Polyethylene glycol in water: a simple and environment friendly medium for C–P bond formation

Abstract

A simple and highly efficient protocol for C–P bond formation under catalyst free conditions at an ambient temperature is reported by using polyethylene glycol in water as an efficient recyclable medium without using any organic co-solvent or additive.

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Introduction

Phosphorus–carbon bond formation reactions have attracted serious attention because of their application in the synthesis of α-functionalized phosphonic acids and their derivatives since they are valuable intermediates for the preparation of compounds of synthetic importance.^1,2 The main interest in phosphonyl and related derivatives resides in their potential biological activity as antibiotics,^3a herbicides,^3b insecticides,^3c fungicides,^3d and antiviral agents.^3e Since α-aminophosphonates are structural mimics of α-amino acids, they exhibit very high enzyme inhibiting potency including HIV protease.^3f Some of these compounds have already been found to act as antibacterial, neuroactive, anticancer agents, and pesticides while some of them being commercialized.⁴ The altered activity of such enzymes has been associated with the inhibition of HIV infections and several pathological disorders, including cancers and cataracts.⁵

A number of synthetic methods for α-amino phosphonates have been developed.⁶ The Kabachnik–Fields and Pudovik reactions are the most general, straightforward and widely applied methods for construction of C–P bonds.⁷ Of these, the nucleophilic addition of phosphites to imines, catalyzed by a base or an acid, is the most convenient route. Lewis acids such as SnCl₄,^8a BF₃·OEt₂,^8b and ZnCl₂^8c have been used for this transformation. However, these reactions could not be carried out in a one-pot single step operation with a carbonyl compound, an amine and a dialkyl phosphite because the amine and water formed during imine formation decompose or deactivate the Lewis acid.^8d This drawback has been partly overcome in some recent methods using lanthanide triflates/MgSO₄,^9a InCl₃,^9b TaCl₅–SiO₂,^9c bismuth nitrate pentahydrate,^9d MgClO₄,^9e TiO₂,^9f Amberlite-IR 120,^9g sulfamic acid,^9h H₃PW₁₂O₄₀,⁹ⁱ trimethylanilinium chloride,^9j lithium perchlorate,^9k Amberlyst-15,^9l and ZrOCl₂·8H₂O.^9m However, the continual search for a new and greener synthetic protocol that is simple, efficient and cost effective remains an ever-challenging objective. In continuation of our program on the development of novel organic synthetic methodologies,¹⁰ we have investigated the synthesis of α-aminophosphonate and α-hydroxyphosphonate derivatives by using polyethylene glycol-600 (PEG-600) in water as a recyclable medium without adding any organic solvent and catalyst.

In the recent years, PEG, a biologically acceptable polymer, emerged as a powerful phase transfer catalyst and performs many useful organic transformations under mild reaction conditions. Moreover, PEG and its monomethyl ethers are inexpensive, thermally stable, recoverable, and are proved to be non-toxic phase-transfer catalysts. The PEG has hitherto not been widely used as a solvent medium but has been used as a support for various transformations.¹¹ The use of water as a reaction medium has received considerable attention in the context of green chemistry, because it is a cheap, safe and environmentally benign medium.¹² This background prompted us to use PEG in water as reaction medium and surprisingly it worked successfully even without any catalyst.

An efficient C–P bond formation by using PEG in water in the absence of a catalyst is not yet reported. This report on the C–P bond formation using PEG in water at an ambient temperature is a successful endeavor that realised this goal.

Results and discussion

We investigated the reaction between 2-amino-5-methyl oxazole, 3-nitro benzaldehyde and diethyl phosphite by stirring equimolar quantities in different solvents at ambient temperature (Table 1) and low yield of desired α-amino phosphonate is obtained in all these experiments. The best result was obtained when the reaction was carried out using PEG in water. We also studied the influence of temperature on the reaction and observed that there is a significant change in the yields of products at elevated temperatures (Table 2). PEG catalyses by increasing the electrophilicity of the C̲=N carbon through hydrogen bonding of hydroxyl oxygen with the imine nitrogen and water plays the role of a proton source. After this success, several aldehydes and diethyl/dimethyl phosphite were reacted using PEG in water. The results are summarized in Table 3. In all the cases, the three component coupling proceeded smoothly and the corresponding α-amino phosphonate was isolated. In these experiments, the catalyst was isolated by cooling the reaction mixture in a dry ice–acetone bath to precipitate the PEG and extracted with ether. The ether extract was dried over MgSO₄ and could be reloaded with fresh reagents for further runs, thus, recyclization of the PEG is possible without significant loss of activity (Table 3, entry 4a).¹³ Surprisingly, from the reaction of aldehydes (2a–l) and dialkyl phosphite (3) in the presence of an amine (1) (Scheme 1), no α-hydroxyphosphonate formation is observed.¹⁴ The examples studied included electron-rich aromatic aldehydes (entries 4e, 4f, 4g, 4h), electron deficient aromatic aldehydes (entries 4a, 4b), heterocyclic aldehydes (entries 4c, 4d, 4i, 4j) and aliphatic aldehydes (entries 4k, 4l). All of them gave α-amino phosphonates in good yields at room temperature only. Ketones do not react under these conditions.

