Malonic chloro

It is possible to prepare 1-acetoxy-4-chloro-2-alkenes from conjugated dienes with high selectivity. In the presence of stoichiometric amounts of LiOAc and LiCl, l-acetoxy-4-chloro-2-hutene (358) is obtained from butadiene[307], and cw-l-acetoxy-4-chloro-2-cyclohexene (360) is obtained from 1.3-cyclohexa-diene with 99% selectivity[308]. Neither the 1.4-dichloride nor 1.4-diacetate is formed. Good stereocontrol is also observed with acyclic diene.s[309]. The chloride and acetoxy groups have different reactivities. The Pd-catalyzed selective displacement of the chloride in 358 with diethylamine gives 359 without attacking allylic acetate, and the chloride in 360 is displaced with malonate with retention of the stereochemistry to give 361, while the uncatalyzed reaction affords the inversion product 362. 

Dimethyl iodo(4-pentenyl)malonate (926) undergoes a Pd-catalyzed intramolecular radical-type reaction to form the alkyl iodides 927 and 928. rather than a Heck-type reaction product(775]. The same products are also obtained by a radical reaction promoted by tin hydride(776]. Although yield was low, a similar cyclization of the n-chloro ester 929 to form the seven-membered ring 930 was ob,served(777(. 

With malonic acid in a mixture of pyridine and piperidine 2-phenyl-4-formyl-5-chlorothiazole yields 2-phenyl-5-chloro-4-thiazoleacrylic acid (103). 

Halogenopyrimidines react with active methylene groups, such as those in diethyl malonate, ethyl cyanoacetate, ketene diethylacetal, etc. For example, 4-chloro-6-methyl-5-nitropyrimidin-2-amine (454) and dimethyl sodiomalonate give dimethyl 2-amino-6-methyl-5-nitropyrimidin-4-ylmalonate (455) (63ZOB3132) 2-chloro-4,6-... 

The addition of nucleophiles to cyclic fluoroolefins has been reviewed by Park et al. [2 ]. The reaction with alcohols proceeds by addition-elimination to yield the cyclic vinylic ether, as illustrated by tlie reaction of l,2-dichloro-3,3-di-fluorocyclopropene Further reaction results in cyclopropane ring opening at the bond opposite the difluoromethylene carbon to give preferentially the methyl and ortho esters of (Z)-3-chloro-2-fluoroacrylic acid and a small amount of dimethyl malonate [29] (equation 8). 

The same methodology was also used starting from the ethyl 6-amino-7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate, prepared by reduction of the nitro derivative. The requisite nitro derivative was prepared by nitration of ethyl 7-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate. A second isomer was prepared from 4-chloro-3-nitroaniline by reaction with diethyl ethoxymethylene-malonate, subsequent thermal cyclization, and further ethylation because of low solubility of the formed quinolone. After separation and reduction, the ethyl 7-amino-6-chloro-l-ethyl-4-oxo-l,4-dihydroquinoline-3-carboxylate 32 was obtained. The ort/io-chloroaminoquinolones 32,33 were cyclized to the corresponding 2-substituted thiazoloquinolines 34 and 35, and the latter were derivatized (Scheme 19) (74JAP(K)4, 79CPB1). 

Azomalonates carrying an electrophilic side chain, as in 100 and 101, could be cyclized to give the title ring system. They were prepared by coupling of dimethyl 2-(2-chloro-N-methyl or phenylacetamido)malonate... 

Condensation of aminopyrazole 116 with ethoxy-methylene malonic ester gives the product of addition-elimination (117), which is then cyclized to the piperidone by heating in diphenyl ether. The product tautomerizes spontaneously to the hydroxypyridine 118. The hydroxyl group is then converted to the chloro derivative by means of phosphorus oxychloride (119). Displacement of halogen by n-butylamine gives... 

Cyclobutanedicarboxylic acid has been prepared by hydrolysis of the ethyl ester,1 or of the half nitrile, 1-cyano-l-car-boxycyclobutane.2 The ethyl ester has been prepared by condensation of ethyl malonate with trimethylene bromide1 or chloro-bromide.3 The half nitrile has been prepared by condensation of trimethylene bromide with ethyl cyanoacetate followed by hydrolysis of the ester to the acid.2... 

Chloro-l,2,3-thiadiazole-4-carboxamides 38 react with the sodium salt of diethyl malonate to give the corresponding malonic acid derivatives 39. The yield in these reactions falls as the electron-releasing properties of the 4-substituents in the aromatic ring increase (Equation 8) <1997JCM396>. 

This sequential substitution of the chloro and acetoxy groups makes the chloroacetates useful as building blocks. An example of the use of the chloroacetate 34 from isoprene for the synthesis of the Monarch butterfly pheromone is given in Scheme 737. Two different nucleophiles, sodium dimethyl malonate and sodium methyl acetoacetate, were employed in Pd(0)-catalyzed allylic substitutions. The transformation of 34 to 36 was also made... 

