Indolizines protonation

The protonation of indolizines in acidic media has been shown by NMR studies to take place exclusively at the 3-position when unsubstituted.102-104 3-Substituted compounds give mixtures of 1- and 3-protonated species depending on the nature and position of other substituents. Deuterium exchange also occurs preferentially in the 1-and 3-positions.108-107 It has also been reported recently that with 3-nitroso- and 3-phenylazo-2-alkyl indolizines, protonation occurs on the 3-substituent.108... 

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... 

Apart from pyrrolo[l,2-(7]pyridazine, all the monoaza-indolizines protonate on the second (non-ring-junction) nitrogen, rather than on carbon. Alkylation similarly goes on nitrogen, however other electrophilic reagents attack with regioselectivity similar to indolizine itself - they effect substitution of the five-membered ring at positions 1 and 3 (where these are carbon). 

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. 

It is of interest to compare the stability of the protonated forms of benzo[u], benzo[Z>] and benzo[c] fused pyrroles, i.e. the cations derived from indolizines, indoles and isoindoles. Indolizine gives a stable pyridinium ion and does not polymerize in the presence of acid. 

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. 

Similar studies have also been carried out on condensed heterocyclic systems with a bridgehead nitrogen. Indolizine [175] and its 2-methyl-, 1,2-, 2,6- and 2,8-dimethyl- and 1,2,3-trimethyl derivatives protonate preferentially on C-3 in trifluoroacetic acid, giving cations [176] (Fraser et al., 1962). In general, when position 3 is... 

The sulphur TT-electron analogue of indolizine, pyrrolo [2,1-6 ]-thiazole [ 178], and some methyl substituted derivatives protonate in... 

The nitrogen rr-electron analogue of indolizine, pyrrolo[l,2-a]-imidazole [180], shows more complicated protonation behaviour... 

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)]. 

The methyl group in 5-methylindolizines is sufficiently active to allow the introduction of functional groups. Indolizines (15) with n-butyllithium followed by A,A-dimethylamides give, after hydrolysis, ketones 16. Cyclodehydration to 1 takes place in glacial acetic acid [Eq. (1)] more severe conditions, such as in hydrogen fluoride, were ineffective, presumably owing to protonation of the indolizine nucleus.1... 

The protons of indolizine at 100 MHz constitute a closely coupled seven-spin system, computer analysis of which yields the coupling constants shown in Table 9 (73JOC4391). 

Indolizines are diatropic compounds, i.e. the possession of a ring current may be deduced from the chemical shift of the ring protons. 

Table 4 Chemical Shifts of Ring Protons of Esters and Nitriles Derived from Indolizine...

It has been shown, by NMR studies, that the protonation of indolizines takes place exclusively at the 3-position when this position is unsubstituted. Depending on the nature and positions of the substituents, 3-substituted indolizines give mixtures of 1- and 3-protonated salts (Table 8). In 3,5-disubstituted indolizines, intramolecular overcrowding is reduced by protonation at the 3-position. 

The hydrogen-deuterium exchange rates of indolizine and some methyl derivatives have been measured at 50 °C in D20/dioxane. It has been shown that the exchange rates reflect the regioselectivity of protonation. Kinetic data have been discussed using HMO and PPP calculations (71T4171). Some pKa values of indolizines and azaindolizines are given in Table 9. 

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). 

The proton NMR spectra of some indolizines have been analyzed in detail by Black and co-workers122 and the chemical shifts compared with those calculated from various theoretical approaches.123-125... 

Nitration of indolizines is seldom attempted in view of accompanying oxidation reactions. Thus the synthesis of 6- and 8-nitro-2-phenyl-indolizine has been achieved by the cyclization of appropriately substituted 2-methyl-1-phenacylpyridinium bromide.179 However, 1-nitro and 1,3-dinitro compounds have been prepared.4 From the behavior of the indolizine nucleus toward other electrophiles, 3-nitroindolizine might be expected to be the primary product. This compound has been synthesized using a dilute solution of nitric acid in acetic acid at - 70°C where the substrate could well be the base and not the 3-protonated cation as in a nitric acid-sulfuric acid mixture.180... 

Substituted indolizines have been shown to undergo cycloadditions with suitably substituted alkenes to give pyrroloindolizines.202 Thus, 2,6-dimethylindolizine with methyl acrylate gives 136. The reactions presumably involve [8 + 2] cycloadditions, with subsequent 1,5-proton shifts. 

In a few cases 1 2 molar adducts such as 75 are formed.278 If the pyridine can form an ylid such as 76, then an alternative cyclization to an indolizine (78) takes place to some extent.278 Many pyridinium ylids corresponding to 76, but not possessing an ionizable proton at the 2- or... 

Thermal addition of DMAD to 3-(T-dimethylaminovinyl)indolizine (49 R = Me or Ph) in toluene gave cyclopenta[c]quinolizine (53) via a cyclobutene601 and the diene 51 (Scheme 18). Formation of 53 involves a rearrangement apparently without precedent. By carrying out the addition in methanol, the zwitterion was intercepted by proton transfer to give 50, which was converted into the isomeric quinolizine 52 in boiling xylene.600... 

Nitration of l-methyl-2-phenylindolizine gives 90% of the l-methyl-2-(4-nitrophenyl) product under these conditions, and the results indicate that nitration occurs on the conjugate acid of the indolizine resulting from protonation at C-3 [69JCS(C)1279] (Fig. 3). 

---