Manganese-Catalyzed Oxophosphorylation Reaction of Carbon–Carbon Double Bonds Using Molecular Oxygen in Air

Abstract

A novel aerobic manganese-catalyzed oxophosphorylation reaction of carbon–carbon double bonds of styrene derivatives and vinyl ethers using diethyl H-phosphonates was developed. This direct transformation of alkenes to β-ketophosphonate readily proceeded at room temperature via the direct incorporation of molecular oxygen present in air (open flask).

Chemical transformations using molecular oxygen as a reagent have attracted considerable attention from both industry and academia owing to its highly atom-economical, abundant, and environmentally friendly characteristics.^1–5) Among many transition metal-catalyzed aerobic chemical transformations, methodologies for directly incorporating oxygen into unactivated carbon–carbon double bonds, such as oxyazidation,⁶⁾ oxytrifluoromethylation,^7–10) oxysulfonylation,^11–14) oxysulfurization,^15–17) and dioxygenation,^18–24) remain highly desirable in synthetic chemistry.

β-Ketophosphonates are not only fundamentally valuable intermediates for the construction of α,β-unsaturated carbonyl compounds via the Horner–Wadsworth–Emmons (HWE) reaction^25–27) but also versatile building blocks in various synthetically useful transformations.^28–31) Therefore, conventional and reliable methods have been used to access β-ketophosphonate scaffolds, including the reaction of α-haloketones with trialkylphosphites (Arbuzov reaction),^32,33) and the acylation of alkylphosphonates with esters under high basicity^34,35) (Charts 1a and 1b). In terms of the recent demand for green and sustainable chemical transformations, however, these C–P or C–C bond formation reactions still have disadvantages such as low atom economy, tedious procedures, harsh reaction conditions, or the requirement of excess amounts of organic halogen compounds and strong bases.

Chart. 1 Comparison of Previous Methods with This Study

In 2011, Wei and Ji pioneered a new route to access β-ketophosphonates via the direct oxophosphorylation of alkenes with dialkyl H-phosphonates by using pure oxygen in the presence of copper/iron salts as catalysts³⁶⁾ (Chart 1c). In contrast to the conventional syntheses of β-ketophosphonates, this straightforward chemical transformation could help pharmaceutical processes become more economic and environmentally friendly in future. Their method generated interest in aerobic oxophosphorylation of alkenes or alkynes focusing on the potential catalytic activity of copper salts.^37–39) Among them, Chen et al. reported the direct oxophosphorylation of alkenes with dialkyl H-phosphonates catalyzed by cationic copper (II)–acetonitrile complex prepared from CuSO₄·5H₂O in situ under open-air conditions at 60°C⁴⁰⁾ (Chart 1c). These approaches provided novel methods for the continuous C–P and C–O bond formation reactions of unactivated alkenes; however, the choice of transition-metal catalyst for the aerobic oxophosphorylation of alkenes has been limited to the copper catalyzed system.

As part of our ongoing studies on manganese-catalyzed oxidative difunctionalization of alkenes,^18,41) we report herein the novel aerobic oxophosphorylation of unactivated alkenes and acid-labile vinyl ethers with diethyl H-phosphonates using a catalytic amount of tris(2,4-pentanedionato)manganese(III) (Mn(acac)₃) (Chart 1d). Concerning the formation of dialkyl phosphonyl radical by a manganese complex, Ishii et al. mentioned it in the hydrophosphorylation reaction of alkenes with diethyl H-phosphonates in the presence of Mn(OAc)₂ in air.⁴²⁾ Lately, Zou’s group reported that the use of excess amount of Mn(OAc)₃ (2 equiv.) in methanol in air at elevated temperatures promoted the oxophosphorylations of the alkene in styrene derivatives with dimethyl H-phosphonates.⁴³⁾ However, to the best of our knowledge, manganese-catalyzed aerobic oxophosphorylation leading to β-ketophosphonates via continuous C–P bond formation and incorporation of molecular oxygen to organic frameworks has not been achieved yet.

