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

Authors: Raghunath B. Toche; Bhausaheb K. Ghotekar; Muddassar A. Kazi; Shivaraj P. Patil; Madhukar N. Jachak
Journal: Scholarly Research Exchange
 (2008)

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## Abstract

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.


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## Body

## 1. Introduction

Heterofused pyrimidines  exhibit promising antiviral
[1], antibacterial [2],
anti-AIDS [3], and antinociceptive [4] activities. Fused pyrimidines are
extensively  used in neurology, particularly
in the treatment of
neurodegenerative disorders such as Parkinson’s disease [5], antianxiety
disorders [6], and depression [7]. Fused pyrimidines are selective inhibitors
for multidrug resistance (MDR) [8]. Folate metabolism has long been recognized
as an attractive target for cancer chemotherapy because of indispensable role
of
fused pyrimidines’ antifolates as antitumor agents [9].
Resperdone is a derivative of pyrido[1, 2-a]pyrimidines[10, 11].
These compounds showed
antipsychotic activity
[12] were used as α2 antagonists
[13–15]. They exhibits high affinity for α2-adrenoceptor with
high selectivity versus the α-receptor and possesses potent in vivo
central activity
[16, 17],
Wamhoff and Korte [18, 19] have
reported the  synthesis of pyrido[1,2-a]pyrimidines by using
2-aminoheterocylic compounds and α-acetyl-γ-butyrolactone by refluxing dioxane or using
PPA, and observed the formation of mixture of products. After the successful
study of the reactions of α-formy-γ-butyrolactone with 2-aminoheterocyles
[20],
our interest was sparked to synthesize old compounds by new method with improved yields.


## 2. Results and Discussion

In the present communication, we have developed new
methodology towards the synthesis of pyrido[1,2-a]pyrimidines with
3-hydroxy or 3-chloroethyl side chain.
Our method gives single product with high yield. Thus, 2-aminopyridines 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 NH2 attack more favorable. In presence of other acid catalysts such as conc. HCl,
conc. H2SO4 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 1690cm−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 1H NMR of 3a showed two triplets at δ2.92 and
4.31 for –CH2 and –OCH2 protons, respectively, with J=7 Hz. The singlet appeared at δ2.50 for CH3 protons as it is attached to olefinic carbon.The broad
singlet appeared atδ10.50 corresponding to NH proton (exchangeable
with D2O). The C13 NMR spectrum of this compound exhibits peaks at δ19.48, 26.26, 65.43, 93.62, 113.9, 117.51,
137.86, 147.83, 152.41, 153.52, and 173.72. 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 1H NMR spectrum of 4 showed two singlets at δ2 and
2.52 for OCH3 and CH3 protons, and two triplets at δ3.03 and 4.27 for –CH2 and –OCH2
protons, respectively. The multiplet appeared
at δ7.07–8.90
corresponding to 4 aromatic protons. The C13 NMR spectrum of this compound exhibits peaks at δ21.06,
22.72, 26.58, 62.59, 111.46, 114.98, 125.83, 127.06, 135.30, 148.79, 157.87,
162.62, and 171.06. Further, the structure of 4 was assigned by HMBC and
COSY experiments, which is in agreement with the structure proposed. The
compound 3 was cyclized to target
pyrido[1,2-a]pyrimidines 5 having 3-hydroxyethyl side chain by refluxing in weak or strong base like NH3 or NaOH, or was cyclized to 6 having 3-chloroethyl side chain by
refluxing in POCl3. These cyclized compounds 5 and 6 were
characterized by IR, H1 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 H1 NMR showed the peaks at δ3.01 and 3.92 with J=7 Hz for –CH2 and –OCH2 protons. The additional broad singlet that
appeared at 4.60δ
is due to
OH  group.The compound3 or 5 when refluxed in POCl3 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 NaN3 in DMF,
which shows characteristic stretching frequency at 2100 cm−1 for N3.
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 δ5.63 with J=16 Hz and at δ6.55
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.


