Synthesis of Five-Membered Heterocycles

Although the Bucherer-Bergs reaction is mainly employed for the synthesis of a-amino acids, the synthesis of interesting hydantoins can be also addressed (Fig. 10.1) [17]. Curiously, hydantoins were initially observed as undesired by-products in the synthesis of peptides [18]. However, nowadays, this motif displays many important biological and pharmacological properties and is commonly used in drug discovery research lines [4a,b, 19]. These features have 

Multicomponent Reactions Concepts and Applications for Design and Synthesis, First Edition. Edited by Raquel R Herrera and Eugenia Marqu s-Ldpez. 2015 John Wiley Sons, Inc. Published 2015 by John WBey Sons, Inc. 

SCHEME 10.1 General Bucherer-Bergs reaction and mechanism. 

SCHEME 10.2 Relative stereochemistry of final amino acids through a Strecker and Bucherer-Bergs sjmthesis. 

FIGURE 10.1 Hydantoins with biological activities nilutamide 4 [10], phenytoin 5 [11], (+)-hydantocidin 6 [12], iprodione [13], fosphenytoin 8 [14], ethotoin 9 [15], and mephenytoin 10 [16]. 

Phosphorus Pentasulfide 1. Synthesis of Five-Membered Heterocycles 

Phosphorus pentasulfide is used to replace oxygen atoms with sulfur atoms the reaction is commonly carried out in a solvent heated under reflux. Solvents employed include carbon disulfide, aromatic hydrocarbons, and pyridine. If an oxygen atom is part of a heterocycle, then the reagent may replace it with sulfur, as in the formation of 2,1-benzisothiazoles from 2,1-benzisoxazoles.119 Such replacements are, however, not general some prior ring opening appears to be necessary before the reagent can act. For example, under normal conditions furan is not attacked. 

A more common usage of phosphorus pentasulfide is to effect replacement of oxygen atoms in an acyclic compound. The thiated intermediate—which may be a fairly complex derivative containing phosphorus, sulfur, and oxygen atoms—then cyclizes with elimination. Except in one case, mentioned below, the intermediates seem not to have been studied in any detail. 

Examples of reactions involving replacement and cyclization are the long-known preparation of thiophenes (89) from 1,4-diketones, and the formation of l,2-dithiole-3-thione (90) from the salicylate ester analog (91).120 In the latter instance, oxidative cyclization with formation of an S—S bond has occurred this is a common feature of these reactions, particularly if such a link is needed to complete a five-membered ring. Another example of this aspect is afforded by the reaction of the propane-1,3-dione derivatives (92) which yield 3,5-diaryl-1,2-dithiolylium salts (93) when heated with phosphorus pentasulfide in carbon disulfide, followed by perchloric acid.121 

The reagent does not replace nitrogen atoms, and N-alkyl or N-aryl anthranilic acids yield 2,l-benzisothiazoline-3-thiones (94) on heating with phosphorus pentasulfide in xylene. Curiously, when alkyl iV-arylanthranilates are treated in the same way, only a very small proportion—less than 10%— of 94 is obtained. The major product (80%) is the cyclic phosphorus-containing compound (95), the identification of which gives some clue about the structures of possible intermediates.122 

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Scheme 1 General reaction schemes tor the synthesis of five-membered heterocycles containing two or more heteroatoms by aldol-related reactions...

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). 

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. 

The concept of transient chirality in stereoselective synthesis of five-membered heterocycles using the retro-Diels-Alder methodology 99CRV1163. Five-member heteryladamantanes 99ZOR183. 

The importance of the 1,3-dipolar cycloaddition reaction for the synthesis of five-membered heterocycles arises from the many possible dipole/dipolarophile combinations. Five-membered heterocycles are often found as structural subunits of natural products. Furthermore an intramolecular variant makes possible the formation of more complex structures from relatively simple starting materials. For example the tricyclic compound 10 is formed from 9 by an intramolecular cycloaddition in 80% yield ... 

Dipolar cycloadditions are the most general method for the synthesis of five-membered heterocycles [51]. Various easily available and efficient 1,3-dipolar reagents are able to react with double or triple bonds to afford many different classes of structurally differentiated, selectively substituted heterocycles... 

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

Reports on the synthesis of five-membered heterocycles by intramolecular nitrogen—nitrogen bond formation (N1—N5) came some years ago from our laboratory [79CC891 81 JCS(Pl) 1891 83JCS(P1)2273]. Thus, 4-alkyl(aryl)amino-l-azabutadienes 2, which are readily available in large scale from alkyl(aryl)imines 1 and aliphatic or aromatic nitriles (70S 142 ... 

Examples of synthesis of five-membered heterocycles following this strategy are limited in number. An approach to 1,3,4-triazoles involves bonding of C-l and C-3 of vinyl isocyanate 150 to both nitrogen atoms of aromatic hydrazines (78JOC402) (Scheme 37). The reaction was run at room temperature and gave quantitatively regioisomer 151 or a mixture of 151 and 152 when p-nitrophenyl and phenylhydrazine, respectively, were employed. 

Paal-Knorr synthesis It is a useful and straightforward method for the synthesis of five-membered heterocyclic compounds, e.g. pyrrole, furan and thiophene. However, necessary precursors, e.g. dicarbonyl compounds, are not readily available. Ammonia, primary amines, hydroxylamines or hydrazines are used as the nitrogen component for the synthesis of pyrrole. 

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. 

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... 

A.2 Synthesis of Five-Membered Heterocycles A. 2.1 3-Benzoyl-4-phenyl-A 1-pyrazoline... 

There have been no reports in the literature between 1996 and 2006 on the synthesis of five-membered heterocycles containing three or more heteroatoms and at least one silicon atom that use this particular synthetic methodology. 

Figures 15.45 and 15.46 illustrate impressively that the significance of 1,3-dipolar cycloadditions extends beyond the synthesis of five-membered heterocycles. In fact, these reactions can provide a valuable tool in the approach to entirely different synthetic targets. In the cases at hand, one can view the 1,3-dipolar cycloaddition of nitrile oxides to alkenes as a ring-closure reaction and more specifically, as a means of generating interestingly functionalized five- and six-membered rings in a stereochemically defined fashion.

C. Methods for the Synthesis of Five-Membered Heterocyclic Compounds. .. 160... 

Dipolar cycloaddition reactions are most commonly applied for the synthesis of five-membered heterocyclic compounds.86 87 [3+2] cycloaddition reactions of transition-metal propargyl complexes have been reviewed.88 Addition of diazomethane to carbene complexes (CO)5Cr= C(OEt)R results in cleavage of the M = C bond with formation of enol ethers H2C = C(OEt)R,3 89 but (l-alkynyl)carbene complexes undergo 1,3-dipolar cycloaddition reactions at the M = C as well as at the C=C bond. Compound lb (M = W, R = Ph) affords a mixture of pyrazole derivatives 61 and 62 with 1 eq diazomethane,90 but compound 62 is obtained as sole... 

The photochemical addition of 2H-azirines to the carbonyl group of aldehydes, ketones and esters is completely regiospecific (77H143). Besides the formation of the isomeric oxazolines 18 from 3 and ethyl cyanoformate, there is also formed the imidazole 19 from addition to the C = N in the expected regioselective manner. Thioesters lead to thiazolines 20, while isocyanates and ketenes produce heterocycles 21 (Scheme 4). 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, vinylphospho-nium salts and p-quinones. 

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