Pyrrole formation

1 endo Cyclization Transition-metal-catalyzed 5-endo-dig cyclization of 

---

The possible ambiguities that may arise in ring syntheses based upon nueleophilic reaetions with a-halo ketones are also exemplified by the reactions with a-lithioaldimines leading to pyrrole formation, as shown in Scheme 73a 73TL3517). A simitar problem could well arise in the related carbazole synthesis indicated in Scheme 73b if a less symmetrical substrate was employed 81TL1475). 

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... 

The reaction pathways for the pyrrole formation are summarized in Scheme 10.3. The group that is eliminated at the final stage is a nitrite ion (Barton-Zard reaction) or a toluenesulfinate ion (Leusen reaction), depending on the reaction pattern. 

DBU is most widely employed as the base in the Barton-Zard reaction. Stronger nonionic bases such as P(MeNCH2CH2)3N and the phosphazene base (supplied by Fluka) are more effective to induce pyrrole formation in the reaction of nitroalkenes with isocyano esters than DBU.39 Sterically hindered nitroalkenes are converted into the corresponding pyrroles using these bases, as shown in Eq. 10.35,39b but DBU is not effective in this transformation. 

Polymer-supported reagents and other solid sequestering agents may be used to generate an array of 1,2,3,4-tetrasubstituted pyrrole derivatives using the Barton-Zard reaction as a key pyrrole formation reaction. Pure pyrroles are obtained without any chromatographic purification... 

In a study being conducted at Case Western Reserve University under the direction of Dr. Lawrence Sayre, trifluoromethyl-substituted analogs of 2,5-hexanedione will be synthesized, compared with the parent compound in chemical model studies, and evaluated for neurotoxicity in rats. This is part of an effort to address how gamma-diketone-induced pyrrole formation at neurofilament-based lysine epsilon-amino groups leads to neurofilament accumulations. Nuclear magnetic resonance (NMR) studies will provide direct visualization of the nature of chemical modification. 

Anthony DC, Boekelheide K, Anderson CW, et al. 1983. The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. II. Dimethyl substitution acccelerates pyrrole formation and protein crosslinking. [Abstract] Toxicol AppI Pharmacol 71 372-382. 

Center MB, Szakal-Quin G, Anderson W, et al. 1986. Evidence that pyrrole formation is a pathogenetic step in gamma-diketone neuropathy. [Abstract] Toxicol AppI Pharmacol 87 351-362. 

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. 

Alkynes, obtained as above, also undergo Chichibabin amination in this case, cyclization occurs in situ to form a pyrrole <2003RCB441>. Although pyrrole formation is expected to involve attack at followed by cyclization onto the acetylene, the possibility of initial attack occurring at the acetylene cannot be excluded, in view of the isolation of ketone 28 (Scheme 11) <2005JHC413>. 

One of the most general pyrrole syntheses is the cyclizative condensation of 1,4-dicarbonyl compounds with ammonia, a primary amine or related compound. The mechanistic pattern involves formation of carbinolamine and imine intermediates followed by aromatization. This method is sometimes referred to as the Paal-Knorr pyrrole synthesis (equation 65) (B-77MI30601). Once the dicarbonyl compound is available, the cyclization normally proceeds in good yield, so ease of access to the diketone is of major importance in determining the applicability of this method to specific pyrroles. Pyrrole formation usually takes place on heating the diketone in a solvent such as benzene or toluene with a catalytic amount of acid. An alternative method involves heating the dicarbonyl compound and an amine salt... 

Thorpe-Ziegler cyclization of CH-acidic 3-aminocrotonitriles (54) was frequently used in the synthesis of 3-aminopyrroles (55) (Scheme 13). Usually this pyrrole formation proceeds more easily than the synthe-... 

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). 

In Fig. 6, a family of typical kinetic curves for cyclohexanone oxime are presented, which imply that pyrrole formation involves an intermediate, evidently, potassium oximate. 

As in the reaction with free acetylene (see Section II.A), acetoxime is least prone to pyrrole formation (the total yield of the pyrroles 126a and 127a is about 30%). The n-alkyl methyl ketoximes 125b,e,f react exclusively via the methylene group of the alkyl radical, whereas ketoxime 134 reacts by the methylene (preferably) and methyl groups to form pyrrole isomers. 

Vinyl azide intramolecular cycloaddition is further illustrated by the formation of azidotriazoline 32 as a minor product in the thermolysis of the bisvinyl azide 31 (Scheme 41).200 An analogy is provided by the formation of 2,5-diphenylpyrrole from the slow decomposition of a-azidostyrene.202 Pyrrole formation is interpreted in terms of cycloaddition of the azide onto the electron-rich double bond of a second molecule to give a triazoline that loses nitrogen and rearranges to a pyrroline followed by hydrogen azide elimination (Section IV,D).203... 

Allyl enaminoesters and ketones were cyclized using IVNaX Oj. <95JOC7357> Dehydro-halogenation leads to pyrrole formation. When the allyl group is incorporated into a cyclohex-2-enyl... 

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. 

---