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Indoles - Sundberg R.J.

Sundberg R.J. Indoles - Academic press, 1996. - 95 p.
ISBN 0-12-676945-1
Download (direct link): indoles1996.djvu
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16.2 Generation and reactions of indole-2,3-quinodimethane inteimediates....................................164
Procedures ........................................................................................................................................................................................................................................................................168
Mixture of 2-butanoyl- and 3-butanoyl-1-methylcarbazole..................................................168
3-Acetyl- 1-methylcarbazole................................................................................................................................................169
References ............................................................................................................................................................................................................................................................................169
-1
Introduction
The synthesis and reactivity of indole derivatives has been a topic of research interest for well over a century. The first preparation of indole dates from 1866 and the Fischer indole synthesis, which remains the most versatile method for preparing indoles, was first reported in 1883[1]. The principal commercial source of indole is extraction from coal tar, although the feasibility of industrial synthesis from starting materials such as aniline and ethylene glycol[2], JV-cthylaniline[3] or 2-ethylaniline[4] has been demonstrated. Reports of several thousand individual indole derivatives appear annually in the chemical literature. The primary reason for this sustained interest is the wide range of biological activity found among indoles[5]. The indole ring appears in the amino acid tryptophan and metabolites of tryptophan are important in the biological chemistry of both plants and animals. Indole-3-acetic acid is a plant growth hormone[6] and 3-(2-ammoethyl)-5-hydroxyindole (serotonin) is one of the key neurotransmitters in animals[7]. Searches for specific agonists and antagonists of the receptors for these and other indole metabolites has been an active pursuit of pharmaceutical chemistry for nearly 50 years. The indole ring also appears in many natural products such as the indole alkaloids[8], fungal metabolites[9] and marine natural products[10].
Among the indole derivatives which have found use as drugs are indo-methacin, one of the first non-stcroidal anti-inflammatory agents[ll], sumatriptan, which is used in the treatment of migraine headaches[12] and pindolol[13], one of the P-adrenergic blockers.
indomelhacin
sumatriptan
pindolol
(1-1)
1 INTRODUCTION
Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of elliplicine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]
vincrisline reserpine
H2N
CH3
о
CH2OCNH2 .OCH3
;nh
N
о
milomycin С
Indole is classified as a ти-excessive aromatic compound. It is isoelectronic with naphthalene, with the heterocyclic nitrogen atom donating two of the ten 7t-electrons.
1.ЗА 1.3В
The aromaticity of the ring is fundamental to the success of many synthetic methods. Most estimates of aromaticity ascribe a stabilization energy which is slightly less than naphthalene[18]. Most indole-forming reactions begin with materials which incorporate a benzene ring, and the additional stabilization resulting from the formation of the fused pyrrole ring provides a driving force for indole ring formation. The most fundamental properties of the indole ring are fully consistent with the expectation for such a heteroaromatic structure. Like pyrrole, indole is a very weak base; the conjugate acid is estimated to have
1 INTRODUCTION
3
а рКл— — 2.4[19] because aromaticity is compromised by protonation at nitrogen. Instead, protonation occurs at C3. Indole itself and some of its simple derivatives are quite reactive toward strong acids as a result. As an electron-rich heteroaromatic, indole has a relatively high-energy HOMO and is subject to oxidative processes, including photosensitized electron transfer. Many indoles are readily oxidized by exposure to atmospheric oxygen, with the initial product being a 3-hydroperoxy-3W-indole.
»
H
From the perspective of laboratory practice, the sensitivity of many indoles to acids, oxygen and light prescribes the use of an inert atmosphere for most reactions involving indoles and the avoidance of storage with exposure to light. This sensitivity is greatly attenuated by electron-withdrawing (EW) substituents.
Many synthetic methods have been developed for addition or modification of substituents on the indole ring. Electrophilic substitution occurs preferentially at C3, a result which is explicable in terms of the contribution of resonance structure 1.3B, and is also consistent with various M.O. calculations which find the highest electron density and highest concentration of the HOMO at C3[20], The C3 position is estimated to be 10'3 more reactive than is benzene to electrophilic attack[21]. The C2 position is the second most reactive site toward electrophiles, but the most reliable means of achieving selective C2 substitution is by heteroatom-directed lithiation. The indole NH is weakly acidic, pK = 16.7 in water[19] and pK = 20.9 in DMSO[22], and the most riucleophilic site in the anion is N1. Selective N1 substitution therefore usually involves base-catalysed processes, including alkylation, acyl-ation and conjugate addition. Regioselective substitution of the carbocyclic ring is problematic. The inherent selectivity is not high and so is strongly influenced by the specific substitution pattern. Usually, regiospecific substitution requires the prior synthesis of a functionalized intermediate. For example, the halo indoles are useful intermediates for introduction of carbocyclic substituents.
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