A palladium-catalyzed oxidative cross-coupling reaction between aryl pinacol boronates and H-phosphonates in ethanol

Abstract

The first successful oxidative coupling reaction of aryl pinacol boronic esters with H-phosphonates to deliver aryl phosphorous compounds is reported herein. These reactions between aryl boronic reagents and H-phosphonates were carried out synergistically using a Pd catalyst, additive and oxidant. Without using bases and ligands, phosphorylation was accomplished in an environmentally-friendly manner under mild conditions in ethanol.

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Introduction

The development of versatile methods for the synthesis of arylphosphorous compounds¹ has attracted much attention, owing to their broad applications in medicinal chemistry,² materials chemistry,³ organic synthesis⁴ and catalysis.⁵ In 1981, Hirao and co-workers reported the first construction of C(sp²)–P bonds through palladium-catalyzed cross-coupling of aryl halides with H-phosphonates.⁶ During the past three decades, the scope of the reactions catalyzed by Pd, Cu and Ni or other metals reagents to form C(sp²)–P bonds employing functionalized arenes with phosphorus reagents has been significantly expanded to various aryl halides,⁷ triflates,⁸ imidazolylsulfonates,⁹ diazonium salts,¹⁰ o-aryl silyl triflates,¹¹ arylhydrazines,¹² arylnitriles,¹³ aryl pivalates,¹⁴ sodium arylsulfinates¹⁵ and diaryliodonium salts.¹⁶ Arylphosphorus compounds can also be produced by the palladium or copper-catalyzed directed C–H/P(O)–H coupling reactions.¹⁷

Aryl boronic acids¹⁸ are extensively used as substrates in transition-metal catalyzed cross-coupling reactions including Suzuki–Miyaura cross-coupling reactions,¹⁹ Cu-catalyzed C–O, C–N, C–S and C–Se coupling reactions,²⁰ and Rh-catalyzed conjugate additions to carbonyl compounds,²¹ owing to their commercial availability and structural diversity. There are only a few examples reported for C–P bond forming reactions using aryl boronic acids (Scheme 1a–c).²² Notably, additional ligands and bases are required in these works. Aryl boronic esters, especially aryl pinacol boronates, have received a great deal of attention in the catalysis community. In general, aryl boronic esters exhibit greater chemical stability and readily soluble in aprotic solvents. In most cases, they also exhibit stability towards column chromatography, which aids in their ease of isolation and purification. In addition, many are liquids at room temperature and can be easily distilled. However, to the best of our knowledge, the preparation of arylphosphorus compounds via oxidative cross coupling reactions of aryl boronic esters with H-phosphonates has never been developed. Herein, we report the first coupling reaction of aryl pinacol boronic esters with H-phosphonates through palladium catalysis (Scheme 1d). The features of this system include that the reactions are performed in ethanol and also declined the requirement of external ligand and base. The most important feature that we observed was that the reaction conditions used in Scheme 1a–c were not successful for the coupling of aryl pinacol boronate with H-phosphonate.

Scheme 1 Synthesis of aryl phosphorous compounds from arylboronic reagents.

