Reaction of Pyrroles, Furans and Thiophenes

The arylation of pyrroles, furans and thiophenes, which are, in general, relatively susceptible to electrophiles, may be considered to proceed through an electrophilic mechanism involving the attack of ArPd(ll) species, as judged by the usual substitution pattern (2- and/or 5-arylation) [9, 10]. However, other mechanisms, such 

One of the earliest significant examples reported is the coupling of 1-substituted indoles with 2-chloro-3,6-dialkylpyridazines (Equation 10.36) [57, 58]. Depending on the 1-substituent, the reaction takes place selectively at either the 2- or 3-posi-tion. Substitution at the 3-position is a rare occurrence, and appears to be driven by the electron-withdrawing tosyl group, although the precise mechanism is still not fully understood. As expected, N-methyUndole (Equation 10.37) [59] and N-SEM-protected indole [60] undergo arylation at the 2-position on treatment with aryl iodides. 

Furan [66, 67] and its 2-formyl derivative (Equation 10.43) [68], as well as 2-alkylfuran [69], are arylated at the 2- and 5- positions. The arylation of 3-ethoxycar-bonylfuran as well as its thiophene analogue occurs selectively at the 2-position in the presence of Pd(PPh3)4 in toluene, whereas the 5-position is attacked preferably using Pd/C in NMP (Equation 10.44) [70]. It has been proposed that carbopallada-tion and electrophihc attack predorrtinantly participate in the 2- and 5-arylations, respectively. 

4 Intermolecular Arylation Reactions of Heteroaromatic Compounds 351 cat. PdCl2/PCy3 

The selective 2-monoarylation of thiophene itself, and furan, can be achieved by the use of an excess of substrate (Equation 10.45) [66]. It has been demonstrated that use of AgF and DMSO as base and solvent, respectively, enables the reaction to proceed at 60°C (Equation 10.46) [71], 

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Predict the product expected from electrophilic aromatic substitution reactions of pyrrole, furan, and thiophene. 

Electrophilic Substitution Reactions of Pyrrole. Furan, and Thiophene 1153... 

Five-Membered Unsaturated Heterocycles 1151 Structures of Pyrrole, Furan, and Thiophene 1152 Electrophilic Substitution Reactions of Pyrrole, Furan, and Thiophene 1153 Pyridine, a Six-Membered Heterocycle Electrophilic Substitution of Pyridine Nucleophilic Substitution of Pyridine Fused-Ring Heterocycles 1158 Nucleic Acids and Nucleotides 1160 Structure of Nucleic Acids 1163 Base Pairing in DNA The Watson-Crick Model Nucleic Acids and Heredity 1166 Replication of DNA 1167... 

All of the reactions of pyrrole, furan, and thiophene we have discussed so far have been variations on reactions of benzene. But heterocycles also do reactions totally unlike those of benzene and we are now going to explore two of them. 

The classical structures of pyrrole, furan and thiophene (31) suggest that these compounds might show chemical reactions similar to those of amines, ethers and thioethers (32) respectively. On this basis, the initial attack of the electrophile would be expected to take place at the heteroatom and lead to products such as quaternary ammonium and oxonium salts, sulfoxides and sulfones. Products of this type from the heteroaromatic compounds under consideration are relatively rare. 

There are examples of ipso attack during the nitration of pyrroles, furans and thiophenes and in the corresponding benzo-fused systems. Reactions resulting in nitro-dealkylation, nitrodeacylation, nitro-decarboxylation and nitro-dehalogenation are to be found in the monograph reactivity chapters of CHEC. Treatment of the 3-azophenylindole (64) with nitric acid in acetic acid at room temperature gives 80% of the 3-nitroindole (65) (81JCS(P2)628). 

Protonation of pyrrole, furan and thiophene derivatives generates reactive electrophilic intermediates which participate in polymerization, rearrangement and ring-opening reactions. Pyrrole itself gives a mixture of polymers (pyrrole red) on treatment with mineral acid and a trimer (146) under carefully controlled conditions. Trimer formation involves attack on the neutral pyrrole molecule by the less thermodynamically favored, but more reactive, (3-protonated pyrrole (145). The trimer (147) formed on treatment of thiophene with phosphoric acid also involves the generation of an a-protonated species. 

Although a limited range of Grignard reagents is available, the most widely used group is undoubtedly the lithio group introduced by direct lithiation (see Section 3.3.1.6.2). The ready formation of the lithio derivatives of pyrroles, furans and thiophenes and their benzo-fused derivatives has had a most important impact on the chemistry of these heterocyclic systems. Reaction of the... 

The order of reactivity for the reaction sites of azole compounds in electrophilic reactions is known to be 5 >4> 2 [18]. Thus arylation at the relatively electron-rich 5-position may be regarded as similar to that of pyrroles, furans, and thiophenes (Scheme 1). In contrast, the reaction at the 2-position may be regarded as proceeding differently [3], Although the precise mechanism is still unclear, it may involve base-assisted deprotonative palladation with the ArPd(II) species (path d in Scheme 2). Insertion of the C=N double bond into the Ar-Pd bond is also a possi-... 

The chemistry of pyrrole, furan, and thiophene is similar to that of activated benzene rings. In general, however, the heterocydes are more reactive toward electrophiles than benzene rings are, and low temperatures are often necessary to control the reactions. Halogenation, nitration, sulfonation, and... 

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