Of pyrrole formation

Sayre LM, Shearson CM, Wongmongkolrit T, et al. 1986. Structural basis of gamma-diketone neurotoxicity Non-neurotoxicity of 3,3-dimethyl-2,5-hexanedione, a gamma-diketone incapable of pyrrole formation. [Abstract] Toxicol AppI Pharmacol 84 36-44. 

However, of all the salts tested (RbCl, CsF, CS2CO3 0.2 mol per 1 mol KOH), only cesium fluoride shows a perceptible catalytic effect (yield gain up to 8%) at the stage of pyrrole formation for only the first three hours (Fig. 2, curve 3). The observed effect can be explained in terms of poor solubility of potassium fluoride in DMSO (86MI1). 

In the course of evaluating the area of application and limitation of pyrrole formation from ketoximes and acetylene, it has been found (82ZOR2620) that this may involve aromatic dioximes. From diacetylben-zene dioxime (18), for example, a one-stage transition to l,4-bis(l-vinyl-2-pyrrolyl)benzene (19) was accomplished (Scheme 11). 

V. A. Yaylayan and A. Keyhani, Elucidation of the mechanism of pyrrole formation during thermal degradation of 13C-labeled L-serines, Food Chem., 2001, 74, 4-9. 

Fabiano, E., Golding, B. T. On the mechanism of pyrrole formation in the Knorr pyrrole synthesis and by porphobilinogen synthase. J. Chem. Soc., Perkin Trans. 11991, 3371-3375. 

Similar results can be obtained by operating double-focusing magnetic sector instruments in the B/E - linked scan mode. In this mode, the ratio of B to E is kept constant as B is scanned. The residting spectrum contains fragment ions from a selected precursor ion. Warburton et al. [31] used the B/E - hnked scan mode to show that the peak at m/z 210 in the lemon juice corresponds to citric acid, and the m/z 369 peak in the egg yolk is due to cholesterol. In our laboratories we have used the same technique to elucidate the mechanism of B-carboline formation in food from tryptophan Amadori product and the mechanism of pyrrole formation from lysine Amadori products [32, 33]. 

Zamora, R., Alaiz, M., and Hidalgo, F.J. 2000. Contribution of pyrrole formation and polymerization to the nonenzymatic browning produced by amino-carbonyl reaction. Journal of Agricultural and Food Chemistry 48 3152-3158. 

Therefore, three intermediates of the pyrrole synthesis from ketoximes and acetylene, namely, O-vinyl oximes, hydroxypyrroUnes, and 3F/-pyrroles, have been isolated and characterized. In certain cases, they are quite stable. Besides, very recently [45], it has been shown that iminoaldehyde is detected (NMR) in catalytic ([(cod)lrCl], AgOTf, NaBH4, THF) version of the O-vinyl oxime rearrangement to pyrroles. This is another evidence in favor of the aforementioned mechanism of pyrroles formation. 

In the light of the previous analysis, one can discuss the following mechanisms of pyrroles formation from ketoximes and acetylene ... 

Trofimov, B.A., A.M. VasiTtsov, A.I. Mikhaleva et al. 1991. Stereochemical aspects of pyrroles formation from substituted piperidin-4-one oximes and acetylene. Khim Geterocicl 10 1365-1370. 

Hantzsch synthesis The formation of pyridine derivatives by the condensation of ethyl acetoacetate with ammonia and an aldehyde. Also applied to similar syntheses of pyrroles. 

Indoles are usually constructed from aromatic nitrogen compounds by formation of the pyrrole ring as has been the case for all of the synthetic methods discussed in the preceding chapters. Recently, methods for construction of the carbocyclic ring from pyrrole derivatives have received more attention. Scheme 8.1 illustrates some of the potential disconnections. In paths a and b, the syntheses involve construction of a mono-substituted pyrrole with a substituent at C2 or C3 which is capable of cyclization, usually by electrophilic substitution. Paths c and d involve Diels-Alder reactions of 2- or 3-vinyl-pyrroles. While such reactions lead to tetrahydro or dihydroindoles (the latter from acetylenic dienophiles) the adducts can be readily aromatized. Path e represents a category Iley cyclization based on 2 -I- 4 cycloadditions of pyrrole-2,3-quinodimcthane intermediates. 

N-Acylation is readily carried out by reaction of the alkaU metal salts with the appropriate acid chloride. C-Acylation of pyrroles carrying negative substituents occurs in the presence of Friedel-Crafts catalysts. Pyrrole and alkylpyrroles can be acylated noncatalyticaHy with an acid chloride or an acid anhydride. The formation of trichloromethyl 2-pyrryl ketone [35302-72-8] (20, R = CCI3) is a particularly useful procedure because the ketonic product can be readily converted to the corresponding pyrrolecarboxyUc acid or ester by treatment with aqueous base or alcohoHc base, respectively (31). 

