2
Metal-Catalyzed Synthesis of 2-Substituted Indoles
For many alkaloids and pharmacologically significant compounds, 2-substituted indoles are important intermediates. Many research groups have focused their work on the synthesis of 2-functionalized indoles, mainly through transition-metal-catalyzed C–H bond activation strategies. Furthermore, photocatalytic approaches have also been used for their synthesis.
In 2012, Maity et al. reported on the ruthenium(II)-catalyzed photocatalytic synthesis of N -arylindoles 8 using an 18 W white-light LED (Scheme [1 ]).[5 ] An appealing methodology involving oxidative C–N bond formation leads to the synthesis of indoles under aerobic oxidation conditions. However, the role of the p -alkoxyphenyl group and the silica gel used in the reaction was not clear, the p -alkoxyphenyl group on the nitrogen atom being essential for the reaction. This methodology is applicable to a broad range of substrates giving the desired indoles in moderate to good yields. Electron-donating and electron-withdrawing groups on the aryl ring were well tolerated. Alkenes with different substituents such as alkanes, alkenes, arenes and furans gave the desired products in good yields and the method was also applicable for the synthesis of 2,3-disubstituted indoles.
Scheme 1 Ruthenium(II)-catalyzed intramolecular photocatalytic synthesis of N -arylindoles
The proposed catalytic cycle for this transformation involves conversion of the amine into a nitrogen-centered radical cation using photoexcited [Ru(bpz)3 ](PF6 )2 , followed by the generation of benzylic radical I . Oxidation of the benzylic radical resulted in benzylic cation II , which finally undergoes aromatization to form the indole ring (Scheme [2 ]).
Scheme 2 Proposed mechanism for the photocatalytic synthesis of N -arylindoles
The involvement of benzylic carbocation II in the visible-light-mediated reaction was further supported by the formation of 2,3-disubstituted indole 10 from gem -styryl-aniline 9 through a 1,2-carbon shift under the optimized reaction conditions (Scheme [3 ]).
Scheme 3 Proof for the involvement of a benzylic carbocation in visible-light-mediated reaction
Scheme 4 Palladium(II)-catalyzed intramolecular synthesis of indoles
In 2012, Yoshikai et al. reported the palladium-catalyzed cyclization reaction of N -arylamines 11 forming C-2 substituted indoles 12 via the oxidative linkage of two C–H bonds (Scheme [4 ]).[6 ] The methodology gave rapid, atom-economic and regioselective access to various indole derivatives under mild reaction conditions using molecular oxygen as the solitary oxidant. Inexpensive and readily available anilines and ketones were used to prepare imines, which were cyclized to form indole moieties; the reaction was also successfully carried out on gram scale. Indole derivatives with heterocyclic substituents such as pyridine and furan at the C-2 position were obtained in excellent yields. This mode of cyclization was also applicable for the synthesis of 2,3-diarylindoles, overcoming the difficulties of the Larock- and Fagnou-type annulation reactions.
The authors observed a KIE value of 5.2 indicating a concerted metalation–deprotonation mechanism. The plausible mechanism for this transformation involves a Pd(II)/Pd(0) redox process proceeding via electrophilic attack of Pd(OAc)2 on enamine III generated via tautomerization (Scheme [5 ]).
Scheme 5 Proposed mechanism for the palladium(II)-catalyzed intramolecular synthesis of indoles
This is followed by elimination of AcOH to give α-palladated imine intermediate IV , which after intramolecular aromatic C–H palladation gave palladacycle V , thus forming a 3H -indole and Pd(0) after reductive elimination. The 3H -indole undergoes tautomerization rapidly to give the indole, while combination of molecular oxygen and AcOH oxidizes Pd(0) back to Pd(II), thus completing the catalytic cycle.
In 2012, Yoshiji Takemoto and co-workers synthesized the indole skeleton 15 using a palladium-catalyzed cascade process involving isocyanide 13 insertion and benzylic C(sp3 )–H activation (Scheme [6 ]).[7 ] This represents the first report on the use of a combination of palladium-catalyzed isocyanide insertion and C(sp3 )–H activation for the synthesis of heterocycles. The synthesis of different 2-arylindoles can be achieved by changing the coupling partners and represents a unique palladium-catalyzed strategy for C–C bond formation between the 2- and 3-position of indole. The slow addition of the isocyanide was adopted to avoid catalyst deactivation. Using different aryl halides 14 as coupling partners resulted in the synthesis of a range of indoles with different substituents. Electron-donating and electron-withdrawing groups at the para position of aryl iodides were well tolerated, whereas the introduction of a methyl group at the ortho position led to a lower yield of the final product. Bromobenzene gave the desired product in good yield, but chlorobenzene did not react under these conditions. Diethylphenyl isocyanide and 2,4-dimethylphenyl isocyanide were also found to unsuitable under the developed conditions.
Scheme 6 A palladium(II)-catalyzed cascade process for the synthesis of 2-substituted indoles
In 2013, Zhang’s group delineated the synthesis N-protected C-2 functionalized indoles 18 through combined gold/zinc catalysis using N -arylhydroxamic acids/N -hydroxycarbamates 16 and alkynes 17 (Scheme [7 ]).[8 ]
Scheme 7 Gold-catalyzed synthesis of 2-susbtituted indoles
The limitations associated with the well-known Fischer indole synthesis and Bartoli reaction, such as strong acidic conditions, regioselectivity, tolerance to sensitive moieties like the Boc protecting group and limited substrate scope, were overcome by employing this synthetic strategy. Indoles with different functional groups, such as aliphatic alkanes, cyclohexane, and cyclopropane, were easily prepared.
Indoles with a methyl group at the C-2 position were favored with high regioselectivity, possibly because of less steric hindrance. The authors proposed that the pathway involves activation of the hydroxamic acid or a related substrate via zinc chelate formation (Scheme [8 ]). Gold-activated alkyne VI was then effectively attacked by the more O-nucleophilic zinc chelate VII , which upon subsequent protodeauration formed a precursor for 3,3-sigmatropic rearrangement. Finally, the Lewis acid Zn(OTf)2 -assisted cyclodehydration leads to the desired indole product.
