HETEROCYCLES

Short Paper | Regular issue | Vol. 85, No. 12, 2012, pp. 2987-2998
Received, 10th September, 2012, Accepted, 24th October, 2012, Published online, 25th October, 2012.
DOI: 10.3987/COM-12-12581

■ Preparation of β-Keto-β-alkanoyloxyphosphonates, Phosphine Oxides and Sulfides and Their Application to the Synthesis of Novel Phosphoryl- and Thiophosphorylpyrazoles

Hosni Slimani and Soufiane Touil*

Department of Chemistry, Faculty of Sciences of Bizerta, 7021-Jarzouna, Tunisia

Abstract

Two synthetic methods leading to β-keto-β-alkanoyloxyphosphonates, phosphine oxides and sulfides 2 are reported. The first method involves the reaction of β-enaminoesters 1 with chlorophosphines and phosphites followed by oxidation or sulfurization and hydrolytic work-up. The second one utilizes the reaction of β-enaminoesters 1 with diethylchlorophosphate and thiophosphate followed by acid hydrolysis. On reaction with hydrazine derivatives, compounds 2 give the corresponding phosphoryl- and thiophosphorylpyrazoles 3. The structures of all obtained products were confirmed by NMR (1H, 31P, 13C) and IR spectroscopies, and by mass spectrometry.

In connection with our work on the applications of multifunctional phosphonates in heterocyclic synthesis1-3 and pursuing our studies on the reactivity of imines and enamines with phosphorus electrophiles,4-6 we have investigated, for the first time, the behaviour of β-enaminoesters towards chlorophosphines, phosphates and thiophosphates, in order to obtain novel types of β-dicarbonyl compounds bearing a phosphoryl or a thiophosphoryl group. Furthermore, and in order to explore the potential of these multifunctional phosphonates and thiophosphonates in heterocyclic synthesis, we show here that their reaction with hydrazine derivatives leads to a new class of phosphoryl- and thiophosphorylpyrazoles. Our interest for these compounds is due to the well known interesting biological properties of pyrazole derivatives including anticancer,7,8 antimicrobial,9,10 antiviral11 and antiinflammatory12,13 activities. Some of these compounds are also known for their applications in agrochemistry as herbicide14 fungicide15 and insecticide16 agents.
In the first part of this work, we focused our efforts to develop new strategies for the synthesis of novel β-keto-β-alkanoyloxyphosphonates, phosphine oxides and sulfides. To access these compounds, we have used two different approaches. The first one (Method A) involves the reaction of β-enaminoesters 117 with chlorophosphines and phosphites followed by oxidation or sulfurization and hydrolytic work-up. Experimentally, treatment of β-enaminoesters 1 with chlorophosphines and phosphites, performed in acetonitrile, at 0 °C, in the presence of an equimolar amount of triethylamine, led to the formation of the phosphine intermediate I1 (Scheme 1). A subsequent oxidation or sulfurization carried out, in a one pot reaction, by treating respectively with dimethyl sulfoxide (DMSO) under reflux or with elemental sulfur at 40 °C, led to the phosphorus (IV) intermediate I2 which, by acid hydrolysis, furnished the β-keto-β-alkanoyloxyphosphonates, phosphine oxides and sulfides 2 in equilibrium with their tautomeric enol forms 2'.
The scope of the reaction was assessed with a range of substrates (Table 1) including a variety of β-enaminoesters and phosphorus (III) derivatives. All the substrates reacted in good to high yields.

The second method (Method B) that we developed to access compounds 2 involved the reaction of β-enaminoesters 1 with diethylchlorophosphate and thiophosphate followed by acid hydrolysis. It was found that, similar to the reaction of chlorophosphines and phosphites, chlorophosphates and thiophosphates can also react with β-enaminoesters 1 in the presence of an equimolar amount of triethylamine and using diethyl ether as solvent, to afford, after acid hydrolysis, the β-keto-β-alkanoyloxyphosphonates, phosphine oxides and sulfides 2 in equilibrium with their tautomeric enol forms 2' (Scheme 2). A variety of compounds 2 were obtained in good yield, by applying this strategy (Table 2).

