Metal-catalyzed cycloisomerization reaction

Considering the mechanistic rationales of the transition metal-catalyzed enyne cycloisomerization, different catalytic pathways have been proposed, depending on the reaction conditions and the choice of metal catalyst [3-5, 45], Complexation of the transition metal to alkene or alkyne moieties can activate one or both of them. Depending on the manner of formation of the intermediates, three major mechanisms have been proposed. The simultaneous coordination of both unsaturated bonds to the transition metal led to the formation of metallacydes, which is the most common pathway in transition metal-catalyzed cycloisomerization reactions. Hydrometalation of the alkyne led to the corresponding vinylmetal species, which reacts in turn with olefins via carbometalation. The last possible pathway involves the formation of a Jt-allyl complex which could further react with the alkyne moiety. The Jt-allyl complex could be formed either with a functional group at the allylic position or via direct C-H activation. Here the three major pathways will be discussed in a generalized form to illustrate the mechanisms (Scheme 8). 

Metal-catalyzed cycloisomerization reactions of w-alkynols (4-pentyn-l-ol derivatives) provide a rapid and efficient access to tetrahydrofurans. In general, these reactions may proceed through two different reaction pathways, formally leading to endo- or r-vo-cycloisomerization products. The formation of the rwn-tetrahydrofuran product can be achieved with catalytic amounts of tungsten pentacarbonyl (Equation 85) <2005CEJ5735>. 

Shortly after the discovery of enyne metathesis, Trost began developing cycloisomerization reactions of enynes using Pd(ll) and Pt(ll) metallacyclic catalysts (429-433), which are mechanistically divergent from the metal-carbene reactions. The first of these metal catalyzed cycloisomerization reactions of 1,6-enynes appeared in 1985 (434). The reaction mechanism is proposed to involve initial enyne n complexation of the metal catalyst, which in this case is a cyclometalated Pd(II) cyclopentadiene, followed by oxidative cyclometala-tion of the enyne to form a tetradentate, putative Pd(IV) intermediate [Scheme 42(a)]. Subsequent reductive elimination of the cyclometalated catalyst releases a cyclobutene that rings opens to the 1,3-diene product. Although this scheme represents the fundamental mechanism for enyne metathesis and is useful in the synthesis of complex 1,3-cyclic dienes [Scheme 42(fe)], variations in the reaction pathway due to selective n complexation or alternative cyclobutene reactivity (e.g., isomerization, p-hydride elimination, path 2, Scheme 40) leads to variability in the reaction products. Strong evidence for intermediacy of cyclobutene species derives from the stereospecificity of the reaction. Alkene... 

A regioselective transition metal-catalyzed cycloisomerization reaction of boron-containing alkynyl epoxides toward C-2- and C-3-borylated furans was developed. It was found that the copper catalyst as well as the gold catalyst with a relatively more basic triflate counterion favored boryl migration toward C-3-borylated furans, whereas employment of the cationic gold hexafluoroantimonate afforded C-2-borylated furans via a formal 1,2-hydrogen shift (14JA13146). 

Yamamoto was first to report that orfho-alkynylanilines, which are fully substituted at the N-site, could undergo a transition metal-catalyzed cycloisomerization reaction to give indoles via a formal 1,3-migration of a suitable migrating group from the... 

Scheme 1.23 Formation of dendralene via Alder-ene or metal catalyzed cycloisomerization reaction.

Scheme 1.24 Representative examples of transition-metal-catalyzed cycloisomerization reactions forming the C2-C3 bond of cyclic [3]dendralenes [69, 99, 106].

Proposed Mechanisms Different mechanistic pathways have been proposed for the metal-catalyzed cycloisomerization reactions. In the case of enynes, these are highlighted as (i) the metaUocyclopentene pathway, (ii) the tf-metal pathway, and (iii) the vinylmetal pathway (Scheme 7.10) [30]. 

With a cascade process in mind, Chen envisaged a transition metal-catalyzed cycloisomerization reaction. 

Jury JC, Swamy NK, Yazici A, Willis AC, Pyne SG (2009) Metal-catalyzed cycloisomerization reactions of c -4-hydroxy-5-alkynylpyrrolidinones and cii-5-hydroxy-6-alkynylpi-peridinones synthesis of furo[3,2-i)]pyrroles and furo[3,2-b]pyridines. J Org Chem 74 5523-5527... 

JV-Tosyl-l,2,3,4-tetrahydropyridines 208, which have at the 4-position a tethered electron-deficient alkyne, undergo metal-catalyzed cycloisomerization to give 2-azahydrindans 209, which can undergo Diels-Alder reactions with acroleins to give highly functionalized 1-azadecalins 210 (Scheme 55) <20040L5023>. 

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. 

Two different research groups independently reported metal-catalyzed cycloisomerizations of alkynyl-substituted pyridines leading to indolizines. Specifically, treatment of pyridine 7 with silver tetrafluoroborate gave indolizine 8 in excellent yield <07OL3433>. This reaction could also be mediated by copper(I) iodide <07JOC7783>. 

