Intramolecular cyclocondensation of α-oxoketene N , N-, N , Sand N , O-acetals : synthesis of novel pyrido [ 1 , 2-a ] pyrimidinium tetrafluoroborates

A facile regioselective synthesis of substituted pyrido[1,2-a]pyrimidinium salts 5a-f from α-oxoketene N,S-acetals 2a-f, 6a-d from N,N-acetals 3a-d, 7b-c from N,O-acetals 4b-c, and 8a-c from N,S-acetals 2a-c is described. The scope and mechanisms of these reactions have been investigated.


Introduction
2][3] These compounds can behave either as enaminones providing C-C-N component in the product heterocycles 4 or act as 1,3bielectrophilic component in their reactions with bifunctional heteronucleophiles furnishing various annulated heterocycles. 5e have reported earlier, a synthetic route to certain functionalized ketene N,S-, N,N-and N,O-acetals. 6In the subsequent work, we further demonstrated the synthetic elaboration of some of these ketene aminals derived from 2-aminopyridine for the construction of imidazo [1,2a] pyridines by cupric chloride induced oxidative cyclization. 7In continuation of our studies on these ketene aminals, we now report acid induced intramolecular cyclocondensation of some of these intermediates (α-oxoketene aminals from 2-aminopyridines) providing a new route to pyrido [1,2-a]primidinium salts.
Pyrido [1,2-a]pyrimidines constitute a class of bioactive heterocycles bearing bridgehead nitrogen atoms. 8This structural motif is present in the tranquilizer pirenperone, 9a the antiallergic agent ramastine, 9b an antiulcerative agent, 9c an antiasthmatic 9d and antiparasitic agent.9e They are also used as synthetic intermediates or as additives to photographic materials and dyes.8a There are several reports of synthesis of pyrido [1,2-a]pyrimidine-2-and -4-ones by reaction of 2-aminopyridines with a variety of acetylenic esters and ketoesters, [10][11] however only a few reports [12][13] concerning pyrido [1,2-a]pyrimidinium salts not bearing oxo or imino substituents have appeared in the literature.Various 1,3-bielectrophilic compounds used for annulation of 2aminopyridine to give pyrido [1,2-a]pyrimidine salts are restricted only to ketoaldehyde,diketones and their dimethoxyacetals, chlorovinylic ketones and propargylic ketones. 12,13n view of these limited studies, a systematic investigation into development of general synthetic routes for these class of bioactive heterocycles and related compounds is desirable.We herein report a direct one step route for these compounds via intramolecular cyclocondensation of α-oxoketene N,S-, N,N-and N,O-acetals derived from 2-aminopyridine.

Results and Discussion
The desired N,S-, N,N-acetals 2a-f and 3a-d required for this transformations were prepared according to our earlier reported 6 procedure via displacement on αoxoketene S,S-acetals 1a-f by 2-aminopyridine in presence of n-butyllithium (Scheme 1).The corresponding N,O-acetals 4a-b were similarly obtained by replacement of methylthio group in N,S-acetals 2b-c by methoxy group in presence of sodium methoxide in refluxing methanol (Scheme 2). 7he use of perchloric acid as the cyclizing agent generally gave lower yields (60-62%) of perchlorates 8a-c from 2a-c (Scheme 6, Table 2) which were found to be less stable than the corresponding tetrafluoroborates 5a-c (Scheme 3).Thus these perchlorate salts 8a-c underwent hydrolysis and ring opening under alkaline conditions (40% NaOH, rt) yielding the starting N, Sacetals 2a-c as the sole products (Scheme 6) whereas the corresponding fluoroborate salts remained unaffected under these conditions.

Conclusion
In summary we have developed an efficient general synthesis of pyrido[1,2-a]pyrimidinium salts by acid induced intramolecular cyclocondensation of α-oxoketene N,S-, N,N-, and O,N-acetals derived from 2-aminopyridine.In view of easy availability of starting materials the methodology is useful to generate libraries of these biologically important bridgehead heterocycles for probing their biological activities.

