Photocyclization of enamides

The photocyclization of enamides to quinolines or isoquinolines has become an important reaction in the synthesis of alkaloids 219,358). It has recently been applied in the preparation of the isoquinoline alkaloid polycarpine 359). The principle of the reaction is demonstrated in the preparation of dihydroquinolines 360 (3.39) and of spirocyclohexaneisoquinoline derivatives (3.40) 361K In each case the electrocyclic ring closure product undergoes a subsequent 1,5-hydrogen shift. 

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The photocyclization of enamides has been the subject of detailed study and provides a valuable approach to the synthesis of alkaloids. A comprehensive review has been published.31 A variety of reaction types has been reported. The N-benzoylenamine 33, for example, is converted on irradiation to the trans-lactam 34 by a process involving conrotatory photocyclization followed by a thermally allowed [l,5]-suprafacial hydrogen migration.32 The influence of substituents on this transformation has been studied.33 The enacylamine 35 undergoes an analogous cyclization to give a mixture of cis- and trans-lactams 36, the ratio of which is solvent... 

The photocyclization of enamides has been widely employed in the construction of heterocyclic systems the N-acryloyl-2-aminopyridines 37, for example, are converted on irradiation to the lactams 38.36 Numerous benzylisoquinoline alkaloids have been prepared using this approach, and in particular, the syntheses of benzo[c]phenanthridine alkaloids have been reviewed.37 Thus, irradiation of the [Z]-l-ethylidene-2-benzoyltetra-hydroisoquinoline 39 affords the corresponding 8-oxoberberine 4038 competing photoisomerization to the E-isomer is observed but cyclization occurs only via the Z-isomer. Examples of syntheses of Amaryllidaceae and indole alkaloids have also been reported. In this way, the precursor 41 of ( )-lycoran has been obtained by oxidative cyclization of the enamide 42.39... 

Hesse s excellent general introduction to alkaloid chemistry naturally contains numerous references to indole alkaloids, and in particular contains a detailed discussion of the structure elucidation of villalstonine, by way of illustration of modern experimental methods used in alkaloid chemistry.1 Indole alkaloids also receive mention in a brief review of hypotensive principles from plants,20 in a review of synthesis via photocyclization of enamides,2 and in another on the use of lactones in alkaloid synthesis.21 Kametani has also reviewed (unfortunately, in Japanese) the synthesis, by his group, of alkaloids by retro mass spectral synthesis .2d The proceedings of the 1979 meeting of the Phytochemical Society of Europe, which were entirely devoted to indole alkaloids, are now available.3... 

Enamides R2C=CHNRCOR (N-acylated enamines) are thermally stable compounds under neutral or basic conditions. However, they show sensitivity to aqueous acid, hydrolysing to form aldehydes or ketones and amides. The photocyclization of enamides has been used to form a wide variety of natural products because it gave higher yields than the conventional thermal syntheses620-623. 

The most widely utilized photoreaction of enamine derivatives is undoubtedly the photocyclization of enamides. Since this subject has already been extensively reviewed3 only a brief discussion is presented here. 

Photocyclization of Enamides of A-(a,/ -Unsaturated Acyl)anilide Type... 

In the photocyclization of enamides of the A-benzoylenamine type and the A-acylanilide type, which are both capable of undergoing nonoxidative photocyclization, the presence of an oxidizing agent causes the abstraction of two hydrogens, therefore forming the dehydrolactam having a double bond, usually at the ring juncture. 

The reaction course of the reductive photocyclization of enamides in Scheme 17 was firmly established by the experiments using deuterated reagents (75). When enamide 14 was irradiated in the presence of sodium borodeuteride in acetonitrile-methanol (10 1) solution, the isolated product 15 in 93% yield was deuterated at the 3 position, whereas irradiation in the presence of sodium borohydride in acetonitrile-deuterium methoxide solution afforded lactam 16, deuterated in the benzene ring as shown in Scheme 18 (55). 

Discovery of reductive photocyclization of enamides has certainly increased its importance as a general and useful synthetic tool. 

Narciprimine and Arolycoricidine. According to the route described in the synthesis of anhydrolycorine (77), arolycoricidine (44) and narciprimine (46) were synthesized by the routes of oxidative photocyclization of enamide 43 and free radical cyclization of o-bromoenamide 45 under irradiation (42) (Scheme 33). 

Nonoxidative photocyclization of enamides of benzanilide and acry-loylenamine types has offered useful routes for the synthesis of ergot alka-... 

The crucial step in this synthetic route is the use of the furoyl moiety in the enamide that facilitated reduction of the number of stereoisomers expected from the photocyclization of enamide and that also was suited for the following modification of the resultant dihydrofuran ring (Scheme 88). 

The hydrogen abstraction, in this instance, presumably occurs at the P-carbon of the enone (139). The resultant biradical ring closes to afford the observed products. The ic-ic excited triplet state is involved in the conversion of the enone (141) into the spiroketone (142). The reaction again involves hydrogen abstraction by the ft-carbon followed by cyclization within the biradical. Photocyclization of enamides such as (143) has led to a new synthetic approach to the yohimbine anreserpine type alkaloids. " The photocyclization of the enone (144) provides a route for the synthesis of 3.10-dimethoxyprotoberberines. ... 

Novel synthetic applications of the photocyclization of enamides have been reported. Preparation of the fused quinolone (23) from the enaraide (24) was achieved by photocyclization and subsequent elimination of a suitably positioned methoxyl group Reductive photocyclization of enamides, usually carried out in the presence of sodium borohydride, is of particular value in the synthesis of alkaloids. Cyclization of the enamide (25) to the... 

Reactions of 1,2-Diketones and other 1,2-Dicarbonyl Compounds. - Further details of the control of the photocyclizations of enamides such as (142) affording (143) have been described. The results obtained are influenced by the nature of the chiral auxiliaries used. The best results are obtained using ionic and covalent auxiliaries in the crystalline phase or in zeolites. " Photochemically induced a-cleavage occurs on irradiation of the ketoamides (144) in water. This results in the release of the carboxylic acid moiety. The by-product of the reaction is the hemiacetal (145). " The irradiation of propellane in the presence of... 

Further studies and numerous synthetic applications of the photocyclization of enamides have been reported. Irradiation of JV-methyl- and JV-benzyl-cyclohex-l-enecarboxanilide (20) affords a mixture of cis- (21) and trans-phen-anthridones (22).17 JV-Methyl-3,4-dihydronaphthalene-l-carboxanilide is analogously converted into the corresponding benzophenanthridones. Formation of... 

This success was now further extended to the indole derivatives by replacing a dimethoxybenzene ring to an indole ring. Thus it was suggested that photocyclization of enamides prepared from harma-lane by acylation with 2- or 3-furoyl chloride would provide a novel synthesis of the biologically useful alkaloid ajmalicine and the hitherto untouched alkaloid hirsuteine. This synthetic strategy was just an another extension of the above emetine synthesis as shown in the scheme. 

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