Exo-dig cyclization reactions

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. 

On the other hand, as discussed below in the case of acetylenic organolithiums 4-, 5- and 6-exo-dig cyclization reactions are possible with appropriate substitution of the triple bond. 

Recently, Curran and Liu [63] encountered an interesting 1-exo dig cyclization reaction during their attempts to use cyclopropanes as radicophiles. Reaction of the bromodinitrile 255 with an excess of BusSnH and AIBN resulted in the formation of the eight-membered enaminonitrile 257, whose formation was explained by initial 1-exo dig cyclization of the radical onto one of the nitriles followed by BusSnH-mediated cleavage of the cyclopropyl imine 256. 

Entry 11 involves generation and cyclization of an alkoxymethyl radical from a selenide. The cyclization mode is the anticipated 5-exo with a cis ring juncture. This is a case in which the electronic characteristics of the radical are not particularly favorable (ERG oxygen in the radical), but cyclization nevertheless proceeds readily. The reaction in Entry 12 was used to prepare a precursor of epibatidine. Entry 13 shows a 6-endo cyclization that is favored by steric factors. The 6-endo cyclization is also favored with a tetrahydropyranyloxy substituent in place of the ester, indicating that the electronic effect is not important. Entries 14 to 16 involve acyl radicals generated from selenides. The preferred 6-endo cyclization in Entry 15 is thought to be due to the preference for the less-substituted end of the double bond. Entry 17 is an example of a 5-exo-dig cyclization. 

A ring opening reaction of (1-lactams promoted by methoxide generated nitrogen nucleophiles in situ that subsequently added to proximal allenes producing trisubstituted pyrroles <06CC2616>. In the event, treatment of (3-lactam 3 with MeONa led to pyrrole-2-acetic ester 4 after cleavage of the amide bond, 5-exo-dig cyclization, and loss of methanol. The sequence was notable as no metal catalyst was required. 

The final cyclization manifold has been realized with a different ruthenium catalyst (Scheme 22). The cationic [Cp Ru(MeCN)3]PF6 induces exclusive endo-dig cyclization of both homopropargylic and bis-homopropargylic alcohols.29 73 The clean reaction to form a seven-membered ring is noteworthy for several reasons intramolecular exo-dig cyclization with bis-homopropargylic alcohols is not well established, the platinum-catalyzed case has been reported to be problematic,80 and the selectivity for seven-membered ring formation over the exo-dig cyclization to form a six-membered ring is likely not thermodynamic. The endo-dig cyclization manifold was thus significant evidence that a re-examination of alkyne hydrosilylation mechanisms is necessary (see Section 10.17.2). 

All these reactions are examples of oxidative cyclocarbonylation-alkoxy-carbonylation. However, the Pdh/KI catalytic system turned out to be a very efficient catalyst also for promoting cyclization-alkoxycarbonylation processes. In fact, optimal conditions were found for selectively converting 4-yn-l-ols into tetrahydrofuran derivatives (Eq. 41) [107] through 5-exo-dig cyclization followed by alkoxycarbonylation (Scheme 19, path a). This kind of process was not possible for the propynyl, 3-yn-l-ol, and 2-ethynylaniline substrates, seen before, for stereoelectronic reasons [302], With the latter substrates, the endo cyclization mode (Scheme 19, path b), although in principle stereo electronically allowed, was not observed. 

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. 

For the alkynyUiydroxylamines 274 smdied by Holmes (309,311), initial intramolecular 1,3-azaprotiocyclotransfer affords the N-oxides 275 via a 5- or a 6-exo-dig process [Baldwin s terminology (312)], which then tautomerize to the cyclic nitrones (276) (Scheme 1.57). The 1-exo-dig cyclization required for the formation of a seven-membered nitrone (277) by this approach from 278 was found to be disfavored with respect to the alternative reaction of hydroxylamine and alkene 5-exo-trig process) to afford a mixture of the alkynylpyiTolidines 279... 

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. 

The formation of compound 175 could be rationalized in terms of an unprecedented domino allene amidation/intramolecular Heck-type reaction. Compound 176 must be the nonisolable intermediate. A likely mechanism for 176 should involve a (ji-allyl)palladium intermediate. The allene-palladium complex 177 is formed initially and suffers a nucleophilic attack by the bromide to produce a cr-allylpalladium intermediate, which rapidly equilibrates to the corresponding (ji-allyl)palladium intermediate 178. Then, an intramolecular amidation reaction on the (ji-allyl)palladium complex must account for intermediate 176 formation. Compound 176 evolves to tricycle 175 via a Heck-type-coupling reaction. The alkenylpalladium intermediate 179, generated in the 7-exo-dig cyclization of bro-moenyne 176, was trapped by the bromide anion to yield the fused tricycle 175 (Scheme 62). Thus, the same catalytic system is able to promote two different, but sequential catalytic cycles. 

A variety of substituted isoindolin-l-ones (18) have been prepared in good to excellent yields under very mild conditions by the reaction of e>-(alk-l-ynyl)benzamidcs (17) with IC1, I2, and NBS,37 as a result of 5(N)-exo-dig cyclization.38 In a few... 

Very recently, an intramolecular version with alkynyl [3-diketones or (3-diketoe-sters has been reported (Scheme 10.23).42 With such substrates, the reaction required a mixture of silver tetrafluoroborate and copper triflate as catalysts. Here, also, nucleophilic addition of a ketoenol to a n complex seemed responsible for an exo-dig cyclization, but depending on substituents, exocyclic or endocyclic alkenes were obtained. 

The fully-unsaturated 1,3-benzodiazepine 310 is formed by a photoreaction of the 1-substituted isoquinoline 7V-imide 309 (Scheme 169) <1980CPB2602>. The same principle has been applied to prepare thieno-, furo-, and pyrrolo-fused 1,3-diazepines <1980CC454, 1981CPB1539>. The imidazolo-fused l,3-benzodiazepin-2-ones 313 can be prepared by the reaction of 5-amino-4-(cyanoformimidoyl)imidazoles 311 with tosyl isocyanate. The mechanism of this reaction includes a 1-exo-dig cyclization of intermediates 312 followed by a Dimroth rearrangement to give the thermodynamic products 313 (Scheme 170) <1996JHC855, CHEC-III(13.05.9.2.2)174>. 

Scheme 33 A domino cross coupling-6jr-electrocyclization reaction featuring a 4-exo-dig cyclization [112,113]...

In light of the facile 5-exo-dig carbolithiation reaction of simple acetylenic alkyllithiums, Bailey and Longstaff have studied the analogous 5-exo cyclization of a benzyne-tethered alkyllithium. Regioselectively 4-functionalized indanes 281 have been prepared... 

In this protocol the pyridine- and the pyrrolidine-ring of 1 are built up in a one-pot radical domino reaction." Photolysis of iodopyridone 11 in the presence of hexamethylditin provides radical 56, which attacks the reactive isonitrile 15. The resulting radical 57 reacts with the alkyne group in a 5-exo-dig cyclization (see Chapter 11). Next, the newly formed vinyl radical 58 cyclizes onto the aryl ring generating speeies 59. Final oxidation via a so far unknown mechanism yields 1 with 31 % yield. For the generation of radical 56 by photolysis two ways (A and B) are possible. 

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