Catalytic cyclization alkynes

We also studied the catalytic cyclization of such epoxide/alkyne functionalities via the selective formation of ruthenium-2-iodovinylidene 77 or it-iodoalkyne 78 intermediate in suitable solvents [26]. The former was preferentially generated in DMF whereas the latter was the dominant species in benzene, as depicted in Scheme 6.27. 

Tanaka and have independently developed effective protocols for the catalytic cyclization/borylsilylation of diynes to form bis(functionalized) dialkylidene cyclopentanes. As an example of the Tanaka procedure, reaction of 1,6-heptadiyne with borylsilane 99 catalyzed by a 1 2 mixture of Pd2(DBA)3 and ETPO (ETPO = 4-ethyl-2,6,7-trioxa-l-phosphabicyclo[2.2.2]octane) at 110°G for 2h gave 100 in 81% yield (Equation (64)). As an example of the Ito procedure, reaction of 1,7-octadiyne with dimethylphenylsilylpinacolborane, catalyzed by the Ni(0) complex generated in situ from a 1 2 2 mixture of Ni(acac)2, DIBAL-H, and P(/ -Bu)3 in toluene at 110°C, gave the bis(functionalized) dialkylidene cyclohexane 101 in 55% yield (Equation (65)). " Tanaka s protocol was also effective for the cyclization/borylsilylation of 1,6-enynes. As an example, reaction of dimethyl allylpropargylmalonate with 99 catalyzed by Pd2(DBA)3/ETPO gave the bis(functionalized) alkylidene cyclopentane 102 in 84% yield with exclusive delivery of the borane to the alkyne moiety of the enyne (Equation (66)). ... 

Unsaturated metallacycles have also had a fascinating history. Often these are readily formed by the coupling of alkyne units and may be involved in the catalytic cyclization of alkynes. There are numerous examples of structurally characterized metallacyclopentadienes, and even some examples of metal-lacycloheptatrienes and 4-benzene complexes (77). More recently metal-lacyclobutadienes have been implicated as the active intermediates in alkyne... 

Oppolzer, W., Robyr, C. Synthesis of ( )-hirsutene by a catalytic allylpalladium-alkyne cyclization/carbonylation cascade. Tetrahedron 1994, 50, 415 24. 

Cyclization of alkynes also involves nickel-alkyne intermediates, and bis(alkyne)nickel species have been proposed as intermediates in the catalytic cyclization of diynes with m situ generated benzynes to give naphthalene derivatives, as shown in Scheme 2. A related, intermolecular [2+2+2]-cycloaddition of an alkene and two alkynes is also catalyzed by iu situ generated Ni(0) species the use of chiral, monodentate oxazoline ligands renders this process enantioselective (Scheme 3). ... 

In an effort to identify a more stereoselective route to dihydroagarofuran (15), trimethylsilylated alkyne 17 was utilized as a substrate for radical cyclization (Scheme 2). Treatment of 17 with a catalytic amount of AIBN and tri-n-butyltin hydride (1.25 equiv) furnishes a mixture of stereoisomeric vinyl silanes 18 (72% combined yield) along with an uncyclized reduction product (13% yield). The production of stereoisomeric vinyl silanes in this cyclization is inconsequential because both are converted to the same alkene 19 upon protodesiiyiation. Finally, a diastereoselective di-imide reduction of the double bond in 19 furnishes dihydroagaro-... 

Hexacarbonyldicobalt complexes of alkynes have served as substrates in a variety of olefin metathesis reactions. There are several reasons for complex-ing an alkyne functionality prior to the metathesis step [ 125] (a) the alkyne may chelate the ruthenium center, leading to inhibition of the catalytically active species [125d] (b) the alkyne may participate in the metathesis reaction, giving undesired enyne metathesis products [125f] (c) the linear structure of the alkyne may prevent cyclization reactions due to steric reasons [125a-d] and (d) the hexacarbonylcobalt moiety can be used for further transformations [125c,f]. 

The guanidinate-supported titanium imido complex [Me2NC(NPr02l2Ti = NAr (Ar = 2,6-Me2C6H3) (cf. Section IILB.2) was reported to be an effective catalyst for the hydroamination of alkynes. The catalytic activity of bulky amidinato bis(alkyl) complexes of scandium and yttrium (cf. Section III.B.l) in the intramolecular hydroamination/cyclization of 2,2-dimethyl-4-pentenylamine has been investigated and compared to the activity of the corresponding cationic mono(alkyl) derivatives. 

