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The heteroatom possessing bis-allylpalladium analogs were reacted by extending the reaction of bis-allylation. The 2-alkynylisocyanobenzenes, allyl methyl carbonate, and trimethylsilyl azide were reacted by palladium-catalyzed three-component coupling reaction to afford good yields of N-cyanoindoles (Scheme 17).[84] The reaction proceeded through the formation of allylpalladium azide, and subsequently the allylpalladium intermediate was produced by the insertion of divalent carbon of isocyanide into the NPd bond of allylpalladium azide. The allylpalladium intermediate eliminated the nitrogen to form the bis-allylpalladium analog (3-allyl)(3-cyanamido)palladium complex.
Yamamoto et al.[85,86] synthesized 2-substituted 3-allylindoles through cyclization of alkynylbenzenes possessing isocyano and isocyanato moieties in the ortho position. The 2-substituted 3-allyl-N-cyanoindoles were formed when o-alkynylisocyanobenzenes, allyl methyl carbonate, and trimethylsilyl azide were reacted through a three-component reaction in Pd2(dba)3.3CHCl3 and tri(2-furyl)phosphine at 100 C. With a number of substituents in the aryl ring good to allowable yields were reported. The Curtius-like rearrangement of p-allylpalladiumintermediate to the palladium-carbodiimide complex was a distinctive and interesting aspect of this mechanism. The palladium-carbodiimide and palladium-cyanamide complexes were in equilibrium. The presence of heteroatom possessing bis-p-allylpalladium complex was also suggested. The insertion of alkyne functionality into the Pd-N bond of intermediate followed by a reductive elimination of Pd(0) formed the N-cyanoindole. At 100 C temperature indoles were obtained whereas, reductive elimination of Pd(0) from the palladium-cyanamide complex occurred to produce allyl cyanamides at lower temperature (up to 40 C).[13,44] Barluenga et al.[87] synthesized indole derivatives by a three-component reaction. This strategy involved a Pd-catalyzed cascade sequence which involved an alkenyl amination, C-arylation and a subsequent intramolecular N-arylation. During the start of the reaction equimolecular amounts of haloalkene, o-dihaloarene, and amines were mixed. The higher reactivity of haloalkene as compared to the haloarene towards the oxidative addition with palladium allowed the unique synthesis of imine intermediate. Further the deprotonation in basic media produced the corresponding aza-allylic anion. The 2-substituted indoles were formed in a subsequent Pd-assisted intermolecular alkylation with the dihalogeno substrate followed by an intramolecular N-arylation. The palladium catalyst was intervened in three different coupling reactions in this cascade reaction. Those three coupling reactions were: intermolecular N-alkenylation, C-arylation, and intramolecular N-arylation (Scheme 18).[88]
Barluenga et al.[87] reported a domino reaction of o-halobenzene or o-dihaloarenes sulfonates (o-chlorononaflates were the best substrates) with imines for the preparation of indoles through a selective palladium-catalyzed imine C-arylation followed by an intramolecular C–N bond formation reaction with palladium catalyst (Scheme 19). Palladium catalyst was utilized for the formation of these precursors in concert with cyclization as well as simply mediated the formation of C–N bonds. Barluenga demonstrated the one example where palladium catalyst was used for the formation of two separate bonds; first through arylation of the azaallylic anion of imine the C–C bond was formed and then C-N bond was formed catalytically.[31b,44]
The reaction showed wide scope with o-dibromobenzene. The alkyl, aryl, and vinyl substituents were introduced at different positions of pyrrole ring of the indole. The regioselective preparation of indoles substituted in the benzene ring was conducted, with the advantage of different reactivities of Cl, Br, and I in oxidative addition reactions, by reacting o-dihalobenzene derivatives with two different halogens
(Scheme 20).[44,89]
A more general approach was developed to influence the regioselectivity using catalyst which affected the alkyne insertion step. Konno[90] found that the bulkier P(o-tol)3 ligand favored the formation of 3-CF3 substituted products whereas PPh3 preferred the generation of 2-CF3 substituted indoles (Scheme 21).