Experimental
Melting points were determined on a "Thomas-Hoover" capillary melting point apparatus and were uncorrected.The IR spectra were recorded on a Perkin-Elmer 983 spectrometer. 1H and 13 C NMR spectra were determined on a Bruker ACF 300 operating in a field strength of 300 and 75.5 MHz, respectively.Chemical shifts were reported in parts per million (δ) and coupling constants (J) in Hertz, using in the case of 1 H NMR, tetramethylsilane (TMS) as internal standard and setting, in the case of 13 C NMR, the references at the signal of the solvent (77.0 ppm for CDCl3 and 39.5 ppm for DMSO-d6).Mass measurements were carried out with Jeol JMS D-300 spectrometer.Masses (MS) were reported in unit of mass over charge (m/z), the molecular or base peaks and relative intensities were indicated by (M) and (%) respectively.Elemental analyses were performed on a Heraeus CHN-O-Rapid Analyzer.Dry benzene was obtained by washing with concentrated sulfuric acid followed by azeotropic distillation and stored over sodium wire.THF was distilled over sodium benzophenone ketyl prior to use.Dry ether was obtained by keeping over calcium chloride (fused) and stored over sodium wire.BF3.Et2O was redistilled before use.
All the α-oxoketene N,S-acetals 2a-f, N,N-acetals 3a-d and N,O-acetals 4b-c were prepared according to our earlier reported procedure. 6,7clization of the N,S-acetals 2a-f, N,O-acetals 4b-c and N,N-acetals 3a-d: General procedure for the synthesis of pyrido[1,2-a] pyrimidinium fluoroborates (5a-f, 6a-d, and 7b-c).To a solution of N,S-/N,O-/N,N-acetals (10 mmol) in dry benzene (30 mL), boron trifluoride etherate (3 mL) was added and the reaction mixture was refluxed with stirring for 45min -1 hour.The reaction mixture was then cooled; benzene layer was separated and distilled off under reduced pressure.The remaining residue was dissolved in minimum amount of acetone, neutralized with saturated sodium bicarbonate solution (20 mL) and the solid separated was collected by filtration, washed with water (50 mL) and then with ether (2x10 mL).Analytically pure products were obtained by recrystallization from glacial acetic acid.The structures of 5a-f were fully established from their spectral and analytical data which are given below.
General procedure for the synthesis of pyrido[1,2-a] pyrimidinium perchlorates 8a-c.N,S-acetal 2a-c (10 mmol) was dissolved in 20 mL of dry methanol and stirred for 15 min.Then 60% perchloric acid (3 mL) was added slowly and the reaction mixture was stirred for 2-3 h.The milky colour solution precipitated slowly.The separated solid was filtered and washed with 10 mL of ether and dried.The crude products were recrystallized from hot ethanol.

Basic hydrolysis of 2-Methylthio-4-aryl[1,2-a]pyrimidin-5-ium perchlorate salts 8a-c.
To a stirred solution of 8a-c (10 mmol) in 10 mL of methanol, 40% NaOH solution (20 mL) was added and continued the stirring for 4 h.Then it was poured to 100 mL of water and extracted with 50 mL of chloroform.The organic layer was dried over sodium sulfate and evaporation of the solvent affords the crude products 2a-c, which were purified by column chromatography.

for the formation of substituted pyridopyrimidines 5,6,7 and 8 from 2-4 is shown in the Scheme 7 involving the following steps
: (1[15]nformational rearrangement of enaminone 2 to 2A; (2) BF3Et2O assisted intramolecular ring closure of the intermediate 2A through participation of pyridine ring nitrogen to give cyclized intermediate 2B and, (3) aromatization of the intermediate 2B to products 5-7 via nitrogen lone pair electron assisted elimination of boron coordinated oxygen.The formation of other regioisomeric product i.e 1,8-naphthyridines 3B via intramolecular cyclization on pyridine ring was not observed under these reaction conditions.[14][15][16]Ourefforts to isolate 1,8-naphthyridines such as 9 from 2 under varying conditions were not successful.