An operationally simple, fast and green synthesis of novel γ-hydroxyphosphonate and phosphine oxide derivatives

ABSTRACT

A green and versatile method for the preparation of γ-hydroxyphosphonate and phosphine oxide derivatives in 5 min, is accomplished through the reduction of γ-phosphonylketones with sodium borohydride supported on alumina, at room temperature, under solvent free conditions.

GRAPHICAL ABSTRACT

KEYWORDS:

• γ-hydroxyphosphonates
• reduction
• fast synthesis
• green synthesis
• solid-supported synthesis

Introduction

An increasing interest has been paid for several years to the synthesis of hydroxyphosphonates due to their promising pharmacological activities. Much of these activities has been attributed to the physical and structural similarity of hydroxyphosphonates and phosphonic acids to the biologically important natural hydroxycarboxylic acids, in which a carboxylic group is replaced by phosphonic or related functionality ( 1). Such structural similarity enables hydroxyphosphonates to inhibit, by mimetic effect, enzymes involved in hydroxycarboxylic acid metabolism and thus affects a variety of physiological processes ( 2). For instance, α-hydroxyphosphonates, which are structural analogs of α-hydroxyacids, are an important class of compounds in medicinal chemistry with potential biological effects as inhibitors of human renin ( 3) and HIV protease ( 4). Some are also medicinally important as antitumor ( 5), antibacterial ( 6), antiviral ( 7) and antioxidant ( 8) agents.

On the other hand, β-hydroxyphosphonates are known for their interesting biological activities as 5′-nucleotidase ( 9), autotaxin ( 10) and sphingomyelinase ( 2) inhibitors, antioxidant ( 11) and antibiotic ( 12) agents.

Although α- and β-hydroxyphosphonates are well described in the literature, their γ-hydroxyphosphonate homologues did not receive sufficient attention despite their structural resemblance to γ-hydroxybutyric acid (GHB), wich is a naturally occurring neurotransmitter and a psychoactive drug used in a medical setting as a general anesthetic and as a treatment for cataplexy, narcolepsy and alcoholism ( 13–15). It is a precursor to GABA, glutamate, and glycine in certain brain areas, and it is an agonist at the GHB and GABA_B receptors ( 16, 17).

There is only a limited number of synthetic approaches to γ-hydroxyphosphonates. This includes (i) the BF₃.OEt₂- or TiCl₄-catalyzed nucleophilic ring opening reaction of epoxides by methanephosphonates ( 18–20) and (ii) the oxazaborolidine-catalyzed catecholborane reduction of γ–ketophosphonates ( 21, 22). However, in spite of their potential utility, these procedures suffer from one or the other drawbacks such as the use of expensive catalysts and hydride reducing agents, where specialized handling techniques and tedious work-up are necessary, as well as long reaction time, use of solvent and lack of generality. Therefore, the development of a simple, mild, eco-benign and low cost protocol is still desirable to obtain a wider variety of γ-hydroxyphosphonates for biological screening.

In recent years, NaBH₄ supported on inorganic solid supports especially alumina, has been reported in literature ( 23) as an efficient and eco-benign reagent for the reduction of aldehydes and ketones. With this in mind, and in the continuation of our interest to develop efficient protocols for the synthesis of biologically active phosphonates ( 24–27), we report herein an operationally simple, green and fast methodology for the synthesis of γ-hydroxyphosphonates and phosphine oxides, in excellent yields, through the reduction of γ-phosphonylketones with NaBH₄ supported on alumina, at room temperature, under solvent-free conditions, within few minutes.

