Applications in heterocycle synthesis

The air-stable BippyPhos ligand (L2) was developed initially by Singer and co-workers at Pfizer as a non-proprietary ligand for use in palladium-catalyzed cross-coupling applications. Stradiotto and co-workers subsequently reported on the 

Air-stable biaryl monophosphine ligands developed by Buchwald and co-workers have played a central role in the advancement of palladium-catalyzed cross-coupling reactions, including BHA chemistry the utility of appropriately configured ancillary ligands of this type in the selective monoarylation of ammonia has been examined. Following on preliminary experimentation that established the capability of the Pd2(dba)j/L3 catalyst system (dba=dibenzylideneacetone) to promote the monoarylation of ammonia at elevated temperature Tsvelikhovsky 

---

An elegant two-step solution-phase methodology was developed for the synthesis of the benzodiazepine-2,5-diones (93 e.g. R1 = PhCH R2 = Me, R3 = Me, R4 = H, R5 = Me, 32%). The first step was a Ugi four-component reaction followed in the second step by a palladium-mediated intramolecular IV-arylation reaction. This methodology has considerable scope for further application in heterocyclic synthesis <06TL3423>. 

An interesting new approach to l,3-diazepin-2-ones 61 via a palladium-catalysed highly regioselective, cyclisation of 2-vinylpyrrolidines 59 with aryl isocyanates 60 has been developed by Zhou and Alper <03JOC3439>. This reaction has considerable potential for further applications in heterocyclic synthesis. 

M. A. P. Martins 4-Alkoxy-l,14-trichloro-3-alken-2-ones Preparation and applications in heterocyclic synthesis 2004CSY391... 

This reaction should have wide applications in heterocycle synthesis but has not yet been extensively explored. 

Oxadiazoles experienced an almost 80-year long period of scientific lethargy before they tickled the curiosity of chemists. The study of chemical and photochemical reactivity of 1,2,4-oxadiazoles opened the way to a series of applications in heterocyclic synthesis. Today, 1,2,4-oxadiazoles are known in medicinal chemistry for their use as bioisosters of esters and amides. Furthermore, fluorinated 1,2,4-oxadiazoles have been applied in materials science either by themselves or for the targeted modification of polymers and macromolecules. Overall, the synthesis of... 

Analogous Benzotriazole-mediated syntheses are available, for example, for diaryl-methanes, dieneamines, and N,N-disubstituted thioureas (Katritzky methodology, 1990 for applications in heterocyclic synthesis, cf Ref [510]). 

Gupton JT, Gall JE, Riesinger SW, Smith SQ, Bevirt KM, Sikorski JA, Dahl ML, Arnold Z (1991)Analternativepreparationofthe2-dimethylaminomethylene-l,3-bis(dimethylimmonio) propane salt from phosphonoacetic acids and some applications in heterocyclic synthesis. J Heterocycl Chem 28 1281-1285... 

Scheme 1.6 Titanium-nitrogen complex and its application in heterocycle synthesis...

As appropriately substituted o-disubstituted benzene derivatives are feadily available, this procedure has found widespread application in the synthesis of benzo-fused flve-membered heterocycles. Examples abound in the various chapters in these volumes and the following few examples illustrate the general trend. 

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). 

Nitrenes have enjoyed appreciable application in the synthesis of a wide variety of heterocyclic systems, and the majority of the methods used for generating nitrenes have been utilized in these syntheses. 

An interesting application of a phosphorus ylide in heterocyclic synthesis is in a ring annulation. The diazopyrazole (592) when treated with various phosphorus ylides gave the 3//-pyrazolo[5,l-c][l,2,4]triazole derivatives (593) with elimination of triphenylphosphine (79TL1567). 

Ring-chain transformations and their application in the synthesis of heterocyclic compounds 99MI31. 

Despite the fact that transition metal complexes have found wide application in the synthesis of carbo- and heterocycles, [3+3] cyclisation reactions mediated or assisted by transition metals remain almost unexplored [3, 86]. However, a few examples involving Fischer carbene complexes have been reported. In all cases, this complex is a,/J-unsaturated in order to act as a C3-synthon and it reacts with different types of substrates acting as C3-synthons as well. 

