Esters intramolecular alkylation

In the case of a y-bromo ester, intramolecular alkylation can be realized ... 

The telomer 145 of nitroethane was used for the synthesis of recifeiolide (148)[121], The nitro group was converted into a hydroxy group via the ketone and the terminal double bond was converted into iodide to give 146. The ester 147 of phenythioacetic acid was prepared and its intramolecular alkylation afforded the 12-membered lactone, which was converted into recifeiolide (148),... 

Stereochemical positioning of a functional group, relative to a separate enamine moiety in the same molecule, can be done in such a manner that a simple intramolecular alkylation or acylation will cause cyclization. Such intramolecular cycloalkylations with alkyl halides have been reported 107,108). Inftamolecular cycloacylations of enamines with esters 109, 110,110a) and with nitriles 110a,l 11,111a) have also been observed. 

Addition to 1,2-dimethyl- -piperideine or 1,2-dimethyl- -pyrroline is followed by intramolecular alkylation by the ester group as a side reaction to give 140 and 141 ( = 1, 2), respectively. Cyclization products 142 and... 

Enamine addition to an unsaturated ester, followed by an intramolecular alkylation, provided a facile synthesis of an adamantane bis-/3-ketoester 674). Michael addition of pyrrolidinocycloheptene to other acrylic esters 668) and of other enamines to acrylic acids 675), a chloroacrylonitrile 676), and an unsaturated cyanocarboxamide (577) were reported. 

The method described above may be used for the preparation of a wide variety of butenolides substituted in the arylidene ring with either electron-withdrawing or electron-releasing substituents. y-Lactones such as a-benzylidene-7-phenyl-A 1 -bu-tenolide are isoelectronic with azlactones, but have received much less attention. Like the azlactone ring, the butenolide ring may be opened readily by water, alcohols, or amines to form keto acids, keto esters, or keto amides.7 a,-Benzylidene-7-phenyl-A3,1 -butenolide is smoothly isomerized by aluminum chloride to 4-phenyl-2-naphthoic acid in 65-75% yield via intramolecular alkylation. 

Olefination of the Aldehyde 178 using a stabilized Wittig reagent followed by protecting group chemistry at the lower branch and reduction of the a,p-unsaturated ester afforded the allylic alcohol 179 (Scheme 29). The allylic alcohol 179 was then converted into an allylic chloride and the hydroxyl function at the lower branch was deprotected and subsequently oxidized to provide the corresponding aldehyde 161 [42]. The aldehyde 161 was treated with trimethylsilyl cyanide to afford the cyanohydrin that was transformed into the cyano acetal 180. The decisive intramolecular alkylation was realized by treatment of the cyano acetal 180 with sodium bis(trimethylsi-lyl)amide. Subsequent treatment of the alkylated cyano acetal 182 with acid (to 183) and base afforded the bicyclo[9.3.0]tetradecane 184. 

Enamine 106 (derived from Meldrum s acid), in a process of mono-decarboxylating transesterification and subsequent intramolecular alkylation, is cyclized to form enamino ester 107 (90H(31)1251). The direct route by flash vacuum thermolysis does not work in the case of 6/7 bicyclic 107. Methylene compound 109 originates (analogously to bicyclic 40b) from... 

This example illustrates the synthesis of cyclic compounds by intramolecular alkylation reactions. The relative rates of cyclization for ca-haloalkyl malonate esters are 650,000 1 6500 5 for formation of three-, four-, five-, and six-membered rings, respectively.28 (See Section 3.9 of Part A to review the effect of ring size on Sn2 reactions.)... 

The intramolecular variant of ester enolate alkylations is a very useful ring-forming reaction. It can often be carried out under milder conditions than the corresponding intermolecular alkylation. Yields and diastereoselectivities are usually high. 

Other examples of the formation of six-membered rings by means of an intramolecular alkylation of an ester enolate are given in Table 7. Entry 6, i.e., stereoselective transformation of the epoxy ester into the cyclohexane derivative, should be discussed briefly as a representative for the other cases. The probable reason for the unexpectedly high selectivity i.e., the nonappearance of the diastereomer 8, can be demonstrated by the two transition-state-like conformations 9 and 10. 9 displays a very severe 1,3-diaxial interaction in comparison to 10, thus, formation of the diastereomer 7 from conformation 10 is highly favored113. 

Table 7. Formation of Six-Membered Rings by Intramolecular Alkylation of Ester Enolates...

In addition, we were able to extend the tandem hetero Michael addition/a-ester-enolate alkylation protocol by an intramolecular variant via a Michael-initiated ring closure (MIRC) reaction leading to diastereo- and enantiomerically pure trans-configured 2-amino-cycloalkanoic acids 30 (Scheme 1.1.7) [14c,d]. 

Intramolecular alkylation is an attractive method for ring construction. Helena M.C. Ferraz of the University of Sao Paulo and Marcos N. Eberlin of the State University of Campinas report (J. Org. Chem. 2005, 70, 110) that the intramolecular displacement of the iodide 1 proceeds by way of the tethered enamine 2, delivering the quaternary center of the keto ester 3 with high diastereocontrol. 

