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Home > Visible light-mediated chemistry of indoles and related heterocycles
Visible light-mediated chemistry of indoles and related heterocycles
Alexey A. Festa, a Leonid G. Voskressensky a and Erik V. Van der Eycken
1. Introduction
Indole, indoline, oxindole and isatin scaffolds are present in numerous natural products, biologically active compounds, drugs and agrochemicals. This made the scientific community focus on the preparation and functionalization of these molecular entities through the whole history of organic synthesis. In the past few years green chemistry and sustainable development have evolved as main themes in new synthetic methodology design.
Since the seminal works of MacMillan,1 Yoon2 and Stephenson,3 the renewable resource of visible light to induce chemical transformations has drawn much attention due to its cheap, mild and practical nature. This review is dedicated to the emerging technique of visible light-mediated chemistry for the modification of indoles and related heterocycles. As most of the organic compounds do not absorb visible light the use of photocatalysts (PC) is usually needed.4–8 The common PCs are based on Ru- or Ir-complexes or different organic dyes. The PC readily absorbs light and undergoes a transition from the ground (S0) to the singlet excited state (S1). Moreover, the best PCs usually have high probabilities for intersystem crossing to form a long-living triplet excited state (T1).
The T1 excited state usually mediates intermolecular processes, inducing further chemical transformations, most often based on single electron transfer (SET). The photoexcited PC becomes both a better oxidant and a better reducing agent, capable of either donating or accepting an electron. In general, mechanistic schemes may be depicted by a reductive quenching cycle(Scheme 1a) and an oxidative quenching cycle (Scheme 1b). In a reductive quenching cycle the photoexcited PC* acts as an oxidant first, taking an electron from an electron donor (ED), which is usually termed a reductive quencher. This generates a PC radical anion with a high reducing potential. The typical reductive quenchers are tertiary amines. Alternatively, the photoexcited PC* acts firstly as a reductant in an oxidative quenching
cycle, donating an electron to an electron acceptor (EA, oxidative quencher). This generates a PC+ radical cation with a higher oxidative potential than that of a PC*. The typical oxidative quenchers are polyhalomethanes, aryldiazonium salts, dicyanobenzenes, etc. Chemical transformations induced by energy transfer from the excited PC to substrate are also known.9,10 PC-free processes are also possible when one of the substrates itself is capable of absorbing light, or through the formation of a photoactive electron donor–acceptor (EDA) complex between the reactants.11,12
2. Visible light-mediated functionalization of indoles
As the synthesis of indoles in general13 and under the action of visible light14 has been recently reviewed, we will not consider indole ring forming reactions in this review although several new examples of photocatalyzed reactions have appeared.15–17
2.1. C–C bond forming reactions
2.1.1 Alkylation reactions. Alkylation of indoles may be achieved through free radical substitution with reactive species generated by SET from bromo-substituted diethylmalonate derivatives. Intramolecular alkylation was realized for the first time by Stephenson and co-workers, employing Ru(bpy)3Cl2 as a PC and NEt3 in DMF at room temperature under irradiation with visible light.18 The transformation of indole 1 afforded compound 2 in 60% yield along with reduced by-product 3. Reductive quenching of photoexcited PC generates Ru(I)-species, able to reduce the C–Br bond, thus producing an electron deficient C-centred free radical 4. The free radical 4 readily undergoes a cyclization on C(2) of the indole ring, and the aromatization completes the sequence (Scheme 2). The reaction works with variously substituted indoles, and even 5-membered rings may be formed.
The intermolecular reaction with bromomalonates was found to be unrealisable under the above-mentioned conditions due to the formation of dehalogenation products. The change of triethylamine to triarylamine prevented the reduction of free radicals through hydrogen atom transfer (HAT) processes. The use of 4-methoxy-N,N-diphenylaniline as a sacrificial reductive quencher was found to be the best to afford the desired coupling products 5 in a wide scope of indoles with moderate to excellent yields (Scheme 3).19 The C(2) selectivity of the process might be rationalized through the formation of a stable benzylic free radical 6. It is worth noting that the indole moiety in NH-Boc-protected Trp-Phe dipeptide may be functionalized by the developed procedure.
The employment of the more strongly reducing Ir(III)-catalyst enables direct alkylation of an indole with tertiary bromomalonates without use of a reductive quencher.20 The reaction between indole and bromomalonate is carried out in acetonitrile at rt in the presence of Ir(ppy)3 and 2,6-lutidine under irradiation with blue LEDs. The reaction works well for indoles with different substitution patterns, containing halogen, alkyl or hydroxyl groups, with most of the examples made with N-unsubstituted indoles. When indole-2-carboxylate is used, the alkylation occurs at the C(3) position. The reaction also
worked smoothly with various bromomalonates, including N-Bocpiperidin-4-yl or allyl-substituted ones, though the interaction of a seven-membered bromolactone and a mixed malonate demanded the use of 20 equiv. of indole to obtain moderate yields.