Results and Discussion

To test whether the manganese-catalyzed oxophosphorylation of alkenes could proceed, the present study commenced with the reaction of 1-methyl-4-vinylbenzene (1a) with diethyl H-phosphonate (2) in the presence of 10 mol% of Mn(acac)₃ in MeCN under open-air conditions at room temperature (Table 1). Fortunately, the catalytic oxophosphorylation reaction proceeded to give the desired β-ketophosphonate 3a in 24% yield, accompanied by β-hydroxy phosphonate 3′a in 34% yield as a side product (Table 1, entry 1). Encouraged by this impressive result, we subsequently sought to improve the product selectivity. The addition of tertiary alkylamines such as Et₃N, ⁱPr₂NEt, and N,N-dicyclohexylethylamine (Cy₂NEt) did not affect the product selectivity. However, a significant effect on the product selectivity was observed by the addition of pyridine to afford exclusively provided β-ketophosphonate 3a in 82% yield without the formation of β-hydroxy phosphonate 3′a (Table 1, entry 5). Given the efficacy of pyridine, we further evaluated the performance of other pyridine analogs. The use of 4-methoxypyridine, 4-(tert-butyl)pyridine, or 4-dimethylaminopyridine (DMAP) afforded the desired product 3a with high product selectivity but lowered the yield of 3a (Table 1, entries 7–9). In contrast, the reactions using sterically hindered pyridine analogs, relatively electron-deficient pyridine analogs, or 2,2′-bipyridyl did not improve the product selectivity (Table 1, entries 10–13). The addition of other bases, such as N,N,N′,N′-tetramethylethylenediamine (TMEDA) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), completely inhibited this oxidative transformation (Table 1, entries 14–16). Consequently, pyridine was essential for a dramatic increase of the product selectivity. A small amount of Mn(acac)₃ (5 mol%) afforded the low conversion (Table 1, entry 6). Other manganese species, such as tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (Mn(dpm)₃), tris(dibenzoylmethanato)manganese(III) (Mn(dbm)₃), MnBr₂, Mn(OAc)₂, Mn(OAc)₃·2H₂O, or manganese(III) phthalocyanine chloride ([Mn^III(Pc)]Cl)), showed no or less catalytic activity (Table 1, entries 17–22). In contrast, Mn(acac)₂ promoted the oxophosphorylation in 76% yield (Table 1, entry 23). These results indicate that the use of Mn(acac)₃ or Mn(acac)₂ with β-diketone ligand such as acetylacetone is indispensable to the success of this catalytic oxophosphorylation reaction. Solvent screening showed that MeCN is the best choice for this reaction, whereas the use of CH₂Cl₂, benzene, tetrahydrofuran (THF), acetone, MeOH, N,N-dimethylformamide (DMF), or dimethyl sulfoxide (DMSO) as a solvent resulted in low yields (for details, see also Table S1 in the Supplementary materials). The best yield of 3a (82%) was obtained by employing 10 mol% of Mn(acac)₃ and 3 eq of pyridine in MeCN at room temperature for 21 h under open-air conditions⁴⁴⁾ (Table 1, entry 5).

Table 1. Optimization of Manganese-Catalyzed Oxophosphorylation Reaction of 1-Methyl-4-vinylbenzene (1a) with Diethyl H-Phosphonate (2) Using Molecular Oxygen in Air^a)

Entry	Catalyst (mol%)	Base	Yield of 3aa (%)	Yield of 3′aa (%)
1	Mn(acac)3 (10)	—	24	34
2	Mn(acac)3 (10)	Et3N	20	19
3	Mn(acac)3 (10)	iPr2NEt	20	28
4	Mn(acac)3 (10)	Cy2NEt	20	30
5	Mn(acac)3 (10)	Pyridine	82	0
6	Mn(acac)3 (5.0)	Pyridine	23	0
7	Mn(acac)3 (10)	4-Methoxypyridine	64	0
8	Mn(acac)3 (10)	4-(tert-Butyl)pyridine	74	0
9	Mn(acac)3 (10)	DMAP	36b)	3b)
10	Mn(acac)3 (10)	4-(Trifluoromethyl)pyridine	23	26
11	Mn(acac)3 (10)	2,6-Dimethylpyridine	33	21
12	Mn(acac)3 (10)	2,4,6-Trimethylpyridine	24	21
13	Mn(acac)3 (10)	DTBMPc)	22	30
14	Mn(acac)3 (10)	TMEDA	N.D.	N.D.
15	Mn(acac)3 (10)	2,2′-Bipyridyl	19b)	20b)
16	Mn(acac)3 (10)	DBU	N.D.b)	N.D.b)
17	Mn(dpm)3 (10)	Pyridine	10b)	N.D.b)
18	Mn(dbm)3 (10)	Pyridine	<1b)	N.D.b)
19	MnBr2 (10)	Pyridine	<1b)	N.D.b)
20	Mn(OAc)2 (10)	Pyridine	N.D.b)	N.D.b)
21	Mn(OAc)3·2H2O (10)	Pyridine	N.D.b)	N.D.b)
22	[MnIII(Pc)]Cl (10)	Pyridine	N.D.b)	N.D.b)
23	Mn(acac)2 (10)	Pyridine	76b)	13

