Synthesis of the new ring systems indeno[1,2-d ]pyrimidinones, indeno[1,2-e ]pyrrolo[1,2-a ]pyrimidinones and indeno[1,2-e ]pyrimido[1,2-a ]izoindoles

Indeno[1,2-d ]pyrimidinones, indeno[1,2-e ]pyrrolo[1,2-a ]pyrimidinones and indeno[1,2-e ]pyrimido[1,2-a ]izoindoles were prepared as new ring systems by ring enlargement of azetidinone 2 and ring closure of amino ester 3 and 1,3-diamine 5 . These ring closures resulted in pure diastereomers, the stereochemistry of which was determined by NMR spectroscopy.


Introduction
In the past two decades, a number of cyclic β-amino acid derivatives have been synthesized.Some of them have useful pharmacological effects, 1 and they are widely used for the preparation of saturated 1,3-heterocycles.][5][6][7][8][9][10] Because of their therapeutic interest, the syntheses of cycloalkane-fused pyrimidinones have been studied, 2 but syntheses of their indane-condensed derivatives have not yet been reported.
Our present aim was to prepare new cis-1-aminoindane-2-carboxylic acid derivatives and to synthesize some indane-fused pyrimidines.

Scheme 1
The indane-condensed pyrimidinones 6-10 were prepared by ring enlargement 2,13 of azetidinone 2 with the corresponding imidates or lactim ethers.When 2 was melted with imidates or lactim ethers at 150 ºC for 8 h, the desired pyrimidinones 6-10, were formed.The first step in the reaction is the splitting-off of alcohol, resulting in an amidine intermediate which, after transamidation, yields the ring enlargement products (Scheme 2).When amino ester 3 was reacted with one equivalent of p-chlorobenzaldehyde in toluene at room temperature Schiff base 11 was formed.This was treated with NH 3 or MeNH 2 in MeOH solution to afford a mixture of indeno [1,2-a]pyrimidin-4-one C-2 epimers (12, 2:1; 13, 3:1); fractional crystallization furnished the major diastereomers.
On reaction with various isocyanates and isothiocyanates, 3 yielded the urea and thiourea derivatives 14a-d.When attempts were made to cyclize 14a-d to pyrimidinones, only Nmethylthiourea 14b was cyclized successfully to pyrimidinone 15 in EtOH containing 22% dry HCl.Under the same conditions, the other derivatives gave the elimination product indene-2carboxylic acid (16) (Scheme 3).When N-methyldiamine 5 was reacted with levulinic acid or 2-formylbenzoic acid in boiling toluene, penta-and tetracycles 19 and 22 were formed in good yields.NMR measurements indicated that 19 and 22 were formed with excellent diastereoselectivity (de ~ 100%) with the relative configurations depicted in Scheme 4. The ring closures of 5 can be categorized as domino reactions. 14The intermediates 17 and 20 possess a ring-chain tautomeric character, the second ring closure step causing a shift in the tautomeric equilibrium.The high diastereoselectivity can be explained as a result of the kinetic control governing the second ring closure. 15 Diamine 5 was condensed in MeOH with seven aromatic aldehydes with different electronic characters.The reaction reached completion in a few hours, even at room temperature.After evaporation and purification, well-defined products 23a-g were obtained.The 1 H NMR spectra clearly proved that these derivatives exist as ring-ring epimers.The ratios of the two ring forms were determined by integration of the well-separated N-CHAr-N (ring) singlets.The epimeric rates were practically constant (23B:23C = 6:4), independently of the electronic character of the aryl substituent.
These results are in accordance with those of our previous studies, because some of the Nsubstituted hexahydropyrimidinones and tetrahydroquinazolinones proved to be ring-chain tautomeric mixtures in CDCl 3 at 300 K, whereas the N-methylhexahydropyrimidine and Nmethyltetrahydroquinazoline derivatives exist solely as ring forms. 14

NMR spectroscopy
For 12 and 13, the relative orientation of the 2-aryl substituent was determined by using characteristic NOE interactions.The clear NOESY cross-peak between H-2 and H-9b in 12 indicates a trans relationship for 2-aryl and H-9b.As regards 18 or 19, the relative spatiality of H-4b was determined by modelling and consideration of the NOE interactions.The rigid structures show that in 18 significant NOE cross-talk should be observed between H-4b and H-11b, but this is not detected in the NOESY spectrum.All the other spectral parameters accord well with structure 19.In 21 or 22, an NOE signal can be detected from Me-3a to H-5ax.H-5ax exhibits a vicinal coupling ca. of 11 Hz and a weak NOESY cross-peak to H-5a.These strongly support Me-3 and H-5a being situated on opposite sides of the heterocyclic ring, indicating structure 22.
In the spectra of 23, we found no sign of the azomethine proton of the open form.The proportions of the two ring forms were calculated from the integrals of the H-2 signals.The chemical shifts of H-2 of ring forms B and C were assigned via the NOESY NMR.The H-2 signal at around δ 4.2 ppm has an NOE cross-peak with H-9b, indicating the cis orientation (ring form B), while the H-2 signal at around δ 4.6 ppm has no NOE cross-peak with H-9b, indicating the trans orientation of these protons (ring form C).

