Endo mode

Furthei-more, the cyclization of the iododiene 225 affords the si.x-membered product 228. In this case too, complete inversion of the alkene stereochemistry is observed. The (Z)-allylic alcohol 229 is not the product. Therefore, the cyclization cannot be explained by a simple endo mode cyclization to form 229. This cyclization is explained by a sequence of (i) e.vo-mode carbopallada-tion to form the intermediate 226, (ii) cydopropanation to form 227. and (iii) cyclopropylcarbinyl to homoallyl rearrangement to afford the (F3-allylic alcohol 228[166]. (For further examples of cydopropanation and endo versus e o cyclization. see Section 1.1.2.2.)... 

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 preference for endo attack in 7,7-dimethylnorbomene is certainly steric in origin, with the 7-methyl substituent shielding the exo direction of approach. The origin of the preferred exo-attack in norbomene is more subject to discussion. A purely steric explanation views the endo hydrogens at C—5 and C—6 as sterically shieldihg the endo approach. There probably is also a major torsional effect Comparison of the exo and endo modes of reproach shows that greater torsional strain develops in the endo mode of... 

The preference for the endo mode of addition is not restricted to cyclic dienes such as... 

When this stereoelectronic requirement is combined with a calculation of the steric and angle strain imposed on the transition state, as determined by MM-type calculations, preferences for the exo versus endo modes of cyclization are predicted to be as summarized in Table 12.3. The observed results show the expected qualitative trend. The observed preferences for ring formation are 5 > 6, 6 > 7, and 8 > 7, in agreement with the calculated preferences. The relationship only holds for terminal double bonds. An additional alkyl substituent at either end of the double bond reduces the relative reactivity as a result of a steric effect. 

The results show that the dediazoniations afforded dihydrofuran derivatives which were functionalized exclusively at the site of the cyclized radical (10.58, Z = 0, n = 1) in very good yields for bromination and iodination, and moderate yields for chlorination, phenylthionation, and cyanation. All cyclizations take place in the exo mode, i.e., at the -CH= (second-last) carbon and not at the CH2 group (endo mode for nomenclature see Beckwith et al., 1980). 

For recent examples of small-ring enyne RCM following the endo mode, see (a) Kita-mura T, Sato Y, Mori M (2002) Adv Synth Catal 344 678 (b) Dolhem F, Lievre C, Demailly G (2003) Eur J Org Chem 2336... 

Another major influence on the direction of cyclization is the presence of substituents. Attack at a less hindered position is favored by both steric effects and the stabilizing effect that most substituents have on a radical center. These have been examined by DFT (UB3LYP/6-31+G ) calculations, and the results for 5-hexenyl radicals are shown in Figure 10.14. For the unsubstituted system, the 5-exo chair TS is favored over the 6-endo chair by 2.7kcal/mol. A 5-methyl substituent disfavors the 5-exo relative to the 6-endo mode by 0.7kcal/mol, whereas a 6-methyl substituent increases the preference for the 5-exo TS to 3.3 kcal/mol.322... 

The product of the previous reaction provides a Baylis-Hillman type product via an intermolecular addition of an allenoate to an epoxide. The first example of a true Morita-Baylis-Hillman reaction of an epoxide has recently been reported <06CC2977>. Treatment of enone 34 with Me3P provides a good yield of the epoxide-opened product 35. The reaction must be carried out at low concentrations in order to avoid the generation of a variety of side products. When the terminal end of the epoxide is substituted (e.g. 34) the exo-mode of cyclization is the only product observed. When the terminal end of the epoxide is unsubstituted (e.g. 36), the endo-mode of cyclization predominates providing 37. 

Finally, allyl radicals have successfully been employed in macrocyclization reactions, in which the slower rate of reaction of allyl radicals with hydrogen donors turned out to be advantageous46. Thus, radical 11 cyclizes in 1 A-endo mode to provide, after trapping with tin hydrogen, the product 12 as a fi -mixture of the C2/C3 double bond. No products derived from 6-exo or 10-exo cyclizations could be found (equation 8). This can be rationalized by assuming a faster rate of addition of the nucleophilic allyl radical to the electron-deficient terminal double bond than to the C6 or CIO double bonds. 

When X is O, the endo-mode becomes the kinetic and the thermodynamic pathway. The resulting metallacarbe-noid is then ideally suited for a 1,2-hydride shift 353, which installs an endocyclic double bond. 

Another possible termination step that has been utilized for the cycloetherification of alkynols involves CO insertion and esterification of the resulting acyl metal with an exogenous alcohol. This process has typically employed MeOH as solvent and a stoichiometric oxidant since the catalyst is turned over in a reduced form. Following this mechanistic motif, a variety of alkynols have been cyclized under Pd(n) catalysis to five- and six-membered oxacycles with incorporation of methyl esters into the products.294,327-329 For the formation of five-membered ring products, this reaction has been carried out in both exo- and endo-mode to provide 1- and 2-substituted... 

Jprgensen and co-workers (247) investigated the asymmetric 1,3-dipolar cycloaddition reaction catalyzed by bis(oxazoline)-copper(II) complexes. In the presence of 25 mol% 269c, nitrone (401) reacts with ethyl vinyl ether and methoxypropene to afford the [3 + 2] adducts in modest diastereoselectivity and high enantioselectivity, Eq. 217. Ethyl vinyl ether preferentially forms the exo adduct while methoxypropene prefers the endo mode for reasons that are unclear. 

