Synthesis and Butyllithium-Induced Cyclisation of 2-Benzyloxyphenylphosphonamidates Giving 2,3-Dihydrobenzo[d][1,3]oxaphospholes

Abstract

A series of fourteen O-ethyl-N-butylphenylphosphonamidates with benzyl ether substituents at the ortho position was prepared and fully characterised. Upon treatment with n-butyllithium in THF at RT, they underwent cyclisation in eight cases to give the novel 2,3-dihydrobenzo[d][1,3]oxaphospholes in moderate to low yield as a single diastereomer, for which the relative configuration was determined by X-ray diffraction in one case.

1. Introduction

The [1,2]-Wittig rearrangement of aryl benzyl ethers 1 to give diarylmethanols 2 (Scheme 1) provides a potentially versatile indirect method for C–C bond formation, but, whilst the reaction has been known for a long time [1,2], it has not been used much recently [3]; this is most likely due to the strongly basic conditions required, which make it incompatible with many of the common functional groups. In recent studies, we reported the use of various activating groups on the aryl ring to facilitate the Wittig rearrangement under milder conditions. The first activating group for this purpose to be discovered was the 4,4-dimethyl-2-oxazoline [4], but when this was in the ortho position to the benzyloxy group, as shown in 3, there was also significant competition from direct cyclisation to give benzofuran products 4, a feature also observed in benzyloxythienyloxazolines [5].

More recently, we discovered the N-butylcarboxamide CONHBu as a more efficient and general activating group, allowing the Wittig rearrangement of ortho-, meta-, or para-oriented benzylic ethers 5 to afford diarylmethanols 6 [6]. A limited degree of success in using a chiral secondary amide group to bring about asymmetric Wittig rearrangement was also described [7]. As far as we are aware, there is only a single report of an enantioselective [1,2]-Wittig rearrangement, and this uses an external chiral bis(oxazoline) ligand [8].

In an earlier paper, we described the synthesis of aryl benzyl ethers bearing the phosphonamidate group EtO-P(=O)-NHBu on the aryl ring, either para- (7) or meta- (9) to a benzylic ether, and their successful Wittig rearrangement to afford the corresponding phosphonamidate-functionalised diarylmethanols 8 and 10, respectively (Scheme 2) [9]. In this paper, we describe the synthesis of a series of the isomeric aryl benzyl ethers 11 bearing an ortho-phosphonamidate group and their reaction with butyllithium, which leads not to Wittig rearrangement but rather to cyclisation, giving 2,3-dihydrobenzo[d][1,3]oxaphospholes 12. Recently, compounds of this type have been of considerable interest as chiral ligands for catalytic asymmetric synthesis, but all the previous synthetic methods involved cyclisation with the formation of the C(2)–O bond [10,11,12,13] as opposed to the method described here where the C(2)–P bond is formed.

2. Materials and Methods

2.1. General Experimental Details

NMR spectra were recorded at 25 °C on solutions in CDCl₃, unless otherwise stated, using Bruker instruments (Bruker, Billerica, MA, USA), and the chemical shifts are given in ppm to high frequency from Me₄Si. IR spectra were recorded using the ATR technique on a Shimadzu IRAffinity 1S instrument. The ionisation method used for high-resolution mass spectra is noted in each case. Column chromatography was carried out using a silica gel of 40–63 μm particle size, and preparative TLC was carried out using 1.0 mm layers of Merck alumina 60G containing 0.5% Woelm fluorescent green indicator on glass plates. Melting points were recorded on a Gallenkamp 50W melting point apparatus or a Reichert hot-stage microscope (Reichert, Vienna, Austria).

Unless otherwise stated, all the reagents and solvents were obtained from standard suppliers and were used as received. Anhydrous nickel(II) chloride was prepared by placing the commercially available hexahydrate in a Schlenk tube under vacuum and heating with a heat-gun until no further loss of mass was observed. The final material was a fine primrose-yellow powder. Dry THF was prepared by the addition of sodium wire, and dry acetone was the commercially available analytical reagent grade.

2.2. Synthesis and Rearrangement of Ethyl P-(4-Benzyloxyphenyl)-N-butylphosphonamidate 16

2.2.1. 1-(Benzyloxy)-2-bromobenzene 13

To a stirred solution of 2-bromophenol (4.36 g, 25.2 mmol) in MeCN (60 mL) at rt was added K₂CO₃ (4.74 g, 34.3 mmol) and benzyl bromide (3.0 mL, 4.32 g, 25.2 mmol), and the mixture was stirred at rt overnight. The reaction was diluted with H₂O (75 mL), the layers separated, and the aqueous layer extracted with EtOAc (3 × 75 mL). The combined organic layers were dried over MgSO₄ and concentrated to give 13 (6.35 g, 96%) as a pale-yellow oil which was used without further purification; ¹H NMR (400 MHz): 7.55 (1H, dd, J = 7.8, 1.6 Hz, ArH), 7.50–7.44 (2H, m, ArH), 7.42–7.34 (2H, m, ArH), 7.34–7.27 (1H, m, ArH), 7.22 (1H, ddd, J = 8.2, 7.4, 1.6 Hz, ArH), 6.92 (1H, dd, J = 8.2, 1.4 Hz, ArH), 6.83 (1H, ddd, J = 7.8, 7.4, 1.4 Hz, ArH) and 5.14 (2H, s, OCH₂); ¹³C NMR (100 MHz) 154.9 (C-O), 136.5 (C), 133.4 (CH), 128.5 (2CH), 128.3 (CH), 127.9 (CH), 126.9 (2CH), 122.1 (CH), 113.8 (CH), 112.4 (C-Br) and 70.7 (OCH₂). The ¹H and ¹³C spectral data were in accordance with those previously reported [14] (Supplementary Materials).

2.2.2. Diethyl (2-Benzyloxyphenyl)phosphonate 14

Following a modified literature procedure [15], 1-(benzyloxy)-2-bromobenzene 13 (3.77 g, 14.2 mmol) and anhydrous NiCl₂ (0.92 g, 7.1 mmol) were placed in a flask set up for distillation, and a dropping funnel containing triethyl phosphite (3.0 mL, 17.2 mmol) was connected to the still head. The mixture was heated at 150 °C while the phosphite was added dropwise until the mixture was dark red. When the initial dark red colour changed to blue, more phosphite was added until the red colour returned. This was repeated until all the phosphite was added; the mixture was then heated for a further 30 min and cooled to rt. The mixture was taken up in CH₂Cl₂ (50 mL), which was washed with dil. HCl (25 mL), dried, and evaporated. Purification via flash column chromatography (gradient elution hexane/EtOAc 9:1 to 100% ethyl acetate), followed by the removal of triethyl phosphate by Kugelrohr distillation, gave 8 (2.88 g, 63%) as a pale-yellow oil; ν_max/cm⁻¹ 1593, 1477, 1443, 1279, 1242, 1020, 959, 756, 733, 696, 573, 536, and 507; ¹H NMR (400 MHz): 7.87 (1H, ddd, J = 14.9, 7.4, 1.8 Hz, ArH), 7.55–7.50 (2H, m, ArH), 7.47 (1H, dddd, J = 8.3, 7.4, 1.8, 0.9 Hz, ArH), 7.41–7.35 (2H, m, ArH), 7.33–7.28 (1H, m, ArH), 7.05–6.96 (2H, m, ArH), 5.19 (2H, s, OCH₂Ph), 4.18–4.05 (4H, m, 2 OCH₂CH₃) and 1.28 (6H, t, J = 7.1 Hz, 2 OCH₂CH₃); ¹³C NMR (100 MHz): 160.1 (d, J = 2.7 Hz, C-O), 136.4 (C), 135.1 (d, J = 7.2 Hz, CH), 134.2 (d, J = 2.1 Hz, CH), 128.4 (2CH), 127.7 (CH), 126.9 (2CH), 120.5 (d, J = 14.6 Hz, CH), 117.0 (d, J = 187 Hz, ArC-P), 112.3 (d, J = 9.3 Hz, Ar CH), 70.0 (OCH₂Ph), 62.0 (d, J = 5.6 Hz, 2 OCH₂CH₃) and 16.2 (d, J = 6.5 Hz, 2 OCH₂CH₃); ³¹P NMR (162 MHz): +17.1; HRMS (ESI⁺): found 343.1058. C₁₇H₂₁NaO₄P (M + Na) requires 343.1075.

2.2.3. Ethyl (2-Benzyloxyphenyl)phosphonochloridate 15

A solution of diethyl (2-benzyloxyphenyl)phosphonate 14 (1.00 g, 3.1 mmol) in dry toluene (15 mL) was stirred at 0 °C while PCl₅ (1.30 g, 6.2 mmol) was added. The mixture was then stirred at rt for 30 min, filtered, and evaporated to give 15 (0.99 g, ~100%) as a yellow oil which was used without further purification; ¹H NMR (400 MHz): 7.94 (1H, ddd, J = 16.9, 7.7, 1.8 Hz, ArH), 7.55 (1H, tdd, J = 8.4, 1.8, 1.0 Hz, ArH), 7.54–7.46 (2H, m, ArH), 7.41–7.36 (2H, m, ArH), 7.35–7.32 (1H, m, ArH), 7.09–6.99 (2H, m, ArH), 5.22 (2H, s, OCH₂Ph), 4.42–4.26 (2H, m, OCH₂CH₃) and 1.35 (3 H, td, J = 7.0, 0.5 Hz, OCH₂CH₃); ¹³C NMR (125 MHz): 159.8 (4ry, d, J = 2.9 Hz, ArC-O), 136.0 (C), 135.6 (d, J = 2.0 Hz, CH), 134.2 (d, J = 8.6 Hz, CH), 128.5 (2CH), 128.0 (CH), 127.0 (2CH), 120.5 (d, J = 16.4 Hz, CH), 118.5 (d, J = 179.5 Hz, C-P), 112.7 (d, J = 9.8 Hz, CH), 70.5 (OCH₂Ph), 63.7 (d, J = 7.7 Hz, OCH₂CH₃) and 15.8 (d, J = 7.7 Hz, OCH₂CH₃); ³¹P NMR (162 MHz): +26.5.

