Enantioselective Catalytic Synthesis of N-Alkylated Indoles

S S symmetry

Review

EnantioselectiveReview Catalytic Synthesis ofEnantioselectiveN-alkylated Indoles Catalytic Synthesis of

DmitriN-alkylated Trubitsõn and Indoles Tõnis Kanger *

DepartmentDmitri Trubitsõn of Chemistry and Tõnis and Biotechnology, Kanger * School of Science, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia; [email protected] * Correspondence:Department of Chemistry [email protected]; and Biotechnology, Tel.: School+372-620-4371 of Science, Tallinn University of Technology, Akadeemia tee 15, 12618 Tallinn, Estonia; [email protected] Received:* Correspondence: 25 June 2020; [email protected]; Accepted: 14 July 2020; Tel.: Published: +372-620-4371 17 July 2020 Received: 25 June 2020; Accepted: 14 July 2020; Published: date Abstract: During the past two decades, the interest in new methodologies for the synthesis of chiralAbstract:N-functionalized During the past indoles two decades, has grown the interest rapidly. in The new review methodologies illustrates for etheﬃcient synthesis applications of chiral of organocatalyticN-functionalized and indoles organometallic has grown strategies rapidly. for The the review construction illustrates of chiral efficientα-N -branchedapplications indoles. of Bothorganocatalytic the direct functionalization and organometallic of strate the indolegies for core the construction and indirect of methods chiral α- basedN-branched on asymmetric indoles. N-alkylationBoth the direct of indolines, functionalization isatins and of the 4,7-dihydroindoles indole core and indirect are discussed. methods based on asymmetric N- alkylation of indolines, isatins and 4,7-dihydroindoles are discussed. Keywords: indole; asymmetric synthesis; organocatalysis; transition-metal catalysis; C-N bond formation;Keywords: enantioselective; indole; asymmetric heterocycles synthesis; organocatalysis; transition-metal catalysis; C-N bond formation; enantioselective; heterocycles

1. Introduction 1. Introduction Heterocyclic compounds are of great interest in medicinal chemistry. According to the U.S. Food Heterocyclic compounds are of great interest in medicinal chemistry. According to the U.S. Food and Drug Administration database, approximately 60% of unique small-molecule drugs contain a and Drug Administration database, approximately 60% of unique small-molecule drugs contain a nitrogen heterocyclic motif [1]. The indole core is the most common nitrogen-based heterocyclic nitrogen heterocyclic motif [1]. The indole core is the most common nitrogen-based heterocyclic fragment applied for the synthesis of pharmaceutical compounds and agrochemicals [2]. The indole fragment applied for the synthesis of pharmaceutical compounds and agrochemicals [2]. The indole moietymoiety can can be foundbe found in ain wide a wide range range of natural of natural products products [3]. Therefore,[3]. Therefore, some some biologically biologically active active indoles containindoles a substitutedcontain a substitutedα-chiral carbonα-chiral center carbon on center the N on1-position the N1-position (Figure (Figure1)[4–7]. 1) [4–7].

H H N O N O O

NH Cl H N 2 Cl N N N N N N Cl N O O OH OH HO O O O O HO OH O O OH N O O HO

Vincamine Staurospporine K-252a α-Neosidomycin β-Ribofuranosyl indole (peripheral vasodilator) (kinase inhibitor) (kinase inhibitor) (antibacterial) (antiviral)

MeO

HO Me N HO O N N NHMe Me Me OH N N O O N EtO2SN F MeHN

CPI-169 (+)-WIN 55,212-2 Human norepinephrine Serotonin (EZH2 inhibitor) (cannabinoid agonist) reuptake inhibitor reuptake inhibitor FigureFigure 1. 1. BiologicallyBiologically active active chiral α--NN-branched-branched indoles. indoles.

Symmetry 2020, 12, x; doi: FOR PEER REVIEW www.mdpi.com/journal/symmetry Symmetry 2020, 12, 1184; doi:10.3390/sym12071184 www.mdpi.com/journal/symmetry Symmetry 2020, 12, 1184 2 of 30 SymmetrySymmetry 2020 2020, ,12 12, ,x x FOR FOR PEER PEER REVIEW REVIEW 22 of of 29 29

TheThe synthesis synthesis of ofof enantioenriched enantioenriched indole indole derivatives derivatives isis ofof greatgreat importanceimportance inin organicorganic organic chemistry.chemistry. chemistry. DuringDuring the the past past two two decades, decades, different didifferentfferent strategies strategies ha havehaveve been been proposed proposed for for the the constructionconstruction of of chiral chiral indoleindoleindole derivatives derivativesderivatives [8–11]. [[8–11].8–11]. TheThe most most typical typical synthetic synthetic modifications modificationsmodifications of of indoles indoles take take place placeplace at atat the thethe C3 C3 positionposition (Scheme(Scheme 1 1).1).). TheTheThe enantioselectiveenantioselectiveenantioselective electrophilicelectrophilielectrophilicc substitutionsubstitutionsubstitution atatat C3C3C3 is isis common commoncommon due duedue to toto the thethe high highhigh 13 nucleophilicitynucleophilicity ofof thisthis position,position, whichwhich isis 10101313 timestimestimes more moremore reactive reactivereactive than than benzene benzene [12,13].[[12,13].12,13]. In InIn contrast contrastcontrast to to enantioselectiveenantioselective C3C3 transfortransformations,transformations,mations, thethe stereoselectivestereoselective NN-alkylation-alkylation ofof indole indole is is still stillstill a aa challenge challengechallenge due duedue tototo the the weak weak nucleophilicity nucleophilicity of of the the nitrogen nitrogen atomatom (Scheme(Scheme 1 1).1).). Despite DespiteDespite this, this,this, a aa number numbernumber of ofof publications publicationspublications havehave been been published published recently recently that that demonstr demonstratedemonstrateate new new synthetic synthetic routes routes affordingaaffordingffording chiralchiral NN-substituted-substituted indoleindoleindole derivatives. derivatives.derivatives. In InIn this this review, review, we wewe will willwill introduce introduceintroduce and andand discuss discussdiscuss methodologies methodologiesmethodologies that thatthat provide provideprovide catalytic catalyticcatalytic stereoselectivestereoselective derivatizationderivatization atat thethe NN-atom-atom ofof indole.indole.

SchemeScheme 1. 1. Regioselectivity Regioselectivity of of the the asymmetric asymmetric functionalization functionalizationfunctionalization of of indoles. indoles.

OnOn a aa structural structural basis, basis,basis, the thethe strategies strategies for forfor the the construction construction of ofof α α---NN-branched-branched-branched indoles indolesindoles can cancan be bebe classified classifiedclassified intointointo two two groups:groups: “direct “direct“direct methods” methods”methods” and andand “indirect “indirect me methods”methods”thods” (Scheme (Scheme 2 2).2).). InInIn thethethe former formerformer case, case,case, indole indoleindole derivativesderivatives are are transformed transformed by by transition-metal transition-metal cata catalysiscatalysislysis or or by byby organocatalysis organocatalysis into intointo chiral chiral compounds compounds (Scheme(Scheme2 2,,2,I ).II).). If IfIf the thethe structure structurestructure of theofof the startingthe startingstarting compound compoucompou doesndnd notdoesdoes contain notnot containcontain an indole anan moiety,indoleindole themoiety,moiety, methods thethe methodsaremethods defined areare as defineddefined indirect asas methods indirectindirect (Scheme methodsmethods2, (SchemeII(Scheme). The indirect2,2, IIII).). TheThe methods indirectindirect are methodsmethods subdivided areare according subdividedsubdivided to accordingtheaccording structure toto thethe of the structurestructure starting ofof compound thethe startingstarting and compcomp theoundound modifications andand thethe modificationsmodifications occurring during occurringoccurring the synthesis duringduring thethe of synthesisαsynthesis-N-branched of of α α--NN indoles-branched-branched (Scheme indoles indoles2, (Scheme (SchemeII). There 2, 2, areIIII).). There severalThere are are ways several several to prepareways ways to to Nprepare prepare-functionalized N N-functionalized-functionalized indoles indolesindirectly.indoles indirectly.indirectly. This review ThisThis covers reviewreview the covers asymmetriccovers thethe asymmetricasymmetricN-alkylation NN of-alkylation-alkylation indolines, isatinsofof indolines,indolines, and 4,7-dihydroindoles, isatinsisatins andand 4,7-4,7- dihydroindoles,followeddihydroindoles, by a redox followed followed reaction, by by a a whichredox redox reaction, providesreaction, which which the corresponding provides provides the the corresponding Ncorresponding-alkylated indoles N N-alkylated-alkylated (Scheme indoles indoles2, III, (SchemeIV(Schemeand V 2,2,respectively). IIIIII,, IVIV andand VV respectively).respectively).

SchemeScheme 2. 2. Strategies Strategies for forfor the thethe enantioselective enantioselectiveenantioselective N NN-functionalization-functionalization-functionalization of ofof indoles. indoles.indoles. 2. Direct Organocatalytic Methods 2.2. DirectDirect OrganocatalyticOrganocatalytic MethodsMethods During the past two decades, organocatalysis has become a powerful methodology in DuringDuring thethe pastpast twotwo decades,decades, organocatalyorganocatalysissis hashas becomebecome aa powerfulpowerful methodologymethodology inin enantioselective synthesis [14–17]. In the ﬁrst part of this review, the direct methods of the stereoselective enantioselectiveenantioselective synthesissynthesis [14–17].[14–17]. InIn thethe firstfirst partpart ofof thisthis review,review, thethe directdirect methodsmethods ofof thethe N-alkylation of indoles based on organocatalysis are discussed. Various electrophiles and diﬀerent stereoselectivestereoselective NN-alkylation-alkylation ofof indolesindoles basedbased onon organocatalysisorganocatalysis areare discussed.discussed. VariousVarious electrophileselectrophiles types of organocatalysts have been used to achieve targets with high enantiomeric purities (Scheme3). andand differentdifferent typestypes ofof organocatalystsorganocatalysts havehave beenbeen usedused toto achieveachieve targetstargets withwith highhigh enantiomericenantiomeric puritiespurities (Scheme(Scheme 3).3).

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Scheme 3. Direct organocatalytic derivatization of indole. 2.1. N-Allylations with Morita-Baylis-HillmanScheme 3. Direct organocatalytic Adducts derivatization of indole. 2.1. N-Allylations with Morita-Baylis-Hillman Adducts Chen and co-workers proposed applying Morita-Baylis-Hillman (MBH) tert-butoxy carbonates Chen2.1. N-Allylations and co-workers with Morita-Baylis-Hillman proposed applying Adducts Morita-Baylis-Hillman (MBH) tert-butoxy carbonates 1 as electrophiles in a reaction with indole derivatives 2 (Scheme4, I)[18]. The activation of MBH 1 as electrophilesChen and in co-workers a reaction proposed with indole applying derivatives Morita-Baylis-Hillman 2 (Scheme 4, (MBH) I) [18]. tert The-butoxy activation carbonates of MBH adducts with a chiral tertiary amine generates in situ tert-butoxy anion which is responsible for the adducts1 as with electrophiles a chiral intertiary a reaction amine with generates indole derivatives in situ tert 2 (Scheme-butoxy 4,anion I) [18]. which The activationis responsible of MBH for the deprotonation of the indole at the N-position. The screening of the reaction revealed that the reaction deprotonationadducts with of thea chiral indole tertiary at the amine N-position. generates The in screeningsitu tert-butoxy of the anion reaction which revealed is responsible that the for reactionthe could be smoothly catalyzed by cinchona alkaloid derived ether 4 (Figure2) in mesitylene. The substrate coulddeprotonation be smoothly of catalyzed the indole atby the ci Nnchona-position. alkaloid The screening derived of theether reaction 4 (Figure revealed 2) thatin mesitylene. the reaction The scopecould was performedbe smoothly with catalyzed either by electron-rich cinchona alkaloid or electron-deﬁcient derived ether 4indoles, (Figure providing2) in mesitylene. products The with substrate scope was performed with either electron-rich or electron-deficient indoles, providing moderatesubstrate to excellent scope was enantiomeric performed with excesses either (62–93%). electron-rich Moreover, or electron-deficient the methyl pyrrole-2-carboxylateindoles, providing products with moderate to excellent enantiomeric excesses (62–93%). Moreover, the methyl pyrrole- was examinedproducts with as amoderate nucleophile, to excellent providing enantiomeric the N-substituted excesses (62–93%). product Moreover, with a the good methyl yield pyrrole- (80%) and 2-carboxylate was examined as a nucleophile, providing the N-substituted product with a good yield moderate2-carboxylateee (73%). was The examined C2- and as C7-brominated a nucleophile, providingN-allylated the indoles N-substituted can be product further with converted a good into yield fused, (80%)(80%) and andmoderate moderate ee ee(73%) (73%). The. The C2- C2- andand C7-brominatedC7-brominated N N-allylated-allylated indoles indoles can canbe furtherbe further cyclic indole systems (Scheme4, II). convertedconverted into intofused, fused, cyclic cyclic indole indole systems systems (Scheme (Scheme 4, IIII).).

SchemeScheme 4. The 4. The reaction reaction of of indole indole derivatives derivatives and Morita–Baylis–Hillman (MBH) (MBH) carbonates. carbonates.

Scheme 4. The reaction of indole derivatives and Morita–Baylis–Hillman (MBH) carbonates.

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Figure 2. ChiralChiral Lewis base catalysts.

Shi et al. reported reported an an effective effective method method in in which which C2-cyano-substituted C2-cyano-substituted pyrroles pyrroles and and indoles indoles 2 were2 were subjected subjected to a to reaction a reaction with with O-Boc-protected O-Boc-protected MBH MBH adducts adducts 1 in the1 in presence the presence of a catalyst of a catalyst 5 [19]. They5 [19]. obtained They obtained corresponding corresponding N-allylatedN-allylated products products 3 under3 underoptimal optimal conditions conditions with good with goodto high to yieldshigh yields (up to (up 99%) to 99%)and moderate and moderate to high to highee valuesee values (up to (up 96%). to 96%). Compared Compared with with Chen’s Chen’s work, work, the introductionthe introduction of a of cyano a cyano group group at atthe the C2-position C2-position of of pyrrole pyrrole instead instead of of a a methyl methyl carboxylate carboxylate group group had a positivepositive impactimpact on on the the reaction reaction stereoselectivty stereoselectivty (73% (73%ee vs.ee vs. 92% 92%ee) ee and) and yield yield (80% (80% vs. vs. 92%). 92%). In the In thecase case of indoles, of indoles, only only 2-cyanoindole 2-cyanoindole was was examined. examined. The Theee eess and and yields yields of of thethe reactionsreactions werewere slightly improved. It It should should be be noted noted that that Chen’s Chen’s group group applied applied indoles indoles with with both both electron-withdrawing electron-withdrawing and electron-donating groups, but Shi’s methodmethod was limited to 2-cyanoindoles. A new method for the the activation activation of of pyrroles, pyrroles, indoles indoles and and carbazoles carbazoles was was proposed proposed by by Vilotijevi Vilotijevićć et al. al. inin 2019 2019 [20]. [20 The]. Thesilyl-protected silyl-protected indole indole derivatives derivatives 6 can act6 can as latent act as nucleophiles latent nucleophiles in the presence in the ofpresence a chiral of Lewis a chiral base Lewis catalyst base catalyst4. Latent4. nucleophiles Latent nucleophiles are compounds are compounds that are that not are nucleophilic, not nucleophilic, but canbut canbe converted be converted into into strong strong nucleophiles nucleophiles when when ac activated.tivated. The The modification modification of of MBH MBH carbonates carbonates by by replacing the O-Boc group group with with a a fluoro fluoro group group affords affords a new type of fluorinated fluorinated MBH MBH adducts adducts 1a1a,, which are the source of fluoride fluoride ions needed for thethe desilylation of the indole derivative. The authors performed aa mechanistic mechanistic study study and and their their proposed proposed mechanism mechanism is outlined is outlined in Scheme in5. TheScheme elimination 5. The eliminationof fluoride ionsof fluoride occurs ions during occurs the during activation the activation of the MBH of the adduct MBH withadduct catalyst with catalyst4. At the4. At same the sametime, time, fluoride fluoride ions deprotections deprotectN-silylindole N-silylindole derivatives. derivatives. As aAs result, a result, simultaneous simultaneous activated activated pairs pairs of ofelectrophiles electrophiles/nucleophiles/nucleophiles occur occur and and the the enantioselective enantioselectiveN N-alkylation-alkylation of of anan indoleindole proceedsproceeds with excellent regioselectivity and moderate to high enan enantioselectivitytioselectivity (up to 98%) with a yield up to 98%. 98%.

Scheme 5. TheThe use use of a latent nucleophile.