Results and discussion

We selected diethyl phosphite (1a) and phenyl pinacol boronate (2a) as model substrates to optimize the reaction conditions (Table 1). Initially, the reaction was carried out with Pd(OAc)₂ (5 mol%) as the catalyst and Ag₂CO₃ (1.5 equiv.) as the oxidant in DMF at 80 °C for 24 h; however, only a trace amount of the desired product diethyl phenylphosphonate 3aa was detected (entry 1). No product or only a trace amount of the product was observed when DMSO, CH₃CN or toluene was used as the solvent (entries 2–4). To our delight, when the solvent was changed to ethanol, the coupling product 3aa was obtained at 22% yield (entry 5). Key role of ethanol in this coupling reaction to obtain the desired product can be explained by the possible coordination of ethanol at boron centre of aryl pinacol boronate. Due to the co-ordination of ethanol with aryl pinacol boronate the electron density at aryl system may be increased. When we chose tetramethylammonium bromide (TMAB), tetramethylammonium chloride (TMAC), LiCl, CsCl and TBACl as the additives, the coupling product 3aa with TMAC and LiCl obtained 76% and 75% yields, respectively (entries 7 and 9), whereas other additives gave inferior results. To our delight, we chose TMAC as additive for this reaction. Enhancement of the yield of product in the presence of TMAC was because of its phase transfer catalytic and inert counter ionic nature. The yield of the product was decreased to 32% when the reaction was conducted with tert-butanol as the solvent (entry 11). The choice of oxidant was crucial in this coupling reaction. When we replaced Ag₂CO₃ with AgOAc and Cu(OAc)₂, both led to 3aa at lower yields (entries 12 and 14); meanwhile, no reaction occurred when K₂S₂O₈ or oxygen (ballon) was used as the oxidant (entries 13 and 15). The superiority of Ag₂CO₃ over other oxidants in this reaction could explained by its additional basic nature that can promote the deprotonation of H-phosphonates. In the screening of the palladium source, Pd(PPh₃)₂Cl₂, Pd(OCOCF₃)₂ and PdCl₂ showed lower reactivity (entries 16–18) compared with Pd(OAc)₂.

Table 1 Pd-catalyzed coupling of PhB(pin) with diethyl phosphite^a

Entry	Additive	Oxidant	Solvent	Yield^b (%)
a Reaction conditions: 1a (0.5 mmol), 2a (1.5 eq.), Pd(OAc)2 (5 mol%), additive (1.5 eq.), oxidant (1.5 eq.), and solvent (3.0 mL) under an atmosphere of N2 for 24 h at 80 °C.b Isolated yield.c Pd(PPh3)2Cl2 as the catalyst.d Pd(OCOCF3)2 as the catalyst.e PdCl2 as the catalyst.
1	—	Ag2CO3	DMF	Trace
2	—	Ag2CO3	DMSO	0
3	—	Ag2CO3	CH3CN	Trace
4	—	Ag2CO3	Toluene	Trace
5	—	Ag2CO3	EtOH	22
6	TMAB	Ag2CO3	EtOH	25
7	TMAC	Ag2CO3	EtOH	76
8	CsCl	Ag2CO3	EtOH	50
9	LiCl	Ag2CO3	EtOH	75
10	TBAC	Ag2CO3	EtOH	35
11	TMAC	Ag2CO3	t-BuOH	32
12	TMAC	AgOAc	EtOH	35
13	TMAC	K2S2O8	EtOH	N.R.
14	TMAC	Cu(OAc)2	EtOH	28
15	TMAC	O2	EtOH	N.R.
16^c	TMAC	Ag2CO3	EtOH	64
17^d	TMAC	Ag2CO3	EtOH	62
18^e	TMAC	Ag2CO3	EtOH	65

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We next investigated the relative reactivity of phenyl boronic acid derivatives (Table 2). When phenyl boronic acid (4) was used as a boron reagent, the coupling product 3aa was obtained at 61% yield. Phenyl boronic esters, such as phenyl hexylene glycol boronate (5) and phenyl neopentyl glycol boronate (6), were also tested, but both gave the product at lower yields when compared with phenyl pinacol boronate (2a).

Table 2 Phosphorylation: relative reactivity of boron sources^a

a Reaction conditions: 0.5 mmol of 1a, 1.5 equivalent of Ph[B], 5 mol% Pd(OAc)₂, 1.5 equivalent of TMACl, 1.5 equivalent of Ag₂CO₃, and 3 mL of ethanol were charged into a Schlenk tube under nitrogen atmosphere and heated at 80 °C for 24 h.

