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