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Synthesis 2024; 56(11): 1677-1686
DOI: 10.1055/a-2133-1963
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New Trends in Organic Synthesis from Chinese Chemists

Synthesis of β-Hydroxyhydrophosphonic Acids from Inorganic Sodium Hypophosphite

Dang-Wei Qian
a   State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, P. R. of China
,
Jin Yang
a   State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, P. R. of China
,
Gang-Wei Wang
a   State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, P. R. of China
,
Shang-Dong Yang∗
a   State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222 South Tianshui Road, Lanzhou 730000, P. R. of China
b   State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. of China
› Author Affiliations

We are grateful to the NSFC (No. 22171119) and Gansu Province Science and Technology plan for major projects (No. 21ZD4WA021) and key research plan (No. 21YF5WA114) for financial support.
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Abstract

An efficient approach to access β-hydroxyhydrophosphonic acid derivatives is reported by ring-opening reaction of readily available epoxides with green, inexpensive, and safe inorganic salt sodium hypophosphate as the phosphorus source in the presence of silver trifluoromethanesulfonate as the catalyst. The reaction is achieved under simple operation and exhibits excellent selectivity as well as good functional group compatibility.


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Key words

sodium hypophosphite - β-hydroxyhydrophosphonic acid - ethylene oxide compounds

Biographical Sketches

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Dang-Wei Qian was born in 1993 in Henan, China. He is working as a postgraduate fellow (since 2016) at Lanzhou University (P. R. China) with Prof. Shang-Dong Yang. His research projects focus on the study on the synthesis of organophosphine compounds from sodium hypophosphite.

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Jin Yang was born in 1996 in Zhejiang, China. She is working as a postgraduate fellow (since 2019) at Lanzhou University (P. R. China) with Prof. Shang-Dong Yang. Her research projects focus on the study on the synthesis of organophosphine compounds from sodium hypophosphite.

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Prof. Dr. Gang-Wei Wang was born in 1987 in Gansu, China. He obtained his B.Sc. (2010) and Ph.D. (2015) from the State Key Laboratory of Applied Organic Chemistry, Lanzhou University (Ph.D. supervisor: Prof. Shang-Dong Yang). After that he moved to University of Bristol (United Kingdom) to conduct his first postdoctoral appointment with Prof. John Bower (2015–2019) and the second postdoctoral appointment with Prof. Igor Larrosa at the University of Manchester (United Kingdom, 2019–2021). In 2022, he returned to Lanzhou University and took a professor position. His current research interest focuses on the development of transition-metal-catalyzed asymmetric catalysis.

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Prof. Dr. Shang-Dong Yang was born in 1973 in Gansu, China. He received his B.Sc. (1997) and Ph.D. (2006) in organic chemistry from Lanzhou University (P. R. China). He worked as a postdoctoral fellow (2006–2007) at Peking University (P. R. China) with Prof. Zhang-Jie Shi. Then he moved to The University of Chicago (USA), doing his postdoctoral work (2007–2009) with Prof. Chuan He. He obtained a professor position at Lanzhou University in 2009 and is working at the State Key Laboratory of Applied Organic Chemistry. His current research interest focuses on the phosphorus chemistry.

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Scheme 1 Representatives of important β-hydroxyhydrophosphonic acid derivatives and different strategies for their synthesis

β-Hydroxyhydrophosphonic acid (β-hydroxyphosphinic acid) and its derivatives are highly useful compounds, which are present in many important natural products, bioactive molecules, flame retardants, ligands and function as intermediates in organic synthesis[1] (Scheme [1] a). As a result, the development of efficient method to access such compounds has attracted a lot of research interest, and many synthetic methods have been achieved in the past few decades[2] (Scheme [1b]). Normally, organic phosphine sources such as trialkyl phosphites, dialkyl phosphites, primary or secondary phosphines, secondary phosphine oxides, which are prepared from phosphorus trichloride (PCl3) are needed for a successful outcome. While phosphorus trichloride is sensitive to air and moisture there is significant barrier to its storage and general synthetic application. Meanwhile, the production of PCl3 from white phosphorus and hazardous chlorine gas is an energy-intensive process and lead to severe pollution issues. Therefore, the search for a stable, cheap, and green phosphorous sources that can be directly used in the synthesis of hydroxyphosphonic acid and its derivatives is highly appealing yet a challenging topic.