Table 1 Influence of the solvent on the synthesis of 4a

Entry	Solvent	Time/h	Yield^a (%)
a Isolated yield.
1	Ethanol	10	20
2	Dioxane	10	13
3	THF	10	30
4	Acetonitrile	10	15
5	Dichloromethane	10	10
6	Toluene	10	35
7	H2O	10	—
8	PEG	03	65
9	PEG/H2O	65 min	93

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Table 2 Influence of temperature on the synthesis of 4a

S. No.	Temp./°C	Time/min	Yield^a (%)
a Isolated yield.
1	RT	65	93
2	50	60	91
3	70	50	88
4	90	50	85
5	120	45	78

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Table 3 One pot synthesis of α-aminophosphonates using PEG in water at rt

Entry	R1	R2	Time/min	Yield (%)
a Isolated yields after recycling of catalysts.
4a	3-NO2–C6H4	Et	65	93 (90, 87, 88, 89)^a
4b	3-NO2–C6H4	Me	72	89
4c	2-Imidazolyl	Et	80	89
4d	2-Imidazolyl	Me	85	82
4e	4-N(CH3)2–C6H4	Et	75	91
4f	4-N(CH3)2–C6H4	Me	83	86
4g	4-OH–C6H4	Et	83	85
4h	4-OH–C6H4	Me	90	79
4i	3-Indolyl	Et	74	92
4j	3-Indolyl	Me	78	86
4k	C6H5CH2CH2–	Et	87	89
4l	CH3–CH–CH3	Et	90	84

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Scheme 1

In assessing the catalytic activity of PEG in water, we extended the reaction and studied the addition of diethyl phosphite to aldehydes. This reaction proceeds smoothly and gave the corresponding α-hydroxy phosphonates in excellent yields. In recent times, α-hydroxyphosphonates are drawing increased attention due to their enzyme inhibitory bioactivity towards rennin,^15a enolpyruvylshikimate-3-phosphate synthase,^15b farnesyl protein transferase,^15c human immunodeficiency virus protease and polymerase.^15d They also exhibit anti-virus^15e and anti-cancer activity.^15f Furthermore, α-hydroxy phosphonates are useful precursors for the preparation of a variety of α-functionalized phosphonates, such as α-amino,^16a α-keto,^16b α-halo^16c and α-acetoxyphosphonates^16d and their extended derivatives. The available methods for the synthesis of α-hydroxyphosphonates involve the nucleophilic addition of di or trialkylphosphite to different carbonyl compounds in the presence of various catalysts, such as, enzymes,^17a alkaloids,^17b phosphoric acids,^17c Lewis acids,^17d alumina,^17e SALEN,^17f BINOL,^17g alumina/potassium fluoride,^17h NH₄VO₃¹⁷ⁱ and polymer/solid supported base.^17j When we tried to improve the yields, none of them was satisfactory. Hence, there arose still a need to search for an efficient method for their preparation. Herein, we report our results for the preparation of α-hydroxy phosphonates from aldehydes and diethyl phosphite using PEG in water at room temperature (Scheme 2).

Scheme 2

Reaction of 3-nitro benzaldehyde with diethyl phosphite in the absence of PEG afforded low (<20%) yield of diethyl 1-hydroxy-3-nitrophenylmethylphosphonate. The same reaction when performed in the presence of PEG in water at room temperature resulted in the formation of the desired products in high yields (Table 4). Further, no byproduct formation occurred in these reactions.

