Cycloisomerization heterocyclics

Enantioselective hydrogenation of 1,6-enynes using chirally modified cationic rhodium precatalysts enables enantioselective reductive cyclization to afford alky-lidene-substituted carbocycles and heterocycles [27 b, 41, 42]. Good to excellent yields and exceptional levels of asymmetric induction are observed across a structurally diverse set of substrates. For systems that embody 1,2-disubstituted alkenes, competitive /9-hydride elimination en route to products of cycloisomerization is observed. However, related enone-containing substrates cannot engage in /9-hydride elimination, and undergo reductive cyclization in good yield (Table 22.12). 

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). 

Under catalysis of Ag+, 2,3-allenylamines can undergo cycloisomerization to afford N-containing heterocycles [135,136]. Such metal-mediated isomerizations are discussed in detail in Chapter 15. 

Cycloisomerizations are one of the most popular methods for the formation of carbo- and heterocyclic compounds [1, 2], Although in most cases alkenes and/or alkynes are still involved, there now exist a significant number of similar applications of allenes which benefit from the higher reactivity of the allene-unit. 

The heteroatom-tethered enynes, If-i, were converted to the corresponding bicyclic heterocycles 2f-i without event, thereby further illustrating the scope of this transformation. The [RhCl(CO)2]2-catalyzed PK reaction with the 1,6-enynes Ij and Ij, which have a methyl group at a terminal position of the olefin moiety, furnishes the corresponding bicyclopentenone 2j and 2j in good to excellent yield. Interestingly, treatment of 1 j with a phosphine ligand-bound catalyst, such as 10, affords a mixture of the desired cyclopentenone 2j with the cycloisomerization product 2j (Eq. 1). 

Chiral carbo- and heterocycles are widespread structural motifs in biologically active compounds. The cycloisomerization of 1,6-dienes (A) offers an elegant and atom-economic [56] approach to five- or six-membered carbo- or heterocycles [57]. Metal complexes based on Pd [58], Ni [59], Rh [60], Ru[61], and Ti[62] have been identified as promising lead structures for catalyst development. Some of the reported systems are highly chemo- and regioselective toward the formation of the individual five-membered ring compounds B-D (Scheme 2.1.5.2). Enantioselec-tive cycloisomerization, however, has been assessed only sparsely so far, and remains a challenging task [46, 63]. 

Our interest in this chapter is in silver-catalyzed cycloisomerization reactions. Therefore, we shall present different silver-catalyzed cycloisomerization reactions as a function of the nucleophilic and electrophilic moiety. Cycloisomerization reactions including the classical ene-yne cycloisomerization (with X = CHR, Scheme 5.1), and the related heterocyclization reactions with heteroatoms embedded in unsaturated systems (X = NR, O Scheme 5.1) belong to the same reaction family. In addition, the alkynyl part can be exchanged for an allene unit. Internal or external nucleophiles (Nu) can then stabilize, through cascade reactions, the positive charge created.24... 

Heterocyclization reactions with saturated moieties (alcohols, amines, thiols, etc.) or acids on unsaturated counterparts (alkenes, allenes, alkynes, etc.) are not covered in this chapter since they are addition, and not isomerization, reactions. Silver is also widely used as an activating agent for producing highly reactive metallic cations (anion metathesis), which, in turn, may catalyze cycloisomerization reactions. This aspect is covered only when the silver control experiments give substantial positive results. 

Porco et al.74 accessed pyrroloisoquinoline heterocycles 46 by employing a domino process. Initially, a metal-catalyzed cycloisomerization of alkynyl iV-benzylidene glycinates 45 gave azomethine ylide CC (Scheme 5.21), which underwent... 

Shin s group80 also used AgOTf (5 mol%) to catalyze the formation of isoquinoline-IV-oxide structures 56 (Scheme 5.26) from cycloisomerization of 2-alkynylbenzaldox-imes 55. This synthesis is of interest since these structures are usually made by oxidation of the parent nitrogen heterocycles. 

Liu et al. obtained diverse carbocyclic and heterocyclic frameworks by employing a silver(I)-catalyzed cycloisomerization of epoxyalkynes.89 With AgSbF6 (2mol%), epoxides 79 were transformed in 3-l//-indenyl ketones 80 in high yields (Scheme 5.36). 

This overview of silver-catalyzed cycloisomerization reactions shows the great flexibility of the method and its usefulness in reaching the core of numerous heterocycles. 

Table 2 Syntheses of heterocycles using ruthenium-catalyzed cycloisomerizations...

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. 

Scheme 18 Assembly of heterocycles by domino cycloisomerization Diels-Alder reactions [73]...

Furthermore, the choice of enyne substrates can lead to cyclized products that contain other functionalities than dienes. Very recently, Muller and Kressierer [148] have shown that yne allyl alcohols 200 can be rapidly cyclo-isomerized by a Pd2dba3-W-acetyl phenyl alanine catalyst system to furnish heterocyclic enals 202 in excellent yields (Scheme 82). The intermediate product of the enyne cycloisomerization in this case is the enol 201, which rapidly tautomerizes to the aldehyde 202. 

The cycloisomerization reaction of hydrazono heterocycles also provides a route for the preparation of a number of dihydrotriazolobenzaze-pines (21) that show good anticonvulsant activity (83EUP72029). 

Transition metal-catalyzed annulations (cycloisomerizations of alkynylimines to pyrroles, alkynylketones to furans, and syntheses of multisubstituted heterocycles, particularly, alkaloids) 03SL2265. 

Finally, the intramolecular cycloaddition methodology also provides access to heterocyclic systems when methylenecyclopropanes with heteroatom-containing side chains are employed. However, as shown above, very complex structural requirements are deary operable. For example, methyl 4-[(l-methyl-2-methylenecyclopropyl)methoxy]but-2-ynoate only yields a complex product mixture mainly containing conjugated dienes (arising from a ring cleavage/ -elimination sequence) upon attempted palladium(0)-catalyzed cycloisomerization. ... 

The synthesis of heterocycles via the olefin metathesis reaction (RCM, ring closing metathesis, section 2) and via the cycloisomerization of dienes, diynes, and enynes (section 3) belongs to category 1... 

Scheme 15. Synthesis of Heterocycles from 1,6-Dienes, Enynes, and Diynes via (a) Cycloisomerization, (b) Tandem Addition—Cyclization, and (c) Cycloaddition...

As 1,/2-alkenes, 1,6-derivatives are used very frequently leading to five-membered heterocycles, while the use of 1,7-derivatives, which produce six-mem-bered heterocycles, is very rare. The reactions of 1,6-dienes, -enynes, and -diynes are classified into three groups (a) cycloisomerization, (b) tandem addition— cyclization, and (c) cycloaddition, such as the Pau-son—Khand reaction, cyclotrimerization, and the Diels—Alder reaction (Scheme 15).97 In these reactions five-membered heterocycles are constructed upon the carbon—carbon bond-forming processes. 

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