Indolizine aromaticity

Indolizines, aromatic heterocycles with 12-jr-elec-tron system salts, isomeric with indole and isoindole, are prepared in good yields from pyrylium salts with active a-methylene groups.215 216 Aromatics derived from pyrylium salts by substitution of one or two fi-CW group(s) with a heteroatom are also possible. 

The aromaticity of indolizine was examined using the nucleus-independent chemical shift values at several different levels of theory confirming the trend indole > isoindole > indolizine <2003JMT157>. 

Despite its 10-electron aromatic Jt-system, indolizine apparently participates as an eight-electron system in its reaction with acetylene dicarboxylate, although the process may be stepwise and not concerted. By carrying out the reaction in the presence of a noble metal as catalyst, the initial adduct is converted into an aromatic cyclazine. 

By contrast to the bases, the cationic species have long been known. In addition to Fozard and Jones bicyclic salts already described (307, 308), benzo-fused derivatives were synthesized in the context of the aromatic cyclodehydration series by Bradsher s group (Scheme 71). Different from the 2-propenylpyridinium salts 316 just mentioned, the cycHzation of 2-benzylpyridinium 318 salts does not give indolizines unless under basic conditions in the acidic medium morphanthridizinium salts, such as 319a and b, are formed (59JA2547). This cyclization (after iodo-chloro metathesis) takes place in several days but in the case of the... 

In the field of hydroxyindolizines the situation is more complicated. No ring carbonyl absorption occurs in the IR spectra of (21) and (22) (76AHC(S1)245), while an aromatic enol tautomer of (23) was excluded completely on the basis of IR and NMR arguments (80JOC5100). This may be due to peri interaction, since an equilibrium between (24) and (25) in DMSO has been deduced from NMR evidence. It was pointed out in Section 3.08.1 that indolizines show pyrroloid as well as pyridinoid properties. This dual character may be used to explain the relative stabilities of some hydroxyindolizines, for example (26) and (27), which have been shown to be the predominantly existing tautomers. 

Cyclazines (229) are stable aromatic compounds, the synthesis of which may involve indolizines, 3H-pyrrolizines or pyridines. Their chemistry has been investigated extensively. 

Cycloaddition of ylide 90, formed from 3-oxopyrido[2,l-6][l,3]thiazin-5-ium iodide (89) on the action of triethylamine, with acrylonitrile or methyl acrylate gave [l,3]thiazino[4,3,2-cd]indolizines (91), which were subsequently aromatized by treatment with chloranil (80CL947). 

Indolizine is an important ring system in view of its similarity to indole. Like indole, it has a delocalized 10ir-electron system that confers aromaticity, in contrast to its analogs, pyrrolizine and quinolizine. Consequently, it has a theoretical and practical interest. 

Recently, the reaction of DMAD with pyridinium arylsulfonyl methylides has been used as a simple route to indolizines.63 The intermediate dihydroindolizines are readily aromatized by 1,4-elimination of p-toluenesulfinic acid. 

Armarego109 has determined the pAa values of indolizines and aza-indolizines from their ultraviolet spectra. He found that indolizine itself has the same basic strength as a-naphthylamine (pAa 3.9) and that a methyl substituent increases the pAa by two to three units. Mason and Smith,110 studying the fluorescence spectra of various aromatic nuclei including indolizine, found no evidence to support the prediction that acid-base properties of aromatic hydrocarbons in the first electronic excited state should differ from those in the ground state. 

The reaction has been applied to 5,6,7,8-tetrahydroindolizines151,152 the length of the methine chain and the position of attachment to the rings have been varied, and a different heterocyclic system used for the second nucleus.151,153 155 Other types of dyes, e.g., 101 and 102, were produced by reaction of indolizines with aromatic aldehydes or ketones.156-158... 

Other products from pyridine and its 3- and 4-methyl and 3,5-dimethyl derivatives and MP are cyclazines (e.g., 100),291 which are probably formed from indolizines of type 97 by further reaction with MP and subsequent aromatization. This type of reaction has been achieved by heating appropriate indolizines with DMAD293 or MP in the presence of palladized charcoal, and the direction of the addition, as shown below, has been established in several instances.294 Heating MP with diethyl-2-pyridylmethylene malonate gave the pyrrolo[2,l,5- /]indolizine corresponding to 100, no trace of the expected indolizine intermediate (cf. 97) being observed.292... 

Many other reactions of pyrylium salts have been described, converting this readily accessible conjugated C5-synthon into monocyclic aromatic systems with five-membered rings (2-acylfurans, isoxazoles, pyrazoles), or aromatic bicyclic systems (naphthalenes, indolizines),... 

Under the amine basic conditions, the subsequently added l-(2-oxoethyl)-pyridinium bromide derivatives 90 are transformed in situ into pyridinium ylides that undergo a [2 + 3] cycloaddition with the alkynone dipolarophiles present in the reaction mixture. The initial cycloadducts instantaneously aromatize to give rise to highly fluorescent indolizine derivatives 91. 

Mason and Smith (1969) found that for a series of mono- and bicyclic aromatic hydrocarbons the changes in the fluorescence spectrum with acidity reflected the ground state protonation reaction. The p Sj )-values calculated for benzene, toluene, naphthalene, azulene, and indolizine do not correspond to observable processes since the rate of protonation is too slow to compete with deactivation of the Sj state. Photochemical deuterium and tritium exchange experiments in 1 mole dm-3 perchloric acid indicate that the radiative deactivation rate of an electronically excited aromatic hydrocarbon is faster than the rate of protonation by a factor >10s. 

This same factor accounts for the 3-substitution predicted for imida-zo[l,2-fl]pyridine, imidazopyrimidines, and imidazol[l,2-a]pyrazine by both frontier electron densities (Scheme 8.10) and ir-electron densities (not shown) (74JHC1013 82AJC1761). The former indicate the 5- or 7-positions to be the next most reactive, whereas the latter indicate it to be the 2-position which is more probably correct (cf. indolizine) in general, frontier electron densities are poorer indices of aromatic reactivity. 

Indolizine reacts with electrophiles on the five-membered rings by substitution reactions as expected but it has one special reaction that leads dramatically to a more complex aromatic system. It does af cycloaddition with diethyl acetylenedi-carboxylate to give a tricyclic molecule. 

The dienophile is the usual sort of unsaturated carbonyl compound—but count the electrons used from the indolizine. The nitrogen lone pair is not used but all the other eight are, so this is a most unusual [2 + 8] cycloaddition. The first formed product is not aromatic (it is not fully conjugated) but it can be dehydrogenated with palladium to make a cyclazine. 

Finally, the compounds in the margin form a medicinally important group of molecules, which includes antitumour compounds for humans and anthelmintics (compounds that get rid of parasitic worms) for animals. They are derived from a 6/5 fused aromatic ring system that resembles the ten-electron system of the indolizine ring system but has three nitrogen atoms. 

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