Epoxides are important building blocks in organic synthesis, because: 1) epoxides are generally stable and readily available, they can be easily prepared from alkene, aldehyde or ketone by using classical methods; 2) epoxides bearing inherently strained nature permit them for facile ring opening; 3) the opening of epoxide normally occurs in redox-neutral form and the product incorporates all atoms, thus is an atom economic reaction; and 4) the resulting hydroxide group in the final product is a useful functional handle for further transformation. To date, epoxide ring-opening reactions mediated by carbon nucleophile,[3] oxygen nucleophile,[4] nitrogen nucleophile,[4a] [5] sulfur nucleophile,[6] etc. have been extensively studied, resulting in reliable routes for the formation of C–C, C–O, C–N, C–S bonds.[7] The use of phosphine nucleophile to achieve the ring opening of epoxide was also reported, producing a series of important β-hydroxyphosphine products with good efficiency.[8] However, these methods normally use phosphite or phosphate that is prepared from PCl3 as the phosphine source. In recent years, the Montchamp group has made outstanding contributions in finding alternative phosphine sources to replace the PCl3 in the synthesis of organic phosphine compound.[9] For example, the use of hypophosphite has obtained huge success.[10] Nevertheless, applying all phosphine sources as the phosphine nucleophiles to mediate the ring opening of epoxides is not suitable for the preparation of β-hydroxyphosphonic acid derivatives. Recently, our group reported the first example that directly used inorganic salt NaH2PO2 as the phosphine source in the multicomponent nickel-catalyzed alkynyl hydrophosphinylation reaction.[11] Undoubtedly, the inorganic salt NaH2PO2 is an ideal reagent for the synthesis of phosphate compounds due to its feature of abundancy, stability (no specific storage or transportation requirements), and green (obtained from white phosphorus and basic solvent, and possessing low toxicity). Herein, we report the first example that directly use NaH2PO2 as the phosphine source in the synthesis of β-hydroxyhydrophosphonic acid derivatives (Scheme [1c]). The reaction was achieved in a simple catalytic system with silver trifluoromethanesulfonate in a catalytic amount and exhibited excellent site selectivity as well as good functional group compatibility.

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Scheme 2 Substrate cope examinations. Reagents and conditions: NaH2PO2 (0.2 mmol), epoxy compound (0.6 mmol), catalyst (5 mol%), ligand (10 mol%), anhydrous solvent (1.0 mL) at the corresponding temperature under argon for 36 h. Isolated yields are shown. a Reaction conducted at 130 °C for 60 h.

In the initial studies, we selected NaH2PO2 (1) and styrene oxide (2) as the standard substrates, to search for the suitable conditions to access β-hydroxyhydrophosphonic acid 3a (Table [1]). The Lewis acids were first evaluated and when silver trifluoromethanesulfonate or bismuth trifluoromethanesulfonate was used as the catalyst, the desired product 3a was obtained in moderate yield (Table1, entries 1–4). It is worth mentioning that 3a was the only product generated in these systems, and the regioisomer that result from styrene oxide-opening from the more reactive benzylic C–O bond was not detected. As silver trifluoromethanesulfonate is cheaper than bismuth trifluoromethanesulfonate, the former was chosen as the catalyst for further condition screening. Then, we found that when the reaction temperature was below 80 °CF, the desired transformation became sluggish, and when the reaction was carried out at 110 °C, 3a was produced in 58% yield (entries 5–9). The screening of other silver salts indicated that AgOTf gave the highest yield of the desired product, while AgTFA and AgOPiv failed to catalyze the reaction (entries 10–13). The testing of different solvents showed that ethyl acetate was the best solvent choice, and the target product 3a was obtained in 85% yield (entries 14–17). Prolonging the reaction time to 36 hours further increased the yield of 3a to 92%.