Experimental Section
General Procedures.Melting points were determined with a Koffler apparatus and are not corrected.Elemental analyses were performed with a Perkin-Elmer 2400 CHNS instrument.Merck Kieselgel 60F254 plates were used for TLC: the eluent was toluene-MeOH 4:1.MS data were obtained with a Finnigan Mat 95S spectrometer in EI mode.Column chromatography was performed on silica gel (Merck 60, 70-230 mesh). 1 H NMR and 13 C NMR spectra were recorded in CDCl 3 solution in 5 mm tubes, at room temperature, on a Bruker DRX 400 spectrometer at 400.13 ( 1 H) and 100.61 ( 13 C) MHz, with the deuterium signal of the solvent as the lock and TMS as internal standard.For the equilibria to be established in the tautomeric compounds, samples were dissolved in CDCl 3 and the solutions were allowed to stand at ambient temperature for 1 day before the 1 H NMR spectra were run.The number of scans was usually 64.3,4-Benzo-6azabicyclo[3.2.0]heptan-7-one (2) and ethyl cis-1-aminoindane-2-carboxylate (3) were prepared according to reported methods. 11s-1-Aminoindane-2-carboxylic acid methylamide (4).3,4-Benzo-6-azabicyclo[3.2.0]heptan-7-one (2; 4.7 g, 0.03 mol) was dissolved in 20 ml dry CH 2 Cl 2 .The solution was stirred, and 0.37 g 4-dimethylaminopyridine (DMAP) was added, followed by di-tert-butyldicarbonate (7.2 g, 0.033 mol).After stirring at room temperature for 5 h, the reaction mixture was left to stand overnight.The brownish reaction mixture was then extracted with brine and dried (Na 2 SO 4 ).After evaporation, 7.1 g 3,4-benzo-6-tert-butoxycarbonyl-6-azabicyclo[3.2.0]heptan-7-one was obtained, as a white crystalline product.The crude protected β-lactam was dissolved in 60 ml of a 40% solution of MeNH 2 in dry MeOH.The reaction mixture was allowed to stand at 4 °C for 2 h and was next evaporated, first at room temperature and then on a 60 °C water bath.A white crystalline powder was obtained.The protected cis-aminocarboxamide hydrochloride was dissolved in 20 ml 3 M HCl solution in EtOH.For removal of the protecting group, the reaction mixture was left to stand at room temperature for 2 h and then evaporated at room temperature.After evaporation, 4.2 g 4 hydrochloride was obtained, which was purified by recrystallization from EtOH.Amide base 4 was obtained from the hydrochloride by alkaline treatment (10% NaOH), extraction (CH 2 Cl 2 ), and evaporation under reduced pressure.(5).To a stirred suspension of LiAlH 4 (1 g, 26 mmol) in 60 ml dry THF was added a solution of 4 amide (2 g, in 10 mmol dry THF).The resulting suspension was refluxed for 4 h and then decomposed by the addition of a mixture of 2 ml water and 10 ml THF.The inorganic material was filtered off and washed with THF (3 x 20 ml).After filtration, the solvent was evaporated off to give an oil, which was dissolved in EtOH (20 ml) and converted to the crystalline hydrochloride of 5 with 20% HCl in EtOH (2 ml) and Et 2 O (50 ml).The crystals were filtered off and recrystallized from MeOH-Et 2 O. Pure diamine base 5 was obtained from the hydrochloride by alkaline treatment (10% NaOH), extraction (CH 2 Cl 2 ), and evaporation under reduced pressure.

General procedure for the preparation of tetrahydroindeno[1,2-d]pyrimidin-4-ones 6-8
A mixture of azetidinone 8 (0.5 g, 3.14 mmol) and the corresponding ethyl benzimidate (3.14 mmol) was kept at 150-160 °C for 8 h.The end of the reaction was detected by means of TLC.After cooling, the products were recrystallized from EtOH.General procedure for the synthesis of 9 and 10 A mixture of azetidinone 2 (0.5 g, 3.14 mmol) and the corresponding lactim ether (6.28 mmol) was kept at 150-160 °C for 8 h.The excess of lactim ether was then evaporated off and the residue was dissolved in Et 2 O (20 ml), treated with charcoal, filtered and left to stand at 4 °C.The product 9 or 10 was filtered off and recrystallized from n-hexane.

General procedure to react diamine 5 with aromatic aldehydes 23a-g
To a suspension of diamine 5 (0.2 g, 1.13 mmol) in 20 ml absolute MeOH, an equivalent amount of aromatic aldehyde was added (liquid aldehydes were freshly distilled), and the mixture was allowed to stand at ambient temperature for 1 day.The solvent was then evaporated off and the evaporation was repeated after the addition of 10 ml toluene.The crystalline products were filtered off and recrystallized from iPr 2 O-EtOAc.The oily product 23b was dried in a vacuum desiccator for 24 h.

Table 1 .
Physical data on compounds 23a-g