Alkylation by Conjugate Addition

The conjugate addition of indoles to electrophilic alkenes has been known for many years with early examples including methyl vinyl ketone [203] and nitroethylene [204]. A range of new catalysts have been explored. These include a variety of protic and Lewis acids. There has also been exploration of various supported catalysts. Both protic and Lewis acids have also been used in conjunction with ionic liquids, usually imidazolium salts. Many of these studies have been carried out with 1,3-diarylpropen-1-ones as the reactants, but some also include enones such as methyl vinyl ketone and cyclic enones. Chiral catalysts can give enantio-selective additions. Much of the work with chiral catalysts has been summarized by Bandini, MeUoni, Tommasi and Umani-Ronchi [205]. For the most part, the successful reactions have used either enones or nitroalkenes. There are few reports, for example, of addition to acrylate esters. 

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Indoles can also be alkylated by conjugate addition under alkaline conditions. Under acidic conditions, alkylation normally occurs at C3 (see Section 11.1). Table 9.1 includes examples of alkylation by ethyl acrylate, acrylonitrile, acrylamide and 4-vinylpyridine. 

In contrast to the reaction of enolate anions with alkyl halides, which require an equivalent of base, alkylation by conjugate addition is catalytic in base. 

In contrast to these ring-opening reactions, it was observed by Horner and Schwahn that 4-arylidene-(isopropylidene and cyclo-hexylidene)-oxazolones react with alkyl Grignard reagents by conjugate addition to give saturated azlactones 29a as the only products [Eq. (18)]. 

Preparation of the quaternary anticholinergic agent benzilonium bromide (47) is begun by conjugate addition of ethylamine to methylacrylate, giving aminoester 42. Alkylation of 42 with methyl bromo-acetate leads to diester 43, which is transformed into pyrrolidone 44 by Dieckmann cyclization, followed by decarboxylation. Reduction of 44 by lithium aluminum hydride leads to the corresponding amino-alcohol (45). Transesterification of alcohol 45 with methyl benzilate leads to 46. Benzilonium bromide (47) is obtained by alkylation of ester 46 with ethyl bromide. 2... 

Silylcuprates have been reported to undergo reactions with a number of miscellaneous Michael acceptors [65]. Conjugate addition to 3-carbomethoxy acyl pyri-dinium salts [65a] affords 4-silyl-l,4-dihydropyridines. Oxidation with p-chlorand generates a 4-acyl pyridinium salt that gives the 4-silylnicotinate upon quenching with water, and methyl 4-silyl-2-substituted dihydronicotinates upon quenching with nucleophiles (nucleophilic addition at the 6-position). The stabilized anion formed by conjugate addition to an a, j8-unsaturated sulfone could be trapped intramolecularly by an alkyl chloride [65b]. 

Ornithine decarboxylase is a pyiidoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putiisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce viny-logue 12 which can alkylate the enzyme by conjugate addition. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an andneoplastic substance [3,4]. 

SECTION 1.10. ALKYLATION OF CARBON NUCLEOPHILES BY CONJUGATE ADDITION... 

Table 2. Asymmetric F-C alkylations by conjugated C-H addition to electron-poor C-C double bonds.

Acyclic stereocontrol remains a challenging problem in synthesis. While enan-tiomerically pure sulfoxides are valuable synthetic intermediates for enantiocon-trolled carbon-carbon bond formation by conjugate addition in cyclic cases, their usefulness for such alkylations in acyclic cases has not been firmly established. Moreover, most sulfoxide directed alkylation protocols utilize the valuable sulfur auxiliary just once, which limits the synthetic versatility of the process. Marino et al. have recently reported SN2 displacements of acyclic allylic mesyloxy vinyl sulfoxides with organocopper reagents (Scheme 10).33 In addition to the excellent observed stereoselectivities, the newly created chiral center is adjacent to a vinyl sulfoxide which should allow for subsequent chirality transfer operations. On treatment with organocopper nucleophiles, both sulfoxide diastereoisomers 40b and 43b underwent SN2 displacements with high Z selectivity to yield products 42b and 45b, respectively (Table 2). The oxidation state on the sulfur was varied... 

Scheme 3.35. Tetrahydrofurar synthesis by means of MOM a-alkoxy alkyl cuprate conjugate additions followed by Lewis acid-promoted cyclization (MOM = methoxymethyl) [129].

One of the most important uses of DABCO is in the Baylis-Hillman reaction, discovered in 1972 by two chemists at the Celanese Corporation in New York. Their reaction is a modification of the aldol reaction (Chapter 27), except that, instead of the enolate being formed by deprotonation, it is formed by conjugate addition. You have seen the enolate products of conjugate addition being trapped by alkylating agents in Chapter 26, but in the Baylis-Hillman reaction, the electrophile is an aldehyde and is present right from the start of the reaction, which is done just by... 

Another type of alkylating species occurs in o. unsatu-nicd L urhonyl compounds. These compounds can alkylate nucleophiles by conjugate addition. Although there arc no established clinical agents of this type, many natural products active against experimental tumors contain a-methylcne lactone or er. unsatunitcd ketone functionalities. For... 

Patterson and Fried found that the clean lithium enolate (14), generated by conjugate addition of the lithium divinylcuprate (15) to cyclopentenone with subsequent trapping of the initial enolate with TMS-Cl and cleavage of the TMS enol ether with lithium amide in liquid ammonia-THF, could be alkylated in a reasonable yield with the (Z)-allylic iodide (16) to give the 11-deoxyprostaglandin derivative (17 ... 

A series of 16a-alkyl-17a -methylpregnan-20-ones has been prepared by conjugate addition of various Grignard reagents on to the 16-en-20-one system, followed by immediate in situ alkylation of the A -enolate with methyl iodide. Byproducts formed along with the 16a, I7a-dimethyl derivative include the 16a-methyl and 16a,21-dimethyl compounds. 21-Methylated corticosteroids have been obtained by base-catalysed methylation of the 17,21-acetonide (182). Acidic hydrolysis of the methylated acetonide (183) gave the product (184). 21-Trifluoroacetyl (185) and 2 -nitroethyl (186) derivatives were prepared similarly, as well as several other compounds with extended side-chains. ... 

Allylic and dienyl sulfones have been prepared by conjugate addition to 1,3-dienes ". Phenylsulfonyhnercuration of conjugated dienes gives mercury adducts which can be treated with base to afford phenylsulfonyldienes. 2-(Phenylsulfonyl)-l,3-dienes can be stereo- and regioselectively functionalized via Michael addition of nucleophiles to give allylic sulfones. A key intermediate in the synthesis of a Monarch butterfly pheromone 4 was prepared by BackvaU and Juntunen by alkylation and subsequent palladium-catalyzed substitution of the allylic sulfone formed by Michael addition of dimethyl malonate to 2-(phenylsulfonyl)-l,3-butadiene (equation 10). 

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