Indoles cycloaddition

Chapters 9, 10 and 11 describe methods for substitution directly on the ring with successive attention to Nl, C2 and C3. Chapters 12 and 13 are devoted to substituent modification as C3. Chapter 12 is a general discussion of these methods, while Chapter 13 covers the important special cases of the synthesis of 2-aminoethyl (tryptaminc) and 2-aminopropanoic acid (tryptophan) side-chains. Chapter 14 deals with methods for effecting carbo cyclic substitution. Chapter 15 describes synthetically important oxidation and reduction reactions which are characteristic of indoles. Chapter 16 illustrates methods for elaboration of indoles via cycloaddition reactions. 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

This category corresponds to the construction of the carbocyclic ring by 2 + 4 cycloaddition with pyrrole-2,3-quinodimethane intermediates. Such reactions can be particularly useful in the synthesis of 5,6-disubstituted indoles. Although there are a few cases where a pyrrolequinodimethane intermediate is generated, the most useful procedures involve more stable surrogates. Both 1,5-di-hydropyrano[3,4-b]pyrrol-5(lf/)-ones[l] and l,6-dihyropyrano[4,3-b]pyrrol-6-(in)-ones[2] can serve as pyrrole-2,3-quinodimethane equivalents. The adducts undergo elimination of CO2. 

Indoles by cycloaddition with pyrrole-2,3-quinodimethane equivalents... 

Synthetic Elaboration of Indole Derivatives using Cycloaddition Reactions... 

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. 

A large number of pyridazines are synthetically available from [44-2] cycloaddition reactions. In one general method, azo or diazo compounds are used as dienophiles, and a second approach is based on the reaction between 1,2,4,5-tetrazines and various unsaturated compounds. The most useful azo dienophile is a dialkyl azodicarboxylate which reacts with appropriate dienes to give reduced pyridazines and cinnolines (Scheme 89). With highly substituted dienes the normal cycloaddition reaction is prevented, and, if the ethylenic group in styrenes is substituted with aryl groups, indoles are formed preferentially. The cycloadduct with 2,3-pentadienal acetal is a tetrahydropyridazine derivative which has been used for the preparation of 2,5-diamino-2,5-dideoxyribose (80LA1307). 

In the case of vinylfurans and vinylpyrroles there is the possibility of cycloaddition involving either the cyclic diene system or the diene system including the double bond. 2-Vinylfuran reacts in high yield with maleic anhydride in ether at room temperature to form the adduct involving the exocyclic double bond. Similarly, 2- and 3-vinylpyrroles react with 7T-electron-deficient alkenes and alkynes under relatively mild conditions to give the corresponding tetrahydro- and dihydro-indoles (Scheme 51) (80JOC4515). 

Benzo[Z)]furans and indoles do not take part in Diels-Alder reactions but 2-vinyl-benzo[Z)]furan and 2- and 3-vinylindoles give adducts involving the exocyclic double bond. In contrast, the benzo[c]-fused heterocycles function as highly reactive dienes in [4 + 2] cycloaddition reactions. Thus benzo[c]furan, isoindole (benzo[c]pyrrole) and benzo[c]thiophene all yield Diels-Alder adducts (137) with maleic anhydride. Adducts of this type are used to characterize these unstable molecules and in a similar way benzo[c]selenophene, which polymerizes on attempted isolation, was characterized by formation of an adduct with tetracyanoethylene (76JA867). 

Aminomethylindoles are particularly important synthetic intermediates. 3-Dimethyl-aminomethylindole (gramine) (153) and especially its quaternary salts readily undergo displacement reactions with nucleophiles (Scheme 60). Indole-2,3-quinodimethanes, generated from 2-methylgramine as shown in Scheme 61, undergo intermolecular cycloaddition reactions with dienophiles to yield carbazole derivatives (82T2745). 

Another triflate ester that recently has found growing application in organic synthesis is commercially available trimethylsilylmethyl trifluoromethanesul fonate. This powerful alkylating reagent can be used for the synthesis of various methylides by an alkylation-desilylation sequence A representative example is the generation and subsequent trapping by 1,3-dipolar cycloaddition of indolium methanides from the corresponding indole derivatives and trimethylsilylmethyl trifluoromethanesulfonate [108] (equation 54)... 

A pseudo 1,2 cycloaddition (actually a 1,3 cycloaddition, but may be considered a 1,2 type if a three-membered ring is considered analogous to an alkene) is observed when the pyrrolidine enamine of cyclohexanone is allowed to react with N-carbethoxyaziridine (129) to produce octahydro-indole 130 91). Octahydroindoles and pyrrolidines can also be produced through the intramolecular alkylation of the enamines of certain halo-ketourethanes 176a). 

Vinyl- and acetylenic tricarbonyl compounds are reactive dienophilic components in Diels-Alder reactions. Cycloadditions of these compounds with substituted butadienes were recently used to develop a new synthetic approach to indole derivatives [14] (Scheme 2.9) by a three-step procedure including (i) condensation with primary amines, (ii) dehydration and (iii) DDQ oxidation. 

The Diels-Alder cycloadditions of both 2-vinylindoles and 3-vinylindoles are very attractive methods for preparing [bjannelated indoles to serve as lead substances and as building blocks for alkaloids. Pindur and coworkers [84] have extensively studied the vinylindole Diels Alder chemistry. 

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). 

Acetylchloride is a trapping agent that allows the reaction to go completion, transforming the product into a less oxidizable compound.The results of other reactions between indole (57) and substituted cyclohexa-1,3-dienes show that the photo-induced Diels-Alder reaction is almost completely regioselective. In the absence of 59 the cycloaddition did not occur the presence of [2+2] adducts was never detected. Experimental data support the mechanism illustrated in Scheme 4.14. The intermediate 57a, originated from bond formation between the indole cation radical and 58, undergoes a back-electron transfer to form the adduct 60 trapped by acetyl chloride. 

Lee L., Snyder J. K. Indole As a Dienophile in Inverse Electron Demand Diels-Alder and Related Reactions Adv. Cycloaddit. 1999 6 119-171... 

Utilizing an alternate mode of Diels-Alder reactivity, Harman has examined the cycloaddition reactions of 4,5-T -Os(II)pentaammine-3-vinylpyrrole complexes with suitably activated dienophiles <96JA7117>. For instance, cycloaddition of the p-vinylpyrrole complex 58 with 4-cyclopentene-l,3-dione, followed by DDQ oxidation affords 59, possessing the fused-ring indole skeleton of the marine cytotoxic agent, herbindole B. 

The inverse electron demand Diels-Alder reaction of 3-substituted indoles with 1,2,4-triazines and 1,2,4,5-tetrazines proceeds in excellent yields both inter- and intramolecularly. The cycloaddition of tryptophan 124 with a tethered 1,2,4-triazine produced a diastereomerically pure cycloadduct 125 <96TL5061>. 

Both ( )-l-phenylsulfonyl and (5)-(+)-3-p-tolylsulfmyl -alk-3-en-2-ones can exhibit high diastereoselectivity in their reactions with vinyl ethers and styrenes, with the dienophile having a dominant influence on the stereochemical outcome <96T1205,96TL3687>. Indol-2-ylideneacetic acid esters can act as both dienophile and heterodiene in cycloaddition reactions in the latter case pyrano[3,2-h]indoles are formed <96SYN519>. 

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