Benzyne with pyrroles

It should be noted that the 1 1 adducts of benzyne with pyrrylmag-nesium iodide, and A -methyl- and iV-benzylpyrrole were isolated and characterized only as the hydrobromide (113), the methiodide (115), and the picrate of 102, respectively. The low yields of all these derivatives are due in part to further reactions of thenaphthalen-l,4-imines with benzyne (see Section III, F and G). Yields are better where the starting pjnrole has an electron-withdrawing N-substituent. Some analogous naphthalen-l,4-imines expected from 1,2,5-trisubstituted pyrroles apparently rearrange spontaneously to j3-naphthylamine derivatives under the conditions for their formation (see Section III, F). The related adducts 107 and 108 are formed from tetrahalobenzynes and N-methy Ipyrrole. 

There is some evidence that the cycloaddition reaction of benzynes with 1-substituted pyrroles may proceed in two steps via a zwitterionic intermediate and that the reaction is thermally reversible, for although 1-methylpyrrole yields the [w4 + w2] adduct (258) with... 

Diels-Alder adducts (e.g., 81-84) have been prepared from N-substituted pyrroles with tetrafluoro- and tetrachlorobenzyne. These adducts are less readily isomerized to naphthylamine derivatives and less prone to react further with benzyne. A minor product of the reaction of tetrachloro-benzyne with N-tert-butylpyrrole is the 1,2-cycloadduct 85 (2%), for which... 

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... 

The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid and with benzyne reacts to give 2-phenylpyrrole rather than a product of cycloaddition (Scheme 47). 

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. 

Despite the fact that the history of hetarynes is older than that of the benzynes (cf. 2), physical data on these compounds are scarce. Numerous trapping experiments furnished evidence for the formation of brradicaloid intermediates in the field of five-membered heterocycles (didehydrofurans, -thiophenes, and -pyrroles)." Direct spectroscopic data on these species, however, do not exist, which may be attributable to the increased ring strain in the five-membered o-arynes, associated with a strong tendency to undergo ring-opening reactions. 

Furans react readily with benzynes, e.g. 2-acetoxyfuran yields (185). A-Methylpyrrole also reacts normally across the 2,5-positions, but pyrrole itself yields 2-phenylpyrrole,... 

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). 

In other examples, reaction of 3,4-dibromo-Af-tosylpyrrole occurs with benzyne <20050L1003> and iV-Boc-pyrrole adds to methyl bromopropynoate (Scheme 102) <1996JOC7189>. 

Fluoride-ion-mediated generation ofbenzyne from silylaryl triflates (41) [20] is mild and excellent in chemical yields andsoithasbeen employed for a variety of electrophilic (42) [21 ], nucleophilic (43) [22], and cycloaddition reactions [23] (Scheme 3.26). N-Phenylations of sulfonamides (44), amines (45) [24], azirines [25], oxazoles [26], pyrroles [27], and imidazoles [28] with benzyne from 41 are also known. 

Benzyne (from benzcnediazonium 2-carboxylate) reacts with a 2-ethyiidene-A -formylpiperidine to form a doubly fused pyrrole ring in low yield. 

Simple pyrroles do not react as 4n components in Diels-Alder cycloadditions exposure of pyrrole to benzyne, for example, leads only to 2-phenylpyrrole, in low yield. However A-substitution, particularly with an electron-withdrawing group, does allow such reactions to occur, for example adducts with arynes are obtained using l-trimethylsilylpyrrole. Whereas pyrrole itself reacts with dimethyl acetylenedicar-boxylate only by a-substimtion, even at 15 kbar, ° A-acetyl- and A-alkoxycarbonyl-pyrroles give cycload-ducts, addition being much accelerated by high pressure or by aluminium chloride catalysis. The most popular A-substituted pyrrole in this context has been A-Boc-pyrrole, with benzyne (from diazotization of anthranilic acid) for example, a 60% yield of the cycloadduct is obtained. ... 

Adducts with the 1,4-epiiminonaphthalene skeleton may be prepared by the Diels-Alder reaction between pyrroles and benzynes.460... 

Let us now explore the reactivity of these compounds as dienes (furan, pyrrole, thiophene) with a dienophile (benzyne) in Diels-Alder reactions. One approach that, for a long time, has been widely employed by chemists, is the use of Frontier Molecular Orbital (FMO) [19] energy gap between two of the reactants. According to this theory, the most reactive reactant pair will be the one that has a lower FMO energy gap. The reaction is predicted to be HOMO diene-controlled. If... 

To conclude this section, it is important to note that alkenes are not the only hydrocarbon dienophiles that are useful partners in the Diels-Alder reaction. Alkynes and even benzyne are quite useful. As a structure proof of an intermediate in Pandey s synthesis of epiboxidine, the methyl carbamate of pyrrole (34) reacted with dimethyl-2-butynoate (35),in the presence of aluminum chloride (see sec. 11.6.A for a discussion of Lewis acid catalysis) to give a 90% yield of azanorbomadiene (36). A benzyne derivative of pyridine was... 

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