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With the optimized protocol from previous works, we examined the scope of the substrates in this catalytic system (Table 3). Various aryl pinacol boronates 2 were found to couple with 1a to produce the corresponding diethyl arylphosphonates 3 at moderate to good yields. It is worth mentioning that higher yields of products were obtained with aryl pinacol boronates 2 bearing electron-donating groups. Thus, with electron-donating substituents such as methyl and methoxy groups at the C-3 or C-4 position of 2, one could obtain the corresponding products at good yields (3aa–3ag). In contrast, substrates with electron-withdrawing trifluoromethyl and chloro groups led to products at lower yields (3ah and 3ai). When we used 3-bromophenyl pinacol boronate as a coupling partner, the desired product was obtained in trace amount along with de-brominated arylphosphonate (3aa) in lower yield. Use of various aryl pinacol boronic esters such as 4-nitrophenyl, 4-methoxycarbonylphenyl, 4-cyanophenyl, naphthyl, 4-hydroxyphenyl pinacol boronates and heteroaryl pinacol boronates such as 3-thienyl, 5-indolyl pinacol boronates as substrates to couple with H-phosphonate, failed to the formation of desired products instead detected the de-borolyted products. Furthermore, we also tested the reaction by using ortho substituted aryl pinacol boronates such as 2-chlorophenyl and mesityl pinacol boronates. Under the reaction conditions, these two substrates also failed to react with H-phosphonate. The formation of de-borolyted product was detected by GC analysis. Another important factor that was responsible for lowering the yield of product was formation trialkylphosphates by the reaction of H-phosphonate with solvent (ethanol).

Table 3 Substrate scope of aryl pinacol boronates^a

a Reaction conditions: 0.5 mmol of 1a, 1.5 equivalent of boronates 2, 5 mol% Pd(OAc)₂, 1.5 equivalent of TMACl, 1.5 equivalent of Ag₂CO₃, and 3 mL of ethanol were charged into a Schlenk tube under nitrogen atmosphere and heated at 80 °C for 24 h.b Reaction at 70 °C.

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The generality of this coupling reaction was further demonstrated by using two other substituted phosphites, dimethyl phosphite (1b) and dibutyl phosphite (1c). When screening with different aryl pinacol boronates 2, both phosphites could produce the corresponding products at moderate to good yields (Table 4).

Table 4 Pd-catalyzed coupling of aryl pinacol boronates 2 with phosphites^a

a Reaction conditions: 0.5 mmol of 1, 1.5 equivalent of boronate 2, 5 mol% Pd(OAc)₂, 1.5 equivalent of TMACl, 1.5 equivalent of Ag₂CO₃, and 3 mL of ethanol were charged into a Schlenk tube under nitrogen atmosphere and heated at 80 °C for 24 h.

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Although the mechanism of this tranformation is not clear at this stage, based on experimental results, we propose that this Pd-catalyzed cross-coupling takes place via the catalytic cycle shown in Scheme 2. Firstly, the Pd(II) complex A reacted with the phosphorous nucleophile generated by deprotonation of the P(O)H compound in the presence of a Ag₂CO₃ to provide intermediate B.^22a,d The resulting intermediate B associated with arylpinacol boronate (2) to give another intermediate C,^22a,d,23 which upon reductive elimination, afforded the desired coupling product (3) and Pd(0) species. Finally, the Pd(0) species was oxidized by Ag₂CO₃, leading to the regeneration of Pd(II) complex A as a catalytically active species.

Scheme 2 Plausible mechanism for the formation of 3.

Conclusion

In conclusion, we demonstrated a novel Pd-catalyzed cross-coupling reaction of aryl pinacol boronates with H-phosphonates, which afforded good yields of arylphosphorus compounds under mild conditions in ethanol. A variety of readily available aryl pinacol boronates can be used in this coupling reaction. We believe that this is a new protocol for the construction of valuable C–P bonds from readily available, environmentally friendly chemical sources.

Experimental

General information

All commercial chemicals were used as received except where noted. Aryl pinacol boronates were all prepared through literature procedures.^24,25 Experiments were performed under a dinitrogen atmosphere using standard Schlenk techniques unless otherwise stated. Flash chromatography was performed on Merck silica gel 60 (230–400 mesh).

