molecules

Article Dialkylation of Indoles with Trichloroacetimidates to Access 3,3-Disubstituted Indolenines

Tamie Suzuki , Nilamber A. Mate , Arijit A. Adhikari and John D. Chisholm *

Department of Chemistry, Syracuse University, 1-014 Center for Science and Technology, Syracuse, NY 13244-4100, USA; [email protected] (T.S.); [email protected] (N.A.M.); [email protected] (A.A.A.) * Correspondence: [email protected]; Tel.: +315-443-6894

Academic Editor: Paula Sério Branco



 Received: 30 October 2019; Accepted: 13 November 2019; Published: 15 November 2019

Abstract: 2-Substituted indoles may be directly transformed to 3,3-dialkyl indolenines with trichloroacetimidate electrophiles and the Lewis acid TMSOTf. These reactions provide rapid access to complex indolenines which are present in a variety of complex natural products and medicinally relevant small molecule structures. This method provides an alternative to the use of transition metal catalysis. The indolenines are readily transformed into spiroindoline systems which are privileged scaffolds in medicinal chemistry.

Keywords: indole; dialkylation; indolenine; trichloroacetimidate; spiroindoline

1. Introduction 3,3-Dialkyl indolenines are common substructures found in many complex alkaloids like strictamine 1 [1] and tubifoline 2 [2] (Figure1). A number of other alkaloids appear to derive from the intramolecular addition of heteroatom nucleophiles to the indolenine. This includes complex alkaloids such as echiboline 3 [3], aspidophylline A 4 [4], and perophoramidine 5 [5] (Figure1). 3,3-Dialkyl indolenines have also been utilized as platforms in medicinal chemistry studies [6,7], as a means to move towards more three-dimensional structures with a greater proportion of sp3 hybridized carbons, which is desirable in order to create molecules which interact with more complex pharmaceutical target receptors [8–11]. Structurally related spiropiperidine-indanes have also been referred to as “privileged scaffolds” [12–14] for the design of medicinally relevant small molecules, including the ghrelin receptor agonists MK-0677 6 [15] and 7 [16], the Akt inhibitor 8 [17] and the P2Y1 antagonist 9 [18]. Besides their presence in natural products, similar indolines are also utilized as precursors to indolenine dyes [19], which have applications in biological imaging [20–23], sensors [24,25], and in solar cells [26,27]. Given the common nature of 3,3-dialkyl indolenines and related structures, researchers have been active in investigating efficient methods to access similar architectures [28–31]. These include intramolecular condensation of an aniline [32–34], the interrupted Fischer indole synthesis [35–37], and the addition of organometallic reagents to benzylic nitriles [38–40]. One popular method is the dearomatization of indoles [41–44] with an electrophilic alkylating agent. Many of these reactions are complicated by competing N-alkylation of the indole. In spite of this issue, a number of acid promoted [45–47], base promoted [48–54], and transition metal catalyzed [55–64] transformations have been described to access indolenines from 3-substituted indoles.

Molecules 2019, 24, 4143; doi:10.3390/molecules24224143 www.mdpi.com/journal/molecules Molecules 2019, 24, 4143 2 of 15 Molecules 2019,, 24,, xx FORFOR PEERPEER REVIEWREVIEW 2 of 14

Figure 1. Natural products containing the 3,3-dialkyl indolenine motif and related spiroindoline Figure 1. Natural products containing the 3,3-dialkyl indolenine motif and related spiroindoline structures. structures. In a recent study on the alkylation of indoles utilizing trichloroacetimidate electrophiles [65], we observedInIn aa recentrecent a smallstudystudy amountonon thethe alkylationalkylation of the dialkylated ofof indolesindoles indolenineutilizingutilizing trichloroacetimidatetrichloroacetimidate13 as a side product electrophileselectrophiles from the TMSOTf [65],[65], wewe observedcatalyzed C3-alkylationa small amount of 2-methyl-5-nitroindoleof the dialkylated indolenine10 with allyl 13 asas imidate aa sideside11 productproductin dichloromethane fromfrom thethe TMSOTfTMSOTf (DCM) catalyzed(Scheme1). C3-alkylation While the formation of 2-methyl-5-nitroindole of indolenines from 10 2,3-disubstituted withwith allylallyl imidateimidate indoles 11 inin dichloromethanedichloromethane with imidates has (DCM)(DCM) been (Schemereported(Scheme 1).1). [66 WhileWhile], the directthethe formationformation dialkylation ofof indoleninesindolenines of indoles fromfrom could 2,3-disubstituted2,3-disubstituted provide a rapid indolesindoles entry to withwith 3,3-dialkyl imidatesimidates indolenine hashas beenbeen reportedintermediates [66], fromthe direct less substituted dialkylation (and of indoles therefore could less expensive)provide a rapid indole entry starting to 3,3-dialkyl materials. Thisindolenine would intermediatesprovideintermediates an effi cientfromfrom alternative lessless substitutesubstitute approachd (and for therefore the direct less C3-dialkylation expensive) indole of indoles starting that doesmaterials. not rely This on wouldcostly transition provide an metal efficient catalysts. alternative The use approach of trichloroacetimidate for the direct electrophilesC3-dialkylation as the of alkylatingindoles that agent does is notattractive rely on because costly they transition can be easilymetal formedcatalysts. from Th readilye use of available trichloroacetimidate alcohols under electrophiles mild conditions as [the67]. alkylatingIntrigued byagent the is potential attractive of because this dialkylation they can be reaction, easily formed we began from optimization readily available studies alcohols to explore under the mildscope conditions of this Lewis [67]. acid Intrigued promoted by the dearomatization potential of this reaction. dialkylation reaction, we began optimization studies to explore the scope of this Lewis acid promoted dearomatization reaction.

SchemeScheme 1. DetectionDetection of of the the dialkylation dialkylation product product 1313 duringduring alkylationalkylation of of 5-nitro-2-methyl-indole 10. 2. Results & Discussion 2. Results & Discussion Our recent studies on promoter free substitution reactions with trichloroacetimidate Our recent studies on promoter free substitution reactions with trichloroacetimidate electrophilesOur recent [68 –74studies] led uson to promoter speculate thatfree imidatessubstitution may reactions be reactive with enough trichloroacetimidate to participate in electrophiles [68–74] led us to speculate that imidates may be reactive enough to participate in indole electrophilesindole dialkylation [68–74] without led us to the spec needulate for that a Lewis imidates acid may catalyst. be reactive Heating enough 2-methyl to participate indole 14 inand indole allyl dialkylation without the need for a Lewis acid catalyst. Heating 2-methyl indole 14 andand allylallyl trichloroacetimidate 11 in refluxing 1,2-dichloroethane (DCE) for 24 h showed no trace of alkylation trichloroacetimidatetrichloroacetimidate 11 inin refluxingrefluxing 1,2-dichloroethane1,2-dichloroethane (DCE)(DCE) forfor 2424 hh showedshowed nono tracetrace ofof alkylationalkylation product, however, so the use of TMSOTf as the Lewis acid was then investigated (Table1). Previous product, however, so the use of TMSOTf as the Lewis acid was then investigated (Table 1). Previous investigations with indoles and trichloroacetimidates have demonstrated that TMSOTf is especially investigationsinvestigations withwith indolesindoles andand trichloroacetimidatestrichloroacetimidates havehave demonstrateddemonstrated thatthat TMSOTfTMSOTf isis especiallyespecially effective in these systems [65,66], and encouraging results were immediately obtained. Use of 20 mol% effective in these systems [65,66],], andand encouragingencouraging resultsresults werewere immediatelyimmediately obtained.obtained. UseUse ofof 2020 TMSOTf led to the formation of indolenine 15 with a 27% yield (Table1, Entry 2). Increasing reaction mol% TMSOTf led to the formation of indolenine 15 with a 27% yield (Table 1, Entry 2). Increasing time, temperature and using excess imidate were then evaluated, but these changes only led to modest reaction time, temperature and using excess imidate were then evaluated, but these changes only led increases in yield (Entries 3–5). Given that a more basic reaction media is being formed after the second toto modestmodest increasesincreases inin yieldyield (entries(entries 3–5).3–5). GivenGiven thatthat aa moremore basicbasic reactionreaction mediamedia isis beingbeing formedformed alkylation (the imine on 15 is a functional base), it was considered that perhaps product inhibition after the second alkylation (the imine on 15 isis aa functionalfunctional base),base), itit waswas consideredconsidered thatthat perhapsperhaps was occurring, with the imine scavenging the Lewis acid and halting the reaction. An increase in the product inhibition was occurring, with the imine scavenging the Lewis acid and halting the reaction. TMSOTf loading would therefore be necessary to obtain higher conversions. Increasing the amount of An increase in the TMSOTf loading would therefore be necessary to obtain higher conversions. IncreasingIncreasing thethe amountamount ofof TMSOTMSOTf provided a 61% yield of 15 when a stoichiometric amount of the

Molecules 2019, 24, 4143 3 of 15

Molecules 2019, 24, x FOR PEER REVIEW 3 of 14 TMSOTf provided a 61% yield of 15 when a stoichiometric amount of the Lewis acid was employed Lewis(Entry acid 7). Further was employed increasing (Entry the amount7). Further of TMSOTf increasing did the not amount significantly of TMSOTf improve did the not yield, significantly nor did improveheating the the reaction. yield, nor Little did indoleheating starting the reaction. material Little14 was indole isolated starting from material the reaction, 14 was with isolated the rest from of thethe reaction, mass balance with being the rest a mixture of the mass of overalkylation balance being products a mixture (alkylation of overalkylation can also occurproducts at C5 (alkylation and C7 of canthe indolealso occur ring). at C5 and C7 of the indole ring).

TableTable 1. Optimization of the diallylation reaction.

