Dimethyl malonate derivatives

As a mechanistically interesting example the reaction of an unsaturated dimethyl malonate derivative with Mn(OAc)3 resulted in the formation of substituted cyclopentanes. The primary radical can either be trapped by CO or cyclize to an unstable radical intermediate, which in turn reacts with CO. Because the trapping of the first-generated radical is reversible, the cyclized acyl intermediate gives the desired product after oxidation [52]. 

The first enantioselective formal total synthesis of paeonilactone A was reported by J.E. Backvall who used a palladium(ll)-catalyzed 1,4-oxylactonization of a conjugated diene as the key step. The lactonization precursor diene acid was obtained from an enantiopure dimethyl malonate derivative via sequential Krapcho decarboxylation and ester hydrolysis. 

Dimethyl malonate derivatives containing an allenyl sulfone substituent at the y- or 3-position undergo endo-mode ring closure to give cyclopentene or cyclohexene derivatives upon treatment with 1.5 equiv of t-BuOK in t-BuOH at rt. The intermediate unsaturated cycloadducts undergo demethoxycarbonylation and double bond isomerization under the reaction conditions (eq 53). Other active methine compounds behave similarly. A threefold excess of i-BuOK is more effective than certain amine bases for the conversion of phenylsulfonyl methyl derivatives of aromatic or heteroaromatic compounds into the corresponding dithio esters upon reaction with an excess of elemental sulfur. ... 

Meldrum s acid, pK 7.4, is exceptionally acidic in comparison to an acyclic analog such as dimethyl malonate, pK 15.9. For comparison, 5,5-dimethyl-1,3-cyclohexane-dione is only moderately more acidic than 2,4-pentanedione (11.2 versus 13.43). The pK values are those for DMSO solution. It is also found that the enhanced acidity of Meldrum s acid derivatives decreases as the ring size is increased. Analyze factors that could contribute to the enhanced acidity of Meldrum s acid. 

Similar results are observed in the conjugative addition of CH-acidic methylene compounds with the metal derivatives of 2-nitro-5,10,15.20-tetraphenylporphyrin (6). The nickel porphyrin 6 (M = Ni) yields with an excess of dimethyl malonate the cyclopropane derivative 7 whereas the copper porphyrin 6 (M — Cu) forms with two equivalents of malononitrile the bisadduct 8.111... 

A similar pathway involving a microwave-driven molybdenum-catalyzed asymmetric allylic alkylation as the key step was elaborated by Moberg and coworkers for the preparation of the muscle relaxant (R)-baclofen (Scheme 6.52) [108]. The racemic form of baclofen is used as a muscle relaxant (antispasmodic) lipophilic derivative of y-aminobutyric acid (GABA). Pharmacological studies have shown that the (R)-enantiomer is the therapeutically useful agonist of the GABAb receptor. Asymmetric alkylation of the allylic carbonate precursor with dimethyl malonate afforded... 

Chloro- and 2-methylthio-l-methylquinolinium iodides were reacted with dimethyl malonate in the presence of l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF at 80°C for 1 hr, or in the presence of triethylamine for 5 hr, to afford dimethyl (1 -methyl-l,2-dihydro-2-quinolinylidene)malonate (86MI3). The use of DBU and the 2-methylthio derivative gave a better yield than that from triethylamine and the 2-chloro derivative. 

Dimethyl malonate was reacted with 2-(iV-nitrosomethylamino)-1,4-benzodiazepines (502, R = H, F n = 0, 1) in the presence of potassium tm-butoxide in DMF under nitrogen to give (1,4-benzo(6)diazepin-2-ylidene)malonates (503, R = H, F n = 0, 1) (75JOC153 83USP4401597). A dichloro derivative of (1,4-benzodiazepin-2-ylidene)malonate (503, R = Cl, = 0) was prepared in the reaction of a 1,4-benzodiazepine derivative (504) and dimethyl malonate under the previous conditions (83USP4401597). 

Imidoyl chlorides (1679) were reacted with dimethyl malonate in THF in the presence of sodium hydride at room temperature to give aminometh-ylenemalonates (1680) in 67-82% yields (89TL4821). The 4-methylphenyl derivative of 1680 (R = 4-MeC6H4) was cyclized by heating in cumene at 200°C to afford 4-hydroxy-2-trifluromethylquinoline-3-carboxylate (1681) in 66% yield. 