Results and discussion

In order to establish the optimum reaction conditions for the formation of the target compounds, we used γ-ketophosphonate 1a as model substrate. The reduction of 1a was initially carried out with one hydride equivalent of LiAlH₄ in anhydrous THF. Unfortunately, the expected γ-hydroxyphosphonate 2a was not obtained (Table 1, entry 1). Although the starting materials were completely consumed, the ³¹P NMR analysis of the reaction mixture showed complete dephosphonylation due to C–P bond cleaving ( 24, 25, 28). When the reaction was conducted with 1 equiv of NaBH₄ in EtOH at room temperature, the desired product 2a was isolated in only 30% yield (Table 1, entry 2). Further improvement of the yield to 65% was observed when using 3 equiv of NaBH₄, under the same reaction conditions (Table 1, entry 3). It was gratifying to observe that performing the reduction with NaBH₄ (3 equiv) supported on alumina (12 equiv), in the presence of few drops of MeOH (5 drops for 1 mmol 1a), at room temperature, under solvent-free conditions, afforded the desired product 2a in 90% yield, within 5 min (Table 1, entry 4).

Table 1. Optimization of the reaction conditions.

Entry	Hydride reagent (equiv)	Solvent	Temp. (°C)	Time	Yield (%)^a
1	LiAlH4 (0.25)	THF	0–25	2 h	0
2	NaBH4 (1)	EtOH	25	12 h	30
3	NaBH4 (3)	EtOH	25	5 h	65
4	NaBH4(3)/Al2O3(12)	Solvent-free^b	25	5 min	90

^aIsolated yield.

^bThe reaction was performed in solvent-free conditions but in the presence of few drops of MeOH as protonating agent.

With optimized reaction conditions in hand, we next studied the scope of this methodology. A variety of structurally diverse γ-phosphonylketones were investigated and a series of γ-hydroxyphosphonates and phosphine oxides of type 2 were afforded in high to excellent yields (Table 2). Pure products can be isolated by simple extraction without the need for chromatography or recrystallization.

Table 2. Substrate scope studies.

Entry	R^1	R^2	R^3	R^4	Product	%(maj/min)^b	Yield (%)^c
1	EtO	H	Ph	Me	2a	61/39	90
2	EtO	H	2-thienyl	Me	2b	84/16	85
3	EtO	H	Ph	Ph	2c	65/35	90
4	Ph	H	2-furyl	Me	2d	54/46	85
5	Ph	H	2-thienyl	Me	2e	62/38	88
6	Ph	H	Ph	Me	2f	52/48	87
7	Ph	H	Ph	Ph	2g	92/08	93
8	EtO	Me	Me	Me	2h	–	91
9	MeO	Me	Me	Me	2i	–	86
10	Ph	Me	Me	Me	2j	–	90

^a5 drops of MeOH for 1 mmol of substrate 1.

^bDetermined from the ³¹P NMR spectra.

^cIsolated yield.

Compounds 2a–g, presenting two stereocenters, were obtained as a mixture of two unseparable diastereoisomers, as evidenced by their NMR spectral data. The relative proportions of these diastereoisomers were estimated from the ³¹P NMR spectra where a singlet for each one was found (Table 2).

Conclusion

We have successfully developed an efficient, green and fast methodology for the synthesis of γ-hydroxyphosphonates and phosphine oxides, through the reduction of γ-phosphonylketones with NaBH₄ supported on alumina, in the presence of few drops of MeOH, at room temperature, under solvent-free conditions. This synthetic strategy offers significant advantages such as high to excellent yields, short reaction time, versatile substituents, mild reaction conditions, easy work-up and environmental safety, what make this protocol more amenable for high throughput library synthesis. These compounds are potential agonists at the GHB and GABA_B receptors. This aspect is currently under study in our laboratory and will be reported in due course.

Experimental

General informations

Commercially available analytical grade reagents were used without further purification. Melting points were measured in an open capillary, using Büchi melting point B-540 apparatus and are uncorrected. ¹H, ³¹P and ¹³C NMR spectra were recorded with CDCl₃ as the solvent, on a Bruker AC-300 spectrometer operating at 300.1 MHz for ¹H, 121.5 MHz for ³¹P and 75.5 MHz for ¹³C. The chemical shifts are reported in ppm relative to Tetramethylsilane (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; quint: quintet; m: multiplet and br s: broad singlet. Mass spectra were determined on a Thermo LTQ Orbitrap XL spectrometer, or on a VOYAGER DE STR spectrometer. IR spectra were recorded on a Nicolet IR200 spectrometer. The progress of the reactions was monitored by TLC (Thin Layer Chromatography), using 5 × 20 cm plates with a layer thickness of 0.25 mm (Silica gel 60 F254), and ether as eluent.