Entry EquivEquiv EquivEquiv Temp. (◦C)ReactionReaction Yield (%) Imidate 11 TMSOTf Time Entry Imidate 11 TMSOTf Temp. (°C) Time Yield (%) 1 2.2 0 84 24 h 0 2 1 2.22.2 0 0.2 84 rt 24 h 3 h0 27 3 2 2.22.2 0.2 0.2 rt rt 3 h 6 h27 20 4 2.2 0.2 84 3 h 41 3 2.2 0.2 rt 6 h 20 5 3.0 0.2 rt 3 h 31 6 4 2.52.2 0.2 0.5 84 rt 3 h 3 h41 39 7 2.5 1.0 rt 3 h 61 5 3.0 0.2 rt 3 h 31 8 2.5 1.5 rt 3 h 59 96 2.52.5 0.5 1.0 rt 84 3 h 3 h39 59 7 Conditions:2.5 1,2-Dichloroethane 1.0 (DCE), rt TMSOTf, 3 rt h or reflux. 61 8 2.5 1.5 rt 3 h 59 The indole dialkylation was then evaluated with regard to the indole nucleophile. The addition of 9 2.5 1.0 84 3 h 59 either electron donating or electron withdrawing groups to the 5-position of the indole was tolerated, with yields in the 40%–70%Conditions: range being 1,2-Dichloroethane observed (Table (DCE),2). Interestingly,TMSOTf, rt or thereflux. 5-nitro-2-methyl indole 10 providedThe indole the diallylation dialkylation product was then13, which evaluated is not with accessible regard using to the palladium indole nucleophile. catalysis, as TheN-alkylation addition ofis favoredeither electron when this donating indole isor employed electron [withdraw6]. Changinging thegroups alkyl to group the 5-position at the 2-position of the ofindole the indole was tolerated,was also explored.with yields Use in ofthe indole 40%–70% (Entry range 7) provided being observed only a complex (Table 2). mixture Interestingly, of products, the 5-nitro-2- and this methylsubstrate indole was not10 pursuedprovided further. the diallylation A more moderate product yield13, which was obtained is not accessible with 2-phenylindole, using palladium likely catalysis,due to steric as N eff-alkylationects from the is largerfavored group when at this the indoleindole 2-position. is employed Indole [6]. 2-carboxylicChanging the acid alkyl methyl group ester at the14h 2-positionwas not reactive of the underindole these was conditions,also explored. returning Use of the indole starting (Entry indole 7) provided and decomposed only a complex imidate mixturefrom the of reaction products, mixture. and this While subs manytrate was of these not pursued yields are further. moderate, A more it is moderate important yield to realize was obtained that two withreactions 2-phenylindole, are actually likely occurring due into sequencesteric effects during from the the dialkylation, larger group so at the the yield indole may 2-position. perhaps beIndole best 2-carboxylicthought of in acid terms methyl of a sequence ester 14h of was two not separate reactive steps under proceeding these co anditions, ~75% yield returning where isolation the starting and indolepurification and decomposed of the intermediate imidate3-alkylindole from the reaction is avoided. mixture. While many of these yields are moderate, it is importantThe efficacy to realize of these that conditions two reactions was are then actu evaluatedally occurring using in asequence number during of allylic the anddialkylation, benzylic soimidates the yield (Table may3 ).perhaps More highlybe best substitutedthought of in allylic terms imidates of a sequence gave lowerof two yields, separate this steps may proceeding be due to athe ~75% electrophile yield where being isolation more highlyand purification stabilized of and the therefore intermediate less reactive. 3-alkylindole Improved is avoided. yields could be achieved by performing many of the reactions in refluxing DCE. Similar results were obtained with propargyl imidate 18, which was less reactive (only providing trace product at room temperature) but would participate when the reaction was heated to reflux, albeit in a moderate yield. Benzylic trichloroacetimidates were also evaluated. The highly reactive 4-methoxybenzyl imidate 19 gave a complex mixture of products due to polyalkylation. Better results were obtained with the less reactive benzyl imidate 20, which gave a 30% yield of the dialkylation product 15m (38% when the reaction was performed under reflux). Benzylic imidates decorated with electron withdrawing groups (21–23) were also less reactive and provided only trace amounts of the dialkylation products at rt, with C3-monoalkylation being the major product [65]. Heating the reaction to reflux provided the desired dialkylation products in much improved overall yields, however.

Molecules 2019, 24, 4143 4 of 15 Molecules 2019, 24, x FOR PEER REVIEW 4 of 14 MoleculesMoleculesMolecules 20192019 2019,,2019, 2424,,, x,,xx 24 24 FORFORFOR,, xx FOR FOR PEERPEERPEER PEERPEER REVIEWREVIEWREVIEW REVIEWREVIEW 44 ofof 141444 ofof 1414 MoleculesMolecules 2019 ,2019, 24,, x,x, 24 FORFOR,, xx FOR FORPEERPEER PEERPEER REVIEWREVIEW REVIEWREVIEW 4 of 144 of 14 Table 2. C3-Dialkylation of functionalized indoles with allyl imidate. TableTableTable 2. 2. C3-Dialkylation C3-Dialkylation2. C3-Dialkylation of of functionalized offunctionalized functionalized indoles indoles indoles with with with allyl allyl allyl imidate. imidate. imidate. TableTableTable 2.2. C3-DialkylationC3-Dialkylation 2. C3-Dialkylation ofof functionalizedfunctionalized of functionalized indolesindoles indoles withwith with allylallyl allyl imidate.imidate. imidate.

Entry Indole Product Yield (%) EntryEntryEntry IndoleIndoleIndole Product Product Product YieldYieldYield (%) (%) (%) EntryEntryEntry IndoleIndoleIndole Product Product Product YieldYieldYield (%)(%) (%)

MeMe 1 MeMe MeMe 61 1 11 1 N MeN Me 6161 61 61 1 1 NN H NN 61 61 1 HNH HN 14a14a 61 H H 14a14a 14a14a 14a 14a 15a15a 15a 15a15a 15a MeO MeO MeO MeOMeO MeO MeO MeMe 2 MeMe MeMe 61 2 22 2 N MeN Me 6161 61 61 2 2 NN H NN 61 61 HN HN 14b HH H 14b14b 14b H 14b14b 14b 15b15b 15b 15b15b 15b Me Me Me MeMe Me Me MeMe 3 MeMe MeMe 41 3 33 3 N MeN Me 4141 41 41 3 3 NN H NN 41 41 3 HN HN 14c 41 HH H 14c14c 14c H 14c 14c 15c15c 15c15c 15c15c 15c Cl Cl Cl ClCl Cl Cl MeMe 4 MeMe MeMe 45 4 44 4 N MeN Me 4545 45 45 4 4 NN H NN 45 45 4 HN HN 14d 45 HH H 14d14d 14d H 14d 14d 15d15d 15d 15d15d 15d F F FF FF F F MeMe 5 MeMe MeMe 68 5 55 5 N MeN Me 6868 68 68 5 5 NN H NN 68 68 5 HN HN 14e 68 HH H 14e14e 14e H 14e 14e 15e15e 15e 15e15e 15e O2N OO NN O22N O222N O222N O22N 2 MeMe 6 MeMe MeMe 70 6 66 6 N MeN Me 7070 70 70 6 6 NN H NN 70 70 6 HN HN 10 70 HH H 1010 10 H 10 10 1313 1313 1313 13

a 7 N 0aaa aa a 7 7 7 N 0 a 0 aa 0 77 7 NN H NN 00 a 0 7 HN 14fHN 14f 0 HH 14f14fH 14f14f H 14f 14f 15f15f 15f 15f15f 15f15f

Ph Ph 8 PhPh PhPh 34 8 8 N PhN Ph 34 34 8 88 8 NN H NN 3434 34 34 8 HN HN 14g14g 34 HH H 14g14g 14g14g H 14g 14g 15g15g 15g 15g15g 15g

CO2Me COCO MeMeCO22Me b 9 N CO222MeCO222Me 0b bb 9 9 CON 22Me 2 0 bb 0 b b 9 99 9 NN H NN 00 bb 0 b 0 9 HN HN 14h 0 HH H 14h14h 14h H 14h 14h 15h15h 15h15h 15h15h a b 15h aa Aaa complex mixture resulted.bb Startingbb material was recovered. aa A complexaaa A complex mixture mixture resulted. resulted. bb Startingb b Starting material material was was recovered. recovered. aa A A complexcomplexAA complex complex mixturemixture mixturemixture resulted.resulted. resulted. resulted. bb Starting StartingStarting Starting materialmaterial material material was was recovered.was recovered.recovered. recovered.