Scheme 8 Proposed mechanism for the gold-catalyzed synthesis of indoles
In 2013, Cossy’s group carried out the synthesis of 1,2-disubstituted indoles from benzyl alcohols through an iridium-catalyzed hydrogen atom transfer process (Scheme [9 ]).[9 ] p -Benzoquinone was used as the co-oxidant in the reaction.
Scheme 9 Iridium-catalyzed synthesis of 2-susbtituted indoles
The proposed mechanism of the reaction involves the conversion of the alcohol into an aldehyde VIII through hydrogen atom transfer involving the iridium catalyst. p -Benzoquinone regenerates the catalyst through oxidation. The intermediate VIII then undergoes intramolecular cyclization in the presence of a base to give IX , which may aromatize with removal of water to give the 1,2-disubstituted indole. Removal of the tosyl protecting group from IX in the presence of the base generates X , which upon further rearrangement gives the expected indole (Scheme [10 ]).
Scheme 10 Predicted mechanism for the synthesis of 2-susbtituted indoles
In 2013, Kiruthika and Perumal disclosed an efficient strategy for the synthesis of 2-amidoindoles 23 through in situ generated ynamides followed by hydroamidation (Scheme [11 ]).[10 ] The method involves the intermolecular coupling of gem -dibromovinylanilide 21 and sulfonamides 22 using Cu(I) iodide as the catalyst.
Scheme 11 CuI-catalyzed synthesis of 2-susbtituted indoles
Acetamide derivatives 21 were used as the product yield was low in the case of an aniline derivative. The presence of an electron-withdrawing group such as tosyl or mesitylsulfonyl was essential on the nitrogen of 22 for the reaction to progress.
The plausible mechanism for the reaction involves the oxidative insertion of the more reactive trans C–Br bond of 21 into XI to furnish intermediate XII (Scheme [12 ]). Reductive elimination followed by dehydrobromination in the presence of a base provides the ynamide. Further base-promoted intramolecular hydroamidation and deacetylation results in the formation of the desired 2-substituted indole.
May and co-workers reported the copper-catalyzed synthesis of N-substituted indoles 25 from the corresponding primary amines and carbonyl compounds 24 through a two-step, one-pot approach (Scheme [13 ]).[11 ] The authors optimized the reaction conditions separately for imine 26 formation and cyclization.
Scheme 12 Plausible catalytic cycle
Scheme 13 Cu(I)-catalyzed synthesis of indoles from primary amines
Imine formation was efficient in benzene whereas for cyclization DMF was used as the reaction medium. The method was applicable for anilines, benzylamines, and aliphatic amines providing the desired indoles in good yields. Further, diversified 3- or 2,3-substituted indoles could also be synthesized through this method by using α-aryl or cyclic ketones, respectively.
Yu et al. reported the synthesis of functionalized indoles 29 through palladium-catalyzed, copper-mediated oxidative annulations of in situ generated enones with N-substituted pyrroles 27 (Scheme [14 ]).[12 ] Various 3-chloroalkyl ketones and pyrrole derivatives were well tolerated under the reported reaction conditions providing the corresponding indole products in moderate to good yields. Although the method was applicable for the synthesis of multi-substituted indoles, the reaction conditions were very harsh which limits the scope of the reaction on industrial scale. The authors proposed that the reaction proceeds through a sequence of dehydrochlorination, C–H activation, Diels–Alder cycloaddition and dehydrogenative aromatization.
Scheme 14 Pd(II)-catalyzed, Cu(II)-mediated synthesis of indoles through annulations of enones with N-substituted pyrroles
Otani and co-workers examined the Lewis acid promoted cycloisomerization of N -imidoyl-2-alkynylanilines 30 with substituents such as alkyl or aryl (Scheme [15 ]).[13 ] They showed the formation of indole derivatives via a 5-endo -dig cyclization mode.
Scheme 15 Silver(I)-promoted intramolecular synthesis of indoles
Scheme 16 Proposed pathway for the silver(I)-promoted intramolecular synthesis of indoles
The electronic effects of the R1 substituent affect the cyclization selectivity; the plausible mechanism for the cyclization involves the Ag–alkyne complex species XIII in the stereoelectronically favorable 5-endo -dig mode of cyclization (Scheme [16 ]).
In 2015, Ghorai’s group developed a two-step, one-pot strategy to synthesize 2-alkylindoles 33 via thiophenol-mediated regioselective ring-opening of 2-(2-haloaryl)-3-alkyl-N -tosylaziridines 32 , followed by copper-mediated intramolecular C–N cyclization with subsequent aromatization by thiophenol elimination (Scheme [17 ]).[14 ] This method overcomes the limitation of the synthesis of halogenated 2-alkylindoles, which otherwise were impossible to synthesize by alpha-lithiation of indoles.[15 ] Various halogenated indoles were prepared in good to excellent yields using either a cis /trans mixture or mono-substituted aziridines, though trans disubstituted aziridines were found to be more reactive than the cis isomer due to steric reasons.
Scheme 17 Synthesis of 2-alkylindoles
The mechanism of the reaction possibly follows the copper-powder-mediated C–N cyclization as described in Ghorai’s earlier report,[16 ] with the final aromatization step involving Cu(I)-mediated desulfonylation via the formation of cationic thioether intermediate XIV (Scheme [18 ]).
Scheme 18 Reaction pathway for the Cu-mediated C–N cyclization
5
Metal-Catalyzed 2,3-Disubstituted Indole Synthesis
Over the last two decades, many new methodologies have been reported for the synthesis of indole derivatives to overcome the existing limitations. Various metal-catalyzed as well as metal-free approaches have been developed for the synthesis of 2,3-disubstituted indole derivatives.[20 ]
5.1
Metal-Catalyzed Intramolecular 2,3-Disubstituted Indole Synthesis
Considering the high importance of the 2,3-disubstituted indole structural motif in the pharmaceutical industry and in medicinal chemistry, a large number of efforts have been made in the last few years to develop simple and cost-effective methods for their synthesis.
