Indoles thiophenes

For commonly encountered heterocycles, the chemical shifts of trifluo-romethyl substituents will depend somewhat upon where in the heterocycle they are located. Examples of trifluoromethyl derivatives for a number of common heterocycles, including pyridines, quinolines, pyrroles, indoles, thiophenes, benzothiophenes, furans, benzofurans, imidazoles, and uracils are given below. 

Falck has recently reported dehydrogenative silylation of heteroarenes with triethylsilane (18) [97]. Coupling with the Si-H bond of triethylsilane, rather than the disilane Si-Si bond, in conjunction with the use of norbomene that presumably acts as a hydrogen acceptor, gives good yields with indoles, thiophenes, and furans, under relatively mild condition (80°C). Unlike the reaction shown in Scheme 7, silylation of indole did not require protection of the N-H group. 

Current work is focused on the benzoheteropines with the fused pyrrole (or indole), thiophene or furan rings, i.e., ortho-fused 6 + 7 + 5 ring systems with carbons only on the six-membered ring, one heteroatom on the five-membered ring and one or more heteroatoms on the seven-membered ring. The variety of heteroatoms is limited to nitrogen, oxygen and sulfur. Several examples of the related cyclic systems with the other heteroatom distribution or peri-fusion are briefly summarized in Section 4.3. The current first specialized review covers synthetic, reactivity and structural aspects reported from the late 1989 until 2007. 

Amine Complexes. The pyridine —SO 3 complex has proved broadly applicable in the laboratory for the sulfonation of certain acid-sensitive ( acidophobic O compounds. This is in fact the preferred procedure for sulfonating five-membered heterocyclic compounds including furan, pyrrole, indole, thiophene, coumarone, and many of their derivatives. Yields are generally good (70-90 per cent), and the technique is simple (heating in a sealed tube at 80-140 C in the presence or absence of a solvent such as ethylene dichloride). The same method also works well in the sulfonation of alkadienes. Butadiene, for instance, yields the 1-sulfonic acid in fair yield. ... 

A great deal of carbanirms, generated from C-H-active compounds, the Grignard reagents, the cyanide ion, all kinds of organometallic carbon-lithium derivatives, aromatic amines, phenols, pyrroles, indoles, thiophenes, furans, and other organic compounds with electron-rich carbon atoms have been involved in the Sn reactions as C-nucleoplules [1, 2, 10, 11, 114—117]. 

The use of [Ru(02CMes)2(p-cymene)] was extended to the hydro-arylation of phenylpyridine, indole, thiophene, phenylpyrazole and phenylimidazole with unactivated alkenes. The eatalytic system was tolerant to valuable functional groups in the alkene sueh as ether, ketone, halides, esters and vinyl silanes. 

In 2011, Ackermann and Lygin [23b] reported the selective Ru-catalyzed directed monoarylation of indoles, thiophenes, and pyrroles (Figure 4.10). 

An intermolecular asymmetric addition of heteroarenes (indoles, thiophenes, pyrroles, and furans) to bicycloalkenes has been developed (with <99% ee). The reaction is catalysed by the complex generated from [(COD)lrCl]2 (1.5mol%) and (5)-TDBM-SEGPHOS (3 mol%) and proceeds in THF at 100 °C over 24 h via the initial activation of the C-H bond vicinal to the heteroatom (even with unprotected indoles, which typically undergo alkylation at the C(3) position), followed by a iy -addition across the C=C bond.128... 

Indoles, thiophenes and imidazoles have also been reduced [549, 550] e.g. Eq. 4.14 ... 

The scope and generality of this methodology with substituted indoles, thiophenes, and furans are summarized in Table 3. 

Millan Rodriguez, J. Martinez Albillos, G. Gomez-Elvira Gonzalez, J.M., "Conducting polymers based on copolymers of indole, thiophene, and pyrrole for use in electric conductor applications", Span.ES 2,092,426 (16 Nov 1996), Appl. 9,300,155,28 (Jan 1993), p. 8. 

Heteroaromatics such as furan, thiophene, and even the 2-pyridone 280 react with acrylate to form 281(244-246]. Benzene and heteroaromatic rings are introduced into naphthoquinone (282) as an alkene component[247]. The pyrrole ring is more reactive than the benzene ring in indole. 

A/-sulfonated ayiridines have also been used in Friedel-Crafts reactions (qv) (63). The successful C-alkylation of the heteroaromatic compounds indole (qv) [120-72-9] (64—66) and thiophene [110-02-1] (67) with a2itidines has also been reported ... 