Jorgensen et al.[91] transformed primary allylamines into indoles and aza-indoles by a novel one-flask strategy through sequential aryl amination and Heck cyclization reactions in the presence of a single catalyst (Scheme 22).[92] The precursors for Heck cyclization were generated by an efficient palladium catalyzed C–N bond forming reactions. Jorgensen[91] has shown that how the tandem C–N bond formation (with the aryl-iodide)/Heck cyclization cascade of starting material and allyl amines in the presence of palladium catalyst can afford one pot synthetic protocol for the formation of indoles (Scheme 23).[92,93] After screening, it was found that the dppf ligand in concert with Pd2dba3 was optimum catalyst for these two steps and it afforded a pathway for the synthesis of a variety of 3-substituted indoles.[31b]
The 2-haloanilines were coupled with vinylbromides in this method. Barluenga[94] has demonstrated that depending upon the used ligand, this method formed either indoles or simple imines. The indole was synthesized exclusively with bulky phosphines (Scheme 24). The o-bromoanilines were reacted with alkenyl halides for the synthesis of indoles through a domino process through an alkenyl amination followed by an intramolecular Heck reaction. The alkenyl halides reacted in the order as follows: alkenyl bromides > aryl bromides > alkenyl chlorides > aryl chlorides. The combination of 2-dicyclohexylphosphino-N,N-dimethylaminobiphenyl (DavePhos), Pd2(dba)3, and t-BuONa at 100 C in toluene afforded the best results. The reaction occurred with alkyl, aryl, and functionalized substituents in both starting substrates. The indoles were only synthesized with 1-substituted-2-bromoalkenes by cyclization of N-substituted o-bromoanilines (which provided N-substituted indoles). A catalytic combination of Pd2(dba)3 and XPhos was needed for employing this strategy to o-chloroanilines.[31b,44]
Ethyl 3-(o-trifluoroacetamidoaryl)-1-propargylic carbonates were reacted with primary or secondary amines to form the N-unsubstituted indole-2-acetamides with the help of 1,10-bis(dimethylphosphino)ferrocene (dppf), Pd2(dba)3, and CO at 80 C in THF (Scheme 25).[95,96] The reaction was employed for the preparation of N-unsubstituted indole 2-acetic acid methyl esters [dppf, Pd2(dba)3, MeOH/THF, CO, 24 h, 80 C].[44] Kondo and coworkers[97] synthesized the indole skeleton through enamine process under solid-phase conditions in which immobilized N-(o-bromo-) and N-(o-iodoaryl) enaminoesters were cyclized to form indolecarboxylate derivatives after a transesterification step (Schemes 26 and 27). The isolated yield increased on adding P(o-tol)3. The Pd2(dba)3.3CHCl3 worked better than Pd(OAc)2 with N-(o-bromoaryl) enaminoesters.
The intramolecular cyclization of immobilized a-acetamido-b-(o-bromophenyl)acrylates was performed as a domino process under solid-phase conditions for the formation of indole through Heck reaction of solid supported N-acetyl-dehydroalanine with 2-bromophenyl triflates or 1,2-dibromobenzenes, then the formed a-acetamido-b-(obromophenyl) acrylate intermediates underwent in situ intramolecular cyclization (Scheme 28).[44,98,99]
The 2-substituted bromoalkenes were reacted for the synthesis of 3-substituted indoles. However, it needed N-substituted-o-haloanilines. Thus, the N-alkyl-3-substituted indoles were furnished in higher yields under similar reaction conditions (Scheme 29).[52,100] The stereoselectivity, which afforded congested quaternary carbon centers in the palladium-catalyzed intramolecular Heck cyclizations, can be inverted with a silver salt (Scheme 30).[101] The coordination of angular vinyl group during the insertion step has shown high selectivity in this case.[102]
