Lactonization/benzylic alkylation reactions

Meldrum s acid, like other 1,3-dicarboxyl compounds, was amenable to radical reactions at C-5. The radical reaction between Meldrum s acid benzyl alkyl ethers mediated by InCl3/Cu(OTf)2 has been reported to proceed regioselectively at the benzylic position of the ether moiety (Scheme 35) <2006AGE1949>. Radical reaction of Meldrum s acid and alkenes was carried out with 2equiv of ceric ammonium nitrate (CAN) to give the a-carboxy-lactones which were subsequently subjected to decarboxylative methylenation affording the a-methylene lactones in 35-50% yield (Scheme 35) <2006SL1523>. 

There are some mechanistic implications in the results of the a-alkylation of the trisubstituted lactone 4027. This reaction was Carried out with LDA in tetrahydrofuran at — 78 °C in the presence of HMPA with reactive electrophiles such as iodomethane, allyl bromide and benzyl bromide. In all cases the observed diastereoselectivity was >95% and the yields between 75-92%. 

The stereospecific C-alkylation of a range of benzylic ketones, such as tetralones, 2-phenylcyclohexanones and cycloheptanones, and 2-phenyl-y-lactones, has also been described [8]. For example, Af-(4-trifiuoromethylbenzyl)cinchonidinium bromide catalyses the reaction of 1,5-dibromopentane with 7-methoxy-l-methyl-2-tetralone to yield the (R)-l-(5-bromopentyl) derivative (75% yield with 60% ee). 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

The endo- and e.vo-Diels - Alder adducts 37a and 38a, which are the products from the reaction of cyclopentadiene and (7 )-angelica lactone 39a, have been alkylated under the usual conditions (LDA, THF, — 78 °C) with iodomethane, ethyl, butyl and benzyl bromide26. The alkylations are all completely diastereoselective as is expected in these tricyclic examples and yields are in the range of 80-95%. Pyrolysis of 37b and 38b at around 250-290°C for 2-6 days led to the butenolides 39b. 

Most stereoselective alkylations to the lactone intermediates are accomplished using the method reported by Kleinman and co-workers.1201 The dianion form is prepared by treating the lactone with lithium or sodium hexamethyldisilanazide. Then, the reaction between the dianion and an alkyl halide produces the 2-alkylated lactone (Scheme 11, Section 10.6.2). Kleinman and co-workers reported that the ratio of the trans- and ds-lactone is 47 3. When a doubly protected a-amino aldehyde [e.g., dibenzylamino aldehyde, (/ert-butoxycarbonyl)-benzylamino aldehyde] is used, the c/.v-lactone is not obtained. As an example, the alkylation of (55,1 5)-5-[l -[/V-(/< rt-butoxycarbonyl)benzylamino]-2 -phenylethyl]dihydrofuran-2(3/7)-one to produce (3/ ,55,l 5)-3-benzyl-5-[1 -[/V-(/ert-butoxycarbonyl)benzylamino]-2 -phenyl-ethyl]dihydrofuran-2(3//)-one is described in this section. 

Because of the special structural requirements of the resin-bound substrate, this type of cleavage reaction lacks general applicability. Some of the few examples that have been reported are listed in Table 3.19. Lactones have also been obtained by acid-catalyzed lactonization of resin-bound 4-hydroxy or 3-oxiranyl carboxylic acids [399]. Treatment of polystyrene-bound cyclic acetals with Jones reagent also leads to the release of lactones into solution (Entry 5, Table 3.19). Resin-bound benzylic aryl or alkyl carbonates have been converted into esters by treatment with acyl halides and Lewis acids (Entry 6, Table 3.19). Similarly, alcohols bound to insoluble supports as benzyl ethers can be cleaved from the support and simultaneously converted into esters by treatment with acyl halides [400]. Esters have also been prepared by treatment of carboxylic acids with an excess of polystyrene-bound triazenes here, diazo-nium salts are released into solution, which serve to O-alkylate the acid (Entry 7, Table 3.19). This strategy can also be used to prepare sulfonates [401]. 

