Of indolizines

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. 

Reduction of isoindoles with dissolving metals or catalytically occurs in the pyrrole ring. Reduction of indolizine with hydrogen and a platinum catalyst gives an octahydro derivative. With a palladium catalyst in neutral solution, reduction occurs in the pyridine ring but in the presence of acid, reduction occurs in the five-membered ring (Scheme 38). Reductive metallation of 1,3-diphenylisobenzofuran results in stereoselective formation of the cw-1,3-dihydro derivative (Scheme 39) (80JOC3982). 

Tominaga and coworkers have reported the formation of indolizine by the reaction of azomethine ylide with l-nitro-2-phenylthioethylene (Eq. 10.86).146... 

Enantiomerically pure triene 395, whose chirality stems from that of /3-D-ribofuranosc, was transformed into the chiral pyrrolidine 396 by intramolecular iodoamination. A subsequent RCM reaction gave indolizine derivative 397. Treatment of this compound with nucleophiles afforded mixtures of indolizine and quinolizine derivatives in... 

Jug and co-workers investigated the mechanism of cycloaddition reactions of indolizines to give substituted cycl[3,2,2]azines <1998JPO201>. Intermediates in this reaction are not isolated, giving evidence for a concerted [8+2] cycloaddition, which was consistent with results of previous theoretical calculations <1984CHEC(4)443>. Calculations were performed for a number of substituted ethenes <1998JPO201>. For methyl acrylate, acrylonitrile, and ethene, the concerted [8+2] mechanism seems favored. However, from both ab initio and semi-empirical calculations of transition states they concluded that reaction with nitroethene proceeded via a two-step intermolecular electrophilic addition/cyclization route, and dimethylaminoethene via an unprecedented two-step nucleophilic addition/cyclization mechanism (Equation 1). 

The reaction of 196 with phenyl chlorocarbene 198 illustrates the synthesis of indolizines by cyclization of pyridinium ylides (Scheme 7). Cyclization of ylide rotamer 199 generates the intermediate product 200, which undergoes elimination of chloride to provide compound 201 <2005EJ01532>. 

Electron-rich heterocyclic systems such as indolizines react readily with DEAZD (and PTAD) to give substitution products (Eq. 16).141 None of the formal [8 + 2] cycloaddition products (e.g., 89) are observed. This is in direct contrast to the reaction of indolizines with electrophilic acetylenes which gives high yields of cycloaddition products, presumably via a stepwise mechanism, in the presence of palladium on charcoal.142 This example of... 

Recently, dipolarophile 1)13 (fumaronitrile) (777) has been used in the synthesis of indolizine lactone (677). Both, intermolecular and intramolecular cycloadditions were studied. Intermolecular 1,3-cycloaddition of nitrone (671) to D13 led to the formation of isoxazolidine (672). Subsequent deprotection and esterification of the obtained alcohol (673) with (674) gave isoxazolidine (675) in 65% yield. Ester (675), when refluxed in xylene for 10 min, after elimination of fumaronitrile by cyclo-reversion, underwent spontaneously intramolecular cycloaddition to give the tricyclic cycloadduct (676) in 84% yield (Scheme 2.291). 

A complete review on the synthesis of indolizines has appeared <2000HOU(10)745>. This chapter is an extension of the reviews in CHEC(1984) <1984CHEC-I(4)443> and CHEC-II(1996) <1996CHEC-II(8)237>, mainly focusing on the development of synthetic methods aimed at the synthesis of natural alkaloids and important bioactive compounds containing the indolizidine nucleus. 

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>. 

The X-ray analysis of compound 2 (Figure 2) was used to confirm its structure and revealed that only the carbomethoxy group at C-l lies on the plane of indolizine nucleus as already evidenced for other 1,2,3-trisubstituted indolizidines <2000CHE1192>. 

Several pyridyl-substituted indolizines are fluorescent and their photophysics have been studied <1999MI155, 2002MI279>. This property has found application in the synthesis of indolizine-substituted /3-cyclodextrins <2005T3939> used as fluorescent chemosensors for organic guest molecules <2005CAR1706, 2005JFC385>. 