As might be anticipated from the behaviour of the parent heterocycles, C-2 of indole, benzo[i]furan and benzo[i]thiophene (Table 13) is shifted to lower field than C-3. However, the shifts for C-2 (O, 144.8 Se, 128.8 S, 126.1 NH, 124.7 Te, 120.8) and C-7a (O, 155.0 Se, 141.3 S, 139.6 NH, 135.7 Te, 133.0) in the benzo[i] heterocycles vary irregularly (80OMR(l3)3l9), and the sequence is different to that observed for C-2 in the parent heterocycles, namely 0>Se>Te>S>NH. Also noteworthy is the upheld position of C-7, especially in indole and benzofuran, relative to the other benzenoid carbons at positions 4, 5 and 6. A similar situation pertains in the dibenzo heterocycles (Table 14), where not only are C-1 and C-8 shifted upheld in carbazole and dibenzofuran relative to the corresponding carbons in dibenzothiophene and fluorene, but similar, though smaller, shifts can be discerned for C-3 and C-6 in the former compounds. These carbon atoms are of course ortho and para to the heteroatom and the shifts reflect its mesomeric properties. Little variation in the carbon-hydrogen coupling constants is observed for these dibenzo compounds with V(qh) = 158-165 and V(c,h) = 6-8 Hz. 

Thiophene 27.2 Benzon>]thiophene° Indole 103.8 Benzo[c]thiophene° 38.9 Dibenzothiophene 186.6... 

The known 3-mercapto derivatives of furan, thiophene, selenophene (77ACS(B)198), ben-zothiophene (70JCS(Q243i) and indole (69TL4465) all exist as the 3-thiol tautomers. 

The major internal comparisons to be made within this chapter are between (13) pyrrole (1), furan (2), thiophene (3), selenophene (4) and tellurophene (5) b) pyrrole (1) and indole (6) (c) indole (6), benzo[6 Jfuran (7) and benzo[6]thiophene (8) d) indole (6), isoindole (9) and indolizine (10) and (e) benzo[6] and benzo[c] fused systems. The names of relevant heterocyclic radicals are given with the structures of the parent heterocycle. 

The reactivity sequence furan > tellurophene > selenophene > thiophene is thus the same for all three reactions and is in the reverse order of the aromaticities of the ring systems assessed by a number of different criteria. The relative rate for the trifluoroacetylation of pyrrole is 5.3 x lo . It is interesting to note that AT-methylpyrrole is approximately twice as reactive to trifluoroacetylation as pyrrole itself. The enhanced reactivity of pyrrole compared with the other monocyclic systems is also demonstrated by the relative rates of bromination of the 2-methoxycarbonyl derivatives, which gave the reactivity sequence pyrrole>furan > selenophene > thiophene, and by the rate data on the reaction of the iron tricarbonyl-complexed carbocation [C6H7Fe(CO)3] (35) with a further selection of heteroaromatic substrates (Scheme 5). The comparative rates of reaction from this substitution were 2-methylindole == AT-methylindole>indole > pyrrole > furan > thiophene (73CC540). 

Indole is sulfonated under similar conditions to pyrrole though in this case the 3-sulfonic acid is formed. Benzo[Z>]thiophene is also sulfonated in the 3-position (71AHC(13)235). 

Methylthiophene is metallated in the 5-position whereas 3-methoxy-, 3-methylthio-, 3-carboxy- and 3-bromo-thiophenes are metallated in the 2-position (80TL5051). Lithiation of tricarbonyl(i7 -N-protected indole)chromium complexes occurs initially at C-2. If this position is trimethylsilylated, subsequent lithiation is at C-7 with minor amounts at C-4 (81CC1260). Tricarbonyl(Tj -l-triisopropylsilylindole)chromium(0) is selectively lithiated at C-4 by n-butyllithium-TMEDA. This offers an attractive intermediate for the preparation of 4-substituted indoles by reaction with electrophiles and deprotection by irradiation (82CC467). 

Benzo[Z)]furans and indoles do not take part in Diels-Alder reactions but 2-vinyl-benzo[Z)]furan and 2- and 3-vinylindoles give adducts involving the exocyclic double bond. In contrast, the benzo[c]-fused heterocycles function as highly reactive dienes in [4 + 2] cycloaddition reactions. Thus benzo[c]furan, isoindole (benzo[c]pyrrole) and benzo[c]thiophene all yield Diels-Alder adducts (137) with maleic anhydride. Adducts of this type are used to characterize these unstable molecules and in a similar way benzo[c]selenophene, which polymerizes on attempted isolation, was characterized by formation of an adduct with tetracyanoethylene (76JA867). 

There are reports of an increasing number of palladium-assisted reactions, in some of which the palladium has a catalytic function. Thus furan and thiophene undergo facile palladium-assisted alkenylation giving 2-substituted products. Benzo[6 Jfuran and TV- acetyl-indole yield cyclization products, dibenzofurans and carbazoles respectively, in addition to alkenylated products (8UOC851). The arylation of pyrroles can be effected by treatment with palladium acetate and an arene (Scheme 86) (81CC254). 

Benzo[b]thiophene-2 -indole indigo, 4, 910 Benzo[b]thiophene-2,3-quinone reactions, 4, 824... 

Similarly, 1-alkylpyrroles, indoles, furans, thiophenes [60], a-picoline [61], enols, malonates [76], and organometallic compounds [56, 62] react with acyl imines of trifluoropyruvates to give derivatives of a-trifluoromethyl a-amino acids... 

Analogous compounds derived by fusion of a benzene ring to a pynole, furan, or thiophene nucleus are called indole, benzofuran, and benzothiophene. 

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