The transformation was also tested under continuous flow conditions giving an improved reaction time and the possibility of generating the target product 7 with a conversion rate of 1.0 mmol per hour (Scheme 4). The use of an Ir(III)-catalyst also allows direct cyanomethylation of the indole ring through an oxidative quenching cycle.21 A photoexcited [Ir(dmppy)2(dtbbpy)]PF6 complex is capable of
donating an electron to bromoacetonitrile to form a bromide anion and a cyanomethyl free radical. Irradiating 1-methylindole and bromoacetonitrile solution in DCE with a blue LED in the presence of the Ir(III)-catalyst and NaHCO3 at room temperature results in the formation of 2-cyanomethylindoles 8. Better yields were obtained for N-protected indoles, giving rise to a wide scope of products. The procedure was shown to be inappropriate for C(2)-cyanomethylation of 5-azaindole or 3-pyridoindole due to the formation of quaternary salts (Scheme 5). If the C(2)-position was blocked with a substituent, the alkylation took place at C(3). Photoinduced generation of (phenylsulfonyl)methyl free radicals has been developed and employed for indole alkylation by Li and a co-worker.22 The reaction of indole and bromomethyl phenyl sulfone 9 in DMSO in the presence of Li2CO3 and Ir(ppy)3 under irradiation with a household 14 W light bulb indeed gives the C(2)-(phenylsulfonyl)methylated product 10(Scheme 6).
The photoexcited Ir(III)* PC reduces bromomethyl phenyl sulfone 9 to produce a (phenylsulfonyl)methyl free radical, which attacks an indole. The recyclation of the catalyst occurs through oxidation of the indolyl radical by Ir(IV). The reaction has been mostly studied on pyrroles, but both N-unsubstituted indole and N-methylindole give the corresponding products. Previously, an elegant indirect two-step methylation of heteroarenes has been realized by Baran et al., 23 who prepared the (phenylsulfonyl)methylated intermediates in a first step. Zinc bis(phenylsulfonylmethanesulfinate) was synthesized initially from the bromomethyl phenyl sulfones 9. As stoichiometric amounts of zinc and an additional synthetic step were needed for this, the photocatalyzed protocol of (phenylsulfonyl)methylation looked more advantageous from the ecological viewpoint. Photocatalyzed trifluoromethylation of indole was realized for the first time by MacMillan and co-workers.24 It has been shown that triflyl chloride may undergo a single-electron reduction by a photoexcited Ru(phen)3Cl2* complex to form reactive CF3 species. The catalyst recyclation was achieved through further oxidation of the indolyl radical. The reaction of indole and triflyl chloride (2 equiv.) was carried out in CH3CN at room temperature in the presence of K2HPO4 and a Ru(phen)3Cl2 (1 mol%) photocatalyst with 26 W household light bulbs as the light source. The use of N-unsubstituted indole led mainly to the C(2) trifluoromethylated product 11(4 : 1 ratio of C(2) : C(3)), while N-acetylindole gave the C(3) alkylation product 12 as the major one (3 : 1 ratio of C(3) : C(2))(Scheme 7).
The use of CF3I for indole trifluoromethylation was further developed by Cho and co-workers,25 who employed the Ru(bpy)3Cl2 complex with TMEDA for reductive generation of the trifluoromethyl radical. Although the reaction worked nicely for C(2) or C(3)-substituted indoles, giving the corresponding products in 81–94% yields, the use of N-methylindoles resulted in the formation of regioisomers (Scheme 8). Later, this catalytic system was employed for trifluoromethylation and perfluoroalkylation of indoles under continuous microflow conditions by Noe¨l and co-workers.26,27 Fukuzumi, Cho, You and co-workers also demonstrated the possibility of using cyclometallated Pt(II) complexes to work as photocatalysts for the trifluoromethylation reaction.28
Another possible source of trifluoromethyl free radicals was Togni’s reagent, which was successfully used for indole trifluoromethylation with methylene blue as a photosensitizer.29 C(3) alkylation of indole is possible when imine or iminium intermediates are involved. In 2012 Stephenson and co-workers realized an amidoalkylation of electron-rich aromatic compounds with dialkylamides under photoredox conditions with Ru(bpy)3Cl2 as a catalyst. Indoles can also be used in the reaction with DMF as a reagent; though N-unsubstituted indole works poorly, N-phenyl and N-benzyl derivatives 13 can be obtained with moderate yields.
The formation of the iminium intermediate 14 is rationalized by the initial reduction of persulfate with photoexcited Ru(II)*. The formed sulfate radical anion abstracts a H-atom from DMF to give
an a-amido radical 15, which is subsequently oxidized by either the Ru(III) PC or persulfate (Scheme 9).30 Analogous generation of reactive imines has been realized by Li and co-workers, who have reported a mild method for the construction of 2-(1H-indol-3-yl)-2-aminocarbonyl compounds 16 by the reaction of indoles with a-amino carbonyl compounds 17 under visible light photoredox catalysis (Scheme 10).31 In this case, the formation of reactive iminium intermediates is explained by the initial single electron oxidation of amine 17 by photoexcited Ru(II)-species.
