3.4- Pyridyne cycloadditions

An attempt to prepare olivacine 745 from 744 (c/740) failed instead, amide 746 was obtained in 40% yield , derived from nucleophilic attack of dimethylamine on 744 no pyridyne adduct was formed. Apparently the 1-methyl substituent in 740 is sufficient to slow down nucleophilic attack by dimethylamine and allow the pyridyne cycloaddition, which is rather sluggish, to occur. With the methyl group adjacent to the carbonyl group absent in 744, nucleophilic attack is faster than the cycloaddition. 

Guitian et al. reported a total synthesis of ellipticine (228) using a modified Gribble methodology (722,723). This approach applied 2-chloro-3,4-pyridyne (1267) as a synthetic equivalent for 3,4-pyridyne and used the polar effect of the chlorine atom for improved yields and regiocontrol of the cycloaddition with the furoindole 544. Silylation of 2-chloro-3-hydroxypyridine (1263), followed by treatment of 1264 with LDA, afforded the 4-trimethylsilylpyridine 1265. This reaction probably involves... 

Mai et al. reported a formal total synthesis of ellipticine (228) starting from the furoindolone 649 (583,724). In this strategy, the key step is the anionic [4+2] cycloaddition of furoindolone 649 with 3,4-pyridyne (1193). Reaction of compound 1270 with 3,4-pyridyne (1193) in the presence of LDA gave ellipticine quinone (1272)... 

Substituted derivatives of 3,4-didehydropyridine have also been prepared, and these have been utilized in a variety of cycloaddition and nucleophilic addition reactions (82T427 89ACR275). A recent example involves the synthesis of azaanthraquinones by reaction of the pyridyne with the lithium salt of 3-cyanophthalide (Scheme 156), in a sequence that also involves the intermediacy of a 3-pyridyl carbanion (88H2643). 

May and Moody (52) have reported a full account of their Diels-Alder cycloaddition route to ellipticine (1) and isoellipticine (27) (Scheme 10). Conversion of indole (50) to 3-indole-2-propionic acid (56) with lactic acid was followed by a Plieninger cyclization to the pyranoindole 57. Reaction of 57 with 3,4-pyridyne (59), as generated from triazene 58, afforded equal amounts of ellipticine (1) and isoellipticine (27). Although the overall yield of 1 from indole is only 3%, the sequence involves only three steps. 

In an effort to overcome the lack of regioselectivity in the cycloaddition of 3,4-pyridyne (59) with dienes, such as 57 (Scheme 10), or furo[3,4-( ]indoles (e.g., 60) (55), Davis and Gribble (54) have utilized unsaturated lactams 61 and 62 as... 

Some interesting cycloadditions to 3-pyridyne (355) are illustrated in Scheme 102. IV-Phenylsydnone (356) gives (357), which spontaneously loses carbon dioxide to give the pyrazolopyridine (358). Benzaldehyde phenylhydrazone is oxidized by lead tetraacetate to the nitrilimine dipole (359), which also reacts with 3-pyridyne to give a pyrazolopyridine (360) (7160858). 

Hetarynes (dehydroaromatic heterocycles) can also act as dienophiles in Diels-Alder reactions. 2 This capacity and the inherent regiochemical problems are illustrated by two syntheses of the alkaloid ellip-ticine, which both feature a [4 + 2] cycloaddition of 3,4-pyridyne (533) (Scheme 126). 2 The first approach used the triazenylcarboxylic acid (534) as a precursor for hetaryne (533), which then underwent an addition to pyranoindolone (535) spontaneous CCh extrusion of the initial cycloadducts (536 X = N, Y = CH) and (536 X = CH, Y = N) gave directly a 50 50 mixture of ellipticine (537) and its undesired regioisomer (538). 2 ... 

For cycloaddition with a pyridyne, see Mariet, N. Ibrahim-Ouali, M. Santelli, M. Tetrahedron Lett. 2002, 43, 5789. 

Pyridyne is difficult to trap with a diene, because nucleophilic attack takes place much faster, even with relatively poor nucleophiles like acetic acid.421 For the reaction with a diene, Coulombic forces are small, and large coefficients on both C-2 and C-3 would help. Since, 2,3-pyridyne is quite strongly polarised, the ionic reaction is made easier than the cycloaddition. 

Finally, an example of a 1,3-dipolar cycloaddition has appeared. Reaction of pyridynes and quinolynes with pyridazine-A-oxides 747 gave pyrido-oxepins 750 in 20-30% yields. The reaction is thought to involve cycloaddition to give 748 which, after a 1,3-shift of the oxygen from N to C and nitrogen loss, gives the product. The pyridynes were produced by lead tetraacetate oxidation of 1-aminotriazolopyridines. 

A pyrrolo[3,4-Z>]indole (320), which can be prepared by an intramolecular aza-Wittig reaction and JV -protection, acts as a quinodimethane and undergoes cycloaddition to 3,4-pyridyne to yield a mixture of isomeric adducts (321) and (322) which are precursors of ellipticine and isoellipticine (Scheme 98) <84CC1552, 92T10645>. 

A synthesis of the furano[3,4-6]indole (86) has been developed and it has been shown to give cycloaddition products with benzyne and 3,4-pyridyne (Scheme 155) <84JOC45i8). 

Desilylation of some compounds can generate very reactive species such as benzynes, pyridynes, xylylenes, and benzofuran-2,3-xylylenes. 1,4-Elimination of o-(a-trimethyl-silylalkyljbenzyltrimethylammonium halides with TBAF in acetonitrile generates o-xylylenes, which undergo intermolecular and intramolecular cycloadditions (eq 15). Treatment of a-silyl disulfides with Cesium Fluoride or TBAF forms thioaldehydes, which have been trapped by cycloaddition with cyclopentadiene (eq 16). ... 

An anionic [4+2] cycloaddition of furoindolone 89 with 3-pyridyne (90) has been demonstrated by Mai et al. in the preparation of indoloquinones 91 and 92 (Scheme 12.27), both of which are useful synthetic intermediates for the total synthesis of the biologically important pyrido[4,3-b]carbazole alkaloids [53]. 

Scheme 1 -234. [2+2]-cycloaddition between "benzyne" or "pyridyne" and enolates. 

---