E-Book, Deutsch, Englisch, 546 Seiten, ePub, Format (B × H): 170 mm x 240 mm
ISBN: 978-3-13-178651-7
Verlag: Thieme
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Content of this volume: Indole and Its Derivatives, 1H-Indol-1-ols (1-Hydroxy-1H-indoles), 1,3-Dihydro-2H-indol-2-ones (1H-Indol-2-ols, 2-Hydroxy-1H-indoles, or Oxindoles), 1,2-Dihydro-3H-indol-3-ones (1H-Indol-3-ols, 3-Hydroxy-1H-indoles, or Indoxyls), 1H-Indole-2,3-diones (Isatins).
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10.13 Product Class 13: Indole and Its Derivatives
J. A. Joule 10.13.1 Product Subclass 1: Indoles
The word indole is derived from the word India: indigo (3), the blue dye, was first exported from India to Europe in the 16th century. Indoles are generally crystalline colorless solids, the simpler ones having characteristic odors: pure 1H-indole itself has a jasmine-like odor while that of 3-methyl-1H-indole (skatole) is notorious for its fecal character. The electron-rich character of indoles brings a tendency to light-catalyzed autoxidation; indoles should be stored away from oxygen and light. Simple indoles are also sensitive to strong acids, a point that must be taken into account in designing synthetic manipulations. Electron-withdrawing substituents have a stabilizing effect on each of these sensitivities. 1H-Indole (1) is the only tautomer detectable under normal circumstances; 3H-indole (2, indolenine in older literature) can be generated, but tautomerizes rapidly to 1H-indole at temperatures above –50°C (? Scheme 1).[1] ? Scheme 1 The Tautomeric Structures of Indole The indole system occurs in the essential amino acid tryptophan (4; ? Scheme 2), and thence in proteins and in thousands of indole and 2,3-dihydro-1H-indole (trivially known as indoline) containing natural products[2] biosynthetically derived therefrom, e.g. the alkaloids reserpine (tranquilizer) and vincristine (cancer chemotherapeutic), in the neurotransmitter substance serotonin (5-hydroxytryptamine), in the plant growth-regulating hormone 1H-indole-3-acetic acid, in lysergic acid diethylamide (LSD), and in several significant modern synthetic drugs, such as indomethacin, ondansetron, pindolol, alosetron, ropinirole, tadalafil, and sumatriptan. As a consequence, the rich chemistry of indoles has been extensively studied, many routes for the ring synthesis of indoles have been developed and some frequently exemplified, as have substitutions and other manipulations of preformed indoles. Functional group transformations of both ring and side-chain substituents (? Section 10.13.1.5) generally proceed normally, with emphasis given at appropriate points in this section to situations where this is not the case; reference should be made to other volumes in this series for particular functional group chemistry; however, many of these transformations are of great importance in the synthesis of indole-containing compounds and consequently are either exemplified in this section and/or reference is made to typical examples. Perhaps most significant to modern indole transformations are: (1) the use of organometallic, particularly organolithium, derivatives as nucleophiles; and (2) cross coupling processes, most often using palladium(0) as catalyst, with halogen, tin, zinc, mercury, thallium, boron, and trifluoromethanesulfonate derivatives of indoles. Enormous use has been made of cross-coupling processes involving both indole halides and trifluoromethanesulfonates and indole boronates and stannanes. There are examples of boronic acids or boronates at all of the carbon positions of the indole ring and there are examples of stannanes at all of the carbon positions of the indole ring (see ? Sections 10.13.1.4.2.4.3 and 10.13.1.4.4.6.4). Several excellent general and specific reviews of indole chemistry are available.