Efficient method for the synthesis of α-amidophosphonates via the michaelis-arbuzov reaction

Article abstract of DOI:10.1080/10426507.2011.645173

A new series of modified β-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. Copyright

Full text of DOI:10.1080/10426507.2011.645173

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Efficient Method for The Synthesis of α-
Amidophosphonates via the Michaelis-
Arbuzov Reaction
Samia Guezane Lakoud a , Malika Berredjem a & Nour-Eddine Aouf a
a Laboratory of Applied Organic Chemistry , Badji-Mokhtar
University , El-Hadjar , Annaba , Algeria
Published 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, DOI: 10.1080/10426507.2011.645173
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
Copyright ꢀC Taylor & Francis Group, LLC
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
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 syn-
thesized by an efficient method, starting from aminoesters and chloroacetyl chloride. We have
established that chloroacetyl chloride is a suitable reagent allowing the introduction a halo-
gen 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
De´veloppement Technologique, DGRS-DT), Algerian Ministry of Scientific Research, (FNR), CMEP 08 MDU
729 and fruitful discussions with Pr. Marc Lecouvey, Universite´ 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: mberredjem@yahoo.fr
762

EFFICIENT METHOD FOR THE SYNTHESIS
763
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 correspond-
ing 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 Michaelis-
Arbuzov 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

764
S. GUEZANE LAKOUD ET AL.
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-
(diethoxyphos◦phoryl) 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 SO2Cl2 in presence of TEA in
CH2Cl2 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 appa-
ratus 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

EFFICIENT METHOD FOR THE SYNTHESIS
765
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 spec-
tra (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 posi-
tive 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 (CH2Cl2), [α]D = −9◦ (c = 1, CH2Cl2), 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, CH3O), 4.05
∗
(s, 2H, CH2Cl), 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 (CH2Cl), 50.1
(CH3O), 51.5 (∗CH), 165.4 (CO–NH), 171.5 (CO2CH3), MS ESI+ 30 eV m/z: 222 [M+1]+,
100%), IR (CCl4, σ cm−1): 3290 (NH), 1747 (CO2CH3), 1645 (CO–NH).
(s)-Methyl 2-[2-Chloroacetamide] 2-Isopropylacetate 1b: yellow oil, yield 90%,
1
Rf = 0.8 (CH2Cl2), [α]D = +13.5◦ (c = 1, CH2Cl2), H 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, CH3O), 4.10 (s,
2H, CH2Cl), 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 (CH2Cl), 51.3 (CH3O), 56.2 (∗CH),
165.0 (CO-NH), 170.7 (CO2CH3), MS ESI+ 30 eV m/z: 208 ([M+H]+ 100%), IR (CCl4,
σ cm−1): 3250 (NH), 1720 (CO2CH3), 1621 (CO–NH).
(s)-Methyl 2-[2-Chloroacetamide] 2-Benzylacetate 1c: white solid, yield 95%,
1
Rf = 0.72 (CH2Cl2), [α]D = +19◦(c = 1, CH2Cl2), H NMR (CDCl3, 250 MHz): δ =
3.05 (m, 2H, CH2Ph), 3.75 (s, 3 H, CH3O), 4.05 (s, 2H, CH2Cl), 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 (CH2Cl), 42.4 (CH2Ph), 52.5 (CH3O), 53.4 (∗CH), 127.2, 128.7, 129.2,
and 135.3 (C Ar), 165.6 (CO–NH), 171.3 (CO2CH3), MS ESI+ 30 eV m/z: 256 ([M+1]+,
100%), IR (KBr, σ cm−1): 3290 (NH), 1747 (CO2CH3), 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.

