Pyrrole reaction with alkynes

Alkynes substituted with one or two trifluoromethyl groups are also highly reactive dienophiles [9] Indeed, hexafluoro-2-butyne is used increasingly as a definitive acetylenic dienophile in "difficult Diels-Alder reactions. It was used, for example, to prepare novel inside-outside bicycloalkanes via its reaction with cir,trnns -l,3-undecadiene [74] (equation 67) and to do a tandem Diels-Alder reaction with a l,l-bis(pyrrole)methane [75] (equation 68) Indeed, its reactions with pyrrole derivatives and furan have been used in the syntheses of 3,4-bis(tri-fluoromethyl)pyrrole [76, 77] (equation 69) and ],4-bis(trifluoromethyl)benzene-2,3-oxide [78] (equation 70), respectively. 

Pyrroles and thiophenes have been found to react with alkynes in the presence of dinuclear palladium complexes with high cis stereoselectivity in almost all cases. Whereas regioselectivity in the reaction with pyrroles depends on the substituents on the nitrogen atom and alkynes, all reactions of thiophenes afforded 2-alkenylthiophenes.85... 

The exploration of the chemistry of azirines has led to the discovery of several pyrrole syntheses. From a mechanistic viewpoint the simplest is based upon their ability to behave as a-amino ketone equivalents in reactions analogous to the Knorr pyrrole synthesis cf. Section 3.03.3.2.2), as illustrated in Schemes 91a and 91b for reactions with carbanions. Parallel reactions with enamines or a-keto phosphorus ylides can be effected with electron-deficient 2//-azirines (Scheme 91c). Conversely, electron-rich azirines react with electron deficient alkynes (Scheme 91d). 

The regioselectivity observed in these reactions can be correlated with the resonance structure shown in Fig. 2. The reaction with electron-rich or electron-poor alkynes leads to intermediates which are the expected on the basis of polarity matching. In Fig. 2 is represented the reaction with an ynone leading to a metalacycle intermediate (formal [4C+2S] cycloadduct) which produces the final products after a reductive elimination and subsequent isomerisation. Also, these reactions can proceed under photochemical conditions. Thus, Campos, Rodriguez et al. reported the cycloaddition reactions of iminocarbene complexes and alkynes [57,58], alkenes [57] and heteroatom-containing double bonds to give 2Ff-pyrrole, 1-pyrroline and triazoline derivatives, respectively [59]. 

As with the reaction of pyrroles, diazoles and triazoles react with propargyl bromide to yield TV-substituted products and, depending upon the base strength, either TV-prop-2-ynylazoles or allenic derivatives are formed [30]. Generally, with potassium carbonate under soliddiquid two-phase conditions at room temperature in the absence of a solvent, the prop-2-ynyl compounds are formed as sole products, whereas with solid potassium hydroxide at elevated temperatures the allenes are obtained as the major products. Benztriazole produces a mixture of the N1- and N2-prop-2-ynyl, and N2-allenic derivatives, whereas with potassium hydroxide only the N -allenic derivative is obtained. The alkynes readily isomerize to the allenes in the presence of base and the quaternary ammonium salt, or upon treatment with methanolic sodium hydroxide. A series of l-(alk-2-ynyl)imidazoles have been prepared, as intermediates in the synthesis of imidazopyridines [31 ] and the reaction of 3-hydroxymethylpyrazoles with propargyl bromide leads to pyrazolooxazines [32]. 

Metallacyclopentadienes undergo a range of synthetically versatile reactions which proceed with extrusion of the metal atom and attendant ligands. Thus, reactions with alkenes and alkynes afford cyclohexa-1,3-dienes and arenes (Scheme 6), and thiophenes, selena-cyclopentadienes, pyrroles and cyclopentadienones (indenones, fluorenones) can be obtained by treatment with sulfur, selenium, nitroso compounds and CO, respectively. The best studied substrates for such reactions are cobaltacyclopentadienes of the type (24a), which have been converted into a wide variety of arenes, cyclohexadienes and five-membered heterocycles, many of which would be very difficult to obtain by conventional organic procedures (74TL4549, 77JOM(139)169, 80JCS(P2)1344). 

The importance of the results obtained with dibromopropane lies in not only that a new simple procedure of introducing the methyl substituent into the position 2(5) of the pyrrole ring has been found, but also that an opportunity of utilizing alkynes and allenes in the reaction with ketoximes to prepare pyrroles is being outlined. 

A number of electrocyclic reactions under PET conditions have been reported. In this way, A-benzyl-2.3-diphcnylaziridinc (40) underwent a 3 + 2-cycloaddition with alkene and alkyne dipolarophiles to afford substituted pyrrole cycloadducts (41) via the radical cation intermediate (42) see Scheme 7.80 Elsewhere, novel arylallenes have been used as dienophiles in a radical cation-catalysed Diels-Alder cycloaddition reaction with 1,2,3,4,5-pentafluromethylcyclopentadiene, which often occurred with peri-, chemo-, facial- and stereo-selectivity.81... 

Secondary thioamides, precursors of N-protonated azomethine ylids, give A1-pyrrol ine derivatives (after elimination of thiol). When the dipolarophiles are dissymmetric alkenes, high regioselectivity is obtained. Reaction with alkynes leads to pyrrole derivatives in good to excellent yields and with ArCHO leads regioselectively to 2,5-disubstituted 2-oxazolidines in moderate yields.264... 

This above result was only obtained with maleimide as the dipolarophile. With dimethyl fumarate and fumaronitrile, A2-pyrrolines are obtained, probably because of the acidity of the hydrogen atoms a- to ester and nitrile functionalities. Reaction with alkynes produces pyrrole derivatives in good to excellent yields and with aromatic aldehydes leads regioselectively to oxazolidines in moderate yields.263... 

Since perfluoroalkyl-substituted olefins and alkynes possess low-lying frontier orbitals, [4 + 2] cycloaddition reactions to oxazoles and thiazoles without strongly electron-donating substituents are unfavorable. On the other hand, five-membered heteroaromatic compounds possessing an electron-rich diene substructure, like furans, thiophenes, and pyrroles, should be able to add perfluoroalkyl-substituted olefins as well as alkynes in a normal Diels-Alder process. A reaction sequence consisting of a Diels-Alder reaction with perfluoroalkyl-substituted alkynes as dienophile, and a subsequent retro-Diels-Alder process of the cycloadduct initially formed, represents a preparatively valuable method for regioselective introduction of perfluoroalkyl groups into five-membered heteroaromatic systems. 

The uncoordinated 3-vinylpyrrole complexes (e.g., 1133) resemble an electron-rich diene and, as such, undergo a facile Diels-Alder reaction with electron-deficient alkenes and alkynes under mild conditions, for example T-phenylmaleimide 1134 to generate, after decomplexation and oxidation, a highly functionalized indole 1135 in ca. 60% overall isolated yield (from pyrrole) (Scheme 221) <1996JA7117>. 

Exposure of the alkyne 426 to BuLi in the presence of /-BuOK, followed by reaction with ethyl isothiocyanate, gave the intermediate 427, which was subsequently alkylated and cyclized to the pyrrole 428 (Scheme 53) <1999EJ02663>. 

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