Conjugate alkylidene malonates

Bond constructions similar to those just discussed can be achieved using an alkylidene malonate which is tethered to an alkyl bromide [72]. Of particular interest in this context is the controlled potential reductive cyclization of 263. As illustrated, the method provides a reasonably facile and modestly efficient entry to cyclobutanes 264. Presumably, the process is initiated by reduction of the alkylidene malonate rather than the alkyl halide, since alkyl bromides are more difficult to reduce. The same substrate, when reduced with L-Selectride undergoes conjugate addition of hydride and a subsequent cyclization leading to the five-membered ring 265. The latter transformation constitutes an example of a MIRC reaction [71-73], a process which is clearly complementary to the... 

The most reactive Michael acceptors, such as alkylidene malonates, gem-dicyanoalkenes and nitroalkenes, react with a-halozinc esters in a conjugate fashion. Beautiful examples were offered by two stereocontrolled conjugate additions to piperidinone 102 and pyrro-lidinone 104 leading to optically active bicyclic lactams 103147 (equation 60) and 105 (equation 61)148. With these electron-poor alkenes a Grignard two-step protocol is to be adopted in order to avoid the single electron transfer reactions from the metal to the Michael acceptor, which should afford olefin dimers. The best solvent is found to be a... 

Asymmetric conjugate addition is a powerful method for the construction of ternary stereogenic centers. Erick Carreria of the ETH-Honggerberg, Zurich reports (Organic Lett. 2004,6,2281) the chiral-auxiliary mediated conjugate addition of alkynes to alkylidene malonate derivatives such as 1, to give, after hydrolysis and decarboxylation, the enantiomerically-enriched acid 3. 

The reactivity profiles of the boronate complexes are also diverse.43 For example, the lithium methyl-trialkylboronates (75) are inert, but the more reactive copper(I) methyltrialkylboronates (76) afford conjugate adducts with acrylonitrile and ethyl acrylate (Scheme 16).44 In contrast, the lithium alkynylboronates (77) are alkylated by powerful acceptors, such as alkylideneacetoacetates, alkylidene-malonates and a-nitroethylene, to afford the intermediate vinylboranes (78) to (80), which on oxidation (peracids) or protonolysis yield the corresponding ketones or alkenes, respectively (Scheme 17).45a Similarly, titanium tetrachloride-catalyzed alkynylboronate (77) additions to methyl vinyl ketone afford 1,5-diketones (81).4Sb Mechanistically, the alkynylboronate additions proceed by initial 3-attack of the electrophile and simultaneous alkyl migration from boron to the a-carbon. 

Another interesting tandem Michael initiated sequence was developed in our laboratory by combining the conjugate addition of unsaturated alkoxides to alkylidene malonates with a palladium-mediated coupling reaction with an organic halide. In this cydization reaction, an organopalladium species acts as the electrophilic partner of the cydization. This reaction results in the trans addition of the organopalladium species and of the nucleophile across the unsaturation, and therefore, in overall difunctionalization of the unsaturated substrates [66,67]. 

Stereocontrolled reduction of alkylidene malonates. The stereochemistry of conjugate hydride reduction of alkylidene malonates such as 1 can be controlled by a ho-moallylic substituent. Thus hydride reduction of la results in predominant syn-reduction. 

The first asymmetric P-C bond formation under heterogeneous conditions has been achieved via a FeaOa-mediated conjugate addition of a chiral phosphite (175) to alkylidene malonates. The easy cleavage of the chiral auxiliary from the addition products (176) leads to optically active p-substituted p-phosphono malonates (177) in good yields and high enantiomeric excesses (Scheme 45). " ... 

The utihty of Cu(II)-box complex 96 for asymmetric Mukaiyama-Michael reaction has been intensively studied by Evans et al. (Scheme 10.91) ]248]. In the presence of HFIP fhe 96-catalyzed reaction of S-t-butyl thioacetate TMS enolate with alkylidene malonates provides fhe Michael adducts in high chemical and optical yield. HFIP plays a crucial role in inducing catalyst turnover. Slow addition of the silyl enolate to a solution of 96, alkylidene malonates, and HFIP is important in achieving high yields, because fhe enolate is susceptible to protonolysis with HFIP in fhe presence of 96. The glutarate ester products are readily decarboxylated to provide chiral 1,5-dicarbonyl synthons. Quite recenfly, Sibi et al. reported enantioselective synthesis of t -amino acid derivatives by Cu( 11)-box-catalyzed conjugate addition of silyl enolates to aminomefhylenemalonates ]249]. 

