Heterocyclic synthesis heteroatoms

Heterocyclic scaffolds form the cores of many pharmaceutically relevant substances. Not surprisingly, therefore, many publications in the area of microwave-assisted organic synthesis, both from academia and industry, deal with the preparation of heterocycles [5], In this final section of this chapter, the description of heterocycle synthesis is structured according to ring-size and the number of heteroatoms in the ring. 

Table 2.19. Synthesis of five-membered carbo- or heterocycles from heteroatom-substituted earbene complexes.

The electrophile-induced cyclization of heteroatom nucleophiles onto an adjacent alkene function is a common strategy in heterocycle synthesis (319,320) and has been extended to electrophile-assisted nitrone generation (Scheme 1.62). The formation of a cyclic cationic species 296 from the reaction of an electrophile (E ), such as a halogen, with an alkene is well known and can be used to N-alkylate an oxime and so generate a nitrone (297). Thus, electrophile-promoted oxime-alkene reactions can occur at room temperature rather than under thermolysis as is common with 1,3-APT reactions. The induction of the addition of oximes to alkenes has been performed in an intramolecular sense with A-bromosuccinimide (NBS) (321-323), A-iodosuccinimide (NIS) (321), h (321,322), and ICl (321) for subsequent cycloaddition reactions of the cyclic nitrones with alkenes and alkynes. 

Most benzo-fused heterocyclic systems are constructed from a substituted benzene by synthesis of the heterocyclic ring. Similarly most bicyclic heterocycles with heteroatoms in both rings commence with a monoheterocycle and build on the second heterocycle. However, substituent modification and, to a lesser extent, substituent introduction are also important, particularly in the later stages of a synthesis, and we now survey available methods for this. 

Formation of a bond between two heteroatoms in the cyclization step is comparatively rare in heterocyclic synthesis. However, in these polyheteroatom systems it is quite common to form such a bond, particularly between nitrogen and sulfur. 

It is abundantly clear from the preceding discussion that dihalocyclopropanes are versatile intermediates in organic synthesis. Although a wealth of chemistry has already been uncovered, prospects remain bright for interesting developments in the future. Areas such as the application of dihalocyclopropanes in heterocyclic synthesis via carbene insertion into C—H bonds adjacent to heteroatoms, reactions of dihalocyclopropanes with organometallics and the synthetic applications of metallated derivatives deserve further exploration. The chemistry of difluoro-, diiodo- and mixed dihalo-cyclopropanes can be expected to attract some attention. Finally, other heteroatom-substituted cyclopropanes derived ftom dihalocyclopropanes will also invoke further investigation. 

With the aid of transition-metal catalysis, heterocycle formations can be achieved not only by carbon-heteroatom bond forming cydizations of an acyclic molecule with a terminal group such as alcohols and amines, but also by intramolecular carbon-carbon bond forming reactions of an acyclic precursor containing one or more heteroatoms in its tether moiety. This section will briefly survey heterocycle synthesis via carbon-carbon bond formations. For details of ruthenium-catalyzed C-C bond formations, see other chapters of this book. 

Ruthenium catalysis has been extensively explored during the past decade [114]. Newly developed carbon-carbon bond forming cyclizations such as [2+2+2] cycloaddition, RCMs, and cycloisomerizations have dramatically expanded the scope of heterocycle synthesis. Relatively unexplored catalytic carbon-heteroatom bond formations have also made significant contributions to this area. Further progress in ruthenium catalysis will not only improve the conventional synthetic methodologies, but will also open the way to an unprecedented class of heterocyclic compounds, which might have a significant potential as pharmaceuticals or functional materials. 

Nucleophilic trapping agents used in the Type II Ac-Pd process are not limited to MeOH and other alcohols. A wide range of heteroatom and carbon nucleophiles may be used as in the cases of the Type II cyclic carbopalladation processes terminated by various nucleophilic reagents (Sect. 2.1.2). A couple of reactions shown in Scheme 58 [ 145] provide additional examples of heterocycles synthesis via Type II Ac-Pd process terminated by cross-coupling. 

Three-membered rings with two heteroatoms, 2, 83 24, 63 Transition organometallic compounds in heterocyclic synthesis, use of, 30,... 

Some of the components shown in the examples above have two electrophilic centres and some have a nucleophilic and an electrophilic centre in other situations components with two nucleophilic centres are required. In general, components in which the two reacting centres are either 1,2- or 1,3-related are utilised most often in heterocyclic synthesis, but 1,4- (e.g. HX-C-C-YH) (X and Y are heteroatoms) and 1,5-related (e.g. 0=C-(C)3-C=0) bifunctional components, and reactants that provide one-carbon units (formate, or a synthon for carbonic acid - phosgene, Cl2C=0, or a safer equivalent) are also important. 

The ability of the Dieckmann reaction to tolerate heteroatoms in the ring-forming sequence of atoms has led to its extensive use in heterocyclic synthesis. Many complex systems containing heterocyclic rings have been prepared by routes that include this reaction, and twth aromatic and alicyclic rings have been constructed. A variety of bases and solvents have been employed and representative examples are illustrated in Scheme 45. 

Heterocyclic synthesis can also be done by ring interconversion. These processes are treated in more detail in the reactivity sections since they involve reaction at the heteroatom. Here, they are only briefly illustrated to provide examples of the transformations. 

Alkylidenephosphoranes (a.La. phosphorus yUdes) of the general formula Ph3P=CR R (1) have been frequently used in key steps of heterocycle synthesis. Numerous papers and review articles [1-4] testify their versatility in the construction of rings with sizes ranging from three to well beyond 20 and with virtually any number, kind and distribution of heteroatoms. The Wittig alkenation of carbonyl groups is doubtless the most common, though not the only, reaction of P-ylides that has been employed in the cyclization of bifunctional precursors. The cycloaddition between acyl ylides (1 = H,... 

Propargyl vinyl ethers as heteroatom-tethered enyne surrogates Diversity-oriented strategies for heterocycle synthesis 13CC2272. 

In this chapter, the readers will be introduced in the different organocatalytic domino (or cascade) reactions that lead to the synthesis of C-C and C-heteroatom bonds. This type of reactions have found considerable applications in enantioselective heterocycle synthesis. The section has been organized by presenting first cascades initiated by a C-C bond formation and then presenting cascades initiated by a C-heteroatom bond formation. 

Herein, we review nonexhaustively our contribution to the field of transition-metal-mediated heterocyclic synthesis. This chemistry is based mainly on using cyclopalladated complexes and their reactions with disubstituted alkynes that in many cases, lead to heterocyclic products by the selective intramolecular formation of carbon-carbon and carbon-heteroatom (C-N, C-O and C-S) bonds. In some instances these reactions also lead to interesting carbocyclic derivatives. Emphasis is placed on the transformations of the alkynes. When they are allowed to react with the metallated ligands, they lead in several instances to heterocyclic or carbocyclic final products. We present in particular some of the more recent results emanating from our laboratory and comment briefly on some similarities of this chemistry to other, selected and related transition-metal-mediated reactions, thus demonstrating that this field of research remains in vogue in many different research groups. 

Several transformations involving CO insertion into a Pd-heteroatom bond have been developed that lead to incorporation of two molecules of CO into the heterocyclic product. This approach to heterocycle synthesis is exemplified by a synthesis of dihydroindolones reported by Gabriele [101]. As shown below, treatment of ortho-alkynyl aniline 157 with a Pd catalyst under CO in methanol afforded 158 in 50% yield (Eq. (1.62)). A similar strategy has been employed for the conversion of alkene 159 to pyrrolidinone 160 (Eq. (1.63)) [102]. 

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