Diisopropyl (E)-(1-hydroxy-3-phenylallyl)phosphonate

Abstract

We report the synthesis and the molecular structure as determined by single-crystal X-ray diffraction of diisopropyl (E)-(1-hydroxy-3-phenylallyl)phosphonate. The compound was fully characterised by ¹H, ¹³C, and ³¹P NMR spectroscopy, IR spectroscopy, and Mass Spectrometry.

1. Introduction

Traditionally, α-ketophosphonates can be easily prepared from acyl chlorides and trialkyl phosphites [1]. These can be converted to α-hydroxyphosphonates which are famous for their bioactive properties and versatility as starting materials [2,3]. Developed in the 1950s, the Pudovik reaction [4] involves the base-promoted nucleophilic addition of the P−H bond to unsaturated systems such as C=N, C=C, C≡C, or C=O bonds [5,6,7,8]. Compound 1 can be prepared by various methods. Racemic 1 can be prepared by reacting trans-cinnamaldeyde with diisopropyl phosphonate in the presence of potassium or caesium fluoride affording the racemic α-hydroxyphosphonate 1 [9,10,11,12]. Using chiral catalysts, diisopropyl cinnamoylphosphonate can be reduced to the α-hydroxyphosphonate 1 affording non-racemic products. The (S)-enantiomer of 1 has also been isolated in 75% yield with a 56% ee (enantiomeric excess) through the oxazaborolidine-catalysed enantioselective reduction of the diisoproply cinnamoylphosphonate [13]. This was improved several years later through the ruthenium(II) catalysed enantioselective transfer hydrogenation of α-ketophosphonates affording (R)-1 in a 78% yield with a 97% ee [14]. Other methods for preparing α-hydroxphosphonates include palladium catalysed asymmetric hydrogenation of the parent α-ketophosphonates [15] or copper-catalysed coupling of alcohols with diaryl/alkyl phosphonates [16].

2. Results and Discussion

2.1. Synthesis and Spectroscopy

The ‘Green’ synthesis of α-hydroxphosphonates was reported recently by utilising catalytic triethylamine to facilitate the Pudovik reaction between aldehydes and dialkyl phosphonates [17]. A similar method was reported by Arseniyadis and Kaïm et al. with the modification of dilution with chloroform afterwards to facilitate crystallisation [18]. These methods were adapted to prepare racemic 1 from trans-cinnamaldehyde and diisopropyl phosphonate (with stoichiometric triethylamine) in a 55% yield after recrystallisation (Scheme 1).

The High Resolution Mass Spectrometry (HRMS) data show two major peaks in the spectrum (Figure S15). The m/z peak is at 619.2555 amu which is indicative of 2M+Na, and the other peak at 321.1225 amu is indicative of M+Na (where M = 1). The peaks appear as the sodium adducts due to the analyte used in the electrospray ionisation (ESI+).

The ³¹P{¹H} NMR spectrum shows a sharp singlet at δ_P 20.2 ppm (Figure S9). The ¹H NMR spectrum displays a set of multiplets in the aromatic region corresponding to the phenyl group (δ_H 7.43−7.22 ppm, H-7-9) (Figure 1 and Figures S1−S5). The signal for the hydroxyl group is apparent using d₆-DMSO as the NMR solvent at δ_H 5.86 ppm. The signal is a doublet of doublets due to coupling with the phosphorus (³J_HP 13.1 Hz) and the hydrogen atom on the α-carbon, H-3 with ³J_HH 5.9 Hz. The two alkene hydrogen atoms appear as two separate doublets of doublets of doublets at δ_H 6.69 and 6.28 ppm, H-5 and H-4, respectively. The largest J-coupling of 15.9 Hz is common to both signals as expected for an (E)-alkene [19]. The other couplings from H-5 (δ_H 6.69 ppm) are ³J_HP 6.0 Hz and ³J_HH 4.8 Hz to H-3, and from H-4 (δ_H 6.28 ppm) are ⁴J_HP 5.0 Hz and ⁴J_HH 1.8 Hz to H-3.

The signal from the hydrogen atom on the α-carbon (H-3) appears as a doublet of doublet of doublet of doublets (dddd) at δ_H 4.49 ppm, which collapses to a doublet of doublet of doublets (ddd) in the ¹H{³¹P} NMR spectrum, although due to similar ³J_HH coupling between the neighbouring hydrogen atoms it appears as a pseudo-doublet of triplets. Due to the stereocentre, the CH groups (H-2 and H-B) of the two isopropoxy groups are inequivalent (diastereotopic) causing them to appear at very slightly different chemical shifts. The ¹H NMR spectrum shows a complex multiplet at δ_H 4.66−4.54 ppm, however the ¹H{³¹P} spectrum shows two closely overlapping heptets (³J_HH 6.1 Hz) at δ_H 4.61 and 4.60 ppm (see Figure S6).

