Synthesis and Wittig Rearrangement of 3- and 4-Benzyloxyphenylphosphonamidates

Abstract

A series of seven O-ethyl-N-butylphenylphosphonamidates with benzyl ether substituents at the para or meta position have been prepared and fully characterised. Upon treatment with n-butyllithium in THF at RT, these undergo Wittig rearrangement in six cases to give the novel phosphonamidate-substituted diarylmethanols in moderate to good yield.

1. Introduction

The [1,2]-Wittig rearrangement of aryl benzyl ethers 1 to give diarylmethanols 2 (Scheme 1) provides a potentially valuable indirect method for C–C bond formation but, although the reaction is well known [1,2], it has not found much recent synthetic use [3], perhaps owing to the strongly basic conditions required which make it incompatible with many common functional groups. In recent studies, we have described the use of activating groups on the aryl ring to promote the Wittig rearrangement under milder conditions. The first such activating group to be discovered was the 4,4-dimethyl-2-oxazoline [4], although when this was in the ortho position to the benzyloxy group as in 3, there was significant competition from direct cyclisation to give benzofuran products 4, a phenomenon also later observed in benzyloxythienyloxazolines [5]. In the meantime, we developed the N-butylcarboxamide, CONHBu as a more effective and general activating group, facilitating Wittig rearrangement of ortho-, meta-, or para-disposed benzylic ethers 5 to give diarylmethanols 6 [6]. Limited success in using a chiral secondary amide group to direct asymmetric Wittig rearrangement was also reported [7].

In this paper, we describe the synthesis of aryl benzyl ethers bearing the phosphonamidate group, EtO-P(=O)-NHBu on the aryl ring, either para- or meta- to a benzylic ether, and their successful Wittig rearrangement to afford the corresponding phosphonamidate-functionalised diarylmethanols.

2. Materials and Methods

2.1. General Experimental Details

NMR spectra were recorded on solutions in CDCl₃ unless otherwise stated using Bruker instruments and chemical shifts are given in ppm to high frequency from Me₄Si with coupling constants J in Hz. 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 silica gel of 40–63 μm particle size and preparative TLC was carried out using 1.0 mm layers of Merck alumina 60 G containing 0.5% Woelm fluorescent green indicator on glass plates. Melting points were recorded on a Gallenkamp 50 W melting point apparatus or a Reichert hot-stage microscope.

2.2. 1-(Benzyloxy)-4-bromobenzene 7

To a stirred solution of 4-bromophenol (10.00 g, 58.2 mmol) in MeCN (50 mL) at rt, K₂CO₃ (10.94 g, 79.2 mmol) and benzyl bromide (6.9 mL, 9.94 g, 58.2 mmol) was added and the mixture was stirred at rt overnight. The reaction was diluted with H₂O (150 mL), the layers separated, and the aqueous layer extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over MgSO₄ and concentrated to give 7 (15.61 g, quant) as a colourless solid which was used without further purification; mp 58−60 °C; (lit. [8] 60−61 °C); ¹H NMR (400 MHz): 7.43−7.31 (7H, m, ArH), 6.85 (2H, d, J = 9.0 Hz, ArH), and 5.03 (2H, s, OCH₂); ¹³C NMR (100 MHz): 158.0 (C-O), 136.6 (C-Br), 132.4 (2CH), 128.8 (2CH), 128.2 (CH), 127.6 (2CH), 116.8 (2CH), 113.2 (C), and 70.3 (OCH₂). The ¹H and ¹³C spectral data were in accordance with that previously reported [9].

2.3. Synthesis and Rearrangement of Ethyl P-(4-Benzyloxyphenyl)-N-butylphosphonamidate 10

2.3.1. Diethyl (4-Benzyloxyphenyl)phosphonate 8

Following a modified literature procedure [10], 1-(benzyloxy)-4-bromobenzene 7 (14.00 g, 53.2 mmol) and anhydrous NiCl₂ (689 mg, 5.32 mmol) were placed in a flask set up for distillation. Then, a dropping funnel containing triethyl phosphite (11.0 mL, 63.8 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 had been added. The mixture was then heated for a further 30 min and cooled to rt. The mixture was taken up in CH₂Cl₂ (100 mL) which was washed with dil. HCl (50 mL), dried, and evaporated to give, after purification via flash column chromatography (gradient elution hexane/EtOAc 9:1 to 100% ethyl acetate), 8 (13.83 g, 81%) as a slightly yellow oil; ¹H NMR (400 MHz): 7.75 (2H, dd, J_HP = 12.8, J_HH = 8.8 Hz, ArH), 7.45−7.37 (4H, m, ArH), 7.37−7.30 (1H, m, ArH), 7.04 (2H, dd, J_HH = 8.8, J_HP = 3.3 Hz, ArH), 5.11 (2H, s, OCH₂Ph), 4.17−4.01 (4H, m, 2 x OCH₂CH₃), and 1.31 (6H, dt, J_HH = 7.1, J_HP = 0.5 Hz, 2 x OCH₂CH₃); ¹³C NMR (100 MHz): 161.8 (d, J_CP = 3.5 Hz, C-O), 136.1 (C), 133.6 (d, J_CP = 11.3 Hz, 2CH), 128.5 (2CH), 128.1 (CH), 127.3 (2CH), 119.7 (d, J_CP = 194.7 Hz, C-P), 114.7 (d, J_CP = 16.0 Hz, 2CH), 69.9 (OCH₂Ph), 61.8 (d, J_CP = 5.3 Hz, 2 OCH₂CH₃), and 16.2 (d, J_CP = 6.5 Hz, 2 OCH₂CH₃); ³¹P NMR (162 MHz): +19.6. The ¹H and ¹³C spectral data were in accordance with that previously reported [11]. The ³¹P spectral data are reported for the first time.