Synthesis of γ-phosphonylketones 1

The starting γ-ketophosphonates and phosphine oxides 1 were prepared according to the reported procedures ( 29, 30) (see Electronic Supplementary Information).

General procedure for the synthesis of γ-hydroxyphosphonates and phosphine oxides 2

A round-bottomed flask equipped with a magnetic stir bar was charged with Al₂O₃ (12 mmol) and NaBH₄ (3 mmol). The mixture was stirred for 30 min at 25°C, under nitrogen atmosphere. The γ-ketophosphonate or phosphine oxide (1 mmol) and five drops of MeOH were added to this mixture and stirring was continued for 5 min (reactions were monitored by TLC). The reaction mixture was poured into ether (15 mL) and then filtred. The filtrate was washed with water (2 × 5 mL). The organic phase was dried over Na₂SO₄ and concentrated under vacuum to afford the pure products in 85–93% isolated yields.

Characterization data of compounds 2

Diethyl (3-hydroxy-1-phenylbutyl) phosphonate (2a) (31). Transparent oil; ¹H NMR (300 MHz, CDCl₃): δ = 1.09 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, min); 1.10 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, min); 1.15 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, maj); 1.16 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, maj); 1.24 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH, min); 1.26 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH, maj); 2.04–2.19 (m, 2H, CH₂-CH); 2.68 (br s, 1H, OH); 3.20–3.47 (m, 1H, CH-P=O); 3.65–3.79 (m, 1H, CH₃-CH); 3.85–4.10 (m, 4H, 2CH₃-CH₂-O); 7.24–7.32 (m, 5H, arom-H); ¹³C NMR (75.5 MHz, CDCl₃): δ = 16.2 (d, ³J_CP = 4.5 Hz, 2CH₃-CH₂-O, maj); 16.3 (d, ³J_CP = 4.5 Hz, 2CH₃-CH₂-O, min); 22.7 (s, CH₃-CH, min); 24.2 (s, CH₃-CH, maj); 39.3 (s, CH₂-CH, maj); 39.9 (s, CH₂-CH, min); 41.2 (d, ¹J_CP = 103.4 Hz, CH-P, min); 41.4 (d, ¹J_CP = 102.6 Hz, CH-P, maj); 62.0 (d, ²J_CP = 6.0 Hz, 2CH₃-CH₂-O, maj); 62.7 (d, ²J_CP = 5.3 Hz, 2 CH₃-CH₂-O, min); 64.7 (d, ³J_CP = 10.6 Hz, CH-OH, min); 65.6 (d, ³J_CP = 8.3 Hz, CH-OH, maj); phenyl carbons: δ = 127.1; 127.2; 127.2; 127.2; 128.5; 128.6; 128.6; 129.1; 129.2; 129.4; 129.4; 136.0; 136.1; 136.5; 136.6; ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 29.1 (s, 61%, maj); 29.8 (s, 39%, min); IR (neat): ν_P = O = 1266 cm⁻¹; ν_OH = 3427 cm⁻¹; ESI-HRMS: m/z calculated for C₁₄H₂₄O₄P [M + H]⁺: 287.14122; found: 287.14208.