## 3. 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 2-aminopyridines. The new methods furnish improved yields up to 80–85% of
dihydrofuranone intermediate and 70–75% of cyclized
pure product.


## 4. 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.H1 NMR spectra were recorded on a Varian Gemini 200 (200 MHz)
spectrometer. C13 NMR spectra were recorded on a Buker AM 360 (90 MHz) spectrometer. The
chemical shifts are reported in δunits 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 F254 (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.


### 4.1. General Procedure for the Synthesis of dihydrofuranone-2-(3H)-one (3a–3c)

The mixture of 2-aminopyridines1 (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.


### 4.2. 3-[1-(Pyridin-2-ylamino)ethylidene]dihydrofuran 2(3H)-one
(3a,C11H12N2O2)

Yield 1.69 g (83%), mp 87-88°C (ligroin,
colorless  flakes); IR: (KBr): 3200 (NH), 3050(CH3),
1690 (C=O lactone), 1640, 1600(C=C), 1570, 1500, 1480, 1410 cm−1; H1 NMR: (CDCl3) δ=2.50
(s, 3H, CH3), 2.92 (t, J=7 Hz, 2H, CH2), 4.31 (t, J=7 Hz, 2H, OCH2), 6.75 (dd, J=2.1 & 8.1 Hz, 1H, C3–H), 6.83 (dt, J=2.4 & 8.3 Hz, 1H, C4–H), 8.75 (dt, J=2.4 & 8.3 Hz, 1H, C5–H), 8.25 (dd, J=2.4 & 8.3 Hz, 1H, C6–H), 10.5 (bs, 1H, NH) ppm. C13 NMR (CDCl3): 19.48 (CH3), 26.26 (CH2), 65.43 (CH2OH), 93.62 (C=C), 113.99 (C5), 117.91 (C4); 137.86 (C6); 147.83 (C2); 153.22(C3); 173.72 (C=O) ppm.


### 4.3. 3-{1-[(6-Methylpyridin-2-yl)amino]ethylidene} dihydrofuran-2(3H)-one
(3b, C12H14N2O2)

Yield 1.74 g (80%), mp 105-106°C (cyclohexane,
colorless flakes); IR (KBr): 3200 (NH), 2920, 2860(w, CH3), 1690(C=O lactone), 1650(NH),
1600(C=C), 1580, 1560, 1480, 1430 cm−1; H1 NMR (CDCl3): δ=2.40
(s, 3H, CH3), 3.95 (t, J=7 Hz, 2H, CH2), 4.42 (t, J=7.1 Hz, 2H, OCH2), 6.63 (dd, J=7.8 & 2.8 Hz, 1H, C3–H), 7.45 (t, J=7.8 & 7.8 Hz, 1H, C4–H); 6.70 (d, J=7.9 & 2.9 Hz, 1H, C5–H); 10.55 (bs, 1H, NH) ppm.


### 4.4. 3-{1-[(4-Methylpyridin-2-yl)amino]ethylidene} dihydrofuran-2(3H)-one
(3c, C12H14N2O2)

Yield 1.85 g
(85%), mp 72-73°C
(cyclohexane, colorless flakes); IR (KBr): 3200 (b, NH), 2910, 2880(w, CH3), 1780 (s, C=O lactone), 1650 (s, NH),
1610, 1560, 1480, 1450, cm−1; H1 NMR (CDCl3) δ2.33 (s,
3H, CH3), 2.52 (s, 3H, CH3), 2.92 (t, J=7 Hz, 2H, CH2), 4.36 (t, J=7 Hz, 2H, OCH2), 6.75 (s, 1H, C3–H), 6.75 (d, J=8 Hz, 1H, C5–H); 8.19 (d, J=8 Hz 1H, C6–H); 10.52 (bs, 1H, NH) ppm.


