Alkylidene malonates, reactions

Rovis and co-workers have recently shown that the NHC derived from triazoUum pre-catalyst 151 catalyses the intermolecular Stetter reaction of glyoxamides 149 with alkylidene malonates 150. Enantioselectivities of np to 91% have been obtained with typically good to excellent yields of the corresponding Stetter prod-nets (Scheme 12.32) [68]. 

Mukaiyama Michael reactions of alkylidene malonates and enolsilanes have also been examined (244). The stoichiometric reaction between enolsilane (342a) and alkylidene malonate (383) proceeds in high selectivity however, catalyst turnover is not observed under these conditions. The addition of HFIP effectively promotes catalyst turnover, presumably by protonation and silyl transfer from the putative copper malonyl enolate generated in this reaction. The reaction proved general for bulky P-substituents (aryl, branched alkyl), Eq. 209. 

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... 

Scheldt and co-workers have synthesized similar products using this reaction manifold [112], While results are limited to primary and secondary alcohols, the authors provided a single example of the use of an amine nucleophile. The reaction of cinnamaldehyde 187 and P-amino alkylidene malonate 188 provide amide product 189, albeit in moderate yield Eq. 18. 

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... 

In a similar manner, Lu and Liu have more recently utilized the hetero-Michael addition of lithium propargylic alkoxides to alkylidene malonates in a synthesis of stereodefined allylidene tetrahydrofurans, based on the use of allylic chloride as coupling partner [98]. In this case, the cydization reaction is initiated by a catalytic amount of palladium salt [Pd(OAc)2] rather than by an organopalladium species as mentioned above. 

The catalytic enantioselective addition of aromatic C - H bonds to alkenes would provide a simple and attractive method for the formation of optically active aryl substituted compounds from easily available starting materials. The first catalytic, highly enantioselective Michael addition of indoles was reported by Jorgensen and coworkers. The reactions used a,fl-unsaturated a-ketoesters and alkylidene malonates as Michael acceptors catalyzed by the chiral bisoxazoline (BOX)-metal(II) complexes as described in Scheme 27 [98,99]. 

The enantioselective reactions of indoles using alkylidene malonates gave the alkylation products 92 in excellent yield and with moderate ee. 

The reaction of both pyrrole and N-methylpyrrole (321) with dimethyl p-nitrobenzylidene malonate (326) in the presence of the catalyst (S)-93 gave the Michael adducts 327-328 in excellent yields (99%) [98], but the enantioselectivity of the products was quite low (28-36% ee), respectively (Scheme 71). Regarding catalyst 93, the Michael adduct 329 was obtained from N-methylpyrrole (321) and the alkylidene malonate in moderate yield (62%) and low enantioselectivity 18% ee (Scheme 71) [100]. But, the bis(oxazoline) 93-catalyzed reaction of both pyrrole (1) and N-methylpyrrole (321) with various (/-hydroxy enones 95 as Michael acceptor worked perfectly (Scheme 71) [99]. The elaboration of these adducts through sequen-... 

The Lewis acid-promoted reactions of acrylates and propiolates with allylsilanes usually afford [2 + 2]-cycloadducts rather than [3 + 2]-cycloadducts (vide infra). The ratio of the two kinds of cycloadducts depends on the reaction temperature.166 Particularly, the product ratio in the reaction of alkylidene malonates and their derivatives is markedly temperature dependent.167,168 Cyclobutanes are major products at low temperature, and [3 + 2]-cycloaddi-tion proceeds predominantly at higher temperature (Equation (42)). 

As shown in Equation (42), the cycloadditions of alkylidene malonates and their derivatives enable selective synthesis of both [2 + 2]- and [2 + 3]-adducts by a proper choice of reaction temperature.167,168 Methyl propiolate undergoes [2 + 2]-cycloaddition predominantly. Use of excess allyltriisopropylsilane induces double [2 + 21-cycloaddition to methyl propiolate, forming a bicyclo[2.2.0]hexane.1 7 The [2 + 2]-cycloadditions of (E)- and (Z)-crotylsilanes proceed stereospecifically. 

A different approach that even obviates the use of a preformed silyllithium reagent takes advantage of the cleavage of the Si-Si bond of a disilane by a copper salt. Hosomi and co-workers185 have reported on the reaction of various enones or enals 250 with hexamethyldisilane or l,l,2,2-tetramethyl-l,2-diphenyldisilane, catalyzed by copper(i) triflate-benzene complex (Scheme 61). The transformation requires heating to 80-100 °C in DMF or DMI and the presence of tri-/z-butylphosphine in order to stabilize the copper catalyst under these harsh conditions. The addition products 251 were obtained with high yield after acidic work-up. The application of the method to alkylidene malonates as the Michael acceptor was recently disclosed.1... 

