Transition-metal-mediated heterocyclic synthesis

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. 

This chapter has taken the reader through a number of microwave-assisted methodologies to prepare and further functionalize 2-pyridone containing heterocycles. A survey of inter-, intramolecular-, and pericyclic reactions together with electrophilic, nucleophilic and transition metal mediated methodologies has been exemplified. Still, a number of methods remain to be advanced into microwave-assisted organic synthesis and we hope that the smorgasbord of reactions presented in this chapter will inspire to more successful research in this area. 

Knoelker H-J (1995) Transition metal-mediated synthesis of carbazole derivatives. Adv Nitrogen Heterocycl 1 173-204... 

Transition metal-mediated synthesis of monocyclic aromatic heterocycles 13CRV3084. 

T. Matsuda, Synthesis of heterocycles via X—H bond addition to diynes. in Transition-Metal-Mediated Aromatic Ring Construction. (Ed K. Tanaka), p. 537. John Wiley Sons, Ltd., New York, 2013. 

Transition-metal-mediated cyclization reactions play an increasing role in the synthesis of heterocycles, as shown by furan syntheses catalyzed by Pd, Cu, and Au. 

Today, many heterocyclic systems (including indole derivatives which are useful precursors for alkaloid synthesis) have been prepared by transition metal-mediated reactions. 

Pyrrolo[3,2-df pyridazines are a class of interesting and useful A -heterocycles [40—42]. However, synthetic methods for such heterocyclic compounds have been very much limited such as condensation of pyrrole-2,3-diones with hydrazine. There are no reports on one-pot multi-component synthesis of pyrrolo[3,2-(f py-ridazines [43]. Moreover, synthetic methods for pyrrole-2,3-diones are also very limited [43]. On the other hand, transition-metal-mediated reactions of azides are of great importance and versatility in organic synthesis, because azides could be readily transformed into a wide variety of valuable A -containing natural products and medicinal agents [44-50]. 

A.V. Gulevich, A.S. Dudnik, N. Chernyak, V. Gevorgyan, Transition metal-mediated synthesis of monocyclic aromatic heterocycles, Chem. Rev. 113 (2013) 3084r 213. 

While the replacement of an alkyne against an olefin unit in the transition-metal-mediated [2 -I- 2 -I- 2] cycloaddition widens the scope of its applicability to more complex carbo- and/or heterocyclic structures, the same accounts for the formal replacement of an alkyne against a heterocumulene moiety [60]. However, as such a strategy led to the development of new concepts for the construction of heterocyclic compounds (i.e., the formation of 2-pyridinones via the [2- -2-1-2] cycloaddition reaction of alkynes with isocyanates [61]), the application in the field of total synthesis is still at its infancy and so is limited to a few examples. 

Synthesis of Substituted Heterocycles Transition-metal-mediated or transition-metal-catalyzed co-cycloaddition of two alkynes and one nitrile is one of the simplest synthetic pathways to construct pyridine framework. However, there is a critical problem in selectivity in the intermolecular coupling of two different alkynes and a nitrile resulting from the reaction mechanism via metalacyclopentadi-ene [17]. For example, in Co-mediated pyridine formation, cobaltacyclopentadiene 37 was first prepared from two different alkynes by sequential addition because aza-cobaltacyclopentadiene could not be formed via selective coupling of one alkyne and a nitrile. A mixture of two pyridine regioisomers was obtained in the final step due to the existence of two possible orientations of the nitrile toward cobaltacyclopentadiene intermediate 37 [Scheme 11.15, Eq. (1)] [17b,c]. To control the... 

Dipolar cycloaddition reactions constitute a powerful and convergent tool for the preparation of various heterocyclic compounds, which have been widely applied in the synthesis of numerous natural products, pharmaceuticals, and functional materials. The chemistry of 1,3-dipolar cycloaddtion reactions has been well documented in a number of reviews [3]. In this section the focus is on transition-metal-mediated 1,3-dipolar cycloaddition reactions with some important 1,3-dipoles, including azides, diazoalkanes, carbonyl ylides, and azomethine ylides, rather than a full review of the reactions of all types of 1,3-dipoles. 

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. 

His present interests include the development of new synthetic methodologies in carbohydrates, free radical chemistry, organometallic chemistry (Pauson-Khand reaction, transition metal (PtCl2, AuCl)-mediated cycloisomerization of polyunsaturated precursors), and synthesis/biologi-cal evaluation of heterocyclic systems (CSIC reaction, tacrine analogs). 

In addition, silver-catalyzed asymmetric aza-Diels-Alder reactions provide a useful route to optically active nitrogen-heterocyclic compounds such as piperidines or pyrid-azines. Substituted dihydrobenzofurans can also be enantioselectively prepared through silver-promoted allylation of aldehydes. Other types of silver-mediated cyclizations can also be used in the synthesis of tetrahydrofnrans, tetrahydropyrans, 1,2-dioxetanes, 1,2-dioxolanes, medium-sized lactones, dihydroisoqninolines, and so on. Silver salts can also be used as cocatalysts with other transition metals. Unique activity was observed for these silver-based systems in several cases. Conseqnently, the use of silver can enrich several available heterocyclization methods, and fnrther developments in the application of chiral silver complexes will hopefnlly appear in the near future. 

Oxygen-containing heterocycles are abundant in nature and are important in fine chemicals. The addition of alcohols across unsaturated C-C bonds represents an atom-economical and direct route for the synthesis of these cyclic ethers. Hydroalkoxylation transformations mediated by a wide range of transition-metal and alkali-metal catalysts yield a variety of vinyl ethers. Organolanthanide complexes offer an alternative agent for the efficient and highly selective synthesis of both aliphatic and vinyl ethers with selectivities often complementary to those of transition-metal catalysts. 

---