Pyrrole, example

Thieno- and Selenolo-pyrroles. Examples of these, e.g. (39 X = S or Se) and (40 X = S or Se), have been prepared by the reaction of ethyl azidoacetate with the monoaldehydes of thiophen or selenophen, followed by cyclization, hydrolysis, and decarboxylation of the product. ... 

To meet the needs of the advanced students, preparations have now been included to illustrate, for example, reduction by lithium aluminium hydride and by the Meerwein-Ponndorf-Verley method, oxidation by selenium dioxide and by periodate, the Michael, Hoesch, Leuckart and Doebner-Miller Reactions, the Knorr pyrrole and the Hantzsch collidine syntheses, various Free Radical reactions, the Pinacol-Pinacolone, Beckmann and Arbusov Rearrangements, and the Bart and the Meyer Reactions, together with many others. 

The preparation of 2 4-dimethyl-3 5-dicarbethoxypyrrole (II) is an example of the Knorr synthesis of pyrrole derivatives, involving the reaction of an -aminoketone (or a derivative thereof) with a reactive methylene ketone (or a derivative thereof). The stages In the present synthesis from ethyl acetoacetate (I) may be represented as follows ... 

Even less dangerous in this respeet are the nitrating systems using alkyl nitrates and sodium ethoxide. Noteworthy examples of the use of these less acidic or basic nitrating systems are found in the pyrrole series. 

The pyridine-like nitrogen of the 2H-pyrrol-2-yiidene unit tends to withdraw electrons from the conjugated system and deactivates it in reactions with electrophiles. The add-catalyzed condensations described above for pyrroles and dipyrromethanes therefore do not occur with dipyrromethenes. Vilsmeier formylation, for example, is only successful with pyrroles and dipyrromethanes but not with dipyrromethenes. 

Because the a-aminoketone is subject to self-condensation, the condensation with a P-dicarbonyl derivative (6) is usually carried out by generating the a-aminoketone in situ through reduction of an oximino derivative (7) 2iac ia glacial acetic acid is used as the reductant. For example, Knorr s pyrrole... 

Paal-Knorr Synthesis. The condensation of a 1,4-diketone, for example, with ammonia or a primary amine generally gives good yields of pyrroles many syntheses have been reported (24). The lack of avaHabitity of the appropriate 1,4-diketone sometimes limits the usefiilness of the reaction. 

Hydroxypyrroles. Pyrroles with nitrogen-substituted side chains containing hydroxyl groups are best prepared by the Paal-Knorr cyclization. Pyrroles with hydroxyl groups on carbon side chains can be made by reduction of the appropriate carbonyl compound with hydrides, by Grignard synthesis, or by iasertion of ethylene oxide or formaldehyde. For example, pyrrole plus formaldehyde gives 2-hydroxymethylpyrrole [27472-36-2] (24). The hydroxymethylpyrroles do not act as normal primary alcohols because of resonance stabilization of carbonium ions formed by loss of water. 

Pyridazinones may undergo ring contraction to pyrroles, pyrazoles and indoles, the process being induced either by an acid or base. The structure of the final product is strongly dependent on the reaction conditions. For example, 4,5-dichloro-l-phenylpyridazin-6(lFT)-one rearranges thermally to 4-chloro-l-phenylpyrazole-5-carboxylic acid (12S), while in aqueous base the corresponding 4-hydroxy acid (126) is formed (Scheme 40). 

There are some recent examples of this type of synthesis of pyridazines, but this approach is more valuable for cinnolines. Alkyl and aryl ketazines can be transformed with lithium diisopropylamide into their dianions, which rearrange to tetrahydropyridazines, pyrroles or pyrazoles, depending on the nature of the ketazlne. It is postulated that the reaction course is mainly dependent on the electron density on the carbon termini bearing anionic charges (Scheme 65) (78JOC3370). 

There are several examples of the formation of pyridazines from other heterocycles, such as azirines, furans, pyrroles, isoxazoles, pyrazoles or pyrans and by ring contraction of 1,2-diazepines. Their formation is mentioned in Section 2.12.6.3.2. 