2.2.4. Ethyl P-(2-Benzyloxyphenyl)-N-butylphosphonamidate 16

Following a literature procedure [16], a solution of n-butylamine (0.67 mL, 0.50 g, 6.8 mmol) in Et₂O (25 mL) was stirred at 0 °C while a solution of ethyl (2-benzyloxyphenyl)phosphonochloridate 15 (1.00 g, 3.2 mmol) in Et₂O (25 mL) was added dropwise. The mixture was allowed to warm to rt and was stirred for 18 h. Water (50 mL) was added, and the layers were separated. The aqueous layer was extracted with Et₂O (2 × 25 mL), and the combined organic layers were dried and evaporated. Purification by column chromatography (SiO₂, EtOAc/hexane 1:1) gave 16 (480 mg, 43%) as a slightly yellow oil; ν_max/cm⁻¹ 2957, 2930, 2872, 1591, 1440, 1277, 1229, 1086, 1032, 951, 756, 735, 696, 571, and 534; ¹H NMR (400 MHz): 7.93 (1H, ddd, J = 14.2, 7.4, 1.8 Hz, ArH), 7.48–7.43 (3H, m, ArH), 7.42–7.32 (3H, m, ArH), 7.04 (1H, tdd, J = 7.4, 2.9, 0.9 Hz, ArH), 6.99 (1H, ddd, J = 8.4, 6.2, 0.9 Hz, ArH), 5.14 (2H, s, OCH₂Ph), 4.09–3.89 (2H, m, OCH₂CH₃), 2.97–2.87 (3H, m, NHCH₂), 1.34–1.27 (2H, m, NHCH₂CH₂), 1.26 (3H, t, J = 7.1 Hz, OCH₂CH₃), 1.21–1.09 (2H, m, NHCH₂CH₂CH₂) and 0.79 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (125 MHz): 159.0 (d, J = 2.8 Hz, ArC-O), 136.1 (C), 134.4 (d, J = 6.4 Hz, CH), 133.3 (d, J = 1.6 Hz, Ar CH), 128.6 (2CH), 128.2 (CH), 127.3 (2CH), 120.8 (d, J = 13.5 Hz, CH), 119.8 (d, J = 167.0 Hz, ArC-P), 111.7 (d, J = 8.5 Hz, CH), 70.3 (OCH₂Ph), 60.2 (d, J = 5.7 Hz, OCH₂CH₃) 40.3 (NHCH₂), 34.0 (d, J = 6.1 Hz, NHCH₂CH₂), 19.6 (NHCH₂CH₂CH₂), 16.3 (d, J = 6.9 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +21.3; HRMS (ESI⁺): found 370.1529. C₁₉H₂₆NNaO₃P (M + Na) requires 370.1548.

2.2.5. 3-Butylamino-2-phenyl-2H-benzo[d][1,3]oxaphosphole 3-Oxide 17

A solution of ethyl P-(2-benzyloxyphenyl)-N-butylphosphonamidate 16 (69.5 mg, 0.2 mmol) in dry THF (2 mL) was stirred at rt under N₂ while n-butyllithium (0.37 mL, 0.66 mmol) was added by syringe. After 20 min, the mixture was added to saturated aqueous ammonium chloride (2 mL), and the mixture was extracted with Et₂O (3 × 2 mL). Drying and evaporation of the combined extracts gave, after purification via preparative TLC, (EtOAc/hexane 1:1) 17 (24.5 mg, 41%) as a pale-yellow oil; ν_max/cm⁻¹3184, 2957, 2930, 2872, 1599, 1578, 1449, 1204, 1155, 1126, 1094, 988, 916, 827, 756, 729, 696, and 515; ¹H NMR (400 MHz): 7.66–7.52 (2H, m, ArH), 7.42–7.38 (4H, m, ArH), 7.37–7.32 (1H, m, ArH), 7.15–7.07 (2H, m, ArH), 5.57 (1H, d, J = 9.9 Hz, CHP), 2.49–2.37 (1H, m, NHCHH), 2.30–2.21 (1H, m, NHCHH), 1.04–0.94 (4H, m, NHCH₂CH₂CH₂) and 0.70 (3H, t, J = 6.9 Hz, NHCH₂CH₂CH₂CH₃); ¹H{³¹P} NMR (400 MHz): 5.57 (1H, s); ¹³C NMR (100 MHz): 164.6 (d, J = 24.0 Hz, ArC-O), 135.5 (d, J = 1.7 Hz, CH), 134.7 (d, J = 3.4 Hz, C), 129.0 (d, J = 5.5 Hz, CH), 128.8 (d, J = 2.0 Hz, 2CH), 128.0 (d, J = 2.5 Hz, CH), 124.9 (d, J = 3.9 Hz, 2CH), 122.4 (d, J = 10.1 Hz, CH), 114.3 (d, J = 6.6 Hz, CH), 113.9 (d, J = 122.8 Hz, ArC-P), 79.7 (d, J = 87.4 Hz, CHP), 40.2 (d, J = 1.2 Hz, NHCH₂), 33.7 (d, J = 5.4 Hz, NHCH₂CH₂), 19.4 (NHCH₂CH₂CH₂) and 13.5 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +44.6; HRMS (ESI⁺): found 302.1295. C₁₇H₂₂NOP (M + H) requires 302.1310.

2.3. Synthesis of Substituted 2-Bromophenyl Benzyl Ethers 18

2.3.1. 2-Bromophenyl 2-Methylbenzyl Ether 18a

To a stirred solution of 2-bromophenol (2.9 mL, 4.33 g, 25.0 mmol) and K₂CO₃ (4.70 g, 34.0 mmol) in MeCN (60 mL) at rt, 2-methylbenzyl bromide (3.4 mL, 4.63 g, 25.0 mmol) was added, and the solution was stirred for 18 h. The reaction mixture was poured into H₂O and extracted with EtOAc (2 × 50 mL), and the combined organic fractions were dried over MgSO₄ and concentrated to afford, after recrystallisation from hexane, 18a (3.92 g, 57%) as colourless crystals, mp 42–44 °C; ν_max/cm⁻¹ 3063, 3032, 2972, 2913, 2855, 1585, 1479, 1439, 1275, 1246, 1049, 1028, 737, and 665; ¹H NMR (300 MHz): 7.56 (1H, dd, J = 7.9, 1.6 Hz, ArH), 7.53–7.45 (1H, m, ArH), 7.32–7.16 (4 H, m, ArH), 6.98 (1H, dd, J = 8.3, 1.3 Hz, ArH), 6.85 (1 H, td, J = 7.5, 1.2 Hz, ArH), 5.11 (2H, s, OCH₂) and 2.40 (3H, s, ArCH₃); ¹³C NMR (75 MHz): 155.1 (C), 136.3 (C), 134.3 (C), 133.5 (CH), 130.3 (CH), 128.4 (CH), 128.2 (2CH), 126.0 (CH), 122.1 (CH), 113.7 (CH), 112.5 (C), 69.4 (CH₂) and 19.0 (CH₃).

2.3.2. 2-Bromophenyl 4-Methylbenzyl Ether 18b

A solution of sodium iodide (5.34 g, 35.6 mmol) in dry acetone (25 mL) was stirred while 4-methylbenzyl chloride (5.00 g, 35.6 mmol) was added dropwise, and the mixture was stirred for 30 min. The mixture was added to H₂O (50 mL) and extracted with Et₂O (2 × 50 mL). Drying and evaporation of the extracts gave 4-methylbenzyl iodide 6.52 g, 79%) as a pale-yellow liquid.

To a stirred solution of 2-bromophenol (3.3 mL, 4.87 g, 28.0 mmol) and K₂CO₃ (7.16 g, 52.0 mmol) in MeCN (90 mL) at rt, 4-methylbenzyl iodide (6.52 g, 28.0 mmol) was added, and the solution was stirred for 18 h. The reaction mixture was poured into H₂O and extracted with EtOAc (2 × 50 mL), and the combined organic fractions were dried over MgSO₄ and concentrated to afford, after column chromatography (SiO₂, hexane/EtOAc 9:1), 18b (6.30 g, 81%) as colourless crystals, mp 54–56 °C; ν_max/cm⁻¹ 1479, 1454, 1441, 1292, 1285, 1275, 1246, 1213, 1180, 1158, 1055, 1028, 1020, 983, 949, 922, 808, 742, and 664; ¹H NMR (300 MHz): 7.55 (1H, dd, J = 7.8, 1.8 Hz, ArH), 7.36 (2H, d, J = 8.1 Hz, ArH), 7.26–7.19 (3 H, m, ArH), 6.93 (1H, dd, J = 8.1, 1.5 Hz, ArH), 6.83 (1H, td, J = 8.1, 7.5, 1.5 Hz, ArH), 5.12 (2H, s, OCH₂) and 2.36 (3H, s, CH₃); ¹³C NMR (125 MHz): 155.0 (ArC-O), 137.6 (C), 133.5 (C), 133.4 (CH), 129.2 (2CH), 128.3 (CH), 127.1 (2CH), 122.0 (CH), 113.9 (CH), 112.5 (C-Br), 70.7 (OCH₂) and 21.2 (CH₃); HRMS (ESI⁺): found 299.0042. C₁₄H₁₃⁷⁹BrNaO (M + Na) requires 299.0047.

2.3.3. 2-Bromophenyl 4-tert-Butylbenzyl Ether 18c

The same procedure as in 2.3.1 using 2-bromophenol (5.79 g, 33 mmol), K₂CO₃ (7.20 g, 52 mmol), and 4-tert-butylbenzyl bromide [17] (7.63 g, 33 mmol) gave 18c (6.20 g, 55%) as a brown oil; ν_max/cm⁻¹ 2963, 1477, 1462, 1443, 1634, 1294, 1277, 1246, 1233, 1109, 1051, 1030, 1015, 837, 818, 745, 691, 656, and 638; ¹H NMR (300 MHz): 7.75 (1H, dd J = 8.1, 1.5 Hz, ArH), 7.41 (4H, s, ArH), 7.23 (1H, m, ArH), 6.95 (1H, dd J = 8.4, 1.2 Hz, ArH), 6.83 (1H, ddd J = 8.1, 7.8, 1.5 Hz, ArH), 5.11 (2H, s, OCH₂) and 1.32 (9H, m, 3 CH₃); ¹³C NMR (125 MHz): 155.1 (ArC-O), 150.9 (C), 133.5 (C), 133.4 (CH), 128.4 (CH), 126.8 (2CH), 125.5 (2CH), 122.0 (CH), 113.8 (CH), 112.5 (C-Br), 70.6 (CH₂O), 34.5 (CMe₃) and 31.3 (3CH₃); HRMS (ESI⁺) found 341.0512. C₁₇H₁₉BrNaO (M + Na) requires 341.0517.

2.3.4. 2-Bromophenyl 2-Methoxybenzyl Ether 18d

The same procedure as in 2.3.1 using 2-bromophenol (6.08 g, 35 mmol), K₂CO₃ (6.64 g, 48 mmol), and 2-methoxybenzyl bromide (6.64 g, 35 mmol) gave 18d (9.10 g, 81%) as a yellow oil; ν_max/cm⁻¹ 1510, 1310, 1270, 1080, 1060, and 760; ¹H NMR (300 MHz): 7.60 (1H, m, ArH), 7.55 (1H, dd J = 8.0, 1.2 Hz, ArH), 7.28 (1H, m, ArH), 7.21 (1H, m, ArH), 7.01–6.95 (2H, m, ArH), 6.87 (1H, m, ArH), 6.82 (1H, ddd J = 8.1, 7.8, 1.5 Hz, ArH), 5.19 (2H, s, OCH₂) and 3.86 (3H, s, OCH₃); ¹³C NMR (75 MHz): 156.3 (ArC-O), 155.1 (ArC-O), 133.3 (CH), 128.6 (CH), 128.4 (CH), 127.8 (CH), 124.9 (C), 121.8 (CH), 120.7 (CH), 113.7 (CH), 112.3 (C-Br), 109.9 (CH), 65.8 (OCH₂) and 55.3 (OCH₃); HRMS (ESI⁺) found 314.9990. C₁₄H₁₃BrNaO₂ (M + Na) requires 314.9997.

