A -Acylpyrroles

The thermal reactions of pyrroles include the rearrangement of A-substituted pyrroles to C-substituted derivatives (Scheme 1). The rearrangement of A-acylpyrroles has also been reported to occur in the vapour phase on irradiation. 

Pyrrole and its simple derivatives do not react easily as dienes. Pyrrole itself only combines with dimethyl acetylenedicarboxylate (DMAD, dimethyl but-2-ynedicarboxylate) under high pressure and then it is by C-2 substitution. However, A-acylpyrroles, such as A-acetyl- and N- tert-butoxycarbonyl)pyrrole, do undergo Diels-AIder addition reactions. Here, internal resonance within the acyl group reduces the availability of the lone-pair electrons, formally on nitrogen, to delocalize into the ring, thus making the carbon unit more diene-like (Scheme 6.12). 

C-Acyl- and C-alkoxycarbonyl-pyrroles show a strong tendency to fragment to the acylium cation (Figure 15), which is well-stabilized by resonance. a-Acylpyrroles also yield a relatively intense fragment at m/e 66 corresponding to complete loss of the acyl group ... 

Simple amines can rapidly add to ketenes in the absence of a catalyst, but less reactive nitrogen nucleophiles such as the pyrroles do not react at room temperature with ketenes such as phenyl ethyl ketene <2002JA10006>. In contrast, additions can proceed swiftly when planar chiral 4-(pyrrolidino)pyridine (PPY) derivative 235 is employed as a catalyst (Equation 58). In the presence of enantiopure PPY derivative 235 and an appropriate pyrrole, the A -acylpyrroles 236 and 237 can be generated in high enantiomeric excess (Equations 58 and 59) <2002JA10006>. With pyrrole itself as the nucleophile, the new stereocenter is produced in moderate ee (42%). It was discovered that l-acyl-l/7-pyrrole-2-carbonitriles 236 can be converted into a wide array of useful compounds with essentially no erosion in enantiomeric excess. 

A sugar-based ligand such as 172 served as a promising chiral ligand for the catalytic enantioselective conjugate addition of cyanide to a, 8-unsaturated A-acylpyrroles as shown in... 

A process which has proved valuable in synthesis is the addition of singlet oxygen to A-alkyl- and especially A-acylpyrroles producing 2,3-dioxa-7-azabicyclo[2.2.1]-heptanes which react with nucleophiles, such as silyl enol ethers, mediated by tin(II) chloride, generating 2-substituted pyrroles which can be used, as shown, for the synthesis of indoles. 

A-Acylimidazoles are even more easily hydrolysed than A-acylpyrroles, moist air is sufficient. The ready susceptibility to nucleophilic attack at carbonyl carbon has been capitalised upon commercially available l,l -carbonyldiimidazole (CDI), prepared from imidazole and phosgene, can be used as a safe, phosgene equivalent, i.e. a synthon for O = C, and also in the activation of acids for formation of amides and esters via the A-acylimidazole. ... 

P- and a-Acylpyrroles can be equilibrated one with the other using acid for V-alkyl-C-acylpyrroles, the equilibrium lies completely on the side of the 3-iso-... 

The addition of nitroalkanes to chalcones is more attractive since the Michael adducts are useful intermediates for a variety of further elaborated stmctures such as chiral aminocarbonyls, pyrrolidines, y-lactams, and y-amino acids. Thus, many elegant organocatalysts such as cinchona alkaloid-derived chiral tertiary amine thiourea 69 [67] or suqaramide 70 [68] and bisquaternary ammonium salts [69] 71a or 71b have been developed for such a reaction in recent years (Scheme 5.33). In addition, a,(3-unsaturated A -acylpyrroles [70] and 4-oxo-enoates [71] were also applicable in the highly enantioselective conjugated addition with nitroalkanes (Scheme 5.34). 

Carbon nucleophiles Alkyl-substituted nitrogen heteroaromatics HetAr-Me, such as a-picoline, have been shown to add to enones R CH=CHCOR and a,)3-unsaturated A-acylpyrroles in a reaction catalysed by (TfO)3Sc or (TfO)3Y to afford Michael adducts HetArCH2-CH(R )CH2COR as a result of formal activation of the benzylic C-H bond. ... 

Another member of the ep -cinchona-based thiourea organocatalyst family, depicted in Scheme 1.19, was applied by Vakulya et al. to the asymmetric Michael addition of nitroalkanes to chalcones, giving excellent yields and enantioselectivities of up to 98% ee. The extension of this methodology was further explored to encompass a,p-unsaturated A-acylpyrroles, as a chalcone mimic. The corresponding Michael products were obtained in high yields and enantioselectivities of up to 94% ee, as shown in Scheme 1.19. This simple novel approach allowed a concise stereoselective synthesis of (i )-rolipram to be accomplished. 

The [Pd(dba)2l-catalysed asymmetric 3+2-cycloaddition of methylene-trimethylenemethane with a, -unsaturated A/-acylpyrroles produced substituted... 

A-acylpyrroles (eq 37) with high enantioselectivity. The conjugate addition of cyanotrimethylsilane to, -disubstituted a,/3-unsaturated carbonyl compounds catalyzed by a chiral Sr complex provides a convenient route for the asymmetric construction of a quaternary carbon (eq 38). ... 

This chemistry was extended to a catalytic conjugate addition of cyanide to cx-substituted cx,p-unsaturated fV-acylpyrroles 15 followed by enantioselective protonation (Scheme 13) [53]. In this reaction, gadolinium enolate was generated in situ via conjugate addition of a gadolinium isonitrile to 15. Products 16 containing cx-secondary alkyl- and a-aryl-substimted tertiary stereocenters, which are usually difficult to access via enantioselective alkylation or arylation, were successfully produced, in addition to a-methyl and ethyl-substituted A -acylpyrroles. 

The U-4CR of lOw, 6zb, 9d, and Ize provided the Ugi product 278, which under acidic conditions afforded the key intermediate A(-acylpyrrole 279 (Scheme 7.88). In the presence of various nucleophiles, 279 afforded amides (280 and 281) and methyl ester 282 under refluxing conditions in good yields. In the presence of LiOH, 279 afforded the acid 283 at room temperature in an excellent yield. Employment of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), NaBH4, and Homer-Wadsworth-Emmons conditions provided the aldehyde 284, alcohol 285, and the a,p-unsaturated ester 286, respectively. These synthetic transformations can be very useful in particular, compound 286 is a valuable intermediate for the synthesis of 3-aza-bicyclo[3.1,0]hexane ring system, constrained amino acids, papain inhibitors, ( )-isocynodine, and ( )-isocynometrine [102],... 

In a subsequent report, they described an alternative synthesis of pyrroles through a two sequential copper-catalyzed vinylations of hydrazydes/cyclization strategy (Scheme 41) [130]. Alternatively, the synthesis of various A -acylpyrroles was accomplished by Li through a copper-catalyzed double A -alkenylation of amides [131]. For more details see the chapter devoted to the synthesis of heterocycles by means of arylation/vinylations. 

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