### 4.5. General Procedure for the Synthesis of
2-(2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl acetate (4C13H14N2O3)

The mixture of 2-aminopyridine1 (10 mmol)
and α-acetyl γ-butyrolactone 2 (10 mmol, 1.28 g, or
1.10 mL) was heated in ammonium acetate (0.05 mol, 3.85 g) at 100–120°C for 1-2 hours. The
reaction mixture was stirred in water, and extracted with chloroform. The
chloroform extract was dried over anhydrous sodium sulphate, and evaporated to
furnish a colorless solid, and the compounds were recrystallized in suitable
solvent.Yield 1.37 g (56%), mp 121-122°C (ligroin,
colorless flakes); IR (KBr): 2980,
2880(w, CH3), 1740(s, C=O lactone), 1670(s, C=O),
1530, 1470, cm−1; H1 NMR (CDCl3): δ= 2.00
(s, 3H, OCH3), 2.52 (s, 3H, CH3), 3.03 (t, J=7 Hz, 2H, CH2), 4.27 (t, J=7 Hz, 2H, OCH2), 7.07 (dt, J=8,3 Hz, 1H, C8–H), 7.56 (dd, J=8,3 Hz, 1H, C9–H); 7.63 (dt, J=8,3 Hz, 1H, C7–H); 8.90 (dd, J=8,3 Hz, 1H, C6–H) ppm. C13 NMR (CDCl3): 21.06 (CH3), 22.72 (CH3), 26.58 (CH2), 62.59 (CH2OH), 111.46 (C2), 114.98 (C6), 125.83 (C8); 127.06 (C7); 135.30 (C9); 148.79 (C9a); 157.87 (C3), 162.62 (C=O), 171.06 (C=O) ppm.


### 4.6. General Procedure for the Synthesis of
3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (5a, 5b)

#### 4.6.1. Method A

The furanone3 (10 mmol) was dissolved in ethanol (20 mL), and the solution was
refluxed with sodium ethoxide (0.23 g of freshly cut sodium metal was dissolved
in 10 mL of dry ethanol) for 1 hour. The solvent was removed under reduced
pressure. The residue was dissolved in cold water (100 mL) and extracted with
chloroform. The chloroform was dried over sodium sulfate and evaporated to
yield 5 in good yield.


#### 4.6.2. Method B

The compound4 (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.


### 4.7. 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
(5a,C11H12N2O2)

Yield 1.42 g (70%), mp 158-159°C
(cyclohexane, colorless needles); IR (KBr): 3260 (b, OH), 2880 (w, CH3), 1670 (s, C=O lactone), 1640(s, NH),
1530, 1470, 1440, cm−1; 1H NMR (CDCl3): δ= 2.62
(s, 3H, CH3), 3.03 (t, J=7.1 Hz 2H, CH2), 3.96 (t, J=7.2 Hz, 2H, OCH2), 7.17 (m, 1H, C8–H), 7.43 (bs, 1H, OH); 7.65 (d, J=8.1 Hz, 1H, C6–H); 7.77 (m, 1H, C7–H); 9.09 (d, J=8.3 Hz, 1H, C9–H) ppm.


### 4.8. 3-(2-hydroxyethyl)-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
(5b,C12H14N2O2)

Yield 1.54 g (71%), mp 175-176°C (ligroin,
colorless needles); IR (KBr): 3250 (b, OH), 2920, 2880(w, CH3), 1670 (s, C=O lactone), 1640, 1570,
1520,1470, cm−1; H1 NMR (CDCl3): δ=2.46 (s, 3H, CH3), 2.52 (s, 3H, CH3), 3.06 (t, J=7 Hz, 2H, CH2), 3.52 (s, 1H, OH), 3.92 (t, J=7 Hz, 2H, OCH2), 6.96 (dd, J=8.3 Hz, 1H, C7–H), 7.22 (d, J=8.1 Hz, 1H, C9–H); 8.89 (d, J=8 Hz, 1H, C8–H) ppm.