Since this scheme regenerates the original coordinatively unsaturated Ti+2 centers upon desorption of the aromatic, it could, in principle, represent a catalytic cycle for heterogeneous alkyne cyclization. The present study reports a test of that h3T>othesis—the feasibility of catal5hic cyclotrimerization—on a reduced Ti02 surface in UHV. 

Although the titanium-based methods are typically stoichiometric, catalytic turnover was achieved in one isolated example with trialkoxysilane reducing agents with titanocene catalysts (Scheme 28) [74], This example (as part of a broader study of enal cyclizations [74,75]) was indeed the first process to demonstrate catalysis in a silane-based aldehyde/alkyne reductive coupling and provided important guidance in the development of the nickel-catalyzed processes that are generally more tolerant of functionality and broader in scope. 

Chiu et al. developed a catalytic reductive aldol cyclization of alkyne-diones such as 115 and 117 using [Ph3PCuH]6 (10mol%) as catalyst and polymethylhydrosiloxane PMHS (200 mol %) as terminal reductant. The... 

Palladium complexes are effective catalysts for the reductive cydization of enyne substrates [53,54], The first report of catalytic cydization of 1,6- and 1,7-enynes 115a,b to cyclopentane 116a and cyclohexane 116b derivatives appeared in 1987 (Eq. 19) [70]. The authors proposed that the Pd(II) species 117 forms by oxidative addition of acetic acid to Pd(0) (Scheme 25). Complex 117 hydrometallates the alkyne to give 118, which cyclizes to provide... 

In a reaction similar to the (>-alkoxide elimination reactions seen with zir-conocenes, catalytic Rh(OH)(cod)2 and 2 eq. of arylboronic acids gave cyclic products 165 from enynes 166 (Scheme 35) [100]. In this reaction, transmet-allation of Rh - OR with B - Ph gave Rh - Ph species 167, which inserted into the alkyne, cyclized to 168, and finally underwent [>-alkoxidc elimination to provide Rh-OCH3. This reaction is limited to the formation of five-membered rings, but it can also undergo cascade type reactions of enediynes to give multicyclic products [100]. 

This chemistry has been extended to terminal alkynes by first carrying out the cross-coupling of the alkyne and aryl halide using catalytic amounts of Pd and Cu salts and then employing catalytic amounts of Cul to affect the cyclization (Scheme 5).6... 

One drawback to this alkyne annulation chemistry is that it requires either symmetrical alkynes or unsymmetrical alkynes in which the two substitutents on the internal alkyne are sterically quite different or else one obtains mixtures of regioisomers. One way to overcome this problem is to prepare the corresponding arylalkyne through catalytic Pd/Cu chemistry and then effect electrophilic cyclization using organic halides and a Pd catalyst (Scheme 8).9... 

The cyclobutenone 70 is transformed to the r/4-vinylketene complex 72 with (t/5-indenyl)Co(PPh3)2 71. The vinylketene complex 72 undergoes cyclization with alkynes to produce the corresponding phenols 73. FeCl3 oxidation of the (2-phenylvinyl)ketene complex, however, leads to the naphthol 74. A catalytic synthesis of phenols via the vinylketene intermediates 72 is achieved by the use of Ni(COD)2 as a catalyst [36]. (Scheme 26)... 

Some early examples involving microwave-assisted solvent-free Sonogashira couplings using palladium powder doped on alumina/potassium fluoride as catalyst were described by Kabalka and coworkers (Scheme 4.4) [150], In addition, this novel catalytic system has been used in microwave-assisted solvent-free Sonogashira coupling-cyclization of ortho-iodophenol with terminal alkynes, and similarly of ortho-ethynylphenols with aromatic iodides, to generate 2-substituted benzo[b]furans... 

Catalytic quantities of transition- or non-transition metals promote the cyclization of 2-alkynynylbiphenyl analogs to phenanthrene or fulvene analogs. The mechanism is thought to involve activation of the alkyne by metal coordination, prior to cyclization (Equations (179) and (180)).146... 

The Conia-ene reaction is a thermal cyclization of an alkyl ketone with an alkyne to give the corresponding a-vinylated ketone.98 The catalytic version of this reaction has been reported to generalize the process to more functionalized substrates.99 The intramolecular carbocupration of alkyne 94 has been investigated under basic conditions in the presence of a catalytic amount of copper iodide (Scheme 28).100 The cyclic product 95 is obtained in high yield. 

