-(iodoe hynyl)s y enes in o he co esponding iodo-subs i u ed naph halene de i a i es ea u ing his iodine- mig a ion p ocess (Scheme 32)[81]. 1,2-Halogen shi e en s in ca aly ic gold-ac i a ion o he e oa om- subs i u ed alkynes: gold inylidenes as likely eac ion in e media es Fü s ne disco e ed he 1,2-halogen shi eac ion in gold-ca - alyzed cycliza ion eac ions o o-alkynyl-subs i u ed biphenyl de i a i es (Scheme 33)[82]. In e es ingly, wi hin he gene al con- ex o a sea ch o ob ain phenan h enes, haloalkynes p o ide a complemen a y syn he ic mani old, which is selec i ely d i en by he ca alys . Thus, a e es ing di e en ca alys , InCl 3 success- ully a o ded he a ge 10-halophenan h ene de i a i es. Mo e- o e , adding AuCl as ca alys , he 9-halo-subs i u ed egioisome was exclusi ely o med [83]. This al e na i e p ocess was explained assuming he o ma ion o a gold inylidene as he eac i e species esul ing om a 1,2- halogen mig a ion. Then, di e en g oups epo ed DFT calcula- ions on he mechanism o hese ans o ma ions. The eached con- clusions om hese heo e ical s udies depend on he accu acy o he chosen unc ional. Thus, o he gold(I) ca alyzed p ocess, ely- ing on B3LYP/6-31G* (LANL2DZ) calcula ions, an ini ial gold com- plexa ion o he haloalkyne, ollowed by he 1,2-halide shi o he inylidene complex and subsequen 6-endo-dig elec ocycliza- ion and hen a 1,2-H shi we e iden i ied as he s eps ou lining he ene ge ically mos a o able eac ion pa hway [84]. Then, yea s la e , subsequen M06/6-31+G* (LANL2DZ) calcula ions o ig- ina ed a di e en sequence o e en s o explain he cycloisome - iza ion leading o 9-halophenan h enes unde gold(I) ca alysis [85]. Now, he ou come o he gold-ca alyzed elec ophilic hyd oa yla ion esul s om an ini ial 6-endo-dig cycliza ion ha ende s he Wheland- ype in e media e, which e ol es h ough a 1,2 mig a ion o H, ollowed by a kine ically a o ed 1,2-B shi [86]. Anyway, he numbe o epo s on CAC bond- o ma ion based on gold-ca alyzed eac ions o haloalkynes ia a 1,2-halogen shi is limi ed. In all he cases, he haloalkyne uni was bounded o he a ene ing and he s a egy was ocused on i s applica ion o he syn hesis o py ene, picene and dibenzo[a,h]an h acene co es h ough ca aly ic e en s in ol ing double mig a ion-cycliza ion p ocesses (Scheme 34)[87]. Conside ing he a en ion payed by ou labo a o y o es ablish di e en hyd oa yla ion s a egies, including iodonium-p omo ed and me al-ca alyzed a yla ion eac ions o di e en unsa u a ed mo i s [88–90], we became in e es ed in b oaching he syn he ic po en ial o ha halogen-dancing cycliza ion mode unde gold ca alysis. Mo eo e , gold-ca alyzed hyd oa yla ion eac ions o e - minal N-p opa gyl aniline and phenol de i a i es usually equi e he p esence o addi ional ac i a ing subs i uen a he a ene pla - o m o be o syn he ic u ili y [91]. On his g ound, we i s es ed he me i o he p ocess o assemble common he e ocyclic ames wi h dis inguishable egiocon ol. Also, we we e a ac ed by he possibili y o doing so on he basis o using as ca alys s only gold- based complexes. Fu he mo e, explo ing he ou come o he eac- ion when addi ional elec on-wi hd awing subs i uen s a e p e- sen a he a ene pla o m is ano he a ac i e ask o conside . On his g ound, he eac ion o N-(3-iodop op-2-ynyl)-N- osylanili- nes wi h di e en gold(I) complexes was es ed, and some ep e- sen a i e examples a e depic ed in below (Scheme 35)[92]. The in ended poin s we e alida ed p o ing ha he na u e o he ancilla y ligand on gold is an essen ial elemen o con ol. Thus, he egula hyd oa yla ion is he main cycliza ion pa hway i he ca alys is based on a phosphi e ligand. The pe o mance o his elec ophilic sys em based on a p -accep o ligand a ached o gold and a e a luo obo a e anion can be addi ionally uned by he sub- s i u ion a he a ene agmen o he p opa gyl aniline de i a i e. In ac , he in oduc ion o a modes dono subs i uen enhances he e iciency and he egioselec i i y o he cycliza ion. Jus swi ching om H o Me-subs i u ion a he pa a-posi ion o he s a ing ma e ial ende s a p epa a i e use ul ans o ma ion. Thus, a o ding a egioselec i e syn hesis o he N- osyl-4-iodo-6- me hyl-1,2-dihyd oquinoline om a common hyd oa yla ion pa hway. The use as ca alys o IP AuNT 2 u nishes as main