2.3.5. 2-Bromophenyl 3-Methoxybenzyl Ether 18e

The same procedure as in 2.3.1 using 2-bromophenol (5.99 g, 34.6 mmol), K₂CO₃ (6.50 g, 47 mmol), and 3-methoxybenzyl bromide (6.98 g, 34.6 mmol) gave 18e (5.42 g, 54%) as a yellow oil; ν_max/cm⁻¹ 3063, 3001, 2938, 2835, 1585, 1477, 1277, 1244, 1049, 1023, and 743; ¹H NMR (300 MHz): 7.53 (1H, dd, J = 7.9, 1.5 Hz, ArH), 7.32–7.14 (2H, m, ArH), 7.09–6.96 (2H, m, ArH), 6.92–6.74 (3H, m, ArH), 5.09 (2H, s, OCH₂) and 3.78 (3H, s, OCH₃); ¹³C NMR (75 MHz): 159.7 (C), 154.8 (C), 138.1 (C), 133.3 (CH), 129.5 (CH), 128.3 (CH), 122.1 (CH), 118.9 (CH), 113.7 (CH), 113.4 (CH), 112.3 (C-Br), 112.2 (CH), 70.4 (CH₂) and 55.1 (CH₃); HRMS (ESI⁺) found 314.9989. C₁₄H₁₃⁷⁹BrNaO₂ (M + Na) requires 314.9997.

2.3.6. 2-Bromophenyl 4-Methoxybenzyl Ether 18f

The same procedure as in 2.3.1 using 2-bromophenol (6.28 g, 36.3 mmol), K₂CO₃ (6.82 g, 49.3 mmol), and 4-methoxybenzyl bromide (7.29 g, 36.3 mmol) gave 18f (4.41 g, 81%) as red crystals, mp 84–87 °C; ν_max/cm⁻¹ 2999, 2909, 2835, 2361, 1607, 1584, 1510, 1474, 1240, 1171, 1028, 826, 808, and 750; ¹H NMR (300 MHz): 7.54 (1H, dd, J = 7.9, 1.6 Hz, ArH), 7.38 (2H, d, J = 9.0 Hz, ArH), 7.26–7.16 (1H, m, ArH), 6.96–6.86 (3H, m, ArH), 6.82 (1H, td, J = 7.7, 1.4 Hz, ArH), 5.07 (2H, s, OCH₂) and 3.80 (3H, s, OCH₃); ¹³C NMR (75 MHz): 159.4 (C), 155.1 (C), 133.4 (CH), 128.7 (2CH), 128.5 (C), 128.3 (CH), 122.1 (CH), 114.1 (CH), 113.9 (2CH), 112.6 (C-Br), 70.7 (CH₂) and 55.2 (CH₃); HRMS (ESI^–) found 291.0023. C₁₄H₁₂⁷⁹BrO₂ (M–H) requires 291.0021.

2.3.7. 2-Bromophenyl 2-Fluorobenzyl Ether 18g

The same procedure as in 2.3.2 using 2-bromophenol (3.58 g, 21 mmol), K₂CO₃ (3.90 g, 28 mmol), and 2-fluorobenzyl iodide (4.89 g, 21 mmol) gave 18g (4.83 g, 83%) as a yellow oil; ν_max/cm⁻¹ 1585, 1493, 1476, 1456, 1443, 1285, 1273, 1246, 1231, 1053, 1030, 1007, 839, 743, and 665; ¹H NMR (300 MHz): 7.64 (1H, m, ArH), 7.56 (1H, dd J = 8.1, 1.8 Hz, ArH), 7.35–7.16 (3H, m, ArH), 7.08 (1H, m, ArH), 6.97 (1H, dd J = 8.1, 1.5 Hz, ArH), 6.86 (1H, td J = 8.1, 1.5 Hz, ArH) and 5.22 (2H, s, OCH₂); ¹³C NMR (100 MHz): 160.0 (d, J = 244.8 Hz, ArC-F), 154.7 (ArC-O), 133.4 (CH), 129.5 (d, J = 8.1 Hz, CH), 129.2 (d, J = 4.2 Hz, CH), 128.5 (CH), 124.3 (d, J = 3.5 Hz, CH), 123.7 (d, J = 13.7 Hz, C), 123.3 (CH), 115.1 (d, J = 20.7 Hz, CH), 113.7 (CH), 112.5 (C-Br) and 64.4 (d, J = 15.0 Hz, OCH₂); ¹⁹F NMR (376 MHz): –118.9; HRMS (ESI⁺) found 302.9788. C₁₃H₁₀BrFNaO (M + Na) requires 302.9797.

2.3.8. 2-Bromophenyl 4-Fluorobenzyl Ether 18h

The same procedure as in 2.3.2 using 2-bromophenol (4.36 g, 25 mmol), K₂CO₃ (4.74 g, 34 mmol), and 4-fluorobenzyl iodide (5.95 g, 25 mmol) gave 18h (6.67 g, 95%) as a yellow oil; ν_max/cm⁻¹ 1603, 1585, 1572, 1508, 1477, 1464, 1443, 1377, 1294, 1277, 1246, 1223, 1157, 1126, 1053, 1030, 1013, 978, 937, 860, 818, 745, 664, and 600; ¹H NMR (300 MHz): 7.65 (1H, dd, J = 7.8, 1.8 Hz, ArH), 7.45 (2H, m, ArH), 7.23 (1H, m, ArH), 7.07 (2H, tt, J = 8.7, 2.1 Hz, ArH), 6.92 (1H, dd J = 8.1, 1.2 Hz, ArH), 6.85 (1H, td J = 7.8, 1.5 Hz, ArH) and 5.10 (2H, s, OCH₂); ¹³C NMR (75 MHz): 162.4 (d, J = 246.4 Hz, ArC-F), 154.8 (ArC-O), 133.5 (CH), 132.2 (d, J = 3.2 Hz, C), 128.8 (d, J ₌ 8.0 Hz, CH), 128.4 (CH), 122.3 (2CH), 115.5 (d, J = 21.6 Hz, 2CH), 113.9 (CH), 112.5 (C-Br) and 70.2 (OCH₂); ¹⁹F NMR (376 MHz): –114.2; HRMS (ESI⁺) found 205.0602. C₁₃H₁₀NaO (M + Na − F − Br) requires 205.0629.

2.3.9. 2-Bromophenyl 2-Naphthylmethyl Ether 18l

The same procedure as in 2.3.1 using 2-bromophenol (4.33 g, 25.0 mmol), K₂CO₃ (4.70 g, 34.0 mmol), and 2-(bromomethyl)naphthalene (5.53 g, 25.0 mmol) gave, after recrystallisation from hexane, 18l (5.05 g, 65%) as light brown crystals, mp 75–77 °C; ν_max/cm⁻¹ 3067, 3055, 2930, 2878, 1572, 1479, 1442, 1279, 1230, 1030, 1004, 814, and 737; ¹H NMR (300 MHz): 7.98–7.75 (4H, m, ArH), 7.66–7.40 (4H, m, ArH), 7.24–7.13 (1H, m, ArH), 6.98 (1H, dd, J = 8.2, 1.3 Hz, ArH), 6.85 (1H, td, J 7.7, 1.4 Hz, ArH) and 5.32 (2 H, s, OCH₂); ¹³C NMR (75 MHz):155.0 (C), 134.0 (C), 133.4 (CH), 133.2 (C), 133.0 (C), 128.4 (2CH), 128.0 (CH), 127.7 (CH), 126.2 (CH), 126.1 (CH), 126.0 (CH), 124.8 (CH), 122.2 (CH), 114.0 (CH), 112.5 (C-Br) and 70.9 (CH₂); HRMS (ESI⁺) found 335.0039. C₁₇H₁₃⁷⁹BrNaO (M + Na) requires 335.0047.

2.4. Synthesis of Substituted Diethyl 2-Benzyloxyphenylphosphonates 19

2.4.1. Diethyl 2-(4-Methylbenzyloxy)phenylphosphonate 19b

Using the method of Section 2.2.2 with 2-bromophenyl 4-methylbenzyl ether 18b (1.00 g, 3.6 mmol), NiCl₂ (0.05 g, 0.36 mmol), and triethyl phosphite (0.72 g, 4.33 mmol) gave, after column chromatography (SiO₂, hexane/EtOAc 1:1) and removal of triethyl phosphate by Kugelrohr distillation, 19b (0.17 g, 13%) as a colourless oil; ¹H NMR (300 MHz): 7.86 (1H ddd, J = 15, 7.5, 1.8 Hz, ArH), 7.49 (1H, m, ArH), 7.40 (2H, d, J = 7.2 Hz, ArH), 7.18 (2H, d, J = 7.2 Hz, ArH), 7.07–6.93 (2H, m, ArH), 5.15 (2H, s, ArOCH₂), 4.22–4.02 (4H, m, 2 OCH₂CH₃), 2.36 (3H, s, Ar-CH₃) and 1.28 (6H, t, J = 6.9 Hz, 2 OCH₂CH₃); ¹³C NMR (125 MHz): 160.3 (ArC-O), 137.5 (C), 135.2 (d, J = 7.1 Hz, CH), 134.2 (CH), 133.4 (C), 129.1 (2CH), 127.1 (2CH), 120.5 (d, J = 14.6 Hz, CH), 116.9 (d, J = 187 Hz, ArC-P), 112.4 (d, J = 9 Hz, CH), 70.1 (OCH₂Ar), 62.1 (d, J = 5.5 Hz, 2 OCH₂CH₃), 21.2 (ArCH₃) and 16.3 (d, J = 6.4 Hz, 2 OCH₂CH₃); ³¹P NMR (162 MHz): +17.2; HRMS (ESI⁺) found 357.1219. C₁₈H₂₃NaO₄P (M + Na) requires 357.1232.

2.4.2. Diethyl 2-(2-Methoxybenzyloxy)phenylphosphonate 19d

Using the method of Section 2.2.2 with 2-bromophenyl 2-methoxybenzyl ether 18d (4.00 g, 13.6 mmol), NiCl₂ (0.18 g, 1.36 mmol) and triethyl phosphite (2.80 mL, 2.72 g, 16.4 mmol) gave, after removal of triethyl phosphate by Kugelrohr distillation, 19d (2.58 g, 54%) as a yellow oil; ν_max/cm⁻¹ 3069, 2938, 2907, 2835, 1589, 1477, 1242, 1026, and 746.; ¹H NMR (300 MHz): 7.64–7.47 (2H, m, ArH), 7.32–7.18 (2H, m, ArH), 7.05–6.95 (2H, m, ArH), 6.92–6.78 (2H, m, ArH), 5.19 (2 H, s, ArOCH₂), 4.18–4.05 (4H, m, 2 OCH₂CH₃), 3.86 (3 H, s, OCH₃) and 1.34 (6H, t, 2 OCH₂CH₃); ³¹P NMR (121 MHz): +17.4; HRMS (ESI⁺) found 373.1175. C₁₈H₂₃NaO₅P (M + Na) requires 373.1181.

