Heterocycle synthesis approaches

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... 

Recent Development of Ring Closing Metathesis Approach to Bioactive Heterocycles Synthesis of Nakadomarin A, Quinolines, and Indoles... 

Our study of heterocyclic compounds is directed primarily to an understanding of their reactivity and importance in biochemistry and medicine. The synthesis of aromatic heterocycles is not, therefore, a main theme, but it is useful to consider just a few examples to underline the application of reactions we have considered in earlier chapters. From the beginning, we should appreciate that the synthesis of substituted heterocycles is probably not best achieved by carrying out substitution reactions on the simple heterocycle. It is often much easier and more convenient to design the synthesis so that the heterocycle already carries the required substituents, or has easily modified functions. We can consider two main approaches for heterocycle synthesis, here using pyridine and pyrrole as targets. 

The reaction of A2-piperideine (115) with methyl vinyl ketone to give (124) is another example of how initial electrophilic attack on the enamine double bond can be used in heterocyclic synthesis (77ACR193). This overall process is an enamine analog of the Robinson annelation and is a useful approach to the perhydroquinoline ring system. 

In a more recent study, Westman and Lundin described the solid-phase synthesis of aminopropenones and aminopropenoates, respectively30 as intermediates for heterocyclic synthesis. Two different three-step methods for the preparation of heterocycles have been developed. The first method involved formation of a polymer-bound ester from a IV-protected glycine derivative and Merrifield resin (Scheme 7.10a), while the second method employed an interesting approach utilising simple aqueous methy-lamine solution for functionalisation of the solid support (Scheme 7.10b). In this latter approach, a variety of hetero cycles were readily synthesised from the generated polymer-bound benzylamine using a two-step protocol (see Section 5.3.3). 

The first two (Acheson and Paquette) are still very good texts even today. Of the more recent pair, both are warmly recommended. Joule and Smith is possibly a more introductory text than Gilchrist, which contains many journal references and is pitched at the advanced undergraduate/postgraduate level. See Gilchrist for a discussion of the nucleophilic/electrophilic fragment approach to heterocyclic synthesis. 

A lot of information about the structure, reactivity, and the best synthetic approaches for pyrimidopyrimidines has been described in CHEC-I. Additionally, some new methods of preparation of pyrimidopyrimidines have been reported in reviews on the synthesis of fused pyrimidines by Delia and Warner starting material in heterocyclic synthesis by Wamhoff, Dzenis, and Hirota <92AHC(55)129>. Pyrimidopyrimidines are especially interesting as structural analogues of natural compounds. 

Figure 12 Catch-and-release PASP synthesis approach to heterocyclic thioethers...

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. 

The synthesis of these heterocycles was approached using two similar strategies. Fmoc-amino acid-derivatized Wang resins were N-deprotected (87) and coupled with either o-nitrobenzoic acid or N-Fmoc-anthranilic acid (88 and 89). Reduction of the nitro group with 2 m Sn( l, /DMF or Fmoc cleavage with piperidine/DMF, respectively, produced 90, which was cyclized with NaOtBu/THF at 60 °C. Extraction of the crude materials yielded 11 different l,4-benzodiazepine-2,5-diones 91 in yields of 45-80% with an average purity of 90% (Scheme 24) [39]. 

Another of Grigg s approaches to heterocyclic synthesis involves the anion-capture termination of the palladium cascade (91TL2545). In a typical example, a 1 1-mixture of benzyl halide 649 was reacted with sodium tetraphenylborate in the presence of Pd(0) to give compound 650 in 69% yield. Likewise, allyl acetate 651 reacted under similar conditions to afford 652 in 80% yield. 

Utility of a,jS- Unsaturated Nitriles in Heterocyclic Synthesis, M. H. Elnagdi and coworkers, 1983". Syntheses of different mono- and polyheterocyclic derivatives via a,j5-unsatur-ated nitriles are surveyed. The scope and limitation of the most important of these approaches are demonstrated. 134 references are given. 

In an approach toward heterocycle synthesis two different three-step methods for solid-phase preparation of aminopropenones and aminopropenoates have been developed [29]. The first involved formation of the respective ester from N-protected glycine derivatives and Merrifield resin (Scheme 16.5) whereas the second used a different approach, use of simple aqueous methylamine solution for functionalization of the solid support [29]. The desired heterocycles were obtained by treatment of the generated polymer-bound benzylamine with the corresponding acetophenones, using N,N-dimethylformamide diethylacetal (DMEDEA) as reagent. The final step in the synthesis of the pyridopyrimidinones involved release of the products from the solid support by intramolecular cyclization. 

The Pauson-Khand reaction provides another new approach to the metal-catalyzed synthesis of heterocycles. This reaction involves the interaction of the multiple bonds of an alkyne with an alkene and carbon monoxide in the presence of dicobalt octacarbonyl (Co2(CO)g), or with just this reagent as a source of CO. The overall process has been described as a [2 -h 2 -h 1] cycloaddition. Only a few applications to heterocyclic synthesis have been reported so far. A 2008 paper that is illustrative of the process describes the use of this reaction for the construction of a heterocyclic ring that is part of an azabicy-clo[3.3.1]nonane derivative. This ring system is present in the alkaloid (-)-alstonerine (4.37), which prompted this study. 

Tandem oxidation processes have also been applied to five-and six-membered heterocycle synthesis. New examples of six-membered rings include pyrimides and p)mdines. In one approach, an cK-arylpropargyl alcohol is oxidized to the corresponding ynone, which then reacts with ethyl a-aminocrotonate or an amidine to afford pyridines or p)Timidines, respectively (eqs 105 and 106). In both cases, the reactions were limited in scope, but the former was subsequently inproved by implementation of 8-keto esters and ammonium acetate in place of the a-amino cro-tonate s)mthon (eq 107). ... 

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