2.3.2. Ethyl (4-Benzyloxyphenyl)phosphonochloridate 9

A solution of diethyl (4-benzyloxyphenyl)phosphonate 8 (0.50 g, 1.56 mmol) in dry toluene (10 mL) was stirred at 0 °C while PCl₅ (0.65 g, 3.12 mmol) was added. The mixture was then stirred at rt for 30 min, filtered, and evaporated to give 9 (0.42 g, 87%) as a pale-yellow oil which was used without further purification; ¹H NMR (400 MHz): 7.82 (2H, dd, J_HP = 14.7, J_HH = 8.9 Hz, ArH), 7.42−7.31 (5H, m, ArH), 7.06 (2H, dd, J_HH = 8.9, J_HP = 4.2 Hz, ArH), 5.13 (2H, s, OCH₂Ph), 4.48−4.30 (2H, m, OCH₂CH₃), and 1.45 (3H, t, J = 7.1 Hz, OCH₂CH₃); ¹³C NMR (100 MHz): 162.8 (d, J_CP = 3.7 Hz, ArC-O), 135.8 (C), 133.2 (d, J_CP = 13.5 Hz, 2CH), 128.7 (2CH), 128.3 (CH), 127.4 (2CH), 122.0 (d, J_CP = 188.6 Hz, C-P), 115.0 (d, J_CP = 18.2 Hz, 2CH), 70.1 (OCH₂Ph), 63.7 (d, J_CP = 7.6 Hz, OCH₂CH₃), and 16.0 (d, J_CP = 7.4 Hz, OCH₂CH₃); ³¹P NMR (162 MHz): +29.8.

2.3.3. Ethyl P-(4-Benzyloxyphenyl)-N-butylphosphonamidate 10

Following a literature procedure [12], a solution of n-butylamine (0.14 mL, 0.10 g, 1.41 mmol) in Et₂O (5 mL) was stirred at 0 °C while a solution of ethyl (4-benzyloxyphenyl)phosphonochloridate 9 (0.20 g, 0.64 mmol) in Et₂O (5 mL) was added dropwise. The mixture was allowed to warm to rt and stirred for 18 h. Water (10 mL) was added and the layers separated. The aqueous layer was extracted with Et₂O (2 × 5 mL) and the combined organic layers were dried and evaporated to give 10 (160 mg, 72%) as a slightly yellow oil which was used without further purification; ν_max/cm⁻¹ 3177, 2957, 2932, 2872, 1597, 1501, 1454, 1383, 1288, 1248, 1206, 1125, 1038, 1011, 957, 752, 700, 592, and 532; ¹H NMR (400 MHz): 7.73 (2H, dd, J_HP = 12.4, J_HH = 8.8 Hz, ArH), 7.44−7.35 (4H, m, ArH), 7.35−7.28 (1H, m, ArH), 7.02 (2H, dd, J_HH = 8.8, J_HP = 3.0 Hz, ArH), 5.09 (2H, s, OCH₂Ph), 4.07 (2H, app quintet, J = 7.2 Hz, OCH₂CH₃), 2.87−2.81 (2H, m, NHCH₂), 1.46−1.39 (2H, m, NHCH₂CH₂), 1.35−1.27 (5H, m, NCH₂CH₂CH₂ and OCH₂CH₃), and 0.86 (3H, t, J = 7.3 Hz, NCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 161.3 (d, J_CP = 3.2 Hz, C-O), 136.2 (C), 133.3 (d, J_CP = 11.1 Hz, 2CH), 128.5 (2CH), 128.0 (CH), 127.3 (2CH), 122.5 (d, J_CP = 179.0 Hz, C-P), 114.5 (d, J_CP = 15.1 Hz, 2CH), 69.8 (OCH₂Ph), 60.1 (d, J_CP = 5.5 Hz, OCH₂CH₃), 40.5 (NHCH₂), 33.7 (d, J_CP = 6.3 Hz, NCH₂CH₂), 19.6 (NCH₂CH₂CH₂), 16.3 (d, J_CP = 6.7 Hz, OCH₂CH₃), and 13.6 (NCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +23.4; HRMS (ESI⁺): found 348.1714. C₁₉H₂₇NO₃P (M + H) requires 348.1729.

2.3.4. Ethyl N-Butyl-P-((4-hydroxy(phenyl)methyl)phenyl)phosphonamidate 11

A solution of ethyl P-(4-benzyloxyphenyl)-N-butylphosphonamidate 10 (173.6 mg, 0.5 mmol) in dry THF (5 mL) was stirred at rt under N₂ while n-butyllithium (0.91 mL, 1.65 mmol) was added by syringe. After 10 min, the mixture was added to saturated aqueous ammonium chloride (5 mL) and the mixture was extracted with Et₂O (3 × 5 mL). Drying and evaporation of the combined extracts gave, after purification via preparative TLC (EtOAc) at R_f 0.19, 11 (122.5 mg, 71%) as a pale-yellow oil; ν_max/cm⁻¹ 3250, 2957, 2930, 2871, 1601, 1452, 1396, 1192, 1125, 1032, 957, 700, 625, and 561; ¹H NMR (400 MHz): 7.69 (2H, dd, J_HP = 12.7, J_HH = 8.2 Hz, ArH), 7.45 (2H, dd, J_HH = 8.2, J_HP = 3.6 Hz, ArH), 7.37−7.24 (5H, m, ArH), 5.85 (1H, s, CHOH), 4.06 (2H, app quintet, J = 7.2 Hz, OCH₂), 2.90−2.77 (2H, m, NHCH₂), 1.43−1.35 (2H, m, NHCH₂CH₂), 1.33−1.24 (5H, m, OCH₂CH₃ and NHCH₂CH₂CH₂), and 0.84 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 147.9 (d, J_CP = 2.9 Hz, C-CHOH), 143.6 (C), 131.5 (d, J_CP = 10.0 Hz, 2CH), 129.6 (d, J_CP = 174.6 Hz, ArC-P), 128.5 (2CH), 127.7 (CH), 126.7 (2CH), 126.4 (d, J_CP = 14.4 Hz, 2CH), 75.7 (CHOH), 60.4 (d, J_CP = 5.6 Hz, OCH₂), 40.6 (NHCH₂), 33.8 (d, J_CP = 6.2 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.4 (d, J_CP = 6.8 Hz, OCH₂CH₃), and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +22.8; HRMS (ESI⁺): found 348.1714. C₁₉H₂₇NO₃P (M + H) requires 348.1729.

