5-endo enyne cyclization

Rhode and Hoffmann have investigated sequential radical-mediated cyclizations of enynes as a method for the stereocontrolled synthesis of heteroannular acetals. The sequence generally followed a S-exo-trigfi-endo-dig-patlmay and gave the products in a stereocontrolled manner <2000T6479>. 

The cyclization of enynes containing propargylic carbonate fragment involves allene intermediate, which takes part in intramolecular acylpalladation by endo-frig-modc to give a six-membered ring (Scheme 23). " ... 

Pancrazi and co-workers have reported a 6-endo-trig cyclization of enyne 112 in a synthetic approach to the A-B ring of forskolin [95TL7247], The tandem addition process using tributyltin hydride provides the tricyclic compound 113 in 60% yield. 

The free-radical cyclization of enynes as a synthetic strategy was introduced by Stork and coworkers using BusSnH/AIBN-mediated ethynyl cyclization (equation 34) ". From a mechanistic point of view, the first step is the selective addition of the stannyl radical to the triple bond of the enyne generating a vinyl radical, which can cyclize onto the double bond. In the absence of the methyl substituents on the olefinic moiety, the groups of Beckwith and Stork have both postulated, and demonstrated with the aid of kinetic studies, that the 6-endo radical 30 arises from a ring expansion of the kinetically favored... 

A metal-mediated rearrangement of 3-alkynyl flavone ethers has been found to involve 5-endo enyne cyclization to a platinum-containing spiro-oxocarbenium intermediate which may be trapped with methanol to give spirodihydrofurans or further rearranged to allenyl chromanediones or benzofuranones (Scheme 150). ... 

Nieto-Oberhuber, C., Munoz, M. R, Bunuel, E., Nevado, C., Cardenas, D. J., Echavarren, A. M. (2004). Cationic gold(I) complexes highly alkynophilic catalysts for the exo- and endo-cyclization of enynes. Angewandte Chemie - International Edition, 43,2402-2406. 

In the alkylative cyclization of the 1,6-enyne 372 with vinyl bromide, formation of both the five-membered ring 373 by exn mode carbopalladation and isomerization of the double bonds and the six-membered ring 374 by endo mode carbopalladation are observed[269]. Their ratio depends on the catalytic species. Also, the cyclization of the 1,6-enyne 375 with /i-bromostyrene (376) affords the endo product 377. The exo mode cyclization is commonly observed in many cases, and there are two possible mechanistic explanations for that observed in these examples. One is direct endo mode carbopalladation. The other is the exo mode carbopalladation to give 378 followed by cyclopropana-tion to form 379, and the subsequent cyclopropylcarbinyl-homoallyl rearrangement affords the six-membered ring 380. Careful determination of the E or Z structure of the double bond in the cyclized product 380 is crucial for the mechanistic discussion. 

The benzene derivative 401 by the intermolecular insertion of acrylate[278], A formal [2 + 2+2] cycloaddition takes place by the reaction of 2-iodonitroben-zene with the 1,6-enyne 402. The neopentylpalladium intermediate 403 undergoes 6-endo-lrig cyclization on to the aromatic ring to give 404[279],... 

Analogously to the carbocycle and oxycycle synthesis, cyclic amines can be obtained by the hydrosilylation of a suitable enyne, such as 46 (Reaction 7.54), which gave the six-membered ring via a 6-endo cyclization of the vinyl radical onto the C=N bond [63]. In another example, the isothiocyanide functionality of compounds 47 or 48 reacts with silane under radical conditions... 

The addition of thiyl radicals to alkenes or alkynes to initiate tandem sequences has also been explored. A highly stereo-controlled phenyl thiyl radical addition, 10-endo macrocyclization, termination process has been used to furnish the macrocycle (37) from the dimethylacrylic ester (36).48 In other work the vinyl radical (38) fonned from addition of a thiyl radical to an enyne gives a mixture of the three products (39)-(41) formed either by 6-exo cyclization (39), addition into the aromatic ring followed by trapping with AIBN (40), or rearomatization and fragmentation to give the sulfide (41) (Scheme 15).49... 