The o-ethynyltrifluoroacetanilide was used for the synthesis of 2-unsubstituted 3-aryl indoles in this process.[103] Much more optimization was required in the reaction of aryl iodides with anilide which possessed an o-terminal alkyne moiety, because under the standard conditions developed for o-alkynyltrifluoroacetanilides, coupling derivatives[104,105] were formed in a significant side reaction. Indeed, under a variety of reaction conditions coupling derivatives were obtained in the presence of a number of phosphine ligands. The coupling derivative was observed in 83% yield from the reaction of o-ethynyltrifluoroacetanilide with p-iodoacetophenone [Pd2(dba)3, 60 C, THF, 7 h] using tris(p-chlorophenyl)phosphine. One more significant side reaction was observed in which 2-unsubstituted 3-aryl indoles were formed with the nucleophilic attack of oxygen at the “internal” carbon of the activated C,C triple bond. The N-/O-cyclization ratio was influenced strongly by both the nature of the catalyst and the solvent. The use of DMSO as the solvent, Pd2(dba)3 as the palladium(0) source, and K2CO3 as the base in the absence of phosphine ligands afforded best results (Scheme 31). Cesium carbonate was also used successfully. The indole was obtained in 80% yield when o-ethynyltrifluoroacetanilide was reacted under same reaction conditions omitting aryl iodides.[44,49b]
The 2-substituted 3-acylindoles were synthesized regioselectively from 2-substituted
3-alkynylindole intermediates. The reaction regioselectivity was promoted by the addition of water in high yield in the presence of catalytic amounts of TsOH at room temperature. The regioselectivity of the acid-induced hydration was not influenced in the presence of electron-donating or electron-withdrawing substituents in the alkyne moiety or in the C2-position. The o-alkynyltrifluoroacetanilides and 1-bromoalkynes were reacted through a one-pot cyclization-hydration process for the convenient synthesis of 2-substituted 3-acylindoles and it omitted the isolation of 2-substituted 3-alkynylindoles (Scheme 32).[44,49b,103]
2,3-Diarylindoles possess a wide range of biological activities. This reaction is especially suitable for a straightforward synthesis of symmetrical and unsymmetrical 2,3-diarylindoles. The regioselectivity was followed from the sequence of events and is unambiguous during the synthesis of unsymmetrical 2,3-diarylindoles which was the major advantage of this protocol. Good to excellent results were observed using Pd(PPh3)4 catalyst with aryl bromides, iodides, and triflates. Aryl chlorides were more reluctant to undergo oxidative addition to Pd(0) and needed XPhos (Scheme 33),[70] one of the biaryl monophosphines which increased the rate of the oxidative addition of aryl chlorides to Pd(0) species.[106–108] One of the major problems realized in this indole synthesis was solved using this ligand with relatively unreactive precursors of organopalladium complexes, like, the competitive formation of simple 2-substituted indoles, the formation of which does not involve the aryl halide partner.[44,65,67–69]
Metal-catalyzed amide C-arylations (Scheme 34) effectively afford the expected oxindole products.[26,109]
This oxindole ring can be formed when aromatic substrates contain a halogen atom situated ortho to a moiety containing a reactive functional group. For example, intramolecular radical cyclizations and Heck cyclizations have been used to form the C3-C4 bond of the oxindole nucleus (Scheme 35).[110–116] Grigg and coworkers[117] described the in situ Pd-catalyzed preparation of tributylstannyl-1,2-carbodialkylidene through one-pot protocol from 1,6-diynes and TBTH which was then further coupled with iodobenzene possessing a proximate alkene group and anion capture to provide the good yields of targeted indoline derivatives (Scheme 36).[91]
The alkyl, aryl, and functionalized geminal bromoalkenes participated in an indolization reaction. A new optimization was done with o-chloroanilines. When XPhos was used as a supporting ligand then only the tandem process was achieved. The indoles were synthesized with similar yields to those observed with o-bromoanilines under these conditions[52,118] (Scheme 37).