TheTheThe efficacy efficacy efficacy of of these ofthese these conditions conditions conditions was was was then then then eval eval evaluateduateduated using using using a anumber numbera number of of allylic ofallylic allylic and and and benzylic benzylic benzylic TheTheThe The efficacyefficacy efficacyefficacy ofof these theseofof thesethese conditionsconditions conditionsconditions waswas waswas thenthen thenthen evaleval evalevaluateduateduateduated usingusing usingusing aa numbernumber aa numbernumber ofof allylic allylicofof allylicallylic andand and and benzylicbenzylic benzylicbenzylic imidatesimidatesimidatesimidates (Table (Table (Table(Table 3). 3). More 3).3). More MoreMore highly highly highlyhighly substituted substituted substitutedsubstituted allylic allylic allylicallylic imidates imidates imidatesimidates gave gave gavegave lower lower lowerlower yields, yields, yields,yields, this this thisthis may may maymay be be due bebe due duedue to to the totothe thethe imidatesimidatesimidatesimidatesimidates (Table(Table(Table (Table(Table 3).3).3). More More More3).3). MoreMore highlyhighlyhighly highlyhighly substitutedsubstitutedsubstituted substitutedsubstituted allylicallylicallylic allylicallylic imidatesimidatesimidates imidatesimidates gavegavegave gavegave lowerlowerlower lowerlower yields,yields,yields, yields,yields, thisthisthis this this maymaymay maymay bebebe duedue due bebe duedue tototo thethethe toto thethe electrophileelectrophileelectrophile being being being more more more highly highly highly stabilized stabilized stabilized and and and th therefore ereforetherefore less less less reactive. reactive. reactive. Improved Improved Improved yields yields yields could could could be be be electrophileelectrophileelectrophileelectrophile beingbeing beingbeing moremore moremore highlyhighly highlyhighly stabilizedstabilized stabilizedstabilized andand and and ththereforeerefore ththereforeerefore lessless less less reactive.reactive. reactive.reactive. ImprovedImproved ImprovedImproved yieldsyields yieldsyields couldcould couldcould bebe bebe achievedachievedachieved by by performingby performing performing ma ma nymany ofny of the ofthe thereactions reactions reactions in in refluxing inrefluxing refluxing DCE. DCE. DCE. Similar Similar Similar results results results were were were obtained obtained obtained with with with achievedachievedachievedachieved byby performing performingbyby performingperforming mama ny nymama ofofnyny thethe ofof thereactionsthereactions reactionsreactions inin refluxingrefluxing inin refluxingrefluxing DCE.DCE. DCE.DCE. SimilarSimilar SimilarSimilar resultsresults resultsresults werewere werewere obtainedobtained obtainedobtained withwith withwith propargylpropargylpropargyl imidate imidate imidate 18 18, 18,which which,, whichwhich was was waswas less less lessless reactive reactive reactivereactive (only (only (only(only providin providin providinproviding gtrace traceg trace product product product at at room atroom room temperature) temperature) temperature) propargylpropargylpropargylpropargyl imidateimidate imidateimidate 1818,,, which18which18which,,, whichwhichwhich waswaswas waswaswas lesslessless lessless less reactivereactivereactive reactivereactivereactive (only(only(only (only(only(only providinprovidinprovidin providinprovidinprovidingg tracetracegg tracetrace productproduct productproduct atat roomroom atat roomroom temperature)temperature) temperature)temperature) butbut butwould would would participate participate participate when when when the the thereaction reaction reaction was was was heated heated heated to to reflux, totoreflux, reflux,reflux, albeit albeit albeitalbeit in in a inin amoderate moderateaa moderatemoderate yield. yield. yield.yield. Benzylic Benzylic BenzylicBenzylic butbut but butwouldwould wouldwould participateparticipate participateparticipate whenwhen whenwhen thethe thethereactionreaction reactionreaction waswas waswas heatedheated heatedheated tototo reflux,reflux, reflux, toto reflux,reflux, albeitalbeitalbeit albeitalbeit ininin aa a inin moderatemoderatemoderate aa moderatemoderate yield.yield.yield. yield.yield. BenzylicBenzylicBenzylic BenzylicBenzylic trichloroacetimidatestrichloroacetimidatestrichloroacetimidatestrichloroacetimidates were were werewere also also alsoalso evaluated. evaluated. evaluated.evaluated. The The The highly highly highly reactive reactive reactive 4-methoxybenzyl 4-methoxybenzyl 4-methoxybenzyl imidate imidate imidate 19 19 gave19 gave gavegave a a aa trichloroacetimidatestrichloroacetimidatestrichloroacetimidatestrichloroacetimidatestrichloroacetimidates werewerewere werewere alsoalsoalso alsoalso evaluated.evaluated.evaluated. evaluated.evaluated. TheThe The The highlyhighly highlyhighly reactivereactive reactivereactive 4-methoxybenzyl4-methoxybenzyl 4-methoxybenzyl4-methoxybenzyl imidateimidate imidateimidate 1919 gave gavegave1919 gavegavegave aaa aaa complexcomplexcomplex mixture mixture mixture of of products ofproducts products due due due to to polyalkylation. topolyalkylation. polyalkylation. Be Better Bettertter tterresults results resultsresults were were werewere obtained obtained obtainedobtained with with withwith the the thetheless less lessless reactive reactive reactivereactive complexcomplexcomplexcomplex mixturemixture mixturemixture ofof productsproducts ofof productsproducts duedue due due toto polyalkylation.polyalkylation. toto polyalkylation.polyalkylation. BeBetterttertter BeBe tter tterresultsresultsresults resultsresults werewerewere werewere obtainedobtainedobtained obtainedobtained withwithwith withwith thethethe lessthelesstheless less less reactivereactivereactive reactivereactive benzylbenzylbenzyl imidate imidate imidate 20 20, 20which, which,, whichwhich gave gave gavegave a a30% 30%aa 30%30% yield yield yieldyield of of the ofofthe thethedialkylation dialkylation dialkylationdialkylation product product productproduct 15m 15m 15m (38% (38% (38%(38% when when whenwhen the the thethereaction reaction reactionreaction benzylbenzylbenzylbenzyl imidateimidate imidateimidate 2020,,, which20whichwhich20,,, whichwhichwhich gavegavegave gavegavegave aaa 30%30%30% aaa 30%30%30% yieldyieldyield yieldyieldyield ofofof thethethe ofofof thethedialkylationthedialkylationdialkylation dialkylationdialkylationdialkylation productproductproduct productproductproduct 15m15m 15m15m (38%(38%(38% (38%(38%(38% whenwhenwhen whenwhenwhen thethethe thethereactionthereactionreaction reactionreactionreaction waswaswas performed performed performed under under under reflux). reflux). reflux). Benzylic Benzylic Benzylic imidates imidates imidates decorated decorated decorated with with with electron electron electron withdrawing withdrawing withdrawing groups groups groups ( 21–(21– (21– waswaswaswas performedperformed performedperformed underunder underunder reflux).reflux). reflux).reflux). BenzylicBenzylic BenzylicBenzylic imidatesimidates imidatesimidates decorateddecorated decorateddecorated withwith withwith electronelectron electronelectron withdrawingwithdrawing withdrawingwithdrawing groupsgroups groupsgroups ((21–21– ((21–21– 2323) 23)were were)) werewere also also alsoalso less less lessless reactive reactive reactivereactive and and andand provided provided providedprovided only only onlyonly trace trace tracetrace amounts amounts amountsamounts of of the ofofthe thethedialkylation dialkylation dialkylationdialkylation products products productsproducts at at rt, atatrt, with rt, rt,with withwith 2323))) 23werewere23were)) werewere alsoalsoalso alsoalso lesslessless less less reactivereactivereactive reactivereactive andandand andand providedprovidedprovided providedprovided onlyonlyonly onlyonly tracetracetrace tracetrace amountsamountsamounts amountsamounts ofofof thethe the ofof thedialkylationthedialkylationdialkylation dialkylationdialkylation productsproductsproducts productsproducts atatat rt,rt,rt, atat with with withrt,rt, withwith C3-monoalkylationC3-monoalkylationC3-monoalkylation being being being the the themajor major major product product product [65]. [65]. [65]. Heating Heating Heating the the thereaction reaction reaction to to reflux toreflux reflux provided provided provided the the thedesired desired desired C3-monoalkylationC3-monoalkylationC3-monoalkylationC3-monoalkylation beingbeing beingbeing thethe themajorthemajor majormajor productproduct productproduct [65].[65]. [65].[65]. HeatingHeating HeatingHeating thethe thereactionthereaction reactionreaction toto refluxreflux toto refluxreflux providedprovided providedprovided thethe thedesiredthedesired desireddesired dialkylationdialkylationdialkylation products products products in in much inmuch much im improved improvedproved overall overall overall yields, yields, yields, however. however. however. dialkylationdialkylationdialkylationdialkylation productsproducts productsproducts inin muchmuch inin muchmuch imimprovedproved imimprovedproved overalloverall overalloverall yields,yields, yields,yields, however.however. however.however.

Molecules 2019, 24, 4143 5 of 15 MoleculesMoleculesMoleculesMoleculesMolecules 20192019 2019,,, 24 242019,2019 24,,, xxx, ,xFOR,FORFOR 24 24FOR,, x x PEERPEERPEER FOR FORPEER PEERREVIEWPEERREVIEWREVIEW REVIEW REVIEWREVIEW 55 5ofof of 1414 1455 ofof 1414 MoleculesMoleculesMolecules 2019, 2019242019, x, , FOR 2424,, xx PEER FORFOR PEER PEERREVIEW REVIEWREVIEW 5 of 1455 ofof 1414 MoleculesMoleculesMoleculesMolecules 2019, 2019 2420192019, x, , ,FOR 24 2424,, , x xx PEER FOR FORFOR PEER PEERPEERREVIEW REVIEW REVIEWREVIEW 5 of 14555 of ofof 14 1414 MoleculesMolecules 2019,, 242019,, xx , FOR FOR24, x PEER PEERFOR PEER REVIEWREVIEW REVIEW 5 of 145 of 14 TableTableTableTableTableTableTable 3.3. 3. DirectDirect Direct 3. 3.3. Direct DirectDirect C3-dialkylationC3-dialkylation C3-dialkylation C3-dialkylation C3-dialkylationC3-dialkylation ofof of 2-methyl2-methyl 2-methyl of ofof 2-methyl 2-methyl2-methyl indoleindole indole indole indoleindole 14a14a 14a withwithwith 14a 14awith14a with trichloroacetimidates.trichloroacetimidates.withtrichloroacetimidates.with trichloroacetimidates. trichloroacetimidates. trichloroacetimidates.trichloroacetimidates. TableTableTableTable 3. Direct 3. 3.3. Direct DirectDirect C3-dialkylation C3-dialkylation C3-dialkylationC3-dialkylation of 2-methyl of ofof 2-methyl 2-methyl2-methyl indole indole indoleindole 14a with 14a 14a14a with trichloroacetimidates.withwith trichloroacetimidates. trichloroacetimidates.trichloroacetimidates. TableTable 3. Direct 3. Direct C3-dialkylation C3-dialkylation of 2-methyl of 2-methyl indole indole 14a withwith 14a withtrichloroacetimidates.trichloroacetimidates. trichloroacetimidates. RRR RRR R RR R 2.52.52.5 equivequiv equiv2.52.5 ROC(NH)CClROC(NH)CCl equivequivROC(NH)CCl ROC(NH)CClROC(NH)CCl3 3 3 R RR RR RR 2.5 equiv2.52.5 ROC(NH)CCl equivequiv ROC(NH)CClROC(NH)CCl33 33 R R R 2.5 equiv1 equiv1 2.5equiv ROC(NH)CCl equiv 1TMSOTf equivTMSOTf ROC(NH)CCl TMSOTf3 R R R RR MeMeMe 2.5MeMe equiv11 equivequiv2.52.5 ROC(NH)CClequiv 1 1equiv TMSOTf TMSOTf equivequiv ROC(NH)CCl ROC(NH)CCl TMSOTfTMSOTf3 33 RMeMeMeR MeMe Me 2.5MeMe equiv1 equiv2.5 ROC(NH)CCl equiv1 TMSOTf equiv ROC(NH)CCl TMSOTf3 33 R Me RMeMe NNN MeNN MeMe1 equivDCE,2.5DCE,DCE, equiv1 1 TMSOTf equivrt, rt,equiv DCE,DCE,rt, 33 ROC(NH)CCl h3h TMSOTf hTMSOTf rt,rt, 33 hh 3 NNN MeNN MeMe NH14a14a14aMeNN 14a14a14aMe1 equivDCE,1 TMSOTf equivrt,DCE,DCE, 3 h TMSOTf rt,rt, 33 hh N MeNN Me HNH 14aMeHNHNH Me DCE, rt,DCE,DCE, 3 h rt,rt, 33 hh N MeNN Me HN 14a NH 14a14a14a DCE, rt,DCE, 3 h rt, 3 h N N NH 14a HNH14a DCE, rt,DCE, 3 h rt, 3 h N N Entry ImidateH H 14a Product Yield (%) EntryEntryEntryEntryEntryEntry ImidateImidateImidateImidateImidateImidate Product Product Product Product Product Product Yield Yield Yield Yield Yield Yield(%)(%) (%) (%) (%)(%) EntryEntryEntryEntry ImidateImidateImidateImidate Product Product Product Product Yield Yield Yield Yield(%) (%) (%)(%) EntryEntry ImidateImidate Product Product Yield Yield (%) (%) a a aa aaa 1 11 1 11 616161 (59(59 (596161 a) ) (59(59)61 (59)) ) 1 1 61 (5961 a) (59 aa) 1 111 111111 111111 61 (59616161 a ) (59 (59(59 a a))) 1 1 11 1111 15a 61 (5961 a)) (59 a) 11 11 15a15a15a 15a15a15a 11 15a 15a15a15a 15a 15a a a aa aaa 2 22 2 22 404040 (46(46 (464040 a) ) (46(46)40 (46)) ) 2 2 40 (4640 a) (46 aa) 2 222 1616 16 40 (46404040 a ) (46 (46(46 a a))) 2 2 1616 1616 40 (4640 a)) (46 a) 16 161616 15i15i15i 15i15i15i 16 16 15i 15i15i15i 15i 15i