Table 4 One pot synthesis of α-hydroxyphosphonates using PEG in water at rt

Entry	R3	Time/min	Yield (%)
7a	3-NO2–C6H4	90	92
7b	4-F–C6H4	122	83
7c	2-Imidazolyl	95	88
7d	3-Indolyl	115	86
7e	2,4-Cl–C6H3	130	90
7f	4-Cl–C6H4	135	83
7g	4-OH–C6H4	110	86
7h	4-Isopropyl–C6H4	120	89
7i	4-(NCH3)2–C6H4	95	84
7j	3,5-OMe–C6H3	130	85

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When this reaction was performed in organic solvents such as ethanol, MeCN, CH₂Cl₂, CHCl₃, THF, dioxane, low (<20%) yields of the α-hydroxy phosphonates were obtained. Ketones and triethyl phosphite did not react under these conditions.

Experimental

General

NMR spectra were recorded on a Bruker instrument at 500 MHz for ¹H NMR, 75.4 MHz for ¹³C NMR, and 121.4 MHz for ³¹P NMR in CDCl₃ solution, using tetramethylsilane as internal and 85% H₃PO₄ as external standard respectively. Positive chemical shifts occurred downfield from that of external 85% H₃PO₄ for ³¹P NMR spectra. Chemical shifts (δ) are indicated in parts per million (ppm) and coupling constants (J) in Hz. Mass spectra were recorded on an ESI-MS mass spectrometer and IR spectra were measured on a Perkin-Elmer FT-IR 240-c spectrophotometer using KBr optics. Elemental analyses were performed on a Thermo Finnigan Instrument. Melting points were determined in open capillaries and are uncorrected. All reagents were purchased from Sigma Aldrich and were used without further purification.

Typical procedure for the synthesis of 4a

A mixture of 2-amino-5-methylisoxazole (1 mmol), 3-nitro benzaldehyde (1 mmol), diethylphosphite (1.2 mmol), PEG-600 (3 g) and water (2 ml) was placed in a 25 ml round-bottomed flask. The mixture was kept for stirring at room temperature. After completion of the reaction, the reaction mixture was cooled in a dry ice–acetone bath to precipitate the PEG and extracted with ether. The ether extract was dried over MgSO₄ and evaporated. The resulting product, though seen as a single compound by TLC, was further purified by passing it over a silica gel column with EtOAc/hexane (1 : 4) as an eluent. The recovered PEG has been reused.¹³

Typical procedure for the synthesis of 7a

A mixture of 3-nitro benzaldehyde (1 mmol), diethylphosphite (1.2 mmol), PEG-600 (3 g) and water (2 ml) was placed in a 25 ml round-bottomed flask. The mixture was kept for stirring at room temperature. After completion of the reaction, the reaction mixture was cooled in a dry ice–acetone bath to precipitate the PEG and extracted with ether. The ether extract was dried over MgSO₄ and evaporated. The resulting product, though seen as a single compound by TLC, was further purified by passing it over a silica gel column with EtOAc/hexane (1 : 6) as an eluent. The recovered PEG has been reused.¹²

Physical and spectral data of the products

Diethyl(5-methyloxazol-2-ylamino)(3-nitrophenyl)methylphosphonate (4a). Pale yellow solid; mp 109–111 °C; IR (KBr): ν_max/cm⁻¹ 3420 (NH), 1270 (P=O), 752 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 7.65–7.82 (m, 4Ar–H), 6.23 (s, isoxazole H), 5.54 (brs, NH), 4.89 (d, J_P-C = 7.2 Hz, P-CH), 3.81–4.19 (m, 4H, P(O)CH₂CH₃), 1.94 (s, -CH₃), 1.21 (t, 6H, ³J = 7.3 Hz, P(O)CH₂CH₃); ¹³C NMR (DMSO-d₆, 75.4 MHz): δ 161.21 (C-5′), 154.16 (C-2′), 141.13 (C-1), 133.86 (C-3), 129.37 (C-6), 122.36 (C-5), 121.72 (C-2), 115.23 (C-4), 113.5 (C-4′), 64.5 (d, ²J_P-C = 7.6 Hz, P(O)CH₂CH₃), 45.9 (P-C), 16.9 (d, ³J_P-C = 5.9 Hz, P(O)CH₂CH₃), 15.2 (-CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 20.56; ESI-MS: 369.25; anal. calcd for C₁₅H₂₀N₃O₆P (369): C, 48.78; H, 5.46; N, 11.38%. Found: C, 48.72; H, 5.43; N, 11.35%.