2.4. Ethyl N-Butyl-P-(4-hydroxyphenyl)phosphonamidate 12

Following a literature procedure [13], to a solution of ethyl P-(4-benzyloxyphenyl)-N-butylphosphonamidate 10 (1.18 g, 3.4 mmol) in MeOH (20 mL) at rt was added 10% Pd/C (0.17 g) and the solution stirred under an H₂ atmosphere for 2 h. The reaction mixture was filtered through celite, and the filtrate concentrated to give 12 (0.86 g, 98%) as a slightly-yellow, viscous oil which was used without further purification; ν_max/cm⁻¹ 3098, 2957, 2932, 2872, 1603, 1584, 1508, 1439, 1285, 1186, 1169, 1125, 1028, 955, 835, and 530; ¹H NMR (400 MHz): 7.59 (2H, dd, J_HP = 12.6, J_HH = 8.3 Hz, ArH), 6.94 (2H, dd, J_HH = 8.3, J_HP = 3.2 Hz, ArH), 4.10−4.02 (2H, m, OCH₂), 2.90−2.80 (2H, m, NHCH₂), 1.46−1.38 (2H, m, NHCH₂CH₂), 1.34−1.27 (5H, m, OCH₂CH₃ and NHCH₂CH₂CH₂), and 0.85 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 161.3 (d, J_CP = 3.1 Hz, CH), 133.3 (d, J_CP = 11.4 Hz, 2CH), 118.9 (d, J_CP = 181.6 Hz, C-P), 115.8 (d, J_CP = 15.5 Hz, 2CH), 60.7 (d, J_CP = 5.6 Hz, OCH₂), 40.5 (NHCH₂), 33.8 (d, J_CP = 6.2 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.3 (d, J_CP = 6.8 Hz, OCH₂CH₃), and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (202 MHz): +25.6; HRMS (ESI⁺): found 258.1248. C₁₂H₂₁NO₃P (M + H) requires 258.1259.

2.5. Synthesis and Rearrangement of Substituted Ethyl P-(4-Benzyloxy)phenyl)-N-butylphosphonamidates 13

2.5.1. Ethyl N-Butyl-P-(4-(4-tert-butylbenzyloxy)phenyl)phosphonamidate 13a

A solution of ethyl N-butyl-P-(4-hydroxyphenyl)phosphonamidate 12 (0.51 g, 2.0 mmol), 4-(tert-butyl)benzyl bromide [14] (0.45 g, 2.0 mmol), and K₂CO₃ (0.83 g, 6.0 mmol) in DMF (10 mL) was stirred at rt for 18 h. The mixture was added to water (50 mL) and extracted with CH₂Cl₂ (20 cm²) followed by Et₂O (3 × 20 mL). The combined organic layers were then washed with water (3 × 25 mL), brine (3 × 25 mL), dried, and evaporated. Purification of the residue via flash column chromatography (gradient elution hexane/EtOAc 1:1 to 100% EtOAc) gave 13a (140 mg, 17%) as a colourless oil; ν_max/cm⁻¹ 2959, 2932, 2870, 1597, 1503, 1207, 1126, 1034, 951, 827, 820, 729, and 546; ¹H NMR (400 MHz): 7.73 (2H, dd, J_HP = 12.2, J_HH = 8.8 Hz, ArH), 7.42 (2H, d, J = 8.4 Hz, ArH), 7.36 (2H, d, J = 8.4 Hz, ArH), 7.02 (2H, dd, J_HH = 8.8, J_HP = 3.0 Hz, ArH), 5.05 (2H, s, OCH₂Ph), 4.08 (2H, app quintet, J = 7.1 Hz, OCH₂CH₃), 2.84 (2H, dtd, J = 8.9, 7.0, 1.8 Hz, NHCH₂), 1.46−1.39 (2H, m, NHCH₂CH₂), 1.33 (9H, s, C(CH₃)₃), 1.31−1.24 (2H, m, NHCH₂CH₂CH₂), and 0.86 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 161.4 (d, J = 3.2 Hz, C-O), 151.1 (C), 133.2 (d, J = 11.0 Hz, 2CH), 133.1 (C), 127.3 (2CH), 125.4 (2CH), 122.4 (d, J = 179.0 Hz, C-P), 114.5 (d, J = 15.1 Hz, 2CH), 69.7 (OCH₂Ph), 60.1 (d, J = 5.5 Hz, OCH₂CH₃), 40.5 (NHCH₂), 34.5 (C), 33.8 (d, J = 6.3 Hz, NHCH₂CH₂), 31.2 (C(CH₃)₃), 19.7 (NHCH₂CH₂CH₂), 16.3 (d, J = 6.7 Hz, OCH₂CH₃), and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +23.5; HRMS (ESI⁺): found 404.2335. C₂₃H₃₅NO₃P (M + H) requires 404.2355.

2.5.2. Ethyl N-Butyl-P-(4-(4-methoxybenzyloxy)phenyl)phosphonamidate 13b

The same procedure as in 2.5.1 using ethyl N-butyl-P-(4-hydroxyphenyl)phosphonamidate 12 (0.51 g, 2.0 mmol), 4-methoxybenzyl bromide (0.40 g, 2.0 mmol), and K₂CO₃ (0.83 g, 6.0 mmol) in DMF (10 mL) followed by purification of the product via flash column chromatography (EtOAc) gave 13b (110 mg, 15%) as a colourless solid, mp 124−126 °C; ν_max/cm⁻¹ 3215, 2957, 2936, 2866, 1612, 1597, 1516, 1389, 1253, 1213, 1036, 1024, 1001, 953, 893, 814, 783, 575, 548, 532, and 525; ¹H NMR (400 MHz): 7.73 (2H, dd, J_HP = 12.4, J_HH = 8.6 Hz, ArH), 7.35 (2H, d, J = 8.7 Hz, ArH), 7.01 (2H, dd, J_HH = 8.6, J_HP = 2.9 Hz, ArH), 6.91 (2H, d, J = 8.7 Hz, ArH), 5.01 (2H, s, OCH₂Ph), 4.07 (2H, app quintet, J = 7.2 Hz, OCH₂CH₃), 3.81 (3H, s, OCH₃), 2.87−2.81 (2H, m, NHCH₂), 1.47−1.38 (2H, m, NHCH₂CH₂), 1.36−1.24 (5 H, m, OCH₂CH₃ and NHCH₂CH₂CH₂), and 0.86 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (125 MHz): 161.4 (d, J_CP = 3.0 Hz, C-O), 159.5 (C-OCH₃), 133.3 (d, J_CP = 11.0 Hz, 2CH), 129.2 (2CH), 128.2 (C), 122.4 (d, J_CP = 178.8 Hz, C-P), 114.6 (d, J_CP = 15.1 Hz, 2CH), 113.9 (2CH), 69.6 (OCH₂Ph), 60.2 (d, J_CP = 5.4 Hz, OCH₂CH₃), 55.2 (OCH₃), 40.5 (NHCH₂), 33.8 (d, J_CP = 6.3 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.3 (d, J_CP = 6.7 Hz, OCH₂CH₃), and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +23.5; HRMS (ESI⁺) found 378.1815. C₂₀H₂₉NO₄P (M + H) requires 378.1834.