Table 1 Optimization of Reaction Conditionsa

Entry

Catalyst

Temp (°C)

Solvent

Time (h)

Yield (%)b of 3a

 1

Sc(OTf)3

110

THF

24

n.r

 2

Al(OTf)3

110

THF

24

n.r

 3

Bi(OTf)3

110

THF

24

60

 4

AgOTf

110

THF

24

58

 5

AgOTf

 25

THF

24

n.r

 6

AgOTf

 40

THF

24

n.r

 7

AgOTf

 60

THF

24

trace

 8

AgOTf

 80

THF

24

25

 9

AgOTf

100

THF

24

45

10

Ag[(CF3SO2)2N]

110

THF

24

44

11

AgOTs

110

THF

24

27

12

AgTFA

110

THF

24

n.r

13

AgOPiv

110

THF

24

n.r

14

AgOTf

110

DME

24

80

15

AgOTf

110

EtOAc

24

85

16

AgOTf

110

TBME

24

65

17

AgOTf

110

1,4-dioxane

24

62

18

AgOTf

110

EtOAc

30

90

19

AgOTf

110

EtOAc

36

92

20

AgOTf

110

EtOAc

48

93

a Reaction conditions: Styrene oxide (0.6 mmol), NaH2PO2 (0.2 mmol), catalyst (10 mol%), anhydrous solvent (1.0 mL) at the corresponding temperature under argon.

b Isolated yield. n.r.: No reaction.

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Scheme 3 Synthesis of β-hydroxyphosphonic acid compounds

After establishing the catalytic protocol for the direct conversion of NaH2PO2 and styrene oxide to β-hydroxyhydrophosphonic acid 3a, we then turned our attention to explore the scope of styrene oxide coupling partner. A series of styrene oxides bearing different substitution on the phenyl ring could react with NaH2PO2 smoothly under standard conditions to obtain the corresponding β-hydroxyhydrophosphonic acid products (Scheme [2]). Indeed, the substituents with different electronic property on the phenyl ring have little effect on the reaction outcome. Styrene oxides bearing either electron-donating substituents or electron-withdrawing substituents were successfully transferred into target products 3b–g and 3h–o, respectively, in excellent yields. However, the reaction proved sensitive to the steric environment of the styrene oxide, and when it bears an ortho-substituent, it was necessary to raise the temperature to obtain a good yield of the product 3b. Functional group such as ether (3e), bromide (3k), iodine (3l), cyano (3m) and ester (3o) group were all tolerated under the standard conditions, leaving room for further product derivatization. Furthermore, epoxides beyond styrene oxides, such as 1-naphthylethylene oxide and 2-naphthylethylene oxide were also suitable substrates, and the desired products 3p,q could be obtained in moderate yields. Epoxides can be easily prepared from acids, aldehydes, and alkenes, and benefiting from this, an epoxide unit was installed into indene and estrone compounds, and then converted into the desired complex β-hydroxyhydrophosphonic acids 3r,s in fair to moderate yields. In addition to mono-substituted styrene oxides, 1,2-diaryl-substituted epoxides were also efficient substrates to react with NaH2PO2 and the corresponding products 3t–v were delivered in good to excellent yields. Moreover, electron-rich heteroarenes, such as thiophene was also tolerated in the epoxide, leading to product 3w in moderate yield. Remarkably, such protocol could be extended to ring-opening of three-membered nitrogen heterocyclic compounds such as 2-phenyl-1-tosylaziridine, and the desired β-aminohydrophosphonic acid 3x was produced in moderate yield. At current stage, alkyl-substituted epoxides were not suitable substrates under standard conditions.

To demonstrate the synthetic usefulness of our reaction, we conducted a gram-scale experiment and obtained the target product 3a in a yield of 92%. Subsequently, (2-hydroxy-2-phenylethyl)phosphinic acid (3a) was transferred into (2-hydroxy-2-phenylethyl)phosphonic acid (4) in excellent yield with a simple operation[12] (Scheme [3]).

