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Efficient Method for The Synthesis of αAmidophosphonates via the MichaelisArbuzov Reaction a
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Samia Guezane Lakoud , Malika Berredjem & Nour-Eddine Aouf
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Laboratory of Applied Organic Chemistry, Badji-Mokhtar University, El-Hadjar, Annaba, Algeria Available online: 05 Apr 2012
To cite this article: Samia Guezane Lakoud, Malika Berredjem & Nour-Eddine Aouf (2012): Efficient Method for The Synthesis of α-Amidophosphonates via the Michaelis-Arbuzov Reaction, Phosphorus, Sulfur, and Silicon and the Related Elements, 187:6, 762-768 To link to this article: http://dx.doi.org/10.1080/10426507.2011.645173
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Phosphorus, Sulfur, and Silicon, 187:762–768, 2012 C Taylor & Francis Group, LLC Copyright ISSN: 1042-6507 print / 1563-5325 online DOI: 10.1080/10426507.2011.645173
EFFICIENT METHOD FOR THE SYNTHESIS OF α-AMIDOPHOSPHONATES VIA THE MICHAELIS-ARBUZOV REACTION
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Samia Guezane Lakoud, Malika Berredjem, and Nour-Eddine Aouf Laboratory of Applied Organic Chemistry, Badji-Mokhtar University, El-Hadjar, Annaba, Algeria GRAPHICAL ABSTRACT
Abstract A new series of modified α-amidophosphonates (or β-ketophosphonate) was synthesized by an efficient method, starting from aminoesters and chloroacetyl chloride. We have established that chloroacetyl chloride is a suitable reagent allowing the introduction a halogen moiety for the Arbuzov reaction. The α-amidophosphonates were prepared in two steps (acetylation, phosphorylation). Supplemental materials are available for this article. Go to the publisher’s online edition of Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental file. Keywords Phosphonate; β-ketophosphonate; α-amidophosphonate; arbuzov reaction; becker reaction
Received 5 September 2011; accepted 26 November 2011. This work was generously supported by the (Direction Generale de la Recherche Scientifique et du D´eveloppement Technologique, DGRS-DT), Algerian Ministry of Scientific Research, (FNR), CMEP 08 MDU 729 and fruitful discussions with Pr. Marc Lecouvey, Universit´e Paris 13, France were greatly appreciated. Address correspondence to Malika Berredjem, Laboratory of Applied Organic Chemistry, Badji-Mokhtar University, BP 12 El-Hadjar, Annaba, 23000, Algeria. E-mail:
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INTRODUCTION Since the discovery of (2-aminoethyl)phosphonic acid in 1959,1 and the isolation of 2-amino-1-hydroxyethylphosphonic acid from Acanthamoeba castellanii,2 there has been a growing interest in the synthesis of phosphorus derivatives of amino acids because of their wide range of applications as antibiotics and antiviral agents as well as insecticides and herbicides.3,4 The 1-aminoalkylphosphonic acid and phosphinic acids and the corresponding phosphono- and phosphinopeptides can interfere in biological mechanisms inducing enzyme inhibitor properties.5 Traditional methods for the preparation of substituted phosphonates are of limited value for the preparation of substituted β-ketophosphonates. Recently, several new methods have been developed with the goal of providing a synthetic route to this class of compounds6 however; as yet, a general synthesis has not become available. To the best of our knowledge, only a few synthetic approaches to obtain amidophosphonates7,8 1, 2, and work to obtain chiral chloro α-amidophosphonate 3 have been reported in the literature. In our attempt to develop the synthesis of new biologically active phosphonate derivatives, we have reported a simple and efficient method for the synthesis of novel β-ketophosphonate (or α-amidophosphonate) from chiral amino acids via the MichaelisArbuzov reaction.
RESULTS AND DISCUSSION The starting chiral methyl-chloroacetamide alkyl esters 1a–c were easily prepared in excellent yield (90–95%) by treatment of the chiral amino esters with chloroacetylchloride in the presence of triethylamine (TEA) in tetrahydrofuran (THF) at 0 ◦ C, followed by the Michaelis–Arbuzov reaction9 with triethyl phosphite or by Michaelis–Becker reaction10 with the nucleophilic addition of a diethyl phosphite in the presence of NaH in a dry THF at 60 ◦ C gave the chiral methyl 2-(diethoxyphosphoryl)acetamide 2-alkylacetate 2a–c in (88–90%) yield (Scheme 1).