a aa aaa a 3 33 3 33 121212 (20(20 (201212 a) ) (20(20)12 (20)) ) 3 3 12 (2012 a) (20 aa) 3 33 171717 1717 12 (201212 a) (20(20 a a )) 3 3 17 17 12 (2012 a )(20 a) 3 3 17 171717 12 (2012 ) (20 ) 17 17 15j15j15j 15j15j15j 15j 15j15j15j 15j 15j a aa aaa a 44 4 44 tracetracetrace trace(24trace(24 (24 a) ) (24(24) )) 4 4 4 trace trace(24 tracea) (24 (24aa) ) 4 444 181818 1818 trace tracetrace(24trace a) (24 (24(24 a a))) 4 4 18 1818 15k15k 15k tracetrace trace(24(24 a)) (24 a) 4 18 181818 15k 15k15k trace (24 ) 18 18 15k 15k15k15k 15k 15k

b bb bbb 55 5 555 00 0 b 000 b 5 5 0 b bb 0 5 55 0 b 00 b 5 5 1919 19 0 b 0 b 5 19 1919 15l15l 15l 0 19 191919 15l 15l15l 19 19 15l 15l15l15l 15l 15l a aa aaa 66 6 66 303030 (38(38 (383030 a) ) (38(38) )) 6 6 30 (3830 a) (38 aa) a 6 6 66 202020 2020 30 (383030 a) (38(3830 a a (38)) ) 6 6 20 20 30 (3830 a )(38 a) 6 6 20 202020 15m15m15m 15m15m15m 30 (3830 ) (38 ) 20 20 15m 15m15m15m 15m 15m

a aa aaa 77 7 77 tracetracetrace (52trace(52trace(52 a) ) (52(52) )) 7 7 trace trace (52 a) (52 aa) a 7 7 77 trace (52tracetrace tracea) (52(52 a a (52)) ) 7 7 2121 21 tracetrace tracetrace(52(52 a)) (52 a) 7 21 2121 15n15n 15n trace (52 ) 21 212121 15n 15n15n 21 21 15n 15n15n15n 15n 15n

a aa aaa 88 8 88 tracetracetrace (45trace(45trace(45 a) ) (45(45) )) 8 8 trace trace (45 a) (45 aa) 8 88 trace (45tracetrace a) (45(45 a )) a 8 8 8 tracetrace tracetrace(45(45 atrace)) (45 a (45) ) 8 222222 222222 15o15o 15o trace (45 ) 22 2222 15o 15o15o 2222 22 15o 15o15o15o 22 15o 15o