Dimethyl(5-methyloxazol-2-ylamino)(3-nitrophenyl)methylphosphonate (4b). Dark red solid; mp 85–87 °C; IR (KBr): ν_max/cm⁻¹ 3416 (NH), 1255 (P=O), 758 (P–C); ¹H NMR (DMSO-d₆, 500 MHz): δ 7.62–7.81 (m, 4Ar-H), 6.26 (s, isoxazole H), 5.49 (brs, NH), 4.78 (d, J_P-C = 7.2 Hz, P-CH), 3.55 (d, ³J_P-H= 10.5 Hz, P-OCH₃), 3.73 (d, ³J_P-H= 10.9 Hz, P-OCH₃), 1.92 (s, -CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 24.80; ESI-MS: 341.02; anal. calcd for C₁₃H₁₆N₃O₆P (341): C, 45.75; H, 4.73; N, 12.31%. Found: C, 45.69; H, 4.69; N, 12.25%.

Diethyl(1H-imidazol-2-yl)(5-methyloxazol-2-ylamino)methylphosphonate (4c). Red solid; mp 97–99 °C; IR (KBr): ν_max/cm⁻¹ 3365 (NH), 1242 (P=O), 761 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 5.90 (s, 1H, NH), 7.45–7.65 (m, 3Ar-H), 5.60 (d, J_P-C = 10.8 Hz, P-CH), 3.81–4.09 (m, 4H, P(O)CH₂CH₃), 1.82 (s, -CH₃), 1.17 (t, 6H, ³J = 7.3 Hz, P(O)CH₂CH₃); ¹³C NMR (DMSO-d₆, 75.4 MHz): δ 159.64 (C-5′), 148.01 (C-2′), 145.72 (C-2), 129.2 (C-4), 120.8 (C-5), 112.79 (C-4′), 63.5 (d, ²J_P-C = 7.3 Hz, P(O)CH₂CH₃), 44.7 (P-C), 14.6 (d, ³J = 6.1 Hz, P(O)CH₂CH₃), 14.1 (-CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 21.61; ESI-MS: 314.16; anal. calcd for C₁₂H₁₉N₄O₄P (314): C, 45.86; H, 6.09; N, 17.83%. Found: C, 45.84; H, 6.04; N, 17.82%.

Dimethyl(1H-imidazol-2-yl)(5-methyloxazol-2-ylamino)methylphosphonate (4d). Yellow solid; mp 82–84 °C; IR (KBr): ν_max/cm⁻¹ 3372 (NH), 1246 (P=O), 759 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 5.85 (s, 1H, NH), 7.28–7.39 (m, 3Ar-H), 5.48 (d, J_P-C = 10.8 Hz, P-CH), 3.44 (d, ³J_P-H= 10.5 Hz, P-OCH₃), 3.69 (d, ³J_P-H= 11.1 Hz, P-OCH₃), 1.84 (s, -CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 22.82; ESI-MS: 286.07; anal. calcd for C₁₀H₁₅N₄O₄P (286): C, 41.96; H, 5.28; N, 19.57%. Found: C, 41.91; H, 5.26; N, 19.52%.

Diethyl(4-(dimethylamino)phenyl)(5-methyloxazol-2-ylamino)methylphosphonate (4e). Brown solid; mp 105–107 °C; IR (KBr): ν_max/cm⁻¹ 3389 (NH), 1281 (P=O), 751 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 6.81–7.01 (m, 4Ar-H), 2.82 (s, 6H), 5.54 (s, NH), 5.12 (d, J_P-C = 11.2 Hz, P-CH), 3.81–4.10 (m, 4H, P(O)CH₂CH₃), 1.18 (t, 6H, ³J = 7.8 Hz, P(O)CH₂CH₃); ¹³C NMR (DMSO-d₆, 75.4 MHz): δ 160.16 (C-5′), 153.42 (C-3′), 139.72 (C-4), 131.14 (C-2 and C-6), 128.83 (C-1), 123.58 (C-3 and C-5), 116.75 (C-4′), 63.6 (d, ²J_P-C = 7.6 Hz, P(O)CH₂CH₃), 46.1 (P-C), 16.9 (d, ³J_P-C = 5.9 Hz, P(O)CH₂CH₃), 14.8 (-N(CH₃)₂), 15.7 (-CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 20.42; ESI-MS: 367.04; anal. calcd for C₁₇H₂₆N₃O₄P (367): C, 55.58; H, 7.13; N, 11.44%. Found: C, 55.54; H, 7.08; N, 11.39%.