Diethyl (3-hydroxy-1-(thiophen-2-yl)butyl) phosphonate (2b). Yellow oil; ¹H NMR (300 MHz, CDCl₃) : δ = 1.04 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH, min); 1.10 (d, 3H, ³J_HH = 9.0 Hz, CH₃-CH, maj); 1.13 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, maj); 1.15 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, min); 1.22 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, maj); 1.29 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, min); 1.85–2.12 (m, 2H, CH₂-CH); 3.21 (br s, 1H, OH); 3.42–3.64 (m, 1H, CH-P=O); 3.66–3.78 (m, 1H, CH₃-CH); 3.64–4.06 (m, 4H, 2CH₃-CH₂-O); 6.88–7.26 (m, 3H, arom-H); ¹³C NMR(75.5 MHz, CDCl₃): δ = 16,2(d, ³J_CP = 6.0 Hz, CH₃-CH₂-O); 16.3 (d, ³J_CP = 6.0 Hz, CH₃-CH₂-O); 22.6 (s, CH₃-CH, min); 24.1 (s, CH₃-CH, maj); 36.3 (d, ¹J_CP = 144,1 Hz, CH-P, maj); 36.4 (d, ¹J_CP = 141,9 Hz, CH-P, min); 40.6 (s, CH₂-CH, maj); 41.1 (s, CH₂-CH, min); 62.3 (d, ²J_CP = 7.5 Hz, CH₃-CH₂-O); 62.8 (d, ²J_CP = 6.8 Hz, CH₃-CH₂-O); 64.3 (d, ³J_CP = 13.6 Hz, CH-OH, maj); 65.2 (d, ³J_CP = 10.6 Hz, CH-OH, min); phenyl carbons: δ = 124.5; 124.5; 125.9; 126.4; 126.5; 126.8; 126.8; 126.9; 127.0; 133.4; 138.1; 138.3; 138.4; 138.6; 138.7; ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 26.9 (s, 16%, min); 27.6 (s, 84%, maj); IR (neat): ν_P=O = 1242 cm⁻¹; ν_OH = 3396 cm⁻¹; MALDI-MS: m/z = 293.2 ([M + H]⁺).

Diethyl (3-hydroxy-1,3-diphenylpropyl) phosphonate (2c). Transparent oil; ¹H NMR (300 MHz, CDCl₃): δ = 1.03 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, min); 1.04 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, min); 1.16 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, maj); 1.17 (t, 3H, ³J_HH = 6.0 Hz, CH₃-CH₂-O, maj); 1.80 (br s, 1H, OH); 2.20–2.46 (m, 2H, CH₂-CH); 2.89–3.50 (m, 1H, CH-P=O); 3.62–3.99 (m, 4H, 2CH₃-CH₂-O); 4.32–4.64 (m, 1H, CH-OH); 7.14–7.34 (m, 10H, arom-H); ¹³C NMR (75.5 MHz, CDCl₃): δ = 16.2 (d, ³J_CP = 6.0 Hz, 2CH₃-CH₂-O, min); 16.4 (d, ³J_CP = 6.0 Hz, 2CH₃-CH₂-O, maj); 39.4 (s, CH₂-CH, maj); 39.5 (s, CH₂-CH, min); 41.1 (d, ¹J_CP = 104.1 Hz, CH-P, maj); 41.4 (d, ¹J_CP = 102.6 Hz, CH-P, min); 62.1 (d, ²J_CP = 7.1 Hz, 2CH₃-CH₂-O, min); 62.7 (d, ²J_CP = 7.2 Hz, 2CH₃-CH₂-O, maj); 72.2 (d, ³J_CP = 14.4 Hz, CH-OH, maj); 72.3 (d, ³J_CP = 13.8 Hz, CH-OH, min); phenyl carbons: δ = 125.6; 126.3; 127.3; 127.3; 127.6; 127.6; 127.9; 127.9; 128.5; 128.5; 128.6; 128.7; 129.2; 129.3; 129.4; 129.5; 135.8; 135.9; 136.1; 136.2; 136.3; 136.3; 143.3; 143.4; ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 28.6 (s, 65%, maj); 29.3 (s, 35%, min) IR (neat): ν_P=O = 1236 cm⁻¹; ν_OH = 3388 cm⁻¹; ESI-HRMS: m/z calculated for C₁₉H₂₆O₄P [M + H]⁺: 349.15687; found: 349.15766.

