Endo-trig cyclizations

Scheme 3.59. Sevenfold domino radical 6-endo-trig cyclization.

The major product of the keto olefin cyclizations often corresponds to what one would predict, assuming the intermediate ketyl behaves like the corresponding monoradical (Eq. 34). For example, given an option between a 5-exo and a 6-endo-trig cyclization, the former predominates in radical cyclizations [51], and constitutes the exclusive cyclization path in the electrochemical counterpart, 110 - 112 [47]. In addition, the stereochemical outcome parallels that of the radical... 

The principle side reaction corresponds to reduction of the carbonyl without cyclization. For example, reduction of 6-methylhept-6-en-2-one (113) leads to a 12% yield of alcohol 114 no cyclized adduct 115 is produced. Were the intermediate to behave precisely like the monoradical, one would have anticipated that the presence of the methyl group on the alkene would have slowed the rate of 5-exo-trig cyclization to a point where closure to form 115, the product of a 6-endo-trig cyclization, would have dominated it did not. 

Scheme 6.2 Preference for 6-endo-trig cyclization of silyl radicals...

The cr-alkenylpalladium 400, formed as an intermediate, is converted into 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-trig cyclization on to the aromatic ring to give 404[279]. 

A facile intramolecular carbomagnesiation becomes possible by inserting one more carbon between the reactive magnesium center and the double bond. For example, when a 6-chloro-l-heptene was refluxed with magnesium, 1,2-dimethylcyclopentane (cis/trans = ca 1/4) was obtained in 88% yield after hydrolysis (Scheme 47) °. The cyclization shows a 5-exo-trig selectivity and the product derived from 6-endo-trig cyclization (methylcyclohexane) is not observed. 

Scheme 17. Bromine substituent was required for the 6-endo-trig cyclization mode...

In contrast to the large body of data pertaining the 5-exo and 6-exo cyclization modes, the 6-endo-trig mode has limited applications. This is simply because the 5-exo-trig cyclization is kinetically favored for S-hexenyl radical intermediates. Nevertheless, when the usually favored 5-exo-trig regioselectivity is surpressed by a substituent (e.g. bromine or ethyl) at the 5-position, the 6-endo-trig cyclization mode prevails. 

Endo-trig cyclization of anion 29, formed from 3-methylpyridazine by LDA in THF with methyl 3-propynoate provided 6H-pyrido[l,2-fc]pyrida-zin-6-one 30 (06TL5063). 

Cyclocondenzation of 2-pyridylacetonitrile and ethoxycarbonyl isothiocyanate in MeCN gave 4-cyano-l-oxo-2,3-dihydro-lH-pyrido[l,2-c]pyrimi-dine-3-thione in 18% yield (08MI2). 6-Endo-trig cyclization of anion, formed from 4-methylpyrimidine by LDA in THF at —78 °C, with methyl 3-propynoate provided 8-methyl-6H-pyrido[2,l-c]pyrimidin-6-one in 47% yield (06TL5063). 

Ottow, E. Neef, G. Wiechert, R. Stereo- and regiospedfic 6-endo-trig-cyclization of aryl radicals, an entry to novel progesterone antagonists of the androstane series. Angew. Chem. Int. Ed. 1989, 28, 773-776. 

Whereas 5-endo-trig processes are unfavorable, 6-endo-trig cyclizations are allowed. For this reason the reaction conditions used for several well-known preparations of six-membered rings cannot be used to prepare the corresponding five-membered rings. For example, treatment of phenethylamines with aldehydes and acid yields tetrahydroisochinolines (Pictet-Spengler synthesis), but treatment of benzylamines under these conditions does not yield dihydroisoindoles (Scheme 9.6). 

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. 

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. 

A combinatorial natural-product-like and diversity-orientated library of 10 000 benzopyran-based small molecules was constructed by Nicolaou and coworkers [74, 75]. They chose a solid-phase approach and an anchoring strategy that does not limit complexity building operations (Scheme 14.11). They used a polystyrene-based selenyl bromide resin (43) on which substrates can be immobilized by electrophilic cyclization reactions. Here, ortho-prenylated phenol 44 was reacted with the selenyl bromide (43) to form the benzopyran scaffold (45) via a 6-endo-trig cyclization. 

Some excellent examples of cationic polycyclizations, especially in the field of steroid synthesis, were described in Chapter 1. However, these polycyclizations can also be performed using a radical as initiator. Such reactions can be divided into those based on serial 6-endo-trig cyclizations from polyene acyl precursors [92], radi-... 

Similar methodology can be used in acyclic systems for the diastereoselective, and sometimes dia-steteoselective (Scheme 18), foimation of 1,3-diols. Widi strnie substrates, the proptMtion of products arising from 6-endo-trig cyclization can be significant. 

Indeed, in certain steroidal systems, 6-endo-trig cyclization becomes preferred, with ultimate legio-and stereo-controlled productions of 1,4-diols (Scheme 19). However, other steroidal systems which react by 5-exo-trig cyclization have been described.ss... 

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