Indolizine basicity

Although it has not been possible to study the protonation of isoindole itself, it is clear that isoindoles are more basic than indoles or pyrroles. For example, 2,5-dimethyl-1,3-diphenylisoindole (40) has a p/sTa of 4-2.05 protonation of isoindoles occurs at positions 1 or 3. The pK for protonation of indolizine (10) at position 3 is 4-3.94 and that for carbazole (41) for protonation on nitrogen is estimated at -6.0. 

Dieckmann reaction, 4, 471 Indolizidine alkaloids mass spectra, 4, 444 Indolizidine immonium salts reactions, 4, 462 Indolizi dines basicity, 4, 461 circular dichroism, 4, 450 dipole moments, 4, 450 IR spectra, 4, 449 reactivity, 4, 461 reviews, 4, 444 stereochemistry, 4, 444 synthesis, 4, 471-476 Indolizine, 1-acetoxy-synthesis, 4, 466 Indolizine, 8-acetoxy-hydrolysis, 4, 452 synthesis, 4, 466 Indolizine, I-acetyl-2-methyI-iodination, 4, 457 Indolizine, 3-acyloxy-cyclazine synthesis from, 4, 460 Indolizine, alkyl-UV spectra, 4, 449 Indolizine, amino-instability, 4, 455 synthesis, 4, 121 tautomerism, 4, 200, 452 Indolizine, 1-amino-tautomerism, 4, 38 Indolizine, 3-amino-synthesis, 4, 461, 470... 

Indolizine, hydroxy-conformations, 4, 451 GLC retention times, 4, 451 synthesis, 4, 121 tautomerism, 4, 198, 452 Indolizine, 2-hydroxy-synthesis, 4, 463 Indolizine, 8-hydroxy-conformation, 4, 452 Indolizine, 2-hydroxymethyl-synthesis, 4, 461 Indolizine, 3-hydroxymethyl-synthesis, 4, 461 Indolizine, 6-hydroxymethyl-synthesis, 4, 461 Indolizine, methyl-mass spectra, 4, 187, 450 NM 4, 448 Indolizine, 2-methyl-diazo coupling, 4, 454 mass spectra, 2, 529, 4, 450 nitration, 4, 50, 454 nitrosation, 4, 454 reaction with diaryl disulfide, 4, 460 reaction with nitroethane, 4, 460 Indolizine, 3-methyl-basicity, 4, 454 Indolizine, 5-methyl-acidity, 4, 461 synthesis, 4, 466 Indolizine, 6-methyl-mass spectra, 4, 450 Indolizine, l-methyl-2-phenyl-nitration, 4, 454 nitrosation, 4, 454, 455 Indolizine, 3-methyl-2-phenyl-reaction... 

The importance of a basic nitrogen atom for strong inhibition by the indolizine type of inhibitor is demonstrated by the finding that I for inhibition by castanospermine A -oxide of the ) -D-glucosidase from almonds is 500-fold larger than of castanospermine itself (760 fiM V5. 1.5 /lA/at pH... 

Indolizine is much more basic than indole (p Ta = 3.9 vs. —3.5), and the stability of the cation makes it less reactive and resistant to acid-catalyzed polymerization. Protonation occurs at C-3, although 3-methylindolizine protonates also at C-l. Introduction of methyl groups raises the basicity of indolizines. Electrophilic substitutions such as acylation, Vilsmeyer formylation, and diazo-coupling all take place at C-3. Nitration of 2-methylindolizine under mild conditions results in substitution at C-3, but under strongly acidic conditions it takes place at C-l, presumably via attack on the indolizinium cation. However, the nitration of indolizines often can provoke oxidation processes. 

A recent method for the synthesis of the indolizine skeleton is represented by a three-component reaction between a-bromo ketones 16, pyridine 17, and ethyl propiolate or diethyl acetylenedicarboxylate. These three reagents, under microwave irradiation and catalysis by basic alumina, afforded a good variety of 3-aroyl indolizines 18 <20030L435> (Scheme 4). 

Alekseeva et al. (1972b) have carried out a comparison of calculated values of localization energies and free valency indices of pyrrolo[ 1,2-a] imidazole, pyrrolo[l,2-a] benzimidazole and indolizine. In all these molecules the a-position of the pyrrole ring is calculated to be more reactive than the / -position. The free valence indices increase in the order indolizine < pyrrolobenzimidazole < pyrroloimidazole, which is also the order of increasing basicity. 

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... 

Little work has been reported. From studies of proton/deuterium exchange rates, 2-methylpyrrolo[2,l-6]thiazole (478) was estimated to have a pKa of 6.4,394 a value comparable with that of 2-methylindolizine (pKa = 5.9).394 In the same way, the basicity of 3,4-dimethylimidazo-[l,5-a]benzimidazole (468b) (pA = 6.01) resembles that of imidazo-[l,2-a]pyridines (pA = 5.05-5.96).398 It would seem, therefore, that the basicity of azapentalenes parallels that of related indolizine derivatives [Eq. (40)]. 

Introduction of methyl groups raises the basicity of indolizines. The influence of methyl groups on the basicity of azaindolizine, on the other hand, seems to be smaller (66JOC1295). The anomalous low basicity of 3-methylindolizine indicates a variation of the site of protonation (see Table 8). 

Indolizine-l-acetic acid has been prepared by reaction of 3-benzoylindolizine with diazoacetic ester followed by basic hydrolysis <68AC(R)1206). 

A novel microwave-mediated three-component coupling of a-acyl bromides, pyridine and internal alkynes was carried out in the absence of a solvent on activated basic alumina to provide a collection of indolizines (Scheme 3.5)7. It was proposed that the reaction proceeded via in situ generation of a dipole from an N-acyl pyridinium salt, followed by a [3+2] cycloaddition reaction. A dedicated laboratory microwave system was... 

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. 

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. 

Addition of a 1,2,4-triazine to a DM AD (two molar proportions) results in the formation of a new fully substituted pyrrole ring [2915aJ. DM AD also reacts with A -substituted pyridazines under basic conditions to give a new fused pyrrole ring [3304]. Reaction of the cyclopropenone (106.1) with 4-picoline and then with pivoloyl chloride gives a high yield of an indolizine [3553]. 

Indolizine, p/faH 3.9, is much more basic than indole (p/faH -3.5) and the implied relative stability of the cation makes it less reactive, and thus indolizines are resistant to acid-catalysed polymerisation (cf. 20.1.1.9). Indolizine protonates at C-3, but 3-methylindolizine protonates mainly (79%) at C-1 the delicacy of the balance is further illustrated by 1,2,3-trimethyl- and 3,5-dimethylindolizines, each of which protonate... 

Yet another procedure used to prepare fused pyrroles is three-component condensation of an acyl bromide, pyridine, and an acetylenic compound, catalyzed by basic alumina, to give the corresponding indolizines 42 in 87-94% yield (Scheme 17.31) [84]. The mixture was irradiated for 8 min in a monomode MW reactor vdth a temperature limit of 250 °C. 

Cycloaddition of 4,4 -bipyridinium ylides 218, generated in situ from 4,4 -bipyridine and substituted phenacyl bromides 216 via 4,4 -bipyridinium diquatemary salts 217, with activated alkynes has been achieved under solvent-free conditions and in the presence of basic catalyst KF on alumina within 7-10 min by MWI to give 7,7 -feir-indolizines 220 in 81-93% yields via intermediate 219 (Scheme 46). On heating in benzene (or in benzene and A-methylpyrrolidone (NMP)), the reaction times were longer (3 h) and the yields were lower (50-59%) (00SL1013). 

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