a) Reaction conditions: 1a (1.0 mmol), 2 (2.0 mmol), manganese salt (10 mol%), MeCN (1.0 mL), O₂ (flask open to air), and room temperature. b) The yield was determined via ¹H-NMR analysis of the crude reaction mixture using 1,1,2,2-tetrabromoethane as an internal standard. c) DTBMP=2,6-di-tert-butyl-4-methylpyridine.

Using these optimized reaction conditions, the substrate scope of this reaction was investigated. As demonstrated in Table 2, a variety of β-ketophosphonates 3 can be directly obtained from alkenes via Mn(acac)₃-catalyzed oxophosphorylation reaction. The styrene derivatives bearing either electron-rich or electron-deficient groups on aromatic rings were converted to the corresponding β-ketophosphonates in moderate to good yields (3a–3k). Notably, internal aromatic alkenes were tolerated in this process, thus leading to the desired products in good yields (3l–3n). Nevertheless, when heteroaromatic alkenes, such as 4-vinylpyridine (1o), or an aliphatic alkene, such as but-3-en-1-ylbenzene (1p), was used as the substrate, the corresponding product was obtained in low yields (3o and 3p). It is noteworthy that this mild transformation was applicable for various acid-liable vinyl ethers, such as 2-methyl-2-(vinyloxy)propane (4a), 2-methyl-1-(vinyloxy)propane (4b), 1-(vinyloxy)butane (4c), 2-(vinyloxy)propane (4d), and (vinyloxy)benzene (4e), to obtain the corresponding 2-(diethoxyphosphoryl)acetate (5a–5e) in acceptable yields (Table 3). The wide substrate scope of both alkenes and vinyl ethers illustrates the potential of our reaction to efficiently produce a broad range of β-ketophosphonates.

Table 2. Substrate Scope of the Mn(acac)₃-Catalyzed Oxophosphorylation Reaction of Alkenes with Diethyl H-Phosphonate^{a), b)}

a) Reaction conditions: 1a–p (1.0 mmol), 2 (2.0 mmol), Mn(acac)₃ (10 mol%), pyridine (3.0 mmol), MeCN (1.0 mL), O₂ (flask open to air), and room temperature. b) Yield of isolated products was based on 1a–p.

Table 3. Substrate Scope of Mn(acac)₃-Catalyzed Oxophosphorylation Reaction of Vinyl Ethers with Diethyl H-Phosphonate^{a), b)}

a) Reaction conditions: 4a–e (1.0 mmol), 2 (2.0 mmol), Mn(acac)₃ (10 mol%), pyridine (3.0 mmol), MeCN (1.0 mL), O₂ (flask open to air), and room temperature. b) Yield of isolated products was based on 4a–e.

Conclusion

In conclusion, we have successfully developed a novel method for the preparation of β-ketophosphonates from alkenes and diethyl H-phosphonates catalyzed by Mn(acac)₃. To the best of our knowledge, this reaction is the first example of oxophosphorylation reaction utilizing manganese catalytic systems via the direct incorporation of molecular oxygen from air. All of the experimental procedures in this reaction can be performed in air without cooling, heating, or high pressure. This methodology serves an alternative approach to produce β-ketophosphonates because of its simplicity and mildness. Experiments aimed at elucidating the reaction mechanism as well as demonstrating the synthetic applications of the aerobic oxophosphorylation reaction are currently underway in our laboratory.

Experimental

General Information

IR spectra were obtained using a JASCO FT/IR 460-plus spectrophotometer. ¹H- and ¹³C-NMR spectra were obtained on Agilent Technologies 400-MR DD2, 400-MR spectrometers. The chemical shifts are expressed in ppm downfield from internal solvent peaks CDCl₃ (7.26 ppm, ¹H-NMR), CDCl₃ (77.0 ppm, ¹³C-NMR), and coupling constant (J values) are given in Hertz. The coupling patterns are expressed by s (singlet), d (doublet), dd (doublet of doublet), t (triplet), td (triplet of doublet), sep (septet), m (multiplet) and br (broad signal). MS spectra were measured with JEOL JMS-AX505HA, JMS-700 V MStation and JEOL JMS-T100LP spectrometers. Commercial reagents and solvents were used without further purification unless otherwise indicated. Flash column chromatography was carried out with Kanto Chemical silica gel (Kanto Chemical Co., Inc., silica gel 60N, spherical neutral, particle size 63–210 µm). TLC was performed on 0.25 mm E Merck silica gel 60 F254 plates.