Based on the above results and literature reports, we propose a tentative reaction mechanism as shown in Scheme [4]. The reaction starts from the activation of epoxide compound by AgOTf functioning as a Lewis acid. Then, the tautomerization of NaH2PO2 forms trivalent phosphorous species that can undergo nucleophilic attack at the less hindered C–O bond of styrene oxide to form the int-A. It is worth mentioning that the Ag cation can also coordinate with trivalent phosphorous species, which would promote that the above attack occurs only at less hindered C–O bond while leaving the more reactive but steric congested benzylic C–O bond untouched. This should respond for excellent site selectivity obtained in our reaction. Then, the epoxide ring-opening occurs to obtain the int-B by tautomerization. Finally, protonation occurs to deliver the product and close the catalytic cycle.

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Scheme 4 Possible reaction mechanism

In summary, by applying inorganic salt NaH2PO2 as a stable, green, and cheap phosphorous source, we have achieved a Lewis acid catalyzed epoxide-opening reaction, to obtain a series of β-hydroxyhydrophosphonic acid products. The reaction is accomplished with excellent selectivity and displays good functional group compatibility. Furthermore, in addition to epoxide, aziridine is also a suitable substrate, and the desired β-aminohydrophosphonic acid can also be obtained under standard conditions.

1H, 13C, 31P, and 19F spectra were recorded at rt using a Bruker Avance-400 instrument (1H NMR at 400 MHz, 13C NMR at 125 MHz, 31P NMR at 121 MHz, and 19F NMR at 282 MHz). Signal patterns are indicated as s, singlet; d, doublet; dd, doublets of doublet; t, triplet, and m, multiplet. The mass spectrometry was performed in the positive electrospray ionization (ESI+) mode. Reactions were monitored by TLC. Column chromatography [petroleum ether (PE)/EtOAc] was performed on silica gel (200–300 mesh). Analytical grade solvents and commercially available reagents were purchased from commercial sources and used directly without further purification, unless otherwise stated.


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Oxirane Compounds 2a–w; General Procedure

The ethylene oxide compounds were generally synthesized through a two-step method.[13] In the first step, a 250 mL round bottom flask equipped with a stirrer was charged with the olefin compound (20 mmol, 1.0 equiv). To this was added acetone (80 mL), H2O (20 mL), N-bromosuccinimide (22 mmol, 1.1 equiv), and NH4OAc (0.2 mmol, 0.1 equiv) at rt, and the reaction mixture was stirred at rt. The completion of the reaction was monitored by TLC, and the reaction system was extracted with EtOAc (3 ×). The combined organic phases were washed with brine, and dried (anhyd Na2SO4). The solvent was removed by rotary evaporation, and the residue was mixed with silica gel to form a dry sample, which was purified by silica gel column chromatography (eluent: PE/EtOAc) to obtain the corresponding β-hydroxy bromide.

In the step 2, the β-hydroxy bromide (10.0 mmol, 1.0 equiv ) was dissolved in THF (120 mL) in the above 250 mL round bottomed flask equipped with a stirrer. The solution was stirred at rt and treated with a strong Na2O solution (2 M, 60 mL) while stirring, and the stirring was continued at rt. The completion of the reaction was monitored by TLC and the reaction system was extracted with EtOAc (3 ×). The combined organic phases were washed with brine and dried (anhyd Na2SO4). The solvent was removed by rotary evaporation and the residue was mixed with silica gel to form a dry sample, which was purified by silica gel column chromatography (eluent: PE/EtOAc) to obtain the corresponding ethylene oxide compound.


