Synthesis of Five-Membered Ring Heterocycles

1 Five-Membered Ring Heterocycies Containing One Nitrogen 

SOLID-PHASE SYNTHESIS OF HETEROCYCLES FROM PEPTIDES AND AMINO ACIDS 

2 Five-Membered Ring Heterocydes Containing Two Nitrogen Atoms 

Synthesis of Hydantoin Cores from UREAyTmouREA-LiKE Intermediates. There are many reports on the solid-phase synthesis of five-atom heterocycles having two nitrogen 

---

Dipolar cycloaddUions. Interest in 1,3-dipolar cycloadditions increased dramatically during the past 20 years, largely because of the pioneering studies of Huisgen [7, 2] The versatility of this class of pericychc reactions in the synthesis of five-membered-ring heterocyclic compounds is comparable with that of the Diels-Alder reaction in the synthesis of six-membered-ring carbocyclic systems (equation 1)... 

Despite the numerous studies devoted to the synthesis of five-membered ring heterocycles using enamines as synthons, most publications on the use of enamines in the synthesis of heterocycles deal with six-membered heterocyclic ring systems, especially pyridine, pyrimidine, and pyran derivatives. 

It is well established that 1,3-dipolar cycloadditions are an important method for the synthesis of five-membered ring heterocycles. In particular, for the l,4-oxa/thia-2-azole system, nitrile oxides or nitrile sulfides are usually employed as the 1,3-dipoles and C=0 and/or C=S groups as the dipolarophiles. There are many examples of all possible dipole-dipolarophile combinations leading to azoline derivatives 176-179 and also to compounds of the general structures... 

This TiCU-promoted allene cycloaddition has also been extended to the synthesis of five-membered ring heterocycles. In this case, increasing the steric shielding about the silicon atom seems to improve the cyclization process by suppressing the unproductive desilylative alkylation. For example, 1,3-di-methyl(r-butyldimethylsilyl)allene (39) reacts smoothly with cyclohexanecarbaldehyde to give in high yield the dihydtofuran predominantly as one stereoisomer (equation 31). Similar reaction with an N-acyl-iminium ion precursor (40) produces the pyrrolizidine system as a mixture of bicyclic isomers (equation... 

The concept of five-membered ring heterocyclic synthesis by transformation of the initial adduct of the ADC compound and substrate is not limited to cyclization of substitution products. l,3,4-Oxadiazol-2-ones (30, Scheme 3) result from heating the initial DEAZD-dichlorocarbene adduct.72 Treatment of the Diels Alder adducts 96 with zinc in acetic acid gives pyrroles in good yield (Eq. 17).151 The reaction has been extended to the synthesis of dipyrroles from the appropriate Diels-Alder adduct (96, R = pyrrol-2-yl). 

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. 

C.W. Bird, G.W. H. Cheeseman, Synthesis of Five-membered Rings with One Heteroatom in Comprehensive Heterocyclic Chemistry , A. R. Katritzky, C.W. Rees (eds.) Vol. 4 (1984), Pergamon Press, Oxford p. 89-153. 

The synthesis of five-membered boron heterocycles with one nonadjacent heteroelement from another ring is exceptional. Only two examples are discussed here, one starting from another five-membered ring, a second from a six-membered heterocycle. 

Use of mesoionic ring systems for the synthesis of five-membered heterocycles with two or more heteroatoms is relatively restricted because of the few readily accessible systems containing two heteroatoms in the 1,3-dipole. They are particularly suited for the unambiguous synthesis of pyrazoles as the azomethine imine is contained as a masked 1,3-dipole in the sydnone system. An attractive feature of their use is that the precursor to the mesoionic system may be used in the presence of the cyclodehydration agent and the dipolarophile, avoiding the necessity for isolating the mesoionic system. 

Utilization of carbenes in the synthesis of five-membered heterocycles with two or more heteroatoms has not been featured prominently in the synthetic strategies developed for these ring systems. The following illustrations show their considerable promise. 

The photocycloaddition of arylazirines with a variety of multiple bonds proceeds in high yield and provides a convenient route for the synthesis of five-membered heterocyclic rings. Some of the dipolarophiles include azodicarboxylates, acid chlorides, vinylphosphonium salts and p-quinones. 

An intramolecular Pd-catalyzed ring closure of an allylic halide, acetate or carbonate containing an allene moiety as 6/1-256, followed by a Suzuki reaction, was used by Zhang and coworkers for the synthesis of five-membered carbo- and heterocycles 6/1-257 and 6/1-258 (Scheme 6/1.67) [125]. 

Table 10 Ring synthesis of five-membered heterocycles containing three oxygen or sulfur atoms in the 1,2,4-positions from nonheterocyclic compounds.

The transition metal catalyzed synthesis of five membered heterocycles, particularly of condensed ring systems, has attracted considerable attention. The ease of the formation of five membered rings has been utilised both in intramolecular ring closure processes, and in the combination of two (three) fragments through the formation of a carbon-carbon and a carbon-heteroatom bond. This chapter is dedicated to examples, where the construction of the five membered heterocycle is achieved in a transition metal catalysed step. 

Synthesis of Six-membered Rings from Other Heterocycles 4.2.4.3.1 From five-membered rings... 

The most general approach to synthesis of five-membered heterocyclic compounds involves cycloaddition of a 1,3-dipole to an appropriate unsaturated substrate, the dipolarophile. Intermolecular cycloadditions result in the formation of one new ring only. When the 1,3-dipole and the substrate are part of the same molecule, cycloaddition is intramolecular and leads to a new bicyclic system. Thus, intramolecular... 

---