In 2010, Cacchi’s group disclosed the synthesis of 2,3-disubstituted indoles 44 from arenediazonium tetrafluoroborates 42 and 2-alkynyltrifluoroacetanilides 43 using a palladium catalyst. The method showed excellent functional group tolerance both in the alkyne and the arenediazonium component, including halo substituents. Arenediazonium salts containing ortho substituents gave the corresponding products in good to high yields (Scheme [24 ]).[21 ]
This reaction proceeds through an iododediazonization step (Scheme [25 ], path a) followed by oxidative addition to Pd(0) to afford the arylpalladium iodide XX that coordinates with the alkyne to give palladium complex XXI . A subsequent intramolecular aminopalladation generates σ-intermediate XXII , which via reductive elimination and hydrolysis gives the desired product.[21 ] Alternative mechanisms, which appear less likely, involve the formation of arylpalladium iodides through the reaction of σ-arylpalladium cation XXIII with iodide anions (Scheme [25 ], path b).
Scheme 24 Synthesis of 2,3-disubstituted indoles
Scheme 25 A plausible catalytic cycle for the synthesis of 2,3-disubstituted indoles
In 2011, the Waser group reported the one-pot synthesis of 3-silylethynyl indoles 47 via the cyclization of 2-alkynylanilines 45 using NaAuCl4 as the catalyst. The intermediate indoles 46 underwent C3-alkynylation with AuCl and TIPS-EBX to afford the products 47 . This reaction was also applicable for unprotected anilines, demonstrated good functional group tolerance and was very easy to carry out (Scheme [26 ]).[22 ]
Scheme 26 Gold-catalyzed synthesis of 2-substituted 3-silylethynyl indoles from unprotected o -alkynylanilines
Ghorai and co-workers reported the palladium-catalyzed synthesis of 3-substituted 2-benzylindoles 49 through oxidative annulations of o -allylanilines 48 with O2 as the oxidant (Scheme [27 ]).[23 ] The same authors also reported the one-pot synthesis of indoles from 48 , which are prepared from aniline and substituted allyl alcohols using an oxorhenium catalytic system.[23 ] The reported catalytic system provided good regioselectivity and was amenable to a broad substrate scope with high functional group tolerance.
Scheme 27 Palladium-catalyzed intramolecular synthesis of 3-substituted 2-benzylindoles from o -allylanilines
The catalytic cycle of this reaction was initiated by palladium-catalyzed aminopalladation of the 2-allylaniline via an intramolecular 5-exo -trig cyclization to generate intermediate XXIV , followed by β-hydride elimination to form intermediate XXV . Isomerization of this intermediate gives the final product 49 and O2 oxidizes Pd(0) to regenerate the active catalytic cycle (Scheme [28 ]).
Scheme 28 A plausible catalytic cycle for the synthesis of 3-substituted 2-benzylindoles from o -allylanilines
In 2014, Li’s group reported the Rh(III)-catalyzed intramolecular annulations of alkynes 50 via C–H activation for the synthesis of 3,4-fused indoles 51 .[24 ] The indoles were synthesized in moderate to good yields with excellent regioselectivity and broad substrate scope. Substrates containing both electron-donating and electron-withdrawing groups at ortho, para and meta positions of the aryl ring of the alkynes were well tolerated. 3,4-Fused indoles with six- to nine-membered rings were generated in relatively low yields (Scheme [29 ]).[24 ]
Scheme 29 Rhodium(III)-catalyzed intramolecular synthesis of 3,4-fused indoles
The reaction was initiated by ortho C–H bond activation of 50 to form intermediate XXVI . Alkyne insertion to XXVI gives rhodacycle XXVII , which on reductive elimination provides the desired product 51 and Rh(I). Finally, the active catalytic species was regenerated by Cu(II) (Scheme [30 ]).
Scheme 30 A plausible catalytic cycle to construct 3,4-fused indoles
In 2016, Dilman et al. described the photocatalyzed conversion of CF2 I-substituted N -arylamines 52 into the corresponding 3-fluoroindoles 53 .[25 ] The starting materials were obtained by nucleophilic iododifluoromethylation of iminium ions. The developed strategy utilized blue LEDs for irradiation of the reaction mixture for 12 hours. A series of 3-fluoroindoles was synthesized effectively with excellent yields using the developed photocatalytic methodology (Scheme [31 ]).
Mechanistic studies involved measurements of the redox potentials of the catalyst, the starting material and triphenylphosphine to check the feasibility of the electron-transfer step. The reduction potential studies suggested the initial conversion of photoexcited Rh(II)* into Rh(I) [ERh(II)*/Rh(I) = +0.84 V] by triphenylphosphine [EPPh3+
.
/PPh3 = +0.77 V]. Rh(I) then generates the difluorinated radical XXVIII via a single electron transfer and the catalyst is regenerated. Intramolecular attack of the radical onto the aromatic ring furnished XXIX , oxidation of which by the triphenylphosphine radical cation produced aromatic cation XXX . Elimination of a proton from XXX followed by removal of HF provided the expected indole product (Scheme [32 ]).
Scheme 31 Photocatalyzed synthesis of 3-fluorinated indoles
Scheme 32 Mechanistic cycle for the ruthenium-photocatalyzed reaction
In 2016, Miao et al. reported the ZnEt2 -mediated anti -azacarboxylation of 2-alkynylanilines 54 with CO2 for the synthesis of 2,3-disubstituted indoles 55 (Scheme [33 ]).[26 ] The method represents an easy access to indole moieties as it involves the use of readily available starting materials and various functional groups are tolerated. Trifluoromethyl- and nitro-substituted reactants provided indoles in good to excellent yields. The utility of this method involves the synthesis of the drug Lotronex, which is used for the treatment of irritable bowel syndrome.
Scheme 33 Diethylzinc-mediated intramolecular cyclization for the synthesis of indoles
The reaction was proposed to proceed through initial activation of the alkyne by diethylzinc making it susceptible to intramolecular nucleophilic attack by nitrogen to generate intermediate XXXI (Scheme [34 ]). The insertion of carbon dioxide into the C–Zn bond leads to the formation of XXXII , which on demetalation in the presence of an acid gives the indole.