This reaction was first reported by Mukaiyama et al. in 1974. It is a Lewis acid-catalyzed Michael conjugate addition of silyl enol ether to o ,/3-unsaturated compounds. Therefore, it is generally referred to as the Mukaiyama-Michael reaction. Because this reaction is essentially a conjugate addition, it is also known as the Mukaiyama-Michael addition or Mukaiyama-Michael conjugate addition. This reaction is a mechanistic complement for the base-catalyzed Michael addition, j and often occurs at much milder conditions and affords superior regioselectivity. s Besides silyl enol ether, silyl ketene acetals are also suitable nucleophiles in this reaction.For the hindered ketene silyl acetals, the Lewis acid actually mediates the electron transfer from the nucleophiles to o ,/3-unsaturated carbonyl molecules.On the other hand, the Q ,j8-unsaturated compounds, such as 3-crotonoyl-2-oxazolidinone, alkylidene malonates, and a-acyl-a,/3-unsaturated phosphonates are often applied as the Michael acceptors. It has been found that the enantioselectivity is very sensitive to the reactant structures —for example, Q -acyl-Q ,j8-unsaturated phosphonates especially prefers the unique syn- vs anft-diastereoselectivity in this reaction. In addition,... 

Finally, an interesting conjugate addition of aldehydes to alkylidene malonates has been reported by Cbrdova employing catalyst 22a (20 mol%) [96]. The reaction, which is usually carried out iu CHCI3 at l(fC or CH3CN at 4°C, is highly diastereo- and enantioselective (up to 87% de, 95% to >99% ee), aud has been successfully employed in the synthesis of poly substituted lactones (Scheme 2.30). 

First studies in relation to the conjugate addition of ketones with alkylidene malonates were performed by Barbas group initially using L-proline [107] and proline-derived diamines such as 31 [49, 138] (Fig. 2.4) as organocatalysts, showing that acetone, cyclohexanones, and cyclopentanone could add to various aryl- and alkylidene malonates with moderate yields and enantioselectivities. Very recently. 

Conjugate Addition of Nitroalkanes to Vinyl Sulfones, Nitroolefins, and Alkylidene Malonates... 

Alkylidene malonates are good candidates as highly electrophilic acceptors in the y-selective conjugate addition of y-butyrolactam under the catalysis of multifunctional chiral guanidine 30a (Scheme 30) [50]. Nearly complete... 

Balme has reported a one-pot threecomponent alkene carboamination between propargylic amines, alkylidene malonates, and aryl halides [43]. For example, treatment of N-methyl propargylamine (2 equiv), dimethyl benzylidene malonate (2 equiv) and 1,4-diiodobenzene (1 equiv) with n-BuLi and a palladium catalyst provided 43 as a single diastereomer (Eq. (1.20)) [43a]. The formation of the C—N bond in this process does not appear to be metal catalyzed. Instead, initial conjugate addition of the nitrogen nucleophile to the activated alkene affords a malonate anion, which undergoes carbopalladation followed by reductive elimination to afford the pyrrolidine product. 

Conjugate addition to acyclic alkyl and aryl enones is also generally highly efficient. Application of the same reaction conditions to aryl alkylidene malonates provides the corresponding /3-silyl malonates in generally good yield (53-84%) (eq 112). 

Metal salt catalyzed conjugate addition of nitrogen nucleophiles has attracted considerable interest as means to access valuable intermediates for the preparation of P-amino acid, P-lactams, isoxazolidinones, aziridines, and so on. However, enantios-elective Cu(II)-catalyzed reactions of this type are limited. Cardillo and coworkers reported the Cu(OTf)2/Bn-BOX (32)-catalyzed additions of O-benzylhydroxylamine (230) and N,0-bis(trimethylsilyl)hydroxylamine (232) to alkylidene malonates (219) (Scheme 17.49) [68]. Yields and enantioselectivities ofthedesired P-amino carbonyl compounds (231) and (233) are moderate to good under optimized conditions. In the latter case the conjugate addition products are readily converted to enantiomerically enriched aziridines (234) in good yields. 

Conjugate Addition. Reagent (1) in THE adds in 1,2-fashion to Q , -unsaturated ketones, whereas in THF/HMPA, 1,4-addition is observed as result of kinetic control (eq 4) The hindered Q , -unsaturated ketone isophorone gave smooth 1,2-addition in THE (89%), while in THF/HMPA, 1,2- and 1,4-addition occurred (1 1) in low conversion. 1,2-Addition of (1) to acrolein afforded a building block for bongkrekic acid. 1,4-Addition of (1) to j" -(dienyl)Fe(CO)3 substituted alkylidene malonates is highly stereoselective. ... 

Other electrophiles, such as Michael acceptors, can also be involved in the a-alkylation step. This has been exploited in the conjugate addition of enantiopure lithium amides 60 to unsaturated esters 61, followed by trapping of the resulting enolate with alkylidene malonates. This constitutes a useful methodology for the asymmetric synthesis of p-amino-a-substituted carboxylic acid derivatives 62 (Scheme 11.24) [65]. 

---