The ¹³C DEPTQ NMR spectrum (see Figures S7 and S8) shows the aromatic signals (C-6−C-9) and the alkene signals (C-4 and C-5) ranging δ_C 136.9−127.7 ppm with C-4, C-5, and C-6 appearing as doublets owing to J-coupling with ³¹P with coupling constants of 3.4, 12.9 and 2.9 Hz, respectively. It is well established that the magnitude of ²J_CP coupling is often much lower than ³J_CP coupling when the phosphorus lone pair is no longer available [20]. In the same vein, C-3 shows a very large ¹J_CP of 165.5 Hz, which is typical of tetravalent phosphorus atoms. Similarly to H-2 and H-B having different chemical shifts, C-2 and C-B also have slightly different chemical shifts and appear as two distinct doublets at δ_C 70.8 and 70.6 ppm, with ²J_CP 7.2 and 7.0 Hz, respectively.

2.2. Structural Study

Crystals of 1 that were of suitable quality for single crystal X-ray diffraction were grown from the vapour diffusion of petroleum ether into a solution of 1 in dichloromethane. The structure of racemic 1 was confirmed from these crystals which crystallised in a centrosymmetric space group (P2₁/c) (Figure 2).

The phosphorus adopts a distorted tetrahedral geometry with angles ranging 101.02(7)° to 115.50(7)° (

Table 1. Selected bond lengths (Å) and angles (°) for 1.

P1−O1	1.472(1)	C8A−C9A	1.318(5)
P1−O2	1.566(1)	C7−O7A	1.381(6)
P1−O3	1.574(1)	O1···H7A	1.75(6)
P1−C7	1.822(2)
O1−P1−O2	115.50(7)	O2−P1−O3	103.34(6)
O1−P1−O3	113.98(7)	C7−P1−O2	101.02(7)
O1−P1−C7	114.51(8)	O1···H7A−O7A	172(5)

). The bonds are all typical length, P1−O1 is 1.472(1) Å, clearly showing the P=O character, with the other P−O bonds being 1.566(1) and 1.574(1) Å [21]. The styryl moiety is disordered over two orientations, which are ~180° rotated around C7–C8 with a small rock around P1–C7 (Figure S16).

The hydroxyl group, in both disordered positions, forms a hydrogen bond to O1 of adjacent molecules (H···O 1.74(2) and 1.78(2) Å, O−H···O 171(6) and 173(6)°, for H7A and B, respectively), giving C(5) chains propagating along [0 0 1] (Figure 3). These chains further pack together into sheets across [0 0 1] through a mixture of weaker aromatic C−H···O interactions (H···O 2.7409(12)–3.3278(12) Å) and edge to face C−H···π interactions (H···centroid 3.192(4) and 2.709(5) Å, for each disordered part, respectively) between adjacent styrene groups. These C-H···π interactions are at or beyond the conventional van der Waals limit, but such interactions have been suggested to be effective at distances beyond this value [22].

3. Materials and Methods

All synthetic manipulations were performed in air. Glassware was dried in an oven (ca. 110 °C) prior to use. Diisopropyl phosphonate was purchased from ThermoFisher and used as received. All other chemicals were used as provided from the laboratory inventory without further purification. The IR spectrum was recorded on a Perkin Elmer Spectrum Two instrument with a Deuterated Triglycine Sulphate (DTGS) detector and diamond Attenuated Total Reflectance (ATR) attachment (Bruker, Billerica, MA, USA). The High Resolution Mass Spectrometry (HMRS) data were acquired from the University of St Andrews Mass Spectrometry Service. All NMR spectra were recorded using a Bruker Avance III 400 MHz spectrometer at 20 °C (Bruker, Billerica, MA, USA). The ¹³C spectrum was recorded using the DEPTQ-135 pulse sequence with broadband proton decoupling. Tetramethylsilane was used as external standard for ¹H and ¹³C NMR (δ_H/δ_C 0.00 ppm), and 85% aqueous H₃PO₄ was used as the external standard for ³¹P NMR (δ_P 0.00 ppm). Where possible, the residual solvent signal was used as a secondary reference (d₆-DMSO, δ_H 2.50, δ_C 39.52 ppm). Spectra were analysed using the MestReNova software package (Santiago de Compostela, Spain) (version 14). The NMR numbering scheme for 1 is provided in Figure 1.

3.1. Synthesis and Characterisation of Diisopropyl (E)-(1-hydroxy-3-phenylallyl)phosphonate (1)

Diisopropyl phosphonate (1.66 g, 1.6 mL, 10 mmol) and trans-cinnamaldehyde (1.32 g, 1.3 mL, 10 mmol) were mixed. To this, triethylamine (2.22 g, 3.1 mL, 22 mmol) was added. The mixture was heated to 75 °C with continuous stirring for 10 h. The solution was cooled to ambient conditions upon which a solid precipitated from the mixture. This was collected via filtration and washed with ice-cold toluene (5 mL) and dried in vacuo to afford 1 (1.65 g, 55%). This was recrystallised from petroleum ether 40/60 affording analytically pure 1 as pale-yellow crystals.