2.2. N-Selective N-Selective Additions Additions to to αα-Oxoaldehydes-Oxoaldehydes The chiralchiralN ,ON-aminal,O-aminal indole indole structural structural motif canmotif be foundcan be in naturalfound productsin natural and pharmaceuticalproducts and pharmaceuticalcompounds [4,5 compounds]. Recently, [4,5]. two organocatalyticRecently, two or approachesganocatalytic to approaches the synthesis to the of N synthesis,O-aminals of N with,O- aminalsindole skeletons with indole were skeletons reported were (Scheme reported6)[ 4 ,(Schem21]. Ine both 6) [4,21]. methods, In both ethyl methods, glyoxylate ethyl derivatives glyoxylate9 derivativeswere used as 9 were electrophiles, used as electrophiles, but diﬀerent but types different of organocatalysts types of organocatalysts were used. Activation were used. with Activation both a withchiral both Lewis a chiral base Lewis and a Lewisbase and acid a Lewis was exploited acid was eexploitedﬃciently efficiently for the same for reaction the same (Scheme reaction6 ).(Scheme Based 6).on theBased achiral on the method achiral for method the preparation for the preparation of N,O-aminals of N of,O indole-aminals derivatives of indole in derivatives the presence in ofthe a presenceBrønsted of base a Brønsted (DABCO), base Qin (DABCO), elaborated Qin anelaborated asymmetric an asymmetric version of version the reaction of the [21 reaction]. The [21]. catalytic The catalytic system derived from BINOL-derived polyether 11 and potassium fluoride provides N,O- aminals with high ee (up to 91%) and with high yields (up to 90%) (Scheme 6, I). Only two examples

Symmetry 2020, 12, 1184 5 of 30 system derived from BINOL-derived polyether 11 and potassium fluoride provides N,O-aminals with high ee (up to 91%) and with high yields (up to 90%) (Scheme6, I). Only two examples of an asymmetric Symmetry 2020, 12, x FOR PEER REVIEW 5 of 29 reaction were demonstrated. The second approach illustrates the application of a SPINOL-based chiral phosphoricof an asymmetric acid 12 in reaction the N-selective were demonstrated. alkylation The of indole second derivatives approach illustrates8 (Scheme the6, applicationII)[4]. Diff oferently a substitutedSPINOL-based indole chiral derivatives phosphoric (substitution acid 12 in the at N both-selective rings) alkylation were applied of indole as derivatives nucleophiles, 8 (Scheme affording products6, II) with[4]. Differently good to excellent substituted enantiomeric indole derivatives excess (up (substitution to 99%) and at with both moderate rings) were to highapplied yields as (up to 96%).nucleophiles, The exception affording was products the product with ofgood a 7-fluorosubstituted to excellent enantiomeric indole excess obtained (up withto 99%) a 55% and yield with and 76%moderateee. The authors to high yields concluded (up to that 96%). the The decrease exception in was stereoselectivity the product of and a 7-fluorosubstituted in the yield of the indole reaction canobtained be explained with a by 55% the yield steric and hindrance 76% ee. The of authors the substituent concluded at that the the C7 decrease position. inThe stereoselectivity transition state of theand reaction in the yield is outlined of the reaction in Scheme can be6, explainedIII. The ethylby the glyoxalatesteric hindrance and theof the indole substituent are both at the activated C7 by chiralposition. phosphoric The transition acid state12 of. Thethe reaction attack is on outlined the aldehyde in Scheme from 6, III the. TheRe ethyl-face glyoxalate is favored, and the aff ordingindole an are both activated by chiral phosphoric acid 12. The attack on the aldehyde from the Re-face is favored, (R)-isomer of the product. Remarkably, BINOL-derived chiral phosphoric acid was not as efficient as affording an (R)-isomer of the product. Remarkably, BINOL-derived chiral phosphoric acid was not as SPINOL-derived and provided the product with a low level of stereocontrol (ee 5–7%). efficient as SPINOL-derived and provided the product with a low level of stereocontrol (ee 5–7%).

SchemeScheme 6. 6.Reactions Reactions ofof indoles with with glyoxylate glyoxylate derivatives. derivatives.

2.3.2.3. N-Selective N-Selective Additions Additions of of Indoles Indoles to to Imine Imine/Iminium/Iminium Activated Adducts Adducts In situ,In situ, generating generating electrophiles electrophiles such such as as imines imines or oriminium iminium ions ions can provide can provide wide access wide for access the for the construction of of chiral chiral indoles. indoles. They They not notonly only bear bearsubstituents substituents at the atC3 theposition, C3 position, but they but are theyalso are alsopowerful powerful tools tools for for the the synthesis synthesis of of NN-substituted-substituted indoles. indoles. The The activa activationtion of electrophiles of electrophiles can canbe be promoted by chiral Brønsted acids such as phosphoric acids. There are a large number of different promoted by chiral Brønsted acids such as phosphoric acids. There are a large number of different BINOL- and SPINOL-derived chiral acids and their ability to act as bifunctional catalysts provides BINOL- and SPINOL-derived chiral acids and their ability to act as bifunctional catalysts provides unique opportunities for the enantioselective functionalization of the C-N bond. unique opportunitiesThe first synthesis for theof chiral enantioselective α-N-branched functionalization indoles 15 via their ofthe addition C-N bond.to the acyliminium ion catalyzedThe first by synthesis chiral phosphoric of chiral acidα-N -branched17 was proposed indoles by 15Huangvia theiret al. addition(Scheme 7) to [22]. the Cyclic acyliminium N- ionacyliminium catalyzed by ions chiral are phosphorichighly reactive acid electrophiles17 was proposed [23]. They by are Huang easily etgenerated al. (Scheme from 7α)[,β- 22]. CyclicunsaturatedN-acyliminium γ-lactams ions (such are as highlycompound reactive 13) by electrophiles accepting an acidic [23]. prot Theyon from are easily a chiral generated phosphoric from α,β-unsaturatedacid, affording γa-lactams chiral conjugate (such base/ as compoundN-acyliminium13) ion by pair. accepting Huang an proposed acidic that proton the acidic from N-H a chiral phosphoricatom of the acid, indole affording is activated a chiral by conjugatethe conjugate base base/N -acyliminiumof chiral phosphoric ion pair. acid Huangthrough proposed the hydrogen that the acidicbond, N-H favoring atom of an the attack indole of the is nitrogen activated atom by theon the conjugate cyclic N-acyliminium base of chiral ion. phosphoric The authors acid conducted through the hydrogena series bond, of labeling favoring and FTIR an attack experiments of the nitrogen that explained atom onthe the formation cyclic N of-acyliminium the N-acyliminium ion. The ion and authors conductedthe indole a series alkylation of labeling step. andThe FTIRreaction experiments was catalyzed that explained by catalyst the 17 formation, providing of thea highN-acyliminium level of stereocontrol (ee up to 95%) and high yields of the reaction (up to 98%). The synthetic method ion and the indole alkylation step. The reaction was catalyzed by catalyst 17, providing a high level of afforded chiral indole derivatives 15 with different substituents in both ring systems. The product 15 stereocontrol1 (2ee up to 95%)3 and high yields of the reaction (up to 98%). The synthetic method afforded (R = Br, R = Me, R = H) was further converted into an N-fused polycyclic compound 16 in two1 chiraladditional indole derivatives steps. Interestingly,15 with Boc diff anderent phenyl substituents N-protected in both α,β-unsaturated ring systems. γ-lactams The product afforded15 (Ronly= Br, 2 3 R =C3Me, alkylated R = H) products was further with low converted ee values. into an N-fused polycyclic compound 16 in two additional

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steps.Symmetry Interestingly, 2020, 12, x FOR Boc PEER and REVIEW phenyl N-protected α,β-unsaturated γ-lactams aﬀorded only C3 alkylated6 of 29 products with low ee values. Symmetry 2020, 12, x FOR PEER REVIEW 6 of 29

SchemeScheme 7. 7. N N-Acyliminium-Acyliminium activated N N-alkylation-alkylation of ofindoles. indoles.

YouYou andand and co-workers co-workers co-workers later later later reported reported reported a modified aa modifiedmodified route route ofroute Huang’s of of Huang’s Huang’s enantioselective enantioselective enantioselective indole indoleN -alkylationindole N- N- withalkylationalkylationN-acyliminium with with N-acyliminium N-acyliminium ions [24]. The ions ions new [24]. [24]. method The The newnew is based method on theis is based based cascade on on the reaction, the cascade cascade involving reaction, reaction, ainvolving ring-closing involving a ring-closing metathesis catalyzed by a Ru complex and chiral SPINOL-derived phosphoric acid- metathesisa ring-closing catalyzed metathesis by acatalyzed Ru complex by a andRu complex chiral SPINOL-derived and chiral SPINOL-derived phosphoric acid-catalyzedphosphoric acid-21 catalyzed 21 indole N-alkylation (Scheme 8). The starting N-allyl-N-benzylacrylamide 18 was first indolecatalyzedN-alkylation 21 indole (SchemeN-alkylation8). The (Scheme starting 8).N The-allyl- startingN-benzylacrylamide N-allyl-N-benzylacrylamide18 was first converted 18 was intofirst α,β-unsaturatedconverted intoγ α-lactam,β-unsaturated13 by a γ Ru-lactam complex 13 by (Zhan-1B a Ru complex) followed (Zhan-1B by the) followed selective by Nthe-alkylation selective N- of the convertedalkylation into of α ,theβ-unsaturated indole in the γ -lactampresence 13 of by catalyst a Ru complex21. The authors (Zhan-1B compared) followed their by method the selective with N- indole in the presence of catalyst 21. The authors compared their method with stepwise reactions and alkylationstepwise of reactions the indole and infound the thatpresence the sequential of catalyst catalysis 21. Theallowed authors for a morecompared efficient their synthesis. method with foundstepwise that reactions the sequential and found catalysis that the allowed sequential for a more catalysis efficient allowed synthesis. for a more efficient synthesis.

MesN NMes Zhan-1B O catalyst 21 Cl MesNRu NMes R2 Cl O Zhan-1B O N Bn catalyst 21 Cl O Ru S O 3 2 1 13 R R R Cl O N Bn NMe2 N O S O 3 Bn1 13 R R Zhan-1B 2 (5 mol%) Zhan-1B 20 N NMe2 O R N (5 mol%) 21 Bn + O Zhan-1B N R3 2 R1 (5 mol%) Zhan-1B 20 N R O R toluene, 50 oC Bn N (5 mol%) 21 33-92% yield O 18 19 H O + O P N R3 R1 85-95% ee R toluene, 50 oC O OH Bn N 33-92% yield O O 18 R1 -H,Alkyl19 R2 -H,AlkylH R3 - H, Hal, MeO R 85-95% ee P O OH R - 2,4,6-(iPr) C H R1 -H,Alkyl R2 -H,Alkyl R3 - H, Hal, MeO 3 6R2 21

R - 2,4,6-(iPr)3C6H2 Scheme 8. Sequential ring-closing/N-alkylation of indoles. 21

Another example of the application of SPINOL-derived phosphoric acid in the N-alkylation of Scheme 8. Sequential ring-closing/ ring-closing/N-alkylation of indoles. indoles was demonstrated by Zeng and Zhong [25]. An enantioselective N-addition of indoles to in situAnother generated example cyclic of N the-acyl application imines from of hydroxy SPINOL-derivedSPINOL-derived isoindolinones phosphoric 23 was acidefficiently in the catalyzed NN-alkylation-alkylation by of hindered bismesityl-substituted chiral phosphoric acid 25 (Scheme 9). The reaction proceeded indoles waswas demonstrateddemonstrated by by Zeng Zeng and and Zhong Zhong [25 [25].]. An An enantioselective enantioselectiveN-addition N-addition of indoles of indoles to in to situ in smoothly with a broad range of indoles and isoindolinone alcohols affording chiral N-alkylated generatedsitu generated cyclic cyclicN-acyl N imines-acyl imines from hydroxyfrom hydroxy isoindolinones isoindolinones23 was e23ﬃ cientlywas efficiently catalyzed catalyzed by hindered by tetrasubstituted aminals 24 with moderate to good yields (up to 77%) and good to excellent bismesityl-substituted chiral phosphoric acid 25 (Scheme9). The reaction proceeded smoothly with a hinderedenantioselectivities bismesityl-substitut (up to 98%).ed chiralThe proposed phosphoric transition acid state 25 indicates(Scheme the 9). dual The activation reaction mode proceeded of broadsmoothlythe range catalyst with of indoles25 a (Schemebroad and range 9). isoindolinone of indoles alcohols and isoindolinone aﬀording chiral alcoholsN-alkylated affording tetrasubstituted chiral N-alkylated aminals 24tetrasubstitutedwith moderate aminals to good 24 yields with (up moderate to 77%) andto good good yields to excellent (up to enantioselectivities 77%) and good (upto excellent to 98%). Theenantioselectivities proposed transition (up to state 98%). indicates The proposed the dual transition activation state mode indicates of the catalyst the dual25 activation(Scheme9 ).mode of the catalyst 25 (Scheme 9).

Symmetry 12 Symmetry 2020,, 12,, 1184x FOR PEER REVIEW 7 of 29 30 Symmetry 2020, 12, x FOR PEER REVIEW 7 of 29

Scheme 9. Enantioselective addition of indoles to N-acyl imines. Scheme 9. Enantioselective addition of indoles to N-acyl imines. A new class of in situ activated electrophiles for the enantioselective N-alkylation of indoles from A new class of in in situ situ activated activated electrophiles electrophiles for the enantioselective enantioselective N-N-alkylationalkylation of indoles from the N-protected p-aminobenzylic alcohol 26 was reported by Sun [26]. These alcohols were easily the N-protected p-aminobenzylic alcohol 26 was reported by Sun [[26].26]. These alcohols were easily converted to aza-p-quinone methides 26a in the presence of the chiral phosphoric acid 29 and used converted toto aza-aza-pp--quinonequinone methidesmethides26a 26ain in the the presence presence of of the the chiral chiral phosphoric phosphoric acid acid29 29and and used used as as alkylating reagents in reactions with 2,3-disubstituted indoles 27 (Scheme 10). The protective alkylatingas alkylating reagents reagents in reactionsin reactions with with 2,3-disubstituted 2,3-disubstituted indoles indoles27 (Scheme 27 (Scheme 10). The 10). protective The protective group group on the nitrogen atom of the electrophile drastically affects the stereoselectivity of the reaction. ongroup the on nitrogen the nitrogen atom of atom the electrophileof the electrophile drastically drastically affects affects the stereoselectivity the stereoselectivity of the reaction.of the reaction. In the In the case of bulky aliphatic acyl groups, such as pivaloyl and 1-adamantanecarbonyl groups, caseIn the of case bulky of aliphatic bulky aliphatic acyl groups, acyl suchgroups, as pivaloylsuch as andpivaloyl 1-adamantanecarbonyl and 1-adamantanecarbonyl groups, excellent groups, excellent enantioselectivities were achieved (ee up to 95%). Other protective groups afforded products enantioselectivitiesexcellent enantioselectivities were achieved were achieved (ee up to (ee 95%). up to Other 95%). protectiveOther protective groups groups afforded afforded products products with with moderate ee values. It is important to mention that C3 unsubstituted indoles gave an exclusive moderatewith moderateee values. ee values. It is important It is important to mention to mention that C3 that unsubstituted C3 unsubstituted indoles indoles gave an gave exclusive an exclusive reaction reaction at the C3 position with good ee (74%). The slight modification of the reaction conditions atreaction the C3 at position the C3 with position good withee (74%). good The ee slight(74%). modification The slight modification of the reaction of conditionsthe reaction improved conditions the improved the enantioselectivity of the reaction and chiral C3 alkylated indoles were obtained with enantioselectivityimproved the enantioselectivity of the reaction of and the chiral reaction C3 alkylated and chiral indoles C3 alkylated were obtained indoles withwere excellent obtained yields with excellent yields (up to 99%) and high ees (up to 94%). The control experiments proved that the reaction (upexcellent to 99%) yields and (up high toee 99%)s (up and to 94%).high ee Thes (up control to 94%). experiments The control proved experiments that the proved reaction that proceeds the reaction due proceeds due to the generation of an aza-p-QM intermediate 26a and, without a nucleophile, the toproceeds the generation due to the of angeneration aza-p-QM of intermediate an aza-p-QM26a intermediateand, without 26a a nucleophile,and, without the a nucleophile, dimerization the of dimerization of the aza-p-QM intermediate occurred. The authors proposed a transition state that thedimerization aza-p-QM of intermediate the aza-p-QM occurred. intermediate The authors occurred. proposed The authors a transition proposed state thata transition demonstrates state that the demonstrates the bifunctional role of the chiral phosphoric acid in the activation of both an bifunctionaldemonstrates role the of thebifunctional chiral phosphoric role of acidthe inchiral the activation phosphoric of both acid an in electrophile the activation and a nucleophile.of both an electrophile and a nucleophile. electrophile and a nucleophile.