The carbanion derived from dimethyl malonate reacts with the cyclic nitro compounds 422 of ring size 5, 6, 7, 8 and 12 to afford the corresponding esters 423. Acyclic allylic nitro compounds 424 (R = Me, CH2OAC or CC Et) are attacked by bulky nucleophiles, such as dimethyl malonate anion, mainly at the terminal primary carbon atom to give rearranged products 425, whereas smaller nucleophiles, e.g. the anion derived from methyl cyanoacetate, react at the tertiary carbon atom to yield 426409a 453 455. 

Electrochemical oxidations of anions lead to radicals that may add to the carbon-carbon double bonds. In this way, the oxidation of anions of dimethyl malonate or methyl acetylacetate in the presence of olefines gives di- or tetrahy-drofurans derivatives in moderate yields (Scheme 43) [60]. 

Finally, Nikishin and coworkers have reported that the mediated oxidations of doubly activated methylene compounds can be used to synthesize cyclopropane derivatives (Scheme 17) [30]. Reactions using dimethyl malonate, ethyl cyanoacetate, and malononitrile were studied. Metal halides were used as mediators. When the activated methylene compound was oxidized in the absence of a carbonyl compound, three of the substrate molecules were coupled together to form the hexasubstituted product. Interestingly, when the ethyl cyanoacetate substrate was used the product was formed in a stereoselective fashion (18b). In an analogous reaction, oxidation of the activated methylene compounds in the presence of ketones and aldehydes led to the formation of cyclopropane products that had incorporated the ketone or aldehyde (20). In the case of 19a, the reactions typically led to a mixture of stereoisomers. 

Using the addition of dimethyl malonate to nitro-olefms as the model reaction, Connon et al. [72] in 2(X)5 reported a highly functionahzed Cinchona alkaloid-derived chiral thiourea. Key functional groups were identified to enhance the catalyst s stereodirecting properties. Aside from the advantage of a bifunctional Cinchona alkaloid... 

Substitution of the 11-ethoxycarbonylmethylthio group of 64 with anilines, 3-dimethylaminopropylamine, thiosemicarbazide, acetylhydrazine, and dimethyl malonate gave the corresponding 11-amine 65 and ll-bis(di-methoxycarbonyl)methylene derivatives 66 (74JHC125). Deprotonation of the 11-amines 65 gave the 11-imino derivatives 67. 

Livinghouse and co-workers report a similar carbocyclization, using a dimethyl malonate diene-ene derivative, in which they obtained 6% ee (69%) with a highly sterically hindered DIOP-based ligand (ref 25). The unaltered DIOP ligand was also highly efficient (83%), but imparted poor enantio-control (10% ee). 

The co-ordinated double bond in PtCl2(vp) (79) is susceptible to nucleophilic attack by class "a nucleophiles to form Pt(II)-carbon tr-bonded complexes such as that in Fig. 19 b (other nucleophilic groups giving similar products include alkoxides, nitromethide anion and dimethyl malonate anion). The C-bonded nucleophilic groups are solvolysed by alcohols to the alkoxy derivatives. 

Dixon et al. screened cinchonine-derived thioureas 117-120 for their performance in the dimethyl malonate Michael addition to tra s-(5-nitrostyrene in dichlo-romethane at room temperature and at -20°C [274]. As shown in Figure 6.38, all candidates revealed comparable activity, but monodentate hydrogen-bond donor 118 exhibited very low asymmetric induction producing the desired Michael... 

Figure 6.38 Cinchonine-derived thioureas (10mol% loading) screened in the Michael reaction of dimethyl malonate to trans- 3-nitrostyrene.

Figure 6.40 (Thio)urea catalysts derived from dihydroquinine and dihydroquinidine screening results obtained from the asymmetric Michael addition of dimethyl malonate to frans-p-nitrostyrene.

On their side, Yin and Linker [216] made use of a 2-C-branched hexopyranoside, the synthesis of which was achieved by addition of dimethyl malonate to tri-O-benzyl-D-glucal (TUPAC name 3,4,6-tri-0-benzyl-l,5-anhydro-2-deoxy-D-araZtino-hex-l-enitol, Scheme 45) [217], Thus, saponification of the 2-C-[bis(meth-oxycarbonyl)]methyl derivative 184 to the corresponding malonic acid 185 was followed by heating in refluxing toluene. This led to decarboxylation and lactoniza-tion giving 186. The method was optimized and applied to the synthesis of pentoses and disaccharides. 

