System with dimethyl malonate

Nearly 100 different ligands have been synthesized and their efficacy has been tested in this reaction, Table 8E.3 summarizes the ligands that give high enantioselectivities (>90% ee) in the alkylation of the 1,3-diphenylallyl system with dimethyl malonate. As is readily seen from the... 

The efficiency of a catalytic system based on the bis(aminophosphane) 53 in the asymmetric alkylation of 3-acetoxycyclohexene with dimethyl malonate has been tested [170]. Concerning the enantioselectivity of this reaction, the ee values are generally quite low and the best result for this ligand is only 31% ee. 

Scheme 1. Asymmetric allylic alkylation of rac-3-acetoxy-l,3-diphenyl-l-propene (rac-I) with dimethyl malonate catalysed by Pd/1 colloidal system. (Reprinted from Reference [44], 2004, with permission from American Chemical Society.)...

The chiral nonracemic bis-benzothiazine ligand 75 has been screened for activity in asymmetric Pd-catalyzed allylic alkylation reactions (Scheme 42) <20010L3321>. The test system chosen for this ligand was the reaction of 1,3-diphenylallyl acetate 301 with dimethyl malonate 302. A stochiometric amount of bis(trimethylsilyl)acetamide (BSA) and a catalytic amount of KOAc were added to the reaction mixture. A catalytic amount of chiral ligand 75 along with a variety of Pd-sources afforded up to 90% yield and 82% ee s of diester 303. Since both enantiomers of the chiral ligand are available, both R- and -configurations of the alkylation product 303 can be obtained. The best results in terms of yield and stereoselectivity were obtained in nonpolar solvents, such as benzene. The allylic alkylation of racemic cyclohexenyl acetate with dimethyl malonate was performed but with lower yields (up to 53%) and only modest enantioselectivity (60% ee). 

Hallberg and his co-workers reported in 1999 the first microwave-promoted asymmetric palladium-catalyzed allylic alkylation of acyclic and cyclic allylic esters with dimethyl malonate, using some chiral ligands 57 and 118 (Equations (65) and (55))3 s,l6Sa,i6Sb both cases, microwave irradiation reduces reaction time without any loss of enantio-selectivity. The same group successfully applied this reaction system to the molybdenum-catalyzed allylic alkylation (Equation ((,7)) 60.160 -l60. 

The Tsuji-Trost ally lie substitution catalyzed by Pd complexes using CH-acidic nucleophiles can be performed in an ionic liquid of type 1 alone [30] as well as in a biphasic system [31]. In the latter case the use of trisulfonated triphenylphosphine (TPPTS) prevents the catalyst from leaching into the organic phase. In comparison with water as the catalyst-supporting phase, the ionic liquid system exhibits higher activity and selectivity. The enantio-selective version of the allylic substitution with dimethyl malonate can also be performed in ionic liquids with a homochiral ferrocenylphosphine as the ligand [32]. 

In 1978, Firmenich published an industrial synthesis of (Z)-jasmone and racemic methyl jasmonate. [99] The starting compound is piperylene, which is brominated. This produces a number of isomers, the crude mixture of which is reacted with cyclopentanone in a two-phase system with a phase-transfer catalyst. A double substitution leads to a hydrogen shift produces remarkably high yields of (Z)-pentenyl-cyclopentenone. This may be converted by methylation and oxidation into jasmone, or into racemic methyl jasmonate by reaction with dimethyl malonate and decarboxylation. 

Nitro-alkenes are good Michael acceptors and the nitro group can be reduced to an amine. For the production of amino acids, this method requires that the nucleophile contain a carbonyl moiety. When nitroethene was treated with dimethyl malonate under basic conditions. 3.70 was obtained.3 As in other systems of this type, catalytic hydrogenation of 3.70 led to an amino-ester that cyclized to 2-pyrro-lidinone derivative 3.71). Acid hydrolysis (which was accompanied by decarboxylation) gave 4-aminobutanoic acid (5.48).37.29... 

Pfaltz and coworkers [29] had previously investigated the allylic alkylation of l,3-diphenylprop-2-enyl acetate with dimethyl malonate as nucleophile (in the presence of A/ ,0-bis(trimethylsilyl)acetamide, BSA) with the well-established BOX ligands as stereodirecting ligands, and this particular system therefore provided the point of reference for the catalytic study at hand (Table 15.3, entry 1) [28]. Under the reaction conditions displayed in Scheme 15.4, the trisoxazoline-based catalysts generally induce a better enantioselectivity compared to their BOX analogs, and this behavior appears to be independent of the substituent, as shown in Table 15.3. 

In 1992, Legros and Fiaud found palladium-catalyzed benzyiic alkylation of naphthylmethyl and 1-naphthylethyl esters 103 with sodium dimethyl malonate 104 in dimethylformamide (DMF) to give the corresponding benzyiic alkylated products 105 in high yields (Equation (41)). " When trifluoroacetyl group is used as a leaving group of the ester partner, catalytic alkylation proceeds quite smoothly even at room temperature. In this reaction system, no reaction occurs with benzyiic acetates. 

Another mechanistically interesting example was reported by Ikariya et al. in 2003 (Scheme 10) [12], The authors focused on the basic character of the Ru-amido complex 21. The reaction of dimethyl malonate with 21 afforded a C-bound Ru-enolate, the structure of which was supported by X-ray analysis. It was considered that the N-H moiety plays a role in bringing the enones to the optimum position by hydrogen bonding, as shown in 22 C-C bond formation then occurs at relatively high reaction temperature, affording the desired adduct in 97 % ee. Before this report appeared, a related catalyst system had been examined by Suzuki et al. for the Type I reaction [4f]. 