2.5.3. Ethyl N-Butyl-P-(4-(4-fluorobenzyloxy)phenyl)phosphonamidate 13c

A solution of NaI (0.33 g, 2.2 mmol) in acetone (5 mL) was added to 4-fluorobenzyl chloride (0.26 mL, 0.32 g, 2.2 mmol) in acetone (5 mL) and the mixture was stirred until no further precipitation of NaCl was observed. The solution was then filtered, and the filtrate evaporated to give 4-fluorobenzyl iodide. This was then reacted as in 2.5.1 with ethyl N-butyl-P-(4-hydroxyphenyl)phosphonamidate 12 (0.51 g, 2.0 mmol), and K₂CO₃ (0.83 g, 6.0 mmol) in DMF (10 mL) to give 13c (110 mg, 15%) as a colourless solid which was used without further purification; mp 72−74 °C; ν_max/cm⁻¹ 3200, 2957, 2930, 2872, 1599, 1512, 1225, 1209, 1126, 1034, 1009, 951, 824, 565, 538, and 525; ¹H NMR (400 MHz): 7.74 (2H, dd, J_HP = 12.4, J_HH = 8.8 Hz, ArH), 7.41 (2H, dd, J_HH = 8.6, J_HF = 5.6 Hz, ArH), 7.08 (2H, t, J = 8.6 Hz, ArH), 7.01 (2H, dd, J_HH = 8.8, J_HP = 2.9 Hz, ArH), 5.06 (2H, s, OCH₂Ph); 4.08 (2H, app quintet, J = 7.2 Hz, OCH₂CH₃), 2.88−2.80 (2 H, m, NHCH₂), 1.47−1.38 (2H, m, NHCH₂CH₂), 1.36−1.26 (5H, m, OCH₂CH₃ and NHCH₂CH₂CH₂), and 0.86 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 162.5 (d, J_CF = 252.2 Hz, C-F), 161.2 (d, J_CP = 8.7 Hz, C-O), 133.4 (d, J_CP = 11.0 Hz, 2CH), 132.2 (d, J_CF = 3.1 Hz, C), 129.3 (d, J_CF = 8.2 Hz, 2CH), 122.7 (d, J_CP = 178.8 Hz, C-P), 115.5 (d, J_CF = 21.6 Hz, 2CH), 114.6 (d, J_CP = 15.1 Hz, 2CH), 69.2 (OCH₂Ph), 60.3 (d, J_CP = 5.4 Hz, OCH₂CH₃), 40.5 (NHCH₂), 33.8 (d, J_CP = 6.3 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.4 (d, J_CP = 6.7 Hz, OCH₂CH₃), and 13.6 (NHCH₂CH₂CH₂CH₃); ¹⁹F NMR (376 MHz): −113.8; ³¹P NMR (162 MHz): +23.2; HRMS (ESI⁺): found 366.1624. C₁₉H₂₆FNO₃P (M + H) requires 366.1634.

2.5.4. Ethyl N-Butyl-P-(4-(1-phenylethoxy)phenyl)phosphonamidate 13d

The same procedure as in 2.5.1 using ethyl N-butyl-P-(4-hydroxyphenyl)phosphonamidate 12 (0.51 g, 2.0 mmol), (1-bromoethyl)benzene (0.27 mL, 0.37 g, 2.0 mmol), and K₂CO₃ (0.83 g, 6.0 mmol) in DMF (10 mL) gave, after purification via flash column chromatography (hexane/EtOAc 1:1) at R_f 0.21, 13d (150 mg, 13%) as a colourless oil; ν_max/cm⁻¹ 2959, 2932, 2872, 1597, 1501, 1450, 1288, 1246, 1206, 1126, 1028, 953, 760, 700, 571, and 542; ¹H NMR (400 MHz): 7.62 (2H, dd, J_HP = 12.3, J_HH = 8.8 Hz, ArH), 7.36−7.28 (4H, m, ArH), 7.28−7.24 (1H, m, ArH), 6.89 (2H, dd, J_HH = 8.8, J_HP = 3.1 Hz, ArH), 5.36 (1H, q, J = 6.4 Hz, OCH(Ph)CH₃), 4.07−4.00 (2H, m, OCH₂), 2.84−2.76 (2H, m, NHCH₂), 2.69 (1H, br s, NH), 1.65 (3H, d, J = 6.4 Hz, OCH(Ph)CH₃), 1.41−1.34 (2H, m, NHCH₂CH₂), 1.32−1.26 (5H, m, OCH₂CH₃ and NHCH₂CH₂CH₂), and 0.84 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (125 MHz): 160.7 (d, J_CP = 3.0 Hz, C-O), 142.4 (C), 133.1 (d, J_CP = 11.0 Hz, 2CH), 128.6 (2CH), 127.6 (CH), 125.4 (2CH), 121.9 (d, J_CP = 179.4 Hz, C-P), 115.5 (d, J_CP = 15.1 Hz, 2CH), 75.9 (OCH(Ph)CH₃), 60.2 (d, J_CP = 5.4 Hz, OCH₂), 40.5 (NHCH₂), 33.8 (d, J_CP = 6.2 Hz, NHCH₂CH₂), 24.4 (OCH(Ph)CH₃), 19.7 (NHCH₂CH₂CH₂), 16.3 (d, J_CP = 6.8 Hz, OCH₂CH₃), and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +23.5; HRMS (ESI⁺): found 362.1873. C₂₀H₂₉NO₃P (M + H) requires 362.1885.

