Nitrogen-containing heterocycle synthesis five-membered ring heterocycles

As part of our current interest in SPOS, we examined the efficient and rapid synthesis of nitrogen- or sulfur-containing five-membered ring heterocycles and their fused counterparts by solid-phase strategies using Merrifield resin 1 and carbon disulfide (Figure 10.1). In this chapter, we review the synthesis of these five-membered ring heterocycles and their fused counterparts on solid support with carbon disulfide and Merrifield resin 1 as a solid support. 

Five-membered ring heterocyclic compoxmds containing nitrogen are one of the most common heterocycles. In fact, the synthesis of a great variety of that such as pyrrole, pyrazole, imidazole, triazole, tetrazole, lactams, and imides involving porous catalytic systems have been investigated. 

The preparation of five-membered rings in solid-phase organic chemistry has been reported in several publications. Versatile syntheses of these heterocycles with different numbers and kinds of heteroatoms have been described. The synthesis of five-membered rings containing one nitrogen atom (Fig. 3.6) as pyrrolidines (231) [311-316] pyrroles (232) [317-320] pyrrolidinones (233) [321-323] pyr-rolinones (234) [324—326] 2,5-pyrrolidinediones (235) [327-329] 2,4-pyrrolidine-diones (236) [330-332] 2,5-pyrrolinediones (237) [333] or heterocycles with one oxygen or one sulfur atom like tetrahydrofurans (238) [334—336] 2,5-dihydrofurans (239) [337], furans (240) [338, 339], yS-lactones (241) [340-343], 2,5-dihydrofura-nones (242) [344] (Scheme 3.35) and thiophenes (243) [345, 346] can be accomplished on solid supports. 

Condensed heterocyclo[n,m-n, b, or cjquinazolines. 52, I Condensed 4-thiazolidinones, 49, I Condensed thiophene systems, tetra- and pentacyclic, 32, 127 Condensed 1,2,4-triazines I. Fused to heterocycles with three-, four-, and five-membered rings, 59, 39 Condensed l,2,4-triazolo[3,4-z) heterocycles, synthesis, 49, 277 Conformational equilibria in nitrogen-containing saturated six-membered rings, 36, I... 

Oxazolines Heterocyclic compounds containing five-membered rings in which one carbon is replaced with an oxygen atom and another with a nitrogen atom. Oxazolines are colorless liquids soluble in organic solvents and water. Used as intermediates, e.g., in synthesis of surfactants. 

Pyrrole is a five-member nitrogen heterocyclic ring that contains two carbon-carbon double bond configurations which gives the solvent a pronounced aromatic character. Pyrrole is an intermediate in the synthesis of a variety of commercial chemical derivatives. 

Cyclization can also be performed via nucleophilic attack of nitrogen nucleophiles as shown for the release of cyclic urea derivatives. Dressman et al. examined a methodology to cleave hydantoins 222 via treatment of carbamate linkers with an intramolecular amide functionahty and base [188]. In the case of resin-bound substrate 221 (Scheme 33), the resulting heterocycle is a five-membered ring system but other heterocycles containing a urea-type unit can also be synthesized as published by diverse other groups (c.f. benzimidazolone-synthesis of li et al. [199]). 

This chapter includes the recent various aspects of four and five membered heterocyclo-quinolines containing one nitrogen atom at the ring junction. They were subdivided according to the number of heteroatoms in the heterocyclic rings. The literature indicates that many of these heterocycles are of potential therapeutic value which leads to intensive research in the topic. On the other hand, there are various classes of heterocycles that fit under this heading but unreported yet. Consequently, efforts towards the synthesis of such unreported classes can be fruitful area of research. 

While the eight-membered ring proved to be an excellent precursor for the synthesis of oxygen-containing sulfur-nitrogen heterocycles with nu-cleophUes, as well as electrophiles, the five-membered rings have shown Lewis basicity on various substrates. 

Under strictly anhydrous conditions, the iminophosphorane intermediate that is formed as a result of the Staudinger reaction can react with aldehydes and ketones in an intermolecular fashion (as in the synthesis of imine 36 described above) or intramolecularly with a variety of carbonyl containing functional groups to afford a host of products. Nitrogen containing ring systems such as cyclic imines (44) represent just one of the many products one can prepare and the reaction is particularly well suited for the facile synthesis of five, six, and seven-membered rings. In addition to aldehydes and ketones, carboxylic acids, esters, thio-esters, and amides can also react in an intramolecular fashion to trap an iminophosphorane to afford a variety of heterocycles. Examples from the current literature are described in Section 2.5.5. 

Five- and six-membered heterocycles, containing either a nitrogen or oxygen atom, and in particular pyrrolidine rings, are very important in natural products synthesis. There are many methods by which all these compounds may be synthesized and new routes to this target are constantly being sought. 

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