Intermolecular Coupling of Alkynes

The first example involves the dimerization of terminal alkynes. It takes place via initial activation of the alkyne C-H bond, but several examples involve a vinylidene intermediate. In most cases, conjugated enynes are obtained by ruthenium-catalyzed tail-to-tail dimerization [84,85], as in the following example [85] (Eq. 63). 

Butatrienes were formed when ferf-butylacetylene was used in the presence of RuH2(CO)(PPh3)3 [86] (Eq. 64). 

These reactions constitute only a few examples of ruthenium vinylidene in catalysis, a topic of increasing importance in organic synthesis that is presented in the chapter Ruthenium Vinylidenes and Allenylidenes in Catalysis of this volume. 

Interestingly, the in situ generated ruthenium acetylide complex C5Me5(PPh3)Ru-C=CPh catalyzed the cross-coupling reaction of terminal and internal alkynes to yield functionalized enynes [87] (Eq. 65). A coordinatively unsaturated enynyl complex is postulated as an intermediate in this mechanism. 

The linear coupling reaction of acetylene and acrylonitrile afforded 2,4,6-hep-tatrienenitrile by dimerization of acetylene and insertion of one molecule of acrylonitrile [88] (Eq. 66). The reaction involves the formation of a ruthena-cyclopentadiene complex, which also catalyzed the reaction. 

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Scheme 1.6 Zirconocene-mediated intermolecular coupling of alkyne with ethylene or two...

Takahashi T, Xi C, Xi Z et al (1998) Selective intermolecular coupling of alkynes with nitriles and ketones via p,p carbon-carbon bond cleavage of ztrconacyclopentenes. J Org Chem 63 6802-6806... 

Zirconocene or titanocene mediated intramolecular cyclization reactions of enynes followed by CO insertion into their corresponding five-membered metallacycles led to the formation of bicyclic cyclopentenones (Eqs.40,41) [37,38]. Intermolecular coupling of alkynes, alkenes, and CO mediated by zirconocene or titanocene affording cyclopentenone derivatives have also been achieved (Eq. 39) [18, 39, 40]. It is noteworthy that, in order to obtain the desired cyclopentenones from the reaction of zirconacyclopentenes with CO, termination of the reaction mixture with I2 is necessary. Alcohols are normally formed if the reaction mixture is treated with aqueous acid. However, in case of titanacy-clopentenes, quenching with 3 N HCl gave cyclopentenones exclusively [18]. 

The benzene derivative 409 is synthesized by the Pd-catalyzed reaction of the haloenyne 407 with alkynes. The intramolecular insertion of the internal alkyne, followed by the intermolecular coupling of the terminal alkyne using Pd(OAc)2, Ph3P, and Cul, affords the dienyne system 408, which cyclizes to the aromatic ring 409[281]. A similar cyclization of 410 with the terminal alkyne 411 to form benzene derivatives 412 and 413 without using Cul is explained by the successive intermolecular and intramolecuar insertions of the two triple bonds and the double bond[282]. The angularly bisannulated benzene derivative 415 is formed in one step by a totally intramolecular version of polycycli-zation of bromoenediyne 414[283,284],... 

Trost and others have extensively studied the ruthenium-catalyzed intermolecular Alder-ene reaction (see Section 10.12.3) however, conditions developed for the intermolecular coupling of alkenes and alkynes failed to lead to intramolecular cycloisomerization due the sensitivity of the [CpRu(cod)Cl] catalyst system to substitution patterns on the alkene.51 Trost and Toste instead found success using cationic [CpRu(MeCN)3]PF6 41. In contrast to the analogous palladium conditions, this catalyst gives exclusively 1,4-diene cycloisomerization products. The absence of 1,3-dienes supports the suggestion that the ruthenium-catalyzed cycloisomerization of enynes proceeds through a ruthenacycle intermediate (Scheme 11). 

For selected reviews encompassing intra- and intermolecular direct reductive coupling of alkynes to carbonyl partners, see [151-158]... 

In a similar way, a novel route for synthesis of cr,/ -unsaturated amide 242 is explored via intermolecular coupling of four components, that is, alkyne, hydrosilane, amine, and GO (Equation (41)). All of these components are assembled in the ordered manner with the assistance of an Rh complex. Pyrrolidine as a nucleophile gives the best results. None of the alcohols can participate in a similar transformation. 

Intermolecular coupling of ketyls with alkynes has proven successful in some instances [63]. Using this protocol, allylic alcohols are typically generated in good yields, but often as a mixture of E/Z isomers (Eq. 54). Additionally, some type of activation of the triple bond is necessary. In particular alkynyloxiranes have proven to be very useful substrates for the generation of to 2,3-pentadiene-l,5-diols (Eq. 55)... 

The use of enals in nickel-promoted intermolecular couplings was initially limited to stoichiometric [3 -1- 2]/[2 + 1] cycloadditions [26], This limitation was overcome with the development of a Ni(COD)2/PCy3/R3SiH/THF reaction system, whereby the reductive coupling of alkynes and enals was achieved to afford a highly chemo- and stereo-selective synthesis of Z-enol silanes (Scheme 8.6) [27]. 

Intermolecular reductive couplings of alkynes and enoates are not yet achievable. 

The dearest empirical evidence for the productive involvement of an 1] , O-bound nickel enolate comes from the intermolecular reductive coupling of alkynes and enals (Scheme 8.9) [27]. The extremely high levels of Z-isomer stereoselectivity (>98 2) can best be rationalized via the metallacycle intermediate 5 which undergoes o-bond metathesis to afford nickel hydride 6, followed by reductive eUmina-tion to yield the Z-selective enol silane product 7. A mechanism consisting of a nickel Jt-allyl species would not be expected to lead to high selectivities of Z-enol silanes, and has been imphcated in reactions leading to the selective production of T-enol silanes [28],... 

The combination of Ni(COD)2/NHC complexes with EtsSiH as the reducing agent has also proved to be effective in intermolecular couplings of aldehydes and alkynes (Scheme 9) [21]. A broad range of substrates underwent couplings, including aromatic, non-aromatic, and terminal alkynes as well as branched, unbranched, and aromatic aldehydes. The regioselectivity with... 

Scheme 10.67 Proposed model to explain the regioselectivity in the intermolecular coupling of internal alkenes with asymmetrically substituted alkynes [52].

As an intermolecular version of the reaction of type IV of Scheme 15, in the presence of halide, the Pd(II)-catalyzed coupling of alkynes and a,/S-unsaturated carbonyls yields the conjugate addition products, -y, unsaturated carbonyls (Scheme 20). 

With suitably placed hydroxy and ester funcdonal groups, tandem lactonization can ensue (Scheme 11.91). The intermolecular coupling of two alkynes with this system is also possible (Scheme 11.92), provided that only one alkyne is terminal, and the acceptor alkyne is electron poor, otherwise extensive self-coupling of the alkynes may result. " ... 

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