Dimethyl(4-(dimethylamino)phenyl)(5-methyloxazol-2-ylamino)methylphosphonate (4f). Brown solid; mp 91–93 °C; IR (KBr): ν_max/cm⁻¹ 3394 (NH), 1265 (P=O), 766 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 6.75–7.93 (m, 4Ar-H), 2.85 (s, 6H), 5.49 (s, NH), 5.19 (d, J_P-C = 11.2 Hz, P-CH), 3.56 (d, ³J_P-H= 10.4 Hz, P-OCH₃), 3.74 (d, ³J_P-H= 11.1 Hz, P-OCH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 22.35; ESI-MS: 339.18; anal. calcd for C₁₅H₂₂N₃O₄P (339): C, 53.09; H, 6.53; N, 12.38%. Found: C, 52.09; H, 6.48; N, 12.33%.

Diethyl(4-hydroxyphenyl)(5-methyloxazol-2-ylamino) methylphosphonate (4g). Yellow solid; mp 112–113 °C; IR (KBr): ν_max/cm⁻¹ 3422 (NH), 1245 (P=O), 763 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 6.58–6.72 (m, 4Ar-H), 5.61 (s, 1H, NH), 5.04 (d, 1H, ²J_P-C = 11.3 Hz, P-CH), 3.72–3.98 (m, 4H, P(O)CH₂CH₃), 1.89 (s, 3H), 1.08 (t, 6H, ³J = 7.8 Hz, P(O)CH₂CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 22.83; ESI-MS: 340.16; anal. calcd for C₁₅H₂₁N₂O₅P (340): C, 52.94; H, 6.22; N, 8.23%. Found: C, 52.90; H, 6.17; N, 8.19%.

Dimethyl(4-hydroxyphenyl)(5-methyloxazol-2-ylamino) methylphosphonate (4h). Dark red solid; mp 99–101 °C; IR (KBr): ν_max/cm⁻¹ 3435 (NH), 1249 (P=O), 779 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 6.52–6.68 (m, 4Ar-H), 5.65 (s, 1H, NH), 4.98 (d, 1H, ²J_P-C = 11.3 Hz, P-CH), 3.46 (d, ³J_P-H= 10.2 Hz, P-OCH₃), 3.76 (d, ³J_P-H= 10.9 Hz, P-OCH₃), 1.86 (s, 3H); ¹³C NMR (DMSO-d₆, 75.4 MHz): δ 161.36 (C-5′), 151.61 (C-2′), 146.03 (C-4), 131.75 (C-1), 129.53 (C-2 and C-6), 124.91 (C-3 and C-5), 110.36 (C-4′), 54.8 (P-OCH₃, d, J = 6.5 Hz), 46.5 (P-C), 14.6 (-CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 21.76; ESI-MS: 312.27; anal. calcd for C₁₃H₁₇N₂O₅P (312): C, 50.00; H, 5.49; N, 8.97%. Found: C, 49.62; H, 5.42; N, 8.91%.

Diethyl(5-methyloxazol-2-ylamino)(1H-indol-3-yl)methylphosphonates (4i). Wine red solid; mp 91–93 °C; IR (KBr): ν_max/cm⁻¹ 3378 (NH), 1231 (P=O), 751 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 6.75–7.58 (m, 6H, Ar-H), 9.98 (s, 1H, Ar-NH), 5.59 (s, 1H, Aliph-NH), 4.88 (d, 1H, ²J_P-C = 11.2 Hz, PCH); 3.68–3.81 (m, 4H, P(O)CH₂CH₃), 2.10 (s, 3H), 1.23 (t, 6H, ³J = 7.8 Hz, P(O)CH₂CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 24.75; ESI-MS: 363.28; anal. calcd for C₁₇H₂₂N₃O₄P (363): C, 56.19; H, 6.10; N, 11.56%. Found: C, 56.13; H, 6.06; N, 11.51%.

Dimethyl(5-methyloxazol-2-ylamino)(1H-indol-3-yl)methylphosphonates (4j). Red solid; mp 75–76 °C; IR (KBr): ν_max/cm⁻¹ 3390 (P-NH), 1225 (P=O), 746 (P-CH); ¹H NMR (DMSO-d₆, 500 MHz): δ 6.84–7.70 (m, 6H, Ar-H), 10.12 (s, 1H, Ar-NH), 5.70 (s, 1H, Aliph-NH), 4.76–4.88 (m, 1H, PCH), 3.28 (d, ³J_P-H= 10.0 Hz, P-OCH₃), 3.57 (d, ³J_P-H= 11.1 Hz, P-OCH₃), 2.10 (s, 3H, Ar-CH₃); ¹³C NMR (DMSO-d₆, 75.4 MHz): δ 122.7 (C-2), 112.5 (C-3), 121.8 (C-4), 120.6 (C-5), 119.6 (C-6), 111.5 (C-7), 131.2 (C-8), 179 (C-9), 151.5 (C-3′), 113.5 (C-4′), 160.9 (C-5′), 54.76 (P-CH), 53.9 (P-OCH₃, d, J = 6.5 Hz), 15.8 (Ar-CH₃); ³¹P NMR (DMSO-d₆, 121.4 MHz); δ 31.29; ESI-MS: 315.11; anal. calcd for C₁₅H₁₈N₃O₄P (315): C, 53.73; H, 5.41; N, 12.53%. Found: C, 53.53; H, 5.31; N, 12.50%.