Analysis

NMR spectra were recorded on a Varian Unity Inova-600 or a Varian Mercury-400 instrument using CDCl₃ as a solvent. Chemical shifts are reported in parts per million (ppm) and referenced to the residual solvent resonance. Coupling constant (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s = singlet, d = doublet, t = triplet, dd = double doublet, q = quartet, quin = quintet, m = multiplet, b = broad. GC-MS analysis were performed on a Agilent Technologies 5977A GC equipped with Agilent 7890B MS. High-resolution mass spectra were carried out on a Jeol JMS-HX 110 spectrometer by the services at the National Chung Hsing University.

General procedure for synthesis of compound 3

To a mixture of aryl pinacol boronic ester (0.75 mmol, 1.5 equiv.), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 1.5 equiv.) and tetramethylammonium chloride (82 mg, 1.5 equiv.) were added H-phosphonate (0.5 mmol) and ethanol (3.0 mL) under nitrogen atmosphere. The resulting suspension was heated at 80 °C for 24 h. After 24 h, the reaction mixture was cooled down to room temperature and diluted with ethyl acetate (20 mL). The resulting solution was directly filtered through a pad of celite and the filtrate was concentrated under vacuum. The crude product was purified by flash column chromatography (ethyl acetate/hexane = 30–80/20–70).

Diethyl phenylphosphonate (3aa):²². Following the general procedure for compound 3, using phenylboronic acid pinacol ester 2a (153 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3aa as a colorless oil (81.3 mg, 76% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.79–7.85 (m, 2H), 7.54–7.58 (m, 1H), 7.45–7.50 (m, 2H), 4.05–4.19 (m, 4H), 1.33 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 132.3 (d, J_C–P = 2.7 Hz), 131.7 (d, J_C–P = 9.9 Hz), 128.4 (d, J_C–P = 14.8 Hz), 128.2 (d, J_C–P = 186.8 Hz), 62.0 (d, J_C–P = 5.3 Hz), 16.2 ((d, J_C–P = 6.4 Hz)); ³¹P NMR (162 MHz, CDCl₃): δ 19.54.

Diethyl 4-methylphenylphosphonate (3ab):²². Following the general procedure for compound 3, using 4-methylphenylboronic acid pinacol ester (163.6 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3ab as a colorless oil (66.1 mg, 58% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.72 (d, J = 8.0 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.26–7.29 (m, 2H), 4.04–4.15 (m, 4H), 2.41 (s, 3H), 1.32 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 142.92 (d, J_C–P = 3.1 Hz), 131.8 (d, J_C–P = 10.2 Hz), 129.2 (d, J_C–P = 15.5 Hz), 124.8 (d, J_C–P = 189.0 Hz), 61.94 (d, J_C–P = 5.3 Hz), 21.6 (d, J_C–P = 1.2 Hz), 16.26 (d, J_C–P = 6.5 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 20.21.

Diethyl 4-methoxyphenylphosphonate (3ac):²². Following the general procedure for compound 3, using 4-methoxyphenylboronic acid pinacol ester (175.6 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3ac as a colorless oil (80.5 mg, 66% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J = 8.8 Hz, 1H), 7.73 (d, J = 8.8, 1H), 6.95–6.99 (m, 2H), 4.01–4.16 (m, 4H), 3.86 (s, 3H), 1.31 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 162.8 (d, J_C–P = 3 Hz), 133.8 (d, J_C–P = 11.3 Hz), 119.4 (d, J_C–P = 193.5 Hz), 114.0 (d, J_C–P = 15.9 Hz), 61.9 (d, J_C–P = 4.9 Hz), 55.3, 16.3 (d, J_C–P = 6.4 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 20.78.

