Malonates in Cyclocondensation Reactions

The use of malonates such as diethyl malonates 9, (chlorocarbonyl)ketenes 15 and bis(2,4,6-trichlorophenyl) malonates 18 as reagents for cyclocondensation with 1,3-dinucleophiles to give six-membered heterocycles is described. Further attempts to use malonates such as bis(trimethylsilyl) malonates 19 and bis(carbamimidoyl) malonates 29 as new cyclocondensation agents are described .


Introduction
2-Substituted malonic acid derivatives are known to be very useful reagents in the field of Organic Synthesis. Besides the preparation of simple derivatives such as malonates or malonamides, malonic acid derivatives 1 react by cyclocondensation with dinucleophiles such as 2 to afford 5-, 6-and 7membered rings and thus give a variety of so-called "malonyl heterocycles" which possess as structural element a 1,3-dicarbonyl moiety 3 or its enolized tautomeric 1-oxo-3-hydroxy form 4 (Scheme 1).

Scheme 2
The first part of this paper (Schemes 3-7) briefly reviews cyclocondensations with reaction paths which are already known. As examples, reaction products are described, which are either new or have not been obtained earlier in the method reported in this paper. The second part (Schemes 8-10) describes our attempts to introduce new cyclocondensation agents such as bis-silyl malonates, bissuccinimidyl-and bis-carbamimidoyl malonates.

Scheme 3
Reported procedures for compounds of type 11 involve multistep procedures (see e.g. ref. [6], which describes the reaction of 8a with bis(2,4,6-trichlorophenyl) 2-(4-methoxyphenyl)malonate 18, R 1 = 4-MeO-C 6 H 4 ). We were able to show that especially 2-arylmalonates 9 (R 1 = Ph) provide at reaction temperatures above 250 o C good synthons for simple and quick cyclization reactions in good to moderate yields [5] (probably via arylketene ester intermediates 10, R 1 = Ph [7]). The only disadvantage of this reaction sequence is its high reaction temperature, which prevents its use for sensitive substrates and substituents. The ketene mechanism is also supported by observations obtained during the reaction: at temperatures below 200 o C the first mole of alcohol is observed to be liberated when the open chain ester or amide is formed, then it needs a temperature of more than 250 o C to liberate the second mole of alcohol and to form the ketene intermediate 10. Thermal investigations of the thermolysis reaction of the phenol 8a and the malonate 9a by differential scanning calorimetry (DSC) show, that at about 160 o C a first exothermic reaction starts immediately after the endothermic boiling point of the phenol 8a (in accordance with findings during the formation of malonamides), then a weak exothermic reaction begins at about 240 o C followed by a strong exothermic reaction (onset 260 o C). These data are in accordance with the observations obtained from the synthetic experiments as described above.

Scheme 5
The most electrophilic malonic acid derivative has been found in carbon suboxide 17 [12], which reacts with dinucleophiles 13 at low temperatures (-78 o C) to give five-or six-membered malonyl heterocycles 16 (Scheme 6). Its preparation is performed either by pyrolysis of diacetyl tartaric anhydride, or from malonic acid 12b and phosphorus pentoxide, or from bis(trimethylsilyl) malonate 19b and phosphorus pentoxide [12].

Scheme 7
The reactive malonate reagents, malonyl dichlorides 14, carbon suboxide 17 and bis(2,4,6trichlorophenyl) malonates 18 are very valuable reagents, but they are expensive and can be stored only for a limited time without decomposition. Another aspect is that malonyl dichlorides 14 and bis(2,4,6-trichlorophenyl) malonates 18 contain chlorine, an element of ill repute in Green Chemistry. Consequently we made several attempts to replace these reagents with other reactive derivatives without such disadvantages.
For this reason we have tried to prepare a new generation of reactive malonates such as trimethylsilyl malonates and mixed anhydrides of malonates. As test substrates we have used aromatic amines which have only weak basic nitrogens, with which suitably reactive malonates should readily form malondianilides 20 or cyclization products at low temperatures. Bis(trimethylsilyl) malonates 19 have been prepared according to a reported method [14], by reacting the appropriate malonic acid 12 with trimethylsilyl chloride in the presence of pyridine. The spectroscopic data of 19 confirmed their structure. The known reaction of anilines with substituted diethyl malonates 9 gives malondianilides at temperatures below 200 o C, and 4-hydroxyquinolones such as 11b are obtained at higher temperatures (Scheme 4). With bis(trimethylsilyl) 2-ethylmalonate 19b, a reaction occured at similar temperatures as observed with malonates 9, but the products were 2ethyl-N,N'-diphenylmalondiamide 20, obtained as a minor byproduct, together with butyranilide 21, which is formed from 19b after a desilylation and decarboxylation step. 2-Cyanomethylbenzimidazole 22 was used as 1,3-dinucleophilic substrate for cyclocondensation with bis(trimethylsilyl) malonates 19. According to a previous investigation [15] the dinucleophile 22 reacts readily with reactive bis(2,4,6-trichlorophenyl) malonates 18 in refluxing bromobenzene at 150 o C to give pyrido[1,2a]benzimidazoles. The reaction of bis(trimethylsilyl) malonates 19 in refluxing bromobenzene, however, gave only C-acylation to yield 2-(2,3-dihydro-1H-benzimidazol-2-yliden)-3-oxoalkanenitriles 23 without cyclization to the nitrogen (Scheme 8). Thus our experiments revealed that bis(trimethylsilyl) malonates 19 are no substitutes for reactive malonyl reagents 14, 15, 17 and 18. Their reactivity for synthetic purposes is too small and decomposition takes place already at rather low reaction temperatures.

