Alkylidene malonates

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]. 

Pseudo-C3-symmetrical trisoxazoline copper(II) complexes prove to be excellent catalysts in the Friedel-Crafts alkylation of indoles with alkylidene malonates (Eq. 7.13). Water tolerance of chiral catalyst trisoxazoline/Cu(OTf)2 was examined, and it was found that the addition of up to 200 equivalents of water relative to the catalyst in /,vo-butyl... 

The utilization of copper complexes (47) based on bisisoxazolines allows various silyl enol ethers to be added to aldehydes and ketones which possess an adjacent heteroatom e.g. pyruvate esters. An example is shown is Scheme 43[126]. C2-Symmetric Cu(II) complexes have also been used as chiral Lewis acids for the catalysis of enantioselective Michael additions of silylketene acetals to alkylidene malonates[127]. 

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. 

Chiral allenyltitanium reagents, prepared from propargylic phosphates as outlined, react with alkylidene malonates to afford 1,4-adducts with excellent anti dia-stereoselectivity (Table 9.26) [42]. The addition is presumed to take place through an open antiperiplanar transition state (Scheme 9.12). 

Scheme 9.12 Proposed transition state for 1,4-additions of allenyltitanium reagents to alkylidene malonates.

Because of the higher CH acidity (by 7-8 pKa units) of alkylidene malonates (441), as compared with that of dialkyl malonates (87JA809), one-pot syntheses of alkylidene aminomethylenemalonates (442) could be carried out readily with a wide variety of primary and secondary aliphatic and cycloaliphatic amines, anilines, naphthylamines and heterocyclic amines, trialkyl orthoformate, and alkylidene malonates (83MI1 86MI9). It was proposed that the higher CH acidity of alkylidene malonates was a consequence of the electrostatic (dipole-dipole) repulsion effects... 

Flumequine was prepared when 6-fluoro-2-methyl-1,2,3,4-tertrahydro-quinoline was first reacted with alkylidene malonates and trimethyl orthoformate in THF in the presence of p-toluenesulfonic acid, and then the products, alkylidene (6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-1 -yl) methylenemalonates, were cyclized in xylene on the action of polyphos-phoric acid or ethyl polyphosphate at 110-115°C for 1 hr (89EUP310849). 

Good yields of 1,4-addition products have also been obtained with alkylidene malonate esters which generally react with organomanganese reagents in the absence of copper salts9 (see Table IV). 

Both butenolides 50 and 51, one tethered to an a, -unsaturated ester, the other to an unsaturated nitrile, failed to undergo cyclization. Instead, the C=C 7i-bond of the butenolide was reduced, leading cleanly and efficiently to saturation of that bond, and to compounds 54 and 55, respectively. In contrast, the corresponding alkylidene malonate 52, as well as the alkylidene malononitrile 53, both cyclize to afford a mixture of the cis-anti-cis and cis-syn-cis linearly fused lactones 56 and 57. 

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... 

Dibromomalonates react with aldehydes under the assistance of dibutyl telluride (2 equiv) to afford alkylidene malonates. ... 

Aliphatic substrates also perform well, forming five membered rings in good yield and high enantioselectivity Eq. 6a. Typical Michael acceptors, however, are not sufficiently electrophilic to induce cyclization to form six-membered aliphatic rings. In order to effect this cyclization, use of a more electrophilic Michael acceptor, such as alkylidene malonate 83, was required Eq. 6b [70]. The difference in reactivity is presumably due to the extra conformational freedom of the aliphatic linker compared to the fused aromatic linker of substrate 79 coupled with potential competing non-productive pathways. 

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... 

Besides enones, other successful partners include alkylidene malonates or acetoacetates and nitroalkenes64. Heteroatoms can also be included in the separating chain between the enone and the alkyne and this methodology was used as a key step in the synthesis of isodomoic acid G65. 

An alternative complementary olefination procedure involving alkylidene malonates was also developed that produces (Z) olefins as major stereoisomers when the R substituent is aliphatic (equation 93)130. The stereoselectivity depends on the bimetallic compounds and may be improved by bulky ester substituents (such as menthyl groups)131. 

One of the first examples of addition of a zinc enolate to an alkyne was a report dealing with the zinc or cadmium stearate-catalyzed addition of substituted malonates to acetylene under pressure250. Later, Schultze described the intermolecular nucleophilic addition of the zinc enolate derived from diethyl bromomalonate to phenylacetylene in refluxing xylene leading to the alkylidene malonate 392 (equation 171)251. 

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. 

Cyclocondensation of 2-aminoquinoline with isopropylidene bis (methylthio)methylene- and [l-(methylthio)alkylidene]malonates in boiling ethanol or dimethylformamide afforded 3-substituted l//-pyrim-ido[l,2-a]quinolin-l-ones (222, R = MeS, Me, Et, Ph) in 85-97% yields (93MI8). 

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. 

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. 

In the study by Alexakis, unsymmetrical ketones (e.g. 2-butanone) yielded mixtures consisting of regioisomers and syn/anti diastereomers with ee of the predominant syn isomers not exceeding 51%. For 3-pentanone and cyclohexanone (Scheme 4.24) Barbas et al. also used the related (S)-l-(pyrrolidinylmethyl)-pyrrolidine 54 to catalyze the addition of ketones to alkylidene malonates (Scheme 4.25) [43],... 

Enantioselective organocatalytic cyclopropanations have been performed using directed electrostatic activation conditions.164 Using a new class of iminium catalysts, cyclopropanation has been conducted with enals but not electron deficient alkenes, such as unsaturated nitrile, nitro, or alkylidene malonate systems. 

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. 

Several pseudo-C3-symmetric homo- and hetero-trisoxazolines have been developed and applied successfully in the asymmetric Michael-type alkylation of indoles with alkylidene malonates. The C3-symmetric trisoxazoline 121a-copper(C104)2 -6H20 complex, as a catalyst, is an air- and water-stable compound (Scheme 34) [108-110]. 

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-... 

Addition of Ketones to Nitroolefins and Alkylidene Malonates 2.3.3.1 Proline... 

Pyrrolidine-amine-based catalysts such as 18 and 19 can also mediate the addition of ketones to alkylidene malonates (Scheme 2.40) [14]. Aldehydes (e.g., isova-leraldehyde) do not react with vinylidenemalonate 16 under these conditions. 

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