(1-(Furan-2-yl)-3-hydroxybutyl) diphenylphosphine oxide (2d). Brown solid; mp 146–148°C; ¹H NMR (300 MHz, CDCl₃) : δ = 1.10 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH, maj); 1.13 (d, 3H, ³J_HH = 6,0 Hz, CH₃-CH, min); 1.85–2.23 (m, 2H, CH₂-CH); 2.94 (br s, 1H, OH); 3.85–4.06 (m, 1H, CH-P=O); 3.62–4.29 (m, 1H, CH₃-CH); 6.10–7.87 (m, 13H, arom-H); ¹³C NMR (75.5 MHz, CDCl₃): δ = 22.6 (s, CH₃-CH, min); 24.2 (s, CH₃-CH, maj); 37.3 (s, CH₂-CH, maj); 37.6 (s, CH₂-CH, min); 38.0 (d, ¹J_CP = 69.6 Hz, CH-P, min); 38.2 (d, ¹J_CP = 68,3 Hz, CH-P, maj); 64.9 (d, ³J_CP = 8.3 Hz, CH-OH, maj); 65.3 (d, ³J_CP = 11.3 Hz, CH-OH, min). Phenyl carbons: δ = 109.1; 109.2; 109.3; 109.3; 110.7; 110.7; 110.8; 110.9; 128.0; 128.2; 128.2; 128.4; 128.6; 128.7; 129.9; 130.5; 130.6; 130.7; 131.2; 131.4; 131.5; 131.6; 131.6; 131.7; 131.8; 131.8; 131.8; 131.9; 132.0; 132.0; 141.6; 141.6; 141.7; 141.8; 149.4; 149.5; 149.6; 149.6; ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 33.0 (s, 46%, min), 33.8 (s, 54%, maj); IR (neat): ν_P=O = 1222 cm⁻¹; ν_OH = 3351 cm⁻¹; ESI-HRMS: m/z calculated for C₂₀H₂₂O₃P [M + H]⁺: 341.13066; found: 341.13105.

(3-Hydroxy-1-(thiophen-2-yl)butyl) diphenylphosphine oxide (2e). White solid; mp 200–202°C; ¹H NMR (300 MHz, CDCl₃): δ = 1.03 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH, maj); 1.04 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH, min); 1.77–2.21 (m, 2H, CH₂-CH); 3.63 (br s, 1H, OH); 3.76–4.00 (m, 1H, CH-P=O); 3.92–4.29 (m, 1H, CH₃-CH); 6.75–7.88 (m, 13H, arom-H); ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.6 (s, CH₃-CH, maj); 23.3 (s, CH₃-CH, min); 37.7 (d, ¹J_CP = 70.9 Hz, CH-P, min); 38.4 (d, ¹J_CP = 68.7 Hz, CH-P, maj); 39.4 (s, CH₂-CH); 63.8 (d, ³J_CP = 8.3 Hz, CH-OH). Phenyl carbons: δ = 123.7; 123.7; 127.0; 127.1; 127.1; 127.3; 127.3; 127.7; 127.9; 127.9; 130.0; 130.0; 130.1; 130.1; 130.2; 130.2; 130.2; 130.2; 130.3; 130.3; 130.4; 130.4; 130.4; 130.4; 130.5; 136.4; 136.5; 136.6; ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 33.1 (s, 38%, min), 34.0 (s, 62%, maj); IR (neat): ν_P=O = 1267 cm⁻¹; ν_OH = 3395 cm⁻¹; ESI-HRMS: m/z calculated for C₂₀H₂₂O₂PS [M + H]⁺: 357.10781; found: 357.10643.

