Pyrroles regioselectivity

Aromatic heterocyclic compounds such as the AMosyl pyrrole 17 can also be used with anhydride catalysis (acid might destroy the pyrrole). Regioselectivity is determined by acylation next to the nitrogen5 and cyclisation follows.6... 

An enantioselective radical substitition (termed SOMO activation ) involving pyrroles has been reported <07SCI582>. For example, treatment of pyrrole 58 with octanal 59 and chiral amine 60 in the presence of CAN gave chiral 2-alkylated pyrrole 61. The mechanism included the formation of an enamine radical. A radical alkylation of 3-substituted pyrroles with xanthates produced 2,3-disubstituted pyrroles regioselectively <07TL4515>. 

The regioselectivity of substitution in pyrrole and thiophene is like that of furan and for similar reasons... 

Photochemical [2 + 2] cycloaddition is a powerful way to produce cyclobutanes, which, in turn, are reactive synthesis intermediates. N-Methylpyrrole adds aldehydes via [2 -I- 2] photocycloaddition to give transient oxetanes with high regioselectivity Ring-opening produces 3-(oi-hydroxyalkyl)pyrroles which are oxidized easily to 3-arylpyrroles, such as 3-BUTYROYL-l-METHYL-PYRROLE. With a special apparatus, ethylene is conveniently added to 3-methyl-... 

A major disadvantage of this procedure is the lack of regioselectivity of the bishydroxylation which can take place on each of the four pyrrole rings of the macrotetracycle so that, in addition to the monoadduct, two bisadducts and one trisadduct are formed. The subsequent pinacol rearrangement of the diols can also occur in two directions, leading to a complex mixture of additional constitutional isomers. 

The corphins 2 and 3 formed can be tautomerized back to pyrrocorphins,6 but less complicated model compounds bearing methyl groups can also be similarly tautomerized.yab When magnesium nonamethylpyrrocorphin is first methylated and then tautomerized, the D pyrrole ring is regioselectively attacked by iodomethane followed by tautomerization to establish a pyrrole ring in the C position of the macrocyclic system 4. 

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]. 

Hoesch reaction. In most cases, a Lewis acid is necessary zinc chloride is the most common. The reaction is generally useful only with phenols, phenolic ethers, and some reactive heterocyclic compounds (e.g., pyrrole), but it can be extended to aromatic amines by the use of BCls. Acylation in the case of amines is regioselectively ortho. Monohydric phenols, however, generally do not give ketones " but are attacked at the oxygen to produce imino esters. Many nitriles... 

In the tris-pentafluorophenyl analog (TFPC), in contrast to other Co corroles, aromatic amines can substitute PPh3 to form six-coordinate trivalent bis(amine) complexes.788 Bis-chlorosulfon-ation of TFPC occurs regioselectively to give the 2,17-(pyrrole)-bis-chlorosulfonated derivative fully characterized as its triphenylphosphinecobalt(III) complex.789 The amphiphilic bis-sulfonic acid was also obtained. 

Reaction of ketocarbenoids with pyrrole and N-alkylpyrroles yields the product of formal insertion into the a-C—H bond (256) in many cases the -insertion product 257 is formed concomitantly, but generally in lower yield 238-241 >. The regioselectivity varies according to the catalyst, the diazo compound and the N-alkyl substituent. Some examples concerning the former two variables are given in Table 18 239 240). 

The influence of substituents on regioselectivity was studied by using a model nitrone 3,4-dihydro-2,2-dimethyl-2/f-pyrrole 1-oxide (DMPO, 256) with different alkylidenecyclopropanes substituted with phenyl (156), electronreleasing (270 and 271) and electron-withdrawing groups (52, 272 and 4) [67,... 

A type Ilac synthesis of functionalized pyrroles was developed that adapted the Larock indole synthesis <06OL5837>. For example, treatment of iodoacrylate 19 and trimethylsilylphenylacetylene 20 with palladium acetate led to the formation of pyrrole-2-carboxylate 21 with excellent regioselectivity. 19 was prepared by iodinating (N-iodosuccinimide) the corresponding commercially available dehydroamino ester. 

Reductive cleavage of 5-silyl-, 3-, 4-, and 5-silylmethylisoxazoles 1 gave silyl (3-enaminones 2, useful synthons in the regioselective synthesis of silyl- and silylmethylpyrazoles 3, as well as pyrrole-, pyrimidine-, and pyridine derivatives <06T611>. 

Tejedor and coworkers have utilized a combination of two domino processes for a microwave-promoted synthesis of tetrasubstituted pyrroles [344]. The protocol combines two coupled domino processes the triethylamine-catalyzed synthesis of enol-protected propargylic alcohols and their sequential transformation into pyrroles through a spontaneous rearrangement from 1,3-oxazolidines (Scheme 6.183). Overall, these two linked and coupled domino processes build up two carbon-carbon bonds, two carbon-nitrogen bonds, and an aromatic ring in a regioselective and efficient manner. The tetrasubstituted pyrroles could be directly synthesized from the enol-protected propargylic alcohols and the primary amines by microwave irradia-... 