Scheme 10. Enantioselective N-alkylation-alkylation of indoles with para-aza-quinone methides. Scheme 10. Enantioselective N-alkylation of indoles with para-aza-quinone methides. Recently, anan asymmetricasymmetricN N-alkylation-alkylation of of indole indole derivatives derivatives via via a Reissert-typea Reissert-type reaction reaction catalyzed catalyzed by Recently, an asymmetric N-alkylation of indole derivatives via a Reissert-type reaction catalyzed aby chiral a chiral phosphoric phosphoric acid 34 acidwas reported34 was byreported You’sgroup by You´s [27]. Thegroup authors [27]. expected The authors the dearomatization expected the by a chiral phosphoric acid 34 was reported by You´s group [27]. The authors expected the ofdearomatization both reagents, of but both the reagents, reaction proceededbut the reaction in another proceeded manner, in another providing manner, the N-alkylated providing adductthe N- dearomatization of both reagents, but the reaction proceeded in another manner, providing the N- 32alkylated(Scheme adduct 11). The32 (Scheme method 11). tolerates The method various tolerates protective variou groupss protective on the aminegroups of on tryptamine the amine 31of, alkylated adduct 32 (Scheme 11). The method tolerates various protective groups on the amine of atryptamineffording products 31, affording with good products yields (72–98%) with andgood moderate yields to(72–98%) good enantioselectivities and moderate ( eeto64–82%). good tryptamine 31, affording products with good yields (72–98%) and moderate to good Substituentsenantioselectivities in the phenyl(ee 64–82%). ringof Substituents the tryptamine in the31 phenyldid not ring have of a the negative tryptamine impact 31 on did the notee havevalues a enantioselectivities (ee 64–82%). Substituents in the phenyl ring of the tryptamine 31 did not have a (63–73%)negative impact or yield on (78–89%) the ee values of the (63–73%) reaction. or Variousyield (78–89%) substituents of the onreaction. the isoquinoline Various substituents core 30 were on testedthenegative isoquinoline and impact their on influencecore the 30 ee valueswere on thetested (63–73%) reaction and or their was yield studied.influence (78–89%) Stericallyon of the reaction.reaction hindered Variouswas isoquinolines studied. substituents Sterically (7- on or the isoquinoline core 30 were tested and their influence on the reaction was studied. Sterically 8-substitutedhindered isoquinolines isoquinolines) (7- or aff orded8-substituted lower yields isoquinolines) (10–40%) andaffordedee values lower (29–50% yieldsee ).(10–40%) Substituents and atee hindered isoquinolines (7- or 8-substituted isoquinolines) afforded lower yields (10–40%) and ee othervalues positions (29–50% were ee). Substituents tolerated, leading at other to N positions-alkylated were products tolerated, with goodleading to excellentto N-alkylated yields products (80–98%) values (29–50% ee). Substituents at other positions were tolerated, leading to N-alkylated products andwith enantioselectivities good to excellent yields (80–94%). (80–98%) It is notable and enantioselectivities that the indole ring (80–94%). bearing It a 3-methylis notable substituent that the indole was with good to excellent yields (80–98%) and enantioselectivities (80–94%). It is notable that the indole alsoring tolerated,bearing a a3-methylffording substituenN-alkylatedt was product also tolerated, with excellent affording yield N (98%)-alkylated and high productee (85%). with The excellent chiral ring bearing a 3-methyl substituen1 2 t was also tolerated, affording N-alkylated product with excellent Nyield-alkylated (98%) and product high32 ee (R(85%).= R The= H)chiral was N easily-alkylated modified product by the 32 reduction(R1 = R2 = H) in 1,2-dihydroisoquinolinewas easily modified by yield (98%) and high ee (85%). The chiral N-alkylated product 32 (R1 = R2 = H) was easily modified by moietythe reduction and the in deprotection 1,2-dihydroisoquinoline of the Boc group, moiety leading and the to free deprotection amine 33. of the Boc group, leading to freethe reductionamine 33. in 1,2-dihydroisoquinoline moiety and the deprotection of the Boc group, leading to free amine 33.

Symmetry 2020, 12, 1184 8 of 30

Symmetry 2020, 12, x FOR PEER REVIEW 8 of 29

SchemeScheme 11. 11.Enantioselective EnantioselectiveN N-alkylation-alkylation of indoles via via Reissert-type Reissert-type reaction. reaction.

2.4. Aza-Michael2.4. Aza-Michael AdditionsScheme Additions 11. Enantioselective N-alkylation of indoles via Reissert-type reaction.

2.4.The Aza-MichaelThe application application Additions of eofﬃ efficientcient organocatalytic organocatalytic strategiesstrategies for for the the synthesis synthesis of of chiral chiral α-Nα-branched-N-branched indolesindoles is limited is limited by by the the low low acidity acidity of of the the N-H N-H atomatom andand low low nucleophilicity nucleophilicity of ofthe the nitrogen nitrogen of the of the The application of efficient organocatalytic strategies for the synthesis of chiral α-N-branched indole.indole. Electron-withdrawing Electron-withdrawing groups groups at C2 C2 or or C3 C3 positions positions increase increase the theacidity acidity of the of N-H the atom N-H of atom indoles is limited by the low acidity of the N-H atom and low nucleophilicity of the nitrogen of the of thethe indole indole [ 28[28],], thusthus improvingimproving its reactivity. Another Another way way to toactivate activate the the nitrogen nitrogen atom atom is the is the indole.introduction Electron-withdrawing of an electron-donating groups group at C2 ator theC3 C3positions position, increase which theincreases acidity the of nucleophilicitythe N-H atom ofof introduction of an electron-donating group at the C3 position, which increases the nucleophilicity thethe indoleindole. [28],Sometimes, thus improving the functionalization its reactivity. at Another the C2 andway C3 to positionsactivate theof thenitrogen indole atomare used is the to of the indole. Sometimes, the functionalization at the C2 and C3 positions of the indole are used to introductionprevent side ofreactions. an electron-donating group at the C3 position, which increases the nucleophilicity of prevent side reactions. the indole.The enantioselective Sometimes, the intramolecularfunctionalization ring-c at thelosing C2 andreaction C3 positions of 2-substituted of the indole indoles are 35used with to preventincreasedThe enantioselective side acidity reactions. under intramolecular phase transfer ring-closing catalysis was reaction reported of 2-substitutedby Bandini and indoles Umani-Ronchi35 with increased et al. acidity(Scheme underThe 12,enantioselective phase I) [29,30]. transfer The catalysisintramolecular authors wasemphasized reportedring-closing the by import Bandinireactionance andof of 2-substituted Umani-Ronchithe tight ion indolespair et al.that (Scheme35 occurs with 12, I)[29increasedbetween,30]. The the acidity authorscinchona-based under emphasized phase salt transfer of the the quinuclidinecatalysis importance was ringreported of theand tightthe by nucleophilicBandini ion pair and that indolate Umani-Ronchi occurs intermediate between et al. the cinchona-based(Scheme(Scheme 12,12, I saltII) ).[29,30]. The of the stereocontrol The quinuclidine authors ofemphasized ringthe reaction and thethe wasnucleophilic import increasedance of indolateby the the tight introduction intermediate ion pair thatof electron- (Scheme occurs 12, II). Thebetweenwithdrawing stereocontrol the cinchona-based substituents of the on reaction salt the ofpara the-position was quinuclidine increased of the ringbenzyl by and the group the introduction nucleophilic of the catalyst of indolate electron-withdrawing37. The intermediate substituents substituents(Schemeat C5 positions on12, theII). para ofThe the-position stereocontrol indole ofring the didof benzyl thenot reaction influence group ofwas stereoselectivity the increased catalyst 37by. Theasthe indole introduction substituents derivatives of at C5electron- 35 positions with withdrawing substituents on the para-position of the benzyl group of the catalyst 37. The substituents of theelectron-withdrawing indole ring did not inﬂuenceor electron-donating stereoselectivity groups as gave indole high derivatives yields (85–93%)35 with and electron-withdrawing high ee values (82– at C5 positions of the indole ring did not influence stereoselectivity as indole derivatives 35 with or electron-donating89%), which could groups be increased gave further high yields by recrystallization. (85–93%) and high ee values (82–89%), which could be electron-withdrawing or electron-donating groups gave high yields (85–93%) and high ee values (82– increased further by recrystallization. 89%), which could be increased further by recrystallization.

Scheme 12. Phase transfer-catalyzed N-alkylation of indoles.

The phase transfer-catalyzedSchemeScheme 12. 12.Phase Phase asymmetric transfer-catalyzed transfer-catalyzed aza-Michael NN-alkylation-alkylation addition of of indoles. indoles.of nitroindoles 38 to α,β- unsaturated carbonyl compounds 39 was investigated by Kanger and co-workers (Scheme 12, III) [31].The TheThe phase phaseauthors transfer-catalyzed transfer-catalyzed determined that theasymmetric asymmetric position ofaza-Michael the aza-Michael nitro group addition on addition the of indole nitroindoles of core nitroindoles was 38 crucial to α, 38βto- to α,β-unsaturatedunsaturatedcontrol the enantioselectivity carbonyl carbonyl compounds compounds of the 39 reaction. was39 was investigated The investigated reaction by didKanger by not Kanger proceedand co-workers and with co-workers 2- and (Scheme 7-substituted (Scheme 12, III) 12, III)[[31].nitroindoles.31]. The The authors authors The determinedindoles determined bearing that that thea thenitro position position group of ofatthe the nitro nitroC5, group C6 group or on C3 onthe positions theindole indole corewere core was non-selective was crucial crucial to to control the enantioselectivity of the reaction. The reaction did not proceed with 2- and 7-substituted control the enantioselectivity of the reaction. The reaction did not proceed with 2- and 7-substituted nitroindoles. The indoles bearing a nitro group at the C5, C6 or C3 positions were non-selective nitroindoles. The indoles bearing a nitro group at the C5, C6 or C3 positions were non-selective

Symmetry 2020, 12, 1184 9 of 30

substratesSymmetry for 2020 the, 12, reaction x FOR PEER as REVIEW the enantioselectivity was too low (35–42% ee). The reaction9 betweenof 29 various trans-crotonophenone derivatives and 4-nitroindole aﬀorded products with good to high yieldssubstrates (67–96%) for and the moderatereaction as tothe good enantioselectivity enantioselectivities was too low (59–75%) (35–42% in ee the). The presence reaction of between a cinchona alkaloid-basedvarious trans phase-crotonophenone transfer catalyst derivatives41. Itand is important4-nitroindol toe afforded mention products that there with was good essentially to high no yields (67–96%) and moderate to good enantioselectivities (59–75%) in the presence of a cinchona correlation between the acidity of the indole and its reactivity in the aza-Michael reaction. alkaloid-based phase transfer catalyst 41. It is important to mention that there was essentially no The introduction of an electron-withdrawing substituent at the C2-position of the indole ring correlation between the acidity of the indole and its reactivity in the aza-Michael reaction. not only increasesThe introduction the acidity of an ofelectron-withdrawing the N-H atom, but subs thistituent substitution at the C2-position pattern also of the opens indole wide ring access to cascadenot only reactions increases that the acidity provide of chiralthe N-HN -alkylatedatom, but this polycyclic substitution indoles pattern in also a single opens step.wide access Wang and Ender’sto cascade groups reactions separately that reported provide achiral method N-alkylated where tricyclicpolycyclic chiral indoles indole in a derivativessingle step. Wang were obtainedand fromEnder’s indole-2-carbaldehyde groups separately reported42 and a various method whereα,β-unsaturated tricyclic chiral aldehydes indole derivatives43 in thewere presence obtained of a Hayashi-Jørgensenfrom indole-2-carbaldehyde catalyst 46 42(Scheme and various 13, Iα)[,β-unsaturated32,33]. The aldehydes cascade reaction 43 in the is presence possible of duea to an iminiumHayashi-Jørgensen/enamine activationcatalyst 46 mode(Scheme and 13, consistsI) [32,33]. of The an cascade aza-Michael reaction reaction is possible followed due to by analdol condensation.iminium/enamine Despite activation diﬀerences mode in and reaction consists conditions, of an aza-Michael both synthetic reaction methods followeddemonstrated by aldol condensation. Despite differences in reaction conditions, both synthetic methods demonstrated moderate to good yields (40–71% and 57–81%) and good to excellent ee values of products (85 to >99% moderate to good yields (40–71% and 57–81%) and good to excellent ee values of products (85 to >99% and 71–96%). In the case of 2-furyl enal, the isomeric achiral product 45 was formed. and 71–96%). In the case of 2-furyl enal, the isomeric achiral product 45 was formed.

SchemeScheme 13. 13.Secondary Secondary amineamine catalyzed cascade cascade reactions. reactions.

EndersEnders et al. et continuedal. continued to to investigate investigate thethe reactionsreactions of of 2-substituted 2-substituted indoles indoles with with unsaturated unsaturated aldehydesaldehydes and and reported reported an an asymmetric asymmetric quadruple quadruple cascade cascade reaction reaction(Scheme 13, (Scheme II) [34]. Indole-2-13, II)[34]. methylene malononitriles 47 derived from indole-2-carbaldehydes 42 were subjected to reactions Indole-2-methylene malononitriles 47 derived from indole-2-carbaldehydes 42 were subjected to with various α,β-unsaturated aldehydes 43 in the presence of the chiral secondary amine 46, reactions with various α,β-unsaturated aldehydes 43 in the presence of the chiral secondary providing tetracyclic aldehydes 48a. The domino reaction consists of a tandem aza-Michael-Michael- amineMichael-aldol46, providing reaction, tetracyclic which exploits aldehydes the iminium-enamine-iminium-enamine48a. The domino reaction activation consists approach. of a tandem aza-Michael-Michael-Michael-aldolBecause of the enolization during the reaction, purification which of aldehydes exploits the 48a iminium-enamine-iminium-enamine, they were trapped with stabilized activationWittig approach.reagent 49. BecauseThe cascade of thereaction enolization and olefination during were the purification easily completed of aldehydes in a one-pot48a manner, they were trappedwith with no impact stabilized on the Wittig reaction reagent outcome.49. TheThe cascadereaction reactionscope was and performed olefination with were both easilyelectron completed rich in a one-potand electron manner poor with aromatic no impact α,β-unsaturated on the reaction aldehydes outcome. 43 and The chiral reaction products scope 48 were was performedobtained as with both electron rich and electron poor aromatic α,β-unsaturated aldehydes 43 and chiral products 48 Symmetry 2020, 12, 1184 10 of 30 Symmetry 2020, 12, x FOR PEER REVIEW 10 of 29 weresingle obtained diastereoisomers as single diastereoisomers(>20:1 dr) with moderate (>20:1 dr) withto good moderate yields to(25–70%) good yields and (25–70%) good to andexcellent good enantioselectivitiesto excellent enantioselectivities (91–99%). A (91–99%).decrease in A enantioselectivity decrease in enantioselectivity and yield was and detected yield was in detectedthe case of in the heteroaromatic case of the heteroaromatic furyl group furyl(33% groupyield, 78% (33% ee yield,). Indoles 78% withee). Indoleselectron-w withithdrawing electron-withdrawing and electron- donatingand electron-donating substituents substituentsat the C5 atposition the C5 positiontolerated tolerated the reaction the reaction without without affecting affecting yields yields or stereoselectivities.or stereoselectivities. An intramolecular intramolecular reaction reaction of of appropriately appropriately C2 C2 substituted substituted indole indole 50 50providedprovided selectively selectively N- alkylatedN-alkylated tricyclic tricyclic indole indole derivatives derivatives 5151 viavia an an aza-Michael aza-Michael reaction reaction in in the the presence presence of of a a phosphoric acid catalyst catalyst 5252 (Scheme(Scheme 14, 14 I,)I [35].)[35 Under]. Under optimal optimal conditions, conditions, the reaction the reaction scope scope was broadened was broadened with withvarious various substituted substituted aromatic aromatic enones enones with withelectr electron-donatingon-donating or electron-withdrawing or electron-withdrawing groups. groups. The Theauthors authors demonstrated demonstrated the tolerance the tolerance of various of various functionalities functionalities such such as carbonyl, as carbonyl, hydroxyl hydroxyl groups groups and aromaticand aromatic rings rings at the at theC3 C3side side chain chain without without any any impact impact on on the the reaction reaction yields yields (82–96%) (82–96%) or enantioselectivities (88–93%). (88–93%). However, However, the the introduction introduction of ofan anelectron-withdrawing electron-withdrawing group group at the at C2- the positionC2-position of the of theindole indole totally totally inhibited inhibited the the reacti reaction.on. Further Further investigations investigations of of the the reaction reaction were concentrated on the combination of mechanisticallymechanistically distinct organocatalysis and transition-metaltransition-metal catalysis (Scheme (Scheme 14,14 ,IIII).). The The indolyl indolyl olefins olefins 5353 andand enones enones 54 54reactedreacted smoothly smoothly in the in thepresence presence of the of chiralthe chiral phosphoric phosphoric acid acid 52 52andand ruthenium ruthenium catalyst catalyst Zhan-1BZhan-1B affordingaffording the the desired desired products products with moderate toto excellentexcellent yields yields (45–96%) (45–96%) with with 87–93% 87–93%ees (Schemeees (Scheme 14, II 14,). Notably, II). Notably, if indole if 56indolewas applied56 was appliedas the substrate, as the substrate, both the bothN-alkylated the N-alkylated product 57productand the 57 C3-alkylationand the C3-alkylation product 58productwere obtained58 were (Schemeobtained 14(Scheme, II). 14, II).