Representative Procedure for Mn(acac)₃-Catalyzed Oxophosphorylation Reaction

A 10 mL test tube was charged with 1-methyl-4-vinylbenzene (1a) (118.2 mg, 1.00 mmol), MeCN (1.0 mL), diethyl phosphonate (2) (258 µL, 2.00 mmol) and pyridine (243 µL, 3.00 mmol). The solution was stirred at room temperature in air (open flask). After 21 h, the reaction was quenched with saturated aqueous NaCl solution (0.5 mL). The resulting mixture was extracted with ethyl acetate (3×1.0 mL). The combined organic phases were washed with brine (1.0 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure. The obtained crude material was purified by column chromatography (silica gel, hexane : EtOAc=1 : 1) to afford 3a (221.5 mg, 0.82 mmol, 82%).

Characterization Data for Products

Diethyl (2-Oxo-2-(p-tolyl)ethyl)phosphonate (3a)⁴⁰⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.90 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.0 Hz, 2H), 4.16–4.08 (m, 4H), 3.59 (d, ²J_P–H=22.8 Hz, 2H), 2.40 (s, 3H), 1.27 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 191.45 (d, ²J_P–C=6.4 Hz), 144.59, 134.07 (d, ³J_P–C=2.0 Hz), 129.25, 129.16, 62.55 (d, ²J_P–C=6.4 Hz), 38.36 (d, ¹J_P–C=129.0 Hz), 21.64, 16.21 (d, ³J_P–C=6.2 Hz); IR (neat): 2986, 2929, 1676, 1607, 1253, 1025, 967, 807 cm⁻¹; high resolution (HR)-MS (electrospray ionization (ESI), trifluoroacetic acid (TFA)-Na): Calcd for C₁₃H₁₉NaO₄P [M+Na]⁺ 293.0919, found 293.0917.

Diethyl (2-Oxo-2-(m-tolyl)ethyl)phosphonate (3b)⁴⁵⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.82–7.80 (m, 2H), 7.41–7.34 (m, 2H), 4.17–4.10 (m, 4H), 3.62 (d, ²J_P–H=22.8 Hz, 2H), 2.42 (s, 3H), 1.28 (td, ³J=7.2, ⁴J_P–H=0.4 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 192.14 (d, ²J_P–C=6.6 Hz), 138.42, 136.60 (d, ³J_P–C=2.2 Hz), 134.44, 129.46, 128.47, 126.36, 62.61 (d, ²J_P–C=6.5 Hz), 38.50 (d, ¹J_P–C=129.2 Hz), 21.32, 16.24 (d, ³J_P–C=6.4 Hz); IR (neat): 2964, 2929, 1680, 1603, 1394, 1260, 1027, 970, 798 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₃H₁₉NaO₄P [M+Na]⁺ 293.0919, found 293.0916.

Diethyl (2-(4-(tert-Butyl)phenyl)-2-oxoethyl)phosphonate (3c)⁴⁰⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.95 (d, J=8.8 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 4.18–4.09 (m, 4H), 3.61 (d, ²J_P–H=22.4 Hz, 2H), 1.34 (s, 9H), 1.28 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 191.34 (d, ²J_P–C=6.5 Hz), 157.33, 133.83 (d, ³J_P–C=2.2 Hz), 128.87, 125.38, 62.45 (d, ²J_P–C=6.6 Hz), 38.17 (d, ¹J_P–C=129.5 Hz), 34.98, 30.85, 16.06 (d, ³J_P–C=6.4 Hz); IR (neat): 2965, 2866, 1679, 1605, 1255, 1063, 1025, 970, 822 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₆H₂₅NaO₄P [M+Na]⁺ 335.1388, found 335.1385.