p oduc he opposi e egioisome (Scheme 35, see X = H). In his case, he IP is a s ong -dona ing NHC ligand and induces a 1,2-I shi p io Scheme 34. Polycyclic a oma ics om mig a ion-cycliza ion. Scheme 35. Ca aly ic assembly o egioisome ic he e ocyclic ames. P. Fe nández-Canelas, P. Ba io and José M. González Te ahed on Le e s 99 (2022) 153857 8 o he cycliza ion e en . Again, he addi ional subs i uen s a he aniline agmen modula e he in ensi y o his beha io . In e es - ingly, an elec on-wi hd awing subs i uen a he pa a-posi ion dis a o s he no mal pa h and magni ies he o ma ion o he cycliza ion p oduc wi h concomi an 1,2-I-shi . Fo he case o a mo e elec on- ich p ecu so he IP AuNT 2 -ca alyzed eac ion s ill gi es he dihyd oquinoline wi h he associa ed iodine shi as he main egioisome om his cycliza ion e en , as shown in Scheme 35 o he p-anisidine de i a i e (X = Me). Those examples e idence he s ong con ol o e he selec i i y exe ed by he ancilla y ligand and he addi ional uning o e he selec i i y dic a ed by he na u e o he a yl moie y. Thus, he com- bina ion o a -dono ligand wi h an a ene moie y deco a ed wi h elec on-wi hd awing subs i uen s is op imal o a o d hyd oa y- la ed p oduc s showing addi ional 1,2-iodine dancing. On he con- a y, a p -accep o ligand ac ing in conjunc ion wi h elec on- ich subs i uen s a he a ene ing ends o a o he o ma ion o a no - mal hyd oa yla ion p oduc o he pa en iodoalkyne. In a ecen pape dealing wi h he design and p epa a ion o s ong p -accep o ligands, Alca azo showed he unique p ope ies o a -ca ionic phosphole gold(I) complexes as ancilla y ligands o access he no mal cycliza ion, which p o ides s ong suppo o he p e iously o mula ed hypo hesis The new ligand allows a nice disc imina ion among he wo compe ing cycliza ion pa hs, a o - ing he no mal hyd oa yla ion ou come wi h ou s anding selec i - i y (Scheme 36)[93]. The esul ing gold ca alys a ge s he p epa a ion o 4-iodo- 2,3-dihyd oquinolines om in amolecula hyd oa yla ion o iodoalkynes wi h exquisi e selec i i y, wi hou showing he p e i- ously no iced dependence on he p esence o addi ional ac i a ing subs i uen s a he a ene. As we we e in e es ed in he less commonly epo ed pa hway leading o cycliza ion wi h a concomi an halogen shi , i was challenging o a ge he syn hesis o ela ed 3-iodo-2H-ch omene de i a i es using his ype o cycliza ion. A he same ime, i is a demanding p ocess as he e he ing e he unc ional g oup is a mo e ac i a ing uni han he al eady s udied sul onamide p ecu so . Thus, on he basis o he p e iously ga he ed knowledge, he gold complex wi h he powe ul -dono IP ligand was selec ed om he onse . Besides, phenolic moie ies con aining elec on- poo subs i uen s we e chosen o conduc his s udy, sea ching o a a ely examined subs i u ion pa e n in alkyne hyd oa yla ion p ocesses. A yl (3-iodop op-2-yn-1-yl) e he s we e cyclized using his app oach. Among o he s, de i a i es o phenol p ecu so s subs i- u ed a he pa a-posi ion by g oups as: CN, CHO, CO 2 E and NO 2 (Scheme 37)[94]. In all cases, he iodo-shi ing p ocess was he majo eac ion pa hway, de ining a highly egioselec i e en y o he ca aly ic syn- hesis o 6-subs i u ed 3-iodo-2H-ch omenes. The eac ion o a subs a e con aining chi al in o ma ion a he p opa gylic posi ion ende s he co esponding 1,2-iodo-shi ed cyclized p oduc wi hou e oding he s e eochemical in o ma ion, highligh ing an addi ional a ac i e ea u e associa ed wi h his elabo a ion o 3-iodo-2H-ch omene sca olds. The o ma ion o his ype o p oduc was a ionalized acco ding o he mechanis ic sce- na io depic ed in he equa ion a, in Scheme 38. Scheme 36. No mal hyd oa yla ion pa hway o iodoalkynes ca alyzed by gold(I) complexes wi h a -ca ionic phospholes. Scheme 37. 1,2-Iodo-shi in he hyd oa yla ion eac ion o iodoalkynes ca alyzed by a gold(I)-complex wi h a NHC-ligand. Scheme 38. Mechanis ic a ionale o he 1,2-iodine shi ing iodoalkyne hyd oa y- la ion eac ion. Scheme 39. In amolecula CAH ac i a ion by gold-ca alyzed ac i a ion o iodoalkynes. P. Fe nández-Canelas, P. Ba io and José M. González Te ahed on Le e s 99 (2022) 153857 9 [49] P. King, S.A.R. Knox, M.S. Legge, A.G. O pen, J.N. Wilkinson, E.A. Hill, J. Chem. 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