766
S. GUEZANE LAKOUD ET AL.
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 (CH2Cl2/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 (CH2Cl2/MeOH: 9.7/0.3) giving the com-
pound 2b as yellow oil, 75% yield, Rf = 0.60 (CH2Cl2/MeOH), [α]D = −32.5◦ (c = 0.2,
1
CH2Cl2), H NMR (CDCl3, 250 MHz): δ = 0.95 (2d, J = 6,18 Hz, 6H, 2CH3iBu), 1.35
(2t, J = 7.05 Hz, 6H, (CH3CH2O)2P), 1.51–1.71 (m, 3H, CHiBu +CH2iBu), 2.82 (d, JH/P
=
4.76, 1 H, CH2P), 2.95 (d, JH/P = 1.29, 1H, CH2P), 3.74 (s, 3H, CH3O), 4.15 (m, 4H,
(CH3CH2O)2P), 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, (CH3CH2O)2P), 21.6 (CH3iBu),
22.8 (CH3iBu), 24.7 (CHiBu), 34.2 (d, CH2P), 41.0 (CH2iBu), 51.1 (CH3O), 52.2 (∗CH), 62.5
(d, CH3CH2O)2P), 164.0 (CO–NH), 173.0 (CO2CH3), 31P NMR: 16.3 ppm, IR (CDCl3,
σ cm−1): 3275 (NH), 1744 (CO2CH3), 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 (CH2Cl2/MeOH: 9.8/0.2) to give
the compound 2a as yellow oil, Rd: 75%, Rf = 0.65 (CH2Cl2/MeOH), [α]D = −8.5◦ (c =
1, CH2Cl2), 1H NMR (CDCl3, 250 MHz): δ = 0.95 (2d, J = 6.9 Hz, 6H, 2CH3iPr), 1.35 (2t,
J = 7.07 Hz, 6H, (CH3CH2O)2P), 2.20 (m, 1 H, CHiPr), 2.85 (d, JH/P = 4.98, 1H, CH2P),
2.95 (d,, JH/P = 5.2, 1H, CH2P), 3.75 (s, 3H, CH3O), 4.15 (m, 4H, (CH3CH2O)2P), 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, CH3CH2O)2P), 18.5 (CH3iPr), 19.2 (CH3iPr), 29.7 (CHiPr), 34.1 (CH2P),
50.9 (CH3O), 52.0 (∗CH), 62.6 (d, CH3CH2O)2P, 163.8 (CO–NH), 171.9 (CO2CH3), Ms
ESI+ 30 eV m/z: 310 ([M+1]+, 100%), IR (CCl4, σ cm−1): 3281 (NH), 1732 (CO2CH3),
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 (CH2Cl2) giving the compound 3c as
viscous oil, 80% yield, Rf = 0.57 (CH2Cl2/MeOH), [α]D = −27.5◦ (c = 0.2, CH2Cl2), 1H
NMR (CDCl3, 250 MHz): δ = 1.25 (2t, J = 7.07 Hz, 6H, (CH3CH2)2P), 2.80 (d, JH/P
=
3.09 Hz, 1 H, CH2P), 2.90 (d, JH/P = 3.2 Hz, 1H, CH2P), 3.05 (m 2H, CH2Ph), 3.75 (s,
∗
3H, CH3O), 4.05 (m, 4H, (CH3CH2O)2P), 4.85 (m, 1H, CH), 7.24 (m, 5H, H–Ar), 13C
NMR (CDCl3, 250 MHz): 16.3 (d, (CH3CH2O)2P), 34.4 (d, CH2P), 37.8 (CH2Ph), 52.3
(CH3O), 53.9 (∗CH), 62.8 (d, (CH3CH2O)2P), 127.1, 128.6, 129.3, and 135.9 (C Ar), 163.8
(CO–NH), 171.5 (CO2CH3). 31P NMR: 16.2 ppm, Ms ESI+ 30 eV m/z: 358 ([M+1]+,
100%), IR (CDCl3, σ cm−1): 3265 (NH), 1746 (CO2CH3), 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/H2O (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

