Photocycloaddition indole

The thermal addition of dimethyl acetylenedicarboxylate to indoles, unlike the photocycloaddition (see Section 3.2.1.4.1.1.), proceeds via a polar stepwise process to yield, initially, 3,4-benzo-2-azabicyclo[3.2.0]hepta-3,6-dienes which in some cases are isolable,13 141 but which, in general, ring open in situ to give the indolylacrylates 3 and/or undergo electrocyclic ring expansion to 1-benzazepines.21... 

A photocycloaddition of a different type has been reported between indole and substituted cyclohexa-1,3-dienes triaryl-pyrylium tetrafluoroborates are used as sensitisers in this electron-transfer process and the [ 4 + 2] adducts are isolated as their W-acyl derivatives (111). High regioselectivity is observed. 

Photocycloaddition of alkenes and cycloalkenes (Chapter 4) with indole often lead to less satisfying results concerning yields and the number of side-products. When transformed into the corresponding carbamate, the enamido group undergoes clean [2+2] cycloaddition to cyclopentene as described by A. C. Weedon. The tetracyclic photoproduct can subsequently be deprotected. When irradiated in absence of an alkene, photodimers are formed in good yields. 

The photocycloaddition reactions of indole discussed in this section involve the participation of the C2-C3 bond of the pyrrole ring only. No photocycloaddition reactions involving the benzene ring of the indole nucleus have been reported. As will be seen, addition across the C2-C3 positions of the pyrrole ring occurs in a 2 + 2 and 2-1-4 sense the use of this nomenclature throughout this section should not, however, be taken to mean that the cycloaddition reactions are concerted. In fact, they are all stepwise. 

Unless the indole nitrogen atom is substituted by an acyl group, the photocycloaddition reactivity of indoles is very limited. In the absence of an N-acyl group, the only reactions reported are the triplet-sensitized 2-1-2 addition of alkynes to AT-methylindoles and the electron-transfer-sensitized 4-1-2 addition of dienes to indoles. When an AT-acyl substituent is present, the C2-C3 bond appears to be activated and will undergo photocycloaddition reactions with a variety of partners such as alkenes, carbonyl groups, and the C2-C3 bond of ground-state N-acylindoles. 

As noted in the introduction to this section, under UV light irradiation, carbonyl groups [42] and alkenes [43] will add photochemically in a 2 + 2 sense across the 2- and 3-positions of indole, but only if an acyl or aroyl group is present on the indole nitrogen atom. The photocycloaddition reaction of carbonyl compounds with acylindoles was first reported by Julian and Tringham in 1973 [42], They found that irradiation of N-acetylindole or N-para-chlorobenzoylindole with benzophenone, benzoyl-formamide, or methyl benzoylformate gave oxetane products, as shown in Scheme 12. The stereochemistry of the products was not reported. No products were obtained when the indoles were irradiated with acetophenone, benzaldehyde, acetone, or propionaldehyde. This observation... 

The intermediate 37 can be viewed as arising from interaction of the triplet excited state of the indole with the alkene partner so as to form the most stable triplet 1,4-biradical intermediate possible. Alternatively, 37 may arise from attack of the 2-position of the triplet-excited indole on the less-substituted, and hence less sterically hindered terminus of the alkene. Either way, the preferential formation of 37 means that with monosubstituted alkenes, the photocycloaddition reaction with AT-acylin-doles is regioselective, while with unsymmetrically 1,2-disubstituted alkenes the reaction will be nonregioselective, as was seen for the reaction between N-benzoylindole and methyl 3-methyl-2-butenoate shown in Scheme 19. Should it be desired, the opposite regiochemistry to that normally obtained with monosubstituted alkenes can be induced by tethering the alkene to the indole [52] the reaction of 1,2-disubstituted alkenes can be made regioselective in the same way [53]. Examples of this are shown in Schemes 20 and 21. 

A wide variety of N-acyl substituents has been found to activate the indole ring toward photocycloaddition reaction with alkenes without themselves undergoing any photochemistry [54]. These are summarized in Scheme 22. Selection of the appropriate substituent allows removal of the activating group from the cycloadducts using conditions that will not disturb any other functional groups that might be present. For example, the... 