a aa aaa 99 9 99 tracetracetrace (63trace(63trace(63 a) ) (63(63) )) 9 9 trace trace (63 a) (63 aa) 9 99 trace (63tracetrace a) (63(63 a )) 9 9 trace tracetrace(63 a) (63 a) a 9 9 9 232323 232323 tracetrace(63 trace) (63 (63) ) 23 23 15p15p15p 15p 15p15p 23 2323 15p 15p a 23 23 b 15p 15p15p aa aaa bb bbb 15p 15p a YieldYieldYield Yield Yieldwhenwhen when when when thethe the reactionreaction reactionthethe reactionreaction waswas was performed performed was wasperformed performedperformed atat at reflux.reflux. reflux. atat reflux.reflux. b AAA complexcomplex complex AA complexcomplex15p mixturemixture mixture 15p mixturemixture resulted.resulted. resulted. resulted.resulted. a Yieldaa Yield when when the reaction the reaction was performedwas performed at reflux. at reflux. b A complex bb A complex mixture mixture resulted. resulted. a Yieldaa YieldYield Yieldwhen when whenwhen the reaction the thethe reaction reactionreaction was performed was waswas performed performedperformed at reflux. at atat reflux. reflux.reflux. b A complex b AAA complex complexcomplex mixture mixture mixturemixture resulted. resulted. resulted.resulted. a Yieldaa Yield Yieldwhen when the reaction the the reaction reaction was was performedwas performed performed at at reflux. reflux. at reflux. b AA complex b A complex mixture mixture mixture resulted. resulted. resulted. WithWithWithWithWith With readyready ready readyreadyready accessaccess access accessaccessaccess toto to 3,3-diallyl3,3-diallyl 3,3-diallyl tototo 3,3-diallyl3,3-diallyl3,3-diallyl indoleninesindolenines indolenines indoleninesindoleninesindolenines viavia via imidateimidate viaviaimidatevia imidateimidateimidate alkylation,alkylation, alkylation, alkylation,alkylation,alkylation, wewe we turned turned weweturnedwe turnedturnedturned ourour our attention attentionour ourourattention attentionattentionattention toto to tototo WithWithWithWith ready readyreadyready access accessaccessaccess to 3,3-diallyl tototo 3,3-diallyl3,3-diallyl3,3-diallyl indolenines indoleninesindoleninesindolenines via imidate viaviavia imidateimidateimidate alkylation, alkylation,alkylation,alkylation, we turned wewewe turnedturnedturned our attention ourourour attentionattentionattention to tototo thethethe functionalizationfunctionalization theWiththethefunctionalization functionalizationfunctionalizationfunctionalizationWith ready ready access accessofof ofto thesethese these of3,3-diallylofof to thesethesethese systemssystems3,3-diallyl systems systemssystemssystems indolenines toto to indolenines three-dithree-di three-di tototo three-dithree-dithree-di viamensionalmensionalmensional imidate viamensionalmensionalmensional imidate scaffoldsalkylation,scaffolds scaffolds scaffoldsscaffoldsalkylation,scaffolds likelike likewe likethosethoselike liketurnedthose we thosethose those turnedusedused used our usedused usedinin attentioninour medicinalmedicinal medicinal inin inattention medicinalmedicinalmedicinal to to the functionalizationthethethe functionalizationfunctionalizationfunctionalization of these ofofof thesethesethese systems systemssystemssystems to three-di tototo three-dithree-dithree-dimensionalmensionalmensionalmensional scaffolds scaffoldsscaffoldsscaffolds like likethoselikelike thosethosethose used usedused usedin medicinal ininin medicinalmedicinalmedicinal thechemistrythechemistrychemistry functionalizationfunctionalizationchemistrythechemistrychemistryWith functionalization studies.studies. readystudies. studies.studies.studies. access Initially InitiallyInitially ofof Initially toInitiallytheseInitiallythese of 3,3-diallyl a athese a spirocyclesystemssystems spirocyclespirocycle aaa spirocyclesystemsspirocyclespirocycle indolenines toto formatio formatiothree-dithree-diformatio to formatioformatioformatiothree-di viamensionalnnn was imidatewaswasmensionalnnn waswasexploredwasexplored explored alkylation, scaffolds exploredexploredexplored scaffolds utilizing utilizingutilizing like weutilizingutilizingutilizing turnedthoselike the thethe those Grubbs GrubbsthetheusedtheGrubbs our GrubbsGrubbsGrubbsused attentionin metathesis metathesismedicinalmetathesis in metathesismetathesismetathesismedicinal to the chemistrychemistrychemistrychemistry studies. studies.studies.studies. Initially InitiallyInitiallyInitially a spirocycle aaa spirocyclespirocyclespirocycle formatio formatioformatioformation wasnnn waswaswasexplored exploredexploredexplored utilizing utilizingutilizingutilizing the Grubbsthethethe GrubbsGrubbsGrubbs metathesis metathesismetathesismetathesis chemistrycatalyst.catalyst.catalyst.functionalizationcatalyst.chemistrycatalyst.catalyst. This This Thisstudies. This This Thisled ledstudies.led of to ledInitiallytoledledto these the the thetotoInitiallyto systemsformation theformationthe theformationa spirocycle formationformationformation a tospirocycle three-dimensionalof ofof spirocycle spirocycleformatio spirocycleofofof spirocyclespirocycleformatiospirocyclen was24 2424n sca (Scheme (Scheme(Scheme 24was(Scheme24explored24ff olds (Scheme(Scheme (Schemeexploredlike 2). 2).2). 2).utilizing those The The The2).2).The2). utilizing The usedTheindolenine Theindolenineindolenineindolenine thethe indolenineindolenine inindolenine GrubbsGrubbsthe medicinal Grubbs15a 15a15a metathesismetathesis 15awas was15awas15a chemistrywas metathesis waswaswasalso alsoalsoalso alsoalsoalso catalyst.catalyst.catalyst.catalyst. This ThisThisThisled toledledled the tototo formationthethethe formationformationformation of spirocycle ofofof spirocyclespirocyclespirocycle 24 (Scheme 242424 (Scheme(Scheme(Scheme 2). The 2).2).2). TheTheTheindolenine indolenineindolenineindolenine 15a 15awas15a15a waswaswasalso alsoalsoalso catalyst.transformedtransformedtransformedstudies.transformedcatalyst.transformedtransformed This Initially intointo Thisintoled aintoa intointo a spiropiperidine-indanespiropiperidine-indanetoled spiropiperidine-indane spirocycle a aathe spiropiperidine-indane spiropiperidine-indanetospiropiperidine-indane formationthe formationformation of spirocycle was thatofthat that spirocycleexplored isthatis thatthat is simsim sim is isisilar24ilar sim similarsim utilizing (Scheme (Schemetotoilar 24ilartoilar thatthat that (Scheme to toto foundthatfound thatthat found the2).2). found foundfound Grubbs The Theinin2). in thethe the Thein inindolenineindoleninein ghrelinghrelin the metathesistheghrelinthe indolenine ghrelin ghrelinghrelin receptorreceptor receptor 15a receptor receptor catalyst.receptor 15awaswas agonistsagonists agonists was also alsoagonists agonistsagonists This also transformedtransformedtransformedtransformed into ainto intointo spiropiperidine-indane a aa spiropiperidine-indane spiropiperidine-indanespiropiperidine-indane that isthat thatthat sim is isisilar sim simsim toilarilarilar that to toto foundthat thatthat found foundfound in the in inin ghrelin the thethe ghrelin ghrelinghrelin receptor receptor receptorreceptor agonists agonists agonistsagonists transformedMK-0677transformedMK-0677MK-0677ledMK-0677transformedMK-0677MK-0677 to the 66 6 andandand formation and intointo 6 66 7and 7andand .7. .a ainto ThisThis.This spiropiperidine-indanespiropiperidine-indaneThis 7 77. .a . This Thisinvolved ofinvolvedThisinvolved spiropiperidine-indane involved spirocycle involved involvedinvolved initialinitialinitial initial 24initial initialinitial reductionreductionreduction (Schemereduction thatthat reduction reductionreduction isisthat2 ofofsimofsim). of thetheisthe Thetheilar ilar of ofsimof indolenineindolenineindolenine the the indoleninetheto indoleninetoilar that that indolenine indolenineindolenine to foundfoundthat 15a15a 15afound15a in into toto 15a 15a15ato the the thethethewas the in to toto ghrelin ghrelin indolineindolineindoline the the theindolinethe also ghrelin indoline indolineindoline transformed receptorreceptor 2525 25 withreceptorwithwith with 25 2525 agonists agonistswith with withlithiumlithiumlithium lithium into agonists lithium lithiumlithium a MK-0677MK-0677MK-0677MK-0677 6 and 6 66 7and andand. This 7 77... ThisThisinvolvedThis involved involvedinvolved initial initial initialinitial reduction reduction reductionreduction of the of ofof indolenine the thethe indolenine indolenineindolenine 15a to 15a 15a15a the to toto indoline the thethe indoline indolineindoline 25 with 25 2525 with withwithlithium lithium lithiumlithium MK-0677aluminumaluminumaluminumspiropiperidine-indanealuminumMK-0677aluminumaluminum 6 andhydride.andhydride. hydride. 6 7 andhydride.hydride.hydride... ThisThis 7 TheThe . The Thisinvolvedinvolved ThesulfonamideThe thatsulfonamideThesulfonamide involved sulfonamidesulfonamide issulfonamide initialinitial similar initial reductionreduction2626 26 to waswaswas that reductionwas262626 waswasthenthenthenwas foundthen ofof thenthe thethenthenformedformedformed formedof in indolenineindolenine the formed theformedformed indolenine withwithwith ghrelinwith with with withTsCl TsClTsCl 15aTsCl receptor TsClto to TsCl TsCl15aandandand and thethe to andtriethylamine. triethylamine.and triethylamine.and indolineindoline triethylamine.the agonists triethylamine. triethylamine.triethylamine.indoline 25 MK-0677 withwith 25 OxidativeOxidativeOxidative Oxidative with lithiumlithium OxidativeOxidativeOxidative6 lithiumand aluminumaluminumaluminumaluminum hydride. hydride.hydride.hydride. The ThesulfonamideTheThe sulfonamidesulfonamidesulfonamide 26 was 262626 waswasthenwas then thenthenformed formedformedformed with with withwithTsCl TsCl TsClTsCland andtriethylamine.andand triethylamine.triethylamine.triethylamine. Oxidative OxidativeOxidativeOxidative aluminumcleavagecleavagecleavage7. Thiscleavagealuminumcleavagecleavage of involvedof ofhydride. thethe the ofofof hydride.alkenesalkenes thethealkenesthe initial alkenesalkenesThealkenes toto Thesulfonamideto reduction thethe the toto tosulfonamide correspondingcorresponding thethethecorresponding correspondingcorrespondingcorresponding of 26 the waswas indolenine26 aldehyaldehywas thenthenaldehy aldehyaldehyaldehy then formedformeddedede15a waswasformed wasdededeto withwith wasexecutedwasexecutedwas theexecuted with executed indolineexecutedTsClTsClexecuted TsCl viavia andandvia ozon ozon 25 via viaozonviaandtriethylamine.triethylamine.with ozonozonolysis.ozonolysis. triethylamine.olysis. lithiumolysis.olysis.olysis. PurificationPurification Purification PurificationOxidativeOxidativePurificationPurification aluminum Oxidative ofof of ofofof cleavagecleavagecleavagecleavage of the ofofof alkenes thethethe alkenesalkenesalkenes to the tototo corresponding thethethe correspondingcorrespondingcorresponding aldehy aldehyaldehyaldehyde wasdedede wasexecutedwaswas executedexecutedexecuted via ozon viaviavia ozonozonozonolysis.olysis.olysis.olysis. Purification PurificationPurificationPurification of ofofof cleavagethisthisthishydride. dialdehydethiscleavagedialdehydethis thisdialdehyde dialdehydedialdehydeofdialdehyde Thethe of alkenes sulfonamideprovedtheproved proved alkenes provedprovedproved todifficultdifficult difficult the to difficultdifficultdifficult26 corresponding the waswhenwhen when corresponding whenthenwhenwhen triphenylphotriphenylpho triphenylpho formed triphenylphotriphenylphotriphenylpho aldehy aldehy withsphinedesphinesphine was TsClsphinedesphinesphine was waswas executedwas and was usedwasusedwas executedused triethylamine. usedused usedtoviato to reducereduce reduceozon toviatoto reducereducereduce ozonolysis. thethe the Oxidative olysis. ozonide,ozonide, thethe ozonide,thePurification ozonide,ozonide,ozonide, Purification cleavagebutbut but the thebut butbutofthe thethe theof this dialdehydethisthisthis dialdehydedialdehydedialdehyde proved provedprovedproved difficult difficultdifficultdifficult when whenwhenwhen triphenylpho triphenylphotriphenylphotriphenylphosphinesphinesphinesphine was wasusedwaswas usedused usedto reduce tototo reducereducereduce the ozonide, thethethe ozonide,ozonide,ozonide, but the butbutbut thethethe thisusethisuseuseof of thedialdehydeofdialdehydeusethis useuseof 1,3-bis(diphenylphosphino)1,3-bis(diphenylphosphino) 1,3-bis(diphenylphosphino) alkenes ofdialdehydeofof 1,3-bis(diphenylphosphino)1,3-bis(diphenylphosphino)1,3-bis(diphenylphosphino) provedproved to the proved correspondingdifficultdifficult difficult whenwhenpropanepropanepropane when triphenylphopropanetriphenylphopropane aldehydepropane triphenylpho(dppp)(dppp) (dppp) (dppp)(dppp)(dppp) was asas sphineas thethe executed the asasassphine reductant reductant the thethereductantwas reductantreductantreductant wasused via ma ozonolysis.usedma toma dedereduce demama mato thethe thedededereduce purification purification thethethepurification Purification purificationozonide,purification purificationthe ozonide, easiereasier easierbut of easiereasier easier the but thisasas as the asasas use ofuseuseuse 1,3-bis(diphenylphosphino) ofofof 1,3-bis(diphenylphosphino)1,3-bis(diphenylphosphino)1,3-bis(diphenylphosphino)propanepropanepropanepropane (dppp) (dppp)(dppp)(dppp) as the asasas reductant thethethe reductantreductantreductant made mamama thededede purification thethethe purificationpurificationpurification easier easiereasiereasier as asasas usethethethedialdehyde bisphosphineofbisphosphine theusethethebisphosphine 1,3-bis(diphenylphosphino) bisphosphineofbisphosphinebisphosphine 1,3-bis(diphenylphosphino) proved oxideoxide oxide di oxideoxideoxideffi waswas cultwas waswasmorewasmore whenmore moremoremorepropane polarpolar triphenylphosphinepolarpropane polarpolarpolar andand and (dppp) andeasierandeasierand easier(dppp) easier easiereasieras toto tothe separateasseparate wasseparate to toto reductantthe separateseparateseparate used reductant fromfrom from to ma from reducefrom from thethe dethe ma product.the product. thethetheproduct.de the purification product.product.theproduct. ozonide, purification TheThe The ThedialdehydeThedialdehyde Thedialdehyde but easier dialdehydedialdehydedialdehyde the easier as use as the bisphosphinethethethe bisphosphinebisphosphinebisphosphine oxide oxideoxideoxide was waswasmorewas moremoremore polar polarpolarpolar and andeasierandand easiereasiereasier to separate tototo separateseparateseparate from fromfrom fromthe product. thethethe product.product.product. The ThedialdehydeTheThe dialdehydedialdehydedialdehyde theprovedtheprovedprovedof bisphosphine 1,3-bis(diphenylphosphino)propanebisphosphineprovedtheprovedproved toto bisphosphineto bebe be tototo unstableunstable unstablebebebe oxide oxideunstableunstableunstable oxideandand andwaswas andreadilyandreadily and readilywasmoremore readilyreadilyreadily more polarpolarself-condensedself-condensed self-condensed polar self-condensedself-condensed self-condensed (dppp)andand andeasiereasier as ,easier,, the, so soso totoso it,itit, reductantseparate ,separate it so sosowastowaswas was itititseparate waswasimmediatelyimmediatelyimmediatelywas immediately fromfrom made immediatelyimmediatelyimmediately from thethe the product.product. thesubjectedsubjected purificationsubjected product. subjectedsubjectedsubjected TheThe toto to Theadialdehydedialdehydea easier a toreductivetoreductiveto reductive adialdehydeaa reductivereductive asreductive the provedprovedproved to be toto unstable bebe unstableunstable and readilyandand readilyreadily self-condensed self-condensedself-condensed, so it,, sosowas itit wasimmediatelywas immediatelyimmediately subjected subjectedsubjected to a toreductiveto aa reductivereductive provedproved to be to unstable be unstable and andreadily readily self-condensed self-condensed3 , 3so ,it, so sowas itit waswasimmediately immediatelyimmediately subjected subjected to a toreductive a reductive provedaminationaminationaminationaminationprovedaminationamination to bewithwith withto unstable withbe withwithbenzylaminebenzylamine benzylamine unstable benzylaminebenzylaminebenzylamine and andreadily andand and readily andNaBH(OAc)NaBH(OAc)andand NaBH(OAc)self-condensed NaBH(OAc)NaBH(OAc)NaBH(OAc) self-condensed33,,, which,whichwhich which,33 ,,so , whichwhichwhich itprovidedprovided,provided provided sowas provideditprovidedprovided wasimmediately thethethe theimmediately desired desireddesired thethedesiredthe desireddesireddesired subjected spiropiperidine-indanespiropiperidine-indanespiropiperidine-indane spiropiperidine-indane subjected spiropiperidine-indanespiropiperidine-indanespiropiperidine-indane to a toreductive a reductive amination with benzylamine and NaBH(OAc)3, which3 provided the desired spiropiperidine-indane aminationaminationaminationamination with with withwithbenzylamine benzylaminebenzylaminebenzylamine and andNaBH(OAc)andand NaBH(OAc)NaBH(OAc)NaBH(OAc)3, which33,,, whichwhichwhich provided providedprovidedprovided the desired thethethe desireddesireddesired spiropiperidine-indane spiropiperidine-indanespiropiperidine-indanespiropiperidine-indane amination272727 withwithwith with27amination2727 with with withaaa a 35%35%35% with35% a aa 35%yield35%yieldyield 35% with yieldbenzylamine yield yieldyield overoveroverbenzylamine over over overtwoovertwotwo two steps.andtwo steps.steps.twotwo steps. steps. NaBH(OAc)andsteps.steps. NaBH(OAc) 33,, whichwhich3, which providedprovided provided thethe desireddesired the desired spiropiperidine-indanespiropiperidine-indane spiropiperidine-indane 27 with2727 withwitha 35% aa 35%yield35% yieldyield over overovertwo steps.twotwo steps.steps. 27 withwith27 with with aa 35%35% aa 35%35%yieldyield yieldyield overover overover twotwo steps.twosteps.two steps.steps.

