Novel 4-Aroyl-3-alkoxy-2(5H)-furanones as Precursors for the Preparation of Furo[3,4-b][1,4]-diazepine Ring System‡

A general synthesis of tetronic acid derivatives, namely 4-aroyl-3-alkoxy-2(5H)-furanones, is achieved via the treatment of an anhydrous dimethylformamide (DMF) solution of 4-aroyl-3-hydroxy-2(5H)-furanones with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base at -10-0°C, followed by the addition of alkyl iodide. Their structural assignments are based on spectroscopic data and confirmed by X-ray crystallography. These furanones were used as starting materials for the preparation of furodiazepines.

Depending upon the reactivity of the alkyl iodide an excess ranging between one to five equivalents was used to favor the formation of the corresponding ether 2 in an SN2-like reaction. Secondary alkyl iodide were also could be used in this reaction. Structural assignments of the ethers 2 are made on spectroscopic ground, which are summarized in Table 2 structures 2 was obtained by X-ray analyses [11]. X-ray structures were obtained for the compounds 2h (R= CH 3 (CH 2 ) 2 CH 2 -), 2j (R= C 6 H 5 CH 2 -), 2k (R= CH 2 =CHCH 2 -), 2l (R= (CH 3 ) 2 CHCH 2 -) and 2o (R= (CH 2 ) 4 CH-). Figure 1 shows the X-ray structure of 2k as a prototype. By using this O-alkylation procedure for the preparation of compounds of type 2, a series of diazepines 1 were synthesized by reacting several compounds of type 2 (R= CH 3 ) with ethylenediamine in chloroform solutions (Table 3). This reaction is not limited to R= CH 3 as demonstrated by the reaction of 2k (R= CH 2 =CHCH 2 -) with 1,2-ethylenediamine which formed the corresponding diazepine 1f in 66% yield (up from 39% for 2f, R= CH 3 ).

Conclusions
We have presented a facile route for the formation of 3-alkoxy-2(5H)-furanones 2. These compounds are key intermediates in the synthesis of furodiazepines. These furodiazepines possess interesting structural similarities to benzodiazepines which are presently under biological evaluation, and shall be reported elsewhere.

General
Melting points were determined on a Melt-Temp apparatus and are uncorrected. TLC was conducted on plated prepared from E. Merck silica gel 60 F 254 , 0.2 mm thickness. Silica gel from EM science in a column with 20 mm diameter was used for flash column chromatography pressured with compressed nitrogen. NMR spectra were acquired on a Bruker AC250 spectrometer with TMS as internal standard. A Hewlett-Packard 6890 Gas chromatograph/mass spectrometer was used to record MS data. For high resolution mass spectra a Kratos MS-801 DS-55 spectrometer was used. Elemental analysis were performed by M-H-W Laboratories, Phoenix, Arizona.
General Procedure: 4-Aroyl-3-alkoxy-2(5H)-furanones (2). DBU (0.37 mL, 2.5 mmol) was added to a solution of 3 (2.5 mmol) in anhydrous DMF (35 mL) in a three-neck-round-bottom flask equipped with a thermometer and a magnetic stirring bar under an inert atmosphere. The solution was cooled to a temperature between -10-0°C and stirred for 10 min. Then an excess of alkyl iodide was added and the solution was stirred for 2 h. The resulting mixture was allowed to come to room temperature and stirring was continued for 24 h. The yellow-brown reaction mixture was poured into ice water (300 mL) and extracted with ether (3 x 25 mL). The organic layers were combined and dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was chilled overnight. Solids were recrystallized from ethanol, while oils were subjected to column chromatography on silica gel using methylene chloride as eluent. Spectroscopic and analytical data are given in Table 2.
To a solution of 2 (2.5 mmol) in chloroform (50 mL) was added 1,2-ethylenediamine (3 mmol) under an inert gas atmosphere. The mixture was stirred at room temperature for 24 h. The solvent was evaporated and the resulting residue was recrystallized from methanol or ethanol. Spectroscopic and analytical data are given in Table 3.    a) Numbers are given so that Ar will match the ones in Table 1; b) in CDCl 3 as solvent