An interesting continuation of this work has been given by Zhang and co-workers, who developed a visible light-induced aerobic double Friedel–Crafts alkylation reaction of glycine derivatives and indole to access 3,30-bisindolylmethanes.32 The reaction proceeds in the presence of the photocatalyst rhodamine-G and citric acid in DCE at room temperature via a similar process, but the originally formed alkylation product undergoes single electron oxidation, iminium ion formation and Friedel–Crafts alkylation to form the target bisindolylmethane derivatives 18 in 95% yield (Scheme 11). The reaction has been investigated with various ester groups in substrate 17, such as methyl ester, isopropyl ester, t-butyl ester, allyl ester, and benzyl ester and different substituents at the benzene ring, showing very
good tolerance. N-Protected indoles and benzene ring substituted indoles show moderate to good yields under optimized conditions, whereas indoles with strong electron withdrawing groups like Boc
at the nitrogen atom fail to give any product. Citric acid is assumed to promote the second alkylation step.
Dihydroisoquinolinium salts may be generated in situ under photoredox catalysis conditions and used for indole alkylation. Firstly, platinum(II) terpyridyl complex 19 has been used for visible light-induced single electron oxidation of N-aryltetrahydroisoquinolines with further oxidation by a superoxide anion radical and trapping of the resulting iminium ion with indole to give products 20 in 56–81% yields (Scheme 12). Addition of iron(II) sulphate is needed to neutralize the formed hydroperoxides and prevent their interaction with the isoquinoline free radical.33 Secondly, the same transformation has been
realized without the need for air or stoichiometric amounts of iron.34 In this case, the catalytic system of Eosin Y with a graphene-supported RuO2 nanocomposite (G-RuO2) has been used, and hydrogen was extruded from the reaction mixture as molecular hydrogen H2. Valuable 3,30-bisindolylmethanes 21 are prepared through a photocatalytic sequential alkylation of indoles with ethers or alcohols.35 Aryldiazonium salt works as an oxidative quencher of the PC’s excited state, and the aryl radical also abstracts a hydrogen from the ether to generate a reactive free radical 22, which, in turn, attacks the indole to form intermediate 23. The SET oxidation of 23 by Ru(III), followed by aromatization with a loss of proton, results in monoindolylated compound 24.
The formation of the desired bisindolylmethane 21 is explained by proton-promoted Friedel–Crafts alkylation of 24 with another equivalent of indole (Scheme 13). An interesting example of indole C(3) benzylation has been discovered by He and co-workers.36 Under the action of Rose Bengal, visible light, and air, indole and dimethyl aniline 25 are found to form 3-arylmethylindoles 26 (Scheme 14). The benzylic CH2 originates from dimethylaniline, taken in excess. Mechanistic investigations showed that energy transfer or photoredox catalysis pathways are both viable. Later, it has been suggested that
dimethylaniline undergoes demethylation and formaldehyde release, which could react with indole to produce an indolyl cation, capable of reacting with another molecule of dimethylaniline to give benzylated products 26. 37 Although the scope is not very wide from the viewpoint of dimethylaniline, the reaction tolerates N-unsubstituted indoles, with different groups in the benzene ring.
Some problems with alkylation of indoles with halides have also been reported, in general stating that in the case of indoles with electron-withdrawing groups at C(3) (EWG = CN, CO2R), the alkylation proceeds without rearomatization of the indole nucleus, and dearomatized products are predominantly formed.
These examples are discussed further in Section 2.6 Dearomatization reactions. In general, it can be concluded that the alkylation of indoles with free radical species occurs mainly at C(2) due to a better
stability of the formed benzylic free radical. When N-acyl, benzoyl or aryl indoles are employed, the free radical substitution occurs at the C(3)-position. The alkylation with common electrophilic species like iminium ions expectedly gives C(3)-alkylated products.
2.1.2 Carbonylation reactions. Li and co-workers have reported a visible light-mediated C(3)-formylation of indoles with Rose Bengal used as a catalyst.38 The reaction is carried out in an MeCN–water mixture with potassium iodide as an additive, TMEDA 17 as a one carbon source and oxygen as a terminal oxidant. A wide scope of indoles may be formylated with moderate to good yields, though – not unexpectedly – N-protection with electron withdrawing groups (N-Boc, N-Ts) gives only trace amounts of product 18. The reaction proceeds through initial iminium salt formation and indole alkylation to provide intermediate 29. Its oxidation results in the formation of iminium salt 30, which is hydrolysed to complete the sequence (Scheme 15). A series of carbazole-based conjugated microporous polymers have been recently synthesized, and their utility for C(3) formylation of indoles instead of Rose Bengal has been realized with TMEDA as a carbonyl source.39 Van der Eycken, Noe¨l and co-workers have reported a combined visible light photoredox catalysis and transition metal-catalyzed C–H activation for the C(2) acylation of N-pyrimidyl indole 31 with various aldehydes in the presence of a fac-[Ir(ppy)3] photocatalyst, Pd(OAc)2, TBHP and protected amino acid in acetonitrile at room temperature to afford acylated products 32.40 The photocatalytic reduction of t-BuOOH by Ir(III)* leads to the formation of t-BuO radicals, able to abstract a hydrogen atom from an aldehyde to give acyl radical 33. Meanwhile, Pd(II) forms a palladacycle 34, which traps the acyl radical 33 to form intermediate 35. The oxidation of
Pd(III) in intermediate 35 by Ir(IV) completes the photocatalytic cycle.
