Thiemann

Facile Direct a-Ethoxycarbonylation and a-Carbamoylation Reaction
on Cyclic Ketones Promoted by s-l PTC and/or by Ultrasound^1,2

Pavel PAZDERA, Jan Šimbera

Research Group for Chemical Syntheses and Technologies of the Sustainable Development, Department of Organic Chemistry, Masaryk University, CZ-611 37 Brno, Czech Republic; [email protected]

Facile methods for direct ethoxycarbonylation and carbamoylation reactions on some cyclic ketones is described and discussed. A principle of this solution is an application of ultrasonic solid-liquid phase-transfer-catalysis for an enolate anion generation. Enolate anion reacts further with electrophilic reagents, i. e. with ethyl chlorocarbonate in the case of ethoxycarbonylation or nitrourea for carbamoylation reaction.

Displacement of toxic and other hazardous reagents, processes and techniques is ones of the purposes for the chemical syntheses and technologies of the sustainable development (Green Chemistry). The sonochemical phase-transfer-catalysis (PTC) under solid-liquid conditions (s-l PTC) is very important and effective method for these purposes. This method allows displacement of strong bases (LDA, NaH, KH, LiH, alkoxides, Grignard reagents, etc.) by environmental friendly reagents (e. g. limestone, lime) and final inorganic wastes can be recycled or such as in this case applicable to cement production.

Preparations of cyclic 2-oxo-carboxylic acid functional derivatives incl. carboxamides are known as multi-step syntheses, generally. These syntheses proceed through cyclic enamines³ or via by strong base (LDA, sodium, lithium hydride, Grignard reagents etc.) generated enolate anions that are alkoxycarboxylated⁴ and an aminolysis of alkyl 2-oxo-carboxylates for carboxamide preparation follow.

Synthetic applications of nitrourea for the preparation of unsymmetrical substituted ureas by reactions with sufficient basic amines are well known⁵. On the other hand, carbamoylation reactions by nitrourea on nucleophilic sites other than nitrogen were not studied.

It is known generally, that both ultrasound and l-l PTC are very important method for the generation of enolate anions from cyclic ketones for their further reactions and are comparable with action of mentioned above strong bases. On the other hand, these strong bases are applicable at low temperatures. A using of highly concentrated aqueous alkaline hydroxide solutions (ca 40%) in l-l PTC evokes competitive condensation reactions and declines yields of target products.

Now it has been found that cyclic ketones IA - ID (cyclopentanone, cyclohexanone, cycloheptanone and camphor, respectively) react with ethyl chlorocarbonate in the presence of a solid inorganic base (equimolar mixture of calcium carbonate and calcium oxide) in an aprotic solvent (dioxane) at the temperature ca 50°C and reactions are accelerated by an action of phase transfer catalyst (Cetrimide) and/or by ultrasound (the participation of both show expressive synergy effect). In the first step acylation proceed as a “hard” reaction on oxygen atom of enolate anion relatively fast and vinylic carbonates II were isolated and identified, if methods i-iii were used (Scheme 1). The next step of ethoxycarbonylation reaction was a rearrangement of II to more stable 2-oxo-carboxylates III, which were isolated as only the product in the case of method iv application. The corresponding racemic ethyl 2-oxo-carboxylates IIIA - IIID were obtained under ultrasonic s-l PTC in very good yields.

Cycle	Procedure i^*	Procedure ii^*	Procedure iii^*	Procedure iv
A	5 h, < 5% II.	5 h, 15% II., 5% III.	5 h, 20% II., 15% III.	3 h, >95% III.
B	5 h, 10% II., < 5% III.	5 h, 26% II., 10% III.	5 h, 30% II., 30% III.	3 h, >95% III.
C	5 h, 10% II., < 5% III.	5 h, 25% II., 10% III.	5 h, 25% II., 20% III.	3 h, >95% III.
D	10 h, 0%	5 h, 0%	5 h, 0%	5 h, >90% III.

Procedure i: without PTC and US support; Procedure ii: PTC action only; Procedure iii: US action only; Procedure iv: both US and PTC actions.

Table 1. Applied procedure, reaction time and yield of products for direct a-ethoxycarbonylation reaction on cyclic ketones I.

Now it has been found that cyclic ketones IA - ID react also with nitrourea under conditions mentioned above. The corresponding racemic 2-oxo-carboxamides IVA - IVD were isolated in very interesting yields and formation of intermediary carbamates were not observed in the course of the reaction (Scheme 2).

Cycle	Procedure i^*	Procedure ii^*	Procedure iii^*	Procedure iv
A	10 h, 2%	5 h, 15%	5 h, 12%	3 h, >85%
B	10 h, 10 %	5 h, 26%	5 h, 20%	3 h, >95%
C	10 h, 5 %	5 h, 20%	5 h, 20%	3 h, >80%
D	10 h, 0%	5 h, 0%	5 h, 0%	5 h, >80%

Procedure i: without PTC and US support; Procedure ii: PTC action only; Procedure iii: US action only; Procedure iv: both US and PTC actions. ^*Yields determined by HPLC.

Table 2. Applied procedure, reaction time and yield of products for direct a-carbamoylation reaction on cyclic ketones I.

IR, ¹H, ¹³C NMR, mass spectra and, in the some case, a comparison with standard data (m. p. and TLC) confirmed identity of all synthesized products.