2.5.5. Ethyl N-Butyl-P-(4-(3-methylbut-2-en-1-yloxy)phenyl)phosphonamidate 13e

The same procedure as in 2.5.1 using N-butyl-P-(4-hydroxyphenyl)phosphonamidate 12 (0.51 g, 2.0 mmol), 3-methylbut-2-en-1-yl bromide (0.30 g, 2.0 mmol), and K₂CO₃ (0.30 g, 6.0 mmol) in DMF (10 mL) but with reaction at 100 °C for 6 h gave, after purification via flash column chromatography (gradient elution hexane/EtOAc 7:3 to 100% EtOAc), 13e (80 mg, 12%) as a yellow oil; ν_max/cm⁻¹ 2957, 2930, 2872, 1599, 1503, 1292, 1204, 1126, 1034, 951, 829, 804, 569, and 534; ¹H NMR (500 MHz): 7.71 (2H, dd, J_HP = 12.3, J_HH = 8.7 Hz, ArH), 6.95 (2H, dd, J_HH = 8.7, J_HP = 3.0 Hz, ArH), 5.48 (1H, ddq, J = 6.8, 5.4, 1.5 Hz, OCH₂CH), 4.55 (2H, d, J = 6.9 Hz, OCH₂CH), 4.09−4.05 (2H, m, OCH₂CH₃), 2.87−2.82 (2H, m, NHCH₂), 1.80 (3H, s, C(CH₃)(CH₃), 1.75 (3H, s, C(CH₃)(CH₃), 1.46−1.40 (2H, m, NHCH₂CH₂), 1.34 (3H, t, J = 7.1 Hz, OCH₂CH₃), 1.31−1.27 (2H, m, NHCH₂CH₂CH₂), and 0.86 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (125 MHz): 161.6 (d, J_CP = 3.1 Hz, C-O), 138.8 (CH=C), 133.3 (d, J_CP = 11.1 Hz, 2CH), 121.8 (d, J_CP = 179.6 Hz, C-P), 119.0 (CH=C), 114.5 (d, J_CP = 15.2 Hz, 2CH), 64.8 (OCH₂CH=C), 60.3 (d, J_CP = 5.5 Hz, OCH₂CH₃), 40.6 (NHCH₂), 33.8 (d, J_CP = 6.4 Hz, NHCH₂CH₂), 25.8 (CH=C(CH₃)CH₃), 19.8 (NHCH₂CH₂CH₂), 18.2 (CH=C(CH₃)CH₃), 16.4 (d, J_CP = 6.7 Hz, OCH₂CH₃), and 13.7 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +23.6; HRMS (ESI⁺): found 348.1692. C₁₇H₂₈NaNO₃P (M + Na) requires M, 348.1704.

2.6. Rearrangement of Substituted Ethyl N-Butyl-P-(4-benzyloxyphenyl)phosphonamidates

2.6.1. Ethyl N-Butyl-P-(4-(4-(tert-butylphenyl(hydroxy)methyl)phenyl)phosphonamidate 14a

Following the method of 2.3.4 using ethyl N-butyl-P-(4-(4-tert-butylbenzyloxy)phenyl)phosphonamidate 13a (80.7 mg, 0.2 mmol) and n-butyllithium (0.37 mL, 0.66 mmol) in THF (2 mL) at rt for 1 h gave, after purification via preparative TLC (EtOAc) at R_f 0.28, 14a (50.9 mg, 63%) as a yellow oil; ν_max/cm⁻¹ 3250, 2959, 2932, 2870, 1603, 1460, 1395, 1198, 1125, 1105, 1034, 957, 685, 581, and 534; ¹H NMR (400 MHz): 7.69 (2H, dd, J_HP = 12.6, J_HH = 8.1 Hz, ArH), 7.46 (2H, dd, J_HH = 8.1, J_HP = 3.6 Hz, ArH), 7.34 (2H, d, J = 8.4 Hz, ArH), 7.26 (2H, d, J = 8.4 Hz, ArH), 5.82 (1H, s, CHOH), 4.10−4.01 (2H, m, OCH₂), 2.86−2.77 (2H, m, NHCH₂), 1.42−1.36 (2H, m, NHCH₂CH₂), 1.34−1.27 (14H, m, OCH₂CH₃, NHCH₂CH₂CH₂ and C(CH₃)₃), and 0.84 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 150.6 (C), 148.0 (d, J_CP = 2.9 Hz, C), 140.5 (C), 131.4 (d, J_CP = 10.1 Hz, 2CH), 129.3 (d, J_CP = 174.3 Hz, C-P), 126.5 (2CH), 126.4 (d, J_CP = 14.3 Hz, 2CH), 125.4 (2CH), 75.5 (CHOH), 60.4 (d, J_CP = 5.6 Hz, OCH₂CH₃), 40.6 (NHCH₂), 34.5 (C), 33.8 (d, J_CP = 6.2 Hz, NHCH₂CH₂), 31.3 (C(CH₃)₃), 19.7 (NHCH₂CH₂CH₂), 16.4 (d, J_CP = 6.8 Hz, OCH₂CH₃), and 13.7 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +22.9; HRMS (ESI⁺): found 404.2347. C₂₃H₃₅NO₃P (M + H) requires 404.2355.

2.6.2. Ethyl N-Butyl-P-(4-(hydroxy(4-methoxyphenyl)methyl)phenyl)phosphonamidate 14b

Following the method of 2.3.4 using Ethyl N-butyl-P-(4-(4-methoxybenzyloxy)phenyl)phosphonamidate 13b (75.5 mg, 0.2 mmol) and n-butyllithium (0.37 mL, 0.66 mmol) in THF (2 mL) at rt for 2 h gave, after purification via preparative TLC (EtOAc) at R_f 0.15, 14b (36.7 mg, 49%) as a yellow oil; ν_max/cm⁻¹ 3270, 2957, 2932, 2872, 1068, 1510, 1246, 1171, 1125, 1030, 959, 766, 590, 571, and 565; ¹H NMR (400 MHz): 7.70 (2H, dd, J_HP = 12.7, J_HH = 8.2 Hz, ArH), 7.43 (2H, dd, J_HH = 8.2, J_HP = 3.5 Hz, ArH), 7.25 (2H, d, J = 8.7 Hz, ArH), 6.85 (2H, d, J = 8.7 Hz, ArH), 5.81 (1H, s, CHOH), 4.13−4.01 (2H, m, OCH₂CH₃), 3.78 (3H, s, OCH₃), 2.84−2.77 (2H, m, NHCH₂), 1.42−1.36 (2H, m, NHCH₂CH₂), 1.32 (3H, t, J = 7.1 Hz, OCH₂CH₃), 1.29−1.23 (2H, m, NHCH₂CH₂CH₂), and 0.84 (3H, t, J = 7.3 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 159.1 (C-O), 148.0 (d, J_CP = 2.9 Hz, C), 135.8 (C), 131.5 (d, J_CP = 10.1 Hz, 2CH), 129.4 (d, J_CP = 174.7 Hz, C-P), 128.0 (2CH), 126.3 (d, J_CP = 14.5 Hz, 2CH), 113.9 (2CH), 75.3 (CHOH), 60.4 (OCH₂CH₃), 55.2 (OCH₃), 40.6 (NHCH₂), 33.8 (d, J_CP = 6.1 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.4 (d, J_CP = 6.8 Hz, OCH₂CH₃), and 13.7 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +22.8; HRMS (ESI⁺): found 400.1646. C₂₀H₂₈NaNO₄P (M + Na) requires 400.1654.