The recyclation of Pd(II) is achieved via reductive elimination from compound 36. The reaction has been investigated in batch and continuous flow. The yields are good for both methods, but the reaction under continuous flow conditions requires less time and a lower catalyst loading. Noteworthily, the reaction works nicely with heteroaromatic and aliphatic aldehydes (Scheme 16). A different carbonylation strategy uses CO gas and a source of aryl radical. For instance, interaction of aryldiazonium tetrafluoroborates, indole, and CO (70 atm) in an autoclave with a quartz window, in the presence of Eosin Y (1 mol%) and under irradiation with visible light gives C(3)-acylated products37. 41 The reaction goes smoothly regardless of the substituent in indole or aryldiazonium salt, except for ortho-substituted
aryldiazoniums which gave slightly lower yields, pointing to the steric dependence of the process. It has been shown that sulfonyl chlorides might also be used as aryl radical precursors.42 In both cases, the reactions start with photoexcited PC* reducing the aryldiazonium salt or sulfonyl chloride. It leads to the extrusion of N2 or SO2, respectively, to give an aryl radical, able to react with CO, producing an acyl radical. The single electron oxidation of the acyl radical by PC+ presumably gave an acylium ion, which finally reacted with an indole to give the target product 37 (Scheme 17).
2.1.3 Carboxylation reaction. Indole-2-carboxylates are derivatives of high demand, present in natural products and valuable for future modifications. Introduction of this moiety should be planned either at the step of indole cyclization or in the very beginning of the synthetic sequence due to the use of aggressive reagents (organolithium compounds). A direct and benign carboxylation has been developed by Bandini, Ceroni, and co-workers.43 In a typical experiment, an indole and CBr4 with diisopropylamine have been irradiated in MeOH at rt in the presence of a Ru(II) PC. Oxidative quenching of the photoexcited PC* with CBr4 generated a CBr3 free radical, which is trapped by the indole. Further rearomatization and methanolysis of the CBr3 group led to the formation of target indole-carboxylate 38 (Scheme 18). The reaction scope is wide, and even substrates with amine, propargylamine, and allylamine moieties are smoothly carboxylated. It is worth noting, that when R2 = H, the carboxylation
occurs at the C(3) position, except for 4-bromo substituted indoles, which are carboxymethylated at C(2).
2.1.4 Annulation reactions. Indole-derived bromides have been found to react with alkynes under visible light photocatalysis conditions to form carbazoles 39.44 The activated C–Br bond is subjected to single electron reduction by a photoexcited Ir(III)* catalyst. The resulting free radical 40 reacts with the alkyne, giving an alkenyl radical, capable of intramolecular cyclization and further rearomatization (Scheme 19). The reaction tolerates both alkyl and aryl substituted alkynes and works smoothly regardless of indole substitution.
The preparation of b-dihydrocarbolines 41 has been achieved by Chen, Shi, and co-workers through a visible light-induced trifluoromethylation of isocyanide-derived indoles 42.45 The interaction of isocyanides 42 with Togni II reagent 43 in CH3CN in the presence of Ir(ppy)3 under irradiation with a blue LED affords annulation of the dihydropyridine ring (Scheme 20). The substituents on the indole’s benzene ring are well tolerated and do not considerably affect the cyclization, but N-Boc derivatives have been found to give only trace amounts of the target product41. It needs mentioning that the reaction does not work for annulation of 7-membered rings, as the dimerization of openchain intermediates takes place. The reaction presumably starts with SET-reduction of Togni’s reagent by a photoexcited Ir(III)* PC, and the resulting CF3 radical combines with the isocyanide moiety to undergo an intramolecular cyclization. Oxidation of the resulting radical recycles the catalyst and furnishes the final product 41.
2.1.5 Arylation reaction. Arylation of indoles was also realized under the action of visible light. It is well-known that aryldiazonium salts may undergo SET reduction by a photoexcited PC, leading to the formation of an aryl free radical. Zhang and co-workers employed this reaction for indole functionalization. Irradiation of indole and aryldiazonium tetrafluoroborate in DMSO at rt in the presence of Rhodamine B with white LED light resulted in the formation of 3-arylindoles 44. The reaction worked smoothly for N-unsubstituted indoles and N-methylindoles, with various aryldiazonium salts. Poor yields were observed for halogen- and nitro-containing indoles (Scheme 21).46 Recently Reiser and co-workers have developed a photocatalytic protocol for arylation of pyrroles and indoles.47 They have found that the reaction of indole with arylsulfonyl chloride in the presence of an Ir(III) PC and Na2CO3 is temperature dependent. When it is carried out at elevated temperature, the sulfonyl derivative undergoes SO2 extrusion to give an aryl free radical. Only two indoles were tested in the reaction – N-methyl-3-isopropylindole and 2-methylindole to correspondingly give arylation products 45 and 46 (Scheme 22).