¹H NMR (400.3 MHz, d₆-DMSO) δ_H 7.43−7.39 (2H, m, H-7), 7.37−7.32 (2H, m, H-8), 7.28−7.22 (1H, m, H-9), 6.69 (1H, ddd, ³J_HH 15.9, ⁴J_HP 5.0, ⁴J_HH 1.8 Hz, H-5), 6.28 (1H, ddd, ³J_HH 15.9, ³J_HH 6.0, ³J_HP 4.8 Hz, H-4) 5.86 (1H, dd, ³J_HP 13.1, ³J_HH 5.9 Hz, OH), 4.66−4.54 (2 × 1H, m, H-2 & H-B), 4.49 (1H, dddd~ddt, ²J_HP 15.8, ³J_HH 5.9, ⁴J_HH 1.7 Hz, H-3), 1.28−1.18 (12H, m, H-1 & H-A). ¹H{³¹P} NMR (400.3 MHz, d₆-DMSO) δ_H 7.43−7.39 (m, H-7), 7.37−7.32 (m, H-8), 7.28−7.22 (m, H-9), 6.69 (dd, ³J_HH 15.9, ⁴J_HH 1.8 Hz, H-5), 6.28 (dd, ³J_HH 15.9, ³J_HH 6.0 Hz, H-4) 5.86 (d, ³J_HH 6.0 Hz, OH), 4.61 (hept, ³J_HH 6.2 Hz, H1/H1′), 4.60 (hept, ³J_HH 6.1 Hz, H1/H1′), 4.49 (ddd ~dt, ³J_HH 6.0, ⁴J_HH 1.7 Hz, H-3), 1.28−1.18 (m, H-2 & H2′). ¹³C DEPTQ (100.6 MHz, d₆-DMSO) δ_C 136.9 (d, ⁴J_CP 2.9 Hz, qC-6), 131.0 (d, ³J_CP 12.9 Hz, C-5), 129.2 (s, H-8), 128.1 (s, H-9), 126.9 (d, ²J_CP 3.4 Hz, C-4), 126.7 (s, C-7), 70.8 (d, ²J_CP 7.2 Hz, C-1/C-1′), 70.6 (d, ²J_CP 7.0 Hz, C-2/C-B), 69.1 (d, ¹J_CP 165.5 Hz, C-3), 24.4 (br-s, C-1/C-A), 24.2 (d, ³J_CP 5.0 Hz, C-1/C-A). ³¹P{¹H} NMR (162.0 MHz, d₆-DMSO) 20.2 (s). HRMS (ESI+) m/z (%) Calcd. for C₁₅H₂₃O₄PNa 321.1232; found 321.1225 [M+Na]⁺ (45); Cacld. For C₃₀H₄₆O₈P₂Na 619.2566; found 619.2555 [2M+Na]⁺ (100). Infrared (IR) ν_max (ATR/cm⁻¹) 3285m (ν_O−H), 2981m (ν_C−H), 1680w (ν_C=C), 1449m (ν_C=C), 1377m (ν_P−C), 1220s (ν_P=O), 984vs (ν_P−O), 761s, 694s, 564s.

3.2. X-Ray Crystallography

X-ray diffraction data for compound 1 were collected at 100 K using a Rigaku MM-007HF High Brilliance RA generator/confocal optics with XtaLAB P200 diffractometer [Cu Kα radiation (λ = 1.54187 Å)]. Data were collected (using a calculated strategy) and processed (including correction for Lorentz, polarisation, and absorption) using CrysAlisPro [23]. The structure was solved by dual-space methods (SHELXT [24]) and refined by full-matrix least-squares against F² (SHELXL-2019/3 [25]). Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were refined using a riding model except for the hydrogen atoms on O7A and O7B which were located from the difference Fourier map and refined isotropically subject to a distance restraint and with U_eq riding on their parent atom. The styryl moiety is disordered (occupancies 51.6:48.4) over two orientations, which are ~180° rotated around C7–C8 with a small rock around P1–C7. The two orientations were modelled with various geometric and thermal restraints on both parts due to their high level of overlap. All calculations were performed using the Olex2 interface [26]. Selected crystallographic data: C₁₅H₂₃O₄P, M = 298.30, monoclinic, a = 10.20384(14), b = 8.16198(8), c = 20.1399(2) Å, β = 102.0831(11)°, U = 1640.16(3) ų, T = 100 K, space group P2₁/c (no. 14), Z = 4, 30669 reflections measured, 3386 unique (R_int = 0.0631), which were used in all calculations. The final R₁ [I > 2σ(I)] was 0.0471 and wR₂ (all data) was 0.1418. CCDC 2443736 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.