Diethyl 1-(5-methyloxazol-2-ylamino)-3-phenylpropylphosphonate (4k). Dark red solid; mp 160–162 °C; IR (KBr): ν_max/cm⁻¹ 3347 (NH), 1264 (P=O), 749 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 6.48–6.92 (m, 5Ar-H), 6.12 (s, oxazole H), 5.62 (brs, NH), 4.56 (d, J_P-C = 7.2 Hz, P–CH), 3.67–4.07 (m, 4H, P(O)CH₂CH₃), 2.16–2.54 (m, 2H), 1.87 (t, ³J_C-H = 7.0 Hz, 2H), 1.28 (t, ³J_H-H = 7.0 Hz, 6H, P(O)CH₂CH₃);³¹P NMR (DMSO-d₆, 121.4 MHz): δ 21.35; ESI-MS: 352; anal. calcd for C₁₇H₂₅N₂O₄P (352): C, 57.95; H, 7.15; N, 7.95%. Found: C, 57.91; H, 7.10; N, 7.91%.

Diethyl 2-methyl-1-(5-methyloxazol-2-ylamino) propylphosphonate (4l). Yellow solid; mp 118–120 °C; IR (KBr): ν_max/cm⁻¹ 3308 (NH), 1189 (P=O), 732 (P-C); ¹H NMR (DMSO-d₆, 500 MHz): δ 6.44 (s, oxazole H), 5.17 (brs, NH), 4.34 (d, J_P-C = 7.2 Hz, P-CH), 3.55–3.85 (m, 4H, P(O)CH₂CH₃), 2.31–2.48 (m, 1H), 1.28 (t, ³J_H-H = 7.0 Hz, 6H, P(O)CH₂CH₃), 1.08 (m, 6H); ³¹P NMR (DMSO-d₆, 121.4 MHz): δ 17.68; ESI-MS: 290; anal. calcd for C₁₂H₂₃N₂O₄P (290): C, 49.65; H, 7.99; N, 9.65%. Found: C, 49.59; H, 7.95; N, 9.60%.

Diethyl hydroxy(3-nitrophenyl)methylphosphonate (7a). Semisolid; IR (KBr): ν_max/cm⁻¹ 3265 (brs, OH), 1221 (P=O, phosphonate), 1009 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 7.63–7.79 (m, 4Ar-H), 5.23 (d, ²J_P-H = 10.2 Hz, P-C-H), 3.93–4.08 (m, 4H, P(O)CH₂CH₃), 1.185 (t, ³J_H-H = 7.2 Hz, 6H, P(O)CH₂CH₃); ¹³C-NMR (CDCl₃, 75.4 MHz): δ 147.47 (C-3), 141.13 (C-1), 133.86 (C-6), 129.37 (C-5), 122.36 (C-2), 121.72 (C-4), 69.05 (P–C), 52.59 (d, ²J_P-C = 7.6 Hz, P-OCH₂CH₃), 18.53 (d, ³J_P-C = 5.8 Hz, P-OCH₂-CH₃); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 21.61 (P=O); ESI-MS: 289.09; anal. calcd for C₁₁H₁₆NO₆P (289): C, 45.68; H, 5.58%. Found: C, 45.65; H, 5.54%.

Diethyl hydroxy(4-fluorophenyl)methylphosphonate (7b). Semisolid; IR (KBr): ν_max/cm⁻¹ 3278 (OH), 1252 (P=O), 1065 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 7.09–7.17 (m, 4Ar-H), 4.69 (d, ²J_P-H = 10.2 Hz, P-C-H), 3.86–4.12 (m, 4H, P(O)CH₂CH₃), 1.18 (t, ³J_H-H = 7.0 Hz, 6H, P(O)CH₂CH₃); ¹³C-NMR (CDCl₃, 75.4 MHz): δ 148.5 (C-4), 139.23 (C-1), 129.36 (C-2), 128.42 (C-6), 121.73 (C-3), 121.54 (C-5), 73.4 (P-C), 56.9 (d, ²J_P-C = 7.5 Hz, P-OCH₂CH₃), 17.8 (d, ³J_P-C = 5.8 Hz, P-OCH₂-CH₃); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 21.52 (P=O); ESI-MS: 262.14; anal. calcd for C₁₁H₁₆O₄PF (262): C, 50.39; H, 6.15%. Found: C, 50.35; H, 6.10%.