Scheme 1
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Figure 1 Examples of α-amidophosphonates.
Both reactions, the Michaelis–Arbuzov and the Michaelis–Becker, have a goal to form the C–P bond, and give access to the phosphonate moieties: the first is a thermal way, the second one is an anionic reaction. The next step is reduction of methyl ester group in chiral (s)-methyl 2(diethoxyphosphoryl) acetamide 2-alkyl acetate with sodium borohydride in THF/Water mixture at 0 ◦ C for 1 h to give a chiral (s) 2-(diethoxyphosphoryl)acetamide 2-alkyl ethanol 4a–c in 60% yield. Chlorination of 3a–c using SO2 Cl2 in presence of TEA in CH2 Cl2 at −78 ◦ C furnished the corresponding chloro α-amidophosphonate derivatives 4a–c (Scheme 2).
Scheme 2
CONCLUSION In summary, we have presented a new approach to the synthesis of α-amido phosphonate with good chemical yield. This synthesis has been performed easily starting from a chiral amino esters following with the Michaelis–Arbuzov reaction or Michaelis–becker reaction to form α-amidophosphonate and finally using reduction then chlorination reactions to obtain the chiral chloro α-amidophosphonate. EXPERIMENTAL SECTION Melting points were determined in open capillary tubes on an Electro thermal apparatus and uncorrected. IR spectra were recorded on a Perkin–Elmer FT-600 spectrometer. Proton nuclear magnetic resonance was determined with a 360 WB or AC 250-MHz
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Bruker spectrometer using CDCl3 and DMSO-d6 as a solvent and tetramethylsilane (TMS) as an internal standard. Chemical shifts are reported in δ units (ppm). All coupling constants (J) are reported in Hertz. Multiplicity is indicated as s (singlet), d (doublet), t (triplet), m (multiplet), and combination of these signals. Electron ionization mass spectra (30 eV) were recorded in positive mode on a Water MicroMass ZQ. High-resolution mass were measured on a Joel SX 102 mass spectrometer and recorded in FAB positive mode. All reactions were monitored by TLC on silica Merck h60 F254 (Art. 5554) percolated aluminum plates and were developed by spraying with ninhydrin solution. Figures S1–S5 (Supplemental Materials) show selected 1H and 13C NMR spectra for 2c, 3c, and 4c. Typical Procedure for the Preparation of Chiral α-Chloroacetamides To a solution of amino esters (1.14 g, 6.28 mmol) in dry THF (10 mL) and TEA (1.92 mL, 2.2 eq, 6.28 mmol) at 0 ◦ C, was added dropwise the chloroacetyl chloride (2 mL, 2 eq, 6.28 mmol). The resulting mixture was then stirred at room temperature overnight. The mixture was washed with HCl (0.1 N) and water (2 × 10 mL). The organic layer was dried over anhydrous sodium sulfate and removed under reduced pressure to give: (s)-Methyl 2-[2-Chloroacetamide] 2-Isobutylacetate 1a: yellow oil, yield 88%, Rf = 