Nucleophilic reactions cycloisomerizations

Marshall et al. noted that under the catalysis of Ag+ or Rh+, 1,2-allenyl ketone or aldehyde 417 may undergo cycloisomerization to afford furans 418. The reaction proceeded via the interaction of Ag+ or Rh+ with the relatively electron-rich C=C bond in the allene moiety followed by nucleophilic attack of the carbonyl oxygen [187]. Through a labeling study, it was found that the reaction proceeds by the mechanism shown in Scheme 10.162 [188]. 

Another rhodium vinylidene-mediated reaction for the preparation of substituted naphthalenes was discovered by Dankwardt in the course of studies on 6-endo-dig cyclizations ofenynes [6]. The majority ofhis substrates (not shown), including those bearing internal alkynes, reacted via a typical cationic cycloisomerization mechanism in the presence of alkynophilic metal complexes. In the case of silylalkynes, however, the use of [Rh(CO)2Cl]2 as a catalyst unexpectedly led to the formation of predominantly 4-silyl-l-silyloxy naphthalenes (12, Scheme 9.3). Clearly, a distinct mechanism is operative. The author s proposed catalytic cycle involves the formation of Rh(I) vinylidene intermediate 14 via 1,2-silyl-migration. A nucleophilic addition reaction is thought to occur between the enol-ether and the electrophilic vinylidene a-position of 14. Subsequent H-migration would be expected to provide the observed product. Formally a 67t-electrocyclization process, this type of reaction is promoted by W(0)-and Ru(II)-catalysts (Chapters 5 and 6). 

Double cyclization of iodoenynes is proposed to occur through a Rh(I)-acetylide intermediate 106, which is in equilibrium with vinylidene lOS (Scheme 9.18). Organic base deprotonates the metal center in the course of nucleophilic displacement and removes HI from the reaction medium. Once alkenylidene complex 107 is generated, it undergoes [2 + 2]-cycloaddition and subsequent breakdown to release cycloisomerized product 110 in the same fashion as that discussed previously (Scheme 9.4). Deuterium labeling studies support this mechanism. 

In research on ketones as nucleophiles, Hashmi et al. studied the cycloisomerization of propargyl ketones. Reaction took place by nucleophilic attack of the ketone followed by aromatization to furan [28] (Scheme 8.25). 

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... 

In particular, the copper-promoted cycloisomerization of unsaturated alkynes bearing a stabilized nucleophile was found to be a general method that allows the cyclization of a variety of 5-acetylenic-stabilized carbanions by using catalytic amounts of base and copper [52]. This copper-catalyzed reaction was applied to disubstituted alkynes such as 43 and converted to the (Z)-isomer 44 as a single product (Scheme 18). This result further supports... 

The comparison of intramolecular carbopalladation reactions of allenes and alkenes outlined in Schemes 9-5 and 9-6 illustrates that not every transition metal catalyzed ring closure necessarily involves a template effect. Others, however, clearly benefit from it. A prototype example is the palladium catalyzed cycloisomerization of alkenyl epoxides carrying distal pre-nucleophiles [38, 39], representing one variant of the famous Tsuji-Trost allylation [40]. 

A number of cycloisomerization reactions involving a,P-unsaturated propargyl ketones have also been employed in the synthesis of substituted fiirans. These reactions are generally catalyzed by either gold(IIl) or copper(I), and are believed to proceed through an oxonium ion intermediate, which is subsequently trapped by a nucleophile as illustrated below. 

The corresponding reaction of but-3-yn-l-ols or pent-4-yn-l-ols with primary or secondary alcohols in the presence of catalytic amounts of Ph3PAuBF4 and p-TsOH afforded tetrahydrofuranyl ethers (Scheme 4-76). This tandem 5-endo-cycloisomerization/hydroalkoxylation proceeds via 2,3-dihydrofurans, which then undergo an intermolecular Bronsted acid-catalyzed addition of the external alcohol. The transformation is not restricted to internal alkynols but can be applied to terminal acetylenes as well. Application of the method to the s thesis of bicyclic heterocycles with a P-lactam structure was reported recently.Under the same conditions, epoxyalkynes undergo a sequence of epoxide opening, 6-exo-cycloisomerization, and nucleophilic addition to afford tetrahydropyranyl ethers. In a closely related transformation, cyclic acetals were obtained from alk-2-ynoates bearing a hydroxy group in 6- or 7-position by treatment with AuCU and MeOH. ... 