(3-Hydroxy-1-phenylbutyl) diphenylphosphine oxide (2f). White solid; mp 133–135°C; ¹H NMR (300 MHz, CDCl₃) : δ = 0.97 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH, min); 0.98 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH, maj); 1.76–2.35 (m, 2H, CH₂-CH); 3.16 (br s, 1H, OH); 3.34–3.59 (m, 1H, CH-P=O); 3.62–3.97 (m, 1H, CH₃-CH); 6.85–7.90 (m, 15H, arom-H); ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.4 (s, CH₃-CH, maj); 23.3 (s, CH₃-CH, min); 37.6 (s, CH₂-CH, maj); 37.9 (s, CH₂-CH, min); 42.0 (d, ¹J_CP = 68.7 Hz, CH-P, min); 43.1 (d, ¹J_CP = 67.2 Hz, CH-P, maj); 63.6 (d, ³J_CP = 12.1 Hz, CH-OH, min); 64.1 (d, ³J_CP = 10.6 Hz, CH-OH, maj). Phenyl carbons: δ = 125.9; 125.9; 126.0; 126.0; 126.8; 126.9; 126.9; 127.0; 127.0; 127.1; 127.2; 127.2; 127.4; 127.4; 127.5; 127.6; 127.8; 128.7; 128.8; 129.0; 129.1; 129.7;129.8; 129.9; 130.0; 130.0; 130.1; 130.1; 130.3; 130.4; 130.4; 130.4; 130.5; 130.7; 130.7; 130.8; 130.9; 131.0; 131.3; 131.8; 134.7; 134.8; 134.8; 134.9; ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 34.2 (s, 48%, min); 34.3 (s, 52%, maj); IR (neat): ν_P=O = 1266 cm⁻¹; ν_OH = 3427 cm⁻¹; MALDI-MS: m/z = 351.2 ([M + H]⁺).

(3-Hydroxy-1,3-diphenylpropyl) diphenylphosphine oxide (2g) (32). White solid; mp 204–206°C; ¹H NMR (300 MHz, CDCl₃): δ = 2.14–2.77 (m, 2H, CH₂-CH); 3.08–3.24 (m, 1H, CH-P=O); 3.33–3.73 (m, 1H, CH-OH); 4.45 (br s, 1H, OH); 7.15–7.57 (m, 20H, arom-H). ¹³C NMR (75.5 MHz, CDCl₃): δ = 38.6 (s, CH₂-CH); 43.4 (d, ¹J_CP = 67.4 Hz, CH-P); 72.2 (d, ³J_CP = 13.6 Hz, CH-OH); Phenyl carbons: δ = 125.5; 126.2; 126.8; 127.1;127.8; 127.9; 128.0; 128.4; 128.4; 128.6; 129.7; 129.1; 129.8; 129.9; 130.3; 130.7; 130.9; 131.0; 131.3; 131.4; 131.6; 131.8; 132.0; 132.6; 135.1; 135.2; 139.3; 143.1. ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 34.1 (s, 8%, min), 34.2 (s, 92%, maj). IR (neat): ν_P=O = 1239 cm⁻¹; ν_OH = 3251 cm⁻¹; MALDI-MS: m/z = 413.3 ([M + H]⁺).

Diethyl (4-hydroxy-2-methylpentan-2-yl) phosphonate (2h). Transparent oil; ¹H NMR (300 MHz, CDCl₃) : δ = 0.92 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH); 1.00 (d, 3H, ³J_PH = 18.0 Hz, CH₃-C); 1.06 (d, 3H, ³J_PH = 15.0 Hz, CH₃-C); 1.09 (t, 6H, ³J_HH = 6.0 Hz, 2 CH₃-CH₂-O); 1.52–1.92 (m, 2H, CH₂-CH), 3.76–3.85 (m, 1H, CH-CH₃); 3.86–4.24 (m, 4H, 2 CH₃-CH₂-O); 4.04 (br s, 1H, OH); ¹³C NMR (75.5 MHz, CDCl₃): δ = 16.2 (d, ³J_CP = 6.0 Hz, 2 CH₃-CH₂-O); 21.6 (s, CH₃-CH); 23.5 (s, CH₃-C); 24.4 (s, CH₃-C); 33.6 (d, ¹J_CP = 139.5 Hz, C–P); 48.2 (s, CH₂-C); 61.9 (d, ²J_CP = 7.5 Hz, 2CH₃-CH₂-O); 72.1 (d, ³J_CP = 9.0 Hz, CH-OH). ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 28.2; IR (neat): ν_P=O = 1238 cm⁻¹; ν_OH = 3462 cm⁻¹; ESI-HRMS: m/z calculated for C₁₀H₂₄O₄P [M + H]⁺: 239.14122; found: 239.14215.