[3–6] Reviews on the synthesis of 3-substituted indoles via reactive alkylidene-3H-indole intermediates;[7] the control of enantio- and regioselectivity in asymmetric Friedel–Crafts alkylations;[8] the asymmetric Pictet–Spengler[9] and Bartoli[10] reactions; cross-coupling reactions;[11] the synthesis of indoles from indol-2-ylacyl radicals;[12] the catalytic synthesis of indoles from alkynes,[13] by rhodium[14] or palladium-catalyzed reactions[15–17] or other transition metal reagents;[18] the alkylation of indoles;[19,20] the synthesis of indoles via isocyanides;[21] the solid-phase synthesis of indoles;[22] halogen-,[23] sulfur-,[24] oxygen-containing indoles;[25] the nucleophilic substitution of indoles;[26,27] on methods and applications of indole ring synthesis;[28] and on indoles in general[29,30] are also available. ? Scheme 2 The Structures of Indigo, Tryptophan, and Tryptamine 1H-Indole is an electron-rich 10 p-electron aromatic system and as such undergoes electrophilic substitution reactions rapidly in the heterocyclic ring; a protodetritiation study showed the indole 3-position to be 5.5 × 1013 more reactive to electrophilic attack than a benzene position.[31] There is a strong preference for electrophilic attack at C3 (the ß-position) though substitution at C2 (the a-position) of 3-substituted indoles 5 also takes place readily (? Scheme 3). In at least some instances, the observed a-substituted product 8 arises via initial ß-attack producing a 3,3-disubstituted 3H-indolium intermediate 6 and then 1,2-rearrangement of 6 to 7,[32] though direct a-attack (to give 7) has also been demonstrated.[33,34] ? Scheme 3 Alternative Mechanisms for Electrophilic 2-Substitution of 3-Substituted Indoles[32–34] In an elegant experiment (? Scheme 4) the intervention of a 3,3-disubstituted 3H-indolium intermediate in an indole overall a-substitution was shown by cyclization of the methanesulfonate of optically active 9 to give an optically inactive product 11, via the achiral, spirocyclic intermediate 10 arising from initial attack at the ß-position.[35] ? Scheme 4 Demonstration of a-Electrophilic Substitution via Initial Attack at C3[35] Indoles are weak bases[36,37] with pKa values of about –3, protonation taking place at C3[38,39] to generate 3H-indolium cations (indoleninium ions) 12 (? Scheme 5). It is the formation of such species and their further oligomerization and polymerization which is responsible for the acid sensitivity of indoles.[40] ? Scheme 5 Protonation of Indoles at C3 (the ß-Position)[38,39] Electrophilic substitution in the benzene ring only occurs in special cases, e.g. where the medium is strongly acidic and attack occurs on a pyrrole-ring-protonated species. Addition of a proton (at C3) then a nucleophile (at C2) can generate 2,3-dihydro-1H-indoles, arylamines in reactivity terms, which can undergo electrophilic substitution in the benzene ring, subsequent reversal of the earlier addition leading overall to benzene-ring-substituted indoles. Selective reduction of the pyrrole ring (best with triethylsilane in trifluoroacetic acid[41]) to produce 2,3-dihydro-1H-indoles (or the use of 2,3-dihydro-1H-indoles from other sources) then benzene ring substitution of these arylamines, and finally dehydrogenation of the five-membered ring, which is easy, can give the same result. However, most benzene-ring-substituted indoles are constructed by ring synthesis, and/or by functional group transpositions. Indoles with an N-hydrogen have pKa values around 16 (in water)[37] or 21 (in DMSO)[42]for the loss of this proton; the acidity is increased by electron-withdrawing groups, in particular when located at C3.[43,44] Thus, N-deprotonation of indoles is readily achieved using strong bases. The resulting indolyl anions 13, which are ambident (? Scheme 6), react with electrophiles to give N-substituted products 14 or 3-substituted products 16 via 15, or mixtures of these depending on the counterion, the reactivity of the electrophile, and the solvent.[45–47] Reaction at nitrogen is favored by polar solvents and by more ionic metal—nitrogen bond character, sodium or potassium counterions; the use especially of zinc and magnesium intermediates can result in a greater proportion of C3 substitution. More reactive alkylating agents favor 3-alkylation. ? Scheme 6 Ambident Nature of Indolyl Anions[46–48] Deprotonation of N-substituted indoles 17 with a strong base, such as butyllithium or lithium diisopropylamide, takes place...