Scheme 34 A plausible reaction mechanism for the synthesis of 2,3-disubstituted indoles
5.2
Metal-Catalyzed Intermolecular 2,3-Disubstituted Indole Synthesis
Beyond intramolecular indole synthesis, Maurizio Taddei and co-workers reported the Ru-catalyzed H-transfer Fischer indole synthesis of 58 , from primary and secondary alcohols 57 and aryl hydrazines 56 (Scheme [35 ]).[27 ] The use of alcohols in place of aldehydes or ketones makes this system more advantageous compared to the classical Fischer indole synthesis.[27 ]
This reaction may proceed through oxidation of the alcohol into a carbonyl compound XXXIII by transfer of a H2 molecule to the crotononitrile. Compound XXXIII is immediately converted into hydrazone XXXIII by reaction with aryl hydrazine 56 and finally, an acid-catalyzed aromatic [3+3] sigmatropic rearrangement gives the desired indole ring (Scheme [36 ]).
Scheme 35 Ruthenium-catalyzed hydrogen transfer Fischer indole synthesis
Scheme 36 A plausible catalytic cycle for the synthesis of substituted indoles from aryl hydrazines and alcohols
In 2013, Liang and Zhan reported the copper-catalyzed formation of enehydrazine intermediates 61 through the coupling of phenyl hydrazines 59 with vinyl halides 60 , and its synthetic application for the synthesis of indoles 62 .[28 ]
Scheme 37 Copper-catalyzed Fischer indole synthesis through formation of enehydrazine intermediates from phenyl hydrazines and vinyl halides
This catalytic system tolerates ester, hydroxy and amine functional groups leading to the selective synthesis of isomeric indoles and has been employed for the interrupted indolization to synthesize the pyrrolidinoindoline 62 (Scheme [37 ]). This catalytic system opens a new way for the asymmetric synthesis of indoles.[29 ]
Zhu and co-workers reported a Rh(III)-catalyzed, C–H activation based intermolecular redox neutral strategy for the synthesis of indoles 65 by cyclization of N -nitrosoanilines 63 with alkynes 64 using the N–N bond as an internal oxidant. This catalytic procedure showed good functional group tolerance and the compatibility of seemingly dichotomous acidic and basic conditions makes it a versatile method (Scheme [38 ]).[30 ]
Scheme 38 Rh(III)-catalyzed synthesis of indoles from N -nitrosoanilines and alkynes using the N–N bond as an internal oxidant
A detailed mechanistic study proved that the generation of [RhCp*]2+ leads to reversible coordination of t BuCOO– and N -nitrosoaniline derivative to give XXXV , and the turnover-limiting C–H activation then forms rhodium intermediate XXXVI via a t BuCOO– -assisted CMD (concerted metallation deprotonation) pathway. Interaction of the alkyne with XXXVI followed by migratory insertion leads to the formation of intermediate XXXVII . Concerted N–N bond cleavage and C–N bond formation leads to formation of the final product with the abstraction of NO+ by H+ and regeneration of the active [RhCp*]2+ species (Scheme [39 ]).[30 ]
Scheme 39 Proposed mechanism for the intermolecular redox neutral synthesis of indoles
In 2013, Senanayake and co-workers disclosed the one-pot synthesis of indoles 69 by reacting 2-bromoanilides 66 , terminal alkynes 67 , and aryl halides 68 via a palladium-catalyzed reaction sequence involving Sonogashira coupling, aminopalladation and reductive elimination (Scheme [40 ]).[31 ] All the reactions were carried under normal conditions without the use of n Bu4 NBr and good to excellent yields were achieved.
Scheme 40 Synthesis of 2,3-disubstituted indoles from 2-bromo- or 2-chloroanilides, terminal alkynes and aryl halides
Scheme 41 Indole synthesis from anilines and vicinal diols by cooperative catalysis of a ruthenium complex and an acid
In 2013, Ding et al. reported the Ru complex and p -TSA catalyzed synthesis of indole derivatives 72 from anilines 70 and vicinal diols 71 . Electron-donating substituents on the aryl ring of the aniline gave the products in higher yields, while strong electron-withdrawing groups (i.e., NO2 or CF3 ) failed to give the expected products. An ortho -substituted aniline gave a lower yield because of steric hindrance (Scheme [41 ]).[32 ]
A year later, Driver and co-workers reported a Suzuki cross-coupling reaction for the regioselective synthesis of 2,3-fused indole heterocycles 76 from 2-azidoarylboronic esters 73 and vinyl triflates 74 .[33 ] The 5-substituted aryl azides smoothly gave the indole products; these products cannot be accessed as single regioisomers using the Fisher indole reaction. The conversion of androsterone into an indole proved that this method is applicable for complex molecules, albeit a reduced yield was obtained (Scheme [42 ]).[33 ]
Scheme 42 The synthesis of 2,3-fused indole heterocycles
In the same year (2104), Cho and co-workers reported the synthesis of ene-hydrazides 79 from bis-Boc-hydrazide 77 and enol triflates 78 , and their subsequent enolization reaction to give the regioselective Fischer indole products 80 . The catalytic system showed broad substrate scope and enabled the synthesis of indole natural products with excellent regioselectivities (Scheme [43 ]).[34 ]
Scheme 43 Regioselective Fischer indole synthesis from ene-hydrazides
In 2014, Wu’s group reported the synthesis of N -(2-pyridyl)indoles 83 from internal alkynes 82 and N -phenylpyridin-2-amines 81 catalyzed by palladium@cerium(IV) oxide. This method affords better yields compared to other heterogeneous catalytic methods and demonstrates good functional group tolerance; however, the nitro functional group was not tolerated (Scheme [44 ]).[35 ]
Scheme 44 Oxidative synthesis of N -(2-pyridyl)indoles
The regio- and enantioselective synthesis of N -allyl indoles 86 and 87 was reported by You’s group in 2014.[36 ] This reaction proceeds through an Ir-catalyzed asymmetric allylic amination with 2-alkynylanilines 84 and subsequent Au-catalyzed cyclization. The catalytic system proved was applicable to a broad substrate scope, affording high yields and good enantiomeric excess. The reaction was also compatible with a one-pot procedure and cascade reaction (Scheme [45 ]).[36 ]
Scheme 45 Ir-catalyzed allylic amination and subsequent Au-catalyzed cyclization
Scheme 46 Pd(II)-catalyzed synthesis of functionalized indoles from pyrroles and enones
The Yu group reported, in 2015, the Pd(II)-catalyzed synthesis of functionalized indoles 90 from simple N-substituted pyrroles 88 and 3-chloropropiophenones 89 and their analogues. This reaction proceeds through the construction of a benzene ring onto a pyrrole backbone using enones 89 (Scheme [46 ]).[12 ]
The proposed catalytic cycle started with palladation at the C-5 position of pyrrole 88 giving intermediate XXXVIII with simultaneous removal of acetic acid. Intermediate XXXVIII then reacts with the enone XXXIX , generated from 3-chloropropiophenone 89 , to form palladium intermediate XL . Reductive elimination leads to the formation of pyrrole derivative XLI , which undergoes a Diels–Alder cycloaddition with another molecule of the enone to form tetrahydroindole XLII . Finally, the tetrahydroindole is oxidized to indole 90 and catalytic system is regenerated by Cu(II) oxidant or air (Scheme [47 ]).
