Diels-Alder cycloaddition carbazoles

Noland and coworkers have developed an interesting methodology for the in situ synthesis of carbazoles. This methodology combines the synthesis of 3-vinylindoles from indoles and acyclic ketones with the subsequent Diels-Alder cycloaddition in one flask to produce a variety of tetrahydrocarbazoles [88] (Scheme 2.36). 

Diels-Alder reaction of vinylindoles with dienophiles has been established as a versatile and flexible methodology for the synthesis of carbazole alkaloids. Among the two different vinylindoles, 3-vinylindoles were the first to be explored for the Diels-Alder cycloaddition methodology with a range of dienophiles to give polyfunctionalized carbazole derivatives. This reaction is catalyzed by tiifluoroacetic acid, and the yield in the absence of the acidic catalyst is very low. The reaction of substituted 3-vinylindoles 550 and 553 with ethylenic dienophiles 551 and acetylenic dienophiles 535 leads, via a tetrahydrocarbazole and a dihydrocarbazole, to the corresponding carbazoles (552 and 554), respectively (530,531) (Scheme 5.18). 

Beccalli et al. reported a synthesis of carbazomycin B (261) by a Diels-Alder cycloaddition using the 3-vinylindole 831 as diene, analogous to Pindur s synthesis of 4-deoxycarbazomycin B (619). The required 3-vinylindole, (Z)-ethyl 3-[(l-ethoxy-carbonyloxy-2-methoxy)ethenyl]-2-(ethoxy-carbonyloxy)indole-l-carboxylate (831), was synthesized starting from indol-2(3H)one (830) (620). The Diels-Alder reaction of the diene 831 with dimethyl acetylene dicarboxylate (DMAD) (535) gave the tetrasubstituted carbazole 832. Compound 832 was transformed to the acid 833 by alkaline hydrolysis. Finally, reduction of 833 with Red-Al afforded carbazomycin B (261) (621) (Scheme 5.99). 

An interesting one-pot, five-component domino process using an intermolecular Diels-Alder reaction of furans with AT-phenylmaleimide as its final step has been used to construct the central core of indolo[2,3- ]carbazoles (Equation 86) <2002AGE4291>. Thus, aminooxazoles produced from an Ugi three-component reaction undergo acylation/intramolecular Diels-Alder/retro-Diels-Alder cycloreversion with pentafluorophenyl arylprop-2-ynoates to give furan derivatives. Subsequent Diels-Alder cycloaddition at elevated temperatures with A -phenylmaleimide produces carbazoles in good yields (Table 5). 

Ene reaction or dimerization competed with the Diels-Alder cycloaddition when 3-(2-propenyl) Af-substituted indoles 136 were employed as diene systems toward NPMI (88HCA467). On the other hand, with /3-substituted 3-vinyl-l//-indoles 137 and the same dienophile, the products include carbazole derivatives and Michael adducts (Scheme 5) (87HCA1419). 

DFT calculations on the intramolecular Diels-Alder reaction of penta-l,3-dienyl acrylates predict stereoselectivities that are in good agreement with the experimen- (g) tal results.85 Another DFT study at the B3LYP/6-31G(d) level of the intramolecular Diels-Alder cycloaddition of 5-vinylcyclohexa-1,3-dienes has been reported. Reaction rates are influenced by dienophile twisting and substituent effects.86 The intramolecular dehydro-Diels-Alder reactions of ynamides (79) provides a new synthesis of benzo[fc]-, tetrahydrobenzo[fc]-, naphtho[l,2-/j -, and dibenzo[a,c]carbazoles... 

The final paragraph in this section details carbazole syntheses that involve the formation of C-C bonds. Intramolecular Diels-Alder cycloaddition of ynamides provided a new route to [b -fused carbazoles <05OL2213>. An electrocyclization of 2,3-divinylindole intermediates produced functionalized carbazoles <05TL4045>. A domino alkynylation/palladium migration/C-H activation approach to 4-vinylcarbazoles was reported <050L701>. For example, treatment of A-arylaniline 134 with diphenylacetylene in the presence of palladium acetate, cesium pivalate (CsPv), and bis(diphenylphosphino)methane (dppm) gave carbazole 136 via post-palladium migration intermediate 135. 

There have been additional studies on the synthesis of carbazoles from vinyl indoles by Diels-Alder cycloaddition. 3-(l-Methoxyvinyl)indoles can be generated in situ by deprotonation of salts of 3-(l-methoxyalkylidene)indolenines. These salts are prepared... 