R2 R2 R

(10 mol%) 52 O O N X N X P O H 4Å M.S. O O OH o toluene, 0 C 72-98% yield R1 R1 R 50 51 69-93% ee R = SiPh3 52

4 II R (10 mol%) 52 R3 (5 mol%) Zhan-1B R4 N R4 5 + R 4Å MS O N toluene, 0 oC H O 45-96% yield 53 54 55 R5 87-93% ee O

(10 mol%) 52 N N + O H 4Å M.S. O toluene, 0 oC 56 57 58 N 82% yield, 65% ee 16% yield Scheme 14. Cyclization of electron rich 2-substituted indoles.

2.5. N-Heterocyclic N-Heterocyclic Carbene-Mediated Cyclizations In recent years, there has been growing interest in the field ﬁeld of N-heterocyclic carbene (NHC) (NHC) catalysis. The functionalization ofof thethe indole indole core core via via various various NHC-intermediates NHC-intermediates has has been been reported reported by byseveral several research research groups groups [36 –[36–40].40]. There Ther aree are only only two two articles articles dedicated dedicated to theto theN-functionalization N-functionalization of ofindoles indoles [41 [41,42].,42]. Both Both synthetic syntheti methodologiesc methodologies were were applied applied to to 7-substituted 7-substituted indole indole derivatives derivatives as as a astarting starting material material and and obtained obtainedN N-fused-fused tricyclic tricyclic structures structures were were characteristic. characteristic. Biju and co-workers demonstrated an asymmetric NHC-catalyzed domino reaction for the synthesis of pyrroloquinolines (Schem (Schemee 15)15)[ [41].41]. The indole substrates 59 used in this reaction had a Michael acceptor moiety at the C7-position and a strong electron-withdrawing group at the C3- position to increase the acidity of the N-H atom of indoles. The cascade reaction was catalyzed by

Symmetry 2020, 12, 1184 11 of 30

Michael acceptor moiety at the C7-position and a strong electron-withdrawing group at the C3-position toSymmetry increase 2020 the, 12, acidityx FOR PEER of theREVIEW N-H atom of indoles. The cascade reaction was catalyzed by carbene11 of 29 generated from the chiral aminoindanol-derived triazolium salt 62 and proceeded smoothly with carbene generated from the chiral aminoindanol-derived triazolium salt 62 and proceeded smoothly various substituted indoles 59 and cinnamaldehyde derivatives 60. The substrate scope revealed that with various substituted indoles 59 and cinnamaldehyde derivatives 60. The substrate scope revealed α,β-unsaturated aldehydes bearing electron-withdrawing and electron-donating substituents at the that α,β-unsaturated aldehydes bearing electron-withdrawing and electron-donating substituents at 4-, 3- and 2-positions of the β-aryl ring of enals had no impact on the reaction outcome, affording the 4-, 3- and 2-positions of the β-aryl ring of enals had no impact on the reaction outcome, affording pyrroloquinoline derivatives with good to high yields (63–95%), good to excellent enantiomeric pyrroloquinoline derivatives with good to high yields (63–95%), good to excellent enantiomeric ratios ratios (87:13 to 99:1) and excellent diastereoselectivities (>20:1). Additionally, heterocyclic enals and (87:13 to 99:1) and excellent diastereoselectivities (>20:1). Additionally, heterocyclic enals and disubstitued β-aryl ring enals reacted smoothly with indole derivatives and products were obtained disubstitued β-aryl ring enals reacted smoothly with indole derivatives and products were obtained with good yields (67–82%) and high er values (90:10 to 97:3). Cyclic and acyclic alkyl groups at the with good yields (67–82%) and high er values (90:10 to 97:3). Cyclic and acyclic alkyl groups at the Michael acceptor moiety of compound 59 could be used without affecting the reactivity/selectivity. Michael acceptor moiety of compound 59 could be used without affecting the reactivity/selectivity. In addition, the influence of solvents with different dielectric constants (DEC) on the reaction selectivity In addition, the influence of solvents with different dielectric constants (DEC) on the reaction selectivity and yield was studied. The authors demonstrated that the aprotic solvents with higher dielectric and yield was studied. The authors demonstrated that the aprotic solvents with higher dielectric constants afforded better ee and yield. For instance, a poor yield and ee value were obtained in toluene constants afforded better ee and yield. For instance, a poor yield and ee value were obtained in toluene (DEC: 2.38), moderate in THF (DEC: 7.58) and high in DMF (36.7). Therefore, the solvent with higher (DEC: 2.38), moderate in THF (DEC: 7.58) and high in DMF (36.7). Therefore, the solvent with higher polarity not only provided good solubility of reactants but it could stabilize zwitterionic intermediates. polarity not only provided good solubility of reactants but it could stabilize zwitterionic intermediates.

Scheme 15.15. N-heterocyclic carbene (NHC)-catalyzed cascadecascade reactionreaction ofof 7-substituted7-substituted indoles.indoles.

ChiChi etet al.al. reported thethe enantioselectiveenantioselective functionalizationfunctionalization of an indoleindole carbaldehydecarbaldehyde N-H group throughthrough NHC catalysis catalysis (Scheme (Scheme 16) 16 )[[42]42.Error!]. The Bookmark indole derivative not defined.63 was The activatedindole derivative by NHC 63 via was a carbaldehydeactivated by NHC moiety via at a thecarbaldehyde C7-position moiety of the at indole. the C7-position The reaction of ofthe indole-7-carbaldehyde indole. The reaction of adducts indole- with7-carbaldehyde derivatives adducts of various with carbonyl derivatives compounds of various64 demonstratedcarbonyl compounds high er 64values demonstrated and yields high in the er presencevalues and of yields a carbene in the catalyst presence generated of a carben frome acatalyst triazolium generated salt 67 from. The a ditriazoliumfferences insalt structure 67. The anddifferences electronic in structure properties and of electronic the starting properties compounds of the did starting not a compoundsffect the reaction did not selectivity affect the orreaction yield. Bothselectivity trifluoroacetophenone or yield. Both trifluoroacetophenone derivatives and aliphatic derivatives trifluoromethyl and aliphatic ketones tolerated trifluoromethyl the reaction ketones well atoleratedffording thethe desiredreaction products well affording with high the yields desired and productser values (89–98%with high yield, yields 94:6 and to 96:4).er values Substitutions (89–98% onyield, the 94:6 indole to 5-96:4). and Substitutions 6-positions gave on thethe desiredindole 5- products and 6-positions with excellent gave yieldsthe desired (90–99%) products and optical with puritiesexcellent (92:8 yields to 97.5:2.5),(90–99%) regardless and optical of purities the electronic (92:8 to properties 97.5:2.5), ofregard the substituents.less of the electronic The reaction properties scope wasof the broadened substituents. with theThe application reaction scope of isatins was68 broadenedas electrophiles with (Schemethe application 16, II). Inof theisatins case of68 theas isatinelectrophiles derivatives, (Scheme another 16, II precatalyst). In the case70 ofwas the used isatin to derivatives, maintain high another yields precatalyst (up to 95%) 70 and waser usedvalues to (upmaintain to 98:2). high yields (up to 95%) and er values (up to 98:2). TheThe authorsauthors proposedproposed thethe mechanismmechanism ofof thethe NHC-catalyzedNHC-catalyzed reaction,reaction, which is outlinedoutlined inin SchemeScheme 1616,, III III.. The The nucleophilic nucleophilic attack attack of of NHC NHC67a 67aon on aldehyde aldehyde63a 63aforms forms a Breslow a Breslow intermediate intermediate63b, which63b, which undergoes undergoes an oxidation an oxidation reaction reaction to generate to generate an acylazolium an acylazolium intermediate intermediate63c, followed 63c, followed by its deprotonation,by its deprotonation, providing providing the intermediate the intermediate63d. Finally, 63d. Finally, a formal a [4 formal+ 2] annulation [4 + 2] annulation reaction betweenreaction intermediatebetween intermediate63d and trifluoroacetophenone 63d and trifluoroacetophenone64a affords the64a desired affords product the desired65a and product regenerates 65a and the NHCregenerates catalyst. the NHC catalyst.

Symmetry 2020, 12, 1184 12 of 30

Symmetry 2020, 12, x FOR PEER REVIEW 12 of 29

I (20 mol%) 67 O (1.2 equiv) DIEA 3 N F R3 O (1.0 equiv) Oxidant R N N N + N F H 1 R1 R2 DCM, r.t. R O O O 2 F 63 64 65 R BF4 F NO2 F R1 =Me,Et,Ar, 85-99%` yield 67 2 R =CF3,CF2H, COOEt 92:8 to 97.5:2.5 er R3 = H, Hal, Me, MeO

II (20 mol%) 70 (1.2 equiv) DIEA O O (1.0 equiv) Oxidant R N F R3 N N N N R1 O DCM, r.t. F H + N O O O 2 BF F 63 68R 69 O 4 F R F 1 R =H,Me,MeO,Hal 70-95% yield 70 2 R =Me,Bn 94:6 to 98:2 er R3 = H, Hal, Me, MeO

III N 67a Ph N * O O CF3 Ar N N N 65a H O 63a O N

Ph CF NHC Ph 3 O 64a O CF3

N H N * N N HO N N O NHC O NHC Ar 63b 63d 63e Breslow intermediate

base [O]

N H O NHC 63c SchemeScheme 16.16. NHC mediated NN-alkylation-alkylation ofof indoles.indoles.

3.3. Organocatalytic Indirect Methods ThereThere areare several several examples examples of organocatalyticof organocatalytic methods methods in which in which the synthesis the synthesis of chiral ofN -alkylatedchiral N- indolesalkylated was indoles performed was performed indirectly. Threeindirectly. routes Three for theroutes preparation for the preparation of N-functionalized of N-functionalized indoles are proposed.indoles are The proposed. ﬁrst two The methods first aretwo based meth onods the are enantioselective based on the Nenantioselective-alkylation of indoline N-alkylation or isatin of andindoline further or redoxisatin transformationand further redox of N -alkylatedtransformation intermediates of N-alkylated into chiral intermediatesN-functionalized into chiral indoles. N- Infunctionalized the last method, indoles. 4,7-dihydroindole In the last method, was 4,7-dihy used asdroindole the starting was used material as the for starting the C2 material Friedel-Crafts for the alkylationC2 Friedel-Crafts followed alkylation the oxidative followed cyclization, the oxidative aﬀording cyclization,N-alkylated affording indole. N-alkylated indole. α β TheThe enantioselectiveenantioselective aza-Michaelaza-Michael reactionreaction betweenbetween indolineindoline derivativesderivatives 7171 andand α,,β-unsaturated-unsaturated ketonesketones 72 was reported by Ghosh Ghosh et et al. al. (Scheme (Scheme 17, 17 ,I)I )[[43].43]. A Aset set of of N-alkylatedN-alkylated indoline indoline adducts adducts 73 73werewere further further oxidized oxidized to corresponding to corresponding N-functionalizedN-functionalized indole indole derivatives derivatives 75 (Scheme75 (Scheme 17, II 17). ,TheII). TheN-alkylationN-alkylation of indolines of indolines was was investigated investigated and and various various thiourea thiourea and and squaramide squaramide based based bifunctional organocatalysts were tested. The best results were obtained with quinine-derived catalyst 74 in xylene at −20 °C. The influence of substituents in the aromatic rings of α,β-unsaturated ketones 72

Symmetry 2020, 12, 1184 13 of 30 organocatalysts were tested. The best results were obtained with quinine-derived catalyst 74 in xylene at 20 ◦C. The influence of substituents in the aromatic rings of α,β-unsaturated ketones 72 was also −Symmetry 2020, 12, x FOR PEER REVIEW 13 of 29 studied. The authors demonstrated that in the case of electron-withdrawing substituents in the phenyl 3 ringwas (R also), both studied. the enantioselectivity The authors demonstrated and yield that increased in the case (83–86% of electron-withdrawing yield, 90-96% ee). Atsubstituents the same in time, 3 thethe introduction phenyl ring of (R an3), electron-donatingboth the enantioselectivity group and (R =yield4-Me-Ph) increased did (83–86% not aff ectyield, the 90-96% selectivity ee). At or the yield 3 (55%same yield, time, 86% theee introduction). The incorporation of an electron-donating of a cyano group group on(R3 the= 4-Me-Ph) phenyl did ring not (R affect) aff ordedthe selectivity a product withor a yield low yield(55% (40%)yield, 86% and highee). Theee (90%).incorporation Notably, of thea cyano heterocyclic group on furan-2-yl the phenyl and ring methyl (R3) afforded substituents a toleratedproduct the with reaction a low well,yield providing(40%) and high good ee yields (90%). and Notably, stereoselectivities the heterocyclic (55–57% furan-2-yl yield, and 80–84% methyl ee). Indolinessubstituents with electron-donatingtolerated the reaction substituents well, providing at the good C5 yields position and a ffstereoselectivitiesorded products (55–57% with high yield, yields with80–84% high levels ee). Indolines of stereocontrol with electron-donat (93–94% yield,ing substituents 95–99% ee at). the Electron-withdrawing C5 position afforded groupsproducts at with the C5 positionhigh yields of the with indoline high decreasedlevels of stereocontrol the reaction (93–94% yield and yield,ee value 95–99% (53–54% ee). Electron-withdrawing yield, 80% ee). The groups oxidation of chiralat the NC5-functionalized position of the indoline indolines decreased73 to the the corresponding reaction yield andN-substituted ee value (53–54% indoles yield,75 with80% ee DDQ). The oxidation of chiral N-functionalized indolines 73 to the corresponding N-substituted indoles 75 (1.05 equivalent) in THF or MnO2 (10 equivalent) in dichloromethane led to products without any loss with DDQ (1.05 equivalent) in THF or MnO2 (10 equivalent) in dichloromethane led to products in enantioselectivity and with high yields (Scheme 17, II). without any loss in enantioselectivity and with high yields (Scheme 17, II).

SchemeScheme 17. 17.Synthesis Synthesis of ofN N-functionalized-functionalized indoles via via alkylation/oxidation alkylation/oxidation of ofindolines. indolines.

AnAn interesting interesting route route for for the the preparation preparation ofof chiralchiral N-functionalized-functionalized indoles indoles 8181 fromfrom N-alkylatedN-alkylated isatinisatin derivatives derivatives80 80was was proposed proposed by by Lu Lu and and co-workersco-workers (Scheme 18, 18 ,I)I )[[44].44 ].The The method method is based is based on on thethe enantioselective enantioselective conjugated conjugated addition addition of of protected protected isatin isatin derivatives derivatives76 76to toα α,,ββ-unsaturated-unsaturated enals enals 77 via77 the via iminium the iminium activation activation of aldehydes of aldehydes by by a prolinol-deriveda prolinol-derived catalystcatalyst 7979. .A A wide wide range range of various of various aliphatic, aromatic linear and branched enals 77 tolerated the reaction, providing products with good aliphatic, aromatic linear and branched enals 77 tolerated the reaction, providing products with good yields (70–82%) and high enantioselectivities (89–95%). Corresponding N-functionalized indoles 81 yields (70–82%) and high enantioselectivities (89–95%). Corresponding N-functionalized indoles 81 were obtained after deprotection and reduction with borane. were obtainedThe unprotected after deprotection N-alkylated and isatins reduction 80a were with further borane. transformed into C2/C3-substituted N- functionalizedThe unprotected indolesN 82-alkylated or 83 (Scheme isatins 18, 80aII). were further transformed into C2/C3-substituted N-functionalized indoles 82 or 83 (Scheme 18, II).