The first example of a transition metal-catalyzed cycloisomerization of cyclopropenes [184,185] into furans was demonstrated by Nefedov (Scheme 8.61) [186]. It was proposed that this rearrangement proceeds via a carbenoid intermediate [187]. Formation of the furan products via the cycloisomerization of potentially involved cyclopropene intermediates in the Rh(II)-catalyzed cyclopropenation reaction of alkynes was later reported by several research groups, including Liebeskind, Davies, and Muller [188-192]. 

In the 1980s, the group of Trost [10,11] discovered and developed intramolecular palladium-catalyzed Alder-ene reactions. Changing the mechanism from the classical pericyclic process to a reaction that proceeds via transition organometal-lic intermediates has enriched the understanding and realization of the concept of atom-economic processes [ 12]. Therefore, the cycloisomerization of 1,/i-enynes has remained an intensively pursued field of synthetic methodologies ever since [13]. In addition, major advances in enantioselective transition-metal-catalyzed cycloisomerizations of enynes have also been explored [14]. 

For secondary ortho-iodo alkynoyl anilides (R = H), Schonhaber et al. [61] observed that the intermediate 33 (R = H) is consumed in a transition-metal-catalyzed cycloisomerization, furnishing the new class of proto- and metal-lochromic luminescent 2,4-diarylpyrano[2,3- ]indoles 35 in moderate yields (Scheme 12.23). The overall reaction proceeds as a sequentially Pd-Cu-catalyzed insertion-coupling-cycloisomerization domino reaction. 

Taking advantage of the rich chemistry of transition-metal-catalyzed cycloisomerization of 1,6-enynes, the electron-rich, conformationally blocked cyclohepta-1,3, 5-triene has been envisioned as a 6-% nucleophilic component [59]. Thus, cycloisomerization of l-(pent-4-ynyl)cyclohepta-l,3,5-trienes in the presence of catalytic amounts of platinum(II) chloride led to a formal intramolecular [64-2] cycloaddition in good to excellent yields [60]. These reactions are conducted at room temperature in toluene as the solvent. A heteroatom in the tether between the unsaturated subunits is tolerated, although in these cases other catalytic pathways were also observed. A mechanism involving cationic intermediates resulting from the nucleophilic attack of the triene on the metal-alkyne moiety has been proposed (Scheme 8.38). The occurrence of ionic intermediates was supported with... 

The close relationship of cyclization modes existed in sesquiterpene biosynthetic machinery, with those presented by the metal-catalyzed cycloisomerizations, justify the vast amount of reports on total synthesis of sesquiterpenes, in which the utilization of enyne or diene cycloisomerizations are the key components of their synthetic strategy. This chapter is intended to cover only selected examples on the topic. Special concern is given on covering catalyzed reactions, which are triggering different cyclization modes, only for the construction of sesqniterpene core strnctnres. Assuredly, cycloisomerization reactions are powerfnl tools in providing also other classes of secondary metabolites, as complex terpenoids and alkaloids, in which the readers are referred to more general reviews on the topic [26,30]. 

Another useful class of palladium-catalyzed cycloisomerizations is based on the general mechanistic pathway shown in Scheme 13. In this chemistry, a hydridopalladium acetate complex is regarded as the catalytically active species.27b-29 According to this pathway, coordination of a generic enyne such as 59 to the palladium metal center facilitates a hydropalladation reaction to give intermediate 60. With a pendant alkene, 60 can then participate in a ring-form-... 

The authors confirmed the formation of vinyl Ru-complex 21 by the reaction of [Cp Ru(SBu-t)]2 with methyl propiolate (Eq. 7.15). To my knowledge, this is the first observation of the insertion of an alkyne into the M-S bond within a catalytically active metal complex. In 2000, Gabriele et al. reported the Pd-catalyzed cycloisomerization of (Z)-2-en-4-yne-l-thiol affording a thiophene derivative 22 (Eq. 7.16) [26]. 

In addition to the reactions discussed above, there are still other alkyne reactions carried out in aqueous media. Examples include the Pseudomonas cepacia lipase-catalyzed hydrolysis of propargylic acetate in an acetone-water solvent system,137 the ruthenium-catalyzed cycloisomerization-oxidation of propargyl alcohols in DMF-water,138 an intramolecular allylindination of terminal alkyne in THF-water,139 and alkyne polymerization catalyzed by late-transition metals.140... 

Allenes, while arguably underused in synthesis as a whole, have become popular functionalities in cycloisomerization chemistry and provide access to a wide variety of products. Ruthenium, cobalt, platinum, palladium, rhodium, and iridium catalysts are efficient in the transition metal-catalyzed Alder-ene reactions of allenes. 

Brummond [28] was the first to illustrate that cross-conjugated trienes could be obtained via an allenic Alder-ene reaction catalyzed by [Rh(CO)2Cl]2 (Eq. 14). Selective formation of the cross-conjugated triene was enabled by a selective cycloisomerization reaction occurring with the distal double bond of the aUene. Typically directing groups on the allene, differential substitution of the aUene termini, or intramolecularization are required for constitutional group selectivity. However, rhodium(f), unlike other transition metals examined, facihtated selective cyclization with the distal double bond of the allene in nearly aU the cases examined. 

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