In addition to the above intermolecular reactions, the intramolecular Diels-Alder cycloadditions of furo[3,4-b]indoles have also been reported. Herndon and coworkers [131] used the coupling reaction of the Af-benzylindolynal derivative 396 with Fischer carbenes 397a-b to obtain the carbazoles 398a-b, presumably via the... 

The pyrrolo[3,4-Z ]indoles offer an alternative approach to access indolo-2,3-quinodimethane analogs and have also been used in Diels-Alder cycloaddition reactions with acetylenes to produce a variety of substituted carbazoles. The most widely used methods developed for the synthesis of pyrrolo[3,4-b]indoles have already been reviewed [126, 127] and thus wiU not be discussed here. 

Back TG, Pandyra A et al (2003) Regiochemical switching in Diels-Alder cycloadditions by change in oxidation state of removable diene sulfur substituents. Synthesis of carbazoles by sequential heteroannulation and Diels-Alder cycloaddition. J Org Chem 68 3299-3302... 

Cycloaddition reactions and the related electrocyclization reactions rank at or near the top of the hierarchy of organic synthesis. Several clever adaptations of these reactions have been described for the synthesis of indoles. Methods that originate with an intact indole ring—for example, to give carbazoles—are not included in this chapter. Thus, the several elegant Diels-Alder cycloadditions of vinylindoles to give carbazoles are not covered. 

The first example of an indole-2,3-quinodimethane (IQM) undergoing a Diels-Alder cycloaddition to furnish a carbazole was reported by Plieninger and coworkers in 1964 [9], Thus, indole-3-acetic acid was readily converted to pyrano[3,4-fe]indol-3-ones upon treatment with carboxylic acid anhydrides (Scheme 1, equation 1). These stable synthetic equivalents of IQMs undergo Diels-Alder reactions with electron-deficient dienophiles (A-phenytma-leimide,maleicanhydride,dimethylacetylenedicarboxylate) (equation 2). Plieninger s discovery notwithstanding, it was Moody and coworkers who parlayed this chemistry into a powerful carbazole synthesis (equations 3,4) [10-18],... 

Like the Diels-Alder cycloaddition reaction of 2- and 3-vinylindoles to give carbazoles, the cycloaddition of 2- and 3-vinylpyrroles to give indoles is a well-established methodology [1],... 

Petillo and colleagues generated a formal bis-pyr-role-2,3-quinodimethane that underwent two subsequent Diels-Alder cycloaddition reactions to form carbazoles... 

In the last decade, several excellent results were also published in the area of enantioselective nickel-catalysed Diels-Alder cycloadditions. Among them, the reactions of cyclopentadiene with 3-alkenoyloxazolidin-2-ones induced by (i )-BINIM-2QN provided cycloadducts in up to >99% yield, >98% de, and 96% ee. Another excellent result was achieved by using a chiral iV,iV -oxide-derived nickel catalyst in Diels-Alder cycloadditions of 3-vinylindoles with methyleneindolinones for the construction of chiral spiro[carbazole-oxindoles] in up to 97% yield, >98% de, and 98% ee. Moreover, the use of the chiral DBFOX-Ph ligand has allowed an inverse-electron-demand Diels-Alder reaction of a range of Af-sulfonyl-l-azadienes with vinyl ethers to be achieved, providing highly functionalised piperidines in up to 75% yield, 96% de, and 92% ee. 

The chiral holmium(III)-complex-catalysed Diels-Alder cycloaddition of siloxyvinylindoles (70) with e-deficient olefins (71) formed exo-substituted hydro-carbazoles (72) in up to 99% yield and 94% ee. Alkylation of these cycloadducts gave tricyclic compounds (73) with four continuous chiral centres (Scheme 20). The thermal 4-i-2-cycloaddition reaction of 7-substituted 4-styrylcoumarins with A-phenylmaleimide and tetracyanoethylene in nitrobenzene yielded 3,4-annulated coumarins. The thermal Diels-Alder cycloaddition of ( )-l,3-dihydro-3-phenacylidene-2//-indol-2-ones (74) with l,2-dihydro-2-oxospiro[3//-indole-3,2 -[2H,9a//-pyrido[2,l-fe][l,3]oxazines]] (75) produced complex dispirooxindoline fused [l,3]oxazines (76) with high regio- and stereo-selectivity (Scheme 21). " ... 

SCHEME 7 Diels-Alder cycloaddition targeted to furo[3,4-b]carbazoles. 