Diethyl 3-methylphenylphosphonate (3ad):²². Following the general procedure for compound 3, using 3-methylphenylboronic acid pinacol ester (163.6 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3ad as a colorless oil (84.4 mg, 74% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.57–7.66 (m, 2H), 7.30–7.37 (m, 2H), 4.04–4.18 (m, 4H), 2.40 (s, 3H), 1.33 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 138.2 (d, J_C–P = 14.8 Hz), 133.08 (d, J_C–P = 3.1 Hz), 132.1 (d, J_C–P = 9.8 Hz), 128.5 (d, J_C–P = 34.2 Hz), 128.4 (d, J_C–P = 40.2 Hz), 127.8 (d, J_C–P = 185.9 Hz), 61.9 (d, J_C–P = 5.3 Hz), 21.2, 16.2 (d, J_C–P = 6.5 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 19.91.

Diethyl 3,5-dimethylphenylphosphonate (3ae):¹². Following the general procedure for compound 3, using 3,5-dimethylphenylboronic acid pinacol ester (174.1 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3ae as a colorless oil (107.7 mg, 89% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.44 (s, 1H), 7.41 (s, 1H), 7.18 (s, 1H), 4.03–4.18 (m, 4H), 2.36 (s, 6H), 1.33* (t, J = 7.2 Hz, 3H), 1.32* (t, J = 7.2 Hz, 3H); *This triplet was merged with other triplet; ¹³C NMR (100 MHz, CDCl₃): δ 138.1 (d, J_C–P = 15.6 Hz), 134.1 (d, J_C–P = 3.0 Hz), 129.3 (d, J_C–P = 9.9 Hz), 127.6 (d, J_C–P = 185.2 Hz), 61.9 (d, J_C–P = 5.3 Hz), 21.1 (d, J_C–P = 1.1 Hz), 16.2 (d, J_C–P = 6.8 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 20.48.

Diethyl (3-methoxy-5-methylphenyl)phosphonate (3af). Following the general procedure for compound 3, using (3-methoxy-5-methyl)phenyl boronic acid pinacol ester (186.1 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3af as a colorless oil (87.8 mg, 68% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.21 (d, J = 13.6 Hz, 1H), 7.13 (d, J = 14.8 Hz, 1H), 6.90 (s, 1H), 4.18–4.04 (m, 4H), 3.82 (s, 3H), 2.37 (s, 3H), 1.33 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 159.3 (d, J_C–P = 20.1 Hz), 140.0 (d, J_C–P = 17.9 Hz), 128.9 (d, J_C–P = 185.2 Hz), 124.7 (d, J_C–P = 9.5 Hz), 119.4 (d, J_C–P = 3.0 Hz), 113.2 (d, J_C–P = 11.4 Hz), 62.0 (d, J_C–P = 4.9 Hz), 55.3, 21.3, 16.24 (d, J_C–P = 6.5 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 19.98; HRMS-EI calcd for C₁₂H₁₉O₄P [M]⁺: 258.1021, found: 258.1028.

Diethyl 3,4-dimethylphenylphosphonate (3ag):¹¹. Following the general procedure for compound 3, using 3,4-dimethylphenylboronic acid pinacol ester (174.1 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3ag as a colorless oil (87.2 mg, 72% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.50–7.61 (m, 2H), 7.21–7.28 (m, 1H), 4.02–4.17 (m 4H), 2.31 (s, 6H), 1.33 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.2 Hz, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 141.7 (d, J_C–P = 3.4 Hz), 137.0 (d, J_C–P = 15.2 Hz), 132.8 (d, J_C–P = 10.3 Hz), 129.6 (d, J_C–P = 45.9 Hz), 129.5 (d, J_C–P = 40.2 Hz), 125.1 (d, J_C–P = 187.8 Hz), 61.9 (d, J_C–P = 5.3 Hz), 19.9, 19.6, 16.3 (d, J_C–P = 6.8 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 20.59.