2.4.3. Diethyl 2-(3-Methoxybenzyloxy)phenylphosphonate 19e

Using the method of Section 2.2.2 with 2-bromophenyl 3-methoxybenzyl ether 18e (5.16 g, 17.6 mmol), NiCl₂ (0.23 g, 1.76 mmol) and triethyl phosphite (3.6 mL, 3.51 g, 21.1 mmol) gave, after column chromatography (SiO₂, hexane/EtOAc 1:1) and removal of triethyl phosphate by Kugelrohr distillation, 19e (3.17 g, 51%) as a colourless oil; ¹H NMR (300 MHz): 7.87 (1H, ddd, J = 14.9, 7.5, 1.8 Hz, ArH), 7.52–7.43 (1H, m, ArH), 7.30–7.25 (1H, m, ArH), 7.16–7.14 (1H, m, ArH), 7.11–6.91 (3H, m, ArH), 6.82 (1H, dd, J = 8.2, 2.2 Hz, ArH), 5.17 (2H, s, ArOCH₂), 4.21–4.05 (4H, m, 2 OCH₂CH₃), 3.83 (3H, s, OCH₃) and 1.29 (6H, t, J = 7.1 Hz, 2 OCH₂CH₃); ¹³C NMR (75 MHz): 160.1 (ArC-O), 159.8 (ArC-O), 138.1 (C), 135.3 (d, J = 7.2 Hz, CH), 134.2 (d, J = 1.6 Hz, CH), 129.4 (CH), 120.6 (d, J = 14.6 Hz, CH), 118.9 (CH), 118.3 (d, J = 122.1 Hz, C-P), 113.4 (CH), 112.4 (CH), 112.3 (CH), 69.9 (ArOCH₂), 62.1 (d, J = 5.5 Hz, 2 OCH₂CH₃), 55.3 (OCH₃) and 16.3 (d, J = 6.6 Hz, 2 OCH₂CH₃); ³¹P NMR (202 MHz): +17.1; HRMS (ESI⁺) found 357.1219. C₁₈H₂₃NaO₄P (M + Na) requires 357.1232.

2.5. Conversion of a Substituted Diethyl 2-Benzyloxyphenylphosphonate into the Phosphonamidate

2.5.1. Ethyl 2-(3-Methoxybenzyloxy)phenylphosphonochloridate 20

Using the method of Section 2.2.3 with diethyl 2-(3-methoxybenzyloxy)phenylphosphonate 19e (2.93 g, 8.36 mmol) and PCl₅ (3.48 g, 16.7 mmol) in dry toluene (30 mL) gave 20 (2.85 g, 100%) as a yellow oil; ³¹P NMR (121 MHz): +26.4. This was used without purification for the following stage.

2.5.2. Ethyl N-Butyl-P-(2-(3-methoxybenzyloxy)phenyl)phosphonamidate 21e

Using the method of Section 2.2.4 with ethyl 2-(3-methoxybenzyloxy)phenylphosphonochloridate 20 (2.85 g, 8.4 mmol) and n-butylamine (2.1 mL, 1.56 g, 21.4 mmol) in Et₂O (30 mL) gave, after purification by column chromatography (SiO₂, hexane/EtOAc 1:1), 21e (1.77 g, 54%) as a yellow oil; ¹H NMR (300 MHz): 7.97–7.85 (1H, m, ArH), 7.55–7.42 (1H, m, ArH), 7.35–7.25 (2H, m, ArH), 7.10–6.93 (3H, m, ArH), 6.90–6.80 (1H, m, ArH), 5.25–5.10 (2H, m, ArOCH₂), 4.20–3.90 (2H, m, P-OCH₂), 3.82 (3H, s, OCH₃), 3.05–2.85 (3H, m, NHCH₂), 1.40–1.11 (7H, m, NHCH₂(CH₂)₂CH₃ and OCH₂CH₃), 0.96–0.68 (3H, t, NCH₂CH₂CH₂CH₃); ³¹P NMR (121 MHz): +21.2; HRMS (ESI⁺) found 400.1648. C₂₀H₂₈NaNO₄P (M + Na) requires 400.1654.

2.6. Formation and O-Benzylation of Ethyl N-Butyl-P-(2-hydroxyphenyl)phosphonamidate

2.6.1. Ethyl N-Butyl-P-(2-hydroxyphenyl)phosphonamidate 22

Using a literature procedure [18], a solution of ethyl P-(2-benzyloxyphenyl)-N-butylphosphonamidate 16 (2.20 g, 6.3 mmol) in MeOH (40 mL) and 5% Pd/C (0.34 g) was stirred under a hydrogen atmosphere at rt for 2 h. The reaction mixture was filtered and concentrated to afford 22 (1.57 g. 96%); ¹H NMR (300 MHz): 10.77 (1H, br s, OH), 7.45–7.28 (2H, m, ArH), 6.98–6.85 (2H, m, ArH), 4.10–3.85 (2H, m, OCH₂CH₃), 3.00–2.78 (3H, m, NHCH₂), 1.50–1.20 (4 H, m, NHCH₂(CH₂)₂CH₃), 1.28 (3H, t, J = 7.1 Hz, OCH₂CH₃) and 0.87 (3H, t, J = 7.3 Hz, NH(CH₂)₃CH₃); ¹³C NMR (75 MHz): 162.2 (d, J = 6.5 Hz, ArCOH), 134.4 (d, J = 2.1 Hz, CH), 131.4 (d, J = 7.1 Hz, CH), 119.2 (d, J = 13.2 Hz, CH), 117.5 (d, J = 10.9 Hz, CH), 111.1 (d, J = 162.8 Hz, ArC-P), 61.6 (d, J = 4.5 Hz, OCH₂CH₃), 40.2 (NHCH₂), 33.8 (d, J = 6.1 Hz, NHCH₂CH₂), 19.6 (NHCH₂CH₂CH₂), 16.2 (d, J = 6.7 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (121 MHz): +28.2; HRMS (ESI⁺): found 280.1073. C₁₂H₂₀NaNO₃P (M + Na) requires 280.1078.

2.6.2. Ethyl N-Butyl-P-(2-(2-methylbenzyloxy)phenyl)phosphonamidate 21a

To a stirred solution of ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 16 (0.25 g, 0.97 mmol) and K₂CO₃ (0.40 g, 2.92 mmol) in DMF (10 mL) at rt, 2-methylbenzyl bromide (0.13 mL, 0.18 g, 0.97 mmol) was added, and the solution was stirred for 18 h. The reaction mixture was poured into H₂O (40 mL) and extracted with CH₂Cl₂ (20 mL) and EtOAc (3 × 20 mL). The combined organic fractions were washed with H₂O (6 × 50 mL), dried over MgSO₄, and concentrated to afford, after purification via column chromatography (SiO₂, EtOAc/hexane 1:1), 21a (0.20 g, 57%) as a yellow oil; ¹H NMR (300 MHz): 7.94 (1H, ddd, J = 14.3, 7.5, 1.8 Hz, ArH), 7.54–7.39 (2H, m, ArH), 7.33–7.20 (3H, m, ArH), 7.14–6.94 (2H, m, ArH), 5.14 and 5.08 (2H, AB pattern, J = 11.1 Hz, OCH₂), 4.05–3.85 (2H, m, OCH₂CH₃), 3.00–2.80 (3H, m, NHCH₂), 2.41 (3H, s, ArCH₃), 1.28–1.05 (4H, m, NHCH₂(CH₂)₂CH₃), 1.22 (3H, t, J = 7.0 Hz, OCH₂CH₃) and 0.78 (3 H, t, J = 7.2 Hz, NHCH₂(CH₂)₂CH₃); ¹³C NMR (75 MHz): 159.2 (d, J = 2.8 Hz, ArCO), 136.4 (C), 134.5 (d, J = 6.5 Hz, CH), 134.0 (C), 133.4 (CH), 130.4 (CH), 128.5 (CH), 128.4 (CH), 126.1 (CH), 120.8 (d, J = 13.5 Hz, CH), 119.8 (d, J = 166.8 Hz, ArC-P), 111.5 (d, J = 8.6 Hz, CH), 68.7 (ArOCH₂), 60.2 (d, J = 5.8 Hz, OCH₂CH₃), 40.2 (NHCH₂), 34.0 (d, J = 6.2 Hz, NHCH₂CH₂), 19.6 (NHCH₂CH₂CH₂), 18.8 (ArCH₃), 16.3 (d, J = 6.9 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (121 MHz): +21.3; HRMS (ESI⁺): found 384.1699. C₂₀H₂₈NaNO₃P (M + Na) requires 384.1705.

2.6.3. Ethyl N-Butyl-P-(2-(4-methylbenzyloxy)phenyl)phosphonamidate 21b

To a stirred solution of NaI (0.16 g, 1.07 mmol) in acetone (1.5 mL), 4-methylbenzyl chloride (0.14 mL, 0.15 g, 1.07 mmol) was added, and the solution was stirred at rt until no further precipitation was observed. The solution was filtered and concentrated to afford 4-methylbenzyl iodide, which was used without further purification.

The 4-methylbenzyl iodide (1.07 mmol) was added to a stirred solution of ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.25 g, 0.97 mmol) and K₂CO₃ (0.40 g, 2.92 mmol) in DMF (10 mL), and the mixture was stirred for 18 h at rt. The reaction mixture was poured into H₂O (40 mL) and extracted with CH₂Cl₂ (20 mL) and EtOAc (3 × 20 mL). The combined organic fractions were washed with H₂O (6 × 50 mL), dried over MgSO₄, and concentrated to afford the product 20 (0.21 g, 60%) as an orange oil; ¹H NMR (400 MHz): 7.93 (1H, ddd, J = 14.3, 7.5, 1.8 Hz, ArH), 7.50–7.42 (1H, m, ArH), 7.35 (2H, d, J = 8.0 Hz, ArH), 7.21 (2H, d, J = 8.0 Hz, ArH), 7.16–7.00 (1H, m, ArH), 7.00–6.95 (1H, m, ArH), 5.09 (2H, s, ArOCH₂), 4.05–3.90 (2H, m, OCH₂CH₃), 3.01–2.82 (3H, m, NHCH₂), 2.38 (3H, s, ArCH₃), 1.34–1.21 (4H, m, NHCH₂(CH₂)₂CH₃), 1.25 (3H, t, J = 7.2 Hz, OCH₂CH₃) and 0.79 (3H, t, J = 7.2 Hz, NHCH₂(CH₂)₂CH₃); ¹³C NMR (100 MHz): 159.2 (d, J = 2.8 Hz, ArCO), 138.1 (C), 134.5 (d, J = 6.5 Hz, CH), 133.3 (CH), 133.2 (C), 129.4 (2CH), 127.5 (2CH), 120.8 (d, J = 13.1 Hz, CH), 120.0 (d, J = 170.2 Hz, ArC-P), 111.8 (d, J = 8.6 Hz, CH), 70.4 (ArOCH₂), 60.3 (d, J = 5.7 Hz, OCH₂CH₃), 40.3 (NHCH₂), 34.1 (d, J = 6.2 Hz, NHCH₂CH₂), 21.2 (ArCH₃), 19.7 (NHCH₂CH₂CH₂), 16.4 (d, J = 6.8 Hz, OCH₂CH₃) and 13.7 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (121 MHz): +21.3.