2.2. C–O bond forming reactions
Highly available gramines 47 can be transformed into 3-formylindoles 48 via visible light-mediated oxygenation.48 In these experiments, N-methylgramines are irradiated with visible light under an oxygen atmosphere in the presence of Ru(bpy)3PF6 and benzoic acid in acetonitrile to give the corresponding 3-formyl-N-methyl-indoles in 35–69% yields (Scheme 23). Interestingly, the reaction works better without the addition of water, stating the molecular oxygen to be the source of oxygen. Visible light-mediated aerobic oxidation of 3-hydroxymethylindole into 3-formyl indole in the presence of Rose Bengal and NH4SCN has been recently realized with a quantitative yield.49
2.3. C–N bond forming reactions
Recently, the exclusive formation of C–N bonds with indole under the action of visible light has been achieved by Mun˜iz and co-workers.50 A hypervalent iodine reagent 49 derived from saccharine has been found to perform oxidative indole C(2) amination with moderate to excellent yields of products 50(Scheme 24). The use of N-protected indoles is possible, with electron-donating PGs giving larger yields. Various substitution patterns of the indole are tolerated, including tryptamine derivatives. The reaction is believed to go through a radical pathway, which has been strengthened by selective formation of C(2) amination products. A catalytic amount of iodine has been found to be necessary at the stage of photoinitiation. Further experiments state that the iodine compound H[I(Sacch)2] undergoes photoinduced electron transfer with the substrate, leading to the formation of an N-centered saccharin radical, attacking the indole.
2.4. C–S bond forming reactions
Zheng and co-workers reported the C(3)-sulfenylation of indoles with arylsulfonyl chlorides by irradiation with visible light in the presence of the photocatalyst Ru(bpy)3Cl2 for 12 h under an Ar atmosphere in acetonitrile (Scheme 25).51 The reaction was screened with different substituents on the indole and arylsufonyl chloride and moderate to good yields of products 51 were obtained, whereas N-Boc protected indole failed to give any desired product. The reaction was hypothesized to proceed with the formation of p-tolyl hypochlorothioite, arising from multiple SET steps. A PC-free sulfenylation was developed, employing diaryl disulfides as a source of phenylthiyl radicals. The addition of sodium iodide was needed to promote the transformation.52 The reaction worked smoothly for variously substituted diaryl disulfides, bearing alkyl, halogen, methoxyl, hydroxyl, nitro and amine groups, and hetaryl disulfides were also well tolerated. The transformation did not work with dibenzyl disulfide. The
scope of indoles was also wide; N-methyl and N-unsubstituted indoles gave moderate yields, though N-acetyl and 5-cyanoindoles failed to give the target product (Scheme 26). Despite the absence of strong absorption bands in the UV-Vis spectrum of the reaction mixture at 450 nm, the transformation was believed to proceed due to SET from iodide to photoexcited disulfide. More atom economical sulfenylation of indoles was achieved with thiophenols as a source of the sulfenyl moiety.53 In this transformation indoles and thiophenols were irradiated with a 415 nm lamp in DCM in the presence of Rose Bengal under an air atmosphere, furnishing sulfenylated products 53 with moderate to good yields (Scheme 27). The reaction proceeded through singlet oxygen 1 O2 generation by photoexcited Rose Bengal, and oxidation of thiophenol to a phenylthiyl radical. Its interaction with indole with further aromatization completed the transformation. Visible light-mediated thiocyanation of indoles was achieved
with the use of a TiO2/MoS2 nanocomposite PC (Scheme 28).54 This PC was presumed to work through effective electron transfer from the photoexcited nanoscale MoS2 conduction band to the conduction band of anatase TiO2. The efficient separation of photoinduced electrons and holes was believed to improve the SET oxidation of the thiocyanate anion to the thiocyanate free radical. The use of MoS2 alone also produced the desired compounds 54, but with moderate yield. The photocatalyzed sulfonylation of pyrroles and indoles with sulfonyl chloride, Na2CO3 and Ir(III) was developed by Reiser and co-workers (Scheme 29).47 In contrast to an elevated temperature reaction (see Scheme 22), at room temperature no SO2 extrusion took place, and compounds 55 and 56 were synthesized.