Spirooxindoles are key intermediates to synthesize (-)-physostigmine, (-)-eptazocine, halenaquinol, and indolizidine alkaloids.[119,120] An indolizidine and spirooxindole skeletons were synthesized as shown in Scheme 38. [121,122]
The starting substrates N-(o-halophenyl)allenamides were utilized in a new protocol for the formation of 3-substituted, 2-unsubstituted, and 2,3-disubstituted indoles through an intramolecular carbopalladation/anion capture domino reaction with boron nucleophiles. The 2-silylindoles were synthesized when an appropriate silicon group was selectively introduced to the a-position of the allenamide functionality. The formed 2-silylindoles were substrates for further functionalization at the C-2 position (Scheme 39). Fuwa and Sasaki[123a] described this approach based on the intramolecular carbopalladation/cyclization-anion capture protocol for the synthesis of 2,3-disubstituted indole derivatives. The palladium p-allyl intermediate was formed from allenamides which contain a substituent at the a-position through a facile carbopalladation/cyclization. The formed palladium p-allyl intermediate was then cross-coupled with a number of orgnanoboron species to provide various 2,3-disubstituted indoles.[44,123b]
Precedent for competitive oxidative amination in a carboamination reaction was seen previously by the Wolfe group.[124,125] For example, as shown in Scheme 40, in the reaction of N-benzyl-2-allylaniline with 4-bromotoluene to form an indoline, the oxidative amination product N-benzyl-2-methylindole was formed as a byproduct. Furthermore, oxidative amination products can even be preferentially formed over carboamination products with proper ligand choice.
The 2-acetylenic anilines en route to 2-amido-indoles were synthesized by aminative cross-coupling of aryl halides through metal-promoted 5-endo-dig cyclization[126–143] (Schemes 41 and 42). The ynamide 7-Br underwent amination in the presence of p-tolNH2 and 2.5 mol% Pd2(dba)3 to afford 2-amido-indole in good yields using either 5 mol% of Buchwald’s X-phos or van Leeuwen’s xantphos as ligands.[144] The reaction time decreased in the presence of X-phos in comparison to xantphos while there was no use of BINAP. On the other hand, the 2-amido-indole was formed in 78% yield by
amination of 7-Cl only with X-phos. In contrast to aryl iodides, aryl chlorides and bromides performed better in this reaction.
The nitrogen behaved as an ambivalent atom in this operation. As a nucleophile, it intervened in the N-allylation step and in the cyclization step as a leaving group which favored the synthesis of a p-allylpalladium complex. With a number of o-alkynyltrifluoroacetanilides and allylic carbonates, these methods afforded good results. In one of the method, o-ethynyltrifluoroacetanilide was utilized to provide 2-unsubstituted 3-allylindoles in allowable yields. The substituent present on the central carbon atom of the allylic compound was tolerated, whereas the cyclization reaction was hampered when the sterically encumbered substituents were present at one end of the alkyne moiety or the substitution was available at both termini of the allylic system. The most challenging situation to the regiochemistry of the new C-C bond was faced when there were small steric differences between the two allylic termini. The best results were observed with tris(2,4,6-trimethoxyphenyl)-phosphine (ttmpp) and the reaction afforded remarkable regioselectivity and the less substituted terminus of the allylic system bears the indole unit almost exclusively. Some loss of olefin geometry was observed in this process[44,145] (Scheme 43).
Previously in the Wolfe group,[83,146,147] the Pd-catalyzed carboamination of c-(N-arylamino) alkenes and c-(N-Boc-amino) alkenes to afford substituted pyrrolidines has been demonstrated. For example, reaction of a 1-substituted c-(N-arylamino) alkene with 4-bromoanisole gave cis-2,5-disubstituted pyrrolidine and a regioisomer in good yield and diastereoselectivity as a 10:1 mixture of regioisomers (Scheme 44).
Conclusion
This review described the utility of palladium catalysts in the construction of nitrogen containing heterocycles. This synthetic approach has a broad utility for the synthesis of a wide range of N-heterocycles and will continue to attract attention in future. In the past decades, several strategies have been identified and pursued in order to establish reliable, efficient, convenient, and environmentally benign synthetic methods. These strategies include the typically mild conditions of Pd-catalysis, compatibility with many diverse types of polar functionality, reactions that exhibit good yield and product
selectivity, and ability to assemble very different molecular frameworks (to explore chemical space).
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