2.6.3. Ethyl N-Butyl-P-(4-(4-fluorophenyl(hydroxy)methyl)phenyl)phosphonamidate 14c

Following the method of 2.3.4 using ethyl N-butyl-P-(4-(4-fluorobenzyloxy)phenyl)phosphonamidate 13c (73.1 mg, 0.2 mmol) and n-butyllithium (0.27 mL, 0.66 mmol) in THF (2 mL) at rt for 2 h gave, after purification via preparative TLC (hexane/EtOAc 1:1) at R_f 0.27, 14c (49.3 mg, 67%) as a pale-yellow oil; ν_max/cm⁻¹ 3258, 2957, 2932, 2872, 1603, 1506, 1396, 1219, 1120, 1125, 1030, 957, 767, 588, and 569; ¹H NMR (400 MHz): 7.69 (2H, dd, J_HP = 12.7, J_HH = 8.2 Hz, ArH), 7.44 (2H, dd, J_HH = 8.2, J_HP = 3.6 Hz, ArH), 7.34 (2H dd, J_HH = 8.4, J_HF = 5.4 Hz, ArH), 7.00 (2H, t, J = 8.5 Hz, ArH), 5.82 (1H, s, CHOH), 4.11−4.06 (2H, m, OCH₂), 2.85−2.80 (2H, m, NHCH₂), 1.44−1.39 (2H, m, NHCH₂CH₂), 1.36−1.33 (5H, m, OCH₂CH₃ and NHCH₂CH₂CH₂), and 0.84 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (125 MHz): 162.1 (d, J_CF = 246.0 Hz, C-F), 147.9 (d, J_CP = 2.6 Hz, C), 139.4 (d, J_CF = 2.9 Hz, C), 131.5 (d, J_CP = 10.1 Hz, 2CH), 129.7 (d, J_CP = 174.5 Hz, C-P), 128.4 (d, J_CF = 8.1 Hz, 2CH), 126.4 (d, J_CP = 14.5 Hz, 2CH), 115.3 (d, J_CF = 21.4 Hz, 2CH), 74.9 (CHOH), 60.5 (d, J_CP = 5.6 Hz, OCH₂), 40.6 (NHCH₂), 33.8 (d, J_CP = 6.1 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.4 (d, J_CP = 6.7 Hz, OCH₂CH₃), and 13.6 (NHCH₂CH₂CH₂CH₃); ¹⁹F NMR (376 MHz): −114.8; ³¹P NMR (162 MHz): +22.7; HRMS (ESI⁺): found 366.1620. C₁₉H₂₆FNO₃P (M + H) requires 366.1634.

2.6.4. Ethyl N-Butyl-P-(4-(1-hydroxy-1-phenylethyl)phenyl)phosphonamidate 14d

Following the method of 2.3.4 using Ethyl N-butyl-P-(4-(1-phenylethoxy)phenyl)phosphonamidate 13d (72.2 mg, 0.2 mmol), n-butyllithium (0.26 mL, 0.66 mmol) and THF (2 mL) gave, after purification via preparative TLC (hexane/EtOAc 1:1) at R_f 0.09, 14d (28.6 mg, 40%) as a pale-yellow oil; ν_max/cm⁻¹ 3250, 2957, 2932, 2872, 1599, 1447, 1394, 1198, 1126, 1098, 1030, 959, 764, 731, 698, 656, 594, and 569; ¹H NMR (300 MHz): 7.73 (2H, dd, J_HP = 12.5, J_HH = 8.3 Hz, ArH), 7.51 (2H, dd, J_HH = 8.3, J_HP = 3.5 Hz, ArH), 7.45−7.39 (2H, m, ArH), 7.37−7.31 (2H, m, ArH), 7.29−7.23 (1H, m, ArH), 4.08 (2H, app quintet, J = 7.3 Hz, OCH₂), 2.87−2.75 (3H, m, NHCH₂), 1.95 (3H, s, O(C)CH₃), 1.48−1.39 (2H, m, NHCH₂CH₂), 1.40−1.31 (5H, m, OCH₂CH₃ and NHCH₂CH₂CH₂), and 0.85 (3H, t, J = 7.2 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (100 MHz): 151.9 (d, J_CP = 2.8 Hz, C-C-OH), 147.4 (C), 131.3 (d, J_CP = 10.1 Hz, 2CH), 129.2 (d, J_CP = 174.7 Hz, C-P), 128.2 (2CH), 127.2 (CH), 125.83 (2CH), 125.82 (d, J_CP = 14.4 Hz, 2CH), 76.0 (C-OH), 60.4 (d, J_CP = 5.6 Hz, OCH₂), 40.6 (NHCH₂), 33.8 (d, J_CP = 6.2 Hz, NHCH₂CH₂), 30.6 (C-CH₃), 19.7 (NHCH₂CH₂CH₂), 16.4 (d, J_CP = 6.8 Hz, OCH₂CH₃), and 13.7 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (162 MHz): +22.7; HRMS (ESI⁺): found 362.1878. C₂₀H₂₉NO₃P (M + H) requires 362.1885.

2.7. 1-(Benzyloxy)-3-bromobenzene 15

To a stirred solution of 3-bromophenol (10.0 g, 58.2 mmol) in MeCN (150 mL) at rt was added K₂CO₃ (10.94 g, 79.2 mmol) and benzyl bromide (6.9 mL, 9.94 g, 58.2 mmol) and the mixture stirred at rt overnight. The reaction was diluted with H₂O (150 mL), the layers separated, and the aqueous layer extracted with EtOAc (3 × 100 mL). The combined organic layers were dried over MgSO₄ and concentrated to give 15 (15.61 g, quant) as a colourless solid which was used without further purification; mp 58−60 °C; (lit. [e5] 61–62 °C); ¹H NMR (400 MHz): 7.42−7.36 (4H, m, ArH), 7.36−7.30 (1H, m, ArH), 7.15−7.10 (2H, m, ArH), 7.08 (1H, dt, J = 7.9, 1.4 Hz, ArH), 6.89 (1H, ddd, J = 7.9, 2.5, 1.4 Hz, ArH), and 5.02 (2H, s, OCH₂); ¹³C NMR (100 MHz): 159.6 (C-O), 136.5 (C-Br), 130.7 (CH), 128.8 (2CH), 128.3 (CH), 127.6 (2CH), 124.2 (CH), 122.9 (C), 118.3 (CH), 113.9 (CH), and 70.3 (OCH₂). The ¹H and ¹³C spectral data were in accordance with that previously reported [15].