Potassium 4-chloro-3,5-dinitrobenzene-sulfonate, 31, 46 Potassium cyanate, 31, 9 Potassium cyanide, 30,84 32,31,63 37,47 Potassium ethyl malonate, 37, 34 Potassium ethyl xanthate, 30, 56 Potassium fluoride, 36, 40 Potassium iodide, 30, 34 31, 31, 66 Potassium metal, 37, 29, 30 Potassium methyl sulfate, 31, 73 Potassium nitrate, 31, 46 Potassium 1-nitropropylnitronate, 37, 24 Potassium oxalate, 34, 83 Potassium permanganate, 30, 87 31, 59 Potassium sulfide, 32, 103 Potassium thiobenzoate, 32, 101 Potassium thiocyanate, 32, 39, 40 Prins reaction, 33, 72 Propane, 1, 3-dibromo-2, 2-Ws-(bromo-methyl)-, 31, 82... 

There are very few precedents for the reaction of cyclic a-halo ethers with carbanions. Zelinski and coworkers114 and Schudel and Rice115 reported the preparation of diethyl DL-tetrahydropyran-2-ylmalonate (137) by treatment of 2-bromo- or 2-chloro-tetrahydropyran (136) with diethyl sodiomalonate. The product was subsequently converted into the malonic and acetic acid derivatives, 138 and 139, respectively. The same sequence has also been reported by other workers.116... 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

Amino-6-chloro-2-(l-piperazinyl)pyrimidines were reacted with EMME at 140-150°C for 9-10 hr to give 4-pyrimidinylaminomethylene-malonates (54) in 77.2-79.0% yields [87JAP(K)142177]. 

Guo et al. prepared N-(3-chloro-4-fluorophenyl)aminomethylenemalo-nate (256, R = 3-C1, R1 = 4-F, R2 = R3 = Et) in 60-70% yields when 3-chloro-4-fluoroaniline was reacted with triethyl orthoformate and diethyl malonate in the presence of a Lewis acid. From the reaction mixture, ethyl A-(3-chloro-4-fluorophenyl)-2-[(3-chloro-4-fluorophenyl)-aminomethylene]malonamate and A-(3-chloro-4-fluorophenyl)formanilide were also isolated as byproducts (88MI3). 

Chloropropyl)-2-piperidone and 1 -(2-chloroethyl)-2-pyrrolidone were reacted with phosgene in toluene, and the 2-chloro derivatives (466, n = 0, 1, R2 = H, R3 = (CH2), C1, m = 2, 3, R5 = Cl) were then reacted with Meldrum s acid (421) in the presence of triethylamine to give isopropylidene [l-(3-chloroalkyl)piperidin-2-ylidene]malonate and [l-(2-chloroethyl)pyrrolidin-2-ylidene]malonate (468, n = 0, 1 R2 = H ... 

The reaction of 5-chloro-6-methyl-3-phenyl-l,2,4-triazine and diethyl malonate in the presence of sodium hydride in THF at ambient temperature for 12-24 hr gave malonate (489) in 65% yield (87H3259). 

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. 

Chloro-3-ethoxy-2-methyl-2//-pyrazolo[4,3-reacted with the sodium salt of dimethyl malonate in DMF to give (pyrazolo[4,3-c/]pyrimidin-7-yl)malonate (499) [88JAP(K)246377]. 

The reaction of tetrahydro-l,3-thiazine-2-thione and diethyl 2-chloro-malonate in the presence of triethylamine in boiling methylene chloride for 1.5 hr gave tetrahydro-1,3-thiazin-2-ylidenemalonate (508) in 33% yield via 507 through Eschenmoser sulfur elimination, together with traces of the mesoionic derivative (509) [77JCS(P 1) 1107]. In a similar reaction, diethyl 2-bromomalonate afforded the mesoionic compound (509) in 80% yield. Tetrahydro-l,3-thiazin-2-ylidenemalonate (508) was also obtained in 42% yield from 509 by irradiation in the presence of tributylphosphine in ethanol for 15 hr under argon [77JCS(P1)1107]. 

It was later claimed that the thermal cyclization of bis(aminomethylene-malonates) (601, R = H, Me, Cl, N02, R1 = Et) by heating in refluxing diphenyl ether for 15-30 min under nitrogen afforded 8-(substituted amino)quinoline-3-carboxylates (603) in 31-75% yields (78USP4123536). In the cases of the methyl and chloro derivatives (601, R = Me, Cl, R1 = Et), l,10-phenanthroline-3,8-dicarboxylates (602, R = Me, Cl, R1 = Et) could also be isolated as byproducts in 3-4% yields. 

The reaction of aminomethylenemalonates (1540, R2 = H, Cl) and (erf-butyl hypochlorite gave the 2-chloro derivatives of the malonates (1541) (79ZOR1552). 

Dialkyl and isopropylidene malonates were reacted with 2-chloro-l,3-thiazinium chlorides (1686) in methylene chloride in the presence of triethylamine to give (1,3-thiazin-2-ylidene)malonates (1687) in 5-13% yields (89AP593, 89GEP3803783). 

In contrast with the reaction of the chloropyridine, but in keeping with its observed reactions with diethyl malonate under classical procedures, 3-chloro-l,2-benzoisothiazole produces not only the SNAr products, (1) and (2) (Scheme 2.3), but also products arising under the basic conditions from ring opening of the isothiazole... 

Reaction of 3-chloro-1,2-benzoisothiazole with diethyl malonate... 

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