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2-Phenyl-1-tosylaziridine (2x)

Chloramine-T (1.0 mmol, 1.0 equiv) and I2 (0.1 mmol, 10 mol%) were added to a 50 mL round bottom flask equipped with a stirrer. The flask was sealed with a reverse plug, and the air inside the flask was replaced three times with argon gas. Then, anhyd MeCN (30 mL) and styrene (20 mmol, 2.0 equiv) were added to the reaction system by syringe. The solution was stirred at rt under N2 atmosphere. After completion of the reaction, the reaction was quenched with H2O and CH2Cl2. The organic phase was separated and washed with brine and dried (anhyd Na2SO4). The solvent was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: PE/EtOAc) to give the 2-phenyl-1-tosylaziridine (2x).[14]


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β-Hydroxyhydrophosphonic Acid (β-Hydroxyphosphinic Acid) Derivatives 3; General Procedure

NaH2PO2 (1; 0.2 mmol, 1.0 equiv) and AgOTf (0.02 mmol, 10 mol%) were added to a 10 mL glass tube equipped with a stirrer. The glass tube was sealed with a reverse plug, and the air inside the tube was replaced three times with argon gas. Then, anhyd EtOAc (1 mL) was added to the reaction system using a syringe. The respective epoxide 2 (0.6 mmol, 3.0 equiv) was added to the reaction system through a micro syringe. If the epoxide was a solid, it can be weighed into the reaction tube before the air was changed to argon. The mouth of the tube mouth was sealed with a medical tape, and the reaction tube was placed in a 110 °C oil bath and the contents were stirred for 36 h. After completion of the reaction, few drops of HCl were added to the reaction system and stirred for a few min. The solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: EtOAc/MeOH/ammonia 8:1.5:1.5, Rf = 0.3–0.4) to obtain the desired product.


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(2-Hydroxy-2-phenylethyl)phosphinic Acid (3a)

White solid; yield: 34.2 mg (91%); mp 189–191 °C; Rf = 0.3.

1H NMR (400 MHz, D2O): δ = 7.38–7.28 (m, 5 H), 6.85 (d, J = 508.0 Hz, 1 H), 3.80 (d, J = 10.0 Hz, 1 H), 3.07 (d, J = 13.5 Hz, 1 H), 2.74 (dd, J = 22.7, 11.0 Hz, 1 H).

13C NMR (101 MHz, D2O): δ = 138.48 (d, J = 14.3 Hz), 129.34 (s), 128.66 (s), 126.62 (s), 71.58 (d, J = 105.3 Hz), 35.38 (d, J = 4.2 Hz).

31P NMR (162 MHz, D2O): δ = 27.84 (s).

MS (ESI): m/z [M + Na]+ = 209.

HRMS (ESI): m/z [M +Na]+ calcd for C8H11O3PNa: 209.0338; found: 209.0336.


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(2-Hydroxy-2-(o-tolyl)ethyl)phosphinic Acid (3b)

White solid; yield: 30.0 mg (75%); mp 163–166 °C; Rf = 0.3.

1H NMR (400 MHz, D2O): δ = 7.33–7.26 (m, 2 H), 7.26–7.22 (m, 2 H), 6.92 (d, J = 508.0 Hz, 1 H), 3.83 (d, J = 11.3 Hz, 1 H), 3.12 (d, J = 14.4 Hz, 1 H), 2.92–2.75 (m, 1 H), 2.35 (s, 3 H).

13C NMR (101 MHz, D2O): δ = 137.15 (s), 136.60 (d, J = 14.1 Hz), 130.37 (s), 130.18 (s), 126.83 (s), 125.99 (s), 70.49 (d, J = 108.8 Hz), 32.58 (d, J = 4.6 Hz), 18.68 (s).

31P NMR (162 MHz, D2O): δ = 28.50 (s).

MS (ESI): m/z [M + Na]+ = 223.

HRMS (ESI): m/z [M + Na]+ calcd for C9H13O3PNa: 223.0495; found: 223.0487.


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(2-Hydroxy-2-(m-tolyl)ethyl)phosphinic Acid (3c)

White solid; yield: 30.8 mg (77%); mp 159–161 °C; Rf = 0.3.

