Reactions with Alkylidene Malonates

Among other types of electrophilic compounds that give alkylation of indoles are alkylidene malonate esters. Jorgensen and coworkers observed 50-70% ee using a Cu(BOX) catalyst [262]. 

Zhou and Tang were able to obtain 80-90% ee using a fris-oxazoline catalyst with Cu(OTf)2 and HFIP as a promoter [263]. 

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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]. 

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)). 

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... 

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>. 

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]. 

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]. 

Hayashi et al. [39] described, in 2007, a new tandem Michael-Henry reaction that gives rise to chiral cyclohexanes (463) with total control of four stereocenters. The reaction between 2,5-dihydroxy-3,4-dihydrofuran (60) and a different set of nitro-styrenes (28) was efficiently catalyzed by the diphenylprolinol derivative VII, rendering the chiral cyclohexanes (61) in high yields and enantioselectivities (Scheme 10.19). In 2009, Cordova and co-workers [40] reported a similar reaction using alkylidene malonates instead of nitrostyrenes, obtaining the corresponding cyclohexanes with good yields and stereoselectivities. 

Lithium trialkylalkynyl borates react with alkylidene malonates and acetoace-tates by an uncatalysed Michael reaction with concomitant migration of an alkyl group from boron to carbon. Oxidation of the resulting borane leads to a... 

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... 

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-... 

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). 

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. 

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 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>. 

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. 

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