Diethyl (2-(4-Methoxyphenyl)-2-oxoethyl)phosphonate (3d)⁴⁰⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 8.00 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 4.17–4.10 (m, 4H), 3.88 (s, 3H), 3.58 (d, ²J_P–H=22.8 Hz, 2H), 1.29 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 190.25 (d, ²J_P–C=6.4 Hz), 163.97, 131.49, 129.62 (d, ³J_P–C=2.0 Hz), 113.74, 62.57 (d, ²J_P–C=6.4 Hz), 55.49, 38.27 (d, ¹J_P–C=129.1 Hz), 16.24 (d, ³J_P–C=6.3 Hz); IR (neat): 2983, 2935, 1671, 1600, 1575, 1512, 1422, 1260, 1176, 1026, 968, 804 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₃H₁₉NaO₅P [M+Na]⁺ 309.0868, found 309.0868.

Diethyl (2-(4-Ethoxyphenyl)-2-oxoethyl)phosphonate (3e)

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.98 (d, J=9.2 Hz, 2H), 6.92 (d, J=9.2 Hz, 2H), 4.17–4.08 (m, 4H), 3.57 (d, ²J_P–H=22.8 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H), 1.28 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 190.24 (d, ²J_P–C=6.4 Hz), 163.42, 131.50, 129.46 (d, ³J_P–C=2.0 Hz), 114.17, 63.82, 62.58 (d, ²J_P–C=6.5 Hz), 38.27 (d, ¹J_P–C=128.8 Hz), 16.25 (d, ³J_P–C=6.3 Hz), 14.62; IR (neat): 2983, 2934, 1671, 1601, 1574, 1511, 1395, 1258, 1176, 1026, 967, 806 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₄H₂₁NaO₅P [M+Na]⁺ 323.1024, found 323.1021.

Diethyl (2-Oxo-2-(3,4,5-trimethoxyphenyl)ethyl)phosphonate (3f)

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.32 (s, 2H), 4.18–4.11 (m, 4H), 3.92 (s, 9H), 3.60 (d, ²J_P–H=22.8 Hz, 2H), 1.30 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 190.64 (d, ²J_P–C=6.4 Hz), 152.97, 143.11, 131.66 (d, ³J_P–C=1.6 Hz), 106.68, 62.68 (d, ²J_P–C=6.4 Hz), 60.93, 56.30, 38.73 (d, ¹J_P–C=128.6 Hz), 16.27 (d, ³J_P–C=6.2 Hz); IR (neat) 2982, 2935, 2836, 1675, 1585, 1505, 1462, 1417, 1335, 1253, 1128, 1024, 969, 895 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₅H₂₃NaO₇P [M+Na]⁺ 369.1079, found 369.1070.

Diethyl (2-(Benzo[d][1,3]dioxol-5-yl)-2-oxoethyl)phosphonate (3g)⁴⁵⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.64 (dd, J=8.0, 1.6 Hz, 1H), 7.48 (d, J=1.6 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.05 (s, 2H), 4.18–4.10 (m, 4H), 3.55 (d, ²J_P–H=22.4 Hz, 2H), 1.30 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 189.84 (d, ²J_P–C=6.4 Hz), 152.35, 148.26, 131.45 (d, ³J_P–C=1.8 Hz), 126.06, 108.51, 107.85, 101.99, 62.63 (d, ²J_P–C=6.6 Hz), 38.45 (d, ¹J_P–C=129.4 Hz), 16.28 (d, ³J_P–C=6.2 Hz); IR (neat): 2984, 2905, 1671, 1604, 1490, 1446, 1353, 1262, 1034, 969, 809 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₃H₁₇NaO₆P [M+Na]⁺ 323.0660, found 323.0656.

Diethyl (2-(Naphthalen-2-yl)-2-oxoethyl)phosphonate (3h)⁴⁶⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 8.56–8.56 (br s, 1H), 8.06 (dd, J=8.0, 2.0 Hz, 1H), 7.99 (d, J=8.0 Hz, 1H), 7.91−7.87 (m, 2H), 7.64−7.60 (m, 1H), 7.59–7.55 (m, 1H), 4.20−4.11 (m, 4H), 3.76 (d, ²J_P–H=22.8 Hz, 2H), 1.28 (td, ³J=7.2, ⁴J_P–H=0.4 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 191.81 (d, ²J_P–C=6.7 Hz), 135.80, 133.89, 132.40, 131.45, 129.79, 128.87, 128.48, 127.76, 126.89, 124.17, 62.67 (d, ²J_P–C=6.6 Hz), 38.63 (d, ¹J_P–C=129.0 Hz), 16.26 (d, ³J_P–C=6.3 Hz); IR (neat): 2984, 2916, 1674, 1289, 1248, 1024, 965, 813 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₆H₁₉NaO₄P [M+Na]⁺ 329.0919, found 329.0910.

