Diels-Alder reaction of vinylpyrroles

CATEGORY lldf AND CATEGORY Wfh CYCLIZATIONS - DIELS-ALDER REACTIONS OF VINYLPYRROLES... 

Pyrroles and their Benzo Derivatives Synthesis Table 9 Diels-Alder reactions of vinylpyrroles and vinylindoles. 

Another pioneer in the Diels-Alder reactions of vinylpyrroles was Noland, who also developed the reactions of vinylindoles to yield carbazoles. Some examples of the former are shown in Scheme 2 (equations 1 and 2) [4-7], Jones and his colleagues were equally active in this cycloaddition chemistry of vinylpyrroles (equations 3 and 4) [8-12], These workers measured the rates of the reaction between 1-methyl-2-vinylpyrrole and seven dienophiles, with maleic anhydride being 4800 to 50,000 times more reactive than the other dienophiles (DMAD, maleonitrile, fumaronitrile, dimethyl maleate, methyl acrylate, and acrylonitrile) [8], In a clever tactic to thwart the formation of dihydroindoles, Jones used an excess of methyl propio-late to convert the initial adduct to a second Diels-Alder cycloadduct that subsequently loses ethene by a retro-Diels-Alder reaction to afford the dimethyl 1-methyl (phenyl)-4,7-dicarboxylates (equation 4). The reactions are concerted and were consistent with FMO calculations (HOMO[vinylpyrrole]-LUMO[alkene]). The yields are 54% to 81%, but attempts to dehydrogenate the tetrahydroindole products to indoles were unsuccessful. 2-Vinylpyrrole itself undergoes Michael additions and polymerization with these dienophiles. Domingo, Jones, and coworkers subsequently... 

A variation of indole synthesis involving intermolecular Diels-Alder reactions of vinylpyrroles (Chapter 60) is mtramolecular electrocyclization reactions of vinyl- and divinylpyrroles to give indoles. 

Diels-Alder reaction of indole-2,3-quinodimethanes, 164-169 of pyrrole-2,3-quinodimethanes, 85-87 of vinylindoles, 159 -164 of vinylpyrroles, 79, 84-85 N.N-dihexyl 2-phenylindole-3-acetamide, procedure for. 62... 

No reaction has been found with simple vinylpyrroles and TCNE. Nevertheless, there are examples of Diels-Alder reaction of some protoporphyrins with this dienophile. It was first reported [73JCS(P1)1424] that compound 184 reacted with TCNE in refluxing chloroform, giving the cycloadduct 185 in 56% yield. A later study reexamined the reaction and found more complicated chemistry (80JOC5196). In initial experiments, reactions of TCNE with protoporphyrin di-ter/-butyl ester were shown to give three major products, 186,187, and 188 but depending on the conditions of the reaction, time, solvent or amount of TCNE, the results were different. The authors also characterized compounds 189 and 190. 

Figure 24. Diels-Alder reaction of P-vinylpyrrole complex 47 and elaboration to indole 123.

Table 10. Yields for Diels-Alder Reaction of r 2-P-Vinylpyrrole...

The reaction of MP with 1-methyl- and l-phenyl-2-vinylpyrrole 20a,b afforded 1-substituted indole-4,7-dicarboxylie esters 27 via a further [4 + 2]-cycloaddition to the initially formed 6,7-dihydroindole-4-carboxylic ester 26 by a second molecule of MP, followed by a retro-Diels-Alder extrusion of ethene (80JOC4515). Maximum yields were obtained with 2 1 ratio of MP to vinylpyrrole. The intermediate adduct 26 could not be isolated and when the reaction was monitored by NMR spectroscopy, signals attributable to the dihydroindole-4-carboxylic ester 26 were of very low intensity, suggesting that the second and third steps of the reaction sequence were either comparable in rate or faster than the initial cycloaddition step. 

The reaction between the less reactive dienophile MP and 2-vinylthiophene 59 in CH2C12 was conducted at 100°C under pressure and four compounds, 64,65,66, and 67, could be isolated and characterized spectroscopically (85T2435). The adduct 67 is the result of a second addition of MP to the normal cycloadduct, followed by Diels-Alder elimination of ethylene in a way similar to that reported for -substituted 2-vinylpyrroles (Section II,A,3) (80JOC4515). It is useful to point out the structure of adducts 61, 62, and 65 because the ene reaction of thiophene compounds is not a common one (75TL4471). 

Phenyl-5-vinylpyrazole 96 also behaves as a diene in reactions with DMAD and MP [90JCS(P)2749], but the reactivity in such cycloadditions was lower, with reaction times much longer than those required for 1-phenyl-4-vinylpyrazole. In the reaction with DMAD the dihydroindazole 97 was isolated, and with MP the obtained indazole 98 was the result of a double Diels-Alder reaction, followed by extrusion of ethene, as has been reported for vinylpyrroles and vinylthiophenes (80JOC4515 87T269). 