The cycloisomerization of a-allenyl ketones to the corresponding substituted furans was the first example of a gold-catalyzed addition of an oxygen nucleophile to an allene (Scheme 4-86). Traditionally, silver or palladium catalysts were employed for cyclizations of this type advantages of gold catalysis incluiie shorter reaction times, milder conditions, an or lower catalyst loadings. Variable amounts of... 

Schmalz and coworkers recently reported an interesting and highly efficient Au(I)-catalyzed cascade cycloisomerization of geminal acyl-alkynylcydopropanes 102 into the densely functionalized furans 103(Scheme 8.41) [160]. This reaction proceeded under very mild reaction conditions and a variety of nucleophiles, such as alcohols, including tert-butanol, phenols, acetic acid, 2-pyrrolidone, and indole could be employed. In addition, this transformation was shown to be catalyzed by Cu(II)-and Ag-trifiates, albeit with somewhat lower efficiency. Two mechanisms, including concerted and stepwise formation of a furan ring, were proposed by the authors for this cascade transformation (Scheme 8.42). 

An extension of Hashmi s Au(III)-catalyzed phenol synthesis [81] to furan substrates 9 bearing an additional alkyne moiety allowed the preparation of C6-C7-heterofused benzofuran 11 (Scheme 9.3) [82]. According to the proposed mechanism, the Au(III)-catalyzed arene formation reaction generates o-alkynylphenol 10. A subsequent Au(III)-catalyzed cycloisomerization of the latter, following the general mechanism for an intramolecular nucleophilic addition of heteroatom to transition metal-activated carbon-carbon multiple bonds, gives 11 (Scheme 9.3). 

Furthermore, Yamamoto and coworkers illustrated that o-(alkynyl)phenylisocya-nates 159 could also be efficiently employed in a similar Pt( 11)-catalyzed cycloisomerization reaction, serving as surrogates of the corresponding carbamate derivatives 160, to provide N-(alkoxycarbonyl)indoles 161 in moderate to excellent yields (Scheme 9.60) [219]. It is believed that a dual-role catalysis with the Pt(II) salt first triggered the initial intermolecular nucleophilic addition of alcohol to isocyanate 159, affording the key transient carbamate 160, which, upon a subsequent Pt(II)-catalyzed 5-endo-dig cyclization, generated the desired product 161. 

Movassaghi and Hill developed a ruthenium-catalyzed cycloisomerization of 3-azadienynes to the corresponding pyridines [11]. The alkynyl imines were produced from a variety of iV-vinyl and iV-aryl amides by amide activation and nucleophilic addition of copper(I) (trimethylsilyl) acetylide sequence reaction. Then by Ru-catalyzed protodesilylation and cycloisomerization, the desired pyridine derivatives were formed selectively in good to excellent yields (Scheme 2.7). For the reaction mechanism, C-silyl metal vinylidene was found to be the key intermediate. 

The cycloisomerization of 1,6-enynes is one of the most widely studied and developed reaction within gold catalysis. In the absence of nucleophiles, a variety of products can be obtained (Scheme 1.14) [8, 159-164]. 

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... 

Alkenes are also capable of acting as nucleophiles and can add intramolecularly to ruthenium vinylidenes. Liu and coworkers described the TpRu(PPh3) (CH3CN)2PF6-catalyzed cycloisomerization of substituted ortlio-alkynylethynyl-styrenes to give different naphthalenes or indenes depending on the nature of the alkene substituents (Scheme 29) [142,143]. In all cases the reaction begins with the formation of the ruthenium vinylidene I. Subsequent 6-endo-dig (path a) or 5-endo-dig (path b) cyclization by nucleophilic attack of the alkene moiety would afford ruthenium species II and HI, respectively. When monosubstituted iodoalkenes... 

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