Diethyl (2-(4-Fluorophenyl)-2-oxoethyl)phosphonate (3i)⁴⁶⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 8.07–8.04 (m, 2H), 7.16–7.12 (m, 2H), 4.17–4.09 (m, 4H), 3.59 (d, ²J_P–H=22.8 Hz, 2H), 1.28 (td, ³J=7.2, ⁴J_P–H=0.4 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 190.32 (d, ²J_P–C=6.4 Hz), 166.09 (d, ¹J_F-C=255.1 Hz), 132.95–132.93 (m), 131.85 (d, ³J_F-C=9.5 Hz), 115.73 (d, ²J_F-C=21.9 Hz), 62.69 (d, ²J_P–C=6.6 Hz), 38.63 (d, ¹J_P–C=128.7 Hz), 16.23 (d, ³J_P–C=6.4 Hz); IR (neat): 2985, 2934, 1681, 1598, 1508, 1414, 1249, 1160, 1026, 970, 823 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₂H₁₆FNaO₄P [M+Na]⁺ 297.0668, found 297.0657.

Diethyl (2-(4-Chlorophenyl)-2-oxoethyl)phosphonate (3j)⁴⁶⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.95 (d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 4.16−4.08 (m, 4H), 3.58 (d, ²J_P–H=22.8 Hz, 2H), 1.27 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 190.68 (d, ²J_P–C=6.4 Hz), 140.22, 134.78 (d, ³J_P–C=1.9 Hz), 130.46, 128.88, 62.70 (d, ²J_P–C=6.5 Hz), 38.62 (d, ¹J_P–C=128.7 Hz), 16.20 (d, ³J_P–C=6.4 Hz); IR (neat): 2987, 2939, 1689, 1412, 1328, 1254, 1170, 1131, 1066, 1026, 970, 822 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₂H₁₆ClNaO₄P [M+Na]⁺ 313.0372, found 313.0357.

Diethyl (2-Oxo-2-(4-(trifluoromethyl)phenyl)ethyl)phosphonate (3k)⁴⁵⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 8.13 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 4.18−4.10 (m, 4H), 3.64 (d, ²J_P–H=23.2 Hz, 2H), 1.28 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 191.07 (d, ²J_P–C=6.7 Hz), 139.08, 135.00–134.34 (m), 129.39, 125.65 (q, ³J_F-C=3.6 Hz), 123.48 (q, ¹J_F-C=271.5 Hz), 62.80 (d, ²J_P–C=6.4 Hz), 38.95 (d, ¹J_P–C=128.6 Hz), 16.21 (d, ³J_P–C=6.2 Hz); IR (neat): 2984, 2937, 1681, 1589, 1402, 1253, 1092, 1025, 969, 814 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₃H₁₆F₃NaO₄P [M+Na]⁺ 347.0636, found 347.0631.

Diethyl (1-Oxo-1-phenylpropan-2-yl)phosphonate (3l)³⁸⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 8.01–7.99 (m, 2H), 7.59–7.56 (m, 1H), 7.49–7.45 (m, 2H), 4.23–4.01 (m, 5H), 1.54 (dd, ³J_P–H=18.0 Hz, ³J=7.2 Hz, 3H), 1.28 (t, J=7.2, 3H), 1.19 (t, J=7.2, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 196.49 (d, ²J_P–C=5.2 Hz), 136.85 (d, ³J_P–C=1.8 Hz), 133.31, 128.84, 128.48, 62.71 (d, ²J_P–C=6.9 Hz), 62.60 (d, ²J_P–C=6.7 Hz), 41.31 (d, ¹J_P–C=129.8 Hz), 16.33 (d, ³J_P–C=6.1 Hz), 16.18 (d, ³J_P–C=6.2 Hz), 12.22 (d, ²J_P–C=6.5 Hz); IR (neat): 2988, 2923, 1680, 1450, 1265, 1024, 970, 803 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₃H₁₉NaO₄P [M+Na]⁺ 293.0919, found 293.0907.