1H NMR (400 MHz, D2O): δ = 7.29 (t, J = 7.5 Hz, 1 H), 7.21 (s, 1 H), 7.15 (d, J = 7.3 Hz, 2 H), 6.86 (d, J = 508.0 Hz, 1 H), 3.81 (dd, J = 8.4, 3.0 Hz, 1 H), 3.18–2.95 (m, 1 H), 2.72 (ddd, J = 14.3, 11.3, 9.6 Hz, 1 H), 2.34 (s, 3 H).

13C NMR (101 MHz, D2O): δ = 138.70 (s), 138.53 (d, J = 14.4 Hz), 129.92 (s), 128.61 (s), 127.18 (s), 126.28 (s), 71.57 (d, J = 107.1 Hz), 35.20 (d, J = 4.9 Hz), 20.39 (s).

31P NMR (162 MHz, D2O): δ = 28.17 (s).

MS (ESI): m/z [M + Na]+ = 223.

HRMS (ESI): m/z [M + Na]+ calcd for C9H13O3PNa: 223.0495; found: 223.0489.


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(2-Hydroxy-2-(p-tolyl)ethyl)phosphinic Acid (3d)

White solid; yield: 34.2 mg (91%); mp 156–158 °C; Rf = 0.3.

1H NMR (400 MHz, D2O): δ = 7.29–7.17 (m, 4 H), 6.85 (d, J = 512.0 Hz, 1 H), 3.79 (d, J = 11.3 Hz, 1 H), 3.05 (d, J = 14.1 Hz, 1 H), 2.71 (dt, J = 14.1, 10.9 Hz, 1 H), 2.31 (s, 3 H).

13C NMR (101 MHz, D2O): δ = 136.52 (s), 135.25 (d, J = 14.4 Hz), 129.26 (s), 129.17 (s), 71.58 (d, J = 107.9 Hz), 34.87 (d, J = 4.9 Hz), 20.08 (s).

31P NMR (162 MHz, D2O): δ = 28.16 (s).

MS (ESI): m/z [M + Na]+ = 223.

HRMS (ESI): m/z [M + Na]+ calcd for C9H13O3PNa: 223.0495; found: 223.0487.


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(2-Hydroxy-2-(3-methoxyphenyl)ethyl)phosphinic Acid (3e)

White solid; yield: 35.9 mg (83%); mp 222–224 °C; Rf = 0.3.

1H NMR (400 MHz, D2O): δ = 7.32 (t, J = 7.9 Hz, 1 H), 7.02–6.92 (m, 2 H), 6.89 (dd, J = 8.2, 2.4 Hz, 1 H), 6.85 (d, J = 508.0 Hz, 1 H), 3.82 (s, 3 H), 3.80 (d, J = 3.7 Hz, 1 H), 3.07 (d, J = 14.1 Hz, 1 H), 2.73 (dt, J = 14.1, 11.2 Hz, 1 H).

13C NMR (101 MHz, D2O): δ = 158.86 (s), 140.37 (d, J = 14.4 Hz), 129.79 (s), 122.19 (s), 114.86 (s), 112.12 (s), 71.50 (d, J = 108.5 Hz), 55.29 (s), 35.41 (d, J = 4.5 Hz).

31P NMR (162 MHz, D2O): δ = 28.03 (s).

MS (ESI): m/z [M + Na]+ = 239.

HRMS (ESI): m/z [M + Na]+ calcd for C9H13O4PNa: 239.0444; found: 239.0426.


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(2-(4-Cyclohexylphenyl)-2-hydroxyethyl)phosphinic Acid (3f)

White solid; yield: 41.8 mg (78%); mp 173-175 °C; Rf = 0.3.

1H NMR (400 MHz, MeOD): δ = 7.06 (d, J = 8.0 Hz, 2 H), 6.97 (d, J = 8.1 Hz, 2 H), 6.75 (d, J = 500.0 Hz, 1 H), 3.50 (d, J = 11.2 Hz, 1 H), 2.92 (ddd, J = 14.3, 4.9, 2.5 Hz, 1 H), 2.55 (ddd, J = 14.2, 11.2, 8.6 Hz, 1 H), 2.45–2.22 (m, 1 H), 1.67 (t, J = 10.0 Hz, 4 H), 1.61 (d, J = 12.4 Hz, 1 H), 1.41–1.07 (m, 5 H).