2.6.4. Ethyl N-Butyl-P-(2-(4-tert-butylbenzyloxy)phenyl)phosphonamidate 21c

Using the method of Section 2.6.2 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.60 g, 2.5 mmol), 4-tert-butylbenzyl bromide [17] (0.56 g, 2.5 mmol) and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave, after purification by column chromatography (SiO₂, hexane/EtOAc 1:1), 21c (0.33 g, 33%) as a pale-yellow oil; ν_max/cm^–1 2959, 2930, 2870, 2423, 1591, 1475, 1443, 1165, 1018, 955, 762, and 550; ¹H NMR (400 MHz): 7.96–7.90 (1H, m, ArH), 7.48–7.42 (1H, m, ArH), 7.43 and 7.39 (2H, AB pattern, J = 8.5 Hz, ArH), 7.06–6.98 (2H, m, ArH), 5.10 (2H, s, OCH₂Ar), 4.08–3.93 (2H, m, OCH₂CH₃), 2.95–2.86 (3H, m, NHCH₂), 1.34 (9H, s, C(CH₃)₃), 1.32–1.20 (2H, m, NHCH₂CH₂), 1.25 (3H, t, J = 7.2 Hz, OCH₂CH₃), 1.16 (2H, sextet, J = 7.2 Hz, NHCH₂CH₂CH₂) and 0.79 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 159.2 (d, J = 2.9 Hz, ArC-O), 151.4 (C), 134.5 (d, J = 6.3 Hz, ArCH), 133.4 (d, J = 1.6 Hz, ArCH), 133.2 (C), 127.3 (2CH), 125.6 (2CH), 120.8 (d, J = 13.6 Hz, ArCH), 119.8 (d, J = 165.5 Hz, ArC-P), 111.8 (d, J = 8.6 Hz, ArCH), 70.3 (OCH₂Ar), 60.3 (d, J = 5.7 Hz, OCH₂CH₃), 40.3 (NHCH₂), 34.6 (CMe₃), 34.1 (d, J = 6.4 Hz, NHCH₂CH₂), 31.3 (C(CH₃)₃), 19.6 (NHCH₂CH₂CH₂), 16.3 (d, J = 6.6 Hz, OCH₂CH₃) and 13.7 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +21.3; HRMS (ESI⁺): found 404.2336. C₂₃H₃₅NO₃P (M + H) requires 404.2355.

2.6.5. Ethyl N-Butyl-P-(2-(2-methoxybenzyloxy)phenyl)phosphonamidate 21d

Using the method of Section 2.6.2 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.60 g, 2.5 mmol), 2-methoxybenzyl bromide (0.50 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave, after purification by column chromatography (SiO₂, hexane/EtOAc 1:1), 21d (0.24 g, 28%) as a pale-yellow oil; ν_max/cm^–1 2957, 2932, 1591, 1441, 1240, 1028, 953, 752, and 571; ¹H NMR (400 MHz): 7.93 (1H, ddd, J = 14.4, 7.6, 2.0 Hz, ArH), 7.51–7.29 (3H, m, ArH), 7.06–6.92 (4H, m, ArH), 5.21 and 5.15 (2H, AB pattern, J = 12.0 Hz, ArOCH₂), 4.06–3.90 (2H, m, OCH₂CH₃), 3.87 (3H, s, OCH₃), 3.15–3.05 (1H, br m, NH), 3.01–2.90 (2H, m, NHCH₂), 1.36–1.29 (2H, m, NHCH₂CH₂), 1.23–1.16 (2H, m, NHCH₂CH₂CH₂), 1.21 (3H, t, J = 7.2 Hz, OCH₂CH₃) and 0.80 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 159.2 (d, J = 2.9 Hz, ArC-O), 156.8 (C), 134.3 (d, J = 6.5 Hz, CH), 133.3 (d, J = 2.1 Hz, CH), 129.3 (CH), 128.8 (CH), 124.4 (C), 120.6 (CH), 120.5 (d, J = 11.2 Hz, CH), 119.6 (d, J = 162.9 Hz, ArC-P), 111.6 (d, J = 8.6 Hz, CH), 110.3 (CH), 65.5 (OCH₂Ar), 60.2 (d, J = 5.6 Hz, OCH₂CH₃), 55.3 (OCH₃), 40.3 (NHCH₂), 34.2 (d, J = 6.8 Hz, NHCH₂CH₂), 19.6 (NHCH₂CH₂CH₂), 16.2 (d, J = 6.8 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +21.5; HRMS (ESI⁺): found 400.1637. C₂₀H₂₈NaNO₄P (M + Na) requires 400.1654.

2.6.6. Ethyl N-Butyl-P-(2-(4-methoxybenzyloxy)phenyl)phosphonamidate 21f

Using the method of Section 2.6.2 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.60 g, 2.5 mmol), 4-methoxybenzyl bromide (0.50 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave, after purification by column chromatography (SiO₂, hexane/EtOAc 1:1), 21f (0.38 g, 44%) as a pale-yellow oil; ν_max/cm^–1 2957, 2932, 2872, 1591, 1514, 1236, 1030, 951, 820, 756, and 567; ¹H NMR (400 MHz): 7.92 (1H, ddd, J = 14.0, 7.2, 1.6 Hz, ArH), 7.48–7.43 (1H, m, ArH), 7.39 (2H, d, J = 8.4 Hz, ArCH), 7.06–6.97 (2H, m, ArH), 6.93 (2H, d, J = 8.4 Hz, ArCH), 5.06 (2H, s, ArOCH₂), 4.06–3.90 (2H, m, OCH₂CH₃), 3.83 (3H, s, OCH₃), 2.95–2.85 (3H, m, NHCH₂), 1.34–1.20 (2H, m, NHCH₂CH₂), 1.25 (3H, t, J = 7.2 Hz, OCH₂CH₃), 1.20–1.10 (2H, m, NHCH₂CH₂CH₂) and 0.79 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 159.6 (C), 159.2 (d, J = 2.9 Hz, ArC-O), 134.4 (d, J = 6.2 Hz, CH), 133.4 (d, J = 2.0 Hz, CH), 129.2 (2CH), 128.2 (C), 120.8 (d, J = 13.2 Hz, CH), 119.7 (d, J = 166.1 Hz, ArC-P), 114.0 (2CH), 111.8 (d, J = 8.5 Hz, CH), 70.2 (OCH₂Ar), 60.3 (d, J = 5.7 Hz, OCH₂CH₃), 55.3 (OCH₃), 40.3 (NHCH₂), 34.0 (d, J = 6.4 Hz, NHCH₂CH₂), 19.6 (NHCH₂CH₂CH₂), 16.3 (d, J = 6.8 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +21.3; HRMS (ESI⁺): found 400.1631. C₂₀H₂₈NaNO₄P (M + Na) requires 400.1654.

2.6.7. Ethyl N-Butyl-P-(2-(2-fluorobenzyloxy)phenyl)phosphonamidate 21g

Using the method of Section 2.6.3 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.64 g, 2.5 mmol), 2-fluorobenzyl iodide (0.59 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave, after purification by column chromatography (SiO₂, hexane/EtOAc 1:1), 21g (0.16 g, 19%) as a pale-yellow oil; ν_max/cm^–1 2949, 2932, 2370, 1620, 1491, 1231, 1105, 1036, 1007, 945, 833, 559 and 509; ¹H NMR (400 MHz): 7.93 (1H, ddd, J = 14.4, 7.6, 1.6 Hz, ArH), 7.57 (1H, td, J = 5.8, 1.7 Hz, ArH), 7.50–7.45 (1H, m, ArH), 7.38–7.33 (1H, m, ArH), 7.19 (1H, td, J = 7.6, 1.2 Hz, ArH), 7.14–7.09 (1H, m, ArH), 7.06 (1H, tdd, J = 7.4, 2.8, 0.9 Hz, ArH), 7.04–7.01 (1H, m, ArH), 5.23 and 5.19 (2H, AB pattern, J = 12.0 Hz, ArOCH₂), 4.06–3.90 (2H, m, OCH₂CH₃), 3.01–2.85 (3H, m, NHCH₂), 1.36–1.29 (2H, m, NHCH₂CH₂), 1.23–1.14 (2H, m, NHCH₂CH₂CH₂), 1.23 (3H, t, J = 7.2 Hz, OCH₂CH₃) and 0.81 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 160.5 (d, J = 245.7 Hz, ArC-F), 158.9 (d, J = 2.9 Hz, ArC-O), 134.6 (d, J = 6.1 Hz, CH), 133.4 (d, J = 2.1 Hz, CH), 130.2 (d, J = 8.0 Hz, CH), 129.9 (d, J = 3.8 Hz, CH), 124.4 (d, J = 3.6 Hz, CH), 123.4 (d, J = 14.2 Hz, C), 121.0 (d, J = 13.2 Hz, CH), 119.9 (d, J = 165.9 Hz, ArC-P), 115.5 (d, J = 21.0 Hz, CH), 111.6 (d, J = 8.5 Hz, CH), 64.2 (d, J = 4.3 Hz, OCH₂Ar), 60.3 (d, J = 5.6 Hz, OCH₂CH₃), 40.4 (NHCH₂), 34.1 (d, J = 6.1 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.3 (d, J = 6.7 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ¹⁹F NMR (376 MHz): –118.5; ³¹P NMR (162 MHz): +21.0; HRMS (ESI⁺): found 388.1437. C₁₉H₂₅FNaNO₃P (M + Na) requires 388.1454.

2.6.8. Ethyl N-Butyl-P-(2-(4-fluorobenzyloxy)phenyl)phosphonamidate 21h

Using the method of Section 2.6.3 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.64 g, 2.5 mmol), 4-fluorobenzyl iodide (0.59 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave, after purification by column chromatography (SiO₂, hexane/EtOAc 1:1), 21h (0.22 g, 26%) as a pale-yellow oil; ν_max/cm^–1 2959, 2930, 2872, 1603, 1512, 1443, 1223, 1157, 1030, 951, 756 and 563; ¹H NMR (400 MHz): 7.92 (1H, ddd, J = 14.4, 7.6, 2.0 Hz, ArH), 7.48–7.44 (3H, m, ArH), 7.10 (2H, t, J = 8.8, Hz, ArH), 7.09–7.04 (1H, m, ArH), 6.97 (1H, dd, J = 8.0, 6.0 Hz, ArH), 5.10 (2H, s, ArOCH₂), 4.07–3.94 (2H, m, OCH₂CH₃), 3.00–2.75 (3H, m, NHCH₂), 1.33–1.23 (2H, m, NHCH₂CH₂), 1.26 (3H, t, J = 7.2 Hz, OCH₂CH₃), 1.22–1.12 (2H, m, NHCH₂CH₂CH₂) and 0.80 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 162.6 (d, J = 245.4 Hz, ArC-F), 159.0 (d, J = 2.9 Hz, ArC-O), 134.4 (d, J = 6.5 Hz, CH), 133.4 (d, J = 2.1 Hz, CH), 132.0 (d, J = 3.5 Hz, C), 129.3 (d, J = 8.1 Hz, 2CH), 121.0 (d, J = 13.4 Hz, CH), 119.9 (d, J = 167.0 Hz, ArC-P), 115.6 (d, J = 21.3 Hz, 2CH), 111.8 (d, J = 8.4 Hz, CH), 69.7 (OCH₂Ar), 60.2 (d, J = 5.7 Hz, OCH₂CH₃), 40.3 (NHCH₂), 34.0 (d, J = 5.9 Hz, NHCH₂CH₂), 19.6 (NHCH₂CH₂CH₂), 16.4 (d, J = 6.9 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ¹⁹F NMR (376 MHz): –113.6; ³¹P NMR (162 MHz): +21.0; HRMS (ESI⁺): found 388.1436. C₁₉H₂₅FNaNO₃P (M + Na) requires 388.1454.