Compounds 2 were characterized on the basis of their Infrared, NMR (31P, 1H, 13C) and mass spectral data, which indicate that they are obtained as a tautomeric mixture of the keto and enol forms 2 and 2’. The relative proportions of these tautomers were estimated from the 31P NMR spectra where a singlet for each one is present (Tables 1 and 2). The enol form 2’ was found to be dominant probably due to conjugation and intramolecular hydrogen bonding. Indeed the infrared spectra of the synthesized compounds showed a broad band centred around 3370 cm-1 being characteristic of the associated O–H vibrations. This band did not disappear on dilution which confirmed the existence of an intramolecular hydrogen bond.

Being multifunctional compounds with two electrophilic centers in 1,3-positions, β-keto-β-alkanoyloxy-phosphonates, phosphine oxides and sulfides 2 can undergo cyclization reactions with binucleophilic agents leading to various heterocyclic systems. With this in mind and pursuing our research program regarding the synthesis of novel heterocyclic compounds bearing phosphoryl or thiophosphoryl groups,18 we report here our results on the reaction of compounds 2 with hydrazines which lead to a new class of phosphoryl- and thiophosphorylpyrazoles. Thus, treatment of compounds 2 with an equimolar amount of hydrazine derivative, using chloroform as solvent and heating the mixture under reflux for 24 h gives the phosphoryl- and thiophosphorylpyrazoles 3 in good yields (Scheme 3). These compounds were isolated as a tautomeric mixture of the keto and enol forms 3 and 3’ as evidenced by their Infrared and NMR (31P, 1H, 13C) spectral data. The relative proportions of these tautomers were estimated from the 31P NMR spectra where a singlet for each one is present (Tables 3). The enol form 3’ was found to be dominant probably due to aromaticity and O-H…X=P intramolecular hydrogen bonding.

In summary, we successfully developed two efficient one-pot methodologies for the synthesis of β-keto-β-alkanoyloxyphosphonates, phosphine oxides and sulfides, which use easily made β-enaminoesters and commercially available chlorophosphines, phosphates and thiophosphates as starting materials. The obtained multifunctional phosphonates and thiophosphonates were used as efficient precursors for the straightforward preparation of novel phosphoryl- and thiophosphorylpyrazoles. Other applications of β-keto-β-alkanoyloxyphosphonates, phosphine oxides and sulfides in heterocyclic synthesis are ongoing in our laboratory and will be reported in due course.

EXPERIMENTAL
1H, 31P and 13C NMR spectra were recorded with CDCl3 as the solvent, on a Bruker-300 spectrometer. The chemical shifts are reported in ppm relative to TMS (internal reference) for 1H and 13C NMR and relative to 85% H3PO4 (external reference) for 31P NMR. The coupling constants are reported in Hz. For the 1H NMR, the multiplicities of signals are indicated by the following abbreviations: s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet. Mass spectra were determined on an Agilent 5975B spectrometer, under electronic impact (EI) conditions. IR spectra were recorded on a Nicolet IR200 spectrometer. The progress of the reactions was monitored by TLC. Purification of products was performed by column chromatography using silica gel 60 (Fluka).
General procedure for the synthesis of β-keto-β-alkanoyloxyphosphonates, phosphineoxides and sulfides 2 (Method A). To a mixture of β-enaminoester 1 (0.01 mol), triethylamine (0.012 mol) and dry MeCN (50 mL), cooled at 0 °C and maintained under a nitrogen atmosphere, was added dropwise with stirring, a solution of chlorophosphine or phosphite (0.01 mol) in dry MeCN (30 mL). Stirring at 0 °C was continued for 1 h. The reaction mixture was then treated with DMSO or sulfur as follows:
- Oxidation: DMSO (0.01 mol) was added and the mixture was heated under reflux for 2 h. After cooling, 6 M aqueous HCl solution (30 mL) was added dropwise and stirring was continued at room temperature for 12 h. The mixture was then extracted with CHCl3 (2 × 25 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The obtained residue was chromatographed on a silica gel column using ether as eluent.
- Sulfurization: Sulfur (0.01 mol) was added and the mixture was heated at 40 °C for 30 min. After cooling, 6 M aqueous HCl solution (30 mL) was added dropwise and stirring was continued at room temperature for 12 h. The mixture was then extracted with CHCl3 (2 × 25 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The obtained residue was chromatographed on a silica gel column using ether as eluent.
General procedure for the synthesis of β-keto-β-alkanoyloxyphosphonates, phosphineoxides and sulfides 2 (Method B). To a mixture of β-enaminoester 1 (0.01 mol), triethylamine (0.012 mol) and dry Et2O (50 mL), cooled at 0 °C and maintained under a nitrogen atmosphere, was added dropwise with stirring, a solution of diethylchlorophosphate or thiophosphate (0.01 mol) in dry Et2O (10 mL). Stirring was continued for 24 h at 25 °C. Then a 6 M aqueous HCl solution (30 mL) was added dropwise and stirring was continued at room temperature for an additional 12 h. The organic phase was washed with water (25 mL), dried over Na2SO4 and concentrated under vacuum. The residue obtained was chromatographed on silica gel column using ether as eluent.