Molecules 2019, 24, 4143 6 of 15

bisphosphine oxide was more polar and easier to separate from the product. The dialdehyde proved to be unstable and readily self-condensed, so it was immediately subjected to a reductive amination with benzylamine and NaBH(OAc)3, which provided the desired spiropiperidine-indane 27 with a Molecules35% yield 2019 over,, 24,, xxtwo FORFOR steps. PEERPEER REVIEWREVIEW 6 of 14

Scheme 2. Elaboration of the 3,3-Diallyl indolenine 15a to spiro-polycyclic systems. Scheme 2. Elaboration of the 3,3-Diallyl indolenine 15a toto spiro-polycyclicspiro-polycyclic systems.systems. Oddly, the spiropiperidine 27 showed a multiplet in the 1H NMR at 0.28 ppm that integrated Oddly, the spiropiperidine 27 showed a multiplet in the 11H NMR at 0.28 ppm that integrated for for aOddly, single the hydrogen spiropiperidine resonance. 27 showed A proton a multiplet with this in chemical the H NMR shift at was 0.28 notppm congruent that integrated with thefor a single hydrogen resonance. A proton with this chemical shift was not congruent with the proposed aproposed single hydrogen structure, resonance. so some additional A proton with studies this were chemical performed. shift was A COSY not congruent experiment with verified the proposed that the structure, so some additional studies were performed. A COSY experiment verified that the upfield structure,upfield proton so some was additional part of the studies piperidine were ring. perfor Somemed. molecular A COSY experiment modeling studies verified indicated that the thatupfield this proton was part of the piperidine ring. Some molecular modeling studies indicated that this unusual protonunusual was chemical part of shift the piperidine is likely to bering. attributed Some molecular to diamagnetic modeling anisotropy studies from indicated the aromatic that this ring unusual of the chemical shift is likely to be attributed to diamagnetic anisotropy from the aromatic ring of the chemicaltoluenesulfonamide, shift is likely which to be prefers attributed to reside to diamagnetic on the opposite anisotropy face of thefrom pyrroline the aromatic ring as ring the methylof the toluenesulfonamide, which prefers to reside on the opposite face of the pyrroline ring as the methyl toluenesulfonamide,group due to steric e whichffects. prefers This holds to reside the -system on the ofopposite the sulfonamide face of the inpyrroline a position ring to as shield the methyl one of group due to steric effects. This holds the -system of the sulfonamide in a position to shield one of groupthe protons due to on steric the piperidine effects. This ring holds (Ha, the Figure -system2). The of molecularthe sulfonamide modeling in a predicts position that to shield in the lowestone of thethe protonsprotons onon thethe piperidinepiperidine ringring (H(Haa,, FigureFigure 2).2). TheThe molecularmolecular modelingmodeling predictspredicts thatthat inin thethe lowestlowest energy conformation Ha is only ~2.8 Å from the center of the aromatic ring. This upfield chemical energy conformation Ha is only ~2.8 Å from the center of the aromatic ring. This upfield chemical energyshift is consistentconformation with H literaturea is only reports~2.8 Å from of similar the center spiropiperidine-indanes of the aromatic ring. [75 ].This In furtherupfield support chemical of shift is consistent with literature reports of similar spiropiperidine-indanes [75]. In further support of shiftthis rationale,is consistent in structureswith literature where reports the C2 of position similar ofspiropiperidine-indanes the pyrroline is unsubstituted [75]. In further [76], or support there is noof this rationale, in structures where the C2 position of the pyrroline is unsubstituted [76], or there is no thisaromatic rationale, sulfonamide in structures [77], where no similar the C2 upfield position shifts of arethe observedpyrroline inis theunsubstituted1H NMR. [76], or there is no 1 aromatic sulfonamide [77], no similar upfield shifts are observed in the 1H NMR.

1 FigureFigure 2. 2. UpfieldUpfield Shift Shift of of Ha Ha in in the the 11HH NMR NMR of of Spiropiperidine Spiropiperidine 2727 dueduedue toto DiamagneticDiamagnetic AnisotropyAnisotropy Anisotropy fromfromfrom thethe the SulfonamideSulfonamide Sulfonamide -System.-System. -System.

3. Materials and Methods

3.1. General Experimental Information All anhydrous reactions were run under a positive pressure of argon. Dichloromethane (DCM) was dried by passage through an alumina column. 1,2-Dichloroethane (DCE) was freshly distilled fromfrom calciumcalcium hydridehydride beforebefore use.use. SilicaSilica gelgel columncolumn chromatographychromatography waswas performedperformed usingusing 6060 ÅÅ silicasilica gel (230−400 mesh). Melting points are uncorrected. The indoles used in this study were purchased fromfrom commercialcommercial sources.sources.

Molecules 2019, 24, 4143 7 of 15

3. Materials and Methods

3.1. General Experimental Information All anhydrous reactions were run under a positive pressure of argon. Dichloromethane (DCM) was dried by passage through an alumina column. 1,2-Dichloroethane (DCE) was freshly distilled from calcium hydride before use. Silica gel column chromatography was performed using 60 Å silica gel (230 400 mesh). Melting points are uncorrected. The indoles used in this study were purchased − from commercial sources.

3.2. Preparation of Trichloroacetimidates Allyl-2,2,2-trichloroacetimidate 11 [78], 1-(1-imino-2,2,2-trichloroethoxy)-3-phenyl-2(E)-propene 17 [79], propargyl-2,2,2-trichloroacetimidate 18 [70], (4-methoxyphenyl)methyl-2,2,2-trichloroacetimidate 19 [69], benzyl-2,2,2-trichloroacetimidate 20 [78], (4-chloro)methyl-2,2,2-trichloroacetimidate 21 [80], (4-trifluoromethyl)methyl-2,2,2-trichloroacetimidate 22 [66], and (4-nitrophenyl)methyl-2,2,2- trichloroacetimidate 23 [81] were synthesized as previously reported. 2-Methyl-2-propenyl trichloroacetimidate (16). A flame dried flask was charged with 2-methyl- 2-propen-1-ol (7.0 mmol, 0.589 mL) and placed under argon. Dry DCM (35 mL) was then added, and the flask was cooled to 0 ◦C. 1,8-Diazabicyclo [5.4.0]undec-7-ene (0.7 mmol, 0.108 mL) was added to the solution, followed by trichloroacetonitrile (8.4 mmol, 0.843 mL). After ~22 h the reaction mixture was concentrated and the residue purified by silica gel column chromatography (10% EA/3% Et3N/87% hexanes). Clear oil (1.502 g, 99%). TLC Rf = 0.42 (60% DCM/40% hexanes); IR (thin film) 3365, 3072, 1 1 2975, 2904, 1637, 1607, 1482, 912 cm− ; H NMR (400 MHz, CDCl3) δ 8.31 (bs, 1H), 5.11 (s, 1H), 4.99 13 (s, 1H), 4.71 (s, 2H), 1.83 (s, 3H); C NMR (100 MHz, CDCl3) δ 162.6, 139.4, 113.3, 91.5, 72.3, 19.4.; + + HRMS (ESI+) calcd for C6H8Cl3NONa [M + Na] : 237.9563. Found: 237.9564.

3.3. Synthesis of 3,30-Disubstituted Indolenines General procedure for C3-dialkylation of indoles. In a flame dried flask, the imidate (2.5 equiv) was dissolved in anhydrous DCE (0.3 M) followed by the addition of the indole (1.0 equiv). To this solution freshly distilled TMSOTf (1.0 equiv) was added and the resulting mixture was stirred at room temp. or heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 10 mL 1 M NaOH. The organic layer was separated and the aqueous layer was extracted with DCM (3 5 mL). The combined organic layers were dried over sodium sulfate, filtered and × concentrated. The residue was purified by silica gel chromatography using the listed solvent system. 3,3-Diallyl-2-methyl-3H-indole (15a). Synthesized by the general procedure from 2-methylindole 14a and imidate 11 [78], purified using silica gel chromatography (3% EA/97% DCM). This compound 1 has been previously reported [58]. Orange oil (0.14 g, 59%); TLC Rf = 0.35 (5% EA/95% DCM); H NMR (300 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.34–7.28 (m, 2H), 7.22–1.17 (m, 1H), 5.18–5.05 (m, 2H), 4.95 (d, J = 17.0 Hz, 2H), 4.85 (d, J = 10.9 Hz, 2H), 2.69 (dd, J = 13.9, 6.1 Hz, 2H), 2.45 (dd, J = 13.9, 7.7 13 Hz, 2H), 2.25 (s, 3H); C NMR (100 MHz, CDCl3) δ 185.2, 154.8, 141.2, 132.1, 127.9, 125.0, 122.2, 119.8, 118.1, 61.8, 40.3, 16.5. 3,3-Diallyl-5-methoxy-2-methyl-3H-indole (15b). Synthesized by general procedure from 5-methoxy- 2-methyl-1H-indole 14b and imidate 11 [78], purified using silica gel chromatography (5% EA/95% DCM). This compound has been previously reported [6]. Brown solid (0.18 g, 61%); mp = 45–46 ◦C; 1 1 TLC Rf = 0.33 (10% EA/90% DCM); IR (ATR) 3077, 3000, 1640, 1591, 1576, 908 cm− ; H NMR (300 MHz, CDCl3) δ 7.44 (d, J = 9.0 Hz, 1H), 6.85–6.83 (m, 2H), 5.20–5.06 (m, 2H), 4.96 (d, J = 16.2 Hz, 2H), 4.87 (d, J = 9.8 Hz, 2H), 3.83 (s, 3H), 2.66 (dd, J = 13.8, 5.8 Hz, 2H), 2.45 (dd, J = 13.9, 7.7 Hz, 2H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 182.9, 157.8, 142.9, 132.1, 119.9, 118.1, 117.5, 112.2, 109.2, 61.9, 55.7, 40.4, 16.4. 3,3-Diallyl-2,5-dimethyl-3H-indole (15c). Synthesized by general procedure from 2,5-dimethyl- 1H-indole 14c and imidate 11 [78], purified using silica gel chromatography (20% EA/80% hexanes). Brown solid (0.13 g, 41%); mp = 38–40 ◦C; TLC Rf = 0.38 (40% EA/60% hexanes); IR (ATR) 3081, 3002, Molecules 2019, 24, 4143 8 of 15

