Preparation of Five-Membered Heterocycles

The initial addition of ozone to alkenes to form molozonides (p. 193) can be regarded as a 1,3-dipolar addition, and many other such additions are of great importance in the preparation of five-membered heterocyclic systems. Thus we have already seen the... 

Transition metal catalyzed insertion reactions offer a convenient route for the preparation of five membered heterocyclic rings. Besides intramolecular Heck-couplings and CO insertion, examples of the intramolecular insertion of an acetylene derivative constitute the majority of this chapter. Although some of these processes involve the formation of a carbon-heteroatom bond, they are discussed here. 

Equation (19) is related to the 1,4-addition reactions reported for divalent Group IV analogs of carhene in the preparation of five-membered heterocycles containing a multiple-bond j8 to the heteroatom [see Eq. (7)]. If a method is developed for the generation of organometallic carhene analogs, reactions with trienes may provide a convenient route to seven-membered ring dienes. 

This reaction has been modified by temporarily terminating the reaction to obtain the dihydrofuran derivatives. In addition, this reaction has been carried out under an acidic conditions, such as in the presence of TFA, and by using 10% EtsN as the base. Moreover, o, j0-dichloroethyl ether has been used to substitute for the a-halo ketones. Other modifications include the reaction of dicarbonyl compounds with acetylenes and aldehydes. Furthermore, a general preparation of five-membered heterocycles, including furans—although not related to the Feist-Benary reaction—is also considered as a relevant modification. ... 

Targets with Two Heteroatoms 1,3-DC reaction was also widely used in the preparation of five-membered heterocycles with two heteroatoms. For instance. 

In comparison to N—S bond formation, O—N bond formation by essentially oxidative procedures has found few applications in the synthesis of five-membered heterocycles. The 1,2,4-oxadiazole system (278) was prepared by the action of sodium hypochlorite on A(-acylamidines (277) (76S268). The A -benzoylamidino compounds (279) were also converted into the 1,2,4-oxadiazoles (280) by the action of r-butyl hypochlorite followed by base. In both cyclizations A -chloro compounds are thought to be intermediates (76BCJ3607). 

Polymers with a backbone of five-membered heterocyclic rings have been developed in the new area of thermally stable materials during the last 10 years (B-80MI40408). The simple polypyrazole (741) is prepared by condensation of polydiethynylbenzene with hydrazine in pyridine with yields of 60-97%. 

The classical age of preparative organic chemistry saw the exploration of the extensive field of five-membered heterocyclic aromatic systems. The stability of these systems, in contrast to saturated systems, is not necessarily affected by the accumulation of neighboring heteroatoms. In the series pyrrole, pyrazole, triazole, and tetrazole an increasing stability is observed in the presence of electrophiles and oxidants, and a natural next step was to attempt the synthesis of pentazole (1). However, pentazole has eluded the manifold and continual efforts to synthesize and isolate it. 

The O-silylated acyloins such as 1920 c and 1927 are useful synthons for preparation of five-membered aromatic heterocycles such as the substituted imidazole 1925, pyrrole 1926, and furan 1928 [119] (Scheme 12.35). 

Table 2.21. Preparation of five-membered, nitrogen-containing heterocycles by rearrangement of chromium-carbene-derived ammonium ylides.

Table 2.22. Preparation of five-membered carbo- and heterocycles with the aid of heteroatom-substituted carbene complexes.

Table 4.7. Preparation of five-membered, oxygen-containing heterocycles by intramolecular carbene 1,5-C-H insertion.

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. 

A series of five-membered heterocycles with two and three heteroatoms were synthesized. 4-Hydroxyisothiazoles 57 were prepared from a-amino ketones with sulfur monochloride (1968BCJ959). Polar solvents, especially N,Af-dimethylfor-mamide, were preferable (Scheme 28). In a similar reaction of 1-amino-l-phenyl-2-propanone with sulfur monochloride 5-chlorinated isothiazole 58 was obtained in high yield. 

The apparently quite broad structural requirements for anticonvulsant activity, noted earlier in this chapter, extend to yet another class of five-membered heterocycles that include an imide function. Imidazo-2,4-diones, better known as hydan-toins, have comprised some of the most widely used drugs for treating severe motor and psychomotor epileptic seizures. The general reaction used to prepare this heterocyclic system involves the treatment of a carbonyl compound with ammonium carbonate and potassium cyanide. The first step in the complex sequence can be visualized as the addition of the elements of ammonia and hydrogen cyanide to give an a-aminonitrile (88-2). Addition of ammonia to the cyano group would then lead to an amidine (88-3). Carbon dioxide or carbonate ion present in the reaction... 

The transition metal catalyzed synthesis of six membered heterocycles attracted less attention than the preparation of five membered rings. The majority of examples discussed in this chapter achieves the formation of the ring through the combination of two fragments, forming a carbon-carbon and a carbon-heteroatom bond. 

Preparations of cinnolines by expansion of five-membered heterocycle rings include the oxidation of /V-aminooxindoles (241 — 242), the treatment of isatogens with ammonia (Scheme 30) and the base-catalyzed conversion of 1-aminodioxindoles (243) into cinnolin-3-ones. 

Many examples of natural furans are recorded as having been prepared from five-membered heterocycles such as 2(5H)-furanones (butenolides), which are reduced to furans with diisobutylaluminum hydride. The facile elimination of selenoxides derived from a-phenylseleneyl-y-lactones with formation of endocyclic a,/3-unsaturated butenolides is reported (75JOC542) as a useful route to 2,4- and 2,3,4-substituted furans via their corresponding butenolides. The mixture of dihydrofurans obtained from the tosylhydrazone of tetrahydro-2-furanone (Scheme 88) was oxidized to furans by 2,3-dichloro-5,6-dicyano-l,4-benzoquinone (66CJC1083). 

The major synthetic routes for the preparation of five-membered group III and IV metal-containing heterocycles with three or four heteroatoms are illustrated in the text and in Table 1. 

In a detailed investigation of the mechanism and scope of palladium catalyzed amination of five-membered heterocycles, the 1-methyl-3-bromoindole 145 was aminated with secondary amines to the 3-aminoindoles 146. Similar results were obtained for l-methyl-2-bromoindole <03JOC2861>. Rhodium-catalyzed cyclopropanation reactions involving 1-methyl-3-diazooxindole and exocyclic alkenes provided novel dispirocyclic cyclopropanes <03SL1599>. New applications of palladium-mediated cross-coupling reactions have been utilized to prepare a variety of functionalized indoles. Suzuki-Miyaura coupling reactions of indole-3-boronates <03H(59)473> and indole-5-boronates <03H(60)865> were utilized to prepare inhibitors of lipid peroxidation and melatonin analogues, respectively. 

As a preparative route mercuration of arenes suffers from a lack of selectivity often all possible ring substitution products are formed. The directing influences of substituents operate, but selectivity is poor. The initial products can isomerize. Isomer distributions in mercuration of toluene under different conditions are given in Table 3. These effects coupled with the ease of polymercuration can be disadvantagous. Mild conditions must be used to limit the extent of mercuration of five-membered heterocyclic aromatics such as pyrrole, thiophene, selenophen and furan. These are among the most reactive aromatics toward Hg salts use of HgCl2 in the presence of Na02CCH3 at RT is... 

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