Diethyl (1-(4-Methoxyphenyl)-1-oxopropan-2-yl)phosphonate (3m)⁴⁰⁾

Yellow oil, ¹H-NMR (400 MHz, CDCl₃) δ: 8.00 (d, J=8.8 Hz, 2H), 6.94 (d, J=8.8 Hz, 2H), 4.21–4.01 (m, 5H), 3.87 (s, 3H), 1.51 (dd, ³J_P–H=18.0 Hz, ³J=6.8 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 1.21 (t, J=7.2 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 194.70 (d, ²J_P–C=4.8 Hz), 163.75, 131.25, 129.74 (d, ³J_P–C=1.9 Hz), 113.62, 62.59 (d, ²J_P–C=6.7 Hz), 62.57 (d, ²J_P–C=6.8 Hz), 55.47, 40.88 (d, ¹J_P–C=129.8 Hz), 16.34 (d, ³J_P–C=6.0 Hz), 16.24 (d, ³J_P–C=6.2 Hz), 12.29 (d, ²J_P–C=6.5 Hz); IR (neat): 2988, 2923, 1680, 1450, 1265, 1024, 970, 803 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₄H₂₁NaO₅P [M+Na]⁺ 323.1024, found 323.1019.

Diethyl (1-(Benzo[d][1,3]dioxol-5-yl)-1-oxopropan-2-yl)phosphonate (3n)

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.63 (dd, J=8.0, 2.0 Hz, 1H), 7.48 (d, J=2.0 Hz, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.05 (s, 2H), 4.17–4.00 (m, 5H), 1.51 (dd, ³J_P–H=18.0, ³J=7.2 Hz, 3H), 1.29 (td, ³J=7.2, ⁴J_P–H=0.4 Hz, 3H), 1.23 (td, ³J=7.2, ⁴J_P–H=0.4 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 194.36 (d, ²J_P–C=4.8 Hz), 152.08, 148.18, 131.60 (d, ³J_P–C=1.8 Hz), 125.50, 108.60, 107.75, 101.92, 62.66 (d, ²J_P–C=6.7 Hz), 62.64 (d, ²J_P–C=6.9 Hz), 41.11 (d, ¹J_P–C=129.7 Hz), 16.36 (d, ³J_P–C=5.8 Hz), 16.28 (d, ³J_P–C=6.2 Hz), 12.45 (d, ²J_P–C=6.5 Hz); IR (neat): 2982, 2943, 1672, 1600, 1511, 1458, 1420, 1391, 1323, 1239, 1174, 1025, 966, 847 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₄H₁₉NaO₆P [M+Na]⁺ 337.0817, found 337.0807.

Diethyl (2-Oxo-2-(pyridin-4-yl)ethyl)phosphonate (3o)⁴⁷⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 8.83 (d, J=6.0 Hz, 2H), 7.80 (d, J=6.0 Hz, 2H), 4.18–4.11 (m, 4H), 3.62 (d, ²J_P–H=23.2 Hz, 2H), 1.29 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 191.60 (d, ²J_P–C=7.0 Hz), 150.97, 142.24 (d, ³J_P–C=1.8 Hz), 121.68, 62.88 (d, ²J_P–C=6.4 Hz), 38.90 (d, ¹J_P–C=128.3 Hz), 16.22 (d, ³J_C−P=6.2 Hz); IR (neat): 2984, 2925, 1695, 1559, 1412, 1258, 1024, 966, 803 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₁H₁₆NNaO₄P [M+Na]⁺ 280.0175, found 280.0710.

Diethyl (2-Oxo-4-phenylbutyl)phosphonate (3p)⁴⁸⁾

Yellow oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.29−7.25 (m, 2H), 7.20–7.17 (m, 3H), 4.15−4.07 (m, 4H), 3.06 (d, ²J_P–H=22.8 Hz, 2H), 2.99−2.95 (m, 2H), 2.93−2.89 (m, 2H), 1.31 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 201.11 (d, ²J_P–C=6.2 Hz), 140.62, 128.46, 128.37, 126.14, 62.55 (d, ²J_P–C=6.6 Hz), 45.45 (d, ³J_P–C=0.9 Hz), 42.60 (d, ¹J_P–C=126.6 Hz), 29.43, 16.30 (d, ³J_P–C=6.2 Hz); IR (KBr): 2984, 2927, 1715, 1395, 1260, 1026, 967, 803 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₄H₂₁NaO₄P [M+Na]⁺ 307.1075, found 307.1071.

tert-Butyl 2-(Diethoxyphosphoryl)acetate (5a)⁴⁹⁾

Colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ: 4.15–4.07 (m, 4H), 2.82 (d, ²J_P–H=21.2 Hz, 2H), 1.42 (s, 9H), 1.29 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 164.81 (d, ²J_P–C=6.2 Hz), 81.90, 62.39 (d, ²J_P–C=6.2 Hz), 35.52 (d, ¹J_P–C=132.3 Hz), 27.83, 16.24 (d, ³J_P–C=6.2 Hz); IR (neat) 2982, 2932, 1729, 1369, 1290, 1256, 1167, 1115, 1026, 971 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₀H₂₁NaO₅P [M+Na]⁺ 275.1024, found 275.1019.