Scheme 47 Proposed mechanism for the synthesis of functionalized indoles from pyrroles and 3-chloropropiophenones
In 2015, Dong and co-workers reported the Ru(II)-catalyzed oxidative coupling via C–H activation of N H protic amides 91 with alkynes 92 for the synthesis of N -acylindole derivatives 93 . This catalytic method shows good functional group tolerance and affords moderate yields of the products (Scheme [48 ]).[37 ]
Scheme 48 Synthesis of indoles via ruthenium(II)-catalyzed C–H activation and annulations
A plausible mechanism was proposed in which the insertion of Ru(II) metal activates the ortho C–H bond of amide 91 to form the six-membered ruthenacycle XLII . Alkyne interaction with XLIII followed by migratory insertion leads to the formation of another ruthenacycle (XLIV ). Finally, reductive elimination provides the product 93 (Scheme [49 ]).[37 ]
Scheme 49 Proposed catalytic cycle for the synthesis of N -acylindoles from N H protic amides and alkynes
In 2015, Hwang’s group reported the visible-light-mediated CuCl-catalyzed regioselective synthesis of indoles 97 via coupling of arylamines 94 , terminal alkynes 95 and quinines 96 at room temperature (Scheme [50 ]). This photoinduced method showed broad substrate scope with good to excellent selectivities. However, the use of meta -substituted anilines resulted in the formation of a mixture of regioisomers.[38 ]
Scheme 50 Photoinduced copper-catalyzed synthesis of indoles from arylamines, terminal alkynes and quinines
This reaction was proposed to commence by photoirradiation of in situ generated XLV by blue LEDs. This produces the photoexcited triplet state XLVI (τ = 15.95 μs) by ligand-to-metal charge transfer (LMCT).[39 ] This is followed by intersystem crossing of the singlet excited state of copper(I) phenylacetylide to the triplet excited state.[40 ] Next, a SET process with benzoquinone gives the copper(II) phenylacetylide XLVII and benzoquinone radical XLVIII , which has the tendency to attack XLVII to regenerate the copper(I) catalyst and form copper(I)-coordinated alkyne complex XLIX . The electrophilicity of the triple bond in the disubstituted alkyne moiety must be enhanced through coordination with CuCl,[41 ] facilitating nucleophilic attack by aniline to provide complex L , thus leading to the formation of complex LI . Friedel–Crafts-type cyclization then generates the intermediate LII
[42 ] and finally, a rearomatization process provides the indole product (Scheme [51 ]).
Scheme 51 Proposed mechanism for the photoinduced synthesis of indoles
Lu’s group reported the Rh(III)-catalyzed synthesis of indoles 100 by annulation of arylnitrones 98 and alkynes 99 without using any external oxidant. Symmetric diarylacetylenes bearing various substituents at the para and meta positions gave the best results.[43 ] While ortho -methyl-substituted diarylacetylene gave a low yield, an unsymmetrical diarylacetylene afforded a mixture of two regioisomers. para -Cyano-substituted N -phenyl-C -mesitylnitrone appeared to be a less effective substrate, affording the desired product in a low yield with a higher catalyst loading at 100 °C (Scheme [52 ]).[43 ]
Scheme 52 Rh(III)-catalyzed synthesis of indole derivatives from arylnitrones and alkynes
The catalytic cycle was initiated with the formation of rhodacycle LIII followed by insertion of the alkyne to give the seven-membered intermediate LIV . Reductive elimination leads to the formation of intermediate LV . This resulting Rh(I) intermediate could be oxidized by the N –O bond via oxidative addition to provide enolate LVI , which upon protonolysis provides intermediate LVII and regenerates Rh(III) to complete the cycle. Enolate intermediate LVII is in equilibrium with keto intermediate LVIII , which gives the indole by imine hydrolysis and intramolecular cyclization (Scheme [53 ]).
Scheme 53 Proposed catalytic cycle for indole synthesis from arylnitrones and alkynes
In 2015, Wan and co-workers reported the synthesis of unsymmetrical 2,3-diaryl-substituted N-unprotected indoles 103 via rhodium-catalyzed C–H annulations of nitrones 101 with symmetrical alkynes 102 (Scheme [54 ]).[44 ] The catalytic system showed tolerance of various functional groups on the aryl rings of the nitrones and the symmetrical alkynes for the regioselective preparation of the 2,3-disubstituted indoles 103 .