Dimethyl (4-hydroxy-2-methylpentan-2-yl) phosphonate (2i) (33). Transparent oil; ¹H NMR (300 MHz, CDCl₃): δ = 0.72 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH); 0.75 (d, 3H, ³J_PH = 15.0 Hz, CH₃-C); 0.81 (d, 3H, ³J_PH = 18.0 Hz, CH₃-C); 1.25–1.44 (m, 2H, CH₂-CH), 3.25–3.31 (m, 1H, CH-CH₃); 3.34 (d, 6H, ³J_PH = 6.0 Hz, 2CH₃-O); 3.91 (br s, 1H, OH); ¹³C NMR (75.5 MHz, CDCl₃): δ = 21.8 (s, CH₃-C); 23.5 (s, CH₃-C); 24.5 (s, CH₃-CH); 33.9 (d, ¹J_CP = 139.7 Hz, C–P); 47.2 (s, CH₂-C); 52.3 (d, ²J_CP = 7.5 Hz, 2CH₃-O); 71.6 (d, ³J_CP = 8.8 Hz, CH-OH); ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 39.5; IR (neat): ν_P=O = 1239 cm⁻¹; ν_OH = 3368 cm⁻¹; ESI-HRMS: m/z calculated for C₈H₂₀O₄P [M + H]⁺: 211.10992; found: 211.11067.

(4-Hydroxy-2-methylpentan-2-yl) diphenylphosphine oxide (2j). White solid; mp 160–162°C; ¹H NMR (300 MHz, CDCl₃) : δ = 0.99 (d, 3H, ³J_HH = 6.0 Hz, CH₃-CH); 1.15 (d, 3H, ³J_PH = 15.0 Hz, CH₃-C); 1.17 (d, 3H, ³J_PH = 15.0 Hz, CH₃-C); 1.31–1.83 (m, 2H, CH₂-CH); 3.92–4.01 (m, 1H, CH-OH); 5.43 (br s, 1H, OH); 7.28–7.88 (m, 10H, arom-H); ¹³C NMR (75.5 MHz, CDCl₃): δ = 22.4 (s, CH₃-CH); 24.6 (s, CH₃-C); 25,7 (s, CH₃-C); 37.0 (d, ¹J_CP = 68.7 Hz, C–P); 49.1 (s, CH₂-CH); 63.0 (d, ³J_CP = 3.8 Hz, CH-OH); Phenyl carbons: δ = 128.1; 128.3; 129.3; 130.0; 130.1; 130.6; 131.2; 131.3; 131.5; 131.5; 131.6; 132.1; 132.2; 132.3; 132.4; ³¹P NMR (CDCl₃, 121.5 MHz): δ (ppm) = 41.8; IR (neat): ν_P = O = 1266 cm⁻¹; ν_OH = 3289 cm⁻¹; ESI-HRMS: m/z calculated for C₁₈H₂₄O₂P [M + H]⁺: 303.15139; found: 303.15082.

Disclosure statement

No potential conflict of interest was reported by the authors.

Notes on contributors

Aicha Mhamdi is studying as a Ph.D. candidate at the University of Carthage – Faculty of Sciences of Bizerte (Tunisia), under supervision of Prof. Soufiane Touil. Her research has focused on the synthesis and reactivity of γ-ketophosphonates and phosphine oxides.

Soufiane Touil is Professor of Chemistry and Head of the Laboratory of Heteroatom Organic Chemistry, at the University of Carthage – Faculty of Sciences of Bizerte (Tunisia). He received his Ph.D. in organic chemistry, from the University of Tunis El Manar – Faculty of Sciences of Tunis (Tunisia) in 1998, and his Habilitation (HDR) in 2003, from the same university. Professor Touil’s research interests involve the chemistry and physical organic chemistry of organophosphorus, organosulfur and heterocyclic compounds: Development of synthetic methods, the study of mechanisms, reactivity, stereochemistry, investigation of biochemical properties and, taking this as a basis, creation of new approaches for finding biologically active substances of medicinal interest.

Additional information

Funding

The authors are grateful to the Tunisian Ministry of Higher Education and Scientific Research for financial support.