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Symmetry 2020, 12, x FOR PEER REVIEW 14 of 29

SchemeScheme 18. 18.Isatin Isatin based based synthetic synthetic route route forfor the the preparation preparation of ofα-αN--branchedN-branched indoles. indoles. Scheme 18. Isatin based synthetic route for the preparation of α-N-branched indoles. The applicationThe application of electron-deﬁcient of electron-deficient 4,7-dihydroindole 4,7-dihydroindole84 for 84 the for construction the construction of N-functionalized of N- indolesfunctionalized86Thewas application investigated indoles 86of was byelectron-deficient Youinvestigated et al. (Scheme by 4,7-dihydroindole You et19 al.)[ 45(Scheme]. Chiral 84 19) for [45].N -functionalizedthe Chiral construction N-functionalized indoles of N- were obtainedindolesfunctionalized in awere one-pot obtained indoles synthesis. in86 a was one-pot First,investigated synthesis. the Friedel-Crafts by First, You the et al.Friedel-Crafts C2-alkylation (Scheme 19) C2-alkylation [45]. between Chiral the N between-functionalized 4,7-dihydroindole the 4,7- dihydroindole 84 and β,γ-unsaturated α-keto ester 85 was catalyzed by chiral N-triflyl 84 andindolesβ,γ-unsaturated were obtainedα -ketoin a one-pot ester 85 synthesis.was catalyzed First, the by Friedel-Crafts chiral N-triﬂyl C2-alkylation phosphoramide between87 theat 4,7-78 C phosphoramide 87 at −78 °C in toluene. The authors determined the importance of 4Å molecular− ◦ in toluene.dihydroindole The authors 84 and determined β,γ-unsaturated the importance α-keto ester of 4Å 85 molecular was catalyzed sieves inby thechiral reaction N-triflyl mixture. sieves in the reaction mixture. Moreover, the stereoselectivty of the reaction was improved when the Moreover,phosphoramide the stereoselectivty 87 at −78 °C of in the toluene. reaction The was authors improved determined when the the importance ester 85 was of 4 addedÅ molecular by syringe estersieves 85 in was the addedreaction by mixture. syringe Moreover,pump to the the reaction stereoselectivty mixture overof the 15 reaction min. was improved when the pump to the reaction mixture over 15 min. ester 85 was added by syringe pump to the reaction mixture over 15 min.

Scheme 19. C2-alkylation of 4,7-dihydroindoles, followed by oxidative intramolecular cyclization. Scheme 19. C2-alkylation of 4,7-dihydroindoles, followed by oxidative intramolecular cyclization. SchemeThe simple 19. C2-alkylation work-up with of 4,7-dihydroindoles, p-benzoquinone after followed the completion by oxidative of intramolecular the first step afforded cyclization. the oxidative intramolecular cyclization of 2-substituted chiral intermediates. Various N-functionalized TheThe simple simple work-up work-up with withp -benzoquinonep-benzoquinone after the the completion completion of ofthe the first first step step afforded afforded the the products 86 were obtained with moderate to good yields (48–87%), good to excellent oxidativeoxidative intramolecular intramolecular cyclization cyclization of of 2-substituted 2-substituted chiral intermediates. intermediates. Various Various N-functionalizedN-functionalized enantioselectivitiesproducts 86 were (75–9 obtained9%) and with poor moderateto moderate to diastereoselectivities good yields (48–87%), (52:48 togood 75:25). to excellent products 86 were obtained with moderate to good yields (48–87%), good to excellent enantioselectivities enantioselectivities (75–99%) and poor to moderate diastereoselectivities (52:48 to 75:25). (75–99%)4. Direct and Organometallic poor to moderate Methods diastereoselectivities (52:48 to 75:25). 4. Direct4. DirectTransition Organometallic Organometallic metal catalysis Methods Methods is often applied in asymmetric synthesis as a highly efficient method for the construction of chiral compounds [46]. Small loadings of transition metal complexes and the TransitionTransition metal metal catalysis catalysis is is often often applied applied inin asymmetric synthesis synthesis as asa highly a highly efficient efficient method method excellent stereocontrol of the reaction make organometallic methods attractive for the stereoselective for thefor construction the construction of chiralof chiral compounds compounds [ 46[46].]. SmallSmall loadings loadings of of transition transition metal metal complexes complexes and the and the N-functionalization of indoles. In this part of the review, direct methods of the stereoselective N-alkylation excellentexcellent stereocontrol stereocontrol of theof the reaction reaction make make organometallicorganometallic methods methods attractive attractive for forthe thestereoselective stereoselective ofN-functionalization indoles based on transitionof indoles. metal In this catalysis part of the are review, discussed. direct Various methods alkylating of the stereoselective agents and different N-alkylation types N-functionalization of indoles. In this part of the review, direct methods of the stereoselective of indolestransition based metal on complexes transition metalwere applied catalysis to are gain disc a ussed.high leve Variousl of stereocontrol alkylating agents (Scheme and 20). different types N-alkylation of indoles based on transition metal catalysis are discussed. Various alkylating agents of transition metal complexes were applied to gain a high level of stereocontrol (Scheme 20). and di fferent types of transition metal complexes were applied to gain a high level of stereocontrol (Scheme 20). Symmetry 2020, 12, 1184 15 of 30 Symmetry 2020, 12, x FOR PEER REVIEW 15 of 29

Symmetry 2020, 12, x FOR PEER REVIEW 15 of 29

SchemeScheme 20. 20.Direct Direct transition-metal transition-metal basedbased stereoselective derivatization derivatization of indole. of indole.

4.1.4.1. C2-Selective C2-Selective Addition SchemeAddition/N-Cyclization/N-Cyclization 20. Direct transition-metal Sequences Sequences based stereoselective derivatization of indole.

Chen4.1.Chen C2-Selective and and Xiao Xiao Addition/N-Cyclization applied applied 3-substituted 3-substituted Sequences indolesindoles 88 asas N1/C2 N1/C2 dinucleophiles dinucleophiles in inenantioselective enantioselective reactionsreactions with with various variousβ, γβ-unsaturated,γ-unsaturatedα α-ketoesters-ketoesters 89 (Scheme(Scheme 21, 21 I,)I [47].)[47 ].A Ahighly highly enantioselective enantioselective Chen and Xiao applied 3-substituted indoles 88 as N1/C2 dinucleophiles in enantioselective cascade reaction consisting of sequential C2 Friedel-Crafts alkylation followedN by N- cascadereactions reaction with consisting various β of,γ-unsaturated sequential C2 α-ketoesters Friedel-Crafts 89 (Scheme alkylation 21, I) [47]. followed A highly by enantioselective-hemiacetalization, providinghemiacetalization, tricyclic chiral providingN-functionalized tricyclic chiral N indoles-functionalized90, was indoles described. 90, was The described. domino The reaction domino was reactioncascade was reaction smoothly consisting catalyzed ofby copper(II)triflatesequential C2 Friedel-Craftsin the presence alky of chirallation bis(oxazoline)followed by ligand N- smoothlyhemiacetalization, catalyzed by providing copper(II)triflate tricyclic chiral in the N presence-functionalized of chiral indoles bis(oxazoline) 90, was described. ligand The91 dominoin toluene at 91 in toluene at 0 °C. The investigation of the substrate scope revealed that the cascade reaction 0 C. Thereaction investigation was smoothly of the catalyzed substrate by scopecopper(II)triflate revealedthat in the the presence cascade of reaction chiral bis(oxazoline) tolerated various ligand esters ◦ tolerated various esters well, electron-withdrawing and electron-donating groups in the γ-aryl ring 91 in toluene at 0 °C. The investigation of the substrate scope revealedγ that the cascade reaction well,of electron-withdrawing ester, heteroaromatic and and vinyl-substituents electron-donating at the groups γ-position. in the γ-Alkyl-substituted-aryl ring of ester, β,γ-unsaturated heteroaromatic tolerated various esters well, electron-withdrawing and electron-donating groups in the γ-aryl ring andα vinyl-substituents-ketoesters also reacted at the smoothly,γ-position. butγ-Alkyl-substituted in the case of the βstraight-chain,γ-unsaturated aliphaticα-ketoesters substrate also (R reacted3 = of ester, heteroaromatic and vinyl-substituents at the γ-position. γ-Alkyl-substituted3 4 β,γ-unsaturated smoothly,propyl, but R4 in= Et) the a case decrease of the in straight-chain the stereoselectivity aliphatic of substratethe cascade (R reaction= propyl, was R detected= Et) a decrease(67% yield, in the α-ketoesters also reacted smoothly, but in the case of the straight-chain aliphatic substrate (R3 = stereoselectivity of the cascade reaction was detected (67% yield, 27% ee, 67:33 dr). Various substituents 27%propyl, ee, 67:33 R4 dr= Et)). Various a decrease substituents in the stereoselectivity with different electronof the cascade and steric reaction properties was detected at the indole (67% coreyield, did withnot di27% ffaffecterent ee, 67:33either electron dr the). Various andreaction steric substituents yield properties or the with stereose atdifferent thelectivity indole electron coreof and the did stericreaction. not properties aff ectTheeither only at the exception the indole reaction core was didyield the or the stereoselectivityreactionnot affect with either 3-phenylindole, ofthe the reaction reaction. whereyield Theor slight the only stereose decreases exceptionlectivity in ee was andof the thedr reaction.were reaction observed The with only (80% 3-phenylindole, exception ee, 86:14 was dr). the where slight decreasesreaction with in 3-phenylindole,ee and dr were where observed slight (80%decreasesee, 86:14in ee anddr). dr were observed (80% ee, 86:14 dr). I O O R3 R1 I O 4 89 OR R3 O O O 2 R3 R R1 64-97% yield 4 N N N 89(5 mol%) 91OR R3 27 to >99% ee O O 2 64-97% yield 90R 4 56:44 to 97:3 dr (5 mol%) Cu(OTf)2 HO CO2R N N (5 mol%) 91 N 27 to >99% ee toluene, 0 oC 91 90 4 56:44 to 97:3 dr (5 mol%) Cu(OTf)2 HO CO2R toluene, 0 oC 91

II O II O R1 Ph O OMeO Ph 89% yield 1 92Ph N N 2 R R OMe N Ph 89%96% yieldee O O O O N (10 mol%)92 Ni(OTf)-94 N N R2 H 96%7:3 dree N H H N 88 DCM 93 N CO Me O O O O N (10 mol%) Ni(OTf)-94 HO 2 R R H 7:3 dr N H H N 88 DCM 93 CO Me HO 2 R R = 2,6-iPrC6H3R R = 2,6-i94PrC6H3 III O 94 III EtOOC O EtOOC R1 O R4 R3 O R1 O N R4 O R3 N 2 O R N O 4 2 95 RN R N 80-96% yield O P 4 95 R N O P EtOOC 80-96%65-99% yieldee NH R3 O P EtOOC 65-99% ee (5 mol%) 97 96 NH R3 >20:1 dr O P (5 mol%) 97 96 1 >20:1 dr (5 mol%) Pd(PPh3)2Cl2 R O (5 mol%) Pd(PPh ) Cl R1 O (10 mol%) AgSbF3 2 2 6 R2 (10 mol%) AgSbFo 6 2 PhCF3,25to90 Co R PhCF3,25to90 C 97 97 Scheme 21. C2-alkylation of indoles followed by intramolecular N-cyclization. SchemeScheme 21. C2-alkylation21. C2-alkylation of of indoles indoles followedfollowed by by intramolecular intramolecular N-cyclization.N-cyclization. Feng et al. investigated the enantioselective intermolecular Friedel-Crafts alkylation reaction at FengFeng et al. et investigated al. investigated the the enantioselective enantioselective inte intermolecularrmolecular Friedel-Crafts Friedel-Crafts alkylation alkylation reactionreaction at thethe C2-position C2-position of of N N-methylated-methylated indoles indoles with with ββ,,γγ-unsaturated-unsaturated αα-ketoesters-ketoesters [48]. [48]. The The cascade cascade reaction reaction at the C2-position of N-methylated indoles with β,γ-unsaturated α-ketoesters [48]. The cascade reaction of the C2-alkylation/N-hemiacetalization of skatole (3-methyl indole) was catalyzed by a chiral N,N0-dioxide 94 Ni(II) complex affording the corresponding product 93 with high yield (89%), excellent Symmetry 2020, 12, 1184 16 of 30 ee (96%)Symmetry and 2020 moderate, 12, x FORdr PEER(7:3) REVIEW values (Scheme 21, II). The results were slightly worse than16 withof 29 the chiral Box–copper(II)-catalyzed method discussed above (95 yield, >99% ee, 95:5 dr). of the C2-alkylation/N-hemiacetalization of skatole (3-methyl indole) was catalyzed by a chiral N,N′- An efficient stereoselective triple cascade reaction of 3-alkylindoles with oxindolyl β,γ-unsaturated dioxide 94 Ni(II) complex affording the corresponding product 93 with high yield (89%), excellent ee α -ketoesters(96%) and95 moderatein the presencedr (7:3) values of a (Scheme chiral diphosphine 21, II). The results97 palladium(II) were slightly worse catalyst than was with reported the by thechiral Wang Box–copper(II)-catalyzed group (Scheme method21, III discussed)[49]. The above domino (95 yield, reaction>99% ee, 95:5 consists dr). of asymmetric Friedel-CraftsAn efficient/N-cyclization stereoselective/Friedel-Crafts triple cascade sequential reaction alkylation of 3-alkylindoles and provides with oxindolyl a wide rangeβ,γ- of spiro-polycyclicunsaturated N1α-ketoesters/C2 functionalized 95 in the presence enantioenriched of a chiral indolesdiphosphine96. The97 palladium(II) various substituents catalyst was at the phenylreported ring and by Nthe-atom Wang of group oxindolyl (Schemeβ,γ-unsaturated 21, III) [49]. Theα-ketoesters domino reaction95 were consists well tolerated, of asymmetric affording the spiro-polycyclicFriedel-Crafts/N-cyclization/Friedel-Crafts products 96 with good sequential to excellent alkylation yields (80–96%),and provides high a wide to excellent range of spiro-ee values (86–99%)polycyclic and excellent N1/C2 functionalized diastereoselectivities enantioenriched (>20:1). indoles The indole 96. The scope various demonstrated substituents at some the phenyl limitations ring and N-atom of oxindolyl β,γ-unsaturated α-ketoesters 95 were well tolerated, affording the of the reaction: electron-withdrawing or electron-donating substituents at the C5 or C6 positions spiro-polycyclic products 96 with good to excellent yields (80–96%), high to excellent ee values (86– provided products with high yields (87–94), enantioselectivities and diastereoselectivities (91–98% 99%) and excellent diastereoselectivities (>20:1). The indole scope demonstrated some limitations of ee, >20:1the drreaction:) but in electron-withdrawing the case of the 4-bromo or electron-don substitutedating indole substituents a decline at in the enantioselectivity C5 or C6 positions (65% ee) was detected.provided products Sterically with hindered high yields indoles (87–94), at enan the C3tioselectivities position were and diastereoselectivities not the best starting (91–98% compounds ee, for this>20:1 cascade dr) but reaction. in the case For of the instance, 4-bromo an substitutedn-hexyl substituent indole a decline negatively in enantioselectivity affected the (65%ee value ee) was of the reactiondetected. (81% eeSterically) and the hinder reactioned indoles with at a bulkierthe C3 positioni-Pr substituted were not the indole best astartingfforded compounds a product for with this a low yieldcascade (<30%). reaction. For instance, an n-hexyl substituent negatively affected the ee value of the reaction (81% Comparedee) and the reaction with Xiao’s with a highlybulkier i enantioselective-Pr substituted indole method afforded based a product on chiral with a Box-copper(II) low yield (<30%). catalysis, Wang’s route,Compared based with on a Xiao’s chiral highly diphosphine enantioselective97 palladium(II) method based catalyst, on chiral has itsBox-copper(II) advantages catalysis, in the use of Wang’s route, based on a chiral diphosphine 97 palladium(II) catalyst, has its advantages in the use isatin-derived electrophiles 95, but is not particularly effective for simple γ-aryl substrates 89. of isatin-derived electrophiles 95, but is not particularly effective for simple γ-aryl substrates 89. 4.2. N-Allylation of Indoles 4.2. N-Allylation of Indoles The enantioselective version of a Tsuji-Trost reaction was applied for the synthesis of chiral indolocarbazoleThe enantioselective derivatives (Scheme version 22of, Ia)[ Tsuji-Trost50]. The reaction reaction of was protected applied bis(indole) for the synthesis98 with of cyclopentyl chiral carbonateindolocarbazole99 in the presence derivatives of a chiral(Scheme ligand 22, 102I) [50].and palladiumThe reaction catalyst of protected proceeded bis(indole) smoothly, 98 providingwith productscyclopentyl100 with carbonate excellent 99ee invalues the presence (99%) and of gooda chiral yields ligand (83% 102and and 75%,palladium depending catalyst on proceeded the protective smoothly, providing products 100 with excellent ee values (99%) and good yields (83% and 75%, group used). The authors conducted a series of NMR experiments and conformational analyses and depending on the protective group used). The authors conducted a series of NMR experiments and found that the preferred site of the alkylation was the nitrogen atom of the indole moiety, which conformational analyses and found that the preferred site of the alkylation was the nitrogen atom of was linearlythe indole conjugated moiety, which to the was carbonyl linearly function conjugated of lactam. to the Catalyticcarbonyl function allylations of lactam. of (bis)indoles Catalytic with sugar-derivedallylations electrophiles of (bis)indoles were with performed sugar-derived and electrophiles cyclic products were108 performedand 109 wereand cyclic successfully products obtained 108 (Schemeand 22 109, II were). successfully obtained (Scheme 22, II).

Scheme 22. Pd-catalyzed N-allylation of (bis)indoles. Symmetry 2020, 12, x FOR PEER REVIEW 17 of 29 Symmetry 2020, 12, 1184 17 of 30 Scheme 22. Pd-catalyzed N-allylation of (bis)indoles.