Scheme 8
Mixed anhydrides of malonic acid (12, R 1 = H) with acetic acid have been used as in situ reagents for reactive 1,3-dinucleophiles, however, the scope of this reaction has been found to be limited to a small number of 1,3-dinucleophiles such as ureas [1] pyridinediones 26. As an example, the synthesis of 4-hydroxy-6,7-diphenyl-pyrano[3,2-c]pyridine-2,5(6H)-dione (26a, R 2 = H) is described. In order to obtain a more versatile reactive anhydride reagent, we tried to synthesize a mixed anhydride 27 of malonic acid and carbonic acid by reaction of malonic acids 12 with ethyl chloroformate in the presence of triethylamine at 0-5 o C in dichloromethane using a standard procedure for benzoyl malonates [16]. However, only 2-substituted diethyl malonates 9 have been isolated, a result which is similar to the findings reported for the mixed anhydrides of the half ester of malonic acids [17] (Scheme 9).

Scheme 9
The reaction of succinimidyl-and O-acylurea esters is a well-known and widely used method for acylations and condensations of carboxylic acids in peptide synthesis [18]. The preparation of succinimidyl esters is in general mediated by the activation with N,N'-diisopropylcarbodiimide [18], which should give as intermediate the bis(carbamimidoyl) malonates 29. Nucleophilic attack by Nhydroxysuccinimide should give succinimidylates 28, and as byproduct N,N'-diisopropylurea. The succinimide-N-oxy group in succinimidylates is reported as a good leaving group in the reaction with nucleophiles [18]. The reaction of malonic acids 12 with N-hydroxysuccinimide has been performed using a recently successfully applied reaction sequence for alkanoic acids [19]. We used this procedure and dissolved the appropriate malonic acid 12 in dry dichloromethane; then a small excess of N-hydroxysuccinimide was added, the solution was cooled and a small excess of N,N'-diisopropylcarbodiimide was then added. After a reaction time of 24 hours, the reaction mixture contained a large number of compounds. The main product was N,N'-diisopropylurea, the other compounds were present in too small quantities and they have not been isolated. Other solvents such as diethylether decreased the number of compounds, however we were unable to isolate bis(succinimidoyl) malonates 28.
Similar reactive derivatives of carboxylic acids have been described in ref. [20]. We used the reported procedure and reacted 2-benzylmalonic acid (12a) with N,N'-diisopropylcarbodiimide in diethylether at 0 o C for 2 hours and then removed the solvent. The resulting oil contained one new main product, probably bis(carbamimidoyl) 2-benzylmalonate 29a as shown by NMR data, and some byproducts in minor quantities. The crude oil was not further purified and reacted with aniline as an example nucleophile in dioxane at room temperature. However, tlc analysis did not show any reaction, which means that at low temperatures no reaction takes place between 29a and aniline (Scheme 10). At higher temperatures only decomposition products have been observed.

5-Benzyl-4-hydroxy
A mixture of aniline (0.93 g, 10 mmol) and bis(trimethylsilyl) 2-ethylmalonate (19b, R 1 = Et) (2.77 g, 10 mmol) was heated in an oil bath at 200 o C for 8 h. After cooling to room temperature, the reaction mixture was digested with ethanol and cooled to 5 o C. The dianilide 20 precipitated and was filtered by suction. The yield of 20 was 0.2 g (7 %), colorless prisms, mp 216-219 o C (ethanol); tlc and spectral data are identical with an authentic sample obtained from diethyl 2-ethylmalonate and aniline. The filtrate was concentrated to 5 mL under reduced pressure and the residue treated with hexane. The precipitate was filtered by suction to yield 0.5 g (31 %) of 21, mp 87-89 o C (hexane); lit. mp. 91-92 o C [25]; tlc and spectral data are identical with an authentic sample obtained from butanoic chloride and aniline.

Bis(carbamimidoyl) 2-benzylmalonate (29a).
To a solution of 2-benzylmalonic acid (12a, R 1 = CH 2 Ph) (1.95 g, 0.01 mol) in diethylether (50 mL) at 0 o C, N,N'-diisopropylcarbodiimide (2.52 g, 0.2 mol) was added and stirred at this temperature for 2 hours. The solvent was removed i.vac. and the oily residue washed with hexane and dried. The yield was 4.2 g of a yellow oil, which contained one new main product (shown by tlc analysis) besides traces of 12a and N,N'-diisopropyl urea. The oil was used without further purification for reactions. 1