2.5. C–P bond forming reactions
An and co-workers reported a photoredox catalyzed phosphonylation of indoles.55 The reaction proceeds between N-methylindole and dimethyl phosphite with Ru(bpy)3(PF6)2 by irradiating with visible light in dichloromethane at room temperature for 10 h, to afford products 57 with 72–82% yields (Scheme 30). The reaction was mostly investigated with N-substituted indoles with various R1-substituents, which smoothly furnished the desired products under optimized conditions.
2.6. Dearomatization reactions
Wang and co-workers have reported a visible light-induced radical dearomatization/cyanation cascade reaction of indole derivatives 58. 56 This strategy provides access to gem-difluorinated and cyanated 3,30-spirocyclic indolines 59. A mixture of the bromodifluoroacetamide derivative of indole 58, trimethyl silylcyanide (TMSCN), K2CO3, hexafluoroisopropanol (HFIP) and the Ir(ppy)3 photocatalyst is irradiated with visible light to afford the desired product 59 in good yield and diastereoselectivity (4.4: 1) (Scheme 31). The reaction proceeds via initial SET reduction of C–Br bonds by photoexcited Ir(III) and spiro-cyclization to deliver an intermediate 60. This radical 60 is oxidized by Ir(IV) to give a carbocation 61, which is trapped by a cyanide anion. This strategy shows good tolerance of electron donating and electron withdrawing substituents on the indole ring. It has been recently found that bromodifluoroacetamide derivatives of indole 62 might undergo a photocatalyzed reaction of oxidative dearomatization.57 Consecutive irradiation of bromodifluoroacetamides with visible light in the presence of Ir(ppy)3 and a base under an argon atmosphere in an organic solvent with addition of water, followed by treatment of the crude intermediate with pyridinium chlorochromate in DCM, affords spirocyclized oxindoles 63 with moderate to very good yields. The use of mono-substituted amides (R2 = H) has been found to be the only limitation of the method. The proposed mechanism starts with the single electron reduction of the C–Br bond by the photoexcited Ir-catalyst, and intramolecular cyclization of the free radical on the indole C(2). Oxidation of the resulting radical to the corresponding cation, and its trapping with water, furnishes 2-hydroxylindoline intermediate 64, which is easily oxidized by PCC to finalize the sequence (Scheme 32).
A PC-free indole dearomatization has been discovered by Zhang, You, and co-workers.58 The reaction between an indole derivative, bearing a remote double bond, and Umemoto’s trifluoromethylative reagent in dichloroethane, under irradiation with visible light, proceeds as a free radical addition/spirocyclization domino sequence, furnishing spiroindolenines 65 with moderate to excellent yields (Scheme 33). The initial cleavage of the CF3 group is rationalized through visible light-induced SET in the electron donor acceptor complex, formed from the p-excessive indole and the electron-deficient Umemoto’s reagent. The reaction works smoothly with electron-donating and electron-withdrawing substituted indoles, though a prolonged reaction time is usually needed for EWG-substituted compounds. Good diastereoselectivity has been obtained for ortho-substituted aryl (R1 = 2-MeC6H4, 2-CF3C6H4, 1-naphthyl) or t-Bu groups at indole C(2).
N-(2-Iodoethyl)indoles were found to react with alkenes under photoredox catalysis conditions to form dearomatized benzindolizidines 66. 59,60 This intramolecular dearomative cyclization is performed in the presence of Ir(ppy)3 or Ir(dtbbpy)- (ppy)2PF6 PCs in combination with tertiary amines, which serve as electron and hydrogen atom donors (Scheme 34). It has been found that instead of a rearomative cyclization pathway, the presence of electron-withdrawing groups at the C(3)-position of the indole (R2 = COMe, CO2Me, CO2Et) led primarily to saturated indoline derivatives. The alkenes with electron-withdrawing groups and 1,1-disubstituted ones formed the desired products with moderate yields. Cyclohexenone and cyclopentenone could also be used successfully to produce polycyclic derivatives. The
presence of a Me-group at C(2) (R1 = Me) impedes the cyclization yielding only 29% of the corresponding product. It has also been shown that the reaction does not work for acrolein, maleimides, and fumarates. It is interesting to note that the choice of tertiary amine affects the diastereoselectivity of the process, and DIPEA has been shown to be the most efficient additive, giving the best stereoselectivity.
A route towards valuable hexahydrocarbazole derivatives has been discovered, while expanding the above-described methodology to 3-(2-iodoethyl)indoles 67. 61 The reaction sequence starts with the
Ir(III)* catalyst being reductively quenched with tertiary amine to give highly reducing Ir(II) species. SET from Ir(II) to iodide generates a free radical, which interacts with the alkene and undergoes an intramolecular cyclization on C(2). The benzylic free radical adds to another alkene moiety to be finally trapped by the H-atom donor. Large excess amounts of alkene (added in three parts) and tertiary amine are needed to furnish the desired products 68 in good yields (Scheme 35).