Minfiensine, a secoiridoid indole alkaloid, was isolated from the African plant Strychnos minfiensis by Massiot and co-workers in 1989. The unique structure feature of the 1,2,3,4-tetrahydro-9a,4a-(iminoethano)-9//-carbazole has received much attention for the synthetic efforts and has culminated in several elegant total syntheses. For example. Overman et al. reported on the first and second total synthesis of (-l-)-minfiensine. " In addition, Qin et al. revealed a synthesis of ( )-minfiensine in 2008. Recently, MacMillan and co-workers reported on a nine-step enantiose-lective total synthesis of (-l-)-minfiensine via the key step reaction of organocatalytic Diels-Alder cyclization and amine heterocyclization cascade (Scheme 21.32). For the key step reaction in their approach, reaction of 2-vinylindole 139 and 3 equivalents of propynal in the presence of secondary amine catalyst 140 followed by the addition of NaBH4, stereoselective afforded the tricyclic alcohol 142 via a iminium activated endo-selectiye Diels-Alder cycloaddition and a 5-exo amine heterocy cliz ation. 

A set of Diels-Alder reactions of fused pyran-2-ones with ethyl vinyl ether (an appropriate synthetic equivalent of acetylene) gave fused carbocyclic systems. DABCO was used as a catalyst for the elimination of ethanol under microwave irradiation (Juranovic et al., 2012). The Diels-Alder cycloaddition reaction in 3-nitro-l-(p-toluenesulfonyl)indole with dienes under microwave irradiation in solvent-free conditions gave carbazole derivatives after elimination of the nitro group and in situ aromatization (Victoria et al., 2009). 

Two types of cycloaddition reactions have found application for the Synthetic elaboration of indoles. One is Diels-Alder reactions of 2- and 3-vinylindoles which yield partially hydrogenated carbazoles. The second is cycloaddition reactions of 2,3-indolequinodimethane intermediates which also construct the carbazole framework. These reactions arc discussed in the following sections. 

These dienes are valuable for the Diels-Alder based synthesis of dibenzofurans, dibenzothiophenes, carbazoles and other classes of complex polycyclic heterocyclic compounds. Scheme 2.32 summarizes some of the cycloadditions [81] of 2-vinylbenzofurans (80). 

Blechert and co-workers successfully employed the [4 -I- 2] cycloaddition for the transformation of indole derivatives [79-81], For instance, using 2-vinyl-indole derivatives as heterodienes, (3-acceptor-substituted cyclic and acyclic ena-mines (dienophile), and triarylpyrylium tetrafluoroborate as the photosensitizer, the corresponding Diels-Alder adducts were formed in moderate to good yields with complete regiochemical and stereochemical control [79], Alternatively, good results could be obtained in the reaction of indoles and exocyclic 1,3-dienes, thus providing an easy excess to multifunctionalized carbazoles [80], Quantum... 

For the first time, application of sequential Diels-Alder reactions to an in situ-generated 2,3-dimethylenepyrrole was shown with various dienophiles 548 to afford 2,3,6,7-tetrasubstituted carbazoles (549). This novel tandem Diels-Alder reaction leads to carbazole derivatives in two steps, starting from pyrrole 547 and 2 equivalents of a dienophile, and is followed by 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (DDQ) oxidation of the intermediate octahydrocarbazole. Mechanistically, the formation of the intermediate octahydrocarbazole appears to involve two sequential [4+2] cycloadditions between the exocyclic diene generated by the thermal elimination of acetic acid and a dienophile (529) (Scheme 5.17). 

The reaction of 2- and 3-vinylindoles with dienophile 214 constitutes the first example of an asymmetric Diels-Alder reaction of vinyl heterocycles. From 3-vinylindoles, enantiomerically pure carbazoles 215a-c were obtained, whereas from the vinylindole 197 together with 215d, diastereomer 216 was obtained as a minor product. Conversely, 2-vinylindoles provided inseparable mixtures of diasteromeric carbazoles. On the other hand, the cycloaddition reactions of 3-vinylindoles with 217 furnish the tetrahy-drocarbazoles 218 with endo-diastereoselectivity (93T2863). 

Although dihydrocarbazole 256 has a fixed 1-aminobutadiene unit and should be able to participate in Diels-Alder reactions as a diene component, no cycloadditions took place with a series of hetero- and carbodie-nophiles. In the reaction with PTAD, 1,2-dihydrocarbazole 256 was dehydrogenated to the corresponding carbazole (91LA357). 

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