While diketene remains a very important synthetic precursor, there has been increasing interest in the chemistry of a-methylene-/3-lactones, 3-methylene-2-oxetanones. However, unlike diketene, which can be readily synthesized by the dimerization of aldehydic ketenes, there are few methods for the synthesis of a-methylene-/3-lactones in the literature. Recent strategies for the preparation of the compounds are discussed in Section 2.05.9.2. The kinetic resolution of racemates of alkyl-substituted a-methylene-/3-lactones has been carried out via a lipase-catalyzed transesterification reaction with benzyl alcohol (Equation 21) <1997TA833>. The most efficient lipase tested for this reaction was CAL-B (from Candida antarctica), which selectively transesterifies the (A)-lactone. At 51% conversion, the (R)-f3-lactone, (R)-74, and (A)-/3-hydroxy ester, (S)-75, were formed in very high enantio-selectivities (up to 99% ee). 

The enantioselective intramolecular C-H insertion of alkyl diazoacetates has been used to prepare a variety of pharmaceutical and natural products [1], One example is the synthesis of (-)-enterolactone (8) shown in Scheme4 [2], The Rh2(4S-MPPIM)4-catalyzed reaction of 6 favors C-H insertion to form the y-lac-tone 7 in 93 % ee, which was the readily converted to 8. Competing C-H insertion at the highly activated benzylic C-H bond to form a /3-lactone was not observed, which illustrates the strong preference for five-membered ring formation over six-membered. 

Phenylseleneny lotion of acetates and lactones. In the presence of zinc iodide, 1 reacts with alkyl acetates to form alkyl phenyl selenides. The reaction is particularly facile with acetates of tertiary, ailylic, and benzylic aicohols. Acetates of primary and secondary alcohols react only at 110°. 

Triphenylsilyl ethers are typically prepared by the reaction of the alcohol with triphenylsilyl chloride (mp 92-94 °C) and imidazole in DMF at room temperature. The dehydrogenative silylation of alcohols can be accomplished with as little as 2 mol% of the commercial Lewis acid tris(pentaf1uorophenyl)borane and a silane such as triphenylsilane or triethylsilane [Scheme 4.98]. Primary, secondary, tertiary and phenolic hydroxyls participate whereas alkenes, alkynes, alkyl halides, nitro compounds, methyl and benzyl ethers, esters and lactones are inert under the conditions. The stability of ether functions depends on the substrate. Thus, tetrahydrofurans appear to be inert whereas epoxides undergo ring cleavage. 1,2- and 1,3-Diols can also be converted to their silylene counterparts as illustrated by the conversion 983 98.4. Hindered silanes such as tri-... 

In the presence of a Lewis acid, silyl enol ethers can be alkylated with reactive secondary halides, such as substituted benzyl halides, and with chloromethylphenyl sulfide (ClCH2SPh), an activated primary halide. Thus, reaction of the benzyl chloride 10 in the presence of zinc bromide with the trimethylsilyl enol ether derived from mesityl oxide allowed a short and efficient route to the sesquiterpene ( )-ar-turmerone (1.22). Reaction of ClCH2SPh with the trimethylsilyl enol ethers of lactones in the presence of zinc bromide, followed by 5-oxidation and pyrolytic ehmination of the resulting sulfoxide (see Section 2.2), provides a good route to the a-methylene lactone unit common in many cytotoxic sesquiterpenes (1.23). Desulfurization with Raney nickel, instead of oxidation and elimination, affords the a-methyl (or a-alkyl starting with RCH(Cl)SPh) derivatives. ... 

Electrophilic quench of aryllithium species with carbonyl electrophiles is particularly efficient. However, alkyl halides (other than iodomethane) are poor electrophiles, probably owing to competing elimination reactions (see Section 2.1). The formation of alkyl-substituted aromatic compounds can be achieved, however, by using epoxide electrophiles or by lithiation and reaction of 2-methylbenzamides, themselves generated by orr/ o-lithiation. For example, the benzamide 128 can be deprotonated at the benzylic position and treated with a variety of electrophiles. Addition of aromatic aldehydes gives, after lactonization, 3-aryl-3,4-dihydroisocoumarins (1.119). 

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