The synthesis of A-fused tricyclic (3-lactams involving a radical cascade sequence in enyne 2-azetidinones 114 and 115 bearing a methylenecyclopropane unit has been reported [82]. Slow addition of Bu3SnH/AIBN to a refluxing solution of 114 gave tricyclic vinylstannane 116 as a single stereoisomer in 42% yield, whereas cyclization of 115 under identical conditions gave fused heterocycles 117 and 118 in 73 and 11% yield, respectively, in all three cases via a 7-endo cyclization. Treatment of vinyl stannanes 117 and 118 with PPTS in dichloromethane yielded a common tricyclic product 119 (Scheme 40). 

Selective activation of alkyne functions of enynes to give products either of alkoxy-cyclization or of exo- and endo-skeletal rearrangement can be achieved by using alkynophilic cationic gold(I) complexes. The endocyclic cyclization catalysed by gold(I) proceeds via a mechanism different from those known for Pd(II), Hg(II), or Rh(I) catalysts.118... 

Here the substrates are 3-silyloxy-l,5-enynes the concept was to combine a metal-induced 6-endo-trig cyclization with a ring contraction by a sigmatropic rearrangement (Scheme 12.12).27 From the cationic intermediate, elimination to the biaryl product can be observed in addition to the aldehyde. 

Radical reaction cascades can be initiated by (TMS)3Si radical addition to unsaturated bonds. Two recent examples are illustrated in equations 54 and 55. The reaction of (TMS)3SiH with the 1,6-enyne derivative 98 afforded the 6-membered cyclic compound having exclusively the exocyclic double bond in E configuration via a 6-exo mode106. On the other hand, hydrosilylation of 99 afforded the 6-membered ring via a 6-endo cyclization of the vinyl radical onto the C=N bond107. 

On the other hand, cyclization of diynes separated with a long chain catalyzed by thiolate-bridged diruthenium complexes led to endo-macrocyclic (Z)-con-jugated enynes with 10-16-membered rings [104] (Eq. 80). A butenynyl intermediate is invoked in this mechanism, probably via a vinylidene intermediate. 

One of the earliest radical cyclization cascades initiated by addition of S-centered radicals to alkynes was reported in 1987 by Broka and Reichert (Scheme 2.25). Thiophenyl radicals, PhS, which were generated under radical chain conditions, undergo addition to the terminal end of the C = C triple bond in enyne 138. The resulting vinyl radical 141 can undergo cychzation in both 6-endo (preferred) and 5-exo fashion, and reduction of the radical intermediates 142 and 143 leads to the final observed products 139 and 140, respectively. 

Endo-skeletal rearrangements also take place with 1,6-enynes, bnt the proposed mechanism is just a variation of the exo-single-cleavage rearrangement. Formed by endo cyclization, bicyclo[4.1.0]hept-4-ene derivatives arise in some cyclizations of 1,6-enynes by proton loss and protodemetalation ofthe endo cyclopropylcarbene. " That is the case from 1,6-enynes tethered as sulfonamides and in the intramolecular cyclization of 1,6-enol ethers with alkynes (equation 40). ... 

The formation of these products can be rationalized as shown in equation (46). Thus, upon complexation of Au(I) to the aUcyne in the reacting enyne, an endo cyclization occurs to form a cyclopropyl gold carbene, which can be trapped by a nucleophile. However, the lack of stereospecificity observed in some of these reactions, suggests the formation of open six-membered ring cations as intermediates, which can be intercepted by an O-Boc group.3-Hydroxy-1,5-allenynes react similarly with Pt(II) catalysts. ... 

Cyclization (7-endo-dig) of the enyne (598) to the enedione (599) followed by conversion into damsinic acid (600) represents a new synthetic route to the pseudoguaianolide framework (Scheme 64). It has also been proposed " that... 

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