Intramolecular reactions terminal alkynes

Transition-metal-mediated C—X bond formation by intramolecular reactions with alkynes is a powerful strategy for the construction of heteroarene rings such as pyridines, pyrroles, and furans. Because of the wide availability of Sonogashira coupling of various haloarenes with terminal alkynes, these transformations provide efficient routes to synthesize fused heteroarenes, including isoquinolines, indoles, and benzofurans. In this chapter the construction of aromatic rings by transition-metal-catalyzed or transition-metal-mediated intramolecular C—X bond formation between C—X or X—H and alkynes is described. As shown in Scheme 19.1, Section... 

The novel intramolecular reaction of the alkenyl bromide with the terminal alkyne in 328, followed by intramolecular Diels-Alder reaction, afforded the highly strained dynemicin A structure 329 in one stepf237]. 

The formation of disubstituted alkynes by coupling of terminal alkynes, followed by intramolecular attack of an alcohol or amine, is used for the preparation of benzofurans and indoles. The benzo[il)]furan 356 can be prepared easily by the reaction of o-iodophenol with a terminal alkyne[262]. The 2-substituted indole 358 is prepared by the coupling of 2-ethynylaniline (357) with aryl and alkenyl halides or triflates, followed by Pd(ll)-catalyzed cycliza-tion[263]. 

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],... 

Oshima et al. explored a cationic rhodium-catalyzed intramolecular [4+2] annulation of l,3-dien-8-ynes in water in the presence of sodium dodecyl sulfate (SDS), an anionic surfactant.132 When the substrate l,3-dien-8-yne was a terminal alkyne, the reaction provided an inter-molecular [2+2+2] product (Eq. 4.68). In water, a reactive cationic rhodium species was formed by the dissociation of the Rh-Cl bond in the presence of SDS. The SDS forms negatively charged micelles, which would concentrate the cationic rhodium species (Scheme 4.15). 

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... 

Trost and coworkers [131] synthesized oxaheterocycles by a Pd-catalyzed addition of terminal alkynes onto hydroxyalkynoates, followed by an intramolecular addition of the hydroxyl functionality on the triple bond. Simple lactonization may take place as a side reaction. 

Denmark pursued intramolecular alkyne hydrosilylation in the context of generating stereodefined vinylsilanes for cross-coupling chemistry (Scheme 21). Cyclic siloxanes from platinum-catalyzed hydrosilylation were used in a coupling reaction, affording good yields with a variety of aryl iodides.84 The three steps are mutually compatible and can be carried out as a one-pot hydro-arylation of propargylic alcohols. The isomeric trans-exo-dig addition was also achieved. Despite the fact that many catalysts for terminal alkyne hydrosilylation react poorly with internal alkynes, the group found that ruthenium(n) chloride arene complexes—which provide complete selectivity for trans-... 

Although terminal acetylenes themselves do not form stable titanium—acetylene complexes upon reaction with 1, the reaction with terminal alkynes having a keto group at the 5- or y-position induces an intramolecular cyclization, apparently via the above titanium-acetylene complex to afford the four- and five-membered cycloalkanols, as shown in Eq. 9.6 [28]. 

When the terminal alkynes 96 are treated with the trimethylsilylalkyne 97 in the presence of HfCl4 as a Lewis acid, the silylated vinylallenes 98 are produced in acceptable yields. In an intramolecular variant of this process, 100 was obtained from the diyne 99 [32]. Vinylallenes, incorporated into a cyclic framework and hence of restricted conformational mobility, are of interest for photochemical studies [33] and are among the photoproducts in ring-enlargement reactions of polycyclic allenes [34]. 

With the bulky metallo-organic Pd(II) catalyst 98, on the other hand, selective formation of 99 was possible here functional groups are tolerated that would react with an Ag(I) catalyst (for example, terminal alkynes, alkyl chlorides, alkyl bromides and alkyl iodides) [59]. With l,n-diallenyl diketones (100), easily accessible by a bidirectional synthesis, up to 52-membered macrocycles (101) could be prepared in an end-group differentiating intramolecular reaction (Scheme 15.26) [60], For ring sizes lager than 12 only the E-diastereomer is formed overall yields of the macrocydes varied between 17 and 38%. Only with tethers shorter than 11 carbon atoms could the Z-diastereomer of the products be observed, a stereoisomer unknown from the intermolecular dimerization reactions of 96. 

When a terminal alkyne is offered intramolecularly as in allenyne 108, the highly substituted phenols 110 were formed (Scheme 15.29) [65]. The reaction proceeds through an initial isomerization to the corresponding furan 109, which could be proved by the direct use of that furans [66-68],... 

The Pd-catalyzed electro-cleavage of the C—O bond of allyl aryl ether proceeds smoothly in a DMF-Bu4NBp4-(Mg)-(Stainless Steel) system, giving depro-tected products in 73 99% yield [437]. The sp-sp intermolecular coupling reaction with the Pd water-soluble catalyst prepared in situ from Pd(II) acetate and sul-fonated triphenylphosphine in an MeCN-H2O system yields diynes in 45 65% yields [438]. Similarly, the sp -sp coupling of 2-iodophenols or 2-iodoanilines and terminal alkynes followed by intramolecular cyclization gives indol and furan... 

This catalyst system was the first to utilize both terminal alkynes and olefins in the intramolecular reaction. Although a mechanistic rationale for the observed stereoselectivity was not offered, the formation of the single stereoisomer 26 may be rationalized through the diastereotopic binding of the rhodium complex to the diene moiety (Scheme 12.3). This facial selective binding of the initial ene-diene would then lead to the formation the metallacycle III, which ultimately isomerizes and reductively eliminates to afford the product [14]. 

This reaction achieves an umpolung cyclization in vhich a terminal alkyne is hydrated and undergoes an intramolecular Michael addition according to the mechanism depicted in Scheme 6.34. 

The formation of vinylcarbamates is restricted to secondary amines and also to terminal alkynes, which is in line with the formation of a metal vinylidene intermediate. It is noteworthy that even starting from secondary amines, the presence of a hydroxy group in propargylic alcohols drove the reaction towards the formation of fi-keto carbamates, resulting from initial Markovnikov addition of the carbamate anion to the triple bond followed by intramolecular transesterification [10]. The proposed general catalytic cycle which applies for the formation of vinylic carbamates is shown in Scheme 10.2. 

The isomerization of terminal epoxyalkynes into furans catalyzed by RuCl(Tp)(PPh3) (MeCN) inthe presence of Et3N as abase at 80 °C in 1,2-dichloroethaneis explained by a related intramolecular nucleophilic addition of the oxygen atom of the epoxide to the a-carbon atom of a ruthenium vinylidene intermediate, as shovm by deuteration in the 3-position of the furan (Scheme 10.10) [45]. This reaction is specific for terminal alkynes and tolerates a variety of functional groups (ether, ester, acetal, tosylamide, nitrile). 

The alkenyl iodide or triflate 369 reacts in the absence of Cul with two moles of terminal alkyne 370 to form the substituted fulvene 371. The reaction can be explained by the intermolecular insertion of the alkyne twice, followed by the intramolecular insertion of the alkene, and / -elimination to form the fulvene 371(268]. 

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