2.6.9. Ethyl N-Butyl-P-(2-(4-chlorobenzyloxy)phenyl)phosphonamidate 21i

Using the method of Section 2.6.2 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.60 g, 2.5 mmol), 4-chlorobenzyl bromide (0.40 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave, after purification by column chromatography (SiO₂, hexane/EtOAc 1:1), 21i (0.67 g, 70%) as colourless crystals, mp 75–77 °C; ν_max/cm^–1 2957, 2932, 2872, 1591, 1443, 1221, 1092, 1030, 955, 760, and 563; ¹H NMR (400 MHz): 7.92 (1H, ddd, J = 14.4, 7.6, 2.0 Hz, ArH), 7.48–7.40 (1H, m, ArH), 7.43 and 7.38 (4H, A₂B₂ pattern, J = 8.8 Hz, ArCH), 7.06 (1H, tdd, J = 7.6, 2.8, 0.8 Hz, ArCH), 6.98–6.94 (1H, m, ArH), 5.11 (2H, s, ArOCH₂), 4.08–3.94 (2H, m, OCH₂CH₃), 2.96–2.78 (3H, m, NHCH₂), 1.34–1.20 (2H, m, NHCH₂CH₂), 1.28 (3H, t, J = 7.2 Hz, OCH₂CH₃), 1.20–1.10 (2H, m, NHCH₂CH₂CH₂) and 0.80 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 158.9 (d, J = 2.9 Hz, ArC-O), 134.7 (C), 134.5 (d, J = 6.4 Hz, CH), 134.1 (C), 133.4 (d, J = 2.0 Hz, CH), 128.9 (2CH), 128.7 (2CH), 121.1 (d, J = 13.6 Hz, CH), 119.9 (d, J = 166.6 Hz, ArC-P), 111.8 (d, J = 8.6 Hz, CH), 69.6 (OCH₂Ar), 60.2 (d, J = 5.6 Hz, OCH₂CH₃), 40.4 (NHCH₂), 34.1 (d, J = 6.2 Hz, NHCH₂CH₂), 19.6 (NHCH₂CH₂CH₂), 16.4 (d, J = 6.9 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +20.9; HRMS (ESI⁺): found 404.1138. C₁₉H₂₅ClNaNO₃P (M + Na) requires 404.1158.

2.6.10. Ethyl P-(2-(4-Bromobenzyloxy)phenyl)-N-butylphosphonamidate 21j

Using the method of Section 2.6.2 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.60 g, 2.5 mmol), 4-methoxybenzyl bromide (0.62 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave 21j (0.86 g, 81%) as colourless crystals, mp 80–82 °C; ν_max/cm^–1 3177, 2953, 2928, 1591,1474, 1445, 1219,1030, 943, 760, 692, and 557; ¹H NMR (400 MHz): 7.92 (1H, ddd, J = 14.0, 7.6, 1.6 Hz, ArH), 7.54 (2H, d, J = 8.4 Hz, ArCH), 7.49–7.43 (1H, m, ArH), 7.37 (2H, d, J = 8.4 Hz, ArCH), 7.06 (1H, tdd, J = 7.6, 2.8, 0.8 Hz, ArCH), 6.98–6.93 (1H, m, ArH), 5.10 (2H, s, ArOCH₂), 4.10–3.95 (2H, m, OCH₂CH₃), 2.95–2.80 (3H, m, NHCH₂), 1.34–1.28 (2H, m, NHCH₂CH₂), 1.28 (3H, t, J = 7.2 Hz, OCH₂CH₃), 1.22–1.12 (2H, m, NHCH₂CH₂CH₂) and 0.80 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 158.9 (d, J = 2.8 Hz, ArC-O), 135.3 (C), 134.5 (d, J = 6.3 Hz, CH), 133.4 (d, J = 1.8 Hz, CH), 131.9 (2CH), 129.0 (2CH), 122.2 (C-Br), 121.1 (d, J = 13.2 Hz, CH), 120.1 (d, J = 166.0 Hz, ArC-P), 111.8 (d, J = 8.6 Hz, CH), 69.7 (OCH₂Ar), 60.3 (d, J = 5.5 Hz, OCH₂CH₃), 40.4 (NHCH₂), 34.1 (d, J = 6.3 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.4 (d, J = 7.0 Hz, OCH₂CH₃) and 13.7 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +20.9; HRMS (ESI⁺): found 426.0814. C₁₉H₂₆⁷⁹BrNO₃P (M + H) requires 426.0834.

2.6.11. Ethyl N-Butyl-P-(2-(1-naphthylmethoxy)phenyl)phosphonamidate 21k

Using the method of Section 2.6.2 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.60 g, 2.5 mmol), 1-bromomethylnaphthalene (0.55 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave 21k (0.81 g, 82%) as a pale-yellow oil; ν_max/cm^–1 3393, 2957, 2930, 2870, 1591, 1472, 1441, 1227, 1084, 1032, 997, 951, 758, and 542; ¹H NMR (400 MHz): 8.13–8.03 (1H, m, ArH), 7.95 (1H, ddd, J = 14.4, 7.6, 2.0 Hz, ArH), 7.94–7.78 (2H, m, ArH), 7.63–7.41 (5H, m, ArH), 7.15 (1H, dd, J = 8.0, 6.0 Hz, ArCH), 7.08 (1H, tdd, J = 7.6, 3.2, 0.8 Hz, ArCH), 5.57 and 5.51 (2H, AB pattern, J = 11.0 Hz, ArOCH₂), 3.85–3.75 (2H, m, OCH₂CH₃), 2.82–2.64 (3H, m, NHCH₂), 1.10–1.00 (2H, m, NHCH₂CH₂), 1.08 (3H, t, J = 7.2 Hz, OCH₂CH₃), 1.00–0.90 (2H, m, NHCH₂CH₂CH₂) and 0.69 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 159.1 (d, J = 2.9 Hz, ArC-O), 134.6 (d, J = 6.5 Hz, CH), 133.8 (C), 133.4 (d, J = 2.1 Hz, CH), 131.5 (C), 131.3 (C), 129.4 (CH), 128.8 (CH), 126.9 (CH), 126.7 (CH), 126.0 (CH), 125.3 (CH), 123.3 (CH), 120.9 (d, J = 13.2 Hz, CH), 120.0 (d, J = 168.0 Hz, ArC-P), 111.4 (d, J = 8.3 Hz, CH), 68.8 (OCH₂Ar), 60.1 (d, J = 5.8 Hz, OCH₂CH₃), 40.2 (NHCH₂), 33.9 (d, J = 5.9 Hz, NHCH₂CH₂), 19.5 (NHCH₂CH₂CH₂), 16.2 (d, J = 6.9 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +20.9; HRMS (ESI⁺): found 420.1688. C₂₃H₂₈NaNO₃P (M + Na) requires 420.1705.

2.6.12. Ethyl N-Butyl-P-(2-(2-naphthylmethoxy)phenyl)phosphonamidate 21l

Using the method of Section 2.6.2 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.60 g, 2.5 mmol), 2-bromomethylnaphthalene (0.55 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave 21l (0.81 g, 82%) as a pale-yellow oil; ν_max/cm^–1 2957, 2930, 2870, 1591, 1441, 1227, 1086, 1030, 951, 813, 756, 565, and 475; ¹H NMR (400 MHz): 7.96 (1H, ddd, J = 15.2, 7.2, 1.6 Hz, ArH), 7.93–7.72 (4H, m, ArH), 7.60–7.44 (4H, m, ArH), 7.08–7.01 (2H, m, ArCH), 5.31 and 5.29 (2H, AB pattern, J = 11.4 Hz, ArOCH₂), 4.10–3.93 (2H, m, OCH₂CH₃), 3.00–2.82 (3H, m, NHCH₂), 1.30–1.20 (2H, m, NHCH₂CH₂), 1.28 (3H, t, J = 7.2 Hz, OCH₂CH₃), 1.12–1.02 (2H, m, NHCH₂CH₂CH₂) and 0.71 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 159.1 (d, J = 2.9 Hz, ArC-O), 134.6 (d, J = 6.5 Hz, CH), 133.8 (C), 133.4 (d, J = 2.1 Hz, CH), 131.5 (C), 131.3 (C), 129.4 (CH), 128.9 (CH), 126.9 (CH), 126.7 (CH), 126.0 (CH), 125.3 (CH), 123.3 (CH), 120.9 (d, J = 13.3 Hz, CH), 120.0 (d, J = 165.7 Hz, ArC-P), 111.4 (d, J = 8.5 Hz, CH), 68.8 (OCH₂Ar), 60.1 (d, J = 5.8 Hz, OCH₂CH₃), 40.2 (NHCH₂), 33.9 (d, J = 5.9 Hz, NHCH₂CH₂), 19.5 (NHCH₂CH₂CH₂), 16.2 (d, J = 6.9 Hz, OCH₂CH₃) and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +21.2; HRMS (ESI⁺): found 420.1686. C₂₃H₂₈NaNO₃P (M + Na) requires 420.1705.