Scheme 54 Rhodium-catalyzed synthesis of 2,3-diaryl-substituted indoles from nitrones and alkynes
The catalytic cycle of this reaction also involves the formation of a rhodacyclic intermediate LIX , which undergoes insertion with the alkyne to give the seven-membered intermediate LX (Scheme [55 ], path a). Reductive elimination then provides the intermediate LXI . Intramolecular oxygen atom transfer and subsequent oxidative addition of LXII and electrophilic cyclization generates intermediate LXIII . Intermediate LXV is formed by transmetalation and subsequent β-hydride elimination,[45 ] finally leading to the formation of product 103 by elimination of PhCHO.[46 ] Alternatively, the reaction can proceed through LIX and intermediate LXVI (Scheme [55 ], path b).
Scheme 55 A plausible catalytic cycle for the synthesis of unsymmetrical 2,3-disubstituted indoles
Wang and Huang, in 2015, developed a general protocol for the synthesis of N -alkylindoles 105 using a traceless nitroso directing group via redox neutral C–H activation (Scheme [56 ]).[47 ] This rhodium-based catalytic system provided N -alkylindoles regioselectively, with a broad scope of substituents, in good to excellent yields and without the use of any oxidant or other additive.
Scheme 56 Redox neutral C–H activation for the regioselective synthesis of N -alkylindoles
Though the full catalytic cycle of the reaction remains elusive, the C–H activation step may proceed via a concerted metalation–deprotonation (CMD) mechanism.
In 2010, the Knochel group reported a microwave-assisted Fischer indole synthesis for the preparation of polyfunctional indoles 109 from aryldiazonium tetrafluoroborates 108 and functionalized alkylzinc halides 107 , which were generated from substituted bromobutanes 106 (Scheme [57 ]).[48 ] The catalytic system showed a broad substrate scope with excellent regioselectivity, and with many functional groups such as nitro, ester, keto, cyano and iodo being tolerated. This catalytic method was successfully used for the synthesis of indole-containing drug molecules.
Scheme 57 Preparation of polyfunctional indoles by the addition of alkylzinc reagents to aryldiazonium tetrafluoroborates
Hui Jiang and co-workers reported the rhodium(III)-catalyzed regioselective synthesis of indole-3-carboxylic acid esters 112 using a pyrimidyl directing group.[49 ] N-Substituted anilines 110 and diazo compounds 111 were used as the starting materials and the reactions proceeded via aromatic C–H bond activation followed by C–N bond formation to give 2,3-difunctionalized indoles (Scheme [58 ]). The presence of the pyrimidyl directing group was essential for the synthesis of the desired indoles under the specified conditions, and it can be reutilized for further functionalization of the synthesized indoles, or can be easily removed to provide different free N–H indoles. The limitations of preactivated substrates, the requirement for excess oxidant and the substrate scope associated with the previous reports of Glorius,[50 ] Jiao[51 ] and Cacchi[21 ] for the synthesis of indole-3-carboxylic acid esters were overcome by using this method. Various alkyl, halogen and ester substituents on the phenyl ring were well tolerated under the reported conditions. Substituents with strong-electron withdrawing effects such as CF3 and NO2 and electron-donating methoxy substituents afforded the expected products, exclusively. The desired indole was obtained with a morpholinyl substituent at the para position of the phenyl ring. Also, the reaction was successful on gram scale.
Scheme 58 Regioselective synthesis of indole-3-carboxylic acid esters
In 2016, Li’s group described the synthesis of 2,3-disubstituted indoles 115 via C–H activation/annulation of imidamides 113 with diaza-ketoesters 114 using a Rh(III) catalyst (Scheme [59 ]).[52 ] This redox-neutral strategy proceeded under mild conditions with a variety of substrates.
Scheme 59 Rhodium-catalyzed synthesis of 2,3-disubstituted indoles
The mechanistic studies of the reaction revealed the kinetic isotope effect (KIE) value to be 3.3, which indicates C–H bond cleavage may be involved in the rate-determining step. The proposed mechanism of the reaction includes the initial generation of an active catalyst through anion exchange. Insertion of the active catalyst into the ortho C–H bond followed by cyclization gives the six-membered rhodacycle LXVII . Elimination of nitrogen with subsequent insertion of the diazo substrate generates LXVIII and migratory insertion of the Rh–C bond into the C=N bond provides LXIX . Protonolysis of LXIX generates LXX and the active catalyst. The elimination of acetamide from LXX gives the final product (Scheme [60 ]).
Scheme 60 Suggested catalytic cycle for the C–H activation/annulation of imidamides with diaza-ketoesters
Scheme 61 Photocatalyzed regioselective synthesis of indoles
Recently, in 2016, Wu et al. developed an oxidant-free intramolecular C–C bond-formation strategy for the regioselective synthesis of indoles 117 using an iridium(II) photosensitizer and a cobaloxime catalyst under visible light irradiation (LEDs, 450 nm). This procedure successfully converted N -arylenamines 116 into indoles in good to excellent yields, while producing H2 as the only side product (Scheme [61 ]).[53 ] The reported method overcomes the limitations of Glorius and co-worker’s[50 ] procedure using a stoichiometric amount of oxidant, which can lead to the formation of side products. Under the optimized reaction conditions, various electron-withdrawing as well as electron-donating substituents were well tolerated, affording the corresponding indoles in high yields. When meta -substituted enamines were used as the starting materials, more than one product could be obtained. The desired indole product could also be obtained on gram scale in 82% yield.
A plausible mechanism for the reaction involves initial photoirradiation of the Ir(ppy)3 photosensitizer to produce Ir(ppy)3 *, which transfers an electron to the cobaloxime complex, thus forming Ir(IV) and Co(II). The Ir(IV) so formed abstracts an electron from 116 to produce LXXI and regenerate the photosensitizer Ir(ppy)3 . Intermediate LXXI loses a proton to give LXXII that undergoes intramolecular radical cyclization to produce LXXIII . Finally, oxidation and deprotonation followed by tautomerization of LXXIII afforded the desired indole product (Scheme [62 ]).
