Alkynes heterocyclic synthesis

Besides iodonium ylides, alkynyliodonium salts are also useful in heterocyclic synthesis. These salts are obtained from the reaction of the alkynes with an appropriate organohypervalent iodine reagent (Scheme... 

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. 

Reviews (a) V. Dave and E. W. Wamhoff, The Reactions of Diazoacetic Esters with Alkenes, Alkynes, Heterocyclic and Aromatic Compounds, in W. G. Dauben, ed., Organic Reactions, Vol. 18, Chap. 3, John Wiley Sons, New York, 1970. (b) G. Maas, Top. Curr. Chem., 137, 75 (1987). (c) J. Salaun, Chem. Rev., 89, 1247 (1989). (d) A. Demonceau, A. J. Hubert, and A. F. Noels, Basic Principles in Carbene Chemistry and Applications to Organic Synthesis, in A. F. Noels, M. Graziani, and A. J. Hubert, eds., Metal Promoted Selectivity in Organic Synthesis, p. 237, Kluwer Academic, Dordrecht, 1991. 

Pyridyldimethylsilane 24 is a reagent for the metal-catalyzed hydrosilylation of alkynes and alkenes <2004EROS1>. 4-(Trifluoromethyl)pyridine 25 has been used as a building block in heterocycle synthesis <2005EROS1>. 

Heterocycle synthesis. Arylhydrazines and 1-alkynes react to form A-heterocycles. l-Aiyl-2-pyrazolene are produced from 3-butynol, whereas 2-methyl-3-aIkylindoles are obtained from other 1-alkynes." ... 

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. 

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. 

In most of the heterocyclizations seen previously, alkynes are used as C-2 units linking the o-bonded carbon atom and the nitrogen atom of the cyclopalladated starting materials. Dienes also play a similar role leading to a broader scope for heterocyclic synthesis. 

An alternative approach to multicomponent heterocycle synthesis involves the use of palladium catalysis to construct keto-alkynes for cycloaddition reactions. Muller has demonstrated the power of this approach in the construction of a range of aromatic heterocycles. For example, the palladium-catalyzed coupling of acid chlorides with terminal alkynes provides a method to assemble 36. The trapping of this substrate can provide routes to aromatic heterocycles. As an example, the addition of amidines provides a multicomponent synthesis of pyrimidines (Scheme 6.69) [97]. This same substrate 36 is available via the carhonylative coupling of aryl halides with terminal alkynes, providing a four-component synthesis of pyrimidines (98j. 36 can also be employed in 1,3-dipolar cydoaddition reactions. For example, cydoaddition... 

Scheme 15.36 Heterocycle synthesis employing Zn-catalyzed intramolecular alkyne hydroamination.

Meso-ionic hetero-arenes are valuable synthons for heterocyclic synthesis. Now, the preparation, isolation, and reactions of salts of the type (299) have been reported. The salts react smoothly with activated alkynes and enol ethers to... 

The cycloaddition of carbon-heteroatom imsaturated bonds to alkynes is a versatile method for the construction of six-membered heterocyclic molecular frameworks such as pyridine and pyran, which are widely distributed in natural products and pharmaceutical drugs. In the past few decades, transition-metal-catalyzed cycloaddition has emerged as apowerful method for the synthesis of structurally diverse heterocyclic compounds [1], Nickel complexes are the most significant transition-metal-based catalysts because as opposed to divalent nickel, which shows ir-Lewis acid behavior toward carbon-carbon unsaturated bonds, zero-valent nickel shows nucleophilic behavior toward carbon-heteroatom unsaturated bonds, thereby facilitating the formation of heteronickelacycles, which are key intermediates for heterocycle synthesis... 

Many cascade reactions, including the reaction between X—H and alkyne, have been reported. A Sonogashira coupling-cyclization cascade (e.g.. Scheme 19.66) is an especially good combination for heterocycle synthesis from haloarenes bearing a nucleophilic functionality at the 2-position. In this section, a quite limited number of useful cascade reactions, especially those including the latest frontiers of modern organic chemistry, are presented. 

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