Diethyl 4-trifluoromethylmethylphenylphosphonate (3ah):²². Following the general procedure for compound 3, using 4-trifluorophenylboronic acid pinacol ester (204.1 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3ah as a colorless oil (25.4 mg, 18% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.97 (d, J = 7.6 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.72–7.75 (m, 2H), 4.10–4.20 (m, 4H), 1.34 (t, J = 6.8 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 134.0 (d, J = 33.0 Hz), 132.7 (d, J = 185.5 Hz), 132.2 (d, J = 9.9 Hz), 125.3 (dq, J = 15.1, 3.8 Hz), 123.5 (q, J = 270.6 Hz), 62.5 (d, J = 5.7 Hz), 16.3 (d, J = 6.5 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 17.02; ¹⁹F NMR (376 MHz, CDCl₃): δ −63.3.

Diethyl 4-chlorophenylphosphonate (3ai):¹². Following the general procedure for compound 3, using 4-chlorophenylboronic acid pinacol ester (178.6 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added diethyl phosphite 1a (67.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3ai as a colorless oil (33.5 mg, 27% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.77 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.44–7.47 (m, 2H), 4.04–4.19 (m, 4H), 1.33 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 138.9 (d, J_C–P = 3.8 Hz), 133.2 (d, J_C–P = 10.7 Hz), 128.8 (d, J_C–P = 15.6 Hz), 126.9 (d, J_C–P = 190.1 Hz), 62.25 (d, J_C–P = 5.7 Hz), 16.3 (d, J_C–P = 6.4 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 18.67.

Dimethyl phenylphosphonate (3ba):²². Following the general procedure for compound 3, using phenylboronic acid pinacol ester (153 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dimethyl phosphite (46.7 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3ba as a colorless oil (49.3 mg, 53% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.78–7.84 (m, 2H), 7.56–7.60 (m, 1H), 7.46–7.51 (m, 2H), 3.78 (s, 3H), 3.75 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 132.6 (d, J_C–P = 3.0 Hz), 131.8 (d, J_C–P = 9.9 Hz), 128.5 (d, J_C–P = 15.2 Hz), 126.8 (d, J_C–P = 187.8 Hz), 52.6 (d, J_C–P = 5.7 Hz); ³¹P NMR (162 MHz, CDCl₃): δ 22.33.

Dimethyl 3-methylphenylphosphonate (3bd). Following the general procedure for compound 3, using 3-methylphenylboronic acid pinacol ester (163.6 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dimethyl phosphite (46.7 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 30–80%) to provide 3bd as a colorless oil (48.0 mg, 48% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.57–7.65 (m, 2H), 7.38 (b, 2H), 3.73–3.78 (m, 6H), 2.40 (s, 3H); ¹³C NMR (100 MHz, CDCl₃): δ 138.4 (d, J_C–P = 15.2 Hz), 133.4 (d, J_C–P = 3.1 Hz), 132.3 (d, J_C–P = 9.8 Hz), 128.7 (d, J_C–P = 39.1 Hz), 128.6 (d, J_C–P = 45.5 Hz), 126.5 (d, J_C–P = 186.7 Hz), 52.6 (d, J_C–P = 5.3 Hz), 21.3; ³¹P NMR (162 MHz, CDCl₃): δ 22.80; HRMS-EI calcd for C₉H₁₃O₃P [M]⁺: 200.0602, found: 200.0597.

Dibutyl phenylphosphonate (3ca):¹¹. Following the general procedure for compound 3, using phenylboronic acid pinacol ester 2a (153 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dibutyl phosphite (101.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 20–70%) to provide 3ca as a colorless oil (93.2 mg, 69% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.77–7.84 (m, 2H), 7.53–7.58 (m, 1H), 7.44–7.49 (m, 2H), 3.96–4.12 (m, 4H), 1.61–1.69 (m, 4H), 1.34–1.44 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 132.3, 131.7 (d, J_C–P = 9.1 Hz), 128.4 (d, J_C–P = 14.5 Hz), 128.3 (d, J_C–P = 186.6 Hz), 65.7 (d, J_C–P = 5.4 Hz), 32.4 (d, J_C–P = 6.4 Hz), 18.7, 13.5; ³¹P NMR (162 MHz, CDCl₃): δ 19.36.