Scheme 62 A plausible mechanism for the photocatalytic synthesis of indole derivatives
In 2014, Zhang et al. developed a regioselective synthesis of polysubstituted indoles 120 via an Ru-catalyzed redox-neutral C–H activation reaction involving N–N bond cleavage.[54 ] The C–H annulation reaction of alkynes 119 was carried out using pyrazolidin-3-one 118 as the internal oxidant as well as the directing group (Scheme [63 ]). The use of ruthenium metal avoided homocoupling of the terminal alkynes, which was a major side reaction when using Rh(III). Also, the oxidative potential of the N–N bond of the aliphatic hydrazine was not enough to regenerate the Ru(II) catalyst. So, the authors used cyclic hydrazides with increased ring strain to activate the N–N bond. The designed protocol was effective for a broad range of functional groups on the arene moiety: electron-withdrawing as well as electron-donating substituents were well tolerated. Symmetrical, unsymmetrical and 1-substituted alkynes gave single regioisomers, exclusively. The utility of the developed method was demonstrated by the synthesis of a P2 inhibitor,[55 ] a SIRT1 activator[56 ] and an NS5B inhibitor.[57 ]
Scheme 63 Ruthenium-catalyzed redox-neutral C–H activation, regioselective synthesis of N-substituted indoles
A plausible Ru(II)–Ru(IV)–Ru(II) catalytic mechanism for the reaction was proposed on the basis of redox-neutral Rh catalysis reported in the literature.[58 ] Ru(II) amido complex LXXIV is obtained by initial insertion of the active Ru(II) acetate into the N–H bond of pyrazolidin-3-one, which undergoes metalation–deprotonation to give LXXV . Subsequent alkyne insertion followed by oxidation to Ru(IV) by the N–N bond gives LXXVI , which upon reductive elimination gives the final product and regenerates the active Ru(II) catalyst (Scheme [64 ]).
Scheme 64 Proposed catalytic cycle for the synthesis of polysubstituted indole derivatives
Scheme 65 Traceless synthesis of indoles at room temperature
In 2016, Zhou et al. developed a versatile, traceless, Rh(III)-catalyzed annulation of arylhydrazines 121 and alkynes 99 for the synthesis of indoles 122 , with a very low catalyst loading (0.1 mol%) on gram-scale reactions (Scheme [65 ]).[59 ] The N -amino-directed C–H alkenylation generated indoles in a step- and atom-economic manner at room temperature and showed tolerance toward a broad range of functional groups on the arylhydrazines and alkynes. The room-temperature conditions for the traceless indole synthesis are unexcelled via C–H activation strategy.
In 2014, Liu’s group reported the Rh-catalyzed synthesis of 1-aminoindole derivatives 124 via oxidative annulation of hydrazines 123 with alkynes 99 (Scheme [66 ]).[60 ] The authors described the use of 1,3-dinitrobenzene as an oxidant in transition-metal-catalyzed C–H activation for the first time.[58a ]
Scheme 66 Oxidative annulations of hydrazines and alkynes to give indoles
The course of the reaction includes formation of rhodacycle LXXVII by insertion of the active metal catalyst into the hydrazine. Alkyne coordination and insertion gives a more stable six-membered intermediate LXXVIII , which undergoes internal oxidation to release the indole in the presence of AcOH. The active catalyst is regenerated by the external oxidant, 1,3-dinitrobenzene (Scheme [67 ]).
Scheme 67 A plausible reaction mechanism
In 2016, Zhang and co-workers developed a new strategy for the synthesis of indoles 126 via Co(III)-catalyzed oxidative annulations of N -arylureas 125 and alkynes 99 possessing a broad range of synthetically useful substituents (Scheme [68 ]).[61 ] However, the strategy is limited to the use of less electrophilic ureas other than acetamide as the directing groups, and gave the products in good to excellent yields.
Scheme 68 Co(III)-catalyzed oxidative coupling of N -arylureas and internal alkynes
Scheme 69 The catalytic cycle for coupling of N -arylureas with internal alkynes
A plausible mechanism for the reaction involves the generation of an active cationic Co(III) catalyst followed by irreversible C–H bond activation affording six-membered metallacycle LXXIX . Coordination and migratory insertion of the alkyne generates the species LXXX , which upon elimination of HX yields intermediate LXXXI . Reductive elimination of the C–N bond generates the desired indole along with Co(I), which is further oxidized by silver and oxygen to regenerate the active catalyst (Scheme [69 ]).
A Co(III)-catalyzed regioselective synthesis of indole motifs 129 was reported by Zhu’s group (Scheme [70 ]).[62 ] Internal and terminal alkynes 128 were compatible with N -aminoaniline derivatives 127 for cyclization. This strategy overcomes the drawbacks of earlier Co(III)-catalyzed redox-neutral methods for indole synthesis including high reaction temperatures, retention of bulky groups in the products and the generation of side products from external oxidants. The method provided the indole skeleton with diverse functional groups in moderate to excellent yields. Both electron-rich and electron-deficient substituents were tolerated, but steric effects played a dictating role in the reaction yield.
Scheme 70 Co(III)-catalyzed regioselective synthesis of indole motifs
The mechanism of the reaction involves the initial cobaltation of 127 and Co(II)-promoted alkyne–allene isomerization. The insertion of allene LXXXIII via the internal C=C bond into five-membered cobaltacycle LXXXII followed by cyclization provided the desired product (Scheme [71 ]).
Scheme 71 Proposed mechanism for the reaction involving cyclization of alkynes with N -aminoanilines
In 2016, Liu reported the synthesis of 3-amidoindoles 132 via Rh(III)-catalyzed cascade cyclization/electrophilic amidation of o -alkynylanilines 130 (Scheme [72 ]).[63 ] The authors used N -pivaloyloxyamides 131 as the electrophilic nitrogen source. The developed strategy provided 3-amidoindoles under mild conditions with good to excellent yields. Different functional groups present on both reactants were tolerated.