0.7 (CH2 Cl2 ), [α]D = −9◦ (c = 1, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz): δ = 0.95 (2d, J = 6.73 Hz, 6H, 2CH3iBu ), 1.65 (m, 3H, CH2iBu + CHiBu ), 3.75 (s, 3H, CH3 O), 4.05 (s, 2H, CH2 Cl), 4.65 (m, 1H, ∗ CH), 7.05 (d, J = 7.58 Hz, 1H, NH), 13C NMR (CDCl3 , 250 MHz): 21.1 (CH3iBu ), 21.5 (CH3iBu ), 24.5 (CHiBu ), 40.0 (CH2iBu ), 41.0 (CH2 Cl), 50.1 (CH3 O), 51.5 (∗ CH), 165.4 (CO–NH), 171.5 (CO2 CH3 ), MS ESI+ 30 eV m/z: 222 [M+1]+, 100%), IR (CCl4 , σ cm−1): 3290 (NH), 1747 (CO2 CH3 ), 1645 (CO–NH). (s)-Methyl 2-[2-Chloroacetamide] 2-Isopropylacetate 1b: yellow oil, yield 90%, Rf = 0.8 (CH2 Cl2 ), [α]D = +13.5◦ (c = 1, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz): δ = 0.95 (2d, J = 5.79 Hz, 6H, 2CH3 iPr ), 2.25 (m, 1H, CH iPr ), 3.75 (s, 3H, CH3 O), 4.10 (s, 2H, CH2 Cl), 4.51 (m, 1H, ∗ CH), 7.05 (d, J = 7.35 Hz, 1H, NH), 13C NMR (CDCl3 , 250 MHz): 16.7 (CH3 iPr ), 17.9 (CH3 iPr ), 30.0 (CH iPr ), 41.5 (CH2 Cl), 51.3 (CH3 O), 56.2 (∗ CH), 165.0 (CO-NH), 170.7 (CO2 CH3 ), MS ESI+ 30 eV m/z: 208 ([M+H]+ 100%), IR (CCl4 , σ cm−1): 3250 (NH), 1720 (CO2 CH3 ), 1621 (CO–NH). (s)-Methyl 2-[2-Chloroacetamide] 2-Benzylacetate 1c: white solid, yield 95%, Rf = 0.72 (CH2 Cl2 ), [α]D = +19◦ (c = 1, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz): δ = 3.05 (m, 2H, CH2 Ph), 3.75 (s, 3 H, CH3 O), 4.05 (s, 2H, CH2 Cl), 4.95 (m, 1H, ∗ CH), 7.05 (d, J = 6.74 Hz, 1H, NH), 7.25 (m, 2H, H–Ar), 7.35 (m, 3H, H–Ar), 13C NMR (CDCl3 , 250 MHz): 37.8 (CH2 Cl), 42.4 (CH2 Ph), 52.5 (CH3 O), 53.4 (∗ CH), 127.2, 128.7, 129.2, and 135.3 (C Ar), 165.6 (CO–NH), 171.3 (CO2 CH3 ), MS ESI+ 30 eV m/z: 256 ([M+1]+, 100%), IR (KBr, σ cm−1): 3290 (NH), 1747 (CO2 CH3 ), 1645 (CO–NH). General Procedure for the Michaelis–Arbuzov Reaction The triethylphosphite (4.25 mL, 5 eq, 4.96 mmol) was heated at (110 ◦ C) under argon, after the compound 1 (1.1 g, 4.96 mmol) was added and the resulting solution was heated at reflux for an additional 6 h. The undesired product was removed by a short distillation system. The residue was then purified by column chromatography on silica gel to give the compound 2 in excellent yield.
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General Procedure for the Michaelis-Becker Reaction These compounds were successively obtained by addition of NaH (60% in mineral oil, 1.3 eq), in dry THF (10 mL), and diethylphosphite (0.75 mL, 1.3 eq, 4.5 mmol) under argon. After stirring at 0 ◦ C (0.5 h), then at reflux (1.5 h), chloroacetamide 1 (1 g, 4.5 mmol) was introduced at 0 ◦ C. After stirring for 24 h at room temperature, the reaction was quenched by addition of water (30 mL). The aqueous layer was extracted with dichloromethane (3 × 30 mL). The organic layer was dried with MgSO4 , concentrated, and the residue purified by chromatography over silica gel (CH2 