EFFICIENT METHOD FOR THE SYNTHESIS
767
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 Na2SO4, filtered and concen-
trated in vacuum. The crude product was purified on a silica-gel column (CH2Cl2/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 (CH2Cl2/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, (CH3CH2O)2P+ CH2iBu), 1.65 (m, 1H,
CHiBu), 2.48 (s, 1H, OH), 2.95 (d, JH/P = 20.89, 2H, CH2P), 3.50 (dd, Jgem = 5.37 Hz,
J = 5.6 Hz, 1H, CH2OH), 3.75 (dd, Jgem = 3.37 Hz, J = 3.47 Hz, 1H, CH2OH), 4.20 (m,
5H, (CH3CH2O)2P+∗CH), 6.70 (d, J = 7.89, 1H, NH), 31P NMR: 16.3 ppm, 13C NMR
(CDCl3, 250 MHz): 16.3 (d, CH3CH2O)2P), 22.0 (CH3iBu), 23.1 (CH3iBu), 24.8 (CHiBu),
35.0 (d, CH2P), 39.86 (CH2iBu), 50.8 (CH2OH), 53.8 (∗CH) 62.7 (d, CH3CH2O)2P), 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
1
85%, Rf = 0.45, [α]D = −58.5◦, H NMR (CDCl3, 250 MHz): δ = 0.94 (2d, J = 6.87
Hz, 6H, 2CH3iPr), 1.25 (2t, J = 6.5 Hz, 6H, (CH3CH2)2P), 1.95 (m, 1 H, CHiPr), 2.85 (dd,
JH/P = 8.5 Hz, 2H, CH2P), 3.75 (m, 2H, CH2OH), 4.15 (m, 5H, (CH3CH2O)2P+∗CH),
6.80 (d, J = 7.5, 1H, NH), 31P NMR: 16.7 ppm, 13C NMR (CDCl3, 250 MHz): 16.2 (d,
(CH3CH2O)2P), 18.1 (CH3iPr), 19.1 (CH3iPr), 29.0 (CHiPr), 35.0 (CH2P), 50.2 (CH2OH),
54.9 (∗CH), 62.3 (d, CH3CH2O)2P), 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 (CH2Cl2/MeOH), [α]D = −93.5◦ (c = 0.15, CH2Cl2), 1H NMR (CDCl3,
250 MHz): δ = 1.35 (2t, J = 7.18 Hz, 6H, (CH3CH2O)2P), 2.82 (d, J = 14.58 Hz, CH2P),
3.05 (s, 1H, OH), 3.55 (dd, J = 4.76 Hz, 1H, CH2Ph), 3.75 (dd, J = 3.38 Hz, J = 3.51 Hz,
2H, CH2OH), 4.15 (m, 5H, (CH3CH2O)2P+∗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, CH3CH2O)2P), 35.0
(CH2P), 38.8 (CH2Ph), 53.0 (CH2OH), 54.0 (∗CH), 62.8 (d, CH3CH2O)2P), 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 atmo-
◦
sphere, 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 (CH2Cl2) to afford the
expected product 4 in good yield.
(s)-2-[2-Diethoxyphosphoryl)acetamide] 2-Isobutylchloroethane 4a: as yellow
oil, 60%, Rf = 0.75 (CH2Cl2/MeOH), [α]D = −59◦ (c = 0.5, CH2Cl2), 1H NMR (CDCl3,
250 MHz), δ = 0.98 (2d, J = 2.16 Hz, 6H, 2CH3iBu), 1.45 (2t, J = 7.08 Hz, 8H,
(CH3–CH2O)2P+ CH2iBu), 2.05 (m, 1H, CHiBu), 2.95 (dd, J = 19.8 HZ, 2H, CH2P),

768
S. GUEZANE LAKOUD ET AL.
3.50 (dd, J = 6.57 HZ, 2H, CH2Cl), 4.15 (m, 5H, (CH3CH2O)2P+∗CH), 6.90 (d, J =
7.9, 1H, NH), 31P NMR: 26.5 ppm, 13C NMR (CDCl3, 250 MHz): 16.3 (d, CH3CH2O)2P),
21.9 (CH3iBu), 22.1 (CH3iBu), 25.5 (CHiBu), 35.5 (CH2P), 41.0 (CH2iBu), 55.0 (CH2Cl),
56.6 (∗CH), 62.7 (d, CH3CH2O)2P, 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
1
oil, 65%, Rf = 0.75 (CH2Cl2/MeOH), [α]D = −40◦ (c = 0.15, CH2Cl2), H NMR
(CDCl3, 250 MHz), δ = 1.05 (2d, J = 6.16 Hz, 6H, 2CH3iPr), 1.45 (2t, J = 7.08 Hz,
6H, (CH3–CH2O)2P), 1.85 (m, 1H, CHiPr), 2.90 (dd, J = 9.9 HZ, 2H, CH2P), 3.65 (dd,
∗
J = 4.5 Hz, 2H, CH2Cl), 4.50 (m, 5H, (CH3CH2O)2P)+ CH), 7.20 (d, J = 8.1, 1H,
NH), 31P NMR: 26.5 ppm, 13C NMR (CDCl3, 250 MHz): 16.2 (d, (CH3CH2O)2P), 18.14
(CH3iPr), 19.2 (CH3iPr), 27.0 (CHiPr), 35.0 (CH2P), 55.0 (CH2Cl), 56.8 (∗CH), 62.6 (d,
CH3CH2O)2P), 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,
1
70%, Rf = 0.68(CH2Cl2/MeOH), [α]D = −150◦ (c = 0.1, CH2Cl2), H NMR (CDCl3,
250 MHz), δ = 1.36–1.46 (2t, 6H, (CH3CH2O)2P), 3.05 (d, J = 7.33 Hz, 2H, CH2P),
3.55 (dd, J = 3.52 Hz, 2H, CH2Ph), 3.70 (dd, J = 4.16 Hz, 2H, CH2Cl), 4.30 (m, 5H,
∗
(CH3CH2O)2P+ CH), 7.15 (d, J = 8.11 Hz, 1H, NH) 7.35 (m, 5H, H–Ar), 13C NMR
(CDCl3, 250 MHz): 16.4 (d, CH3CH2O)2P), 37.1 (CH2P), 45.7 (CH2Ph), 52.7 (CH2Cl), 53.5
(∗CH), 66.8 (d, (CH3CH2O)2P), 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).
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