Eine einfache Synthese von Malonsäure-mono- und -bis-phenylestern<sup>1</sup>

Copper ion catalyzed carbon-carbon bond forming reaction of N-acyliminium ions with diaryl malonates was achieved with high enantioselectivity. The key intermediates in the method were 2-methoxy-3,4-didehydropiperidines, which were easily prepared through electrochemical oxidation of 1-(p-methoxybenzoyl)piperidine in methanol followed by the conversion of the oxidation product to didehydropiperidine derivative, which was subjected to a chiral Cu(II) catalyzed coupling reaction with diaryl malonates affording diaryl 2-piperidylmalonates. The maximum %e.e. (e.e., enantiomeric excess) was 97% when di-p-chlorophenyl malonate was used as a nucleophile.

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“…Malonate 2s [9], 2u,w [10], 2v [11], and 2x [12] Cu(SbF 6 ) 2 were prepared according to the reported method [13].…”

Section: Generalmentioning

confidence: 99%

Highly enantioselective introduction of bis(alkoxycarbonyl)methyl group into the 2-position of piperidine skeleton

Matsumura

Minato

Onomura

2007

Journal of Organometallic Chemistry

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“…Only a limited number of examples of monosaponification of dimethyl or diethyl malonate have been reported, [14][15][16] but they require a long time and more than one step. Some modified methods are reported applying Meldrum's acid, 17,18) but Meldrum's acid is costly and not suitable for large-scale production of monoalkyl malononate. The enzymatic monohydrolysis of dialkyl malonates reported utilizes an enzyme not commercially available.…”

mentioning

confidence: 99%

Practical Large Scale Synthesis of Half-Esters of Malonic Acid

Niwayama

Cho

2009

Chem. Pharm. Bull.

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Half-esters of malonic acid such as monomethyl malonate and monoethyl malonate are very important building blocks. They have been frequently applied to synthesis of a variety of significant pharmaceuticals and natural products. [2][3][4][5][6][7][8][9][10][11][12][13] However, their commercial availability is still limited and quite expensive, and they are more commonly available as the corresponding potassium salts. In particular, monomethyl malonate became commercially available only last year, but is expensive, or the purities are typically less than 99%, such as 96%. Therefore, development of a more efficient synthetic method for monoalkyl malonates on a large scale is essential.One method for preparation of half-esters is monosaponification of symmetric diesters, but successful distinction of the two identical ester groups remains challenging. In fact, monosaponification typically produces a dirty mixture of the starting diester, the corresponding halfester, and the diacid, even with the use of one equivalent of a base. In particular, the synthesis of half-esters of malonic acid is still difficult especially on a large scale, because of potential decarboxylation. Only a limited number of examples of monosaponification of dimethyl or diethyl malonate have been reported, [14][15][16] but they require a long time and more than one step. Some modified methods are reported applying Meldrum's acid, 17,18) but Meldrum's acid is costly and not suitable for large-scale production of monoalkyl malononate. The enzymatic monohydrolysis of dialkyl malonates reported utilizes an enzyme not commercially available. 19) Other methods by carbalkoxylation of malonic acid are also reported, but the yields are rather modest. 20)Herein we describe a large-scale synthesis of monomethyl malonate and monoethyl malonate applying the selective monohydrolysis of symmetric diesters we reported before. Earlier, we reported a selective monohydrolysis that enables a series of symmetric diesters with the use of an aqueous NaOH or KOH and a co-solvent such as tetrahydrofuran (THF) or CH 3 CN at 0°C (Chart 1).21) This reaction is practical, mild, and environmentally benign, and has been of interest in process chemistry, exhibiting the potential of scaling up. The selectivity of this reaction was initially found to be particularly high for cyclic 1,2-diesters with the two ester groups in close proximity, even with the use of almost 2 equivalents (or greater) of the base, producing the corresponding half-esters in near-quantitative yields. We reasoned that electrostatic attractive interaction between the two closely located carbonyl groups may play a role in this high selectivity. We recently modified the conditions of this reaction and applied them to monohydrolysis of a series of dialkyl malonates and their derivatives on the scale of 1.2 mmol. 22) They show that the yields are around 80% to near quantitative. Here we examined the possibility of scaling up this reaction, focusing on monomethyl malonate and monoethyl malonate, which are among...

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“…Junek and coworkers described [9] the possibility for the synthesis of monoesters of malonic acid via Meldrum's acid. Several alcohols and thioalcohols were utilized to synthesize monoesters by this method via methyl-Meldrum's acid in the following way: The yields of monoesters obtained from methylmalonic acid by different methods are compared in Table 1.…”

mentioning

confidence: 99%

Synthesis of ethyl [¹⁴CH₃]methylmalonyl thioglycolate as a possible substrate analogue of [¹⁴CH₃]methylmalonyl coenzyme‐A

Kovács¹

1991

Labelled Comp Radiopharmac

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Ethyl methylmalonyl thioglycolate is a potential substrate analogue of methylmalonyl-coenzyme-A (methylmalonyl-CoA) in the investigation of propionic acid metabolism. To prove this hypothesis , the tracer ethyl [ 4 C 4 ]methylmalonyl thioglycolate was synthesized via methyl-Meldrum's acid to carry out the biochemical examinations. The method described can also be used to synthesize [ 4CH dmethylmalonyl-CoA by transesterif ication of active label led methylmalonyl thiophenyl ester. This latter intermediate is chemically 1 4 stable when stored at room temperature, and the unstable [ CH3]methylmalonyl-CoA can be prepared in one Step just preceeding the biochemical experiments. thioglycolatc , ,,methyl-Meldrum's acid, [ C%]methylmalonyl thiophenolate, [ C% ]methylmalonyl-CoA.

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Eine einfache Synthese von Malonsäure-mono- und -bis-phenylestern¹

Cited by 29 publications

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Highly enantioselective introduction of bis(alkoxycarbonyl)methyl group into the 2-position of piperidine skeleton

Highly enantioselective introduction of bis(alkoxycarbonyl)methyl group into the 2-position of piperidine skeleton

Practical Large Scale Synthesis of Half-Esters of Malonic Acid

Synthesis of ethyl [¹⁴CH₃]methylmalonyl thioglycolate as a possible substrate analogue of [¹⁴CH₃]methylmalonyl coenzyme‐A

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Eine einfache Synthese von Malonsäure-mono- und -bis-phenylestern1

Cited by 29 publications

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Highly enantioselective introduction of bis(alkoxycarbonyl)methyl group into the 2-position of piperidine skeleton

Highly enantioselective introduction of bis(alkoxycarbonyl)methyl group into the 2-position of piperidine skeleton

Practical Large Scale Synthesis of Half-Esters of Malonic Acid

Synthesis of ethyl [14CH3]methylmalonyl thioglycolate as a possible substrate analogue of [14CH3]methylmalonyl coenzyme‐A

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Eine einfache Synthese von Malonsäure-mono- und -bis-phenylestern¹

Synthesis of ethyl [¹⁴CH₃]methylmalonyl thioglycolate as a possible substrate analogue of [¹⁴CH₃]methylmalonyl coenzyme‐A