Chiral nonracemic bidentate 2-[o-(diphenylphosphino)phenyl]-5,6-dihydro-4//-l,3-oxazine derivatives proved to be effective P,N-ligands in Pd-catalyzed asymmetric transformations. When used in the Pd-catalyzed allylic alkylations of 1,3-diphenylallyl acetate with dimethyl malonate, phosphino-oxazines 147 and 148 and the... 

Treatment of the (—)-menthone-derived 2/7-1,3-benzoxazin-4(3//)-one 202 with triflic anhydride gave the triflate 203 in quantitative yield. Palladium-catalyzed cross-coupling of 203 with 2-pyridylzinc halide resulted in formation of an approximately 3 1 mixture of the 4-(2-pyridyl)-2//-l,3-benzoxazine 204 and a 4-imino-l,3-benzodioxane derivative 205 (Scheme 36). Compound 205 was formed by the isomerization of 203, which occurred with complete retention of stereochemistry. The 4-(2-pyridyl)-l,3-benzoxazine derivative 204 was applied in enantioselective allylic alkylations of 1,3-diphenyl-2-propenyl acetate with dimethyl malonate as a chiral ligand inducing a 62% ee in the product <2005JOM(690)2027>. 

Among the methods described in Section 10.6.5, the syntheses reported by Umezawa et alJ78 and Garcfa-Lopez et al.179,80 have been most widely used. As summarized in Scheme 33, the synthesis is initiated with the preparation of a diazo ketone through the reaction between a N-protected a-amino acid and isobutyl chloroformate followed by treatment with diazomethane. The chloromethyl ketone is prepared by adding 2.5 M hydrochloric acid to the diazo ketone. Transhalogenation is exploited to obtain the iodomethyl ketone. Through in situ reaction with the sodium derivative of dimethyl malonate, the 4-oxo diester is obtained. 

Treatment of diethyl malonate and related compounds with 1,2-dihaloethane in the presence of base constitutes a classical method of cyclopropane synthesis296"300. The reaction can be conveniently carried out under PTC conditions. An improved method utilizing solid-liquid phase transfer catalysis has been reported298. The reaction of dimethyl or diethyl malonate with 1,2-dibromoalkanes except for 1,2-dibromethane tends to give only low yields of 2-alkylcyclopropane-l, 1-dicarboxylic esters. By the use of di-tm-butyl malonate, their preparations in satisfactory yields are realized (equation 134)297. The 2-alkylcyclopropane derivatives are also obtained from the reaction of dimethyl malonate and cyclic sulfates derived from alkane-1,2-diols (equation 135)301. Asymmetric synthesis... 

There have been no significant advances in the area of platinum-catalyzed allylic alkylations since the first work in 1985 [208], With the platinum complex derived from DIOP, low ee (11%) and modest regioselectivity (4 1) were obtained for the alkylation of (E)-crotyl acetate with dimethyl malonate. 

Methyl-2-diphenylphosphino-3-(l -isoquinolyl)indole with pallada-cycle derived from dimethyl-1-naphthyl ethylamine and potassium hexa-fluorophosphate yields chelate 310 (97T4035). With [(r)3-PhCH = CH = CHPh)Pd( j.-Cl)]2, allyl 311 follows in the presence of silver tetrafluor-oborate. Addition of ligands 312 (R = R1 = H, Me) to [(r 3-PhCHCHCHPh)Pd (Cl) ]2 under conditions of allylic alkylation of 1,3-diphenylprop-2-enyl acetate with dimethyl malonate leads to the formation of P,N-chelates 313 (R = R1 = H, Me), the active species of the catalytic reaction (00T(A)4753). 

Dixon and co-workers independently reported the asymmetric hydrogenbonding catalyzed 1,4-additions of dimethyl malonate to nitroolefins using a cinchonine-derived thiourea catalyst 30 [54]. Catalyst 30 gave good to high yields (81-99%) and good to high enantioselectivities (82-97% ee) for a variety of aromatic, heteroaromatic and aliphatic nitroolefins (Scheme 6.4). Optical purity... 

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