Ring openings of pyrrole commonly occur at the carbon—nitrogen bond. Treatment of pyrrole or 2,5-dimethylpyrrole [625-84-3] (23, R = CH3) with hydroxjlamine leads to ring opening and formation of dioximes (31) (39). 

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. 

Treatment of pyrrole, 1-methyl-, 1-benzyl- and 1-phenyl-pyrrole with one mole of A -bromosuccinimide in THF results in the regiospecific formation of 2-bromopyrroles. Chlorination with IV-chlorosuccinimide is less selective (8UOC2221). Bromination of pyrrole with bromine in acetic acid gives 2,3,4,5-tetrabromopyrrole and iodination with iodine in aqueous potassium iodide yields the corresponding tetraiodo compound. 

The nitrosation of pyrroles and indoles is not a simple process. The 3-nitroso derivatives (84) obtained from indoles exist largely in oximino forms (85) (80IJC(B)767). Nitrosation of pyrrole or alkylpyrroles may result in ring opening or oxidation of the ring and removal of the alkyl groups. This is illustrated by the formation of the maleimide (86) from 2,3,4 -trime thylpyrrole. 

The reactions of pyrroles with dimethyl acetylenedicarboxylate (DMAD) have been extensively investigated. In the presence of a proton donor the Michael adducts (125) and (126) are formed. However, under aprotic conditions the reversible formation of the 1 1 Diels-Alder adduct (127) is an important reaction. In the case of the adduct from 1-methylpyrrole, reaction with a further molecule of DMAD can occur to give a dihydroindole (Scheme 48) (82H(19)1915). 

A-Substituted pyrroles, furans and dialkylthiophenes undergo photosensitized [2 + 2] cycloaddition reactions with carbonyl compounds to give oxetanes. This is illustrated by the addition of furan and benzophenone to give the oxetane (138). The photochemical reaction of pyrroles with aliphatic aldehydes and ketones results in the regiospecific formation of 3-(l-hydroxyalkyl)pyrroles (e.g. 139). The intermediate oxetane undergoes rearrangement under the reaction conditions (79JOC2949). 

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 course of the photochemically mediated isomerization of vinylazirines is dependent on the stereochemistry of the vinyl group, as is illustrated in Scheme 94a (75JA4682). Under thermal conditions the isomerization proceeds through formation of the butadienylnitrene and subsequent pyrrole formation. Analogous conversions of azirines to indoles have also been effected (Scheme 94b). It is possible that some of the vinyl azide cyclizations discussed in Section 3.03.2.1 proceed via the azirine indeed, such an intermediate has been observed... 

These reactions are related to the formation of pyrroles and quinolines from aminocarbonyl compounds and acetylenes (582,583) and may be contrasted with the formation of pyran derivatives by electrophilic attack on an enamine, followed by addition of an oxygen function to the imonium carbon (584-590). 

Despite its apparent simplicity, the PK pyrrole synthesis has retained its mystique since being discovered. Several investigations into the PK mechanism have been reported, including a gas phase study. Current evidence (intermediate isolation, kinetics, isotope effects) suggests the following (abbreviated) mechanism for the formation of pyrrole 13. However, the specific PK mechanism is often dependent on pH, solvent, and amine and dicarbonyl structure, especially with regard to the ringclosing step. 

Other PK variations include microwave conditions, solid-phase synthesis, and the fixation of atmospheric nitrogen as the nitrogen source (27—>28). Hexamethyldisilazane (HMDS) is also an excellent ammonia equivalent in the PK synthesis. For example, 2,5-hexanedione and HMDS on alumina gives 2,5-dimethylpyrrole in 81% yield at room temperature. Ammonium formate can be used as a nitrogen source in the PK synthesis of pyrroles from l,4-diaryl-2-butene-l,4-diones under Pd-catalyzed transfer hydrogenation conditions. 

The idea that dichlorocarbene is an intermediate in the basic hydrolysis of chloroform is now one hundred years old. It was first suggested by Geuther in 1862 to explain the formation of carbon monoxide, in addition to formate ions, in the reaction of chloroform (and similarly, bromoform) with alkali. At the end of the last century Nef interpreted several well-known reactions involving chloroform and a base in terms of the intermediate formation of dichlorocarbene. These reactions included the ring expansion of pyrroles to pyridines and of indoles to quinolines, as well as the Hofmann carbylamine test for primary amines and the Reimer-Tiemann formylation of phenols. 

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