Scheme 72 Rh(III)-catalyzed cascade cyclization/electrophilic amidation of o -alkynylanilines
The proposed mechanism of the reaction involves the initial coordination of rhodium with 130 . This makes the triple bond more susceptible to intramolecular nucleophilic attack by nitrogen and generates intermediate LXXXIV . The intermediate LXXXIV then reacts with 131 to furnish LXXXV through deprotonation of 131 and ligand exchange on LXXXIV . The expected product can be obtained from LXXXVI via two pathways (paths a and b). Path a, involves concerted N–O bond cleavage with C–N bond formation and regeneration of the catalyst. In path b, reductive elimination followed by oxidative addition through pivaloyl group migration generates intermediate LXXXVI , which on protonolysis furnishes the indole product (Scheme [73 ]).
Scheme 73 Proposed mechanistic pathways
6
Metal-Free 2,3-Disubstituted Indole Synthesis
6.1
N-Protected 2,3-Disubstituted Indole Synthesis
Zhao et al. reported the synthesis of indoles 135 via intramolecular amination (Scheme [74 ]).[64 ] They used an organoselenium catalyst under mild conditions and obtained product yields of up to 99%. Polar solvents were ineffective in this transformation and an electron-donating protecting group on the nitrogen disfavored the transformation, probably because the nitrogen of the substrate becomes less nucleophilic, hence preventing attack by the intermediate seleniranium ion. Only a trace amount of the product was obtained when using unsubstituted terminal alkenes. Different substituents on the aromatic ring of the substrate only slightly influenced the nitrogen nucleophilicity and hence the C–H bond amination. Electron-donating Me and electron-withdrawing CF3 groups at the same position of the benzene ring gave the desired products in high yields (91% and 93%).
Scheme 74 Organocatalyst-catalyzed intramolecular synthesis of indoles
Otani and co-workers examined the Lewis acid- or base-promoted cycloisomerization of N -imidoyl-2-alkynylanilines 136 with substituents such as alkyl or aryl.[13 ] They described the formation of indole derivatives 137 via a 5-endo -dig cyclization mode (Scheme [75 ]).
Scheme 75 Lewis acid/base-promoted cycloisomerization of N -imidoyl-2-alkynylanilines
In 2012, Li’s group reported the reaction of enaminones 138 with 2,2-dihydroxyindene-1,3-dione (139 ) on heating in acetic anhydride at 120 °C under microwave irradiation conditions. Polyfunctionalized tetracyclic indeno[1,2-b ]indoles 140 were obtained with different substitution patterns.[65 ] This catalytic system showed excellent regioselectivity, short reaction times, mild conditions and good functional group tolerance at the N-protected aryl ring of the enaminones 138 (Scheme [76 ]).
Scheme 76 Synthesis of indeno[1,2-b ]indoles under microwave irradiation
In 2014, Youn’s group reported a metal-free synthesis of substituted indoles 142 and 143 via C–H amination of N -Ts-2-alkenylanilines 141 .[66 ] This method showed broad substrate scope, good functional group tolerance and afforded good to excellent yields of the products. In the case of electron-withdrawing groups [CO2
n Bu, CONMe2 , CN, PO(OEt)2 ] on the alkene moiety, no product was formed and mostly starting material was recovered. The reactions of β,β-disubstituted 2-alkenylanilines proceeded as expected to generate 2,3-disubstituted indoles, which showed that electron-rich aryl groups migrated preferentially (Scheme [77 ]).
Scheme 77 Metal-free C–H amination for the synthesis of indoles
The mechanism of the reaction was proposed after conducting a series of experiments. It was suggested that intramolecular nucleophilic attack by the N-tosyl group of LXXXVII towards an olefin radical cation generates intermediate LXXXVIII . Oxidation of carbon radical of LXXXVIII gives the corresponding benzylic carbocation intermediate LXXXIX . This was followed by deprotonation to form the product via path a, which is much faster than alternative path b (Scheme [78 ]).
Scheme 78 Proposed mechanism for the metal-free indole synthesis
In 2015, Deng’s group reported the metal-free synthesis of indoles 145 from N -Ts-2-alkenylanilines 144 via a NIS-mediated cascade C–N bond formation/aromatization.[67 ] This reaction showed broad substrate scope and provided good to excellent yields under mild reaction conditions (Scheme [79 ]).
Scheme 79 NIS-mediated metal-free indole synthesis
Primarily, the iodonium ion intermediate XC is formed as NIS reacts with the substrate alkene, which undergoes intramolecular amination by the amino group to form indoline XCI . This is followed by aromatization to form the indole product or 1,2-arylation occurs to form intermediate XCII , which after aromatization gives the final product (Scheme [80 ]).
Scheme 80 Proposed mechanistic pathway for the metal-free indole synthesis
6.2
N-Unprotected 2,3-Disubstituted Indole Synthesis
König and co-workers reported the synthesis of functionalized indoles 148 in a tartaric acid–dimethylurea [l -(+)-TA–DMU] melt under solvent- and catalyst-free conditions, starting from phenylhydrazine (146 ) and aldehydes/ketones 147 .[68 ] Examination of substrate scope showed that it tolerated sensitive functional groups such as N -Boc, N -Cbz and azides with excellent yields of products regioselectively. In addition, the method is environmentally benign and applicable for the synthesis of bioactive indoles (Scheme [81 ]).
Scheme 81 Fischer indole synthesis in low melting mixtures
Zheng’s group reported a one-pot procedure for the Fischer indole synthesis of compounds 151 from quinone monoketals 149 and aliphatic hydrazines 150 in chloroform with two equivalents of pyridine or under microwave conditions.[69 ] The method showed good functional group tolerance, broad substrate scope and gave good to excellent yields of the indole products. An unsymmetrical hydrazine gave the cyclization product regioselectively (Scheme [82 ]).
Scheme 82 Synthesis of indoles by condensation of quinone monoketals and aliphatic hydrazines
The condensation of quinone monoketals 149 with hydrazines 150 through 1,2-addition gave intermediate XCIII , which on dehydration gave intermediate XCIV . Subsequent aromatization gave the alkylaryldiazene XCV , which underwent isomerization to afford intermediate XCVI . The indole product was obtained after elimination/cyclization process (Scheme [83 ]).
Scheme 83 Proposed mechanism for the Fischer indole synthesis of compounds 151
