Synthesis by Photocyclization

The photocyclization of stilbene and its simple derivatives to phenanthrene and substituted phenanthrenes is now a well-documented and useful synthetic reaction the scope and mechanism of this reaction have been thoroughly reviewed by Stermitz.344 There 

Increasingly, this process has been adapted to the synthesis of heterocyclic systems. One or both of the phenyl substituents in stilbene can be replaced by a heteroaromatic system, and some of the more important of these cyclizations are recorded in Table I. The formation of benz[A]isoquinoline by photolysis of 4-styrylpyridine in cyclohexane is accompanied by the formation of 1- and 3-cyclo-hexylbenz[A]isoquinoline.346 

The photocyclization of stilbenes to phenanthrenes has been used in the synthesis of the aporphine ring system347,348 conversion of the 

A cyclization has also been reported in which the carbon-carbon double bond of styrene forms part of a heterocyclic system in this, 2,3-diphenylfuran (322) is converted by irradiation in benzene into phenanthra[9,10-6]furan (323).349 

It has been known for some time that irradiation of azobenzene (324) in either 22 N sulfuric acid350 351 or acetic acid with added ferric chloride 352 yields benzo[c]cinnoline (325). This is accompanied by the formation of an almost equal quantity of benzidine (326), undoubtedly arising by rearrangement of hydrazobenzene (327). The mechanism of this reaction differs, therefore, from that of the stilbene cyclodehydrogenation, and azobenzene itself functions as the hydrogen acceptor. Yields of not more than 50% of benzo[c]cinnoline are generally observed. 

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Aza-Payne rearrangements, 60, 1 Azaphenanthrenes, synthesis by photocyclization, 30, 1 Azides, synthesis and rearrangement of, 3, 9... 

Polycyclic aromatic compounds, synthesis by photocyclization of stilbenes, 30, 1... 

Synthesis by Photocyclization. A. Oxidative Photocyclization Heterocyclic Analogs of 87... 

Scheme 37. Synthesis of chelerythrine (205) and sanguinarine (206) by photocyclization. Reagents a, hv, benzene b, Pd-C, p-cymene c, DDQ, benzene.

Scheme 39. Synthesis of norchelerythrine (222) by photocyclization. Reagents a, KOBu, benzophenone, dioxane b, CH2N2, CH2C12 c, hv, benzene.

A variety of approaches to the synthesis of heterocycles by photocyclization have been reported. These will be considered under three headings. 

Stilbenes, photocyclization of, 30, 1 StiUe reaction, 50, 1 Stobbe condensation, 6, 1 Substitution reactions using organocopper reagents, 22, 2 41, 2 Sugars, synthesis by glycosylation with sulfoxides and sulfinates, 64, 2 Sulfide reduction of nitroarenes, 20, 4 Sulfonation of aromatic hydrocarbons and aryl halides, 3, 4 Swem oxidation, 39, 3 53, 1... 

Beccalli et al. reported a new synthesis of staurosporinone (293) from 3-cyano-3-(lH-indol-3-yl)-2-oxo propionic acid ethyl ester (1464) (790). The reaction of 1464 with ethyl chlorocarbonate and triethylamine afforded the compound 1465, which, on treatment with dimethylamine, led to the corresponding hydroxy derivative 1466. The triflate 1467 was prepared from 1466 by reaction with trifluoromethanesulfonic anhydride (Tf20) in the presence of ethyldiisopropylamine. The palladium(O)-catalyzed cross-coupling of the triflate 1467 with the 3-(tributylstannyl)indole 1468 afforded the vinylindole 1469 in 89% yield. Deprotection of both nitrogen atoms with sodium ethoxide in ethanol to 1470, followed by photocyclization in the presence of iodine as the oxidizing agent provided the indolocarbazole 1471. Finally, reductive cyclization of 1471 with sodium borohydride-cobaltous chloride led to staurosporinone (293) in 40% yield (790) (Scheme 5.248). 

The synthesis of [3.3.3]cyclazinylium salts (287) by photocyclization of 1,2,6-triaryl-pyridinium cations (288) has been described <80JCS(P1)1879>. 

Wessig, P., Wettstein, P., Giese, B., Neuburger, M., and Zehnder, M. (1994) Asymmetric synthesis of 3-hydroxy-prolines by photocyclization of N-(2-benzoylethyl)glycinamides. 

Steiner, A., Wessig, P., and Polborn, K. (1996) Asymmetric synthesis of 3-hydroxyprolines by photocyclization of... 

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... 