2a⇄2’a: Yellow oil; 1H NMR (300 MHz, CDCl3): 2a: δ = 1.18 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2-O); 1.75 (s, 3H, CH3-C=O); 4.32 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-O); 4.77 (d, 1H, 2JPH = 24.0 Hz, CH-P); 7.03-8.28 (m, 10H, arom-H); 2'a: δ = 1.07 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2-O); 2.14 (s, 3H, CH3-C=C); 4.04 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-O); 7.03-8.28 (m, 10H, arom-H); 10.15 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 2a: δ = 18.6 (s, CH3-CH2-O); 30.7 (s, CH3-C=O); 48.2 (d, 1JCP = 90.6 Hz, CH-P); 58.1 (s, CH3-CH2-O); 173.9 (s; O-C=O); 199.5 (s, CH3-C=O); 2'a: δ = 12.5 (s, CH3-CH2-O); 28.6 (s, CH3-C=C); 59.7 (s, CH3-CH2-O); 99.3 (d, 1JCP = 118.5 Hz, P-C=C-O); 165.7 (s; O-C=O); 175.6 (s, C=C-OH); phenyl carbons (for 2a and 2'a): δ = 112.7, 115.6, 123.4, 124.3, 126.7, 127.1, 129.3, 129.5, 129.6, 129.8, 130.3, 136.1, 138.7, 139.9, 142.5, 145.1; IR (neat): νP=S = 698 cm-1; νC=O (ketone) = 1642 cm-1; νC=O (ester) = 1745 cm-1; νOH = 3370 cm-1; EI-HRMS: calculated for C18H19O3PS, 346.0792 (M+); found: 346.0793.

2b⇄2’b: Yellow oil; 1H NMR (300 MHz, CDCl3): 2b : δ = 1.27 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2-O); 3.44 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-O); 5.70 (d, 1H, 2JPH = 27.0 Hz, CH-P); 7.17-7.92 (m, 15H, arom-H); 2'b: δ = 1.19 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2-O); 4.14 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-O); 7.17-7.92 (m, 15H, arom-H); 9.90 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 2b : δ = 7.0 (s, CH3-CH2-O); 42.8 (d, 1JCP = 129.0 Hz, CH-P); 64.1 (s, CH3-CH2-O); 169.8 (s; O-C=O); 191.1 (s, Ph-C=O); 2'b: δ = 12.4 (s, CH3-CH2-O); 59.8 (s, CH3-CH2-O); 125.6 (d, 1JCP = 90.3 Hz, P-C=C-O); 166.0 (s, O-C=O); 171.6 (s, C=C-OH); phenyl carbons (for 2b and 2'b): δ = 124.4, 125.7, 126.7, 126.7, 126.9, 127.0, 127.6, 129.2, 127.6, 129.1, 129.6, 129.7, 129.9, 130.3, 131.6, 132.1, 134.3, 134.4, 134.6, 135.4, 136.0, 136.1, 138.6, 139.9; IR (neat): νP=S = 696 cm-1; νC=O (ketone) = 1694 cm-1; νC=O (ester) = 1748 cm-1; νOH = 3384 cm-1; EI-HRMS: calculated for C23H21O3PS, 408.0949 (M+); found: 408.0955.