2.6.13. Ethyl N-Butyl-P-(2-(2-thienylmethoxy)phenyl)phosphonamidate 21m

Using the method of Section 2.6.2 with ethyl N-butyl-P-(2-hydroxyphenyl)phosphonamidate 22 (0.60 g, 2.5 mmol), 2-bromomethylthiophene (0.44 g, 2.5 mmol), and K₂CO₃ (1.04 g, 7.5 mmol) in DMF (4 mL) gave 21m (0.88 g, >95%) as a dark-orange oil; ν_max/cm^–1 3401, 2957, 2930, 2872, 1591, 1441, 1232, 1032, 953, 700, 577, and 540; ¹H NMR (400 MHz): 7.94 (1H, ddd, J = 14.0, 7.2, 1.6 Hz, ArH), 7.50–7.45 (1H, m, ArH), 7.36 (1H, dd, J = 4.8, 1.2 Hz, ArCH), 7.14 (1H, dd, J = 3.6, 1.2 Hz, ArCH), 7.07 (1H, tdd, J = 7.6, 3.2, 0.6, ArH), 7.04–6.99 (2H, m, ArCH), 5.31 and 5.28 (2H, AB pattern, J = 11.8 Hz, ArOCH₂), 4.07–3.90 (2H, m, OCH₂CH₃), 3.00–2.85 (3H, m, NHCH₂), 1.35–1.25 (2H, m, NHCH₂CH₂), 1.24 (3H, t, J = 7.2 Hz, OCH₂CH₃), 1.25–1.15 (2H, m, NHCH₂CH₂CH₂) and 0.81 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 158.6 (d, J = 2.9 Hz, ArC-O), 138.2 (C), 134.6 (d, J = 6.4 Hz, CH), 133.3 (d, J = 2.1 Hz, CH), 127.1 (CH), 126.9 (CH), 126.5 (CH), 121.2 (d, J = 13.2 Hz, CH), 120.2 (d, J = 165.4 Hz, ArC-P), 111.7 (d, J = 8.6 Hz, CH), 65.3 (OCH₂Ar), 60.3 (d, J = 5.8 Hz, OCH₂CH₃), 40.4 (NHCH₂), 34.1 (d, J = 6.0 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.3 (d, J = 7.0 Hz, OCH₂CH₃) and 13.7 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +20.8; HRMS (ESI⁺): found 376.1097. C₁₇H₂₄NaNO₃PS (M + Na) requires 376.1112.

2.7. Base Treatment of Substituted Ethyl P-(2-Benzyloxyphenyl)-N-butylphosphonamidates

2.7.1. 3-Butylamino-2-(4-tert-butylphenyl)-2H-benzo[d][1,3]oxaphosphole 3-Oxide 23c

Using the method of Section 2.2.5 with ethyl N-butyl-P-(2-(4-tert-butylbenzyloxy)phenyl)phosphonamidate 21c (100 mg, 0.25 mmol) and n-butyllithium (0.33 mL, 0.83 mmol) in THF (2 mL) at rt for 20 min gave, after purification via preparative TLC (hexane/EtOAc 1:3), 23c (9.5 mg, 11%) as a pale-yellow oil; ¹H NMR (400 MHz): 7.64–7.53 (2H, m, ArH), 7.42–7.40 (2H, m, ArH), 7.36–7.30 (2H, m, ArH), 7.15–7.07 (2H, m, ArH), 5.54 (1H, d, J = 10.0 Hz, CHP), 2.46–2.40 (1H, m, NHCHH), 2.32–2.27 (1H, m, NHCHH), 2.16–2.10 (1H, br m, NH), 1.32 (9H, s, C(CH₃)₃), 1.01–0.85 (4H, m, NHCH₂CH₂CH₂) and 0.69 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (176 MHz): 164.6 (d, J = 23.9 Hz, ArC-O), 151.1 (d, J = 2.5 Hz, C), 135.4 (d, J = 1.7 Hz, CH), 131.5 (C), 129.0 (d, J = 5.1 Hz, CH), 125.6 (2CH), 124.7 (2CH), 122.3 (d, J = 10.2 Hz, CH), 114.3 (d, J = 7.0 Hz, CH), 114.0 (d, J = 122.0 Hz, ArC-P), 79.7 (d, J = 87.8 Hz, CHP), 40.2 (NHCH₂), 34.5 (C(CH₃)₃), 33.5 (d, J = 5.4 Hz, NHCH₂CH₂), 31.2 (C(CH)₃)₃), 19.4 (NHCH₂CH₂CH₂) and 13.4 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +44.6; HRMS (ESI⁺): found 380.1746. C₂₁H₂₈NaNO₂P (M + Na) requires 380.1755.

2.7.2. 3-Butylamino-2-(2-methoxyphenyl)-2H-benzo[d][1,3]oxaphosphole 3-Oxide 23d

Using the method of Section 2.2.5 with ethyl N-butyl-P-(2-(2-methoxybenzyloxy)phenyl)phosphonamidate 21d (100 mg, 0.26 mmol) and n-butyllithium (0.34 mL, 0.86 mmol) in THF (5 mL) at rt for 20 min gave, after purification via preparative TLC (hexane/EtOAc 1:3), 23d (3.1 mg, 4%) as colourless crystals; ¹H NMR (400 MHz): 7.61–7.51 (2H, m, ArH), 7.32–7.22 (2H, m, ArH), 7.14–7.05 (2H, m, ArH), 6.97–6.92 (2H, m, ArH), 5.82 (1H, d, J = 12.4 Hz, CHP), 3.90 (3H, s, OMe), 2.41–2.35 (1H, m, NHCH₂), 2.15–2.08 (1H, br m, NH), 1.08–0.98 (4H, m, NHCH₂CH₂CH₂) and 0.72 (3H, t, J = 6.8 Hz, NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +45.6; HRMS (ESI⁺): found 354.1217. C₁₈H₂₂NaNO₃P (M + Na) requires 354.1235.

2.7.3. 3-Butylamino-2-(3-methoxyphenyl)-2H-benzo[d][1,3]oxaphosphole 3-Oxide 23e

Using the method of Section 2.2.5 with ethyl N-butyl-P-(2-(3-methoxybenzyloxy)phenyl)phosphonamidate 21e (100 mg, 0.26 mmol) and n-butyllithium (0.34 mL, 0.86 mmol) in THF (5 mL) at rt for 20 min gave, after purification via preparative TLC (hexane/EtOAc 1:3), 23c (6.7 mg, 8%) as a pale-yellow oil; ¹H NMR (400 MHz): 7.64–7.51 (2H, m, ArH), 7.31 (1H, t, J = 8.0 Hz, ArH), 7.15–7.10 (2H, m, ArH), 7.00–6.85 (3H, m, ArH), 5.54 (1H, d, J = 10.4 Hz, CHP), 3.82 (3H, s, OMe), 2.53–2.47 (1H, m, NHCHH), 2.35–2.28 (1H, m, NHCHH), 2.15–2.10 (1H, br m, NH), 1.05–0.98 (4H, m, NHCH₂CH₂CH₂) and 0.72 (3H, t, J = 6.8 Hz, NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +44.5; HRMS (ESI⁺): found 354.1221. C₁₈H₂₂NaNO₃P (M + Na) requires 354.1235.

2.7.4. 3-Butylamino-2-(2-fluorophenyl)-2H-benzo[d][1,3]oxaphosphole 3-Oxide 23g

Using the method of Section 2.2.5 with ethyl N-butyl-P-(2-(2-fluorobenzyloxy)phenyl)phosphonamidate 21g (100 mg, 0.27 mmol) and n-butyllithium (0.36 mL, 0.89 mmol) in THF (5 mL) at rt for 20 min gave, after purification via preparative TLC (hexane/EtOAc 1:3), 23c (6.9 mg, 8%) as a pale-yellow oil; ¹H NMR (400 MHz): 7.65–7.52 (2H, m, ArH), 7.35–7.26 (2H, m, ArH), 7.18–7.09 (4H, m, ArH), 5.74 (1H, d, J = 11.6 Hz, CHP), 2.52–2.39 (2H, m, NHCH₂), 2.28–2.20 (1H, br m, NH), 1.10–1.00 (4H, m, NHCH₂CH₂CH₂) and 0.72 (3H, t, J = 6.8 Hz, NHCH₂CH₂CH₂CH₃); ¹⁹F NMR (376 MHz): –114.3; ³¹P NMR (162 MHz): +44.6; HRMS (ESI⁺): found 342.1019. C₁₇H₁₉FNaNO₂P (M + Na) requires 342.1035.

2.7.5. 3-Butylamino-2-(4-fluorophenyl)-2H-benzo[d][1,3]oxaphosphole 3-Oxide 23h

Using the method of Section 2.2.5 with ethyl N-butyl-P-(2-(4-fluorobenzyloxy)phenyl)phosphonamidate 21h (100 mg, 0.27 mmol) and n-butyllithium (0.36 mL, 0.89 mmol) in THF (5 mL) at rt for 20 min gave, after purification via preparative TLC (hexane/EtOAc 1:3), 23c (7.0 mg, 8%) as a pale-yellow oil; ¹H NMR (400 MHz): 7.66–7.54 (2H, m, ArH), 7.41–7.36 (2H, m, ArH), 7.16–7.08 (4H, m, ArH), 5.53 (1H, d, J = 9.6 Hz, CHP), 2.50–2.42 (1H, m, NHCHH), 2.31–2.22 (1H, m, NHCHH), 2.20–2.10 (1H, br m, NH), 1.08–0.98 (4H, m, NHCH₂CH₂CH₂) and 0.72 (3H, t, J = 7.0 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 135.6 (d, J = 1.8 Hz, CH), 129.1 (d, J = 5.5 Hz, CH), 126.7 (dd, J = 8.2, 4.0 Hz, 2CH), 122.6 (d, J = 10.1 Hz, CH), 115.8 (dd, J = 21.7, 2.2 Hz, 2CH), 114.3 (d, J = 6.5 Hz, CH), 79.3 (d, J = 87.9 Hz, CHP), 40.2 (NHCH₂), 33.8 (d, J = 5.2 Hz, NHCH₂CH₂), 19.4 (NHCH₂CH₂CH₂) and 13.5 (NHCH₂CH₂CH₂CH₃) [only non-quaternary signals observed due to small amount of material]; ¹⁹F NMR (376 MHz): –113.9; ³¹P NMR (162 MHz): +44.1; HRMS (ESI⁺): found 342.1018. C₁₇H₁₉FNaNO₂P (M + Na) requires 342.1035.

2.7.6. 3-Butylamino-2-(1-naphthyl)-2H-benzo[d][1,3]oxaphosphole 3-Oxide 23k

Using the method of Section 2.2.5 with ethyl N-butyl-P-(2-(1-naphthylmethoxy)phenyl)phosphonamidate 21k (100 mg, 0.25 mmol) and n-butyllithium (0.33 mL, 0.83 mmol) in THF (2 mL) at rt for 20 min gave, after purification via preparative TLC (hexane/EtOAc 1:3), 23c (6.6 mg, 7%) as a pale-yellow oil; ³¹P NMR (162 MHz): +45.6; HRMS (ESI⁺): found 352.1456. C₂₁H₂₃NO₂P (M + H) requires 352.1456.

