Cyclization modes

ETP2 base, see phosphazene base 2 Evans auxiliary, see Darzens reaction 13 exo cyclization mode 272... 

A resident stereocenter in the enone part can control the formation of two new stereocenters in one step, guided by a synclinal transition state and an axial cyclization mode. The major product on cyclization of 4-methyl-3-[6-(trimethylsilyl)-4-(Z)-hexenyl]-2-cyclohexenone was formed in a ratio of 7.5 13S. 

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. 

The results in Table 7 for methyl-substituted phenylnitrenes show that 2-methyl (11a) and 4-methyl (lid), which can both cyclize toward an unsubstituted ortho carbon, have barriers that are ca. 1.5-2 kcal/mol smaller than 2,6-dimethyl (lib) and 2,4,6-trimethyl (11c), both of which can only cyclize toward a substituted carbon.92 This agrees well with the predicted 2.0 kcal/mol difference in barrier heights for the two cyclization modes of 2-methylphenylnitrene (11a).87... 

J(P1)427>. The regioselectivity of the second radical cyclization depends on the electronic nature of the homoallylic double bond pyrrolizinones 240 which result from a final 5-o -cyclization mode are preferred in the case of electron-poor carbon-carbon double bonds, such as enones or enoates electron-rich double bonds lead to indolizinones via a final 6-f db-cyclization. The best yields of pyrrolizinones were observed with iodide precursors. The cir-isomers of 240 predominate in this 5-f rf6i-5-f3co-cyclization. 

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. 

A variety of other 2-nitro-fer -butylbenzenes 14) has been transformed into N-hydroxy-2-indohnones (20) 48,53,58), in some instances, both cyclization modes of the intermediate diradical i. e. modes a and b) are effective as derived from byproducts. Nitrones 18) have not been isolated except for R = (CH3)8C... 

The PET-oxidative cyclization of unsaturated O-alkyl-O-trimethylsilyl ketene acetals 23 and 27 yields cyclic esters 24, 25, and 28, accompanied by the formation of considerable amounts of non-cyclic esters 26 and 29, respectively [89], The cyclization mode is found to be in accordance with free radical cyclizations of the appropriate esters 26 and 29, performed by heating with organic peroxides [90]. Since organic electrochemistry can be used to oxidize... 

According to the authors, the 1,5-cyclization mode of o-diethynylbenzene (see Scheme 7.25) is determined by electron state symmetry, which is different from that of the neutral molecule of o-diethynylbenzene (Ramkumar et al. 1996). 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

Six- and seven-membered rings (dihydroisoquinolines 178, isoquinolinones 179, 180 and benzazepines 181) were obtained starting from orf/io-halobenzaldehydes or orf/to-halobenzoic acids [144, 145]. In all the cases, the exo-trig cyclization mode was strongly favoured. However, for 178 and 180, isomerization of the double bond from exocyclic to endocyclic occurred spontaneously under the Heck conditions. 

Four distinct cyclization modes may be possible endo-endo, endo-exo, exo-endo and exo-exo. As before, the first two modes of cyclization produce heterocycles (309, 310) directly (equation 113) while the other two cyclizations give imine-carbocycles (311, 312) (equation 114). Five- or srx-membered cycles may be easily produced directly by this strategy. A wide variety of structurally different hetero- and carbocyclic systems can be obtained. 

Scheme 9.23 Metal-dependent cyclization modes in intramolecular alkyne hydroarylation.

With the long chain a-diazo ketone. 6-diazo-7-tridecanone, 1,5-insertion could proceed with placement of the carbonyl outside the ring, or included in the ring. In fact, only the product 7, from the first of these two cyclization modes, is observed67. The alternative cyclopentane 9 is not formed. As with the a-diazo ester, the relative proportion of 1,2- and 1,5-products depends on the rhodium carboxylate employed. Throughout these studies, it has been observed that the olefin 8, obtained from 1,2-elimination, is cleanly Z-configured67 68. 

Substituent Cyclization Mode Azirine CASSCF CASPT2 ... 

Intramolecular metallo-ene reactions are thermodynamically favored and are thus more efficient than the intermolecular versions. The classical distinction of the cyclization modes, suggested by Oppolzer, depends on the carbon of the allylic organometallic (ene-component) to which the alkene or the alkyne (enophile) is linked (equation 77)5,6. 

The presence of a silicon atom in the tether strongly influences the cyclization mode. The 6-endo mode and even the 1-endo are favored over the 5-exo because of the greater Si-O bond length, compared with that of C-O [94,97]. 

Shibasaki and co-workers have described a regioselective Heck cyclization of aryl triflate 12.1, which ultimately provides tricyclic enone 12.4, a key intermediate in a number of diterpene syntheses (Scheme 8G.12) [25], Treatment of 12.1 under typical cationic conditions resulted in preferential 6-exo closure to give 12.2 and 12.3 as a 3 1 mixture in 62% overall yield and with 95% ee for both products. The complete selectivity for 6-exo cyclization is noteworthy because 6-endo, 5-exo, and 7-endo cyclization modes were also possible. An analysis of the steric interactions involved in the various cyclization modes was presented and was used to rationalize the observed selectivity. Non-conjugated diene 12.2 could be isomerized to the fully conjugated diene 12.3 in quantitative yield by using catalytic naphthalene Cr(CO)3. Both Heck products could be converted to the enone 12.4,... 

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. 

According to the Baldwin rule, the exo cyclization mode is favored in intramolecular reactions of alkynyloxiranes with alcohols to afford cyclic ethers. However, the unfavorable endo cyclization mode is observed by the complexation. Thus exclusive endo cyclization of epoxide complex 146 takes place regioselectively to give 147, without forming the five-membered ether 148 by exo mode reaction [37]. 

An intramolecular radical cyclization provides the basis for an asymmetric synthesis of 3-aminochromans. The chirality of the cyclization precursor 473 is derived from either L- or D-serine, and the separable regioisomeric chromans, S)-tert-buty 5-acetylchroman-3-ylcarbamate and R)-tert-butyl 7-acetylchroman-3-ylcarbamate arise due to two possible cyclization modes A or B of the radical intermediate 474 (Scheme 105) <2003OL4253>. 

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