Diethyl hydroxy(1H-imidazol-2-yl)methylphosphonate (7c). Semisolid; IR (KBr): ν_max/cm⁻¹ 3323 (NH), 3245 (brs, OH), 1219 (P=O, phosphonate), 1026 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 9.38 (s, 1H, imidazole NH), 7.32–7.39 (m, 2Ar-H), 5.12 (d, ²J_P-H = 10.3 Hz, P-C-H), 3.52–3.78 (m, 4H, P(O)CH₂CH₃), 1.23 (t, ³J_H-H = 7.3 Hz, 6H, P(O)CH₂CH₃); ¹³C-NMR (CDCl₃, 75.4 MHz): δ 149.3 (C-1), 125.2 (C-3), 124.6 (C-4), 72.8 (P-C), 60.1 (d, ²J_P-C = 7.6 Hz, P-OCH₂CH₃), 15.6 (d, ³J_P-C = 5.7 Hz, P-OCH₂-CH₃); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 21.72 (P=O); ESI-MS: 235.21; anal. calcd for C₈H₁₆N₂O₄P (235): C, 40.85; H, 6.86%. Found: C, 40.82; H, 6.81%.

Diethyl hydroxy(1H-indol-3-yl)methylphosphonate (7d). Semisolid; IR (KBr): ν_max/cm⁻¹ 3356 (NH), 3259 (brs, OH), 1119 (P=O, phosphonate), 1005 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 9.94 (s, 1H, indole NH), 7.02–8.66 (m, 5Ar-H), 4.76 (d, ²J_P-H = 10.2 Hz, P-C-H), 3.61–3.77 (m, 4H, P(O)CH₂CH₃), 1.18 (t, ³J_H-H = 7.3 Hz, 6H, P(O)CH₂CH₃); ¹³C-NMR (CDCl₃, 75.4 MHz): δ 138.36 (C-4), 135.52 (C-9), 121.06 (C-2), 120.64 (C-6), 119.04 (C-7), 117.35 (C-8), 116.38 (C-1), 115.15 (C-5), 76.26 (P-C), 59.96 (d, ²J_P-C = 7.6 Hz, P-OCH₂CH₃), 16.12 (d, ³J_P-C = 5.8 Hz, P-OCH₂-CH₃); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 20.69 (P=O); ESI-MS: 283.18; anal. calcd for C₁₃H₁₈NO₄P (283): C, 55.12; H, 6.41%. Found: C, 55.09; H, 6.38%.

Diethyl [2,4-dichlorophenyl] hydroxymethylphosphonate (7e). Semisolid; IR (KBr): ν_max/cm⁻¹ 3257 (brs, OH), 1218 (P=O, phosphonate), 1011 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 7.13–8.09 (m, 3Ar-H), 5.06 (s, 2H), 4.94 (d, ²J_P-H = 10.0 Hz, P-C-H), 3.92–4.09 (m, 4H, P(O)CH₂CH₃), 1.27 (t, ³J_H-H = 7.2 Hz, 6H, P(O)CH₂CH₃); ¹³C-NMR (CDCl₃, 75.4 MHz): δ 158.8 (C-6), 128.7 (C-2), 128.6 (C-4), 128.0 (C-1), 125.3 (C-3), 124.1 (C-5), 76.1 (P-C), 63.0 (d, ²J_P-C = 7.5 Hz, P-OCH₂CH₃), 16.3 (d, ³J_P-C = 5.7 Hz, P-OCH₂-CH₃); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 22.57 (P=O); ESI-MS: 313.05; anal. calcd for C₁₁H₁₅O₄PCl₂ (313): C, 42.19; H, 4.83%. Found: C, 42.14; H, 4.81%.