2.8. Synthesis and Rearrangement of Ethyl P-(3-Benzyloxy)phenyl)-N-butylphosphonamidate 18

2.8.1. Diethyl (3-(Benzyloxy)phenyl)phosphonate 16

Following the method of 2.3.1 using 1-(benzyloxy)-3-bromobenzene 15 (14.00 g, 53.2 mmol), P(OEt)₃ (11.0 mL, 63.8 mmol), and NiCl₂ (689 mg, 5.32 mmol) gave, after purification via flash column chromatography (gradient elution hexane/EtOAc 9:1 to 100% ethyl acetate), 16 (15.43 g, 91%) as a yellow oil; ν_max/cm⁻¹ 1591, 1576, 1483, 1420, 1391, 1244, 1016, 959, 785, 743, 693, and 561; ¹H NMR (400 MHz): 7.48−7.31 (8H, m, ArH), 7.20−7.14 (1H, m, ArH), 5.10 (2H, s, OCH₂Ph), 4.18−4.05 (4H, m, 2 x OCH₂CH₃), and 1.31 (6H, t, J = 7.1 Hz, 2 x OCH₂CH₃); ¹³C NMR (125 MHz): 158.5 (d, J_CP = 18.9 Hz, C-O), 136.3 (C), 129.7 (d, J_CP = 17.5 Hz, CH), 129.5 (d, J_CP = 186.6 Hz, C-P), 128.5 (2CH), 128.0 (CH), 127.4 (2CH), 124.1 (d, J_CP = 9.1 Hz, CH), 119.4 (d, J_CP = 3.2 Hz, CH), 117.3 (d, J_CP = 11.3 Hz, CH), 70.0 (OCH₂Ph), 62.1 (d, J_CP = 5.4 Hz, 2 x OCH₂CH₃), and 16.2 (d, J_CP = 6.5 Hz, 2 x OCH₂CH₃); ³¹P NMR (162 MHz): +18.5; HRMS (ESI⁺): found 343.1059. C₁₇H₂₁NaO₄P (M + Na) requires 343.1075.

2.8.2. Ethyl (3-Benzyloxy)phenyl)phosphonochloridate 17

Following the method of 2.3.2 using diethyl (3-benzyloxylphenyl)phosphonate 16 (2.00 g, 6.2 mmol) and PCl₅ (2.60 g, 12.5 mmol) in toluene (40 mL) gave 17 (1.77 g, 91%) as a yellow oil which was used without further purification; ¹H NMR (400 MHz): 7.54−7.50 (1H, m, ArH), 7.47−7.34 (7H, m, ArH), 7.25−7.19 (1H, m, ArH), 5.11 (2H, s, OCH₂Ph), 4.49−4.33 (2H, m, OCH₂CH₃), and 1.46 (3H, dt, J = 7.1, 1.5 Hz, OCH₂CH₃); ¹³C NMR (100 MHz): 158.6 (d, J_CP = 21.6 Hz, C-O), 136.1 (C), 131.7 (d, J_CP = 179.2 Hz, C-O), 130.1 (d, J_CP = 20.0 Hz, CH), 128.7 (2CH), 128.2 (CH), 127.6 (2CH), 123.4 (d, J_CP = 11.0 Hz, CH), 120.6 (d, J_CP = 3.6 Hz, CH), 116.6 (d, J_CP = 13.7 Hz, CH), 70.3 (OCH₂Ph), 63.9 (d, J_CP = 7.6 Hz, OCH₂CH₃), and 16.0 (d, J_CP = 7.5 Hz, OCH₂CH₃); ³¹P NMR (162 MHz): +28.9.

2.8.3. Ethyl P-(3-Benzyloxyphenyl)-N-butylphosphonamidate 18

Following the method of 2.3.3 using ethyl (3-benzyloxyphenyl)phosphonochloridate 17 (1.77 g, 5.7 mmol) in Et₂O (50 mL) and n-butylamine (1.20 mL, 0.89 g, 12.5 mmol) in Et₂O (50 mL) gave, after purification via flash column chromatography (EtOAc/hexane 7:3) at R_f 0.29, 18 (600 mg, 30%) as a colourless solid, mp 62−65 °C; ν_max/cm⁻¹ 2955, 2930, 2864, 1589, 1454, 1418, 1250, 1207, 1126, 1026, 947, 731, 692, and 555; ¹H NMR (400 MHz): 7.45−7.29 (8H, m, ArH), 7.12−7.07 (1H, m, ArH), 5.07 (2H, s, OCH₂Ph), 4.08 (2H, app quintet, J = 7.2 Hz, OCH₂CH₃); 3.02 (1H, br s, NH), 2.87−2.79 (2H, m, NHCH₂), 1.46−1.36 (2H, m, NHCH₂CH₂), 1.33 (3H, t, J = 7.1 Hz, OCH₂CH₃), 1.31−1.23 (2H, m, NHCH₂CH₂CH₂), and 0.85 (3H, t, J = 7.4 Hz, NHCH₂CH₂CH₂CH₃); ¹³C NMR (125 MHz): 158.3 (d, J_CP = 17.8 Hz, C-O), 136.4 (C), 132.4 (d, J_CP = 171.2 Hz, C-O), 129.4 (d, J_CP = 16.6 Hz, CH), 128.4 (2CH), 127.8 (CH), 127.3 (2CH), 123.6 (d, J_CP = 9.1 Hz, CH), 118.4 (d, J_CP = 2.4 Hz, CH), 117.0 (d, J_CP = 10.9 Hz, CH), 69.9 (OCH₂Ph), 60.2 (d, J_CP = 5.5 Hz, OCH₂CH₃), 40.4 (NHCH₂), 33.7 (d, J = 6.1 Hz, NHCH₂CH₂), 19.6 (NHCH₂CH₂CH₂), 16.2 (d, J_CP = 6.7 Hz, OCH₂CH₃), and 13.5 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (202 MHz): +22.5; HRMS (ESI⁺): found 348.1713. C₁₉H₂₇NO₃P (M + H) requires 348.1729.

