New Approach for the Synthesis of Pyrido[1,2-a]pyrimidines

A novel method was successfully demonstrated towards the synthesis of pyrido[1,2-a]pyrimidines having chloroethyl as an intractable side chain, through dihydrofuranone intermediates. The dihydrofuranone intermediates were synthesized by condensation of 2-aminopyridines with α-acetyl-γ-butyrolactone, which upon cyclization using phosphorus oxychloride or ethanol in sodium ethoxide furnished the pyrido[1,2-a]pyrimidines in good yield.


Results and Discussion
In the present communication, we have developed new methodology towards the synthesis of pyrido[1,2-a]pyrimi-dines with 3-hydroxy or 3-chloroethyl side chain. Our method gives single product with high yield. Thus, 2aminopyridines 1 and α-acetyl-γ-butyrolactone 2 were refluxed in toluene in presence of catalytic amount of PTSA using Dean-Stark apparatus (furnished dihydrofuran-2(3H)-one intermediate 3) in 80-85% yield. Here, PTSA is selective catalyst for protonation of carbonyl carbon to make NH 2 attack more favorable. In presence of other acid catalysts such as conc. HCl, conc. H 2 SO 4 yields mixture of products as these acids also protonated the ester carbonyl. The structure of furanone 3 was characterized by spectral and analytical methods. The IR of 3a showed the bands at 3200 and 1690 cm −1 for NH and lactone CO stretching frequencies; the lactone carbonyl frequency lowered by 30-40 cm −1 due to hydrogen bonding between CO and NH groups. The 1 H NMR of 3a showed two triplets at δ 2.92 and 4.31 for -CH 2 and -OCH 2 protons, respectively, with J = 7 Hz. The singlet appeared at δ2.50 for CH 3 protons as it is attached to olefinic carbon.
The broad singlet appeared at δ10.50 corresponding to NH proton (exchangeable with D 2 O). The 13  Further, the structure of 3a was assigned by HMBC and COSY experiments, which is in agreement with the structure proposed. We have also tried the above reactions in ammonium acetate without using any solvent. Thus, 2-aminopyridine and α-acetyl-γ-butyrolactone were fused in ammonium acetate at 120 • C, and the reaction mixture was stirred in water to remove excess of ammonium acetate and unreacted pyridine if any to yield 4 in 56% yield. Interestingly, it was observed that in ammonium acetate the 3-hydroxyethyl side chain gets acylated to yield 3-acetyl derivative 4. The ammonium acetate worked as acetylating agent, and reaction demonstrates green approach for the synthesis of pyrido [1,2-a]pyrimidines. Similarly, the structure of compound 4 was characterized by spectral and analytical methods. The IR of 4 shows peaks at 1670 (amide) and 1740 (ester) cm −1 . The 1 H NMR spectrum of 4 showed two singlets at δ 2 and 2.52 for OCH 3 and CH 3 protons, and two triplets at δ 3.03 and 4.27 for -CH 2 and -OCH 2 protons, respectively. The multiplet appeared at δ 7.07-8.90 corresponding to 4 aromatic protons. The 13  was cyclized to target pyrido[1,2-a]pyrimidines 5 having 3-hydroxyethyl side chain by refluxing in weak or strong base like NH 3 or NaOH, or was cyclized to 6 having 3chloroethyl side chain by refluxing in POCl 3 . These cyclized compounds 5 and 6 were characterized by IR, 1 H NMR, and elemental analysis. Thus, in the IR spectrum of 5, the bands at 1690 and 3050 cm −1 due to lactone and NH stretching in 3 disappeared, and new bands at 1670 and 3260 cm −1 for OH and C=O groups were observed. The 1 H NMR showed the peaks at δ 3.01 and 3.92 with J = 7 Hz for -CH 2 and -OCH 2 protons. The additional broad singlet that appeared at 4.60δ is due to OH group.
The compound 3 or 5 when refluxed in POCl 3 to finish the pyridopyrimidines 6 having 3-chloroethyl side chain. These compounds were characterized by comparing their mp and spectroscopic data with those of literature-reported compounds [19]; further the product was confirmed by preparing its azido derivative 7, with NaN 3 in DMF, which shows characteristic stretching frequency at 2100 cm −1 for N 3 . The elimination of terminal halide in 6 was carried out using strong base to yield pyrido[1,2-a]pyrimidine 8 with 3-ethylene side chain. Compound 8 shows IR stretching at 1630 cm −1 for carbon-carbon double bond. Two doublets were observed at δ 5.63 with J = 16 Hz and at δ 6.55 with J = 8 Hz for two olefinic protons due to cis-and transcoupling. The =C-H proton appears as triplet at 6.83 with J = 16 and 8 Hz.

Conclusion
The work demonstrates the new methodology towards the synthesis of pyrido[1,2-a]pyrimidines having intractable chloroethyl side chain using cyclic β-ketoesters and 2aminopyridines. The new methods furnish improved yields up to 80-85% of dihydrofuranone intermediate and 70-75% of cyclized pure product.

Experimental
Melting points were determined in open capillary tubes on a Gallenkamp melting point apparatus (Mod. MFB-595 in open capillary tubes), and were uncorrected. Infrared spectra were recorded on a Perkin-Elmer 298 spectrophotometer in potassium bromide pellets unless otherwise stated. 1 H NMR spectra were recorded on a Varian Gemini 200 (200 MHz) spectrometer. 13 C NMR spectra were recorded on a Buker AM 360 (90 MHz) spectrometer. The chemical shifts are reported in δ units relative to internal standard tetramethylsilane. Elemental analyses were performed on Fisons EA 1108 C,H,N-automatic analyzer, and were within ±0.3 of the theoretical percentage. All reactions were monitored by thin layer chromatography on 0.2 mm silica gel 60 F 254 (Merck, Mumbai, India) plates using UV light (254 and 365 nm) for detection. All the reagents were used as received from commercial sources. The solvents were dried over the 40 nm molecular sieves.

General Procedure for the Synthesis of dihydrofuranone-
The mixture of 2-aminopyridines 1 (10 mmol) and α-acetyl γ-butyrolactone 2 (10 mmol, 1.28 g, or 1.10 mL) was refluxed in toluene (30 mL) for 24 hours in presence of catalytic amount of PTSA (0.02 g). The water separator was attached between the reaction flask and the water condenser. The separation of equivalent amount of water indicates the completion of reaction. The solid obtained after cooling the reaction mixture was filtered and washed with toluene and then recrystallized in suitable solvent.

Method B.
The compound 4 (10 mmol) was refluxed in ethanol in presence of catalytic amount of sodium hydroxide for about 3-4 hours (TLC check). The excess of solvent was removed under reduced pressure, and the obtained precipitate was dissolved in water and stirred for 1 hour. Then, it was filtered, washed with water, dried, and recrystallized from proper solvent to afford 5 in good yield.  To a stirred solution of 6 (10 mmol) in DMF/ H 2 O (9 : 1), the sodium azide (2.60 g, 40 mmol) was added and temperature was raised slowly to 80 • C. The mixture was kept at this temperature for about 2 hours until TLC showed no more starting material. The temperature was raised to 110 • C for 1 hour, and then the solvent was removed under reduced pressure; an oily residue was poured in ice-cold water and stirred for 1 hour; the solid obtained was filtered, washed with water, dried, and recrystallized from the proper solvent to afford 7 in good yield.