6-Endo-dig product

When 174 reacted with KOH in aqueous acetonitrile, the 5-exo-trig product (175) was favored over formation of the 6-endo-trig product (176) by a ratio of 18 1. The alkynyl derivative (177) reacted 10 times slower than 174 and gave only the 5-exo-dig product (178). The 6-endo-dig product (179) was not isolated from the reaction, although the actual product distribution was probably > 100 1 favoring 178 over 179. It was suggested that sp atoms generally prefer the exo mode of attack to the endo mode. ... 

In the same report <01BMCL211>, similar acetylide adducts 106 were formed in ihe same manner. After demethylation, the resultant phenol cyclized onto the alkynes using either NaOMe or DBU as the base promoter. All of the cyclizalion processes afforded exclusively the 6-endo-dig products 107. 

In contrast with the reaction of 4-yn-l-ols, both 6-endo-dig and 5-exo-dig cyclization modes were observed in the Pdl2/KI-catalyzed oxidative car-bonylation of2-(l-alkynylbenzyl)alcohols (Eq. 43) [120]. The preferential formation of the lH-isochromene or the 1,3-dihydroisobenzofuran derivative turned out to be dependent on the substitution pattern of the substrate. In particular, lH-isochromenes were obtained as the main reaction products when the triple bond was substituted with an alkyl group and with a primary alcoholic group, while the isobenzofurans were preferentially formed with a tertiary alcoholic group and when the triple bond was terminal or conjugated with a phenyl group. 

Stabilized ketene 6S. For l, 2 -disubstituted epoxide, species 6S undergoes 6-endo-dig electrocyclization (path b) [24] to form the six-membered ketone 66, ultimately giving naphthol products. l, 2, 2 -Trisubstituted epoxide species 6S undergoes 5-endo-dig cyclization (path a) to give the ketone species 67, finally producing l-alkylidene-2-indanones. The dialkyl substituent of the epoxide enhances the 5-endo-dig cyclization of species 65 via formation of a stable tertiary carbocation 67. We observed similar behavior for the cyclization of (o-styryl)ethynylbenzenes [15, 16]. Formation of 2,4-cyclohexadien-l-one is explicable according to 6-endo-dig cyclization of a ruthenium-stabilized ketene, vhich ultimately afforded the observed products [25]. 

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). 

A facUe synthesis of 3,4-disubstituted isocoumarins and their benzologues is based on the Pd-catalysed annulation of internal alkynes by 2-iodobenzoate esters (Scheme 27). Tri- and tetra- substituted pyran-2-ones are also available by this route <99JOC8770>. 3-Substituted isocoumarins result from the Pd-catalysed 6-endo-dig cyclisation of 2-ethynylbenzoic acids. The 5-exo-dig products, phthalides, are also formed when there is a terminal bulky group on the alkyne moiety <99S1145>. 

Under the same conditions of NaH/THF, the ester 3 gave ltf-2-benzopyran derivative 5 in 60% yield, apparently by 6-endo-dig ring closure. Closer study of this latter transformation, however, revealed that the initial product of base-induced cyclisation was in fact the isobenzofuran 4, which was extremely labile, and that 5 was formed from 4 by acid-catalysed rearrangement during work-up of the reaction mixture. 

Whereas acid-catalysed cyclization of (21) undergoes the 6-endo-dig cyclization to afford (23), as discussed earlier, application of a base results in the formation of (22) as a product of 5-exo-dig ring closure.39... 

A tungsten-catalyzed cycloisomerization of the D-ribose-derived alkynyl alcohol 181 provides a 6-endo-dig cyclization route to 3,4-dihydropyrans. Excellent endo-modc selectivity, and hence minimal tetrahydrofuran production is... 

Z)-2-En-4-ynoic acids 624 undergo ZnBr2 promoted 6-endo-dig lactonizations to afford 2//-pyran-2-ones 625 as the major product along with the alternate 5-exo-dig lactonization product 626 (Equation 251) <2002TL5673>. 

Iridium(m) hydrides catalyze a 6-endo-dig cyclization of ortho-alkynyl benzoic acids to afford isocoumarins (Equation 323) <2005OL5437>. Likewise, the intramolecular cyclization of ortho-alkynyl benzoic acids can be catalyzed by palladium(ll) and silver(ll) to afford isocoumarins as the major product along with formation of the 5-endo-dig cyclization product (Equation 323) <1999S1145, 2000T2533>. 

With gold(III), no conversion was observed (Table 12.16, entry 1) the coordina-tively saturated gold complex gave a low yield of the 6-endo-dig cyclization product (entry 2). The cationic gold complex with a free coordination site gives an excellent yield with the same selectivity (entry 3) the same is true for AgSbF6 alone (entry 4). But this is not true for all silver catalysts with a systematic increase in the pK.A value of the conjugate acid of the silver counterion, increased portions of the 5-exo-dig product were produced (entries 5 and 6). 

With a sulfone capable of giving 5-exo-dig vs. 6-endo-dig, or 6-exo-dig vs. 1-endo-dig cyclisations, mixtures are obtained, with exo cyclisation dominating. With alkynyl sulfides, solely exo products are obtained. 

Cyclization. The modes of Ag(I)-catalyzed cycUzation of 2-alkynyl-3-formyl-quinolines in MeOH have been correlated with tbe pKa values of tbe silver salts used. Both 5-exo-dig and 6-endo-dig pathways are equally favored in the presence of AgOAc, products arising from the former pathway predominate in using more basic silver salts (e.g., Ag20, AgO). 

As shown in Scheme 43, treatment of o-ethynylbenzoic acids with PdCl2(MeCN)2 catalyst in THF results in the 6-endo-dig cyclization to give 3-substituted isocoumarins as the major product. ... 

Cationic gold(I) complexes favor the formation of six- and seven-membered rings by 6-endo-dig, 6-exo-dig, and 1-exo-dig cyclization. However, indoloazo-cines V are selectively obtained with AuCls via %-endo-dig cyclization. Internal alkynes are also active in the intramolecular process leading to allenes VI and tetracyclic compounds VII (Scheme 1.10). In Scheme 1.10, the proposed mechanism for the formation of the different products is shown. Nucleophilic attack of the indole on the activated alkyne affords intermediate VIII, which arises from a 1,2-shift of the initially formed seven-membered ring iminium cation. Proton loss from VIII forms azocine V, while protonation of intermediate VIII leads to an open intermediate IX, which rearranges to the final allene VI or the tetracyclic compound VII via Michael-type addition of the XH group in intermediate X. 

An intramolecular hydroarylation of A-arylpropiolamides through alkyne activation affords 6-endo-dig cyclization products, while the intramolecular hydroarylation through aromatic C—H bond activation gives 5-exo-dig cyclized products (Scheme 18.46). Pd(OAc)2-catalyzed intramolecular hydroarylation of N-arylpropiolamides in the presence of DPPF (l,l -bis(diphenylphosphino)ferrocene)... 

Messerle and coworkers [99-103] in particular, have studied a range of these catalysts (Scheme 48). As seen in Xue et al. study, substrates where 5-exo-dig and 6-endo-dig cyclization can compete (i.e., where n = 2) give a mixture of spiroacetals. In additimi, where n = 1, the benzopyran 220 is often obtained as a minor product, with varying selectivity. 

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