2.8.4. Ethyl N-Butyl-P-(3-(hydroxy(phenyl)methyl)phenyl)phosphonamidate 19

Following the method of 2.3.4 using ethyl P-(3-benzyloxyphenyl)-N-butylphosphonamidate 18 (173.7 mg, 0.5 mmol) and n-butyllithium (0.91 mL, 1.65 mmol) in THF (5 mL) at rt for 20 min gave, after purification via preparative TLC (EtOAc) 19 (73.7 mg, 42%) as a yellow oil as an inseparable 1:1 mixture of diastereomers; ν_max/cm⁻¹ 3234, 2959, 2932, 2872, 1452, 1420, 1188, 1117, 1032, 957, 908, 729, 698, 556, and 525; ¹H NMR (500 MHz): 7.86−7.79 (1H, m, ArH), 7.65−7.59 (1H, m, ArH), 7.54−7.46 (1H, m, ArH), 7.39−7.33 (3H, m, ArH), 7.31−7.27 (2H, m, ArH), 7.25−7.22 (1H, m, ArH), 5.824 and 5.816 (2 × 1 H, s, CHOH diastereomer 1 and 2), 4.06−3.98 (2H, m, OCH₂), 2.81−2.74 (2H, m, NHCH₂), 1.36−1.32 (2H, m, NHCH₂CH₂), 1.31−1.27 (3H, m, OCH₂CH₃), 1.25−1.20 (2H, m, NHCH₂CH₂CH₂), and 0.84−0.80 (3H, m, NHCH₂CH₂CH₂CH₃); ¹³C NMR (125 MHz): 144.7 (d, J_CP = 13.7 Hz, C), 143.8 (d, J_CP = 5.2 Hz, C), 130.71 and 130.64 (2 x d, J_CP = 179.8 Hz, P–C), 130.20 and 130.17 (2 x d, J_CP = 9.5 Hz, CH), 130.01 and 129.99 (2 x d, J_CP = 16.4 Hz, CH), 129.46 and 129.43 (2 x d, J_CP = 10.6 Hz, CH), 128.39 and 128.38 (2 x d, J_CP = 13.6 Hz, CH), 128.4 (2CH), 127.4 (CH), 126.60 and 126.56 (2CH), 75.5 (CHOH), 60.4 (d, J_CP = 5.7 Hz, OCH₂), 40.5 (NHCH₂), 33.7 (d, J_CP = 6.2 Hz, NHCH₂CH₂), 19.7 (NHCH₂CH₂CH₂), 16.3 (d, J_CP = 6.7 Hz, OCH₂CH₃), and 13.6 (NHCH₂CH₂CH₂CH₃); ³¹P NMR (202 MHz): +22.9; HRMS (ESI⁺): found 348.1713. C₁₉H₂₇NO₃P (M + H) requires 348.1729.

3. Results and Discussion

Starting from 4-bromophenol, the known benzyl ether 7 was prepared in essentially quantitative yield (Scheme 2). The phosphonate functionality was installed by the nickel-catalysed Michaelis–Arbuzov-type reaction with triethyl phosphite introduced by Tavs [10]. We found that to obtain a good yield of product 8, it was essential to use anhydrous nickel(II) chloride. The diethyl phosphonate 8 was treated with phosphorus pentachloride in toluene to afford 9 which reacted directly with two equivalents of butylamine giving phosphonamidate 10.

The Wittig rearrangement of compound 10 occurred readily on treatment with 3.3 equiv. of n-butyllithium in THF at RT to afford the benzhydrol-4-phosphonamidate 11 in good yield. The process creates a new stereogenic centre but the C and P centres are too far apart to affect one another and only a single set of NMR signals was observed for what is almost inevitably an equal mixture of all four possible diastereomers. The rearrangement was most obvious from the change from PhCH₂O [δ_H 5.09 (2H, s), δ_C 69.8] to PhCH(OH) [δ_H 5.85 (1H, s), δ_C 75.7] (see Supplementary Materials).

We now wished to explore the scope of the process for substituted benzyl and other analogous groups and, rather than repeat the four-step synthetic sequence used for 10 with different benzyl halides, we were able to remove the O-benzyl group from 10 in excellent yield using catalytic hydrogenation to give the hydroxyphenylphosphonamidate 12. This was then O-alkylated to give a range of derivatives 13a–e (Scheme 3). The low yield of these after chromatographic purification was disappointing and compound 12 seems to be deactivated towards O-alkylation. In each case, there was a significant amount of unreacted 12 remaining even after overnight reaction and the products partly decomposed during chromatography, resulting in a poor recovery. Despite this, the products were obtained in sufficient quantity for full characterisation and a study of their reactivity. All the phosphonamidates in this paper show ³¹P signals in the narrow range δ_P +22.5–25.6, and the expected phosphorus coupling is observed in the ¹³C NMR spectra for all signals of the phosphorus-bearing benzene ring, both carbons of OEt but interestingly only C–2 of NHBu.

When compounds 13a–d were subjected to treatment with butyllithium under the same conditions as for 10, the Wittig rearrangement was again observed and the products 14a–d were obtained in moderate to good yield (Scheme 4). The 3-methylbut-2-enyl (“prenyl”) ether 13e did give some indication of forming the rearranged product but this was accompanied by a myriad of other byproducts from which it could not be separated, so we conclude that the process is not likely to be useful for such non-benzylic allyl ethers. This is consistent with the corresponding N-butyl carboxamides 5 where the prenyl ether did rearrange in the para-position, but in low yield [7].

We now turned to the isomeric meta-substituted system and starting from 3-bromophenol, the same four-step sequence as for 10 gave the desired product 18 by way of intermediates 15, 16, and 17 (Scheme 5). Only the final stage was rather low yielding.

When compound 18 was subjected to the usual rearrangement conditions, the expected product 19 was obtained in moderate yield. Now for the first time, the two stereogenic centres were close enough to affect one another and this compound showed doubling of the ¹³C NMR signals for the phosphorus-bearing benzene ring carbons and the ortho-CHs of the other benzene ring, indicating a 1:1 mixture of diastereomers for the (racemic) compound.

In conclusion, the phosphonamidate group EtO-P(=O)-NHBu is effective in promoting the Wittig rearrangement of meta- or para-disposed aryl benzyl ethers, allowing access to novel phosphonamidate-substituted diarylmethanols. We have also investigated the synthesis and base-treatment of the corresponding ortho-benzyloxyphenylphosphonamidates but this takes a quite different course as will be reported shortly.