In these reactions, the cydization mode is also determined by the substitution patterns of the aryl ring. If one or both ortho-positions are occupied by a methoxy group, the reaction affords spiro-endo mode cydization products 411 (Scheme 10.159) [185]. The formation of a 408-type intermediate was supported by the fact that 2-halo-l-alkyl ketones 412 were formed in some cases [184, 185]. 

A limitation of this cyclization is that at least two methoxy substituents should be on the aryl ring. Hashmi et al. [186] observed that by using 1 mol% of Hg(C104)2, the reaction ofp-methoxybenzyl 1,2-propadienyl ketone 413 also went smoothly to afford the spiro-endo mode cyclization product 414 (Scheme 10.160). Here the presence of water is important. The high efficiency shown by Hg(II) may be due to the fact that Hg(II) can coordinate with both the carbonyl oxygen and the terminal C=C bond. 

An a-allenic sulfonamide undergoes Pd-catalyzed carbonylative cyclization with iodobenzene, affording a mixture of isomeric heterocycles (Scheme 16.12) [17]. The coupling reaction of an allene with a PhCOPdl species takes place at the allenyl central catrbon to form a 2-acyl-Jt-allylpalladium complex, which is attacked by an internal sulfonamide group in an endo mode, affording a mixture of isomeric heterocycles (Scheme 16.13). 

Free-radical cyclization on to unsaturated CN bonds and also the cyclization of a range of nitrogen-centred radicals have continued to attract interest and have been reviewed. Aryl radicals, generated from BusSnH- or TTMSS-mediated homolytic cleavage of aryl-bromide bonds, have been shown to cyclize on to the nitrogen atom of imidate esters in the 5-exo mode (Scheme 9). Loss of an ethyl radical leads to the observed A-acylindolines. No cyclization in the 6-endo mode was detected. 

Early work was focused to establish the preference for exo- vs endo-mode of cyclization. However, the absence of an effective method for generation of alkyl and/or aryl substituted silyl radicals made this task difficult. The reaction of prototype alkanesilane I with thermally generated t-BuO radicals at 145 °C after 4 h afforded a 48 % yield of unreacted starting material and 19 % yield of a six-membered cyclic product (Scheme 6.1) [1]. Moreover, EPR studies of the same reaction recorded the spectra at temperatures between —30 and 0°C, which were identified as the superimposition of two species having allylic-type (2) and six-membered ring (3) structures, respectively [2]. At higher temperatures radical 2 predominates therefore, the low yield detected in the product studies could derive from the extensive t-BuO attack on the allylic hydrogens. 

The endo-mode of cyclization is found to be the preferred path also in the lower homologues. Reaction (6.2) shows the reactions of two silanes (8) with thermally generated t-BuO radicals to afford the five-membered ring in low yields via a 5-endo-trig cyclization [1], EPR spectra recorded from these two silanes with photogenerated t-BuO radicals are assigned to secondary alkyl radical intermediates formed by an intermolecular addition involving the expected silyl radical and the parent silane [2],... 

Fig. 19 Transition states involved in the cycloaddition (endo-mode) of the model diene with benzaldehyde, both in the absence (TS-endo) and the presence (TS-(Si)-4b, TS-(Si)-4b) of the TADDOL catalyst corresponding activation energies Occal mol ](B3LYP/6-31G(d)//B3LYP/6-31G(d) PM3)...

For an unsymmetrical dienophile, there are two possible stereochemical orientations with respect to the diene. The two possible orientations are called endo and exo, as illustrated in Fig. 6.3. In the endo transition state, the reference substituent on the dienophile is oriented toward the % orbitals of the diene. In the exo transition state, the substituent is oriented away from the % system. For many substituted butadiene derivatives, the two transition states lead to two different stereoisomeric products. The endo mode of addition is usually preferred when an electron-attracting substituent such as a carbonyl group is present on the dienophile. The empirical statement which describes this preference is called the Alder rule. Frequently, a mixture of both stereoisomers is formed, and sometimes the exo product predominates, but the Alder rule is a useful initial guide to prediction of the stereochemistry of a Diels-Alder reaction. The endo product is often the more sterically congested. The preference for the endo transition state... 

Reactions of 5-siloxy-5-en-l-ynes are summarized in Table 5.2. In every case the reaction proceeds at rt in the presence of H2O to give cyclized p,y-unsaturated ketones in good yield without isomerization of the double bond, even using only 10 mol% W(CO)5(thf). The most characteristic feature of this reaction is that the endo mode of cyclization occurs more readily than in other related cyclization reactions such as HgCl2-mediated reactions. 

Epoxidation of 632c with m-CPBA to 634, followed by silylation with bis(trimethylsilyl) acetamide (BSA) to 635, and TMSOTf-indnced cyclization gives 6-hydroxymethyl-3-phenyl-l,2,4-trioxane 636 (Scheme 181) °. Epoxides 638, which are characterized by geminal dimethyl substitnents, are obtained by m-CPBA oxidation of the (0-3,3-dimethyl-allyl)hydroperoxy acetals 637. While the strnctnral change in 638, as compared to epoxide 634, direct the acid-catalyzed cyclizations to the endo mode yielding the 7-membered... 

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