The dearomatization of indole is also realizable through the formation of C–N bonds, and the efforts in the field are promoted by the presence of the resulting core in numerous pyrroloindoline alkaloids. First, the photocatalyzed transformation of aryloxyamine-derived indole 69 in the presence of eosin Y, DIPEA and radical acceptor 70 towards pyrroloindoline 71 has been developed.62 The reaction proceeds through photoexcited eosin Y reduction of arylamide, followed by N–O bond cleavage and the formation of an amidyl radical, which cyclizes on the indole C(2). The resulting C(3) carbon radical is trapped by a radical acceptor. A wide variety of substitutions has been studied and no strict limitations were found. The methodology has been applied for the total synthesis of marine natural product Flustramide B in racemic form. Further studies showed that the addition of an H-atom donor to the reaction mixture ceases the process with C(3)–H bond formation, providing pyrroloindolines 72. Carrying
out the transformation under an oxygen atmosphere gives hydroxyamination products 73. 63 The latter one has been used to prepare another marine alkaloid flustraminol B (Scheme 36).
An approach to an enantioselective dearomative cyclization has been developed by Knowles and co-workers.64 It has been found that tryptamines can be enantioselectively converted into TEMPO-derived pyrroloindolines 74 (Scheme 37). In the first step of the reaction a photoexcited PC oxidizes tryptamine to a tryptamine radical cation that exists as a hydrogen-bonded complex with a chiral phosphate base. A persistent TEMPOradical traps this cation radical in an asymmetric fashion. Iodonium oxidant TIPS-EBX has been proved to be an effective terminal hydrogen and electron acceptor, preventing the formation of TEMPO-H, which inhibited the process. The reaction proceeds with moderate to very good yields and with excellent enantioselectivity. The resulting compounds are excellent substrates for the preparation of pyrroloindoline alkaloids, which has been demonstrated through the total syntheses of ()-calycanthidine, ()-chimonanthine, and ()-psychotriasine.
Analogous transformation has been investigated by Xia and co-workers.65 Under standard conditions, a tryptamine derivative and an aminoxyl radical were irradiated with a blue LED in the presence of chiral phosphoric acid, DMAP, and cyclohexyl isocyanate in toluene at 15 1C. The resulting pyrroloindolines 75 were prepared with 63–93% yields and 72–98% ee. It has been found that TEMPO-H, the product of TEMPO capturing the hydrogen from the indole, inhibited the reaction, and some scavenging partner for it had to be introduced. The use of Ac2O or CDI for this purpose has been shown to decrease the enantioselectivity through an interaction with phosphoric acid, and the addition of CyNCO to bind TEMPO-H has been found to be optimal. The approach has been successfully applied to a key step of the total synthesis of the alkaloid ()-verrupyrroloindoline(Scheme 38).
Photocatalyzed modification of natural products towards pyrroloindoline alkaloids has been realized by Stephenson and a co-worker.66 Commercially available (+)-catharanthine 76 under treatment with TMSCN in MeOH and visible light irradiation in the presence of an Ir(dF(CF3)ppy)2(dtbbpy)PF6 PC transforms into compound 77 (Scheme 39). This fragmentation starts with the photoexcited Ir(III)* oxidizing 76 to its cation radical, which can be depicted by a tautomeric form 78. The iminium ion in the intermediate 78 is trapped by a cyanide anion, and 79 is subsequently oxidized by Ir(II). The fragmentation product 77 has been shown to undergo an acid-catalyzed Pictet–Spengler cyclization, resulting in alkaloid ()-pseudotabersonine 80. Initial reduction of compound 77, which is followed by photoredoxinduced cyclization, furnishes alkaloid ()-pseudovincadifformine 81. In that case, diethyl bromomethylmalonate 82 has been used as a terminal oxidant. An uncommon scaffold of spiro-[(1,3)oxazinan-3,60-oxindoles] is present in melodinoxanine and mitradiversifoline natural products. It has been shown for the first time by Awang and co-workers that light-induced autooxidation of the alkaloid reserpine 83 incorporates this moiety into the resulting product 84 with low yield.67 Recently, Brasholz and co-workers have developed a more practical process. They have found that irradiating reserpine in CH3CN in the presence of 1,5-diaminoanthraquinone for 150 min at rt produces spiro-[(1,3)oxazinan-3,60-oxindole]-containing molecule 84 with 63% yield (Scheme 40).68
Combination of photoredox with enzymatic catalysis allowed dearomatization of 2-arylindoles, leading to asymmetric formation of 2,2-disubstituted indol-3-ones 85.69 The reaction was carried out under an oxygen atmosphere at rt in DMF for 48–84 h in the presence of Ru(II) and wheat germ lipase (WGL). Initial oxidation of the indole with Ru(II)* to a cation radical, its interaction with superoxide O2, and water elimination gave an imine intermediate. This imine underwent an asymmetric alkylation, catalyzed by wheat germ lipase (WGL). In general, aryl substituents in indole bearing electron-withdrawing groups
gave lower yields than those with electron-donating groups. In turn, the substituents at the indole benzene ring did not significantly affect the reaction. The highest enantioselectivity(93 : 7 e.r.) was detected in the case of 2-phenylindole reacting with butanone, and the lowest one (66 : 34) in the case of penta-2,4-dione. The lowest chemical yield, 10%, was determined for the cyclohexanone reaction with 5-bromo-2-phenylindole. N-Substituted indoles were found to be unreactive (Scheme 41).