The preferred site of the allylation of bis(indole)bis(indole) depends on the acidity of the N-H atom of the indole derivative. When When the the bis(indole)-bearing conjugated conjugated dione dione moiety moiety 103 at the C3 position was subjected to a reaction, a cyclopentenyl acetate 104 product 105 was formed. The authors also proposed a strategy for the the construction construction of of the the chiral chiral indolocarbazole indolocarbazole 106106 fromfrom the the (bis)indole (bis)indole adduct adduct 105105. . Later, Trost etet al.al. demonstrated a ge generalneral method for the enantioselective N-allylation of electron deficientdeficient pyrroles 110 and indoles 111 with vinyl aziridines 112112 as electrophiles (Scheme (Scheme 23,23, II))[ [51].51]. The Pd-catalyzed asymmetric allylic alkylation provided a wide range of the heterocycle-containing chiral 1,2-diamines 113. The The desired desired branched branched N-alkylated-alkylated products products were obtained with a similar catalytic system that was previously applied for allylation of of bis(indole) bis(indole) adducts adducts 9898 (Scheme(Scheme 22,22, II).). The alkylation of of indoles indoles and and pyrroles pyrroles was was catalyzed catalyzed by bya palladium a palladium complex complex in the in presence the presence of a ofchiral a chiralligand ligand114 in dichloroethane114 in dichloroethane at room temperature. at room temperature. The authors determined The authors the determined positive impact the positiveof a naphthyl impact moiety of a naphthyl of the chiral moiety ligand of the on chiral the enantioselectivity ligand on the enantioselectivity of the reaction. of The the scope reaction. of Theelectron-deficient scope of electron-deficient indoles demonstrated indoles demonstrated exclusively exclusively N-alkylationN-alkylation with withmoderate moderate to to high enantioselectivity (73–93%)(73–93%) and and moderate moderate to highto high yields yields (57–99%). (57–99%). Weak electron-withdrawingWeak electron-withdrawing groups (suchgroups as (such bromo as or bromo chloro) or negatively chloro) negatively affected the affected reaction the yield reaction and ee .yield 2-Phenylindole and ee. 2-Phenylindole afforded only traceafforded quantities only trace of the quantities desired product.of the desired It should produc be notedt. It should that the be amidenoted that anion the of amide the vinyl anion aziridine of the invinyl the aziridineπ-allyl Pd in intermediate the π-allyl Pd was intermediate sufficiently basicwas sufficiently to deprotonate basic the to indoledeprotonate N-H and the facilitateindole N-H the reactionand facilitate in most the ofreaction the cases in most (Scheme of the 23 ,casesII). (Scheme 23, II).

Scheme 23. Pd-catalyzed N-allylation-allylation of of electron-deficient electron-deﬁcient pyrroles and indoles.

A highly enantioselective iridium-catalyzed N-allylation of electron-deﬁcientelectron-deficient or C3-substituted indoles was reported byby HartwigHartwig etet al.al. (Scheme 24)[) [52].52]. The authors used a chiral phosphoramidite ligand 119, which was previously studied in N-allylation reactions with more acidic and nucleophilic benzimidazoles, imidazolesimidazoles andand purines. purines. The The initial initial results results showed showed that that the the reaction reaction proceeded proceeded in the in presencethe presence of metallacycle of metallacycle120 and 120 cesium and cesium carbonate, carbonate, aﬀording affording an exclusively an exclusivelyN-substituted N-substituted product 117productwith 117 excellent with excellent branched-to-linear branched-to-linear selectivity selectivity (117/118 (117= 97:3)./118 = The97:3). reaction The reaction scope scope of the of ethyl the indole-2-carboxylateethyl indole-2-carboxylate115 with 115 various with various allylic carbonates allylic carbonates116 revealed 116 revealed that allylation that allylation proceeded proceeded smoothly atsmoothly the N-position, at the providingN-position, corresponding providing corresponding products 117 withproducts moderate 117 towith excellent moderate regioselectivities to excellent (77:23regioselectivities to 99:1), excellent (77:23 to enantioselectivities 99:1), excellent enantiosel (96–99%)ectivities and moderate (96–99%) toand high moderate yields (54–95%).to high yields Indoles (54– bearing95%). Indoles various bearing substituents various atsubstituents the C2, C3 at and the C5C2, positions C3 and C5 were positions also tested were also with testedtert-butyl with cinnamyltert-butyl carbonate,cinnamyl carbonate, providing providing excellent excellent branched-to-linear branched-to-linear selectivities selectivities (94:6 (94:6 to to 99:1), 99:1), enantioselectivities enantioselectivities (96–99%) and and yields (21–95%). (21–95%). It Itshould should be be noted noted that that the the parent parent indoles, indoles, 2-methylindole 2-methylindole and and 2- 2-phenylindole,phenylindole, were were allylate allylatedd selectively selectively at at the the C3 C3 position. position. At At the the same same time, 7-azaindole successfully underwent N-allylation-allylation in in a a high high NN toto C3 C3 ratio ratio (9:1) (9:1) and and branched-to-linear branched-to-linear selectivity selectivity (91:9). (91:9). The The chiral chiral N- Nsubstituted-substituted 7-azaindole 7-azaindole product product was wasisolated isolated with witha 79% a yield 79% yieldand 99% and ee 99%. ee.

Symmetry 2020, 12, 1184 18 of 30 Symmetry 2020, 12, x FOR PEER REVIEW 18 of 29 Symmetry 2020, 12, x FOR PEER REVIEW 18 of 29

Scheme 24. Ir-catalyzed N-allylation of indoles. Scheme 24.24. Ir-catalyzed N-allylation ofof indoles.indoles.

An eefficientfficient routeroute forfor thethe synthesissynthesis ofof chiralchiral indolopiperazinonesindolopiperazinones was proposed by You andand coworkers (Scheme 2525))[ [53].53]. The The intramolecular allylic allylic amination amination of of indole derivatives 121 waswas catalyzed byby an iridium(I) NHCNHC complexcomplex generatedgenerated fromfrom thethe saltsalt 123123 andand [Ir(cod)Cl][Ir(cod)Cl]2 in the presence catalyzed by an iridium(I) NHC complex generated from the salt 123 and [Ir(cod)Cl]22 in the presence of DBU in dichloromethane at room temperature. The model reaction provided N-selective products withwith highhigh yieldsyields (82%)(82%) andand excellentexcellent eeee valuesvalues (99%).(99%). The amount of Ir complex could be reduced to 1.251.25 mol%mol% withoutwithout aaffectingffecting thethe reactionreaction outcomeoutcome (80%(80% yield,yield, 96%96% ee).ee). Indole derivatives containing electron-donating and electron-withdrawing groups at the C5 or C6 positionspositions were examinedexamined inin allylation reactions, aaffordingffording the desired productsproducts 122 withwith goodgood yieldsyields (77–91%)(77–91%) andand excellentexcellent 2 enantioselectivities (97–99% ee). Substrates with variousvarious substituents R2 (Bn, Me, allyl and PMB) onon thethe amide nitrogen atomatom werewere wellwell toleratedtolerated (77–89%(77–89% yieldsyields andand 96–99%96–99% eeee,, respectively).respectively). The authors also separately synthesized an Ir complex 124 and demonstrated its catalytic eefficiencyfficiency in asymmetric intramolecularintramolecular cyclizationcyclization (93%(93% yield,yield, 99%99% eeee).). These results were comparable to the results obtainedobtained withwith anan inin situsitu formedformed catalystcatalyst (82%(82% yield,yield, 99%99% eeee).).

Scheme 25. Ir-catalyzed synthesis of chiral indolo- and pyrrolopiperazinones. Scheme 25. Ir-catalyzed synthesis of chiral indolo- and pyrrolopiperazinones.

Xiao etet al.al. reported a highlyhighly stereoselectivestereoselective Pd-catalyzedPd-catalyzed NN-functionalization of indoles in thethe presencepresence ofof chiral sulfoxide-phosphines (Scheme(Scheme 2626))[ [54].54]. The reaction of methyl indole-2-carboxylate withwith racemicracemic ((EE)-1,3-diphenylallyl)-1,3-diphenylallyl acetate was eefficientﬃcient andand stereoselective in the presence of a catalytic system derived from [Pd(C3H5)Cl]2, sulfoxide-phosphine ligand 128 and cesium carbonate catalytic systemsystem derivedderived fromfrom [Pd(C[Pd(C33HH55)Cl]2,, sulfoxide-phosphine sulfoxide-phosphine ligand ligand 128 and cesium carbonatecarbonate in dichloromethane at 40 °C (99% yield, 97% ee). The scope of the reaction was performed with various inin dichloromethane dichloromethane at at 40 40 °C◦ C(99% (99% yield, yield, 97% 97% ee). eeThe). scope The scope of the ofreaction the reaction was performed was performed with various with varioussubstituted substituted indoles indoles125 and125 allyland acetates allyl acetates 126. Both126. C2- Both and C2- C3-substituted and C3-substituted indoles indoles tolerated tolerated the thereaction, reaction, demonstrating demonstrating good good to excellent to excellent enantiosel enantioselectivitiesectivities (75–97%) (75–97%) and moderate and moderate to high to yields high yields(58–95%) (58–95%) of the corresponding of the corresponding N-alkylatedN-alkylated indoles indoles 127. Interestingly,127. Interestingly, 2-vinyl 2-vinyl indole indole afforded aﬀorded an N/C- an dialkylated product as a single diastereomer with good yields (74%) and high enantioselectivity (93%). At the same time, 2-vinyl 7-chloroindole gave an exclusively C3-alkylated product. The scope

Symmetry 2020, 12, 1184 19 of 30

N/C-dialkylated product as a single diastereomer with good yields (74%) and high enantioselectivity Symmetry(93%).Symmetry At 2020 2020 the, ,12 12 same, ,x x FOR FOR time, PEER PEER 2-vinyl REVIEW REVIEW 7-chloroindole gave an exclusively C3-alkylated product. The scope1919 of of 29 of29 allyl acetates revealed that acetates containing phenyl rings aﬀorded products with high yields (89–95%) of allyl acetates revealed that acetates containing phenyl rings afforded products with high yields andof allyl excellent acetatesee values revealed (94–96%). that acetates The reaction containing with phenyl a sterically rings less afforded hindered products 1-methyl-3-phenylallyl with high yields (89–95%) and excellent ee values (94–96%). The reaction with a sterically less hindered 1-methyl-3- acetate(89–95%) was and regioselective excellent ee and values had (94–96%). a high yield The (98%), reaction but a with decrease a sterically in enantioselectivity less hindered was 1-methyl-3- detected phenylallyl acetate was regioselective and had a high yield (98%), but a decrease in enantioselectivity (65%).phenylallyl The cyclic acetate acetate was regioselective aﬀorded the desired and had product a high yield with a(98%), low ee butvalue a decrease (23%). in enantioselectivity waswas detected detected (65%). (65%). The The cyclic cyclic acetate acetate afforded afforded the the desired desired product product with with a a low low ee ee value value (23%). (23%).

SchemeSchemeScheme 26. 26.26. Pd-catalyzed Pd-catalyzedPd-catalyzed N NN-functionalization-functionalization-functionalization of ofof indoles. indoles.indoles. Recently, Krische and co-workers demonstrated an efficient asymmetric intermolecular Recently,Recently, Krische Krische and and co-workers co-workers demonstrated demonstrated an an efficient efficient asymmetric asymmetric intermolecular intermolecular Tsuji– Tsuji– Tsuji–Trost-type indole N-allylation, where complete N-regioselectivity and regioselectivity towards Trost-typeTrost-type indoleindole NN-allylation,-allylation, wherewhere completecomplete NN-regioselectivity-regioselectivity andand regioselectivityregioselectivity towardstowards branched products were achieved (Scheme 27, I)[6]. The reaction was smoothly catalyzed by branchedbranched productsproducts werewere achievedachieved (Scheme(Scheme 27,27, II) ) [6].[6]. TheThe reactionreaction wawass smoothlysmoothly catalyzedcatalyzed byby cyclometallated p-allyliridium C,O-benzoates modified with (S)-tol-BINAP 132 under basic conditions. cyclometallatedcyclometallated pp-allyliridium-allyliridium C,OC,O-benzoates-benzoates modifiedmodified withwith (S)-tol-BINAP(S)-tol-BINAP 132132 underunder basicbasic A wide range of various substituted indoles 129 reacted with high levels of enantiomeric enrichment conditions.conditions. A A wide wide range range of of various various substituted substituted indoles indoles 129 129 reacted reacted with with high high levels levels of of enantiomeric enantiomeric (88–93%), affording products 131 with moderate to excellent yields (60–96%). The parent indole was enrichmentenrichment (88–93%), (88–93%), affording affording products products 131 131 with with moderate moderate to to excellent excellent yields yields (60–96%). (60–96%). The The parent parent successfully alkylated with diverse α-substituted allyl acetates 130 containing alkyl groups, phenyl, indoleindole waswas successfullysuccessfully alkylatedalkylated withwith diversediverse αα-substituted-substituted allylallyl acetatesacetates 130130 containingcontaining alkylalkyl benzyl ether and methyl sulfide moieties (65–79% yield, 91–93% ee). Furthermore, α-cycloalkyl groups,groups, phenyl, phenyl, benzyl benzyl ether ether and and methyl methyl sulfide sulfide moieties moieties (65–79% (65–79% yield, yield, 91–93% 91–93% ee ee).). Furthermore, Furthermore, α α-- substituted allyl acetates 130 tolerated the reaction well, affording N-functionalized indoles with cycloalkylcycloalkyl substitutedsubstituted allylallyl acetatesacetates 130130 toleratedtolerated thethe reactionreaction well,well, affordingaffording NN-functionalized-functionalized good yields (60–76%) and high ee values (90–92%). The authors also demonstrated the intramolecular indolesindoles with with good good yields yields (60–76%) (60–76%) and and high high ee ee values values (90–92%). (90–92%). The The authors authors also also demonstrated demonstrated the the cyclization of the racemic indole adduct 133 under optimized conditions (Scheme 27, II). The desired intramolecularintramolecular cyclization cyclization of of the the racemic racemic indole indole adduct adduct 133 133 under under optimized optimized conditions conditions (Scheme (Scheme 27, 27, chiral tricyclic N-allylated indole 134 was isolated with high yields and high enantioselectivity (80% IIII).). TheThe desireddesired chiralchiral tricyclictricyclic NN-allylated-allylated indoleindole 134134 waswas isolatedisolated withwith highhigh yieldsyields andand highhigh yield, 89% ee). enantioselectivityenantioselectivity (80% (80% yield, yield, 89% 89% ee ee).).

SchemeSchemeScheme 27. 27.27. Highly HighlyHighly selective selectiveselective Ir-catalyzed Ir-catalyzedIr-catalyzed allylation allylationallylation of ofof indoles. indoles.indoles. 4.3. Aminations of Alkenes with Indoles 4.3.4.3. Aminations Aminations of of Alkenes Alkenes with with Indoles Indoles An iridium-catalyzed highly selective intermolecular N-H addition of indoles 135 to inactivated AnAn iridium-catalyzed iridium-catalyzed highly highly selective selective intermolecular intermolecular N-H N-H addition addition of of indoles indoles 135 135 to to inactivated inactivated terminal oleﬁns 136 was investigated by Hartwig’s group [55]. The reaction proceeded according terminalterminal olefins olefins 136 136 was was investigated investigated by by Hartwig’s Hartwig’s group group [55]. [55]. The The reaction reaction proceeded proceeded according according to to to Markovnikov’s selectivity in the presence of a catalytic amount of [Ir(cod)Cl]2 2 and a chiral bulky Markovnikov’sMarkovnikov’s selectivityselectivity inin thethe presencepresence ofof aa catalyticcatalytic amountamount ofof [Ir(cod)Cl][Ir(cod)Cl] 2 andand aa chiralchiral bulkybulky DTMB-SEGPHOS ligand 139 (Scheme 28, I). The authors found that the addition of ethyl acetate to the DTMB-SEGPHOSDTMB-SEGPHOS ligand ligand 139 139 (Scheme (Scheme 28, 28, I I).). The The authors authors found found that that the the addition addition of of ethyl ethyl acetate acetate to to thethe reaction reaction mixture mixture increased increased the the rate rate and and yield yield of of the the reaction. reaction. Various Various substituted substituted indoles indoles and and α α-- olefinsolefins substrates substrates were were examined examined in in an an enantiosel enantioselectiveective hydroamination hydroamination reaction. reaction. The The study study of of the the scopescope ofof thethe indolesindoles withwith 1-octene1-octene revealedrevealed thatthat C3-,C3-, C5-C5- andand C6-substitutedC6-substituted indolesindoles toleratedtolerated thethe reactionreaction successfully successfully affording affording products products with with moderate moderate to to good good enanti enantioselectivitiesoselectivities (45–75% (45–75% ee ee)) and and

Symmetry 2020, 12, 1184 20 of 30 reaction mixture increased the rate and yield of the reaction. Various substituted indoles and α-olefins substrates were examined in an enantioselective hydroamination reaction. The study of the scope of the indoles with 1-octene revealed that C3-, C5- and C6-substituted indoles tolerated the reaction successfullySymmetry 2020, 12 aff, ordingx FOR PEER products REVIEW with moderate to good enantioselectivities (45–75% ee) and yields20 of 29 (58–88%). There were no reactions in the case of 2- or 7-substituted indoles. The electron density of yields (58–88%). There were no reactions in the case of 2- or 7-substituted indoles. The electron the indole core did not noticeably affect the reaction outcome. The scope of α-olefins demonstrated density of the indole core did not noticeably affect the reaction outcome. The scope of α-olefins the influence of the β-substituent on the reaction rate, yield and enantioselectivity (39–70%, 4–67% demonstrated the influence of the β-substituent on the reaction rate, yield and enantioselectivity (39– ee, respectively). For instance, yields of products derived from bulky substituted olefins were lower 70%, 4–67% ee, respectively). For instance, yields of products derived from bulky substituted olefins than with 1-octene based products. Moreover, significant amounts of vinylindoles 138 as side products were lower than with 1-octene based products. Moreover, significant amounts of vinylindoles 138 as were determined (20–30%). In some cases, the reaction conditions were modified in order to get better side products were determined (20–30%). In some cases, the reaction conditions were modified in results. A drastic decline in ee value (4–5%) was detected when tert-butylpropene was used as a order to get better results. A drastic decline in ee value (4–5%) was detected when tert-butylpropene starting compound. was used as a starting compound.