Topics which have formed the subjects of reviews this year include photoinduced organic synthesis, photoisomerisations involving super-cyclophanes, regioselec-tive and stereoselective [2+2] photocycloadditions, position- and stereoselective photocyclisation, the photochemistry of indoles, five-membered heterocyclic compounds of the indigo group, pyrazoles and isothiazoles, and heterocyclic N-oxides, photochromic reactions of naphthopyran derivatives, photodegradation reactions of photochromic spirooxazines and 2H-chromenes, ° and chiral photo-chromic compounds. ... 

The photocycloaddition chemistry of pyridines substituted with electron-donor and electron-acceptor groups at the 2- and 3- positions continues to be exploited. The results of irradiation of such pyridines in the presence of 2-cyanofuran have now been described. The yields of the (47r+47r) cycloadducts (29) and (30), the pyridine dimer (31) and the transposition isomer (32) are dependent on the level of methyl substitution on the heteroarene and are given in Scheme 2. Other photocycloadditions to heteroarenes reported within the year include the reactions of benzodithiophene (33) with butadiyne derivatives and dimethyl acetylene dicarboxylate, giving low yields of (34) and (35) respectively, the latter from photorearrangement of the primary adduct (36). The (271+471) photocycloaddition of indoles (37) to cyclohexa-1,3-dienes (38) is sensitized by the aromatic ketones (39), and yields (14-46%) of the exo and endo isomers of the adduct (40) in ratios which are dependent on the substituents on the addends. 

The regiochemical and stereochemical courses of the photocycloaddition of A-acylindoles with monosubstituted olefins such as methyl acrylate and vinyl acetate, as well as the possible mechanistic pathways for these reactions, have been the subject of several reports. In one of the earliest examples, the photocycloaddition of 1 -benzoylindole (8) and methyl acrylate (9) produced the compound 10, which was then converted via a short synthetic sequence to a variety of 2a,7b-dihydrocyclobut[h]indole derivatives 11 (Scheme 2). These compounds were in turn converted to the corresponding l//-l-benzazepines 12, through silver ion-catalyzed thermolysis reactions at 100-160°C [14, 15]. 

While further investigating the origin of the regiochemical course of the photocycloaddition reactions between A/ -benzoylindoles and monosubstituted alkenes, Weedon and Hastings demonstrated that the reactions involve the triplet excited state of the indole derivatives (Scheme 4). The reactions then proceed through the formation of a 1,4-biradical intermediate 20, resulting from the bonding of the 2-position of the indole to the unsubstituted terminus of the aUcene, which is least able to support a radical center [18-20]. 

The intramolecular variant of the [2+2] photocycloaddition of indoles has also been reported. In an elegant formal synthesis of vindorosine (44, Scheme 9), Winkler and coworkers employed the intramolecular photocycloaddition reaction of a vinylo-gous amide carbon-carbon double bond to the alkene of an indole in a substrate... 

The excellent stereoselectivity of the above photocycloaddition reaction is explained by the preferred approach of the vinylogous amide from the a-face of the indole 45. The approach of the amide from the p-face 46, (Scheme 10) is disfavored because of the steric interaction of the indole aromatic ring and the R substituent alpha to the vinylogous amide. 

Davis PD, Neckers DC (1980) Photocycloaddition of dimethyl acetylenedicarboxylate to activated indoles. J Org Chem 45 456 62... 

Several examples of inter- and intra-molecular [2 + 2] and [4 + 4] photocycloaddition of dihydronaphthalenone (74), 2-pyridone (77, 88), indole (85) derivatives have been reported in this series. Efficient intramolecular photocycloaddition of 4-alkenyloxycoumarin derivatives (90, 92) was achieved by use of flow microreactor/ Caged compounds (94) can be prepared by successive Diels-Alder reaction and [2 + 2] photocycloaddition via double tandem sequence. ... 

Nishio, T. and Oka, M., Synthesis of indole derivatives by [2+2] photocycloaddition of indohne-2-thiones with alkenes and photodesulfurization of indohne-2-thiones, Helv. Chim. Acta, 80, 388, 1997. 

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