Dihydro-1-vinylnaphthalene (67) as well as 3,4-dihydro-2-vinylnaphtha-lene (68) are more reactive than the corresponding aromatic dienes. Therefore they may also undergo cycloaddition reactions with low reactive dienophiles, thus showing a wider range of applications in organic synthesis. The cycloadditions of dienes 67 and 68 and of the 6-methoxy-2,4-dihydro-1-vinylnaphthalene 69 have been used extensively in the synthesis of steroids, heterocyclic compounds and polycyclic aromatic compounds. Some of the reactions of dienes 67-69 are summarized in Schemes 2.24, 2.25 and 2.26. In order to synthesize indeno[c]phenanthrenones, the cycloaddition of diene 67 with 3-bromoindan-l-one, which is a precursor of inden-l-one, was studied. Bromoindanone was prepared by treating commercially available indanone with NBS [64]. 

Abstract Controlled microwave heating has foimd many important applications in the synthesis of heterocycles. Almost all kinds of heterocycles have been prepared (or their preparation attempted) with the aid of microwaves. Many examples of cyclocondensations, reactions where two or more fimctional groups combine with the loss of another small molecule (usually water), have been described. Moreover, microwave irradiation successfully induces cycloaddition reactions, especially in the cases where high temperatures are required. This review collects the most representative examples of the application of microwaves to these two kinds of transformations. Except for a few examples, all the reactions selected have been carried out imder controlled microwave irradiation using dedicated instruments. 

In addition to nitrones, azomethine ylides are also valuable 1,3-dipoles for five-membered heterocycles [415], which have found useful applications in the synthesis of for example, alkaloids [416]. Again, the groups of both Grigg [417] and Risch [418] have contributed to this field. As reported by the latter group, the treatment of secondary amines 2-824 with benzaldehyde and an appropriate dipolarophile leads to the formation of either substituted pyrrolidines 2-823, 2-825 and 2-826 or oxa-zolidines 2-828 with the 1,3-dipole 2-827 as intermediate (Scheme 2.184). However, the yields and the diastereoselectivities are not always satisfactory. 

The preparation of condensed rhodacyclopentadienes via the diyne reaction, and examples of their use in heterocyclic synthesis have been described earlier (see Schemes 79 and 86 in Sections IV,B,5 and IV,C,2). An example showing the application of this approach to the synthesis of a condensed triazole is shown in Scheme 127.192... 

Thioamides and their use in the preparation of the heterocyclic compounds are widely reported in the literature. Also they attract considerable interests in peptide chemistry. Molecular and crystal structures of some thioamide derivatives have been confirmed by X-ray diffraction data.8 10 Lawesson s reagent or phosphorus pentasulfide (P4S10) is actively used for the synthesis of thio-carbonyl compounds. Their preparation methods, reactions, applications in the synthesis of heterocycles and biological effects are mainly described in this section. 

Reviews of saturated oxygen heterocycles <00JCS(P1)1291>, routes to 2,2-dimethyl-2H-[l]benzopyrans <00H(53)1193> and pyranonaphthoquinone antibiotics <00T1937>, HIV-1 active Calophyllum coumarins <00H(53)453> and of the application of (3-halovinylaldehydes in heterocyclic synthesis <00H(53)941> have appeared. 

Less well-established cycloaddition chemistry has also found application in the synthesis of heterocyclic compounds in recent years. An example is the intramolecular cycloaddition of silyl nitronates that has been employed by Ishikawa and Saito to afford 136 in their synthesis of amino polyols (Scheme 14) <2003OL3875>. 

Dehydrochlorination of pentachlorocyclopropane, formed from trichloroethylene and sodium trichloroacetate as a source of dichlorocarbene, yields tetrachloro-cyclopropene [150], a particularly versatile reagent for various applications. It is a reasonably reactive dienophile [151], a reagent applicable to heterocyclic synthesis [152], and an electrophile for aromatic substitutions [153] and additions to alkenes [154] in the presence of Lewis acids. 

---