### 4.9. General Procedure for the Synthesis of
3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6a–6c)

Compound3 or 5 (10 mmol) was
refluxed in phosphorus oxychloride (20 mL) for 1 hour (TLC check). After
completing the reaction, the excess of phosphorus oxychloride was removed under
reduced pressure. The residue obtained was stirred in ice-cold water (100 mL)
for 30 minutes, then neutralized with solid sodium carbonate and further
stirred overnight. The solid precipitated was filtered and washed with water
and recrystallized from suitable solvent.


### 4.10. 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
(6a,C11H11ClN2O)

Yield 1.60 g (72%), mp 140–142°C
(cyclohexane, colorless needles); IR (KBr): 2950 (w, CH3), 1670(s, C=O lactone), 1640, 1580,
1540, 1480, 1430 cm−1; H1 NMR (CDCl3): δ=2.55 (s, 3H, CH3); 3.23 (t, J=7 Hz, 2H, CH2), 3.88 (t, J=7 Hz, 2H, CH2Cl), 7.15 (t, J=8.3 Hz 1H, C8–H), 7.69 (d, J=8 Hz 1H, C9–H); 7.78 (t, J=8Hz 1H, C7–H); 9.07 (d, 1H, C6–H) ppm.


### 4.11. 3-(2-chloroethyl)-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
(6b,C12H13ClN2O)

Yield 1.65 g (70%), mp 113-114°C
(cyclohexane, colorless needles); IR (KBr): 2980 (w, CH3), 1670(s, C=O lactone), 1640, 1580,
1540, 1470, 1440 cm−1; H1 NMR (CDCl3): δ=2.55 (s, 3H, CH3); 3.09 (s, 3H, CH3); 3.18 (t, J=7 Hz, 2H, CH2), 3.87 (t, J=7 Hz, 2H, CH2Cl), 7.38 (t, J=8.3 Hz, 1H, C8–H), 6.66 (d, J=8 Hz, 1H, C9–H) ppm.


### 4.12. 3-(2-chloroethyl)-2,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
(6c,C12H13ClN2O)

Yield 1.77 g (75%), mp 116-117°C
(cyclohexane, colorless needles); IR (KBr):
1670 (s, C=O lactone), 1640, 1560, 1530, 1470, cm−1; 1H NMR (CDCl3); δ=2.42 (s, 3H, CH3), 2.53 (s, 3H, C8–CH3), 3.24 (t, J=7 Hz, 2H, CH2), 3.89 (t, J=7 Hz, 2H, CH2Cl), 6.92 (d, J=8.2 Hz, 1H, C7–H), 8.96 (d, J=8Hz,
1H, C6–H), 7.41 (d, J=2.8 Hz, 1H, C9–H) ppm.


### 4.13. General Procedure for the Synthesis of
3-(2-azidoethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (7,C11H11N5O)

To a stirred solution of6 (10 mmol) in DMF/ H2O (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.Yield 1.60 g (70%), mp 65-66°C
(cyclohexane, colorless solid); IR (KBr):
2980(w, CH3), 2100(N3), 1660(s, C=O  lactone), 1640, 1560,
1530,1470, cm−1.