1 1 1638, 1574, 820 cm− ; H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.07 (s, 1H), 5.16–5.06 (m, 2H), 4.95 (d, J = 17.0 Hz, 2H), 4.85 (d, J = 9.9 Hz, 2H), 2.66 (dd, J = 13.9, 6.0 13 Hz, 2H), 2.43 (dd, J = 13.9, 7.8 Hz, 2H), 2.39 (s, 3H), 2.22 (s, 3H); C NMR (100 MHz, CDCl3) δ 184.0, 152.7, 141.3, 134.7, 132.3, 128.5, 122.9, 119.3, 118.0, 61.5, 40.4, 21.5, 16.5; HRMS (ESI+) m/z calcd for + + C16H19NNa [M + Na] : 248.1409, found: 248.1409. 3,3-Diallyl-5-chloro-2-methyl-3H-indole (15d). Synthesized by general procedure from 5-chloro- 2-methyl-1H-indole 14d and imidate 11 [78], purified using silica gel chromatography (10% EA/90% hexanes). Yellow oil (0.10 g, 45%); TLC Rf = 0.42 (30% EA/70% hexanes); IR (ATR) 3076, 1728, 1577, 1 1 1451, 920, 825 cm− ; H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.4 Hz, 1H), 7.31–7.26 (m, 2H), 5.18–5.08 (m, 2H), 4.99 (d, J = 16.8 Hz, 2H), 4.91 (d, J = 10.4 Hz, 2H), 2.68 (dd, J = 13.6, 6.0 Hz, 2H), 2.47 (dd, J 13 = 14.0, 7.6 Hz, 2H), 2.26 (s, 3H); C NMR (100 MHz, CDCl3) δ 185.7, 153.4, 143.1, 131.5, 130.9, 128.1, + + 122.7, 120.6, 118.6, 62.3, 40.1, 16.5; HRMS (ESI+) m/z calcd for C15H16ClNNa [M + Na] : 268.0863, found: 268.0864. 3,3-Diallyl-5-fluoro-2-methyl-3H-indole (15e). Synthesized by general procedure from 5-chloro- 2-methyl-1H-indole 14e and imidate 11 [78], purified using silica gel chromatography (10% EA/90% hexanes). Purple oil (0.16 g, 68%); TLC Rf = 0.37 (30% EA/70% hexanes); IR (ATR) 3077, 1727, 1581, 1 1 1462, 918, 821 cm− ; H NMR (400 MHz, CDCl3) δ 7.41 (dd, J = 8.2, 4.7 Hz, 1H), 7.00–6.94 (m, 2H), 5.15–5.04 (m, 2H), 4.94 (d, J = 16.8 Hz, 2H), 4.85 (d, J = 10.0 Hz, 2H), 2.63 (dd, J = 13.9, 6.3 Hz, 2H), 2.43 13 (dd, J = 13.6, 7.7 Hz, 2H), 2.21 (s, 3H); C NMR (100 MHz, CDCl3) δ 184.8 (d, J = 3.5 Hz), 161.0 (d, J = 242.1 Hz), 150.8 (d, J = 1.8 Hz), 143.2 (d, J = 8.5 Hz), 131.6, 120.3 (d, J = 8.8 Hz), 118.5, 114.6 (d, J = + 23.4 Hz), 109.9 (d, J = 23.3 Hz), 62.3 (d, J = 2.0 Hz), 40.2, 16.4; HRMS (ESI+) m/z calcd for C15H16FNNa [M + Na]+: 252.1159, found: 252.1158. 3,3-Diallyl-5-nitro-2-methyl-3H-indole (13). Synthesized by the general procedure from 2-methyl- 5-nitro-1H-indole 10 and imidate 11 [78], purified using silica gel chromatography (5% EA/95% DCM). 1 Brown oil (0.21 g, 71%); TLC Rf = 0.47 (10% EA/90% DCM); IR (ATR) 3007, 1703, 1571, 1518, 1338 cm− ; 1 H NMR (300 MHz, CDCl3) δ 8.28 (dd, J = 8.5, 2.3 Hz, 1H), 8.16 (d, J = 2.0 Hz, 1H), 7.62 (d, J = 8.5 Hz, 1H), 5.17–5.04 (m, 2H), 5.03–4.88 (m, 4H), 2.77 (dd, J = 14.0, 6.1 Hz, 2H), 2.53 (dd, J = 14.0, 7.1 Hz, 2H), 13 2.35 (s, 3H); C NMR (100 MHz, CDCl3) δ 191.6, 159.6, 145.6, 142.4, 130.7, 124.9, 119.9, 119.4, 117.9, + + 62.9, 40.0, 17.0; HRMS (ESI+) m/z calcd for C15H16N2O2Na [M + Na] : 279.1104, found: 279.1103. 3,3-Diallyl-2-phenyl-3H-indole (15g). Synthesized by general procedure from the known indole 14g and imidate 11 [78], purified using silica gel chromatography (5% EA/95% hexanes). This compound has been previously reported [6]. Yellow oil (0.09 g, 34%); TLC Rf = 0.52 (5% EA/95% DCM); 1H NMR (300 MHz, CDCl3) δ 8.14–8.10 (m, 2H), 7.67 (d, J = 7.5 Hz, 1H), 7.49–7.47 (m, 3H), 7.40–7.26 (m, 3H), 13 5.18–5.05 (m, 2H), 4.79–4.71 (m, 4H), 2.90 (d, J = 6.9 Hz, 4H); C NMR (100 MHz, CDCl3) δ 180.3, 154.4, 142.9, 133.9, 131.8, 130.6, 128.6, 128.1, 128.0, 125.7, 121.7, 120.7, 118.3, 62.4, 41.8. 2-Methyl-3,3-bis(2-methyl-2-propenyl)-3H-indole (15i). Synthesized by general procedure from 2-methylindole 14a and imidate 16, purified using silica gel chromatography (10% EA/90% hexanes). Yellow oil (0.13 g, 46%); TLC Rf = 0.52 (5% EA/95% DCM); IR (ATR) 3074, 2967, 2918, 1642, 1575,1447, 1 1 765 cm− ; H NMR (400 MHz, CDCl3) δ 7.42 (d, J = 8.0 Hz, 1H), 7.25–7.21 (m, 2H), 7.12–7.09 (m, 1H), 4.48–4.47 (m, 2H), 4.40 (s, 2H), 2.63 (d, J = 13.6 Hz, 2H), 2.53 (d, J = 14.0 Hz, 2H), 2.26 (s, 3H), 1.06 (s, 13 6H); C NMR (100 MHz, CDCl3) δ 185.8, 155.2, 141.7, 140.9, 127.8, 124.6, 122.9, 120.0, 114.2, 62.3, 45.5, + + 23.4, 17.2; HRMS (ESI+) m/z calcd for C17H21NNa [M + Na] : 262.1566, found: 262.1566. 3,3-Bis[(E)-3-phenyl-2-propenyl]-2-methyl-3H-indole (15j). Synthesized by the general procedure from 2-methylindole 14a and imidate 17 [79], purified using silica gel chromatography (100% DCM). 1 Yellow oil (0.055 g, 20%); TLC Rf = 0.26 (100% DCM); IR (ATR) 3024, 2919, 1576, 1447, 906, 730 cm− ; 1 H NMR (400 MHz, CDCl3) δ 7.53 (d, J = 7.6 Hz, 1H), 7.35–7.31 (m, 3H), 7.26–7.12 (m, 10H), 6.35 (d, J = 15.7 Hz, 2H), 5.60–5.52 (m, 2H), 2.89 (dd, J = 14.0, 6.7 Hz, 2H), 2.63 (dd, J = 13.9, 8.0 Hz, 2H), 2.33 13 (s, 3H); C NMR (100 MHz, CDCl3) δ 185.0, 154.8, 141.2, 136.9, 133.3, 128.5, 128.4, 128.1, 127.3, 126.1, + + 125.1, 123.7, 122.3, 120, 62.1, 39.4, 16.7; HRMS (ESI+) m/z calcd for C27H25NNa [M + Na] : 386.1879, found: 386.1878. Molecules 2019, 24, 4143 9 of 15

2-Methyl-3,3-di(prop-2-yn-1-yl)-3H-indole (15k). Synthesized by the general procedure from 2-methylindole 14a and imidate 18 [70], purified using silica gel chromatography (3% EA/97% DCM). Yellow oil (0.06 g, 24%); TLC Rf = 0.55 (10% EA/90% DCM); IR (ATR) 3285, 2924, 2119, 1579, 1468, 770, 1 1 624 cm− ; H NMR (400 MHz, CDCl3) δ 7.53 (t, J = 7.7 Hz, 2H), 7.36 (dt, J = 7.6, 1.2 Hz, 1H), 7.22 (t, J = 7.4 Hz, 1H), 2.76 (dd, J = 16.7, 2.6 Hz, 2H), 2.60 (dd, J = 16.8, 2.6 Hz, 2H), 2.37 (s, 3H), 1.98 (t, J = 2.6 Hz, 13 2H); C NMR (100 MHz, CDCl3) δ 183.1, 154.4, 140.0, 128.7, 125.4, 122.4, 120.0, 78.6, 71.5, 57.6, 24.4, + + 16.7; HRMS (ESI+) m/z calcd for C15H13NNa [M + Na] : 230.0940, found: 230.0939. 3,3-Dibenzyl-2-methyl-3H-indole (15m). Synthesized by the general procedure from 2-methylindole 14a the imidate 20 [78], purified using silica gel chromatography (1% EA/99% DCM). This compound 1 has been previously reported [58]. Brown oil (0.10 g, 30%); TLC Rf = 0.49 (5% EA/95% DCM); H NMR (400 MHz, CDCl3) δ 7.18–7.14 (m, 2H), 7.06 (td, J = 7.2, 1.6 Hz, 1H), 7.02–6.95 (m, 7H), 6.68 (dd, J = 7.2, 13 1.2 Hz, 4H), 3.28 (d, J = 13.6 Hz, 2H), 2.99 (d, J = 13.6 Hz, 2H), 2.32 (s, 3H); C NMR (100 MHz, CDCl3) δ 184.1, 155.1, 140.5, 135.7, 129.4, 127.9, 127.8, 126.7, 124.4, 23.7, 119.8, 64.0, 42.3, 17.3. 3,3-Bis[(p-chlorophenyl)methyl]-2-methyl-3H-indole (15n). Synthesized by the general procedure from 2-methylindole 14a and imidate 21 [80], purified using silica gel chromatography (3% EA/97% DCM). Yellow oil (0.08 g, 18%); TLC Rf = 0.24 (30% EA/70% hexanes); IR (ATR) 3046, 2918, 2848, 1595, 1 1 1491, 1013, 837 cm− ; H NMR (300 MHz, CDCl3) δ 7.32–7.17 (m, 3H), 7.11 (d, J = 6.9 Hz, 1H), 7.02 (d, J = 8.4 Hz, 4H), 6.66 (d, J = 8.4 Hz, 4H), 3.32 (d, J = 13.7 Hz, 2H), 3.04 (d, J = 13.6 Hz, 2H), 2.42 (s, 3H); 13 C NMR (100 MHz, CDCl3) δ 183.3, 155.1, 139.8, 133.9, 132.7, 130.5, 128.3, 128.0, 124.6, 123.3, 120.2, + + 63.8, 41.5, 17.3; HRMS (ESI+) m/z calcd for C23H19Cl2NNa [M + Na] : 402.0787, found: 402.0785. 2-Methyl-3,3-bis{[p-(trifluoromethyl)phenyl]methyl}-3H-indole (15o). Synthesized by the general procedure from the known indole 14a and imidate 22 [66], purified using silica gel chromatography (2% EA/98% DCM). Yellow oil (0.23 g, 45%); TLC Rf = 0.51 (5% EA/95% DCM); IR (ATR) 3049, 2924, 1 1 1919, 1726, 1616, 1319, 1100 cm− ; H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.4 Hz, 4H), 7.26–7.19 (m, 3H), 7.15 (d, J = 7.2 Hz, 1H), 6.84 (d, J = 8.0 Hz, 4H), 3.42 (d, J = 13.6 Hz, 2H), 3.15 (d, J = 13.6 Hz, 13 2H), 2.40 (s, 3H); C NMR (100 MHz, CDCl3) δ 182.8, 154.9, 139.4, 129.5, 129.4 (q, J = 32.3 Hz), 128.6, 124.8 (q, J = 3.7 Hz), 124.0 (q, J = 270.3 Hz), 123.2, 120.3, 63.6, 42.0, 17.2; HRMS (ESI+) m/z calcd for + + C25H19F6NNa [M + Na] : 470.1314, found: 470.1311. 2-Methyl-3,3-bis[(p-nitrophenyl)methyl]-3H-indole (15p). Synthesized by general procedure from 2-methylindole 14a and imidate 23 [81], purified using silica gel chromatography (50% EA/50% hexanes). Yellow oil (0.29 g, 63%); TLC Rf = 0.50 (10% EA/90% DCM); IR (ATR) 3076, 1728, 1577, 1451, 1 1 920, 825 cm− ; H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.8 Hz, 4H), 7.31–7.20 (m, 4H), 6.88 (d, J = 13 8.4 Hz, 4H), 3.48 (d, J = 13.6 Hz, 2H), 3.26 (d, J = 13.6 Hz, 2H), 2.44 (s, 3H); C NMR (100 MHz, CDCl3) δ 182.0, 154.9, 147.0, 142.6, 138.7, 129.9, 129.0, 125.3, 123.1, 123.0, 120.6, 63.6, 41.9, 17.2; HRMS (ESI+) + m/z calcd for C23H19N3O4 [M + H] : 402.1448, found: 402.1451.