Scheme 28. Ir-catalyzed hydroamination of alkenesalkenes withwith indoles.indoles.

According to mechanisticmechanistic and computationalcomputational studies,studies, the authors proposed the mechanismmechanism of thethe reactionreaction thatthat isis outlinedoutlined inin SchemeScheme 2828,, IIII.. TheThe olefinolefin insertioninsertion intointo thethe IrIr−N bond of anan NN-indolyl-indolyl − complex 135c135cis is faster faster than than the the insertion insertion of olefin of olefin into theinto Ir theCbond Ir−C ofbond the isomericof the isomeric C-2-indolyl C-2-indolyl complex − 135bcomplex(resting 135b state). (resting This state). feature This determines feature determines the N-selectivity the N-selectivity of the addition of the of addition olefin. The of olefin. formation The offormation vinylindole of vinylindole as a side product as a side and product the racemization and the racemization of the product of were the product also explained were also and explained discussed basedand discussed on mechanistic based on studies. mechanistic studies. Chiral N,,O-aminals-aminals 143 werewere obtainedobtained byby thethe stepwisestepwise metal-catalyzedmetal-catalyzed synthesissynthesis from alkoxyallenes 141 and indoles 140 (Scheme(Scheme 2929,, II)[) [5].5]. The addition of indoleindole 140 toto alleneallene proceededproceeded exclusively at the N-position aaffordingffording unsaturatedunsaturated adductsadducts 142142.. The obtained N,OO--aminalsaminals 142 were subjected toto a ring-closing metathesis reactionreaction catalyzedcatalyzed byby GrubbsGrubbs 1st1st generationgeneration catalyst.catalyst. The cyclic productsproducts 143143were were isolated isolated with with a nearly a nearly quantitative quantitative yield. yield. The authorsThe authors determined determined the critical the impactcritical ofimpact the chiral of the ligand chiral 102ligandon the102 Pd-catalyzedon the Pd-catalyzed reaction. reaction. In the caseIn the of case ligand of ligand114 the 114 conversion the conversion of the reactionof the reaction nearly stopped.nearly stopped. The scope The of scope the reaction of the reaction demonstrated demonstrated that indoles thatwith indoles electron-donating with electron- ordonating electron-withdrawing or electron-withdrawing groups tolerated groups tolerated the reaction the reaction well, providing well, providing products products with high with yields high yields (87–98%) and ee values (85–93%). It is important to mention that the ester group at the C7 position of the indole decreased the rate of the reaction but the product was still isolated with good yields and excellent enantiomeric excess (70%, >99%, respectively). Indoles bearing substituents at C2-position afforded chiral products with good yields (74–93%) and excellent ees (95–98%). The obtained products were successfully converted into various pyranosylated and furanosylated glycosides 144 through stereoselective dihydroxylation by osmium tetraoxide. According to their

Symmetry 2020, 12, 1184 21 of 30

(87–98%) and ee values (85–93%). It is important to mention that the ester group at the C7 position of the indole decreased the rate of the reaction but the product was still isolated with good yields and excellent enantiomeric excess (70%, >99%, respectively). Indoles bearing substituents at C2-position aﬀorded chiral products with good yields (74–93%) and excellent ees (95–98%). The obtained products wereSymmetry successfully 2020, 12, x FOR converted PEER REVIEW into various pyranosylated and furanosylated glycosides 144 through21 of 29 stereoselective dihydroxylation by osmium tetraoxide. According to their DFT calculations, the authors proposedDFT calculations, the mechanism the authors of the proposed Pd-catalyzed the mechanism reaction that of isthe outlined Pd-catalyzed in Scheme reaction 29, II that. is outlined in Scheme 29, II.

SchemeScheme 29.29. Pd-catalyzed synthesis of chiral N,,OO-aminals.-aminals.

TheThe enantioselective NN-alkylation-alkylation ofof indoles via an intermolecular intermolecular aza-Wacker-type reactionreaction waswas reportedreported byby SigmanSigman etet al.al. (Scheme 3030,, II)[) [56].56]. The formation of the desired productproduct 147 waswas possiblepossible onlyonly ifif selectiveselective ββ-H-Hbb eliminationelimination of of the unsaturated comp compoundound was guaranteed (Scheme 30,30, II). Otherwise,Otherwise, thethe classicclassic enamineenamine productproduct waswas formed.formed. TheThe Pd-catalyzedPd-catalyzed reactionreaction proceededproceeded betweenbetween 3-substituted3-substituted indoles 145 andand 1,2-disubstituted1,2-disubstituted alkene 146 inin thethe aproticaprotic solventsolvent (dichloromethane)(dichloromethane) inin thethe presencepresence ofof aa chiralchiral ligandligand 148148,, basebase (DTBMP)(DTBMP) andand oxidantoxidant ((pp-benzoquinone).-benzoquinone). ItIt isis importantimportant thatthat C2C2 productsproducts werewere notnot detected;detected; thethe alkylationalkylation proceededproceeded exclusivelyexclusively atat thetheN N-position.-position. TheThe reactionreaction scopescope waswas performedperformed withwith aa widewide rangerange ofof substitutedsubstituted alkenols,alkenols, demonstratingdemonstrating lowlow toto goodgood yieldsyields (27–78%)(27–78%) andand goodgood toto highhigh erer valuesvalues (91:1(91:1 toto 98:2).98:2). An excellentexcellent functional group tolerance was achievedachieved and highly reactive tosyl- or halide-containing alkenols were compatible with the reaction. TheThe indoleindole scopescope revealedrevealed thatthat thethe electronic nature ofof 3-phenylindole did not signiﬁcantlysignificantly aaffectﬀect thethe reactionreaction outcomeoutcome (69–82%(69–82% yields,yields, 95:595:5 toto 96:496:4 erer).). The authors conducted a series of deuterium-labeled experimentsexperiments thatthat provedproved aa syn-aminopalladationsyn-aminopalladation pathwaypathway forfor thisthis reaction.reaction.

Scheme 30. N-alkylation of indoles via an aza-Wacker-type reaction.

Symmetry 2020, 12, x FOR PEER REVIEW 21 of 29

DFT calculations, the authors proposed the mechanism of the Pd-catalyzed reaction that is outlined in Scheme 29, II.

Scheme 29. Pd-catalyzed synthesis of chiral N,O-aminals.

The enantioselective N-alkylation of indoles via an intermolecular aza-Wacker-type reaction was reported by Sigman et al. (Scheme 30, I) [56]. The formation of the desired product 147 was possible only if selective β-Hb elimination of the unsaturated compound was guaranteed (Scheme 30, II). Otherwise, the classic enamine product was formed. The Pd-catalyzed reaction proceeded between 3-substituted indoles 145 and 1,2-disubstituted alkene 146 in the aprotic solvent (dichloromethane) in the presence of a chiral ligand 148, base (DTBMP) and oxidant (p-benzoquinone). It is important that C2 products were not detected; the alkylation proceeded exclusively at the N-position. The reaction scope was performed with a wide range of substituted alkenols, demonstrating low to good yields (27–78%) and good to high er values (91:1 to 98:2). An excellent functional group tolerance was achieved and highly reactive tosyl- or halide-containing alkenols were compatible with the reaction. The indole scope revealed that the electronic nature of 3-phenylindole did not significantly affect the Symmetryreaction2020 outcome, 12, 1184 (69–82% yields, 95:5 to 96:4 er). The authors conducted a series of deuterium-labeled22 of 30 experiments that proved a syn-aminopalladation pathway for this reaction.

SchemeScheme 30.30. NN-alkylation-alkylation ofof indolesindoles viavia anan aza-Wacker-typeaza-Wacker-type reaction.reaction.

4.4.Symmetry Copper-Catalyzed 2020, 12, x FOR N-Selective PEER REVIEW Additions of Indoles to Alkylhalides 22 of 29

4.4.In recentCopper-Catalyzed years, stereoselective N-Selective Addi visible-lighttions of Indoles photocatalysis to Alkylhalides has received considerable attention from the synthetic community due to the unique activation mode of the substrates [57,58]. The photoinduced In recent years, stereoselective visible-light photocatalysis has received considerable attention Cu-catalyzed enantioconvergent N-selective cross-coupling of 3-substituted indoles and carbazoles from the synthetic community due to the unique activation mode of the substrates [57,58]. The with racemic tertiary alkyl halides was described by Fu et al. (Scheme 31, I)[59]. The strategy of photoinduced Cu-catalyzed enantioconvergent N-selective cross-coupling of 3-substituted indoles the reactionand carbazoles is based with on racemic the activation tertiary alkyl of hali andes electrophile was described via theby Fu formation et al. (Scheme of the 31, stableI) [59]. tertiaryThe radicalstrategy that isof involvedthe reaction in theis based enantioselective on the activation process. of an A electrophile copper salt via serves the formation as the photocatalyst of the stable and, togethertertiary with radical the chiral that ligandis involved152, isin responsible the enantioselective for the enantioselective process. A copper bond-forming salt serves process. as the The reactionphotocatalyst was studied and, with together a wide with range the chiral of carbazole ligand 152 derivatives,, is responsible 3-substituded for the enantioselective indoles 149 and bond- various α-halocarbonylforming process. compounds The reaction150 was. The studied scope with of the a wiNde-coupling range of carbazole partner demonstrated derivatives, 3-substituded high levels of stereocontrolindoles 149 despite and various its electronic α-halocarbonyl and steric naturecompounds (88–94% 150.ee The); the scope products of the were N-coupling obtained partner with good to excellentdemonstrated yields high (79–89%). levels of The stereocontrol electronic edespﬀectsite of its the electronic indoline and amide steric group nature and (88–94% variations ee); the of the amideproducts groups were tolerated obtained the with reaction good well,to excellent providing yields products (79–89%).151 Thewith electronic excellent effects enantioselectivities of the indoline (90–96%amideee group) and moderateand variations to high of the yields amide (73–92%). groups tolerated the reaction well, providing products 151 with excellent enantioselectivities (90–96% ee) and moderate to high yields (73–92%).

SchemeScheme 31. 31.Cu-catalyzed Cu-catalyzedN N-functionalization-functionalization of of indole indole derivatives. derivatives.

Fu andFu and co-workers co-workers continued continued to to study study thethe enantioselectiveenantioselective Cu-catalyzed Cu-catalyzed N-alkylationN-alkylation of indole of indole derivativesderivatives with withα-halocarbonyl α-halocarbonyl compounds compounds (Scheme(Scheme 31,31 ,IIII))[ [60].60]. Secondary Secondary alkyl alkyl iodides iodides 154 154werewere usedused as coupling as coupling partners partners in in a photocatalytica photocatalytic reactionreaction for the the preparation preparation of ofchiral chiral 3-indolyl 3-indolyl lactams lactams 155 but the results were unsatisfactory (<1% ee, 24% yield). The screening of the reaction conditions 155 but the results were unsatisfactory (<1% ee, 24% yield). The screening of the reaction conditions revealed that the reaction occurred under nonphotocatalytic conditions in the absence of light and in revealed that the reaction occurred under nonphotocatalytic conditions in the absence of light and the presence of Cu-Mes, a chiral monodentate phosphine ligand 156 and cesium carbonate at room temperature in m-xylene. The catalytic method was not air- or moisture-sensitive. The scope of the electrophiles showed that various N-substituted aromatic and alkyl lactams 154 tolerated the reaction well despite the electronic properties of the substituents. When alkyl bromide was used instead of iodide as an electrophile, a slight decrease in yield (60% vs. 73%) and a comparable value of ee were determined (ee 88%). The yield was improved up to 85% by an increase in the amount of electrophile from 1.5 equivalent to 2.0 equivalent. The authors conducted a series of experiments where the ee of the unreacted electrophile and the yield of the product were monitored during the reaction. These experiments revealed that the asymmetric N-alkylation of an indole with racemic alkyl bromide proceeded via a simple kinetic resolution but, in the case of alkyl iodide, a dynamic kinetic resolution occurred.

5. Other Direct Methods Chiral N,N′-acyl aminals were prepared from indoles and N-Boc or N-Cbz imines in the presence of a dinuclear zinc–prophenol complex (Scheme 32) [61]. The method was characterized by high N/C3 regioselectivity, which was maintained due to the application of carbamate-protected imines 160. The choice of the solvent also drastically affected the regioselectivity of the reaction. For example, the N-

Symmetry 2020, 12, 1184 23 of 30 in the presence of Cu-Mes, a chiral monodentate phosphine ligand 156 and cesium carbonate at room temperature in m-xylene. The catalytic method was not air- or moisture-sensitive. The scope of the electrophiles showed that various N-substituted aromatic and alkyl lactams 154 tolerated the reaction well despite the electronic properties of the substituents. When alkyl bromide was used instead of iodide as an electrophile, a slight decrease in yield (60% vs. 73%) and a comparable value of ee were determined (ee 88%). The yield was improved up to 85% by an increase in the amount of electrophile from 1.5 equivalent to 2.0 equivalent. The authors conducted a series of experiments where the ee of the unreacted electrophile and the yield of the product were monitored during the reaction. These experiments revealed that the asymmetric N-alkylation of an indole with racemic alkyl bromide proceeded via a simple kinetic resolution but, in the case of alkyl iodide, a dynamic kinetic resolution occurred.

5. Other Direct Methods

Chiral N,N0-acyl aminals were prepared from indoles and N-Boc or N-Cbz imines in the presence of a dinuclear zinc–prophenol complex (Scheme 32)[61]. The method was characterized by high N/C3 regioselectivity, which was maintained due to the application of carbamate-protected imines Symmetry 2020, 12, x FOR PEER REVIEW 23 of 29 160. The choice of the solvent also drastically affected the regioselectivity of the reaction. For example, the N-substituted product was formed with a 61% yield if THF was used as a solvent and with a 14% substituted product was formed with a 61% yield if THF was used as a solvent and with a 14% yield yield with toluene. Although the complete N-selectivity of the alkylation was not achieved, N-alkylated with toluene. Although the complete N-selectivity of the alkylation was not achieved, N-alkylated products 161 were easily separable from C3-alkylated products. The study of the substrate scope was products 161 were easily separable from C3-alkylated products. The study of the substrate scope was performed with a wide range of substituted indoles. Higher yields were obtained when 3-substituted performed with a wide range of substituted indoles. Higher yields were obtained when 3-substituted indoles were applied. Moreover, the sterical hindrance of the protection group of the imine affected indoles were applied. Moreover, the sterical hindrance of the protection group of the imine affected the reaction yield. Substrates with the Cbz group were more reactive than the Boc-substrates. The the reaction yield. Substrates with the Cbz group were more reactive than the Boc-substrates. The reactions of Cbz-imines with indoles proceeded at a lower temperature (4 C) without any loss of reactions of Cbz-imines with indoles proceeded at a lower temperature (4 ◦°C) without any loss of yield and with improved enantioselectivity. To demonstrate the generality of the proposed method, yield and with improved enantioselectivity. To demonstrate the generality of the proposed method, the authors extended the reaction scope to other nitrogen-containing heterocycles, such as carbazole the authors extended the reaction scope to other nitrogen-containing heterocycles, such as carbazole 159 and methyl pyrrole-2-carboxylate 157. The reactions proceeded smoothly affording N-alkylated 159 and methyl pyrrole-2-carboxylate 157. The reactions proceeded smoothly affording N-alkylated products 161 with moderate to high yields (52–86%) and with high to excellent er values (96:4 to products 161 with moderate to high yields (52–86%) and with high to excellent er values (96:4 to 99.5:0.5). The chiral N-alkylated products could be efficiently functionalized further, providing new 99.5:0.5). The chiral N-alkylated products could be efficiently functionalized further, providing new classes of valuable heterocycles. classes of valuable heterocycles.

