Benzyne with isoindoles

Hydroxy-THISs react with electron-deficient alkynes to give nonisol-able adducts that extrude carbonyl sulfide, affording pyrroles (23). Compound 16 (X = 0) seems particularly reactive (Scheme 16) (25). The cycloaddition to benzyne yields isoindoles in low- yield. Further cyclo-addition between isoindole and benzyne leads to an iminoanthracene as the main product (Scheme 17). The cycloadducts derived from electron-deficient alkenes are stable (23, 25) unless highly strained. Thus the two adducts, 18a (R = H, R = COOMe) and 18b (R = COOMe, R = H), formed from 7, both extrude furan and COS under the reaction conditions producing the pyrroles (19. R = H or COOMe) (Scheme 18). Similarly, the cycloadduct formed between 16 (X = 0) and dimethylfumarate... 

However, some failures in this general approach have been noted. The attempted cycloaddition-retro reaction of benzyne with the mesoionic 3-methyl-2,4-diphenylthiazolium-5-olate (26) is reported to give only very low yields of the expected isoindole.47... 

Benzynes and substituted benzynes react with isoindoles to give the 9,10-dihydroanthracene-9,10-imines (92).33 A considerable number of substituted compounds of this type have been prepared.27 Triptycene derivatives (i.e., the benzyne adducts of the anthracene system) have been encountered as unexpected products from the reaction of benzyne with 2-benzyl-1,3,4,7-tetramethylisoindole.114... 

Tetrafluorobenzyne, generally generated by the treatment of pentafluoro-benzene with butyllithium at -78 °C in ether in the presence of the substrate diene, is a versatile dienophile [9, 103, 104], In an interesting study of the use of substituted benzynes to synthesize isoindoles, tetrafluorobenzyne, 4-fluorobenzyne, and 4-(tntIuoromethyl)benzyne were shown to react in moderate yields with A7-(trimethylsiIyl)pyrroles, with the adducts being easily converted to the respective fluorinated isoindoles [705] (equation 87). 

Use has been made of the C-N cleavage in the conversion of the bicyclic tertiary amines, derived from the 4tc + 2tc cycloaddition of pyrroles and isoindoles with benzynes, into aromatic systems, e.g. naphthalen-l,4-imines and anthracen-9,10-imines yield naphthalenes and anthracenes with the extrusion of the nitrogen bridge [24] in yields which are higher than those obtained by standard oxidation procedures. 

The formation of anthracene in reactions of 185 and 186 with benzyne, which was unexplained by Wittig et aZ., possibly is due to an alternative reaction of the intermediate zwitterion (202) with another molecule of benzjme or with a benzyne precursor. Benzyne reacted with the isoindole (206) to give the tetramethyltriptycene (208) and, in a separate run using excess of the benzyne precursor, W-benzylcarbazole. The latter product would appear to be made up of the iV-benzyl group from an intermediate anthracen-9,10-imine (207) and two molecules of benzyne. Mass spectral evidence also implicated the adduct 207, and the formation of 208 was attributed to benzyne-induced deamination of 207 to 1,4,9,10-tetramethylanthracene, which was trapped by further addition of benzyne across the 9- and 10-positions. 

Synthesis of benzo[c]furans and isoindoles (181) is also possible by the addition of benzyne to the respective monocycles (178), followed by reduction (179 — 180) and pyrolysis. In an alternative procedure, (179) is reacted with 3,6-bis(2-pyridyl)-l,2,4,5-tetrazine, which affords (181) under far less vigorous conditions via a retro Diels-Alder reaction of the intermediate (182). 4-Phenyl-1,2,4-triazoles pyrolyze to form isoindoles (Section 3.4.3.12.2). 

The [,4 + 2] cycloaddition of dienophiles with 1-substituted pyrroles is also a reversible reaction, which has been utilized in the synthesis of 3,4-disubstituted pyrroles (b-77MI305oq) and, via the initial reaction of the pyrrole with benzyne, for the synthesis of isoindoles (81 AHC(29>341). The retro-reaction can be controlled and aided by a 1,3-dipolar cycloaddition of the intermediate adduct with benzonitrile oxide (74TL2163, 76RTC67) (Scheme 61). 

Pyrazinium-l-dicyanomethylide (237) with benzyne (generated in situ) gave pyrazino[2.1 -a]isoindole-6-carbonitrile (238) ( diphenyliodonium-2-carboxy-late monohydrate , MeOCH2CH2OCH2CH2OCH2CH2OMe, 210°C, <2 h 19%) 1531 also analogous reactions.582... 

N-phenylation. The further reaction of 87 and 88 with benzyne to give 9-aminoanthracene derivatives 91 (cf. the mechanism outlined in Scheme 12) is blocked by the presence of substituents at the bridgehead positions as in 86. Anthracene (9%) is also produced from the reaction of 87 with benzyne,48 and the formation of the tetramethyltriptycene 93 from benzyne and the isoindole 92 is attributed to a similar deamination of an intermediate anthracen-9,10-imine.68 Deamination of 86 and 87 is more conveniently accomplished by treatment with hydrogen peroxide.72... 

Benzyl-2 -isoindole reacts with benzyne generated in refluxing THF <88JOC2565>. 2-Methyl, 1,2-dimethyl and l,2,3-trimethyl-2//-isoindole react similarly <79J0C1519>. Adducts have also been obtained from 1,2-naphthyne and 2,3-naphthyne (Equation (158)) <83JOC2364>. 

Treatment of the o-chlorobenzylamine derivative (333) with potassium amide in liquid ammonia yields, inter alia, the isoindole (334) by benzyne cyclization. The stable fluorescent isoindole (335) is formed from phthalaldehyde, t-butyl mercaptans, and propylamine. The base-induced elimination of methanesul-phinic acid from compound (336) affords the bis-isoindole (337) the benzo[l,2-f> 4,5-c ]dipyrrole (338) has been prepared in two steps from 5,6-dibenzoyl- 1 -methylindole. ... 

---