2c⇄2’c: Yellow oil; 1H NMR (300 MHz, CDCl3): 2c: δ = 0.91 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2-O); 4.06-4.22 (m, 3H, CH3-CH2-O and CH-P); 7.13-8.77 (m, 15H, arom-H); 2'c : δ = 1.17 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2-O); 3.81 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-O); 7.13-8.77 (m, 15H, arom-H); 10.75 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 2c: δ = 7.1 (s, CH3-CH2-O); 41.5 (d, 1JCP = 80.0 Hz, CH-P); 59.7 (s, CH3-CH2-O); 169.8 (s, O-C=O); 191.1 (s, Ph-C=O); 13C NMR (75.5 MHz, CDCl3): 2'c: δ = 12.5 (s, CH3-CH2-O); 44.3 (s, CH3-CH2-O); 99.8 (d, 1JCP = 91.5 Hz, P-C=C-O); 166.0 (s; O-C=O); 171.6 (s, C=C-OH); phenyl carbons (for 2c and 2'c): δ = 124.4, 125.1, 125.4, 125.8, 125.9, 126.2, 126.5, 126.8, 127.0, 127.2, 127.5, 127.7, 128.1, 128.7, 129.6, 129.8, 130.6, 131.1, 131.4, 131.6, 132.2, 133.0, 135.2, 136.4; IR (neat): νP=O = 1217 cm-1; νC=O (ketone) = 1690 cm-1; νC=O (ester) = 1745 cm-1; νOH = 3370 cm-1; EI-HRMS: calculated for C23H21O4P, 392.1177 (M+); found: 392.1172.

2d⇄2’d: Yellow oil; 1H NMR (300 MHz, CDCl3): 2d: δ = 0.91 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2); 3.06 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2); 3.36 (s, 3H, CH3-O); 4.49 (d, 1H, 2JPH = 15.0 Hz, CH-P); 7.03-7.87 (m, 10H, arom-H); 2'd: δ = 1.00 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2); 2.83 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2); 3.54 (s, 3H, CH3-O); 7.03-7.87 (m, 10H, arom-H); 10.52 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 2d: δ = 6.9 (s, CH3-CH2); 23.6 (s, CH3-CH2); 34.6 (s, CH3-O); 45.9 (d, 1JCP = 118.0 Hz, CH-P); 172.5 (s; O-C=O); 207.1 (s, CH2-C=O); 2'd: δ = 10.0 (s, CH3-CH2); 19.5 (s, CH3-CH2); 24.6 (s, CH3-O); 101.5 (d, 1JCP = 92.0 Hz, P-C=C-O); 173.8 (s; O-C=O); 179.6 (s, C=C-OH); phenyl carbons (for 2d and 2'd): δ = 124.1, 124.8, 125.9, 126.3, 127.0, 127.2, 129.0, 129.1, 129.4, 129.8, 130.0, 130.8, 130.9, 131.1, 131.6, 131.8; IR (neat): νP=S = 697 cm-1; νC=O (ketone) = 1693 cm-1; νC=O (ester) = 1747 cm-1; νOH = 3368 cm-1; EI-HRMS: calculated for C18H19O3PS, 346.0792 (M+); found: 346.0784.