2.7. Ring-cleavage reactions
Oxidative cleavage of indole under the action of visible light has been discovered by Jiang and co-workers.70 The visible lightinduced reaction of indole under an oxygen atmosphere in the presence of the dicyanopyrazine-derived chromophore (DPZ) and K3PO4 delivers formylformanilides 86 – ring cleavage products. It has been found that the addition of a phosphate base suppresses the redox potential of DPZ and directs the reaction to an energy transfer (ET) pathway, with photoexcited DPZ* generating singlet oxygen species 1 O2, performing cycloaddition with indole (Scheme 42). The reaction was shown to be tunable and medium-dependent. For example, when LiBr was used as an additive, isatins are produced with good yields (see‘‘Construction of isatins’’ section), and the change of base and solvent leads to indoxile formation (see ‘‘Construction of indolin-3-ones (indoxiles)’’ section). Liu, Wang and co-workers have expanded the visible lightmediated oxidative ring-cleavage reaction on N carbonylated indoles 87. 71 The best conditions harness the cheap and commercially available methylene blue dye as a photocatalyst and trifluoroethanol as a solvent. The reaction has been shown to
work for a wide scope of substrates, exemplified by tryptophan, tryptamine, and free-hydroxyl group containing derivatives.
Moreover, oxidation of cyclopentyl- and cyclohexyl-annulated indoles gives the corresponding medium-sized cyclic amides 88. Oxidation of indol-3-yl acetic acid 89 derivatives and treatment of the resultant products 90 with silica gel gives the products of the Witkop–Winterfeldt reaction – 4-quinolone-3-carboxylates 91 with 54–85% yields (Scheme 43). It has been concurrently reported that the addition of base leads to a direct formation of 4-quinolones 92 through indole ring cleavage.72 Performing the reaction of indole in the presence of Ru(bpy)3Cl26H2O and KOH under an oxygen atmosphere in a CH3CN–H2O mixture irradiating it with a blue LED for 48 h has been shown to be the optimal conditions and gave the target products with 25–92% yields. In this case, mainly N-alkyl-4-quinolones are prepared, with N-H or N-Ts-indoles not giving products. Although N-allyl, N-benzyl, and N-SEMfunctionalized substrates work well, N-phenylindole transformation is less effective, producing target quinolone with 25% yield. A large variety of substituents in the indole ring are tolerated, and it is worth noting that cycloheptano- and cyclohexano-fused indoles can be smoothly transformed into the corresponding fused quinolones(Scheme 44).
Indole ring cleavage products are obtained in the reaction of 3-(5-aminopyrazol-3-yl)indoles 93 with 3-formylindoles, catalyzed by Yb(OTf)3 and eosin Y.73 The reaction is presumed to start with Lewis
acid-catalyzed imine formation, followed by electrocyclization. Further single electron oxidation by photoexcited eosin Y and H-atom abstraction by a perhydroxyl radical cleave the ring, to form an intermediate amide, which after protonation furnishes the final indazole 94. Various aryl substituents on the pyrazole nitrogen might be present, and even NH-pyrazoles gave target products 94 with 39–42% yields (Scheme 45).
2.8. Miscellaneous reactions
Oxidative condensation of indoles with anthranilic acid, accompanied by C(3) oxidation of the indole, has been reported by Wang and co-workers. They have developed a visible lightmediated photochemical process with O2 as a terminal oxidant and 1,1,3,3-tetramethylguanidine (TMG) as an organocatalyst, without the need for an external photosensitizer (Scheme 46).74 This strategy opens a new route for the synthesis of structurally diverse tryptanthrins 95 by dual organo-photochemical processes. The reaction scope has been tested with various substituted indoles and showed good compatibility with anthranilic acid. Substrates bearing electron withdrawing or electron donating substituents undergo condensation smoothly under optimized conditions.
Desulfonylation of N-Ts-indole under visible light irradiation in the presence of 1,3-dimethyl-2-hydroxynapthylbenzimidazoline (HONap-BIH) has been reported by Hasegawa and co-workers.75 This HONap-BIH additive acts as a visible light absorbing agent, and as an electron and hydrogen atom donor. Under photoexcitation of a naphthoxide chromophore, the proton transfer between HONap and BIH moieties occurs to generate excited species. It leads via single electron transfer to the sulfonylated substrate, which promotes loss of the sulfonyl group. Only N-Ts-indole and methyl N-Ts-indole-2-carboxylate have been studied under the reported conditions, giving deprotected indoles 96 with 83 and 99% yields, respectively (Scheme 47).
Indole, indoline, oxindole and isatin scaffolds are present in numerous natural products, biologically active compounds, drugs and agrochemicals:
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