Koenigs method for quinuclidine ring closure was applied by Rubtsov90,91 and Grob 92,93 to the intramolecular alkylation of a-halogeno acids and esters of piperidines. Rubtsov and Dorokhova 90 developed a simple five-step method for the synthesis of quinuclidine-2-carboxylic acid (39). 

For the most part, alkynic and allenic ketones have found limited use in conjugate addition-enolate trapping sequences 69,81-83 their analogous esters have been used with far greater frequency (vide infra). Alkynic ketones, in particular, have found use in development of a new anionic polycyclizadon method consisting of intramolecular Michael addition followed by intramolecular alkylation (equation 15).84... 

In 1050 Sheehan and Bose reported the formation of an asetidi-none by intramolecular alkylation of an -haloa( ]aminomalonk ester (Eq. 40). ThiB was the first example of a -lactam synthesis in which the amide bond was first established, and it is the only case 3 which any azetidine ring has been formed by cydisation of a hetero-ehain at a C—C bond. 

The alkylation of amides by alkyl halides or simple sulfonic acid esters is usually of little importance because the alkylation equilibrium is placed on the side of the starting compounds. This is not the case, however, in either the alkylation of vinylogous amides (which has been achieved even with alkyl iodides ) or if intramolecular alkylation is possible, e.g. in -(2-haloethyl)amides. In the latter case cyclic iminium compounds (81 equation 51) are readily available by replacing the more nucleophilic halide by less nucleophilic complex anions, which can be achieved by addition of Lewis acids or AgBF4. °-2 ... 

As shown in Scheme 69, Kim and coworkers have reported highly stereoselective routes to ci5-1,2-dialkylcycloalkanecarboxylates by intramolecular alkylations of tosyloxy esters such as (142). The reaction appears to proceed via the eclipsed conformations of the enolate (143), rather than the bisected one that would result from a 180 rotation about the a, 3-sigma bond. 

Intramolecular alkylations of nitrile-stabilized carbanions have been used to synthesize large rings such as those with 10 and 14 members. Tsuji and coworkers carried out a synthesis of the macrocy-clic antibiotic zearalenone by this route. As shown in Scheme 70, conversion of either of the protected cyanohydrins (144) or (145) to the corresponding dianions, resulting from deprotonation at the benzylic positions and a to the nitrile groups, gave the same cyclization product (146) in excellent yields. Dianion formation (i) provided control of the conformation of the side chain (ii) protected the ester from nucleophilic attack and (iii) appeared to increase the rate of the intramolecular cyclization. 

Kim, D., Shin, K.J., Kim, I.Y., and Park, S.W., A total synthesis of (-)-reiswigin A via sequential Claisen rearrangement-intramolecular ester enolate alkylation. Tetrahedron Lett., 35, 7957, 1994. 

The second Tsuji synthesis, which appeared (see Scheme 1.6) in the latter part of 1978, employed a strategy similar to his earlier work for construction of the basic carbon framework. Ketal diene 19 was transformed to halo alcohol 22 by the use of chemistry established in his previous synthesis. Acylation with phenylthioacetyl chloride readily afforded ester 23. Intramolecular alkylation resulting in ring closure was brought about by deprotonation with sodium hexa-methyldisilazane to give lactone 24 in 71% yield. Synthetic 1 was then obtained in 90% yield following Raney nickel reduction. 

Conversion to benzoate ester 96, obtained by conversion of 94 into the corresponding acid chloride 95 followed by addition of alcohol 91, then set the stage for macrolide formation. This cyclization was effected by deprotonation and intramolecular alkylation at the benzylic position in 41% yield. Desulfurization and concomitant reduction of the olefin then provided 0-methyl lasiodiplodin (97) in 68% yield. Although Tsuji was readily able to construct the six-membered ring at the proper oxidation level, the symmetry implicit in this strategy precluded the required differentiation of the phenolic hydroxyl groups. 

Acylation of 145 with acid chloride 95 afforded ester 146 in 90% yield. Ester 146, containing all the necessary carbons at easily adjustable oxidation states, required only cyclization and minor functional group manipulations to afford the zearalenone system. As in Tsuji s previous synthesis of di-O-methyl lasiodi-plodin, macrocyclization was effected via deprotonation at the benzylic position and intramolecular alkylation to give 147 in 85% yield. Oxidative elimination of the thiophenyl group and removal of the ketal with acid afforded 127 (67%). the Merck group had previously demonstrated the ready conversion of 127 to zearalenone (119). 

Ring closure of enamines and add chlorides , esters or nitriles (equation 40) or intramolecular alkylation of enaminone (equation 41) are general methods for the preparation of cyclic enaminones. 

Danishefsky and co-workers have used activated cyclopropanes to promote intramolecular alkylation of an amino function, followed by lactam formation to provide a new entry to the pyrrolizidine ring system.20 This route is outlined in Scheme 1. Cyclopropanation of the phthalimido-olefin (19) was achieved with dimethyldiazomalonate in the presence of copper bronze. Treatment of the cyclopropane derivative (20) with hydrazine released the amine, which gave the lactam ester (21) in quantitative yield. This corresponds to intramolecular homoconjugate addition entirely in the spiro mode.21 It seems reasonable that the first step in this process is internal alkylation of the amine by the activated cyclopropane. The alternative... 

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