Diethyl(4-chlorophenyl)hydroxymethylphosphonate (7f). Semisolid; IR (KBr): ν_max/cm⁻¹ 3278 (brs, OH), 1208 (P=O, phosphonate), 1028 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 6.84–7.17 (m, 4Ar-H), 4.74 (d, ²J_P-H = 10.2 Hz, P-C-H), 3.87–4.16 (m, 4H, P(O)CH₂CH₃), 1.33 (t, ³J_H-H = 7.0 Hz, 6H, P(O)CH₂CH₃); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 23.71 (P=O); ESI-MS: 278.19; anal. calcd for C₁₁H₁₆O₄PCl (278): C, 47.41; H, 5.79%. Found: C, 47.37; H, 5.74%.

Diethyl(4-hydroxyphenyl)hydroxymethylphosphonate (7g). mp: 110–112 °C; IR (KBr): ν_max/cm⁻¹ 3291 (brs, OH), 3249 (brs, OH), 1205 (P=O, phosphonate), 1025 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 6.56–6.94 (m, 4Ar-H), 4.80 (d, ²J_P-H = 10.4 Hz, P-C-H), 3.65–3.84 (m, 4H, P(O)CH₂CH₃), 1.13 (t, ³J_H-H = 7.2 Hz, 6H, P(O)CH₂CH₃); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 22.63 (P=O); ESI-MS: 260.04; anal. calcd for C₁₁H₁₇O₅P (260): C, 50.77; H, 6.58%. Found: C, 50.72; H, 6.51%.

Diethyl hydroxy(4-isopropylphenyl)methylphosphonate (7h). Semisolid; IR (KBr): ν_max/cm⁻¹ 3273 (brs, OH), 1240 (P=O, phosphonate), 1042 (P-O-C); ¹H NMR (CDCl₃, 500 MHz): δ 7.19–7.38 (m, 4Ar-H), 4.94 (d, ²J_P-H = 10.4 Hz, 1H), 3.92–4.08 (m, 4H, P(O)CH₂CH₃), 2.85–2.92 (m, 1H), 1.17–1.26 (m, 6H), 1.165 (t, ³J_H-H = 7.2 Hz, 6H, P(O)CH₂CH₃); ³¹P NMR (CDCl₃, 121.4 MHz): δ 22.83 (P=O); ESI-MS: 286.15; anal. calcd for C₁₄H₂₃O₄P (286): C, 58.73; H, 8.10%. Found: C, 58.69; H, 8.07%.

Diethyl(4-(dimethylamino)phenyl)hydroxymethylphosphonate (7i). Semisolid; IR (KBr): ν_max/cm⁻¹ 3246 (brs, OH), 1237 (P=O, phosphonate), 1061 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 6.87–7.01 (m, 4Ar-H), 5.18 (d, ²J_P-H = 10.3 Hz, P-C-H), 4.02–4.29 (m, 4H, P(O)CH₂CH₃), 1.19 (t, ³J = 7.3 Hz, 6H, P(O)CH₂CH₃), 2.82 (s, 6H); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 21.40 (P=O); ESI-MS: 287.21; anal. calcd for C₁₃H₂₂NO₄P (287): C, 54.35; H, 7.72%. Found: C, 54.31; H, 7.69%.

Diethyl(3,5-dimethoxyphenyl)hydroxymethylphosphonate (7j). mp: 101–103 °C; IR (KBr): ν_max/cm⁻¹ 3272 (brs, OH), 1212 (P=O, phosphonate), 1032 (P-O-C); ¹H-NMR (CDCl₃, 500 MHz): δ 6.78–7.07 (m, 4Ar-H), 4.87 (d, ²J_P-H = 10.2 Hz, P-C-H), 3.90–4.19 (m, 4H, P(O)CH₂CH₃), 3.86 (s, 3H), 3.57 (s, 3H), 1.28 (t, ³J = 7.2 Hz, 6H, P(O)CH₂CH₃); ³¹P-NMR (CDCl₃, 121.4 MHz): δ 22.20 (P=O); ESI-MS: 304.08; anal. calcd for C₁₃H₂₁O₆P (304): C 51.31, H 6.96%. Found: C 51.29, H 6.92%.

Conclusions

In conclusion, low molecular weight PEG in water has been utilized for the first time as a new solution medium for the efficient one-pot synthesis of α-amino and α-hydroxy phosphonates. The advantages of this procedure are operational simplicity, reusability, wide substrate scope, and high yields. We believe that this method serves as a better alternative to the existing one for the synthesis of α-amino and α-hydroxy phosphonates.

Acknowledgements

The authors express their grateful thanks to Prof. C. D. Reddy, Department of Chemistry, Sri Venkateswara University, Tirupati, for his helpful discussions and also thank BRNS, BARC, Mumbai, for providing financial assistance (2010/37C/26/BRNS/1424).

Notes and references

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