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. 

This cycloaddition has found application in the combinatorial synthesis of indolizines on solid support <1999TL8741 2005BML453> and on soluble support as poly(ethyleneglycol) <2004SL1231>. 

Allene-substituted lactams or cyclic imines are useful intermediates in the synthesis of indolizine derivatives. While the former are stable and need a Pd(0) catalyst and the presence of phenyl iodide to react < 1997TL6275>, the latter are produced in situ and react immediately (Scheme 37) <2001JA2074>. 

The Chichibabin reaction for the synthesis of indolizines has been revisited and some variations have been proposed. The modified benzotriazole 168 reacted with substituted pyridines 167 in refluxing dimethylformamide (DMF). The indolizine 169 bears a triazole moiety that proved useful for the construction of benzo-annulated indolizines <2000JOC8059>. Also, cyclic iminium ylides like 170 can be used in the Chichibabin reaction. Their solvolysis produced the corresponding indolizinones 171 (Scheme 40). 

A series of indolizines 281 and azaindolizines 282 were screened as possible inhibitors of 15-lipoxygenase (15-LO) from soybeans and rabbit reticulocytes. Most compounds studied were significantly more active than quercitin (IC50 51 pi) <2003BML5409>. The indolizine and azaindolizine sulfonates were particularly studied and showed high activity <2005BMC5409>. 

Cycloaddition reactions of indolizines such as 547 can generally be performed with moderately electron-poor alkenes only, because alkenes with strong acceptor substituents predominantly give Michael adducts. The cycloaddition of 2-methylindolizine... 

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... 

A vinylogous indole derivative like 264 reacts with DMAD to give a phenanthridone derivative (267) (Scheme 42). An interesting case of the reaction of an enamine system is observed in the case of the 2H-pyrrolizine (268), which gives a mixture of the azepino[2,l,7-crflpyrrolizine derivative (271) and the 1 1 adduct (275) (Scheme 43) 164,165 reaction of 3-ethoxycarbonylmethylene-3 -pyrrolizine, on the other hand, yields a pyrrolo[2,l,5-croom temperature, the primary adduct (278) is isolated and undergoes thermal cyclization to 281 (Scheme 44). ... 

In the thioaldehyde of pyrrolo[2,l-h]thiazole (73JCS(P1)657) (150), the C=S group is directed preferentially toward nitrogen (Z-form), as occurs in the aldehyde of indolizine 10, while bulky R substituents change this... 

The chemical shifts and coupling constants for compounds 1-3 are shown in Table III. In this table a uniform numbering is adopted for all compounds, as shown in the formula of indolizine at the head of the table. No spectrum is available for compound 4, although that of compound 5 is reported.204 From the figures available for the simple derivatives 142 and 143, chemical shifts and coupling constants for compound 4 can be included in Table III. 

This method of synthesis is not general since a carbonyl substituent at the 3-position of indolizines is usually deactivated toward nucleophilic attack.17,18... 

The reaction of indolizines with dialkyl acetylenedicarboxylates in the presence of a dehydrogenating catalyst leads to 1,2-dicarbalkoxycycl-[3,2,2]azines.22 23 Methyl phenylpropiolate may be used instead, although attempts to effect reaction between indolizine and certain other dienophiles including diphenylacetylene, diethyl azodicarboxylate, and 1,3-cyclohexadiene were unsuccessful. Hydrolysis of the diesters yielded the corresponding acids. Subsequent decarboxylation proceeded in high yield using copper chromite in quinoline [Eq. (5)]. 

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). 

Quantum chemical calculations of indolizine and its aza derivatives have been reviewed (77HC(30)117). Attempts to correlate the results with various physical and chemical properties have not always been crowned with success. (A critical discussion of semi-empirical molecular orbital methods is given in Section 3.01.7.) A qualitative discussion using single structures may be appropriate. 

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