2e⇄2’e: Yellow oil; 1H NMR (300 MHz, CDCl3): 2e: δ = 1.13-1.30 (m, 9H, CH3-CH2-O-C and CH3-CH2-O-P); 2.02 (s, 3H, CH3-C=O); 3.86-4.21 (m, 6H, CH3-CH2-O-C and CH3-CH2-O-P); 4.82 (d, 1H, 2JPH = 27.0 Hz, CH-P); 2'e: δ = 1.13-1.30 (m, 9H, CH3-CH2-O-C and CH3-CH2-O-P); 2.02 (s, 3H, CH3-C=C); 3.86-4.21 (m, 6H, CH3-CH2-O-C and CH3-CH2-O-P); 10.63 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 2e: δ = 8.7 (s, CH3-CH2-O-C); 15.5 (d, 3JCP = 7.5 Hz, CH3-CH2-O-P); 30.8 (s, CH3-C=O); 48.3 (d, 1JCP = 159.2 Hz, CH-P); 59.8 (s, CH3-CH2-O-C); 62.7 (d, 2JCP = 5.3 Hz, CH3-CH2-O-P); 175.3 (s, O-C=O); 200.5 (s, CH3-C=O); 2'e: δ = 14.0 (s, CH3-CH2-O-C); 15.8 (d, 3JCP = 8.3 Hz, CH3-CH2-O-P); 30.0 (s, CH3-C=C); 61.1 (s, CH3-CH2-O-C); 66.1 (d, 2JCP = 7.5 Hz, CH3-CH2-O-P); 100.6 (d, 1JCP = 92.0 Hz, P-C=C-O); 173.7 (s; O-C=O); 177.3 (s, C=C-OH); IR (neat): νP=S = 706 cm-1; νC=O (ketone) = 1690 cm-1; νC=O (ester) = 1742 cm-1; νOH = 3320 cm-1; EI-HRMS: calculated for C10H19O5PS, 282.0691 (M+); found: 282.0693.

2f⇄2’f: Yellow oil; 1H NMR (300 MHz, CDCl3): 2f : δ = 1.13-1.28 (m, 9H, CH3-CH2-O-C and CH3-CH2-O-P); 3.87-4.19 (m, 7H, CH3-CH2-O-C, CH3-CH2-O-P and CH-P); 7.20-7.85 (m, 5H, arom-H); 2'f : δ = 1.13-1.28 (m, 9H, CH3-CH2-O-C and CH3-CH2-O-P); 3.87-4.19 (m, 6H, CH3-CH2-O-C and CH3-CH2-O-P); 7.20-7.85 (m, 5H, arom-H); 12.55 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 2f : δ = 13.3 (s, CH3-CH2-O-C); 14.8 (d, 3JCP = 8.3 Hz, CH3-CH2-O-P); 59.8 (d, 1JCP = 80.0 Hz, CH-P); 60.2 (s, CH3-CH2-O-C); 61.8 (d, 2JCP = 5.3 Hz, CH3-CH2-O-P); 171.3 (s, O-C=O); 192.5 (s, Ph-C=O); 2'f : δ = 13.0 (s, CH3-CH2-O-C); 14.6 (d, 3JCP = 9.1 Hz, CH3-CH2-O-P); 61.2 (s, CH3-CH2-O-C); 65.7 (d, 2JCP = 6.8 Hz, CH3-CH2-O-P); 126.0 (d, 1JCP = 117.0 Hz, P-C=C-O); 167.4 (s; O-C=O); 173.1 (s, C=C-OH); phenyl carbons (for 2f and 2'f): δ =127.0, 127.1, 128.1, 128.2, 129.2, 131.2, 133.0, 133.2; IR (neat): νP=S = 698 cm-1; νC=O (ketone) = 1697 cm-1; νC=O (ester) = 1750 cm-1; νOH = 3380 cm-1; EI-HRMS: calculated for C15H21O5PS, 344.0847 (M+); found: 344.0850.