To probe the reaction mechanism of the silane-mediated reaction, EtjSiD was substituted for PMHS in the cyclization of 1,6-enyne 34a.5 The mono-deuterated reductive cyclization product 34b was obtained as a single diastereomer. This result is consistent with entry of palladium into the catalytic cycle as the hydride derived from its reaction with acetic acid. Alkyne hydrometallation provides intermediate A-7, which upon cw-carbopalladation gives rise to cyclic intermediate B-6. Delivery of deuterium to the palladium center provides C-2, which upon reductive elimination provides the mono-deuterated product 34b, along with palladium(O) to close the catalytic cycle. The relative stereochemistry of 34b was not determined but was inferred on the basis of the aforementioned mechanism (Scheme 24). 

Catalytic cycles involving both alkyne hydrorhodation and silylrhodation are proposed.613 However, mechanistic studies performed on related hydrogen-mediated enyne reductive cyclizations (vide supra) suggest oxidative cyclization of the enyne followed by hydrosilylytic cleavage of the resulting metallacycle via cr-bond metathesis is also plausible (Scheme 27). 

The inter- and intramolecular catalytic reductive couplings of alkynes and aldehydes recently have experienced rapid growth and are the topic of several recent reviews.5 h-8k 107 With respect to early transition metal catalysts, there exists a single example of the catalytic reductive cyclization of an acetylenic aldehyde, which involves the titanocene-catalyzed conversion of 77a to ethylidene cyclopentane 77b mediated by (EtO)3SiH.80 This process is restricted to terminally substituted alkyne partners (Scheme 53). 

The very first example of the catalytic reductive cyclization of an acetylenic aldehyde involves the use of a late transition metal catalyst. Exposure of alkynal 78a to a catalytic amount of Rh2Co2(CO)12 in the presence of Et3SiH induces highly stereoselective hydrosilylation-cyclization to provide the allylic alcohol 78b.1 8 This rhodium-based catalytic system is applicable to the cyclization of terminal alkynes to form five-membered rings, thus complementing the scope of the titanocene-catalyzed reaction (Scheme 54). 

Recently, the silane-mediated reductive cyclization of activated alkynes with tethered ketones using Stryker s reagent as a catalyst was reported.112,90b Alkynyl ketone substrate 84a was treated with a catalytic amount of Stryker s reagent in the presence of polymethylhydrosiloxane (PMHS) to afford the cA-fused hydrindane 84b as a single diastereomer. This method is applicable to both five- and six-membered ring formation, but often suffers from competitive over-reduction of the reaction products (Scheme 59). 

The key features of the catalytic cycle are trapping of the radical generated after cycliza-tion by an a,P-unsaturated carbonyl compound, reduction of the enol radical to give an enolate, and subsequent protonation of the titanocene alkoxide and enolate. The diaster-eoselectivity observed is essentially the same as that achieved in the simple cyclization reaction. An important point is that the tandem reactions can be carried out with alkynes as radical acceptors. The trapping of the formed vinyl radical with unsaturated carbonyl compounds occurs with very high stereoselectivity, as shown in Scheme 12.21. 

As an extension of the Heck reaction, Pd-catalyzed hydroarylation of alkynes and alkenes continnes to attract high level of research interest in simple couphng processes and in cyclization reactions. The use of this type of transformation as part of a domino reaction will be of increasing interest. The research in the field of domino reactions is attracting considerable attention in synthetic organic chemistry since it enables the rapid assembly of complex molecirles in one-pot processes. Very elegant examples of palladium-catalyzed cascade processes where a single catalytic cycle entails several sequential bond transformations have been recently reported [la, b, 2a, b, c]. 

Particularly interesting is the reaction of enynes with catalytic amounts of carbene complexes (Figure 3.50). If the chain-length between olefin and alkyne enables the formation of a five-membered or larger ring, then RCM can lead to the formation of vinyl-substituted cycloalkenes [866] or heterocycles. Examples of such reactions are given in Tables 3.18-3.20. It should, though, be taken into account that this reaction can also proceed by non-carbene-mediated pathways. Also Fischer-type carbene complexes and other complexes [867] can catalyze enyne cyclizations [267]. Trost [868] proposed that palladium-catalyzed enyne cyclizations proceed via metallacyclopentenes, which upon reductive elimination yield an intermediate cyclobutene. Also a Lewis acid-catalyzed, intramolecular [2 + 2] cycloaddition of, e.g., acceptor-substituted alkynes to an alkene to yield a cyclobutene can be considered as a possible mechanism of enyne cyclization. 

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