These compounds typically react with electrophiles on carbon and in this respect they resemble enamines, enol ethers and enol thioethers. For example, both pyrrole and 1-pyrrolidinocyclohexene can be C-acetylated (Scheme 4). 

Alkyl substituents. The steric effect of 1-alkyl substituents in the pyrrole series has been demonstrated in, for example, Vilsmeier formylation reactions. Thus as the bulk of the alkyl substituent on nitrogen is increased e.g. from Me to Bu ) so does the proportion of /3 substitution (70JCS(C)2573). A similar trend has been observed in a series of experiments on the trifiuoroacetylation of A-alkylpyrroles with trifluoroacetic anhydride (80JCR(S)42). 

Although it has not been possible to study the protonation of isoindole itself, it is clear that isoindoles are more basic than indoles or pyrroles. For example, 2,5-dimethyl-1,3-diphenylisoindole (40) has a p/sTa of 4-2.05 protonation of isoindoles occurs at positions 1 or 3. The pK for protonation of indolizine (10) at position 3 is 4-3.94 and that for carbazole (41) for protonation on nitrogen is estimated at -6.0. 

From the preceding examples it can be seen that oxidants and electrophilic reagents attack pyrroles and furans at positions 2 and 5 in the case of indoles the common point of attack is position 3. Thus autoxidation of indoles e.g. 99) gives 3-hydroperoxy-3H-indoles (e.g. 100). Lead tetraacetate similarly reacts at the 3-position to give a 3-acetoxy-3H-indole. Ozone and other oxidants have been used to cleave the 2,3-bond in indoles (Scheme 30) (81BCJ2369). 

There are examples of preferential arylation of Af-substituted pyrroles, thiophenes and furans in the 2-position. A preparatively useful reaction of this type is the o-nitrophenylation of thiophene (Scheme 40). A phase transfer catalytic technique has been recommended for this reaction (77TL1871). 

A mild and effective method for obtaining N- acyl- and N- alkyl-pyrroles and -indoles is to carry out these reactions under phase-transfer conditions (80JOC3172). For example, A-benzenesulfonylpyrrole is best prepared from pyrrole under phase-transfer conditions rather than by intermediate generation of the potassium salt (81TL4901). In this case the softer nature of the tetraalkylammonium cation facilitates reaction on nitrogen. The thallium salts of indoles prepared by reaction with thallium(I) ethoxide, a benzene-soluble liquid. 

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). 

Some examples of ring opening reactions with carbanions leading to five-membered heterocyclic ring formation are shown in Scheme 85. Pyrrole syntheses from functionally substituted oxiranes and amines are often described and typical examples are shown in Scheme 86. 

The ring opening of 2//-azirines to yield vinylnitrenes on thermolysis, or nitrile ylides on photolysis, also leads to pyrrole formation (B-82MI30301). Some examples proceeding via nitrile ylides are shown in Scheme 92. The consequences of attempts to carry out such reactions in an intramolecular fashion depend not only upon the spatial relationship of the double bond and the nitrile ylide, but also upon the substituents of the azirine moiety since these can determine whether the resulting ylide is linear or bent. The HOMO and second LUMO of a bent nitrile ylide bear a strong resemblance to the HOMO and LUMO of a singlet carbene so that 1,1-cycloadditions occur to carbon-carbon double bonds rather than the 1,3-cycloadditions needed for pyrrole formation. The examples in Scheme 93 provide an indication of the sensitivity of these reactions to structural variations. 

The replacement of rhodium from a wide range of rhodacycles to form condensed furans, thiophenes, selenophenes, tellurophenes and pyrroles has been widely explored and a range of examples is shown in Scheme 97. The rhodacycles are readily generated from the appropriate dialkyne and tris(triphenylphosphine)rhodium chloride. Replacement of the rhodium by sulfur, selenium or tellurium is effected by direct treatment with the element, replacement by oxygen using m-chloroperbenzoic acid and by nitrogen using nitrosobenzene. 

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