2g⇄2’g : Yellow oil; 1H NMR (300 MHz, CDCl3): 2g : δ = 0.94-1.21 (m, 9H, CH3-CH2-C and CH3-CH2-O); 2.41 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-C); 3.34 (s, 3H, CH3-O); 3.88-3.98 (m, 4H, CH3-CH2-O); 4.84 (d, 1H, 2JPH = 24.0 Hz, CH-P); 2'g: δ = 0.94-1.21 (m, 9H, CH3-CH2-C and CH3-CH2-O); 3.08 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-C); 3.59 (s, 3H, CH3-O); 3.88-3.98 (m, 4H, CH3-CH2-O); 11.41 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 2g: δ = 7.9 (s, CH3-CH2-C); 15.9 (d, 3JCP = 6.8 Hz, CH3-CH2-O); 21.3 (s, CH3-CH2-C); 47.4 (d, 1JCP = 165.9 Hz, CH-P); 50.7 (s, CH3-O); 61.0 (d, 2JCP = 6.1 Hz, CH3-CH2-O); 167.6 (s, O-C=O); 208.7 (s, CH2-C=O); 2'g : δ = 8.6 (s, CH3-CH2-C); 11.6 (d, 3JCP = 6.0 Hz, CH3-CH2-O); 52.1 (s, CH3-O); 63.4 (d, 2JCP = 5.3 Hz, CH3-CH2-O); 128.0 (d, 1JCP = 113.2 Hz, P-C=C-O); 162.7 (s, O-C=O); 175.4 (s, C=C-OH); IR (neat): νP=O = 1217 cm-1; νC=O (ketone) = 1695 cm-1; νC=O (ester) = 1749 cm-1; νOH = 3370 cm-1; EI-HRMS: calculated for C10H19O6P, 266.0919 (M+); found: 266.0912.

2h⇄2’h : Yellow oil; 1H NMR (300 MHz, CDCl3): 2h: δ = 0.88-1.28 (m, 9H, CH3-CH2-C and CH3-CH2-O); 2.40 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-C); 3.34 (s, 3H, CH3-O); 4.00 (d, 1H, 2JPH = 12.0 Hz, CH-P); 4.09-4.21 (m, 4H, CH3-CH2-O); 2'h: δ = 0.88-1.28 (m, 9H, CH3-CH2-C and CH3-CH2-O); 3.06 (q, 2H; 3JHH = 6.0 Hz, CH3-CH2-C); 3.34 (s, 3H, CH3-O); 4.09-4.21 (m, 4H, CH3-CH2-O); 15.60 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 2h : δ = 7.4 (s, CH3-CH2-C); 15.8 (d, 3JCP = 8.3 Hz, CH3-CH2-O); 26.3 (s, CH3-CH2-C); 48.5 (s, CH3-O); 44.4 (d, 1JCP = 167.5 Hz, CH-P); 62.7 (d, 2JCP = 4.5 Hz, CH3-CH2-O); 166.4 (s, O-C=O); 208.6 (s, CH2-C=O); 2'h : δ = 8.0 (s, CH3-CH2-C); 15.5 (d, 3JCP = 6.8 Hz, CH3-CH2-O); 49.1 (s, CH3-O); 66.0 (d, 2JCP = 6.8 Hz, CH3-CH2-O); 127.6 (d, 1JCP = 107.9 Hz, P-C=C-O); 162.7 (s, O-C=O); 175.5 (s, C=C-OH); IR (neat): νP=S = 696 cm-1; νC=O (ketone) = 1697 cm-1; νC=O (ester) = 1750 cm-1; νOH = 3380 cm-1; EI-HRMS: calculated for C10H19O5PS, 282.0691 (M+); found: 282.0687.

General procedure for the synthesis of phosphoryl- and thiophosphorylpyrazoles 3. A mixture of β-keto-β-alkanoyloxyphosphonate, phosphine oxide or sulfide 2 (0.01 mol), hydrazine derivative (0.01 mol) and dry CHCl3 (30 mL), was heated under reflux for 24 h. The reaction mixture was then concentrated under vacuum. The residue obtained was chromatographed on a silica gel column using ether as eluent.