SchemeScheme 32.32. SynthesisSynthesis ofof chiralchiral NN,,NN0′-acyl aminals.

PropargylicPropargylic compoundscompounds areare importantimportant buildingbuilding blocksblocks inin syntheticsynthetic chemistrychemistry becausebecause theythey cancan bebe transformedtransformed intointo aa widewide rangerange ofof organicorganic derivatives,derivatives, includingincluding heterocyclesheterocycles [[62,63].62,63]. ShaoShao andand coworkerscoworkers investigatedinvestigated the the enantioselective enantioselectiveN -propargylationN-propargylation of indolesof indoles and and carbazoles carbazoles (Scheme (Scheme 33)[ 6433)]. The[64]. method The method was based was onbased the inon situ the generation in situ generation of alkynyl ofN alkynyl-Cbz or NN-Boc-Cbz imines or N-Boc163a iminesfrom N 163a,O-acetals from 163N,Ofollowed-acetals 163 by followed the nucleophilic by the nucleophilicN-addition N of-addition indole derivatives of indole derivatives164. The reaction 164. The was reaction smoothly was catalyzedsmoothly bycatalyzed chiral lithium by chiral SPINOL lithium phosphate SPINOL166 phosphate, which was 166 responsible, which was for responsible the elimination for the of ethanolelimination from ofN ,Oethanol-acetal andfrom participated N,O-acetal inand the participated transition state in ofthe the transition reaction, providingstate of the an excellentreaction, providing an excellent level of stereocontrol (ee up to 99 %). The reaction proceeded with a very low catalyst loading without a significant loss of enantioselectivity or yield. Even 0.1 mol% of the catalyst still provided high enantioselectivity and yield (92% and 72%, respectively).

Scheme 33. Asymmetric N-propargylation of indoles.

A CuH-catalyzed regiodivergent method for the synthesis of chiral indoles was recently reported by Buchwald et al. (Scheme 34) [7]. This synthetic route has two distinctive features: the application of indole 167 as an electrophile and facile access to either N- or C3-alkylated indole

Symmetry 2020, 12, x FOR PEER REVIEW 23 of 29

substituted product was formed with a 61% yield if THF was used as a solvent and with a 14% yield with toluene. Although the complete N-selectivity of the alkylation was not achieved, N-alkylated products 161 were easily separable from C3-alkylated products. The study of the substrate scope was performed with a wide range of substituted indoles. Higher yields were obtained when 3-substituted indoles were applied. Moreover, the sterical hindrance of the protection group of the imine affected the reaction yield. Substrates with the Cbz group were more reactive than the Boc-substrates. The reactions of Cbz-imines with indoles proceeded at a lower temperature (4 °C) without any loss of yield and with improved enantioselectivity. To demonstrate the generality of the proposed method, the authors extended the reaction scope to other nitrogen-containing heterocycles, such as carbazole 159 and methyl pyrrole-2-carboxylate 157. The reactions proceeded smoothly affording N-alkylated products 161 with moderate to high yields (52–86%) and with high to excellent er values (96:4 to 99.5:0.5). The chiral N-alkylated products could be efficiently functionalized further, providing new classes of valuable heterocycles.

Scheme 32. Synthesis of chiral N,N′-acyl aminals.

Propargylic compounds are important building blocks in synthetic chemistry because they can be transformed into a wide range of organic derivatives, including heterocycles [62,63]. Shao and coworkers investigated the enantioselective N-propargylation of indoles and carbazoles (Scheme 33) [64]. The method was based on the in situ generation of alkynyl N-Cbz or N-Boc imines 163a from SymmetryN,O-acetals2020, 12163, 1184 followed by the nucleophilic N-addition of indole derivatives 164. The reaction24 ofwas 30 smoothly catalyzed by chiral lithium SPINOL phosphate 166, which was responsible for the elimination of ethanol from N,O-acetal and participated in the transition state of the reaction, level of stereocontrol (ee up to 99 %). The reaction proceeded with a very low catalyst loading without providing an excellent level of stereocontrol (ee up to 99 %). The reaction proceeded with a very low a signiﬁcant loss of enantioselectivity or yield. Even 0.1 mol% of the catalyst still provided high catalyst loading without a significant loss of enantioselectivity or yield. Even 0.1 mol% of the catalyst enantioselectivity and yield (92% and 72%, respectively). still provided high enantioselectivity and yield (92% and 72%, respectively).

SchemeScheme 33.33. AsymmetricAsymmetric NN-propargylation-propargylation ofof indoles.indoles.

AA CuH-catalyzedCuH-catalyzed regiodivergent regiodivergent method method for thefor synthesisthe synthesis of chiral of indoleschiral wasindoles recently was reportedrecently byreported Buchwald by Buchwald et al. (Scheme et al. 34 (Sch)[7].eme This 34) synthetic [7]. This route synthetic has two route distinctive has two features: distinctive the features: application the ofapplication indoleSymmetry167 2020 ofas, 12indole an, x FOR electrophile 167PEER asREVIEW an and electrophile facile access andto facile either accessN- or to C3-alkylated either N- or indole C3-alkylated products24 of indole29 (169 or 172). The regioselectivity of the reaction was eﬃciently controlled by a chiral ligand 170 or 173 products (169 or 172). The regioselectivity of the reaction was efficiently controlled by a chiral ligand a ﬀording either N-alkylated products 169 with high selectivity (>20:1) or C3-alkylated products 172 170 or 173 affording either N-alkylated products 169 with high selectivity (>20:1) or C3-alkylated with a moderate to high ratio (3:1 to >20:1). N-alkylation was achieved via N-oxidative addition of the products 172 with a moderate to high ratio (3:1 to >20:1). N-alkylation was achieved via N-oxidative alkylcopper(I)addition of the complex alkylcopper(I) followed complex reductive followed elimination. reductive elimination.

SchemeScheme 34. 34.Ligand-controlled Ligand-controlled regiodivergentregiodivergent Cu-catalyzed Cu-catalyzed alkylation alkylation of indoles. of indoles.

TheTheN-alkylation N-alkylation of indoles of indoles was was performed performed with with various various styrene styrene derivatives derivatives168 a ff168ording affording products withproducts moderate with to goodmoderate yields to (41–85%)good yields with (41–85%) good to with excellent goodee tovalues excellent (81–99%). ee values The (81–99%). exceptions The were 4-methoxy-exceptions and were 4-trifluoromethylstyrenes, 4-methoxy- and 4-trifluoromethylstyrenes, which gave the desired which productsgave the withdesired low products yields (10%with and low yields (10% and 17%, respectively). The scope of indole electrophiles revealed that a wide range 17%, respectively). The scope of indole electrophiles revealed that a wide range of substituted indoles of substituted indoles tolerated the reaction well. Notably, the 2-carbomethoxyindole was not tolerated the reaction well. Notably, the 2-carbomethoxyindole was not reactive enough and provided reactive enough and provided a racemic product with a low yield. Moreover, C3-substituted indole ee a racemicreacted product with a low with yield a low and yield. ee (16% Moreover, yield, 17% C3-substituted ee). indole reacted with a low yield and (16% yield, 17% ee). 6. Transition-Metal Catalyzed Indirect Methods 6. Transition-Metal Catalyzed Indirect Methods Chiral α-N-branched indoles were obtained from the corresponding indolines by transition- metalChiral catalyzedα-N-branched N-alkylation/oxidation indoles were obtained sequences from (Scheme the corresponding 35). The application indolines of this by route transition-metal was first catalyzedreportedN-alkylation by You’s group/oxidation in 2012 sequences (Scheme (Scheme35, I) [65]. 35 The). The chiral application N-allylindoles of this 177 route were was synthesized first reported by You’svia a groupone-pot in iridium-catalyzed 2012 (Scheme 35 ,allylicI)[65 ].amination The chiral ofN indolines-allylindoles 174 followed177 were by synthesized dehydrogenation via a one-pot of iridium-catalyzedthe resulting N-substituted allylic amination indolines of 176 indolines with DDQ174 followed(2,3-dichloro-5,6-dicyano-1,4- by dehydrogenation benzoquinone). of the resulting The method was characterized by a broad substrate scope. The electron deficient and electron rich aryl allyl carbonates afforded the desired products with excellent yields (87–92%) with superb ees (96–98%). The 2-thienyl- and alkyl-substituted allylcarbonates tolerated the reaction well and the corresponding products were obtained with good to high yields (up to 86%), with high branched-to- linear selectivity (up to 97:3) and excellent ee-values (up to 99%). Various indolines with electron- donating and electron-withdrawing groups at different positions were tested, demonstrating high levels of stereocontrol (92–99% ee; 96:4 to >99:1 r.r.). The same group also described the asymmetric one-pot Pd-catalyzed version of the reaction (Scheme 35, II) [66]. The allylation proceeded smoothly in THF in the presence of 5 mol% of the palladium catalyst, 11 mol% of the Phox ligand 182 and 2 equivalents of Na2CO3 as a base. The obtained chiral indolines 180 were oxidized with DDQ in situ affording corresponding α-N-branched indoles 181. The substrate scope was performed with a wide range of indolines. The electronic properties of the substituents of the indoline core did not affect the reaction outcome, providing the desired chiral indoles with moderate to good yields (72–82%) with excellent ees (93–97%). However, the reaction of 2-phenylindoline with 1,3-diaryl allyl acetate gave a moderate yield but still high enantioselectivity (53% yield, 96% ee, respectively). A drastic decrease in ee was detected when (E)- 1,3-dimethylallyl acetate was used as a coupling partner (48% yield, 39% ee).

Symmetry 2020, 12, 1184 25 of 30

N-substituted indolines 176 with DDQ (2,3-dichloro-5,6-dicyano-1,4- benzoquinone). The method was characterized by a broad substrate scope. The electron deficient and electron rich aryl allyl carbonates afforded the desired products with excellent yields (87–92%) with superb ees (96–98%). The 2-thienyl- and alkyl-substituted allylcarbonates tolerated the reaction well and the corresponding products were obtained with good to high yields (up to 86%), with high branched-to-linear selectivity (up to 97:3) and excellent ee-values (up to 99%). Various indolines with electron-donating and electron-withdrawing groups at different positions were tested, demonstrating high levels of stereocontrol (92–99% ee; 96:4 to >99:1 r.r.). Symmetry 2020, 12, x FOR PEER REVIEW 25 of 29

Scheme 35. Indirect metal-catalyzed strategies for the construction of α-N-branched indoles. Scheme 35. Indirect metal-catalyzed strategies for the construction of α-N-branched indoles. The efficient copper-catalyzed propargylation of indolines with propargylic esters 183 followed The same group also described the asymmetric one-pot Pd-catalyzed version of the reaction by the DDQ oxidation of N-substituted indolines 184 was described by Hu et al. (Scheme 35, III) [67]. (Scheme 35, II)[66]. The allylation proceeded smoothly in THF in the presence of 5 mol% of the Copper salts were used as a metal source which made the method cheaper and easy to handle palladium catalyst, 11 mol% of the Phox ligand 182 and 2 equivalents of Na CO as a base. The obtained compared with the two methods discussed above. A disadvantage of this synthetic2 3 route is stepwise α chiralsynthesis. indolines The180 copperwere oxidized catalyst withmust DDQ be removed, in situ aﬀ ordingand the corresponding methanol evaporated-N-branched after indolesthe 181.propargylation The substrate scopereaction; was then performed the dehydrogenation with a wide of range the chiral of indolines. intermediate The 184 electronic proceeds properties in DCM of the substituentsat room temperature of the indoline in 5 min. core The did propargylation not aﬀect the was reaction catalyzed outcome, with the providing bulky and the structurally desired chiral indolesrigid with chiral moderate tridentate to ketimine good yields P,N, (72–82%)N-ligand 186 with in excellentthe presenceees (93–97%).of Cu salt and However, base. The the authors reaction of admitted that the type of copper salt did not noticeably affect the reaction outcome, but the role of the base was critical. When the reaction was performed without a basic additive, the product was formed with a low yield and enantioselectivity (45% yield, 25% ee). The addition of a base increased the yield and stereoselectivity of the reaction. Among the bases, the best results were obtained with Hünig’s base (90% yield, 92% ee). Interestingly, the reaction was also catalyzed by an inorganic base, such as potassium carbonate. A one-pot version of the reaction was possible, but the reaction was low-yielding (35% yield, 92% ee). The scope of propargylic esters revealed that the substitution

Symmetry 2020, 12, 1184 26 of 30

2-phenylindoline with 1,3-diaryl allyl acetate gave a moderate yield but still high enantioselectivity (53% yield, 96% ee, respectively). A drastic decrease in ee was detected when (E)-1,3-dimethylallyl acetate was used as a coupling partner (48% yield, 39% ee). The efficient copper-catalyzed propargylation of indolines with propargylic esters 183 followed by the DDQ oxidation of N-substituted indolines 184 was described by Hu et al. (Scheme 35, III)[67]. Copper salts were used as a metal source which made the method cheaper and easy to handle compared with the two methods discussed above. A disadvantage of this synthetic route is stepwise synthesis. The copper catalyst must be removed, and the methanol evaporated after the propargylation reaction; then the dehydrogenation of the chiral intermediate 184 proceeds in DCM at room temperature in 5 min. The propargylation was catalyzed with the bulky and structurally rigid chiral tridentate ketimine P,N,N-ligand 186 in the presence of Cu salt and base. The authors admitted that the type of copper salt did not noticeably affect the reaction outcome, but the role of the base was critical. When the reaction was performed without a basic additive, the product was formed with a low yield and enantioselectivity (45% yield, 25% ee). The addition of a base increased the yield and stereoselectivity of the reaction. Among the bases, the best results were obtained with Hünig’s base (90% yield, 92% ee). Interestingly, the reaction was also catalyzed by an inorganic base, such as potassium carbonate. A one-pot version of the reaction was possible, but the reaction was low-yielding (35% yield, 92% ee). The scope of propargylic esters revealed that the substitution pattern and electronic properties of the phenyl ring had an impact on the yield and stereocontrol of the reaction. For instance, a 2-choloro substituted substrate gave a corresponding product in decreased yield and ee (79% yield, 85% ee) compared with a 4-choloro substituted substrate (91% yield, 91% ee). The reaction with an electron-rich 4-metoxy substituted indoline was slightly less enantioselective (85% yield, 83% ee). The heterocyclic 2-thienyl and 2-naphtyl tolerated the reaction well, affording the products with high yields (88–89%) with 87–91% ee. Methyl- and fluoro-substituted indolines were also applied as coupling partners, providing high yields and ee values (86–91% yield, 88–94% ee). The preparation of chiral N-allylindoles was reported by Dong et al. [68]. The synthetic route was based on the hydroamination of alkynes 187 with indolines via rhodium catalysis, followed by the dehydroaromatization of N-substituted indolines 188 (Scheme 35, IV). Both the parent indoline and 3-methylated indoline tolerated the one-pot reaction well, affording the desired N-substituted indoles with good yields and high ee values (72–77% yield, 85–90% ee, respectively).

7. Conclusions Significant progress has been made over the past two decades in the synthesis of chiral N-alkylated indoles. Direct methods provide an opportunity for the synthesis of chiral N-functionalized indoles in one step from substrates containing an indole core. In some cases, the desired N-regioselectivity could not be gained due to the side reactions that occur at C3- or C2-positions. To avoid this problem C3- or C2-substituted indoles are usually used as starting compounds for the enantioselective N-functionalization. The review illustrates the progress of N-selective functionalization, as only recently was high regioselectivity achieved. Sometimes, the introduction of specific substituents into an indole core is necessary for the activation of the N-position and for the stereocontrol of the reaction. Indirect methods are not as thoroughly studied as direct methods. These methods can afford selective N-alkylation and exclude the problem of regioselectivity. At the same time, multistep synthesis is required for the construction of N-functionalized chiral indoles that make indirect routes less efficient and attractive. The stereoselective functionalization of the N-atom of the indole was successfully achieved by different types of organocatalytic and transition metal catalysis-based methods. These approaches demonstrated efficient routes for the preparation of chiral N-functionalized indoles that could be further modified and could provide facile access to biologically active compounds. Moreover, some methods may be used not only for the construction of chiral N-indoles, but may also find applications in the enantioselective functionalization of other N-heterocyclic compounds, such as indoline, pyrrole and carbazole derivatives. Symmetry 2020, 12, 1184 27 of 30

Author Contributions: Both authors contributed substantially to the work reported. All authors have read and agreed to the published version of the manuscript. Funding: This research was funded by Estonian Ministry of Education and Research (grant No. PRG657) and the Centre of Excellence in Molecular Cell Engineering (2014–2020.4.01.15-0013). Conﬂicts of Interest: The authors declare no conﬂict of interest.

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