### 4.14. General Procedure for the Synthesis of
2-methyl-3-vinyl-4H-pyrido[1,2-a]pyrimidin-4-one
(8,C12H10N2O)

To a  stirred
solution of6 (10 mmol) in ethanol, the solution of sodium ethoxide (prepared by reacting 0.27 gms,
11.5 mg atoms of sodium in 50 mL of
absolute ethanol) was added. The reaction mixture was refluxed for about 10-11 hours. (TLC
check). Then, the excess of solvent was removed under reduced pressure, and
the obtained solid was filtered, washed with ethanol, dried, and recrystallized
from the proper solvent to afford 8 in good yield.Yield 1.20 g (60%), mp 110-111°C
(cyclohexane, colorless solid) IR (KBr):
3020(w, CH3), 1670(s, C=O lactone), 1640, 1560,
1530, 1470, cm−1; H1 NMR (CDCl3): δ=2.61 (s, 3H, CH3); 5.63 & 6.55 (dd, J=16,8 Hz, 2H, = CH2); 6.83 (t, J=16,8 Hz, 1H, =C–H); 7.13 (dt, J=8,3 Hz, 1H, C8–H), 7.66 (dt, J=8,3 Hz, 1H, C9–H); 7.75 (dt, J=8,3 Hz, 1H, C7–H); 9.12 (dd, J=8.3 Hz, 1H, C6–H) ppm.Table 1
Elemental analysis.
Serial  no.CompoundsCalculatedFound13aC, 64.69, H, 5.92; N,
13.72C, 64.85, H, 5.97, N,
13.8123bC, 66.04; H, 6.47; N,
12.84C, 65.80; H, 6.40; N,
12.7633cC, 66.04; H, 6.47; N,
12.84C, 66.22, H, 6.62, N,
12.9344C, 63.40; H, 5.73; N,
11.38C, 63.42, H, 5.68, N,
11.3655aC, 64.69; H, 5.92; N,
13.72C, 64.88; H, 5.86; N,
13.6865bC, 66.04; H, 6.47; N,
12.70C, 65.82, H, 6.55, N,
13.0076aC, 59.33; H, 4.98; N,
12.58C, 59.28 H, 4.92, N,
12.3886bC, 60.89; H, 5.54; N,
11.84C, 60.31; H, 5.44; N,
11.6296cC, 60.89; H, 5.54; N,
11.84C, 60.31; H, 5.44; N,
11.61107C 57.63; H, 4.84; N,
30.55C, 57.79; H, 4.86; N,
30.70118C, 70.95; H, 5.41; N,
15.04C, 71.014; H, 5.24; N,
14.99Scheme 1


## 4.1. General Procedure for the Synthesis of dihydrofuranone-2-(3H)-one (3a–3c)

The mixture of 2-aminopyridines1 (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.


## 4.2. 3-[1-(Pyridin-2-ylamino)ethylidene]dihydrofuran 2(3H)-one
(3a,C11H12N2O2)

Yield 1.69 g (83%), mp 87-88°C (ligroin,
colorless  flakes); IR: (KBr): 3200 (NH), 3050(CH3),
1690 (C=O lactone), 1640, 1600(C=C), 1570, 1500, 1480, 1410 cm−1; H1 NMR: (CDCl3) δ=2.50
(s, 3H, CH3), 2.92 (t, J=7 Hz, 2H, CH2), 4.31 (t, J=7 Hz, 2H, OCH2), 6.75 (dd, J=2.1 & 8.1 Hz, 1H, C3–H), 6.83 (dt, J=2.4 & 8.3 Hz, 1H, C4–H), 8.75 (dt, J=2.4 & 8.3 Hz, 1H, C5–H), 8.25 (dd, J=2.4 & 8.3 Hz, 1H, C6–H), 10.5 (bs, 1H, NH) ppm. C13 NMR (CDCl3): 19.48 (CH3), 26.26 (CH2), 65.43 (CH2OH), 93.62 (C=C), 113.99 (C5), 117.91 (C4); 137.86 (C6); 147.83 (C2); 153.22(C3); 173.72 (C=O) ppm.


## 4.3. 3-{1-[(6-Methylpyridin-2-yl)amino]ethylidene} dihydrofuran-2(3H)-one
(3b, C12H14N2O2)

Yield 1.74 g (80%), mp 105-106°C (cyclohexane,
colorless flakes); IR (KBr): 3200 (NH), 2920, 2860(w, CH3), 1690(C=O lactone), 1650(NH),
1600(C=C), 1580, 1560, 1480, 1430 cm−1; H1 NMR (CDCl3): δ=2.40
(s, 3H, CH3), 3.95 (t, J=7 Hz, 2H, CH2), 4.42 (t, J=7.1 Hz, 2H, OCH2), 6.63 (dd, J=7.8 & 2.8 Hz, 1H, C3–H), 7.45 (t, J=7.8 & 7.8 Hz, 1H, C4–H); 6.70 (d, J=7.9 & 2.9 Hz, 1H, C5–H); 10.55 (bs, 1H, NH) ppm.