Dibutyl p-tolylphosphonate (3cb):¹⁵. Following the general procedure for compound 3, using p-tolylphenylboronic acid pinacol ester (163.6 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dibutyl phosphite (101.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 20–70%) to provide 3cb as a colorless oil (86.7 mg, 61% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.72 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.25–7.29 (m, 2H), 3.96–4.09 (m, 4H), 2.40 (s, 3H), 1.65 (quin, J = 6.8 Hz, 4H), 1.34–1.44 (m, 4H), 0.90 (t, J = 7.2, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 142.7 (d, J_C–P = 2.3 Hz), 131.6 (d, J_C–P = 10.2 Hz), 129.0 (d, J_C–P = 15.2 Hz), 124.7 (d, J_C–P = 189.4 Hz), 65.5 (d, J_C–P = 5.7 Hz), 32.2 (d, J_C–P = 6.5 Hz), 21.4, 18.5, 13.4; ³¹P NMR (162 MHz, CDCl₃): δ 20.09.

Dibutyl 4-methoxyphenylphosphonate (3cc):²⁶. Following the general procedure for compound 3, using 4-methoxyphenylboronic acid pinacol ester (175.6 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dibutyl phosphite (101.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 20–70%) to provide 3cc as a colorless oil (102.1 mg, 68% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.75 (d, J = 8.8 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 6.95–6.99 (m, 2H), 3.94–4.07 (m, 4H), 3.85 (s, 3H), 1.60–1.68 (m, 4H), 1.35–1.44 (m, 4H), 0.90 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 162.7 (d, J_C–P = 2.8 Hz), 133.6 (d, J_C–P = 10.9 Hz), 119.3 (d, J_C–P = 192.9 Hz), 113.8 (d, J_C–P = 15.4 Hz), 65.5 (d, J_C–P = 5.4 Hz), 55.1, 32.3 (d, J_C–P = 6.3 Hz), 18.6, 13.4; ³¹P NMR (162 MHz, CDCl₃): δ 20.47; HRMS-EI calcd for C₁₅H₂₅O₄P [M]⁺: 300.1490, found: 300.1484.

Dibutyl 3-methylphenylphosphonate (3cd). Following the general procedure for compound 3, using 3-methylphenylboronic acid pinacol ester (163.6 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dibutyl phosphite (101.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 20–70%) to provide 3cd as a colorless oil (78.1 mg, 55% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.56–7.65 (m, 2H), 7.34–7.37 (m, 2H), 3.95–4.11 (m, 4H), 2.40 (s, 3H), 1.62–1.70 (m, 4H), 1.34–1.45 (m, 4H), 0.91 (t, J = 7.6 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 138.1 (d, J_C–P = 14.5 Hz), 133.0, 132.2 (d, J_C–P = 10 Hz), 128.5 (d, J_C–P = 40 Hz), 128.4 (d, J_C–P = 46.4 Hz), 128.0 (d, J_C–P = 187.5 Hz), 65.6 (d, J_C–P = 5.5 Hz), 32.3 (d, J_C–P = 7.3 Hz), 21.2, 18.6, 13.5; ³¹P NMR (162 MHz, CDCl₃): δ 19.91; HRMS-EI calcd for C₁₅H₂₅O₃P [M]⁺: 284.1541, found: 284.1540.

Dibutyl 3,5-dimethylphenylphosphonate (3ce). Following the general procedure for compound 3, using 3,5-dimethylphenylboronic acid pinacol ester (174.1 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dibutyl phosphite (101.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 20–70%) to provide 3ce as a colorless oil (99.8 mg, 67% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.43 (s, 1H), 7.39 (s, 1H), 7.17 (s, 1H), 3.96–4.09 (m, 4H), 2.35 (s, 6H), 1.62–1.70 (m, 4H), 1.36–1.43 (m, 4H), 0.91 (t, J = 7.2, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 138.0 (d, J_C–P = 15.4 Hz), 133.95 (d, J_C–P = 2.7 Hz), 129.3 (d, J_C–P = 10 Hz), 127.8 (d, J_C–P = 184.8 Hz), 65.6 (d, J_C–P = 5.5 Hz), 32.4 (d, J_C–P = 7.3 Hz), 21.1, 18.6, 13.5; ³¹P NMR (162 MHz, CDCl₃): δ 20.40; HRMS-EI calcd for C₁₆H₂₇O₃P [M]⁺: 298.1698, found: 298.1707.