The first vinylpyrroles studied as diene systems in Diels-Alder reactions were the /3-nitrovinyl-A/-methylpyrroles because they are stable and readily available from condensation of the corresponding carboxaldehydes with nitromethane. The /3-nitro vinylpyrrole 117 added to MA and yielded the corresponding N-methylindole-4,5-dicarboxylic anhydride 118. The process is believed to follow the normal Diels-Alder [4 + 2]-cycloaddition pathway, with subsequent loss of nitrous acid to give the fully aromatized adduct [73JCS(P 1)2450]. 

The uncoordinated portion of the 3-vinylpyrrole complexes described above resembles an electron-rich diene, and undergoes a Diels-Alder reaction under mild conditions with electron-deficient alkenes and al-kynes to give functionalized 5,6,7,7a-tetrahydroindole complexes 122 and 149-164 in moderate to excellent yields (Table 10). In most cases, only one stereoisomer is observed even though up to four new stereocenters are formed. For tetrahydroindole complexes 122 and 150, relative stereochemistry has been assigned and is consistent with cycloaddition occurring through an endo-transition state as well as dienophile attack occurring anti to metal coordination. Furthermore, no isomerization occurs to the 4,5,6,7-tetrahydroindole system, which predominates for uncoordinated tetrahydroindoles.23... 

The most fully explored synthetic applications of Diels-Alder reaction in annotation of pyrroles and indoles involves use of vinyl derivatives. Because of the donor character of the heteroaromatic ring, vinylpyrroles and vinylindoles react as electron-rich dienes. Various aspects of both the synthesis and cycloaddition reactions of vinylindoles have been reviewed. <85JHC585, 86CZ95, 88H(27)1253>. 

One of the few high-yielding indole syntheses featuring a vinylpyrrole Diels-Alder reaction was reported by Baell and colleagues (Scheme 6, equation 1) [24]. In nifty fashion, using the Jones mro-Diels-Alder tactic [8], indole 13 was converted to an indole peptidomimetic (14) that inhibits the Kvl.3 potassium channel in T-lymphocytes. The starting... 

Utilizing an alternate mode of Diels-Alder reactivity, Harman has examined the cycloaddition reactions of 4,5-T -Os(II)pentaammine-3-vinylpyrrole complexes with suitably activated dienophiles <96JA7117>. For instance, cycloaddition of the p-vinylpyrrole complex 58 with 4-cyclopentene-l,3-dione, followed by DDQ oxidation affords 59, possessing the fused-ring indole skeleton of the marine cytotoxic agent, herbindole B. 

N-Methyl- and N-phenyl-2-vinylpyrroles 20a,b react with DMAD at reflux temperature in chloroform to give, in moderate yields, the dihydroindoles 22 via a 1,3-H shift from the Diels-Alder intermediate 21 (55-75%) (80JOC4515). These adducts were readily converted into the corresponding indoles 23 with Dichlorodicyanoquinone (DDQ). 2-Vinyl-pyrrole failed to give [4 + 2]-cycloadducts with acetylenic esters (80JOC4515). Spectroscopic analysis of the product mixtures indicated the presence of polymeric compounds resulting from Michael addition reactions. 

A final and interesting example of the use of vinylpyrroles as diene systems in Diels-Alder cycloadditions is the reaction of divinylporphyrins with DMAD and other activated dienophiles [/V-phenylmaleimide (NPMI), Tetracyanoethylene (TCNE)], which provide a general route to bacterichlorin-like chromophores for the treatment of malignant tumors (86JOC1094 91TL2875). 

Sulfur-substituted 3-vinylpyrroles generated from A -methyl-3-thioace-tylpyrrole have been used to accomplish the synthesis of functionalized indoles by Diels-Alder cycloaddition. In the reactions with MA, NPMI, and naphthoquinone the [4 + 2]-cycloadducts were obtained with low to moderate yields and directly transformed to the corresponding indoles by treatment with DDQ (91CPB489). 

Whereas the reaction of l-methyl-2-vinylpyrrole with dimethyl acetylenedicarboxylate at 80°C affords mainly the rearranged Diels-Alder product... 

Vinylpyrroles take part in Diels-Alder processes as 4-7t components this reactivity is best controlled by the presence of a phenylsulfonyl group on the pyrrole nitrogen as illustrated below, the presumed initial product easily isonierising in the reaction conditions to reform an aromatic pyrrole. 

Like the Diels-Alder cycloaddition reaction of 2- and 3-vinylindoles to give carbazoles, the cycloaddition of 2- and 3-vinylpyrroles to give indoles is a well-established methodology [1],... 

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