3a⇄3’a: Yellow solid; mp 212-214 °C; 1H NMR (300 MHz, CDCl3): 3a : δ = 1.28 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2); 3.33 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2); 5.23 (br s, 1H, NH); 5.85 (s, 1H, CH-P); 7.02-7.26 (m, 10H, arom-H); 3'a: δ = 1.11 (t, 3H, 3JHH = 6.0 Hz, CH3-CH2); 2.46 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2); 5.23 (br s, 2H, NH and OH); 7.02-7.26 (m, 10H, arom-H); 13C NMR (75.5 MHz, CDCl3): 3a : δ = 10.9 (s, CH3-CH2); 23.6 (s, CH3-CH2); 45.8 (s, CH-P); 163.2 (s, C=N); 175.0 (s, C=O); 3'a : δ = 11.9 (s, CH3-CH2); 26.1 (s, CH3-CH2); 101.5 (d, 1JCP = 51.3 Hz, HO-C=C-P); 154.9 (s, C=N); 173.9 (s, C=C-OH); phenyl carbons (for 3a and 3'a): δ = 125.8, 127.2, 127.4, 128.8, 137.1; IR (neat): νP=S = 698 cm-1; νC=O = 1651 cm-1; νOH = 3310 cm-1; νNH = 3310 cm-1; EI-HRMS: calculated for C17H17N2OPS, 328.0799 (M+); found: 328.0796.

3b⇄3’b: Yellow solid; mp 156-158 °C; 1H NMR (300 MHz, CDCl3): 3b : δ = 1.28 (t, 6H, 3JHH = 6.0 Hz, CH3-CH2-O); 2.16 (s, 3H, CH3-C=N); 3.98-4.16 (m, 5H, CH3-CH2-O and CH-P); 5.19 (br s, 1H, NH); 3'b : δ = 1.28 (t, 6H, 3JHH = 6.0 Hz, CH3-CH2-O); 2.39 (s, 3H, CH3-C=N); 3.98-4.16 (m, 4H, CH3-CH2-O); 5.81 (br s, 1H, NH); 6,52 (br s, 1H, OH); 13C NMR (75.5 MHz, CDCl3): 3b : δ = 15.8 (d, 3JCP = 8.2 Hz, CH3-CH2-O); 20.7 (s, CH3-C=N); 46.2 (d, 1JCP = 89.8 Hz, CH-P=S); 62.9 (d, 2JCP = 4.5 Hz, CH3-CH2-O); 156.0 (s, C=N); 163.3 (s, C=O); 3'b : δ = 15.8 (d, 3JCP = 8.2 Hz, CH3-CH2-O); 20.7 (s, CH3-C=N); 63.8 (d, 2JCP = 5.3 Hz, CH3-CH2-O); 102.8 (d, 1JCP = 110.2 Hz, HO-C=C-P); 155.8 (s, C=N); 168.3 (s, C=C-OH); IR (neat): νP=S = 712 cm-1; νC=O = 1642 cm-1; νOH = 3370 cm-1; νNH = 3370 cm-1; EI-HRMS: calculated for C8H15N2O3PS, 250.0541 (M+); found: 250.0540.

3c⇄3’c: Yellow solid; mp 118-120 °C; 1H NMR (300 MHz, CDCl3): 3c : δ = 0.97-1.23 (m, 9H, CH3-CH2-C and CH3-CH2-O); 3.06 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-C); 3.78-4.02 (m, 5H, CH3-CH2-O and CH-P ); 5.12 (br s, 1H, NH); 3'c: δ = 0.96-1.13 (m, 9H, CH3-CH2-C and CH3-CH2-O); 2.32 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-C); 3.78-4.02 (m, 4H, CH3-CH2-O); 5.12 (br s, 2H, NH and OH); 13C NMR (75.5 MHz, CDCl3): 3c : δ = 10.2 (s, CH3-CH2-C); 15.7 (d, 3JCP = 4.5 Hz, CH3-CH2-O); 44.5 (s, CH3-CH2-C); 45.2 (d, 1JCP = 95.8 Hz, CH-P); 62.7 (d, 2JCP = 4.5 Hz, CH3-CH2-O); 152.9 (s, C=N); 168.0 (s, C=O); 3'c: δ = 12.1 (s, CH3-CH2-C); 15.7 (d, 3JCP = 4.5 Hz, CH3-CH2-O); 44.5 (s, CH3-CH2-C); 63.1 (d, 2JCP = 4.5 Hz, CH3-CH2-O); 101.7 (d, 1JCP = 98.1 Hz, HO-C=C-P); 152.3 (s, C=N); 168.0 (s, C=C-OH); IR (neat): νP=S = 701 cm-1; νC=O = 1652 cm-1; νOH = 3365 cm-1; νNH = 3365 cm-1; EI-HRMS: calculated for C9H17N2O3PS, 264.0697 (M+); found: 264.0691.

