Pyrrole, Michael addition

Remarkably few examples of this type of ring construction are available. The cobalt carbonyl hydride catalyzed hydroformylation of A/,A/ -diallylcarbamates has provided 3-pyrrolidinones (Scheme 61a) (81JOC4433). The pyrrole synthesis shown in Scheme 61b depends on Michael addition of ethyl a-lithioisocyanoacetate to ethyl a-isocyanocrotonate (77LA1174). 

Michael addition reactions, 4, 302 reactions with ally halides, 4, 301 Pyrrole-2-carboxylic acid, 1-methyl-conformation, 4, 194 esters... 

The mechanism is presumed to involve a pathway related to those proposed for other base-catalyzed reactions of isocyanoacetates with Michael acceptors. Thus base-induced formation of enolate 9 is followed by Michael addition to the nitroalkene and cyclization of nitronate 10 to furnish 11 after protonation. Loss of nitrous acid and aromatization affords pyrrole ester 12. 

Battersby and coworkers have developed selective methods for total synthesis of chlorins on a model system, as shown in Scheme 10.15, in which the Michael addition of 5-f3-nittoethyl pyrrole to enone and reductive cyclizadon are used as key steps. "... 

An analogous cyclization to eventually form five-membered rings has also been observed for l-metalla-l,3,5-hexatrienes with an additional heteroatom within the chain, such as in the complexes 157. These are obtained by Michael additions of imines to alkynylcarbene complexes in good to excellent yields (reaction type F in Scheme 4), and their configurations were determined to be Z (>91%) in all cases. Upon warming in THF solution, complexes 157 underwent cyclization with reductive elimination to furnish 2Ff-pyrroles 158 in up to 97% yield (Scheme 34). With two cyclopropyl substituents at the terminus in... 

Besides the domino Michael/SN processes, domino Michael/Knoevenagel reactions have also been used. Thus, Obrecht, Filippone and Santeusanio employed this type of process for the assembly of highly substituted thiophenes [102] and pyrroles [103]. Marinelli and colleagues have reported on the synthesis of various 2,4-disubstituted quinolines [104] and [l,8]naphthyridines [105] by means of a domino Michael addition/imine cyclization. Related di- and tetrahydroquinolines were prepared by a domino Michael addition/aldol condensation described by the Hamada group [106]. A recent example of a domino Michael/aldol condensation process has been reported by Brase and coworkers [107], by which substituted tetrahydroxan-thenes 2-186 were prepared from salicylic aldehydes 2-184 and cycloenones 2-185 (Scheme 2.43). 

Langer and coworkers constructed diverse O- and N-heterocydic scaffolds, such as y-alkylidene-a-hydroxybutenolides and pyrrolo[3,2-b]pyrrol-2,5-diones, exploiting the well-established cyclization strategy of bisnucleophiles with oxalic acid derivatives [163], while Stockman s research group reported in this context on a novel oxime formation/Michael addition providing the structural core of the alkaloid perhydrohistrionicotoxin [164]. 

The Michael addition of nitroalkanes to a, P-unsaturated ketones gives y-nitroketones, which are converted into pyrroles by reduction of the nitro group with Bu3P and PhSSPh (Eq. 10.2).4... 

Another pyrrole synthesis based on intramolecular substitution of the nitro group by amino function is presented in Eq. 10.7, in which the Michael addition of enamines to nitroalkenes is used.9... 

The Michael addition to nitroalkenes followed by cyclization provides a general method for the synthesis of various pyrroles. The reaction of nitroalkenes with acetoacetate followed by reduction with Zn in acetic acid provides another route to 2-methyl-3-pyrrolecarboxylates (Eq. 10.8).10... 

A one pot samarium-catalyzed three-component reaction of aldehydes, amines, and nitroal-kanes leads to pyrroles. The reaction proceeds via imines, generated from the amine and carbonyl compound, followed by the Michael addition of the nitro compound (Eq. 10.10).12a In... 

The Michael addition of lithium enolates to nitroalkenes followed by reaction with acetic anhydride gives acetic nitronic anhydrides, which are good precursors for 1,4-diketones, pyrroles, and pyrrolidines (Eq. 10.73).113... 

Stang etal. (94JA93) have developed another alkynyliodonium salt mediated approach for the synthesis of y-lactams including bicyclic systems containing the pyrrole moiety. This method is based on the formation of 2-cyclopentenones 114 via intramolecular 1,5-carbon-hydrogen insertion reactions of [/3-(p-toluenesulfonyl)alkylidene]carbenes 113 derived from Michael addition of sodium p-toluenesulfinate to /3-ketoethynyl(phenyl) iodonium triflates 112 (Scheme 32). Replacing 112 by j8-amidoethynyl (phenyl)iodonium triflates 115-119 provides various y-lactams as outlined in Eqs. (26)-(30). 

The solid-state interaction of enamines (428, 333a) with trans-l,2-diben-zoylethene (87) provides quantitative yields of the pyrrole derivatives 445 or 446 [140]. These remarkable 5-cascades consist of initial vinylogous Michael addition, enol/keto tautomerism, imine/enamine tautomerism, cyclization, and elimination, all within the crystal without melting. A waste-free extraordinary atom economy is achieved that cannot nearly be obtained in solution. The milling times are unusually long here (3 h) but it s certainly worth the effort... 

An attempt to introduce a bulky triphenylmethyl substituent at N-(y of methyl 677-furo[2,3-7]pyrrole-5-carboxylate 31a led to C-2 triphenylmethyl substitution giving the product 157, which with ethyl propynoate in acetonitrile gave the Michael addition product 158 <2000PJC207> (Scheme 16). 

Nitroketones are reduced to pyrroles by diphenyl disulfide and triphenylphosphine (86JCS(Pl)2243). Since 7-nitroketones are accessible by Michael additions of nitroalkanes to enones, this is a potentially versatile method (Scheme 40). 

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). 

In contrast to the reactivity of the nitroethylenes, acrylonitrile generally reacts with indoles to form the l-(2-cyanoethyl) derivatives (B-70MI30500,79MI30501), whereas Michael addition at the 3-position requires the catalytic effect of copper(II) salts. The addition-elimination reaction of pyrroles and indoles with l,l-dicyano-2-ethoxyethylene proceeds in low yield (<30%) to give the dicyanovinyl derivatives, which can be converted by standard procedures into the formyl compounds (81H(16)1499). Tetracyanoethylene forms charge transfer complexes with indoles, which collapse to the Michael adduct anions and subsequently eliminate a cyanide ion with the formation of the tricyanovinylindole (B-70MI30500). 

Pyrrole and 1-alkylpyrroles generally react with ir-deficient alkenes and alkynes to give Michael addition products (see Section 3.05.1.2.6), but Diels and Alder (3lLA(490)267) reported that 1-methylpyrrole also gave a 1 2 adduct with DM AD formulated as (229), which could be derived from a [w4+w2] cycloaddition of a second molecule of DM AD with the initially formed Michael adduct (cf. Section 3.05.2.3). Subsequent work, however, has shown structure (229) for the 1 2 adduct to be incorrect, the true structure being (230) (63AHC(i)i25, 78AHC(23)265). The formation of the dihydroindole (230) requires the initial... 

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