## 4.4. 3-{1-[(4-Methylpyridin-2-yl)amino]ethylidene} dihydrofuran-2(3H)-one
(3c, C12H14N2O2)

Yield 1.85 g
(85%), mp 72-73°C
(cyclohexane, colorless flakes); IR (KBr): 3200 (b, NH), 2910, 2880(w, CH3), 1780 (s, C=O lactone), 1650 (s, NH),
1610, 1560, 1480, 1450, cm−1; H1 NMR (CDCl3) δ2.33 (s,
3H, CH3), 2.52 (s, 3H, CH3), 2.92 (t, J=7 Hz, 2H, CH2), 4.36 (t, J=7 Hz, 2H, OCH2), 6.75 (s, 1H, C3–H), 6.75 (d, J=8 Hz, 1H, C5–H); 8.19 (d, J=8 Hz 1H, C6–H); 10.52 (bs, 1H, NH) ppm.


## 4.5. General Procedure for the Synthesis of
2-(2-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl)ethyl acetate (4C13H14N2O3)

The mixture of 2-aminopyridine1 (10 mmol)
and α-acetyl γ-butyrolactone 2 (10 mmol, 1.28 g, or
1.10 mL) was heated in ammonium acetate (0.05 mol, 3.85 g) at 100–120°C for 1-2 hours. The
reaction mixture was stirred in water, and extracted with chloroform. The
chloroform extract was dried over anhydrous sodium sulphate, and evaporated to
furnish a colorless solid, and the compounds were recrystallized in suitable
solvent.Yield 1.37 g (56%), mp 121-122°C (ligroin,
colorless flakes); IR (KBr): 2980,
2880(w, CH3), 1740(s, C=O lactone), 1670(s, C=O),
1530, 1470, cm−1; H1 NMR (CDCl3): δ= 2.00
(s, 3H, OCH3), 2.52 (s, 3H, CH3), 3.03 (t, J=7 Hz, 2H, CH2), 4.27 (t, J=7 Hz, 2H, OCH2), 7.07 (dt, J=8,3 Hz, 1H, C8–H), 7.56 (dd, J=8,3 Hz, 1H, C9–H); 7.63 (dt, J=8,3 Hz, 1H, C7–H); 8.90 (dd, J=8,3 Hz, 1H, C6–H) ppm. C13 NMR (CDCl3): 21.06 (CH3), 22.72 (CH3), 26.58 (CH2), 62.59 (CH2OH), 111.46 (C2), 114.98 (C6), 125.83 (C8); 127.06 (C7); 135.30 (C9); 148.79 (C9a); 157.87 (C3), 162.62 (C=O), 171.06 (C=O) ppm.


## 4.6. General Procedure for the Synthesis of
3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (5a, 5b)

### 4.6.1. Method A

The furanone3 (10 mmol) was dissolved in ethanol (20 mL), and the solution was
refluxed with sodium ethoxide (0.23 g of freshly cut sodium metal was dissolved
in 10 mL of dry ethanol) for 1 hour. The solvent was removed under reduced
pressure. The residue was dissolved in cold water (100 mL) and extracted with
chloroform. The chloroform was dried over sodium sulfate and evaporated to
yield 5 in good yield.


### 4.6.2. Method B

The compound4 (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.