The phenanthridine skeleton is synthesized by photocyclization of the enamides prepared from cyclohexanonimines and benzoyl chlorides (17,18). The benzo[c]phenanthridine skeletons are formed from the enamides prepared from 2-tetralonimines and benzoyl chlorides (19,20). More conveniently, the skeletons of protoberberine alkaloids are readily synthesized from the enamides prepared by simple acylation of 1 -methyl-3,4-dihy-droisoquinolines with benzoyl chlorides (21-24). This berbine synthesis is one of the most typical examples of the application of enamide photocyclization to alkaloid synthesis and can be further extended to the facile synthesis of the skeletons of the yohimbine group of indole alkaloids (25,26). 

Corunnine, Nandazurine, ( )-Caaverine, ( )-Isoboldine, ( )-Thalicmi-dine, and ( )-Domesticine. Relative to the aporphine synthesis by enamide photocyclization, Kupchan and O Brien (141) have developed the oxidative photochemical synthesis of aporphine alkaloids. 

Miscellaiieoiis Additions.—Aoyama and his co-workershave reported the synthesis of p-lactams (115) by photocyclization of the methacrylamides (116). Photocyclization of the azetidinones (117) affording the penicillin derivatives (118) has been the subject of a patent application. ... 

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... 

Miscellaneous syntheses. Moody et al. (90TL4375 92T3589) have described a synthesis of ascididemin 28 that involves the epoxidation of 1,10-phenanthroline 181, ring opening of the epoxide 182 with 2-iodoaniline to afford the amino alcohol 183, and oxidation followed by photocyclization of the o-iminoquinone 184 (Scheme 29). 

Photocyclization of iV-chloroacetyl amines has been used previously in the synthesis of nitrogen heterocycles, and the reaction of the substituted amine (166) leads to a benzazepinone that can be elaborated to give pseudoprotopine alkaloids. Y-Chloroacetyl derivatives of the seven isomeric indolylethylamines give azepinoindoles and azocinoindoles by photocyclization. Quantum yields for the reaction are correlated with calculated (CNDO/2 and INDO) electron densities, and on this basis mechanisms are suggested the conclusion is that both indole radical cations and indolyl radicals (for the 1-substituted compounds) are... 

Lactams by intramol. amidation, 291 by photocyclization, 295-296 Lactams, macrocydic synthesis, 240-241,247, 249-250, 328-329... 

Polycyclic Thiophens. - Castle and coworkers are continuing their extensive work on the synthesis of polycyclic thiophens as possible constituents in coal. All of the monomethyl isomers of (332), (333) , and (334) have been prepared by photocyclization of 3- and 2-styrylbenzo[blthiophens. The pentacyclic thiophens (335) and (336) have been synthesized from 3-methylphenanthro-... 

Furthermore, the following compounds were synthetically prepared racemic cheilanthifoline (58c) (47), kikemanine (58d) (129), canadine (58e), berberine (59a) (590, 614), tetrahydropalmatine (58g) (475), sinac-tine (58h), cavidine (68d) (616,617), nandinine (58i) (590, 614, 615), capaurine (58p) (618), capaurimine (58o) (128, 618a), xylopinine (60c) (610, 615, 619), O-methylcaseanadine (62b) (70, 620), thalictricavine (68b), and corydaline (68h) (615). Xylopinine (60c) and some other alkaloids were synthesized by benzoylation of 1-alkyl-3,4-dihydroisoquinolines followed by photocyclization. This method provides a useful route to the synthesis of other protoberberine alkaloids (619). It is also applicable to the synthesis of cularine (51) and spirobenzyltetrahydroisoquinoline alkaloids (188). Xylopinine was also synthesized from the corresponding enamide under benzyne reaction conditions (615). Kametani etal. summarized their findings on the synthesis of these alkaloids and described the formation of protoberberines by debenzylation and photolysis of tetrahydroisoquinolines (622, 623). The total stereospecific synthesis of racemic ophiocarpine (70a) from the 3,4-dihydroisoquinoline derivative by Mannich cyclization was also described (624). 

The synthesis of 6-oxochelirubine (prepared by photocyclization) showed that the alkaloids chelilutine, sanguirubine, sanguilutine, and chelirubine (bocconine)—independently isolated by Slavik (45) and Onda (44, 769)— have the fundamental structure 185 (770, 770a, 770b). 

Pheuanthrene synthesis. Stilbene derivatives are oxidatively cyclized to phenanthrenes by vanadyl trifluoride in TFA-CH2CI2 at 0°. An example is the conversion of 1 into 2. This reaction had been conducted by photocyclization. 

However, the structure of this photocyclized lactam was the one which often appears in the alkaloids as shown in the table. These alkaloids belong to a relatively new class of indole alkaloids and often carry remarkable biological activity. Apparently, these alkaloids were very suited targets for the synthesis by enamide... 

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