Dibutyl telluride 59 reacts with iodomethyl triphenylphosphonium iodide to give triphenylmethylidene phosphor-ane, which reacts with aldehydes leading to the methylenation products in good yields.119 The same reagent 59 also assists the reaction of dibromomalonates 60 with aldehydes and activated olefins affording alkylidene malonates 61 and cyclopropanes 62 derivatives, respectively (Scheme 30). 

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]. 

The reaction of an alkylidene malonate with dibromomalonate in the presence of zinc gives the 1,4-adduct of the Reformatsky reagent 175). 

The intermediate Reformatsky reagent BrZnC(Br)(COOEt)2 is an a-halogenoorganozinc compound, which can be regarded as a bis-(carbethoxy)carbenoid of zinc. The reaction of alkylidene malonate with polyhaloacetate in the presence of zinc gives cyclopropane derivatives 176). Addition of ethyl bromocyanoacetate to aromatic aldehydes in the... 

Alkylidene malonates also react with silylketene thioacetals under catalysis by the Cu[(5, 5 )-/-Bu-box] (SbF6)2 complex. The reaction adducts are obtained with good efficiency (up to 91% yield) and high levels of enantiocontrol (up to 93% ee), especially for alkylidene malonates bearing sterically demanding substituents in the p-position. 

Suitably substituted isoxazolidines can undergo a thermally induced cycloreversion to nitrone and alkene. For example, the adducts of nitrones with alkylidene malonates or tolylsulfinylfuran-2(577)-ones suffer an easy cycloreversion, which determines significant changes in the diastereomeric composition of the cycloaddition mixtures depending on the reaction conditions (kinetic vs. thermodynamic control) <20040L1677, 2005JOC8825>. 

Enantioselective cycloadditions of nitrones with alkylidene malonates were catalyzed by the complex of Go(ll) with trisoxazoline 528. The cycloaddition was reversible and the diastereoselectivity could be controlled by reaction temperature. For example, A, C-diphenyl nitrone and diethyl 2-benzylidenemalonate reacted at —40°C under kinetic control, affording mainly the m-adduct 530, but at 0°C the thermodynamically more stable /ra r-isomer 529 was the major product (Equation 85) <20040L1677>. 

In contrast to allyl halides substituted with one ASG, the cyclopropanation reaction proceeds relatively smoothly when a second ASG is present. Generally, the best results are obtained with sodium borohydride, sodium cyanide, potassium cyanide, and the sodium salts of alcohols or thiols as the nucleophilic species (Table 22, entries 3-26). Even spiroalkanes can be synthesized with the nucleophiles described above (Table 23). Examples illustrating this route are the conversion of a tetracyclic enamino ester with potassium cyanide to the corresponding electrophilic cyclopropane 2, and the facile one-pot synthesis of 1,1 -bis(hydroxymethyl)cyclo-propanes 3 by reduction of halogenated alkylidene malonates with lithium aluminium hydride. ... 

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]. 

The complex of Co(II) with trisoxazoline 76 catalysed the 1,3-DC between a variety of nitrones and alkylidene malonates to give the corresponding isoxazolidines with both high enantio- and diastereoselectivity. The cycloaddition was reversibile and the endo/exo selectivity could be effectively controlled by reaction temperature. For example, 66 and 73 reacted in the presence of catalytic amounts of Co(C104)2 6H20 (5 mol%) and 76 (3.3 mol%) at -40 °C under kinetic control affording mainly the cis isoxazolidine 74, but at 0 °C the thermodinamically more stable trans isomer 75 was the major product <04OL1677>. 

Scheme 8.33. Asymmetric Diels-Alder reaction of chiral alkylidene malonates.

M. C. Willis has described a tandem reaction process where pyrrolidine is coupled with vinyl bromides (81) to give an enamine.120 In the same reaction vessel, an alkylidene malonate 82 is then added at 80 °C to give the Michael addition product 83. 

Knoevenagel900 applied weak bases (ammonia or an amine) as catalysts for this type of reaction, thereby enabling the condensation and the decarboxylation of the intermediate arylidene- or alkylidene-malonic acids to be effected at lower temperatures and thus achieving higher yields. 

In 1974,Mukaiyama and co-workers reported the first examples of Lewis acid-catalyzed Michael reactions between silyl enolates and a,p-unsaturated carbonyl compounds [33]. Evans and co-workers developed a catalytic asymmetric Michael reaction of silyl enol ethers of thiol esters to alkylidene malonates. For example, the reaction of alkylidene malonate 23 with 2.2 equiv of silyl enol ether 22 was carried out in the presence of 10 mol % of catalyst 25 and 2 equiv of hexa-fluoro-2-propanol (HFIP) in PhMe/CH2Cl2 (3 1) at -78 °C to give the expected adduct 24 in 93% ee (Scheme 5) [34]. Borane complex-catalyzed asymmetric Michael addition has also been reported [35]. 

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