Pyrrolyl)-4,5-dihydroisoxazole derivatives 402 have been synthesized (Scheme 1.48) in good yields (66%-78%) by regioselective 1,3-dipolar cycloaddition of nitrile oxides to 1-phenylsulfony 1-1,3-dienes, followed by Barton-Zard pyrrole annulation using ethyl isocyanoacetate anion (444). 

Oxazoles and benzoxazoles are viable participants in the heteroaryl Heck reactions. In their monumental work published in 1992, Ohta and colleagues demonstrated that oxazoles and benzoxazoles, along with other rc-sufficient aromatic heterocycles such as furans, benzofurans, thiophenes, benzothiophenes, pyrroles, thiazole and imidazoles, are acceptable recipient partners for the heteroaryl Heck reactions of chloropyrazines [22b]. Therefore, treatment of 2-chloro-3,6-diethylpyrazine (27) with oxazole led to regioselective addition at C(5), giving rise to adduct 28. By contrast, a similar reaction between 2-chloro-3,6-diisobutylpyrazine (29) and benz[fc]oxazole took place at C(2) exclusively to afford pyrazinylbezoxazole 30. 

Electrophilic substitutions at the pyrrole nucleus were described only with 1,2-dihydropyrrolizines which react with the same regioselectivity as would do equivalently substituted monocyclic pyrroles. 

For example, rhodium catalyzed hydroformylation of 2-formyl-N-allyl-pyrrol gives an approx. 1 1 mixture of iso- and u-aldehydes. The latter cyclizes immediately in an aldol reaction followed by dehydration giving 7-formyl-5,6-indolizine in up to 46% (Scheme 29) [83]. Since here only one of the aldehyde groups can act as the enolate nucleophile this cyclization proceed with high regioselectivity (Scheme 29). 

A study of the regioselectivity of the 1,3-dipolar cycloaddition of aliphatic nitrile oxides with cinnamic acid esters has been published. AMI MO studies on the gas-phase 1,3-dipolar cycloaddition of 1,2,4-triazepine and formonitrile oxide show that the mechanism leading to the most stable adduct is concerted. An ab initio study of the regiochemistry of 1,3-dipolar cycloadditions of diazomethane and formonitrile oxide with ethene, propene, and methyl vinyl ether has been presented. The 1,3-dipolar cycloaddition of mesitonitrile oxide with 4,7-phenanthroline yields both mono-and bis-adducts. Alkynyl(phenyl)iodonium triflates undergo 2 - - 3-cycloaddition with ethyl diazoacetate, Ai-f-butyl-a-phenyl nitrone and f-butyl nitrile oxide to produce substituted pyrroles, dihydroisoxazoles, and isoxazoles respectively." 2/3-Vinyl-franwoctahydro-l,3-benzoxazine (43) undergoes 1,3-dipolar cycloaddition with nitrile oxides with high diastereoselectivity (90% de) (Scheme IS)." " ... 

The aromatic silylation of five-membered heteroarenes under the same conditions (catalyst, temperature, solvent) also proceeded in regioselective fashion. Both, thiophene and furane derivatives are exclusively silylated at the a-position, but 1-triisopropylsily 1-pyrrole and -indole each produce selectively ]3-silyl products (Equations 14.9 and 14.10). 

Derivatives of azabutadiene react with Gly-OEt to give pyrrole-2-carbox-ylates. This reaction, which is assumed to occur via an azapentadienyl anion, allows the synthesis of 3,5-diarylpyrrole-2-carboxylates in a regioselective manner (Scheme 10) (82JOC1696). 

Gly or sarcosine to give the corresponding pyrroles in a regioselective manner (Scheme 11) (90JOC4735 92JOC5480). 

Similarly, methylation of pyrrolo-benzothiazepines 172 (Scheme 34, Section 2.3.1 (1994MI283)) and 307 (Scheme 66, Section 3.3.1.2 (2005FES385)) with methyl iodide in acetone in the presence of potassium carbonate proceeds regioselectively and produces N-methyl pyrrole derivatives as sole products. Methylation on the thiazepine ring nitrogen requires stronger base, i.e. potassium ferf-butoxide, to give dimethyl 174 and 311, respectively. 

Regioselective synthesis of 2-substituted pyrroles using oximinocyanoacetate esters or related compounds in a Knorr-type reductive condensation with diketones was described . Thus, oximinocyanoacetates 63 reacted with pentane-2,4-diones 64 in hot... 

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