Disubstituted pyrroles reaction

Whereas the cycloaddition of arylazirines with simple alkenes produces A -pyrrolines, a rearranged isomer can be formed when the alkene and the azirine moieties are suitably arranged in the same molecule. This type of intramolecular photocycloaddition was first detected using 2-vinyl-substituted azirines (75JA4682). Irradiation of azirine (54) in benzene afforded a 2,3-disubstituted pyrrole (55), while thermolysis gave a 2,5-disubstituted pyrrole (56). Photolysis of azirine (57) proceeded similarly and gave 1,2-diphenylimidazole (58) as the exclusive photoproduct. This stands in marked contrast to the thermal reaction of (57) which afforded 1,3-diphenylpyrazole (59) as the only product. 

Scheme 3 Synthesis of 1,4-disubstituted pyrroles via Paal-Knorr reaction...

Vinamidinium salts have been used for the preparation of 2,3- or 2,5-disubstituted pyrroles. Thus, reaction of sarcosine ethyl ester with 18 results in an amine-exchange reaction at the least hindered position. Anion mediated cyclization and elimination of dimethylamine leads to 19 <96T6879>. 

Many other biologically active pyrroles have been prepared by this reaction. 2-Cyano-3,4-disubstituted pyrroles are prepared by the reaction of isocyanoacetonitrile with [1-nitro acetates. 

A reaction of JV-alkyl-and N-phenyl-2,5-disubstituted pyrroles with complex 219 at 0 °C gave the best yields of the corresponding pentathiepins 221 under conditions which include treatment with non-premixed sulfur monochloride and DABCO and with complex 220 (2005OL5725 Scheme 117). 

Disubstituted thiophenes 96 and 1,2,5-tri- and 2,5-disubstituted pyrrole derivatives 97 are available readily from m-3,6-disubstituted-3,6-dihydro-l,2-dioxins in a one-pot synthesis. The reaction proceeds by an initial Kornblum-de la Mare rearrangement of the 3,6-dihydro-l,2-dioxin to its isomeric 1,4-diketone followed by the condensation with Lawesson s reagent, ammonium carbonate, or a primary amine (Scheme 21) <2002TL3199>. 

The Mukaiyama reaction with the dimethoxy acetal of azidoacetaldehyde gives 2,3-disubstituted pyrroles (Scheme 50) (90AG(E)777). 

Pyrroles are obtained by reduction of 1,2-diazines (80JMC481). This reaction has been used in conjunction with inverse electron demand Diels-Alder reactions to prepare 3,4-disubstituted pyrrole-2, 5-dicarboxylic acid derivatives(Scheme 67). Silyl enol ethers or enamines can also serve as the electron-rich dienophiles thus, silyl ethers of ester enolates give 3-methoxypyrroles (84JOC4405). 

Reaction of an -substituted pyrrole with an alkynic dienophile provides access to a 3,4-disubstituted pyrrole through a Diels-Alder/retro-Diels-Alder cycloaddition process (73CJC1089). The 3,4-pyrroledicarboxylic ester (206) prepared in this way has been converted to the antimitotic agent Verrucarin E (207 Scheme 44). 

Michael adducts are also formed from the reactions of pyrroles with ethyl propiolate and with but-l-yn-3-one. In addition to the expected acrylic ester, 1-methylpyrrole also yields ethyl 3,3-bis(l-methyl-2-pyrrolyl)propanoate in its reaction with ethyl propiolate (67MI30500, 67MI30501), whilst if both a -positions of the pyrrole ring are unsubstituted, a twofold Michael addition with but-l-yn-3-one occurs to give the 2,5-disubstituted pyrrole (76JHC1145). 

The acid-catalyzed addition of aliphatic ketones to 2,3,4- or 2,3,5-trisubstituted pyrroles generally produces bispyrrolylalkanes, analogous in structure to the products of the corresponding reactions with aldehydes, whereas 2,5-disubstituted pyrroles react with acetone to form a 2 3 adduct (113). Pyrrole and 3,4-disubstituted pyrroles react with aliphatic ketones to give porphyrinogens (114), which, unlike the macrocycles obtained from the... 

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). 

Annelation of 2,5-disubstituted pyrroles provides a useful route to isoindoles as shown in reactions (140)-(142). These reactions can be formulated as electrophilic aromatic substitutions of the pyrrole ring and proceed under the influence of acid catalysts (66T2481, 68JCS(C)3036, 72JCS(P1)904). 

A gold(I)-catalyzed domino reaction sequence involving pentenynyl tosylamides led to the formation of 2,3-disubstituted pyrroles containing a quaternary center in the 2-substituent <07OL3181>. The mechanism of the reaction involved a 5-endo-dig cyclization followed by an aza-Claisen rearrangement. 

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