Pyrroles as Substrates

Pyrrole derivatives are of little use as substrates for making pyrazines. However, treatment of 2,3,4,5-tetraphenylpyrrole (74) with potassium in THF for 6 h gave, among other products, 2,3,5,6-tetraphenylpyrazine (75) in 7% yield 564 3-amino- 

6- bis(carbamoylmethyl)-3,6-dihydro-2,5(177, 47/)-pyrazinedione (77) in 10% yield and hydrogenation of 2-nitromethylenepyrrolidine gave 2,5-bis(3-amino-propyl)pyrazine (26%) (cf. Section 2.1.3). 145.46  

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From Other Heteromonocyclic Substrates/Synthons 1.5.12. Pyrroles as Substrates/Synthons... 

In contrast, when the irradiation is performed on 2-cyanopyrrole, the isomeric products are observed. In fact, in this case, the corresponding Dewar pyrrole shows a lower energy than in the previous case, allowing the formation of the isomeric products (Fig. 6). When 2-methylpyrrole is used as substrate, the formation of the triplet state is favored, but this triplet state cannot evolve through the formation of the biradical intermediate. 

Finally, the intramolecular coupling reaction between an olefin and a pyrrole ring has been examined (Scheme 40). In this example, a 66% isolated yield of the six-membered ring product was obtained. A vinyl sulfide moiety was used as the olefin participant and the nitrogen protected as the pivaloyl amide in order to minimize the competition between substrate and product oxidation. Unlike the furan cyclizations, the anodic oxidation of the pyrrole-based substrate led mainly to the desired aromatic product without the need for subsequent treatment with acid. 

Metal complexes of pyrrole have also been investigated as substrates for lithiation reactions, with both iron and rhenium Tj -pyrrole derivatives having been found to undergo a-lithiation [90H(31 )383]. Azaferrocene was the first derivative of this type to be studied [83JOM(25l)C41], but it was found that lithiation was not selective and occurred equally in both rings. However, notwithstanding this, it has recently been reported that isomer-ically clean products can be obtained in certain circumstances from reaction with certain carbonyl compounds (Scheme 12) (89MI2). 

Pyrrole, like thiophene, does not react with benzophenone to give the corresponding oxetane. However, pyrrole reacts with aliphatic aldehydes and ketones to the corresponding 3-pyrryl carbinols. The alcohols derive from the cleavage of the corresponding oxetanes (Scheme 3.48) [94]. The yields increase when A -methylpyrrole is used as substrate, while the reactivity is depressed in the presence of substituents on the pyrrole ring. 

Photochemical substitution of some iodo-substituted pyrroles 597 in the presence of aromatic compounds depends on the structure of the pyrrole and on reaction conditions and gives the corresponding aryl derivatives 598 and/or dehalogenated product 599 (Scheme 120) <1997J(P1)2369>. Use of 4,5-diiodopyrrole-2-carbaldehyde 597 (R = I, = H, R = CHO) as substrate and irradiation in benzene, w-xylene, thiophene and 2-chlorothiophene as solvents gives solely the corresponding 5-aryl derivatives 598 in good yields (57-100%). There is no competition between 4-and 5-substitution. 

Side reactions became even more prevalent when 2-methyl-A -BOC-pyrrole 1046 was used as substrate (the addition of the methyl group increased the electronic density on the pyrrole and this led to enhanced formation of products derived from zwitterionic intermediates) (Equation 247). Thus, rhodium(ll) octanoate-catalyzed decomposition of diazoalkane 1042 in the presence of pyrrole 1046 resulted in the formation of three types of products two isomeric tropanes, 1047 (38% and 56% for R = Me and R = EtC02CH2, respectively) and 1048 (16% and 8% for R = Me and R = EtC02CH2, respectively), as well as two other products, the l,3a,6,6a-tetrahydrocyclopenta[ ]pyr-role 1049 (10% and 8% for R = Me and R = EtC02CH2, respectively) and the 7-azabicyclo[4.2.0]octa-2,4-diene 1050 (27% and 12% for R = Me and R = EtC02CH2, respectively) <1995TL7205>. 

Metalation of the amine substrate 184, followed by annulation promoted by tetramethylethylenediamine (TMEDA), gave the intermediate 185, which could thereafter be converted to the fused 3-pyrroline system 186 (Scheme 22). Subsequent dehydrogenation with DDQ gave the corresponding fused pyrrole. This methodology was used for preparation of an extended set of related pyrroles, as well as a series of indole derivatives, which were accessed by lithiation of iV-bromoallyl-2-bromoanilines <2001CEJ2896>. 

It has also been demonstrated that ketimines may participate in reactions with nitrostyrenes providing fused pyrroles, as shown by the preparation of the system 311. The series of events leading to this outcome were suggested to involve a Michael-type addition of the enamine tautomer of the substrate 312 to the olefin, followed by annulation with concomitant elimination of the nitro functionality (Equation 92) <1999TL4177>. In addition, solid-state reactions of enamine esters or ketones with ( )-l,2-dibenzoylethene induced by milling gave excellent yields of pyrroles <1999AGE2896>. 

It has been demonstrated that reactions of ketene dithioacetals with suitable glycine derivatives provides convenient access to a variety of densely substituted pyrroles, as illustrated for instance by conversion of the readily available substrate 412 into the product 413 (Equation 117) <2005SC693>. 

Treatment of the substrate 511 with 1,3-dicarbonyl compounds under basic conditions is followed by an acid-induced rearrangement, producing a set of pyrroles, as illustrated by the synthesis of the system 512 via the 2,3-dihydrofuran intermediate 513 (Scheme 67) <2002TL4491, 2003EJO2635>. 

The lone-pair electrons on the pyrrole nitrogen of the porphyrin ring are more accessible to chelation of metal ions in the ring-strained conformation and leads to metalation of mesoporphyrin IX. Antibody 7G12 catalyzes the incorportain of Zn +, Cn +, Co, and Mn into mesoporphyrin IX, whereas ferrochetalase uses Fe, ZrP , and Ni as substrates in... 

Furthermore, Ohta s group successfully conducted heteroaryl Heck reactions of chloropyrazines with many K-clcctron-rich heteroaryls including furan, thiophene, benzo [A] furan, and benzo[Z ] thiophene [81, 82]. In reactions of chloropyrazines with furan, thiophene, and pyrrole, disubstituted heterocycles were also isolated, albeit in low yields. Along with the disubstituted furan 161, the mono-arylation product 160 was isolated when 2-chloro-3,6-diethylpyrazine and furan were refluxed in the presence of Pd(Ph3P)4 and KOAc. In the case of 2-chloro-3,6-dimethylpyrazine and thiophene, monothienylpyrazine 162 was the sole product. When 2-chloro-3,6-diisobutylpyrazine was used as substrate, 9% of the disubstituted thiophene was detected. Analogous to the couplings with furan and thiophene, the heteroaryl Heck reactions of chloro-3,6-diethylpyrazine with benzo[Z ]furan and benzo[Z ]thiophene produced 163 and 164, respectively. 

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