Dibutyl (3-methoxy-5-methylphenyl)phosphonate (3cf). Following the general procedure for compound 3, using (3-methoxy-5-methyl)phenyl boronic acid pinacol ester (186.1 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dibutyl phosphite (101.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 20–70%) to provide 3cf as a colorless oil (72.3 mg, 46% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.10–7.23 (m, 2H), 6.89 (s, 1H), 3.97–4.10 (m, 4H), 3.82 (s, 3H), 2.37 (s, 3H), 1.62–1.70 (m, 4H), 1.35–1.45 (m, 4H), 0.91 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 159.4 (d, J_C–P = 19.8 Hz), 139.9 (d, J_C–P = 17.4 Hz), 129.0 (d, J_C–P = 185.2 Hz), 124.7 (d, J_C–P = 9.5 Hz), 119.4 (d, J_C–P = 3.4 Hz), 113.3 (d, J_C–P = 11 Hz), 65.75 (d, J_C–P = 5.7 Hz), 55.3, 32.4 (d, J_C–P = 6.5 Hz), 21.31 (d, J_C–P = 1.5 Hz), 18.7, 13.5; ³¹P NMR (162 MHz, CDCl₃): δ 19.69; HRMS-EI calcd for C₁₆H₂₇O₄P [M]⁺: 314.1647, found: 314.1655.

Dibutyl 3,4-dimethylphenylphosphonate (3cg). Following the general procedure for compound 3, using 3,4-dimethylphenylboronic acid pinacol ester (174.1 mg, 0.75 mmol), Pd(OAc)₂ (5.6 mg, 5 mol%), Ag₂CO₃ (0.21 g, 0.75 mmol) and tetramethylammonium chloride (82 mg, 0.75 mmol) were added dibutyl phosphite (101.5 μL, 0.50 mmol) in ethanol (3.0 mL), then purified by column chromatography (SiO₂, ethyl acetate/hexane = 20–70%) to provide 3cg as a colorless oil (76.0 mg, 51% yield). ¹H NMR (400 MHz, CDCl₃): δ 7.49–7.59 (m, 2H), 7.20–7.24 (m, 1H), 3.93–4.10 (m, 4H), 2.30 (s, 6H), 1.61–1.69 (m, 4H), 1.34–1.44 (m, 4H), 0.91 (t, J = 7.2 Hz, 6H); ¹³C NMR (100 MHz, CDCl₃): δ 141.6, 136.9 (d, J_C–P = 15.4 Hz), 132.8 (d, J_C–P = 10.0 Hz), 129.6 (d, J_C–P = 43.7 Hz), 129.4 (d, J_C–P = 38.2 Hz), 125.2 (d, J_C–P = 188.4 Hz), 65.6 (d, J_C–P = 6.4 Hz), 32.4 (d, J_C–P = 7.3 Hz), 19.9, 19.6, 18.7, 13.5; ³¹P NMR (162 MHz, CDCl₃): δ 20.51; HRMS-EI calcd for C₁₆H₂₇O₃P [M]⁺: 298.1698, found: 298.1700.

Acknowledgements

The Ministry of Science and Technology, Taiwan (Most 105-2113-M-005-001-) and the National Chung Hsing University are gratefully acknowledged for financial support.

References

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Footnotes

† Electronic supplementary information (ESI) available: For ¹H and ¹³C spectra of componunds 3. See DOI: 10.1039/c7ra04619g

‡ Both authors contributed equally to this work.

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