Gutman,50 in his process route, which did not report any yields, hydrogenated the pyridine ring first to access the piperidine moiety and constructed the indanone ring system via an intramolecular Friedel-Crafts acylation (Scheme 5). Hydrogenation of diester 31, obtained from condensation of 4-pyridine carboxaldehyde and dimethyl malonate, followed by benzylation of the piperidine intermediate afforded A-benzylated piperidine 32. Alkylation of 32 with 3,4-dimethoxybenzyl chloride (33) and subsequent hydrolysis gave dicarboxylic acid 34. Subjection of 34 to strong acid resulted in intramolecular Friedel-Crafts acylation and in situ decarboxylation to provide 3. 

The stereochemical course of the subsequent Michael addition of malonic ester to the unsaturated ketone (23) proved to be unexpected. The kinetically controlled product 27 of addition was obtained in the presence of sodium methoxide and an excess of dimethyl malonate however, the thermodynamically preferred ester 28, also obtainable by base-catalyzed equilibration of 27, was the major product of the reaction. According to the IR (absence of Bohlmann bands) and NMR spectra, both 27 and 28 contained cis-quinolizidine ring systems formed possibly by reversible retro-Michael cleavage of the C-3 to Aj, bond in 23. This possibility explains the observed rapid destruction of 23 in the presence of very strong base with simultaneous appearance of a UV maximum at 410 nm presufiaably due to the conjugated enone system present in 29. 

Ring contraction of the 3,6-dihydro-2//-thiopyrans 41, which are readily available in two steps from dimethyl malonate, was shown to give the tetrahydrothiophenes 42 upon treatment with A -iodosuecinimide (NIS) in the presence of a carboxylic acid. The reaction was suggested to proceed via a bicyclic thiiranium ion intermediate. Moreover, base induced elimination of HI from 42 (with for example R = Bn) gave the partially unsaturated system 43 <04EJO74>. 

The methodology has been honed in a parallel approach employing phosphine-containing amino acids in conjunction with natural amino acids to develop a sensitive ligand system. Ligand candidates were screened both attached to a polymer support and also in solution. Selectivities in the addition of dimethyl malonate to cyclopentenyl acetate of... 

Oxazolo[2,3-fe]oxazoles (191 R = CF3, n-C7F,5) have been prepared by acid-catalyzed dehydration of A,A-bis(hydroxyalkyl)amides <82JFC(2l)359>. The imidazo[l,5-6f]imidazole (193) was prepared by reaction of aminoacetonitrile with excess trimethylorthoformate in the presence of catalytic amounts of formic acid <84JOCl2i2>. The reaction is believed to involve the initial formation of the imidate (192) which reacts successively with aminoacetonitrile and the ortho-ester to give the observed product. Pyrazolo[5,l-Z>]oxazoles (198) have been synthesized by reaction of hydrazino alcohols (195) with the Michael adduct (194), prepared from A-isobutylidene-r-butylamine and dimethyl-methoxymethylene malonate <93JHC1529>. The reaction is believed to involve cyclization of the intermediate hydrazones (196) to give pyrazoles (197), which subsequently cyclize to the bicyclic system with loss of dimethyl malonate. 

In the initial work by Uemura [36] ACTC complexes 43 to 46 were employed as ligands and, again, the catalytically active species was formed in situ. For the standard allyl system, the reaction of 1,3-diphenylacetoxy propene with sodium dimethyl malonate an enantiomeric excess of 94% in favour of the (S)-enantiomer was achieved with 44, while ACTC 43 gave a closely related value of 92% ee. Under the same conditions, a catalysis relying on ligands ent-27 and 46 led to a moderate ee of only 61 and 48%, respectively, and the reaction had to be carried out at a much lower temperature (-78 °C) in order to obtain at least 86% ee. Sub-... 

Nucleophilic additions to the carbon-carbon double bond of ketene dithioacetal monoxides have been reported [84-86]. These substrates are efficient Michael acceptors in the reaction with enamines, sodium enolates derived from P-dicarbonyl compounds, and lithium enolates from simple ester systems. Hydrolysis of the initiEil products then led to substituted 1,4-dicarbonyl systems [84]. Alternatively, the initial product carbanion could be quenched with electrophiles [85]. For example, the anion derived from dimethyl malonate (86) was added to the ketene dithioacetal monoxide (87). Regioselective electrophilic addition led to the product (88) in 97% overall yield (Scheme 5.28). The application of this methodology to the synthesis of rethrolones [87] and prostaglandin precursors [88] has been demonstrated. Recently, Walkup and Boatman noted the resistance of endocyclic ketene dithioacetals to nucleophilic attack [89]. 

In the total synthesis of fredericamycin A reported by Kita et al, the condensation of dimethyl malonate anion with aryne 36 was used to construct the AB-ring system. The intermediate homophthalic esters 37 and 38 were thus obtained in a 58% combined yield with a modest regioselectivity (2 3) (Scheme 12.14) [32]. 

Given the rather moderate selectivities reached with the helix-type peptides, Gilberston explored shorter peptide sequences exhibiting a p-turn secondary structure brought by the Pro-o-Yyy motif. As a starting point, the pentapeptide Ac-Pps-Pro-D-Ala-Pps-Gly was shown to catalyze the all)dic addition of dimethyl malonate to cyclopentenyl acetate with 60% ee in the presence of [Pd(r -allyl) (p-Cl)]2 [96]. The catalytic system was further improved by introducing more... 

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