Pyrrole 2-phenylpyrrole

Acetylenic compounds have often been used as precursors to certain pyrroles. Thus, 2-butyne-l,4-diol reacts with aniline ia the presence of alumina to produce A/-phenylpyrrole [635-90-5] (27). 

Acetylenedicaiboxylic esteis also react with phenyUiydioxylamines to give pyrroles (28), eg, N-phenylpyrrole-2,3,4,5-tetracarboxylic acid, tetramethyl ester [37802-39 ] (14). 

A comparison of the relative basicities of pyrrole, furan and thiophene may be made by comparing the pK values of their 2,5-di-t-butyl derivatives, which were found to be -1.01, —10.01 and —10.16, respectively. In each case protonation was shown by NMR to occur at position 2. The base-strengthening effect of alkyl substitution is clearly apparent by comparison of pyrrole and its alkyl derivatives, e.g. A-methylpyrrole has a pKa. for a-protonation of -2.9 and 2,3,4,5-tetramethylpyrrole has a pK of 4-3.7. In general, protonation of a-alkylpyrroles occurs at the a -position whereas /3-alkylpyrroles are protonated at the adjacent a-position. As expected, electron-withdrawing groups are base-weakening thus A-phenylpyrrole is reported to have a p/sTa of -5.8. The IR spectrum of the hydrochloride of 2-formylpyrrole indicates that protonation occurs mainly at the carbonyl oxygen atom and only to a limited extent at C-5. 

The reactions of pyrroles with dienophiles generally follow two different pathways involving either a [4 + 2] cycloaddition or a Michael-type addition to a free a-position of the pyrrole ring. Pyrrole itself gives a complex mixture of products with maleic anhydride or maleic acid and with benzyne reacts to give 2-phenylpyrrole rather than a product of cycloaddition (Scheme 47). 

The simplicity of the PK pyrrole synthesis often makes it the method of choice. The preparation of 2,5-dimethyl-1-phenylpyrrole from 2,5-hexanedione and aniline is an undergraduate laboratory experiment," and applications of the PK reaction in research... 

Silylated acetylenic alcohols such as 1500 cyclize on treatment with HMDS-Li to give, via 1501 and 1502, 2-phenylpyrrole 1503 [46] (Scheme 9.27 compare also the formation of 2-pyridyl-2-pyrrole 543 in Chapter 5). 

Two unique type Had syntheses of pyrroles that were reported both involved cyclopropane fragmentations. The first allowed for a synthesis of 2-arylpyrroles <06SL2339>. In the event, treatment of stannylcyclopropane 25 with -BuLi followed by benzonitrile produced 2-phenylpyrrole 26 via tin-lithium exchange, addition to the nitrile, ring fragmentation of ketimine intermediate, intramolecular condensation, and loss of dibenzylamine. 

The N-pyrrolylzinc chloride 53 undergoes Pd-catalyzed coupling with perfluoroalkyl iodides to afford the 2-substituted pyrroles 54 in good yield [52], Smaller amounts (15-20%) of 2-perfluoroalkanoyl pyrroles, which presumably arise by hydrolysis of the benzylic difluoromethylene group, are also formed. This reaction, which is performed in one pot, also affords 2-phenylpyrrole (75%) and 3-phenylpyrrole (5%) with iodobenzene. Some biphenyl (15%) is also formed. 

Bailey described the first application of the Stille coupling to pyrroles, and one of the earliest examples of any such reaction involving heterocycles [66]. Lithiation of IV-methylpyrrole and quenching with trimethylstannyl chloride gives 2-(trimethylstannyl)pyrrole (76), and palladium-catalyzed coupling with iodobenzene affords l-methyl-2-phenylpyrrole (46) in good yield. 