Cl2 /MeOH: 9.8/0.2) to give compound 2 in excellent yield. (s)-Methyl 2-[2-Diethoxyphosphoryl)acetamide] 2-Isobutylacetate 2a: the crude product was purified by column chromatography (CH2 Cl2 /MeOH: 9.7/0.3) giving the compound 2b as yellow oil, 75% yield, Rf = 0.60 (CH2 Cl2 /MeOH), [α]D = −32.5◦ (c = 0.2, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz): δ = 0.95 (2d, J = 6,18 Hz, 6H, 2CH3iBu ), 1.35 (2t, J = 7.05 Hz, 6H, (CH3 CH2 O)2 P), 1.51–1.71 (m, 3H, CHiBu +CH2iBu ), 2.82 (d, J H/P = 4.76, 1 H, CH2 P), 2.95 (d, J H/P = 1.29, 1H, CH2 P), 3.74 (s, 3H, CH3 O), 4.15 (m, 4H, (CH3 CH2 O)2 P), 4.55 (m, 1H, ∗ CH), 7.12(d, J = 7.81, 1H, NH), Ms ESI+ 30 eV m/z: 324 ([M+1]+, 100%). 13C NMR (CDCl3 , 250 MHz): 16.3 (d, (CH3 CH2 O)2 P), 21.6 (CH3iBu ), 22.8 (CH3iBu ), 24.7 (CHiBu ), 34.2 (d, CH2 P), 41.0 (CH2iBu ), 51.1 (CH3 O), 52.2 (∗ CH), 62.5 (d, CH3 CH2 O)2 P), 164.0 (CO–NH), 173.0 (CO2 CH3 ), 31P NMR: 16.3 ppm, IR (CDCl3 , σ cm−1): 3275 (NH), 1744 (CO2 CH3 ), 1655 (CO–NH), 1246 (P = O), 1161 (OEt). (s)-Methyl 2-[2-Diethoxyphosphoryl)acetamide] 2-Isopropylacetate 2b: the crude product was purified by column chromatography (CH2 Cl2 /MeOH: 9.8/0.2) to give the compound 2a as yellow oil, Rd: 75%, Rf = 0.65 (CH2 Cl2 /MeOH), [α]D = −8.5◦ (c = 1, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz): δ = 0.95 (2d, J = 6.9 Hz, 6H, 2CH3iPr ), 1.35 (2t, J = 7.07 Hz, 6H, (CH3 CH2 O)2 P), 2.20 (m, 1 H, CHiPr ), 2.85 (d, J H/P = 4.98, 1H, CH2 P), 2.95 (d,, J H/P = 5.2, 1H, CH2 P), 3.75 (s, 3H, CH3 O), 4.15 (m, 4H, (CH3 CH2 O)2 P), 4.52 (m, 1 H,∗ CH), 7.15 (d, J = 8.1Hz, 1H, NH), 31P NMR: 16.5 ppm, 13C NMR (CDCl3 , 250 MHz): 16.2 (d, CH3 CH2 O)2 P), 18.5 (CH3iPr ), 19.2 (CH3iPr ), 29.7 (CHiPr ), 34.1 (CH2 P), 50.9 (CH3 O), 52.0 (∗ CH), 62.6 (d, CH3 CH2 O)2 P, 163.8 (CO–NH), 171.9 (CO2 CH3 ), Ms ESI+ 30 eV m/z: 310 ([M+1]+, 100%), IR (CCl4 , σ cm−1): 3281 (NH), 1732 (CO2 CH3 ), 1651 (CO–NH), 1251 (P = O), 1155 (OEt). (s)-Methyl 2-[2-Diethoxyphosphoryl)acetamide] 2-Benzylacetate 2c: the crude product was purified by column chromatography (CH2 Cl2 ) giving the compound 3c as viscous oil, 80% yield, Rf = 0.57 (CH2 Cl2 /MeOH), [α]D = −27.5◦ (c = 0.2, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz): δ = 1.25 (2t, J = 7.07 Hz, 6H, (CH3 CH2 )2 P), 2.80 (d, J H/P = 3.09 Hz, 1 H, CH2 P), 2.90 (d, J H/P = 3.2 Hz, 1H, CH2 P), 3.05 (m 2H, CH2 Ph), 3.75 (s, 3H, CH3 O), 4.05 (m, 4H, (CH3 CH2 O)2 P), 4.85 (m, 1H, ∗ CH), 7.24 (m, 5H, H–Ar), 13C NMR (CDCl3 , 250 MHz): 16.3 (d, (CH3 CH2 O)2 P), 34.4 (d, CH2 P), 37.8 (CH2 Ph), 52.3 (CH3 O), 53.9 (∗ CH), 62.8 (d, (CH3 CH2 O)2 P), 127.1, 128.6, 129.3, and 135.9 (C Ar), 163.8 (CO–NH), 171.5 (CO2 CH3 ). 31P NMR: 16.2 ppm, Ms ESI+ 30 eV m/z: 358 ([M+1]+, 100%), IR (CDCl3 , σ cm−1): 3265 (NH), 1746 (CO2 CH3 ), 1655 (CO–NH), 1246 (P = O), 1161 (OEt).