## 4.6.1. Method A

The furanone3 (10 mmol) was dissolved in ethanol (20 mL), and the solution was
refluxed with sodium ethoxide (0.23 g of freshly cut sodium metal was dissolved
in 10 mL of dry ethanol) for 1 hour. The solvent was removed under reduced
pressure. The residue was dissolved in cold water (100 mL) and extracted with
chloroform. The chloroform was dried over sodium sulfate and evaporated to
yield 5 in good yield.


## 4.6.2. Method B

The compound4 (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.


## 4.7. 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
(5a,C11H12N2O2)

Yield 1.42 g (70%), mp 158-159°C
(cyclohexane, colorless needles); IR (KBr): 3260 (b, OH), 2880 (w, CH3), 1670 (s, C=O lactone), 1640(s, NH),
1530, 1470, 1440, cm−1; 1H NMR (CDCl3): δ= 2.62
(s, 3H, CH3), 3.03 (t, J=7.1 Hz 2H, CH2), 3.96 (t, J=7.2 Hz, 2H, OCH2), 7.17 (m, 1H, C8–H), 7.43 (bs, 1H, OH); 7.65 (d, J=8.1 Hz, 1H, C6–H); 7.77 (m, 1H, C7–H); 9.09 (d, J=8.3 Hz, 1H, C9–H) ppm.


## 4.8. 3-(2-hydroxyethyl)-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
(5b,C12H14N2O2)

Yield 1.54 g (71%), mp 175-176°C (ligroin,
colorless needles); IR (KBr): 3250 (b, OH), 2920, 2880(w, CH3), 1670 (s, C=O lactone), 1640, 1570,
1520,1470, cm−1; H1 NMR (CDCl3): δ=2.46 (s, 3H, CH3), 2.52 (s, 3H, CH3), 3.06 (t, J=7 Hz, 2H, CH2), 3.52 (s, 1H, OH), 3.92 (t, J=7 Hz, 2H, OCH2), 6.96 (dd, J=8.3 Hz, 1H, C7–H), 7.22 (d, J=8.1 Hz, 1H, C9–H); 8.89 (d, J=8 Hz, 1H, C8–H) ppm.


## 4.9. General Procedure for the Synthesis of
3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (6a–6c)

Compound3 or 5 (10 mmol) was
refluxed in phosphorus oxychloride (20 mL) for 1 hour (TLC check). After
completing the reaction, the excess of phosphorus oxychloride was removed under
reduced pressure. The residue obtained was stirred in ice-cold water (100 mL)
for 30 minutes, then neutralized with solid sodium carbonate and further
stirred overnight. The solid precipitated was filtered and washed with water
and recrystallized from suitable solvent.


## 4.10. 3-(2-chloroethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
(6a,C11H11ClN2O)

Yield 1.60 g (72%), mp 140–142°C
(cyclohexane, colorless needles); IR (KBr): 2950 (w, CH3), 1670(s, C=O lactone), 1640, 1580,
1540, 1480, 1430 cm−1; H1 NMR (CDCl3): δ=2.55 (s, 3H, CH3); 3.23 (t, J=7 Hz, 2H, CH2), 3.88 (t, J=7 Hz, 2H, CH2Cl), 7.15 (t, J=8.3 Hz 1H, C8–H), 7.69 (d, J=8 Hz 1H, C9–H); 7.78 (t, J=8Hz 1H, C7–H); 9.07 (d, 1H, C6–H) ppm.


## 4.11. 3-(2-chloroethyl)-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
(6b,C12H13ClN2O)

Yield 1.65 g (70%), mp 113-114°C
(cyclohexane, colorless needles); IR (KBr): 2980 (w, CH3), 1670(s, C=O lactone), 1640, 1580,
1540, 1470, 1440 cm−1; H1 NMR (CDCl3): δ=2.55 (s, 3H, CH3); 3.09 (s, 3H, CH3); 3.18 (t, J=7 Hz, 2H, CH2), 3.87 (t, J=7 Hz, 2H, CH2Cl), 7.38 (t, J=8.3 Hz, 1H, C8–H), 6.66 (d, J=8 Hz, 1H, C9–H) ppm.