A typical example of steric control over spin delocalization has been described for the cation-radical of 3,4-bis(thioisopropyl)-2,5-dimethyl-l-phenylpyrrole (Domingo et al. 2001). Scheme 3.15 depicts this sitnation. In this cation-radical, one thioisopropyl group is almost coplanar with the pyrrole ring, whereas the other one occupies an orthogonal position. Accordingly, the ESR spectra established an eqnilibrinm between the symmetrical and asymmetrical conformations of the cation-radical. This equi-librinm is shifted toward the asymmetrical form at low temperatmes. The main feature of the equilibrium is the widening of spin delocalization, which includes not only the pyrrole ring but also one donor sulfur atom at the expense of the other sulfur atom. The steric control predetermines the discrimination of the other sulfur atom in the spin-delocalization process. 

The ring closure of aminoalkynes bearing a leaving group in the appropriate position might lead to the formation of pyrroles in an addition-elimination sequence. 2-Phcnylcthynyl-1 -amino-sec-butanol. for example, gave 4-ethyl-2-phenylpyrrole on treatment with palladium dichloride in acetonitrile in excellent yield (3.46.),57... 

Although the oxidation of indoles by air and light has been studied extensively, e.g., the photooxidation of tryptophan to kynurenine and 3-hydroxykynurenine in the presence of methylene blue as sensitizer,311 313 little is known about the course of pyrrole photooxidation.173180 184 Under very mild conditions, irradiation of 2,3,4,5-tetra-phenylpyrrole in methanol and in the presence of air and methylene blue effected its oxidation to 5-methoxy-3,4-epoxy-2,3,4,5-tetraphenyl-A -pyrroline (CXVI) and a-A-benzoylamino-a -benzoyl stilbene(CXVII).303 Photooxidation in the presence of potassium hydroxide gave the lactam (CXVIII). 

Furans react readily with benzynes, e.g. 2-acetoxyfuran yields (185). A-Methylpyrrole also reacts normally across the 2,5-positions, but pyrrole itself yields 2-phenylpyrrole,... 

The formation of 3-pyrrolylcarbinols (280) from the photochemically induced reaction of pyrrole, or its 1-alkyl derivatives, with aliphatic aldehydes and ketones is thought to proceed via an oxetane intermediate (279) (79JOC2949). In contrast, the analogous reaction of 1 -phenylpyrrole with benzophenone leads to the formation of the diphenyl(2-pyrrolyl)car-binol, whilst the oxetane (281) has been isolated from the photoaddition of 1-benzoylpyrrole and benzophenone (76JHC1037, B-77MI30500). 2-Benzoyl-1-methylpyrrole undergoes a normal Paterno-Buchi photocyclization with 2,3-dimethylbut-2-ene, via the n -> v triplet... 

Molecular orbital calculations have also been made for carbonyl derivatives of pyrrole 97,98 and for 2-phenylpyrrole."... 

Substituted pyrroles do not react with Grignard reagents or alkali metals, but 1-methyl and 1-phenylpyrrole have been reported to react with w-butyllithium to give the a-lithio derivative.218... 

The observed moment for 1-phenylpyrrole indicates a certain degree of interannular conjugation (cf. NMR data,201 Section III,B, 3,a) which opposes the it moment of the pyrrole ring.252 Further evidence is provided by a comparison of the moment of 1-... 

Three l-hydroxy-3-phenylpyrroles (46) were formed (72JOC1561) in 26-44% yields, instead of the anticipated 6//-oxazines, when the corresponding E-oximes (44) were treated successively with one equivalent of sodium hydride in dimethylformamide (DMF) followed by triphenylvinylphosphonium bromide Z-benzil oxime gave no pyrrole. The cyclization probably proceeds via cyclization to the N-oxide 45 and tautomerism to the 1-hydroxypyrrole. 

Rubidium chloride even slows the reaction, this is especially well seen within a time span of 1-3 hr after the start of the process (Fig. 2, curve 2). In this case the normal salt effect is likely to prevail over the effect of oximate ion pair separation due to substitution of the potassium cation by the rubidium cation. The addition of cesium carbonate during the first 1.5 hr does not much affect the rate of the formation of 2-phenylpyrrole. The accelerating effect of these additives becomes evident only 2 hr after the beginning of the reaction and gradually increases (5 hr later the yield gain of pyrrole is 7% as compared with a standard run, Fig. 2, curve 4) which seems to result from a slow rate of heterophase exchange process ... 

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