5- Exo-dig product

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>. 

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). 

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. ... 

Clive and coworkers have developed a new domino radical cyclization, by making use of a silicon radical as an intermediate to prepare silicon-containing bicyclic or polycyclic compounds such as 3-271 and 3-272 (Scheme 3.69) [109], After formation of the first radical 3-267 from 3-266, a 5-exo-dig cyclization takes place followed by an intramolecular 1,5-transfer of hydrogen from silicon to carbon, providing a silicon-centered radical 3-269 via 3-268. Once formed, this has the option to undergo another cyclization to afford the radical 3-270, which can yield a stable product either by a reductive interception with the present organotin hydride species to obtain compounds of type 3-271. On the other hand, when the terminal alkyne carries a trimethylstannyl group, expulsion of a trimethylstannyl radical takes place to afford vinyl silanes such as 3-272. 

Cyclization of. V-alkeny lam ides to 2-oxazolines was achieved in very mild conditions with fert-butyl hypoiodite <06OL3335>. The 5-exo-dig gold(I)-catalyzed cyclization of propargylic trichloroacetimidates 129 proceeded with remarkably efficiency under very mild conditions to give 4-methylene-4,5-dihydrooxazoles 130 in good yields. The mildness of the protocol was clearly responsible for the lack of isomerization of the final products to the corresponding, thermodynamically more stable, oxazoles <06OL3537>. 

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. 

Apart from PET-reductive cyclization, chemical reduction has also been applied to the total synthesis of natural products such as capnellenediol 186 [184]. Naphthalene sodium is shown to be a suitable oxidant for generating ketyl radical anions which cyclize efficiently in a 5-exo-dig mode. In contrast, electroreductive cyclization of 184 does not lead to 185, but exclusively to the thermodynamically preferred 5-exo isomer with a remaining double bond in the endocyclic position [185] (Scheme 35). The steroid precursor 4.5-secocholes-tan-5-one 187, in which the lOa-side chain is varied, has been cyclized under the same conditions [186-188] (Scheme 36). Reduction with naphthalene sodium or sodium in ether exclusively produces the A B-cis steroid 188 with an exo double... 

In a similar manner, the reaction of 5-dimethylsilyl-l-hexyne (111) catalyzed by H2PtCl6 affords 5-exo-dig cyclization product 112 exclusively (equation 47)130. 

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... 

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>. 

Cascade reactions using alkyne cyclisations have not been explored, and the isolated example of 416 is unique in a number of ways.145 For a start, 5-exo-dig cyclisation onto the alkyne to give 417 must be sufficiently fast that it competes with halogen-metal exchange of the second iodine atom, which instead traps the product vinyllithium 417, giving the bicyclic product 418 in 47% yield. 

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. 

It is impossible for the endo-dig cyclisations to proceed via the usual syn-carbolithiation mechanism because this would place a trans double bond in the ring. Unlike exo-dig cyclisations onto alkynylsilanes, however, the product of the 5-exo-dig cyclisation of 424 appears to arise by an unexplained trans carbolithiation, perhaps due to O-Li coordination. 

Curran s elegant approach to the natural products ( )-hypnophilin and ( )-coriolin is among the best examples of a Sml2-mediated sequence and consists of a 5-exo-trig cyclisation followed by a stereoselective 5-exo-dig cycli-sation in a radical-radical cascade (Chapter 7, Section 7.4).4 More recently, Kilburn employed a Sml2-mediated radical-radical sequence involving a methylenecyclopropyl ketone in the preparation of paeonilactone B.5,6 In... 

The kinetics of the cyclization reaction of 5-hexynyllithiums 19 was also studied showing that (6-phenyl-5-hexynyl)lithium (19, R = Ph) has a half-life of ca 6 min at —50.6 °C, whereas cyclization reaction of 5-decynyllithium (19, R = Bu) is some 106 times slower. The rather dramatic increase in the rate of cyclization on going from an alkyl-substituted 5-hexyn-l-yllithium to a phenyl-substituted substrate is most likely a consequence of a reduction in A// due to stabilization of the incipient vinyllithium product by the phenyl group19. It is also interesting to note that the 5-exo-dig cyclization reaction of 19 (R = Bu) is slower than the corresponding 5-exo-trig carbolithiation reaction of 5-hexenyllithium. 

After the reaction reached completion, the solid product was filtered off and identified by NMR spectroscopy and X-ray crystallography. By analyzing the data, the unexpected formation of amide product 40 from benzaldehyde 37C and its corresponding intermediate 39C was revealed. This represented a new transformation pathway, for which only a few related systems have been reported [58-60]. Scheme 14 displays the proposed mechanistic formation of amide product 40, supported by density functional theory (DFT) calculations [61]. In the presence of triethylamine as catalyst, the key intermediate 39C was formed from nitroaldol (Henry) reaction of 2-cyanobenzaldehyde 37C and nitroethane 38. The nitroaldol adduct 39C then underwent internal cyclization (5-exo-dig) to give iminolactone 41,... 

An interesting observation was made in the case of the 5-exo dig radical cyclization of the glucosyl pyridyl sulfone derivative 6 (Fig. 9b). An ( ) (Z)-stereoselectivity of greater than 50 1 was observed in the product, which was a fourfold increase in selectivity, compared with the previously reported tin hydride method. Closer examination of this reaction revealed that the stabilized vinylic radical was reduced to an alkenyl organosamarium species, as shown by a remarkably high incorporation of deuterium at this position (91%) when the reaction was performed in the presence of MeOD (Fig. 12). Compared with other studies on similar reductions of stabilized alkenyl radicals, this... 

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