## 4.12. 3-(2-chloroethyl)-2,8-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one
(6c,C12H13ClN2O)

Yield 1.77 g (75%), mp 116-117°C
(cyclohexane, colorless needles); IR (KBr):
1670 (s, C=O lactone), 1640, 1560, 1530, 1470, cm−1; 1H NMR (CDCl3); δ=2.42 (s, 3H, CH3), 2.53 (s, 3H, C8–CH3), 3.24 (t, J=7 Hz, 2H, CH2), 3.89 (t, J=7 Hz, 2H, CH2Cl), 6.92 (d, J=8.2 Hz, 1H, C7–H), 8.96 (d, J=8Hz,
1H, C6–H), 7.41 (d, J=2.8 Hz, 1H, C9–H) ppm.


## 4.13. General Procedure for the Synthesis of
3-(2-azidoethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (7,C11H11N5O)

To a stirred solution of6 (10 mmol) in DMF/ H2O (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.Yield 1.60 g (70%), mp 65-66°C
(cyclohexane, colorless solid); IR (KBr):
2980(w, CH3), 2100(N3), 1660(s, C=O  lactone), 1640, 1560,
1530,1470, cm−1.


## 4.14. General Procedure for the Synthesis of
2-methyl-3-vinyl-4H-pyrido[1,2-a]pyrimidin-4-one
(8,C12H10N2O)

To a  stirred
solution of6 (10 mmol) in ethanol, the solution of sodium ethoxide (prepared by reacting 0.27 gms,
11.5 mg atoms of sodium in 50 mL of
absolute ethanol) was added. The reaction mixture was refluxed for about 10-11 hours. (TLC
check). Then, the excess of solvent was removed under reduced pressure, and
the obtained solid was filtered, washed with ethanol, dried, and recrystallized
from the proper solvent to afford 8 in good yield.Yield 1.20 g (60%), mp 110-111°C
(cyclohexane, colorless solid) IR (KBr):
3020(w, CH3), 1670(s, C=O lactone), 1640, 1560,
1530, 1470, cm−1; H1 NMR (CDCl3): δ=2.61 (s, 3H, CH3); 5.63 & 6.55 (dd, J=16,8 Hz, 2H, = CH2); 6.83 (t, J=16,8 Hz, 1H, =C–H); 7.13 (dt, J=8,3 Hz, 1H, C8–H), 7.66 (dt, J=8,3 Hz, 1H, C9–H); 7.75 (dt, J=8,3 Hz, 1H, C7–H); 9.12 (dd, J=8.3 Hz, 1H, C6–H) ppm.Table 1
Elemental analysis.
Serial  no.CompoundsCalculatedFound13aC, 64.69, H, 5.92; N,
13.72C, 64.85, H, 5.97, N,
13.8123bC, 66.04; H, 6.47; N,
12.84C, 65.80; H, 6.40; N,
12.7633cC, 66.04; H, 6.47; N,
12.84C, 66.22, H, 6.62, N,
12.9344C, 63.40; H, 5.73; N,
11.38C, 63.42, H, 5.68, N,
11.3655aC, 64.69; H, 5.92; N,
13.72C, 64.88; H, 5.86; N,
13.6865bC, 66.04; H, 6.47; N,
12.70C, 65.82, H, 6.55, N,
13.0076aC, 59.33; H, 4.98; N,
12.58C, 59.28 H, 4.92, N,
12.3886bC, 60.89; H, 5.54; N,
11.84C, 60.31; H, 5.44; N,
11.6296cC, 60.89; H, 5.54; N,
11.84C, 60.31; H, 5.44; N,
11.61107C 57.63; H, 4.84; N,
30.55C, 57.79; H, 4.86; N,
30.70118C, 70.95; H, 5.41; N,
15.04C, 71.014; H, 5.24; N,
14.99Scheme 1



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*Source: 434329-2008-09-16.xml*