3.4. Elaboration of the 3,30-Disubstituted Indolenines 2’-Methylspiro[3-cyclopentene-1,3’-indole] (24). The diallyl indoline 15a (0.236 mmol, 50 mg) was dissolved in 2 mL of DCM. In a round bottom flask, Grubbs II catalyst (0.024 mmol, 21 mg) was taken in DCM (4 mL) and flushed with argon. The indoline in DCM was then added dropwise to the flask and stirred for 6 h at rt. Evaporated the solvent, purified using silica gel chromatography (5% EA/95% DCM). This compound has been previously prepared [7]. Yellow oil (21 mg, 46%); TLC Rf = 0.43 1 (10% EA/90% DCM); H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.29 (dt, J = 7.6, 0.8 Hz, 1H), 7.18 (t, J = 7.6 Hz, 1H), 5.92 (s, 2H), 2.68 (s, 4H), 2.27 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 186.9, 153.7, 146.4, 129.8, 127.6, 125.5. 121.0, 119.5, 61.4, 41.4, 15.6. 3,3-Diallyl-2-methylindoline (25). The diallyl indoline 15a (2.37 mmol, 0.50 g) was dissolved in 10 mL THF and cooled to 0 ◦C using an ice bath. LiAlH4 solution (1 M in THF, 8.3 mmol, 8.3 mL) was then slowly added. After 5 min the reaction mixture was allowed to warm to room temperature. After 30 min the reaction mixture was recooled to 0 ◦C and quenched by dropwise addition of 15 mL solution of saturated aqueous Rochelle’s salt (potassium sodium tartrate). The reaction was poured Molecules 2019, 24, 4143 10 of 15 into another 15 mL solution of saturated aqueous Rochelle’s salt and extracted to with EA (3 20 mL). × The organic layers were combined and washed with saturated aqueous sodium chloride (50 mL), dried over sodium sulfate, filtered and concentrated. Purification using silica gel chromatography (60% DCM/40% hexanes) provided indoline 25. Colorless oil (0.35 g, 70%); TLC Rf = 0.42 (60% DCM/40% 1 1 hexanes); IR (ATR) 3365, 3072, 2975, 2904, 1637, 1607, 1482, 912 cm− ; H NMR (400 MHz, CDCl3) δ 7.04 (dt, J = 7.6, 1.2 Hz, 1H), 6.99 (d, J = 7.4 Hz, 1H), 6.74 (dt, J = 7.4, 0.8 Hz, 1H), 6.65 (d, J = 7.8 Hz, 1H), 5.80–5.68 (m, 2H), 5.06–4.97 (m, 4H), 3.78 (q, J = 6.6 Hz, 1H), 2.53 (dd, J = 14.2, 6.6 Hz, 1H), 2.39 (dd, J = 14.0, 7.9 Hz, 2H), 2.16 (dd, J = 13.8, 7.8 Hz, 1H), 1.24 (d, J = 6.6 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 149.5, 134.92, 134.91, 134.6, 127.5, 124.4, 118.6, 117.7, 117.5, 109.7, 62.5, 49.3, 40.5, 37.5, 15.3. + + HRMS (ESI+) calcd for C15H19NH [M + H] : 214.1590, found: 214.1594. 3,3-Diallyl-2-methyl-1-(p-tolylsulfonyl)indoline (26). The diallyl indole 25 (5.02 mmol, 1.07 g) was dissolved in 20 mL of DCM and p-toluene sulfonyl chloride (8.78 mmol, 1.67 g) was added followed by triethylamine (10.97 mmol, 1.52 mL). After 16 h the reaction was quenched with 1M aq. HCl (50 mL) and extracted with DCM (3 50 mL). The combined organic extracts were washed with sat. aq. NaCl × (50 mL), dried over Na2SO4, filtered and concentrated. Purification using silica gel chromatography (70% DCM/30% hexanes) provided sulfonamide 26. Colorless oil (1.49 g, 81%); TLC Rf = 0.48 (80% 1 1 DCM/20% hexanes); IR (ATR) 3073, 2979, 1637, 1457,1351, 1163, 915 cm− ; H NMR (300 MHz, CDCl3) δ 7.70–7.67 (m, 3H), 7.25–7.19 (m, 3H), 6.98–6.96 (m, 2H), 5.80–5.66 (m, 1H), 5.41–5.27 (m, 1H), 5.11 (s, 1H), 5.07 (d, J = 7.6 Hz, 1H), 4.83 (d, J = 13.6 Hz, 1H), 4.59 (d, J = 16.8 Hz, 1H), 3.99 (q, J = 6.6 Hz, 1H), 2.49 (dd, J = 14.9, 7.7 Hz, 1H), 2.35 (s, 3H), 2.30 (dd, J = 14.8, 6.3 Hz, 1H), 1.92 (dd, J = 13.9, 13 7.2 Hz, 1H) 1.46–1.39 (m, 4H); C NMR (100 MHz, CDCl3) δ 143.9, 140.2, 136.5, 135.6, 133.9, 132.7, 129.5, 128.2, 127.0, 124.6, 123.2, 118.7, 118.6, 115.5, 67.4, 49.6, 42.8, 36.3, 21.5, 17.5. HRMS (ESI+) calcd + + for C22H25NO2SNa [M + Na] : 390.1498, found: 390.1495. 1’-Benzyl-2-methyl-1-(p-tolylsulfonyl)spiro[indoline-3,4’-piperidine] (27). The diallyl indole 26 (0.517 mmol, 0.190 g) was dissolved in 5 mL DCM and cooled to 100 C (dry ice/ethyl ether bath). Ozone − ◦ was then bubbled through the solution for about 2 min until the color changed to blue. The reaction mixture was then purged with argon until the blur color dissipated. 1,3-Bis(diphenylphosphino)propane (0.517 mmol, 0.213 g) was then added and reaction mixture was allowed to warm to room temp. The reaction mixture was then stirred for 1.5 h and then the solvent was evaporated. The resulting residue was purified by silica gel chromatography (75%EA/25%DCM) to provide the corresponding crude dialdehyde. The dialdehyde was dissolved in DCE (5.3 mL) and benzylamine (0.269 mmol, 0.029 mL) was added. After 5 min, sodium triacetoxyborohydride (1.07 mmol, 0.227 g) was added. After 16 h, the reaction was quenched with addition of water (5 mL) and extracted with DCM (3 10 mL). × The combined organic extracts were washed with sat. aq. NaCl (20 mL), dried over sodium sulfate and concentrated. Purification of the residue using silica gel chromatography (20% EA/80% DCM) provided piperidine 27.Off-white powder (0.08 g, 35% over 2 steps); TLC Rf = 0.47 (80% DCM/20%EA); 1 1 IR (ATR) 2927, 2802, 2757, 2359, 2341, 1598, 1493, 1348, 1132 cm− ; H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H), 7.33–7.28 (m, 5H), 7.23–7.17 (m, 3H), 7.06–6.99 (m, 2H), 4.30 (q, J = 6.6 Hz, 1H), 3.51–3.43 (m, 2H), 2.88 (d, J = 9.1 Hz, 1H), 2.44 (d, J = 11.7 Hz, 1H), 2.32 (s, 3H), 2.07–1.94 (m, 3H), 1.76 (d, J = 11.8 Hz, 1H), 1.34 (d, J = 6.6 Hz, 3H), 1.14 (t, J = 11.1 Hz, 1H), 0.28 (d, J = 13 13.2 Hz, 1H); C NMR (100 MHz, CDCl3) δ 143.8, 139.3, 136.3, 129.6, 129.1, 128.3, 128.2, 127.1, 126.6, + 124.0, 123.0, 115.7, 64.5, 63.4, 51.4, 50.1, 45.7, 38.6, 28.9, 21.5, 17.6; HRMS (ESI+) calcd for C27H31N2O2S [M + H]+: 447.2101. Found: 447.2108.

4. Conclusions A new method for the synthesis of 3,3-dialkyl indolenines has been developed utilizing the Lewis acid promoted alkylation of indoles with trichloroacetimidates. This method is differentiated from past methods in that it does not depend on transition metal mediated alkylation or the use of strong base, instead a Lewis acid and a trichloroacetimidate leaving group are utilized to perform the alkylation. Notably even electron poor indoles undergo the dialkylation, which are difficult substrates for other Molecules 2019, 24, 4143 11 of 15 alkylation reactions. The indolenines generated from this reaction provide ready access to spirocyclic structures which are useful platforms for the development of three dimensional architectures that may interact with more complex biological receptors of interest to the medicinal chemistry community.

Supplementary Materials: Copies of 1H and 13C spectra are available at http://www.mdpi.com/1420-3049/24/22/ 4143/s1. Author Contributions: Conceptualization, J.D.C., T.S., N.A.M. and A.A.A.; investigation, T.S., N.A.M., and A.A.A.; formal analysis, J.D.C., T.S. and N.A.M.; writing—original draft preparation, J.D.C., T.S. and N.A.M.; writing—review and editing, J.D.C., T.S. and N.A.M.; supervision, J.D.C. Funding: Acknowledgement is also made to the Donors of the American Chemical Society Petroleum Research Fund for a New Directions award in support of this research (54823-ND1). The National Institute of General Medical Sciences (R15-GM116054) also provided partial financial support. Conflicts of Interest: The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Sample Availability: Samples of the compounds are not available from the authors.

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