2.7.7. 3-Butylamino-2-(2-naphthyl)-2H-benzo[d][1,3]oxaphosphole 3-Oxide 23l

Using the method of Section 2.2.5 with ethyl N-butyl-P-(2-(2-naphthylmethoxy)phenyl)phosphonamidate 21l (100 mg, 0.25 mmol) and n-butyllithium (0.33 mL, 0.83 mmol) in THF (2 mL) at rt for 20 min gave, after purification via preparative TLC (hexane/EtOAc 1:3), 23l (8.1 mg, 9%) as a pale-yellow oil; ¹H NMR (400 MHz): 7.90–7.80 (4H, m, ArH), 7.68–7.46 (5H, m, ArH), 7.19–7.10 (2H, m, ArH), 5.73 (1H, d, J = 10.0 Hz, CHP), 2.46–2.37 (1H, m, NHCHH), 2.28–2.19 (1H, m, NHCHH), 2.18–2.08 (1H, br m, NH), 0.90–0.80 (4H, m, NHCH₂CH₂CH₂) and 0.50 (3H, t, J = 7.0 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (176 MHz): 164.6 (d, J = 23.7 Hz, ArC-O), 135.6 (d, J = 1.2 Hz, CH), 133.3 (d, J = 2.0 Hz, C), 132.10 (C), 132.07 (C), 129.1 (d, J = 5.6 Hz, CH), 128.6 (d, J = 1.9 Hz, CH), 127.82 (CH), 127.80 (CH), 126.6 (CH), 126.2 (CH), 123.7 (d, J = 5.1 Hz, CH), 122.8 (d, J = 2.9 Hz, CH), 122.5 (d, J = 10.2 Hz, CH), 114.4 (d, J = 6.5 Hz, CH), 114.1 (d, J = 121.9 Hz, ArC-P), 80.0 (d, J = 86.7 Hz, CHP), 40.3 (NHCH₂), 33.7 (d, J = 5.2 Hz, NHCH₂CH₂), 19.3 (NHCH₂CH₂CH₂) and 13.3 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +44.5; HRMS (ESI⁺): found 374.1271. C₂₁H₂₂NaNO₂P (M + Na) requires 374.1286.

2.8. X-ray Structure Determination of 23d

The X-ray diffraction data for compound 23d were collected at 173 K using a Rigaku MM-007HF High Brilliance RA generator/confocal optics with an XtaLAB P200 diffractometer [Cu Kα radiation (λ = 1.54187 Å), Tokyo, Japan]. The data were collected and processed (including correction for Lorentz, polarisation, and absorption) using CrysAlisPro [19]. The structures were solved by dual-space methods (SHELXT) [20] and refined by full-matrix least squares against F² (SHELXL-2019/3) [21]. Non-hydrogen atoms were refined anisotropically, and hydrogen atoms were refined using a riding model, except for the hydrogen atoms on N3 and N23 which were located using the difference Fourier map and refined isotropically, subject to a distance restraint. All the calculations were performed using the Olex2 interface [22].

Crystal data for C₁₈H₂₂NO₃P: M = 331.33 g mol⁻¹, colourless prism, crystal dimensions 0.06 × 0.06 × 0.04 mm, monoclinic, space group P2₁/c (No. 14), a = 11.01041(14), b = 16.9371(2), c = 18.6444(2) Å, β = 100.5651(12)°, V = 3417.95(7) ų, Z = 8, D_calc = 1.288 g cm⁻³, T = 173 K, R₁ = 0.0409 wR₂ = 0.1143 for 6052 reflections with I > 2σ(I) and 494 variables, R_int 0.0451, and goodness of fit on F² 1.076. The data were deposited at the Cambridge Crystallographic Data Centre as CCDC 2299148. The data can be obtained free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/getstructures (accessed on 16 October 2023).

3. Results and Discussion

Starting from 2-bromophenol, the known benzyl ether 13 was prepared in excellent yield (Scheme 3). To prepare 14 the phosphonate functionality was installed by the nickel-catalysed Michaelis–Arbuzov-type reaction, with triethyl phosphite introduced by Tavs [15]. We found that to obtain a good yield of product 14, it was essential to use anhydrous nickel(II) chloride. The diethyl phosphonate 14 was treated with phosphorus pentachloride in toluene to afford 15, which reacted directly with two equivalents of butylamine, giving phosphonamidate 16. As previously observed in the para and meta series [9], the reaction sequence was accompanied by distinctive changes in the ³¹P NMR shift: from +17.1 ppm for 14 to +26.5 ppm for 15 to +21.3 ppm for 16. Compound 16 showed an interesting and highly informative pattern of phosphorus couplings in the ¹³C NMR spectrum (Figure 1), with coupling observed to all carbons of the phosphorus-bearing benzene ring and both carbons of the O-ethyl group, but only to C-2 of the N-butyl group.

When a solution of compound 16 in dry THF was treated with 3.3 equiv. of n-butyllithium at RT, there was a rapid reaction to afford, after aqueous work-up and chromatographic purification, a new product identified as the 1,3-benzoxaphosphole 17. The ³¹P NMR shift had moved dramatically from +21.3 to +44.6 ppm and both the ¹H and the ¹³C NMR spectra showed the absence of the OEt group. Most significantly, the signals for the benzylic CH₂ group of 16 had been replaced in the proton NMR spectrum by a 1H doublet at 5.57 ppm (²J_H–P 9.9 Hz), which collapsed to a singlet upon ³¹P decoupling, and a corresponding carbon signal at 79.7 ppm (¹J_C–P 87.4 Hz), which was consistent with P–CH(Ph)–O. The pattern of phosphorus coupling throughout the structure (Figure 1) showed interesting differences from that of 16, with a drop in the value at ArC–P from J = 167.0 to 122.8 Hz and a corresponding increase in the value at the oxygen-bearing benzene ring position from 2.8 to 24.0 Hz. It was also clear from the spectra that the product had been formed as a single diastereomer with complete control of the relative configuration of the two adjacent newly formed stereocentres. It was not possible to determine which isomer had been formed at this stage since the material was obtained as an oil. This aspect is addressed below for a crystalline analogue.

As far as we are aware, this method, in which there is cyclisation with formation of the C(2)–P bond, represents a new synthetic approach to the dihydrobenzo[d][1,3]oxaphosphole ring system. As noted in a recent review [23], previous approaches involved either cyclisation with the formation of the C(2)–O bond [10,11,12,13] or the introduction of a C-1 unit to an ortho-hydroxyarylphosphine (Figure 2).

We now wished to explore the scope of the process for substituted benzyl groups and prepared a range of ethers 18 from 2-bromophenol (Scheme 4). Where the relevant benzylic bromide was available, this was used directly, but the benzylic chlorides were first activated towards substitution by Finkelstein conversion into the corresponding benzyl iodide (examples b, g and h). It should be noted that the isomeric fluorobenzyl iodides are severely lachrymatory and care is required in handling them. The resulting products 18, all previously unknown, gave the expected spectroscopic and analytical data.

When we attempted to introduce the diethyl phosphonate group in these substituted examples using the previously described nickel catalysed reaction with triethyl phosphite, it quickly became apparent that the reaction was unreliable. In some cases, it worked well and gave the products in reasonable yield, but in most cases, it failed. Three new phosphonates were obtained by this method (Scheme 5) and gave analytical and spectroscopic data that were consistent with 14.

As compound 19e was available in the greatest quantity, it was subjected to reaction with phosphorus pentachloride to give the phosphonochloridate 20, followed by treatment with n-butylamine to give the first substituted phosphonamidate 21e in satisfactory overall yield (Scheme 6).

However, it was clear that this approach to accessing a wider range of substituted phosphonamidates was unsatisfactory. Instead, we were able to remove the O-benzyl group from 16 in excellent yield using catalytic hydrogenation to give the hydroxyphenylphosphonamidate 22. This was then O-alkylated to give a range of derivatives, 21a–d and f–m, in varying yields (Scheme 7).

All the phosphonamidates in this paper show ³¹P signals in the narrow range of δ_P +20.8–21.5, and the expected phosphorus coupling is observed in the ¹³C NMR spectra for all the signals of the phosphorus-bearing benzene ring and both carbons of OEt but, interestingly, only C–2 of NHBu. The magnitude of the values was consistent with that shown for 16 in Figure 1. In the substituted examples, the benzylic CH₂ protons were magnetically non-equivalent only in the more sterically hindered examples, leading to the observation of an AB pattern in the ¹H NMR spectra for 21a, d, g, k, l, and m.

When compounds 21a–m were subjected to treatment with butyllithium under the same conditions as for 16, a varying pattern of reactivity was observed. In each case, a complex mixture of products was obtained, but by using preparative TLC, the cyclised products 23 could be obtained in seven cases (Scheme 8). The final isolated yields were low in all cases, but the spectroscopic data were in good agreement with those already established for 17. The main competing reaction seemed to be O-debenzylation to regenerate compound 22, which was observed in all cases. The reaction was complete within 20 min, and leaving it for longer resulted in reduced yields of 23. The failure of the cyclisation for 21i and 21j was not surprising as the lithium–halogen exchange was expected to occur. Significantly, each benzophosphole product was obtained as a single diastereomer with consistent values of ²J_H–P 9.6–12.4 Hz for the 2-CH signal observed at 5.53–5.82 ppm in the ¹H NMR spectra and ¹J_C–P 86.7–87.9 Hz for the corresponding 2-C signal observed at 79.3–80.0 ppm in the ¹³C NMR spectra. The two N–CH₂ protons were also magnetically non-equivalent in each case, leading to two separate multiplets in the ¹H NMR spectrum in each case.

In the case of the ortho-methoxyphenyl compound 23d, crystals suitable for X-ray diffraction were obtained, and the resulting structure (Figure 3) showed two independent but closely similar molecules linked in an R²₂(8) [24] dimer by N–H···O=P hydrogen bonding. Not unexpectedly, there was significant disorder within the flexible N-butyl groups.

The structure clearly shows a cis arrangement of the 2-CH and P=O groups with the 2-aryl group cis to the NHBu, as depicted in Scheme 8. Based on the consistency of the NMR data, we assume all the cyclic products 17 and 23 obtained have this relative configuration. The hydrogen bonding parameters (

Table 1. Hydrogen bonding parameters for 23d (Å, °).

D—H···A	D—H	H···A	D···A	D—H···A
N(3)–H(3)···O(23)	0.922(14)	1.984(15)	2.9006(16)	172.4(18)
N(23)–H(23)···O(3)	0.935(15)	2.007(15)	2.9392(16)	174.3(19)

) fall within normal ranges.

A mechanistic explanation for the high stereoselectivity of the ring closure process is complicated by the fact that such substitutions at phosphorus are well known to involve a trigonal bipyramidal intermediate with the associated possibility of pseudo-rotation. Despite this complication, such substitutions usually proceed with net inversion of the configuration at P. With this in mind, we suggest that the ring closure of carbanion 24 in preference to the isomer 24’ is favoured on steric grounds, with the aryl group preferring to be cis to OEt rather than N(Li)Bu. Loss of ethoxide from the resulting intermediate 25 is then expected to afford the product with the observed relative configuration (Scheme 9).

In conclusion, when the phosphonamidate group EtO-P(=O)-NHBu, which is effective in promoting the Wittig rearrangement of meta- or para-disposed aryl benzyl ethers, is placed in the ortho-position, a quite different process is observed upon treatment with butyllithium, resulting in cyclisation with the loss of ethanol to give access to the novel 2-aryl-3-butylamino-2H-benzo[d][1,3]oxaphosphole 3-oxides in moderate to low yield. These are all formed as a single diastereomer, which was shown to have the cis arrangement of aryl and NH-butyl groups by an X-ray structure determination in one case.