Typical Procedure for the Reduction with NaBH4 To a solution of 2 (0.73 g, 2.2 mmol) in a THF/H2 O (4/1) mixture at 0 ◦ C, sodium borohydride (0.4 g, 4 eq, 2.2mmol) was added; the resulting solution was stirred for 1 h
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at room temperature. The reaction was quenched by the addition of neutralized HCl (5%) solution. The solution was evaporated and the residue was extracted with ethyl acetate (3 × 20 ml), the layer organic extracts were dried over anhydrous Na2 SO4 , filtered and concentrated in vacuum. The crude product was purified on a silica-gel column (CH2 Cl2 /MeOH: 9.7/0.3) to afford the expected product 3 in good yield. (s)-2-[2-Diethoxyphosphoryl)acetamide] 2-Isobutylethanol 3a: yellow oil, yield 88%, Rf = 0.44 (CH2 Cl2 /MeOH), [α]D = −86.4◦ , 1H NMR (CDCl3 , 250 MHz): δ = 0.98 (2d, J = 2.87 Hz, 6H, 2CH3iBu ), 1.45 (m, 8 H, (CH3 CH2 O)2 P+ CH2iBu ), 1.65 (m, 1H, CHiBu ), 2.48 (s, 1H, OH), 2.95 (d, J H/P = 20.89, 2H, CH2 P), 3.50 (dd, Jgem = 5.37 Hz, J = 5.6 Hz, 1H, CH2 OH), 3.75 (dd, J gem = 3.37 Hz, J = 3.47 Hz, 1H, CH2 OH), 4.20 (m, 5H, (CH3 CH2 O)2 P+∗ CH), 6.70 (d, J = 7.89, 1H, NH), 31P NMR: 16.3 ppm, 13C NMR (CDCl3 , 250 MHz): 16.3 (d, CH3 CH2 O)2 P), 22.0 (CH3iBu ), 23.1 (CH3iBu ), 24.8 (CHiBu ), 35.0 (d, CH2 P), 39.86 (CH2iBu ), 50.8 (CH2 OH), 53.8 (∗ CH) 62.7 (d, CH3 CH2 O)2 P), 164.8 (CO–NH), Ms ESI+ 30 eV m/z: 296 ([M+1]+, 100%), IR (CCl4 , σ cm−1): 3250–3490 (OH), 3101(NH), 1650 (CO–NH), 1231(P = O), 1112(OEt). (s)-2-[2-Diethoxyphosphoryl)acetamide] 2-Isopropylethanol 3b: yellow oil, yield 85%, Rf = 0.45, [α]D = −58.5◦ , 1H NMR (CDCl3 , 250 MHz): δ = 0.94 (2d, J = 6.87 Hz, 6H, 2CH3iPr ), 1.25 (2t, J = 6.5 Hz, 6H, (CH3 CH2 )2 P), 1.95 (m, 1 H, CHiPr ), 2.85 (dd, JH/P = 8.5 Hz, 2H, CH2 P), 3.75 (m, 2H, CH2 OH), 4.15 (m, 5H, (CH3 CH2 O)2 P+∗ CH), 6.80 (d, J = 7.5, 1H, NH), 31P NMR: 16.7 ppm, 13C NMR (CDCl3 , 250 MHz): 16.2 (d, (CH3 CH2 O)2 P), 18.1 (CH3iPr ), 19.1 (CH3iPr ), 29.0 (CHiPr ), 35.0 (CH2 P), 50.2 (CH2 OH), 54.9 (∗ CH), 62.3 (d, CH3 CH2 O)2 P), 163.8 (CO–NH), Ms ESI+ 30 eV m/z: 282 ([M+1]+, 100%), IR (CCl4 , σ cm−1): 3298–3484 (OH), 3102 (NH), 1650 (CO–NH), 1241 (P = O), 1151 (OEt). (s)-2-[2-Diethoxyphosphoryl)acetamide] 2-Benzylethanol 3c: yellow oil, yield 90%, Rf = 0.55 (CH2 Cl2 /MeOH), [α]D = −93.5◦ (c = 0.15, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz): δ = 1.35 (2t, J = 7.18 Hz, 6H, (CH3 CH2 O)2 P), 2.82 (d, J = 14.58 Hz, CH2 P), 3.05 (s, 1H, OH), 3.55 (dd, J = 4.76 Hz, 1H, CH2 Ph), 3.75 (dd, J = 3.38 Hz, J = 3.51 Hz, 2H, CH2 OH), 4.15 (m, 5H, (CH3 CH2 O)2 P+∗ CH), 7.05 (d, J = 8.07, 1H, NH), 7.30 (m, 5H, Harm ), 31P NMR: 16.3 ppm, 13C NMR (CDCl3 , 250 MHz): 16.3 (d, CH3 CH2 O)2 P), 35.0 (CH2 P), 38.8 (CH2 Ph), 53.0 (CH2 OH), 54.0 (∗ CH), 62.8 (d, CH3 CH2 O)2 P), 127.2, 128.7, 129.6, and 136.0 (C Ar), 164.0 (CO–NH), Ms ESI+ 30 eV m/z: 330 ([M+1]+, 100%), IR (CCl4 , σ cm−1): 3280–3580 (OH), 3186 (NH), 1650 (CO–NH), 1296 (P = O), 1142 (OEt). General Procedure for Chlorination The compound (s)-Methyl 2-[2-diethoxyphosphoryl) acetamide] 2-alkylethanol 3 (0.71 g, 2.4 mmol) was dissolved in dry dichloromethane (10 mL) under an argon atmosphere, trietylamine (0.84 mL, 2.5 eq, 2.4 mmol) was added to the solution at –78 ◦ C. Sulfuryl chloride (0.25 mL, 0.5 eq, 2.4 mmol) was added dropwise to the solution, and the reaction mixture was kept under constant stirring at –78 ◦ C for 3 h, the reaction mixture was allowed to warm to room temperature for 10 h. The mixture was washed with HCl 1 N and water, the organic layer was dried over anhydrous sodium sulfate and removed under reduced pressure. The residue was purified on a silica gel column (CH2 Cl2 ) to afford the expected product 4 in good yield. (s)-2-[2-Diethoxyphosphoryl)acetamide] 2-Isobutylchloroethane 4a: as yellow oil, 60%, Rf = 0.75 (CH2 Cl2 /MeOH), [α]D = −59◦ (c = 0.5, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz), δ = 0.98 (2d, J = 2.16 Hz, 6H, 2CH3iBu ), 1.45 (2t, J = 7.08 Hz, 8H, (CH3 –CH2 O)2 P+ CH2iBu ), 2.05 (m, 1H, CHiBu ), 2.95 (dd, J = 19.8 HZ, 2H, CH2 P),
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3.50 (dd, J = 6.57 HZ, 2H, CH2 Cl), 4.15 (m, 5H, (CH3 CH2 O)2 P+∗ CH), 6.90 (d, J = 7.9, 1H, NH), 31P NMR: 26.5 ppm, 13C NMR (CDCl3 , 250 MHz): 16.3 (d, CH3 CH2 O)2 P), 21.9 (CH3iBu ), 22.1 (CH3iBu ), 25.5 (CHiBu ), 35.5 (CH2 P), 41.0 (CH2iBu ), 55.0 (CH2 Cl), 56.6 (∗ CH), 62.7 (d, CH3 CH2 O)2 P, 165.2 (CO–NH), Ms ESI+ 30 eV m/z: 336 ([M+23]+, 100%), IR (CCl4 , σ cm−1): 3151 (NH), 1649 (CO–NH), 1251 (P = O), 1108 (OEt). (s)-2-[2-Diethoxyphosphoryl)acetamide] 2-Isopropylchloroethane 4b: as yellow oil, 65%, Rf = 0.75 (CH2 Cl2 /MeOH), [α]D = −40◦ (c = 0.15, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz), δ = 1.05 (2d, J = 6.16 Hz, 6H, 2CH3iPr ), 1.45 (2t, J = 7.08 Hz, 6H, (CH3 –CH2 O)2 P), 1.85 (m, 1H, CHiPr ), 2.90 (dd, J = 9.9 HZ, 2H, CH2 P), 3.65 (dd, J = 4.5 Hz, 2H, CH2 Cl), 4.50 (m, 5H, (CH3 CH2 O)2 P)+ ∗ CH), 7.20 (d, J = 8.1, 1H, NH), 31P NMR: 26.5 ppm, 13C NMR (CDCl3 , 250 MHz): 16.2 (d, (CH3 CH2 O)2 P), 18.14 (CH3iPr ), 19.2 (CH3iPr ), 27.0 (CHiPr ), 35.0 (CH2 P), 55.0 (CH2 Cl), 56.8 (∗ CH), 62.6 (d, CH3 CH2 O)2 P), 164.5 (CO–NH), Ms ESI+ 30 eV m/z: 322.5 ([M+23]+, 100%), IR (CCl4 , σ cm−1): 3151 (NH), 1649 (CO–NH), 1251 (P = O), 1108 (OEt). (s)-2-[2-Diethoxyphosphoryl)acetamide] 2-Benzylchloroethane 4c: as yellow oil, 70%, Rf = 0.68(CH2 Cl2 /MeOH), [α]D = −150◦ (c = 0.1, CH2 Cl2 ), 1H NMR (CDCl3 , 250 MHz), δ = 1.36–1.46 (2t, 6H, (CH3 CH2 O)2 P), 3.05 (d, J = 7.33 Hz, 2H, CH2 P), 3.55 (dd, J = 3.52 Hz, 2H, CH2 Ph), 3.70 (dd, J = 4.16 Hz, 2H, CH2 Cl), 4.30 (m, 5H, (CH3 CH2 O)2 P+ ∗ CH), 7.15 (d, J = 8.11 Hz, 1H, NH) 7.35 (m, 5H, H–Ar), 13C NMR (CDCl3 , 250 MHz): 16.4 (d, CH3 CH2 O)2 P), 37.1 (CH2 P), 45.7 (CH2 Ph), 52.7 (CH2 Cl), 53.5 (∗ CH), 66.8 (d, (CH3 CH2 O)2 P), 127.1, 128.8, 129.3, and 136.2 (C Ar), 156.0 (CO–NH), Ms ESI+ 30 eV m/z: 370 ([M+23]+, 100%) 31P NMR: 26.8 ppm, IR (CDCl3 , σ cm−1): 32681 (NH), 1651 (CO–NH), 1291 (P = O). REFERENCES 1. Horiguchi, M.; Kandatsu, M. Nature 1959, 184, 901-902. 2. Kom, E. D.; Dearborn, D. G.; Fales, H. M.; Sokoloski, E. A. J. Biol. Chem. 1973, 248, 2257-2259. 3. (a) Sikorski, J. A.; Logusch, E. W. In: R. Engel, (Ed.), Handbook of Organophosphorus Chemistry; Chapter 15: Aliphatic carbon-Phosphorus compounds as Herbidices, Marcel Dekker: New York, 1992; pp. 739-805; (b) Eto, M. In: R. Engel, (Ed.), Handbook of Organophosphorus Chemistry; Chapter 16: Phosphorus containing Insecticides, Marcel Dekker: New York, 1992; pp. 807-873. 4. (a) Kalir, A.; Kalir, H. H. In: F. R. Hartley, (Ed.), The Chemistry of Organophosphorus Compounds; Wiley and Sons: New York, 1996; 4, pp. 767-780; (b) Engel, R. Chem. Rev. 1977, 77, 349-367; (c) Fields, S. C. Tetrahedron. 1999, 55, 12237-12273; (d) Knowles, J. R.; Orr, G. A. Biochem. J. 1974, 141, 721-723; (e) Kim, C. U.; Misco, P. F.; Luh, B. Y.; Hitchcock, M. J. M.; Ghazzouli, I.; Martin, J. C. J. Med. Chem. 1991, 34, 2286-2294; (f) Varki, A. Glycobiology 1993, 3, 97-130. 5. Kafarski, P.; Lejczak, B. In: V. P. Kukhar, H. R. Hudson, (Eds.), (Aminophosphonic and Aminophosphinic Acids Chemistry and Biological Activity; John Wiley: Chichester, 2000; pp. 407-443. 6. (a) Demir, A. S.; Tural, S. Tetrahedron. 2007, 63, 4156-4161; (b) Pousset, C.; Larchevˆeque, M. Tetrahedron Lett. 2002, 43, 5257-5260; (c) Tay, M. K.; About-Jaudet, E.; Colignon, N.; Savignac, P. Tetrahedron. 1989, 45(14), 4415-4430; (d) Chauhan, S. C.; Varshney, A.; Varma, B.; Pennington, M. W. Tetrahedron Lett. 2007, 48, 4051-4054. 7. Mario, O.; Eugenio, H. F.; Hydr´ee, R. C.; Victoria, L. G.; Tetrahedron Asymmetry. 2008, 19, 2767-1770. 8. Castelot-Deliencourt, G.; Pannecoucke, X.; Quirion, J.-C. Tetrahedron Lett. 2001, 42, 1025-1028. 9. Bhattacharya, A. K.; Thyagarajan, G. Chem. Rev. 1981, 81, 415-430. 10. Ye, W. Z.; Liao, X. G. Synthesis 1985, 986-988.