13C NMR (101 MHz, MeOD): δ = 145.56 (s), 136.67 (d, J = 14.7 Hz), 128.94 (s), 126.23 (s), 72.35 (d, J = 109.0 Hz), 44.31 (s), 35.41 (d, J = 4.8 Hz), 34.42 (s), 26.67 (s), 25.91 (s).

31P NMR (162 MHz, MeOD): δ = 27.39 (s).

MS (ESI): m/z [M + Na]+ = 291.

HRMS (ESI): m/z [M + Na]+ calcd for C14H21O3PNa: 291.1121; found: 291.1123.


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(2-Hydroxy-2-(4-(trifluoromethoxy)phenyl)ethyl)phosphinic Acid (3g)

Light yellow solid; yield: 37.8 mg (70%); mp 265–268 °C; Rf = 0.3.

1H NMR (400 MHz, MeOD): δ = 7.19 (dd, J = 9.0, 2.2 Hz, 2 H), 6.97 (d, J = 8.3 Hz, 2 H), 6.70 (d, J = 496.0 Hz, 1 H), 3.45 (d, J = 10.1 Hz, 1 H), 2.91 (ddd, J = 14.2, 4.9, 2.5 Hz, 1 H), 2.58 (ddd, J = 14.1, 11.1, 8.8 Hz, 1 H).

13C NMR (101 MHz, MeOD): δ = 147.54 (d, J = 1.8 Hz), 138.84 (d, J = 14.9 Hz), 130.60 (s), 120.58 (q, J = 252.5 Hz, OCF3), 119.32 (s), 71.98 (d, J = 109.2 Hz), 35.14 (d, J = 4.7 Hz).

31P NMR (162 MHz, MeOD): δ = 26.73 (s).

19F NMR (376 MHz, MeOD): δ = –59.49 (s).

MS (ESI): m/z [M + Na]+ = 293.

HRMS (ESI): m/z [M + Na]+ calcd for C9H10F3O4PNa: 293.0161; found: 293.0159.


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(2-([1,1′-Biphenyl]-4-yl)-2-hydroxyethyl)phosphinic Acid (3h)

White solid; yield: 34.1 mg (65%); mp 180–183 °C; Rf = 0.3.

1H NMR (400 MHz, MeOD): δ = 7.45 (t, J = 1.6 Hz, 1 H), 7.43 (d, J = 0.9 Hz, 1 H), 7.40 (s, 1.0 H), 7.38 (s, 1 H), 7.29–7.24 (m, 3 H), 7.23 (s, 1 H), 7.18–7.13 (m, 1 H), 6.15 (d, J = 500.0 Hz, 1 H), 3.56 (ddd, J = 6.5, 5.5, 2.7 Hz, 1 H), 3.00 (ddd, J = 14.3, 5.1, 2.6 Hz, 1 H), 2.65 (ddd, J = 14.3, 11.2, 8.6 Hz, 1 H).

13C NMR (101 MHz, MeOD): δ = 141.05 (s), 138.90 (s), 138.66 (s), 138.52 (s), 129.54 (s), 128.40 (s), 126.66 (s), 126.41 (d, J = 4.7 Hz), 72.23 (d, J = 109.0 Hz), 35.45 (d, J = 4.9 Hz).

31P NMR (162 MHz, MeOD): δ = 27.36 (s).

MS (ESI): m/z [M + Na]+ = 285.

HRMS (ESI): m/z [M + Na]+ calcd for C14H15O3PNa: 285.0651; found: 285.0643.


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(2-(4-Fluorophenyl)-2-hydroxyethyl)phosphinic Acid (3i)

White solid; yield: 35.4 mg (87%); mp 200–203 °C; Rf = 0.4.