Isobutyl 2-(Diethoxyphosphoryl)acetate (5b)⁵⁰⁾

Colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ: 4.18–4.11 (m, 4H), 3.90 (d, J=6.8 Hz, 2H), 2.94 (d, ²J_P–H=21.6 Hz, 2H), 1.98–1.88 (m, 1H), 1.32 (t, J=6.8 Hz, 6H), 0.92 (d, J=6.8 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 165.80 (d, ²J_P–C=6.2 Hz), 71.55, 62.54 (d, ²J_P–C=6.2 Hz), 34.25 (d, ¹J_P–C=133.7 Hz), 27.60, 18.90, 16.25 (d, ³J_P–C=6.2 Hz); IR (neat) 2965, 1736, 1472, 1394, 1273, 1118, 1026, 972, 838 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₀H₂₁NaO₅P [M+Na]⁺ 275.1024, found 275.1020.

Butyl 2-(Diethoxyphosphoryl)acetate (5c)⁵¹⁾

Colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ: 4.19–4.11 (m, 6H), 2.94 (d, ²J_P–H=21.6 Hz, 2H), 1.65–1.58 (m, 2H), 1.43–1.34 (m, 2H), 1.33 (t, J=7.2 Hz, 6H), 0.92 (t, J=7.2 Hz, 3H); ¹³C-NMR (100 MHz, CDCl₃) δ: 165.84 (d, ²J_P–C=6.2 Hz), 65.37, 62.59 (d, ²J_P–C=6.4 Hz), 34.30 (d, ¹J_P–C=133.7 Hz), 30.46, 18.92, 16.26 (d, ³J_P–C=6.2 Hz), 13.57; IR (neat) 2963, 1737, 1394, 1277, 1117, 1025, 971, 841 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₀H₂₁NaO₅P [M+Na]⁺ 275.1024, found 275.1020.

Isopropyl 2-(Diethoxyphosphoryl)acetate (5d)⁵⁰⁾

Colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ: 5.05 (sep, J=6.0 Hz, 1H), 4.21–4.13 (m, 4H), 2.93 (d, ²J_P–H=21.6 Hz, 2H), 1.35 (t, J=7.2 Hz, 6H), 1.26 (d, J=6.0 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 165.32 (d, ²J_P–C=6.2 Hz), 69.14, 62.59 (d, ²J_P–C=6.4 Hz), 34.66 (d, ¹J_P–C=133.1 Hz), 21.65, 16.31 (d, ³J_P–C=6.2 Hz); IR (neat) 2984, 1731, 1276, 1107, 1025, 968, 802 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₉H₁₉NaO₅P [M+Na]⁺ 261.0868, found 261.0860.

Phenyl 2-(Diethoxyphosphoryl)acetate (5e)⁵²⁾

Colorless oil; ¹H-NMR (400 MHz, CDCl₃) δ: 7.39 (t, J=7.6 Hz, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.13–7.10 (m, 2H), 4.27–4.20 (m, 4H), 3.20 (d, ²J_P–H=21.6 Hz, 2H), 1.38 (t, J=7.2 Hz, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 164.39 (d, ²J_P–C=6.5 Hz), 150.41, 129.38, 126.06, 121.25, 62.83 (d, ²J_P–C=6.2 Hz), 34.43 (d, ¹J_P–C=132.3 Hz), 16.25 (d, ³J_P–C=6.2 Hz); IR (neat) 2984, 2928, 1756, 1599, 1486, 1262, 1188, 1103, 1023, 970 cm⁻¹; HR-MS (ESI, TFA-Na): Calcd for C₁₂H₁₇NaO₅P [M+Na]⁺ 295.0711, found 295.0706.

Acknowledgments

This work was supported by Japan Society for the Promotion of Science (JSPS) KAKENHI (Grant Number 17K08217 to D. Y.) and a Kitasato University Research Grant for Young Researchers. We thank Dr. K. Nagai and Ms. M. Sato of Kitasato University for instrumental analyses.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

The online version of this article contains supplementary materials.

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