3d⇄3’d: Yellow oil; 1H NMR (300 MHz, CDCl3): 3d : δ = 0.96-1.13 (m, 9H, CH3-CH2-C and CH3-CH2-O); 3.07 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-C); 3.80-4.01 (m, 5H, CH3-CH2-O and CH-P ); 6.69-7.89 (m, 5H, arom-H); 3'd : δ = 0.96-1.13 (m, 9H, CH3-CH2-C and CH3-CH2-O); 2.77 (q, 2H, 3JHH = 6.0 Hz, CH3-CH2-C); 3.80-4.01 (m, 4H, CH3-CH2-O); 5.09 (br s, 1H, OH); 6.69-7.89 (m, 5H, arom-H); 13C NMR (75.5 MHz, CDCl3): 3d : δ = 11.8 (s, CH3-CH2-C); 15.3 (d, 3JCP = 8.3 Hz, CH3-CH2-O); 26.6 (s, CH3-CH2-C); 45.1 (d, 1JCP = 94,6 Hz, CH-P); 65.8 (d, 2JCP = 4.5 Hz, CH3-CH2-O); 154.7 (s, C=N); 170.3 (s, C=O); 3'd : δ = 12.1 (s, CH3-CH2-C); 15.7 (d, 3JCP = 7.5 Hz, CH3-CH2-O); 25.8 (s, CH3-CH2-C); 65.8 (d, 2JCP = 4.5 Hz, CH3-CH2-O); 100.0 (d, 1JCP = 120.0 Hz, HO-C=C-P); 152.4 (s, C=N); 163.2 (s, C=C-OH) ; phenyl carbons (for 3d and 3'd): δ = 128.1, 128.4, 129.4, 129.5, 130.0, 131.3, 133.2, 133.7; IR (neat): νP=S = 702 cm-1; νC=O = 1670 cm-1; νOH = 3442 cm-1; EI-HRMS: calculated for C15H21N2O3PS, 340.1010 (M+); found: 340.1018.

3e⇄3’e: Yellow oil; 1H NMR (300 MHz, CDCl3): 3e: δ = 2.37 (s, 3H, CH3-C=N); 3.40 (d, 1H, 2JPH = 15.0 Hz, CH-P); 5.29 (br s, 1H, NH); 6.93-7.57 (m, 10H, arom-H); 3'e: δ = 2.28 (s, 3H, CH3-C=N); 5.29 (br s, 2H, NH and OH); 6.93-7.57 (m, 10H, arom-H); 13C NMR (75.5 MHz, CDCl3): 3e: δ = 20.9 (s, CH3-C=N); 45.3 (d, 1JCP = 91.6 Hz, CH-P=O); 148.7 (s, C=N); 163.0 (s, C=O); 3'e: δ = 21.1 (s, CH3-C=N); 103.8 (d, 1JCP = 98.1 Hz, HO-C=C-P); 147.0 (s, C=N); 164.1 (s, C=C-OH); phenyl carbons (for 3e and 3'e): δ = 124.8, 125.9, 126.3, 128.6, 129.7, 131.8, 133.0, 134.8; IR (neat): νP=O = 1212 cm-1; νC=O = 1644 cm-1; νOH = 3354 cm-1; νNH = 3354 cm-1; EI-HRMS: calculated for C16H15N2O2P, 298.0871 (M+); found: 298.0869.

ACKNOWLEDGMENTS
We thank the Tunisian Ministry of Higher Education and Scientific Research for financial support.

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