1H NMR (400 MHz, D2O): δ = 7.22 (dd, J = 8.0, 5.8 Hz, 2 H), 7.00 (t, J = 8.8 Hz, 2 H), 6.76 (d, J = 508.0 Hz, 1 H), 3.69 (d, J = 10.0 Hz, 1 H), 2.97 (d, J = 13.6 Hz, 1 H), 2.65 (dd, J = 22.2, 10.9 Hz, 1 H).

13C NMR (101 MHz, D2O): δ = 161.43 (d, J C,F = 241.4 Hz,), 134.14 (dd, J = 14.4, 3.0 Hz), 130.87 (s), 130.79 (s), 115.11 (d, J = 21.3 Hz), 71.57 (d, J = 107.5 Hz), 34.61 (s).

31P NMR (162 MHz, D2O): δ = 27.96 (s).

19F NMR (376 MHz, D2O): δ = –117.54 (s).

MS (ESI): m/z [M + Na]+ = 227.

HRMS (ESI): m/z [M + Na]+ calcd for C8H10FO3PNa: 227.0244; found: 227.0239.


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(2-(4-Chlorophenyl)-2-hydroxyethyl)phosphinic Acid (3j)

White solid; yield: 37.4 mg (85%); mp 207–210 °C; Rf = 0.4.

1H NMR (400 MHz, D2O): δ = 7.43–7.21 (m, 5 H), 6.86 (d, J = 508.0 Hz, 1 H), 3.82 (d, J = 10.9 Hz, 1 H), 3.09 (d, J = 13.9 Hz, 1 H), 2.76 (dd, J = 23.8, 10.9 Hz, 1 H).

13C NMR (101 MHz, D2O): δ = 137.08 (d, J = 14.5 Hz), 131.57 (s), 130.81 (s), 128.40 (s), 71.37 (d, J = 108.0 Hz), 34.82 (d, J = 5.0 Hz).

31P NMR (162 MHz, D2O): δ = 28.08 (s).

MS (ESI): m/z [M + Na]+ = 242.

HRMS (ESI): m/z [M + Na]+ calcd for C8H10ClO3PNa: 242.9948; found: 242.9958.


#

(2-(4-Bromophenyl)-2-hydroxyethyl)phosphinic Acid (3k)

White solid; yield: 47.5 mg (90%); mp 219–221 °C; Rf = 0.4.

1H NMR (400 MHz, D2O): δ = 7.49 (d, J = 8.1 Hz, 2 H), 7.22 (d, J = 8.3 Hz, 2 H), 6.84 (d, J = 512.0 Hz, 1 H), 3.77 (d, J = 10.9 Hz, 1 H), 3.03 (d, J = 14.1 Hz, 1 H), 2.88–2.51 (m, 1 H).

13C NMR (101 MHz, D2O): δ = 137.56 (d, J = 14.5 Hz), 131.36 (s), 131.18 (s), 119.68 (s), 71.27 (d, J = 107.9 Hz), 34.85 (s).

31P NMR (162 MHz, D2O): δ = 27.78 (s).

MS (ESI): m/z [M + Na]+ = 286.

HRMS (ESI): m/z [M + Na]+ calcd for C8H10BrO3PNa: 286.9443; found: 286.9436.


#

(2-Hydroxy-2-(4-iodophenyl)ethyl)phosphinic Acid (3l)

White solid; yield: 56.8 mg (91%); mp 223–226 °C; Rf = 0.4.

1H NMR (400 MHz, D2O): δ = 7.67 (d, J = 7.6 Hz, 2 H), 7.07 (d, J = 7.7 Hz, 2 H), 6.80 (d, J = 512.0 Hz, 1 H), 3.74 (d, J = 11.1 Hz, 1 H), 2.99 (d, J = 14.0 Hz, 1 H), 2.77–2.55 (m, 1 H).

13C NMR (101 MHz, D2O): δ = 138.19 (d, J = 14.5 Hz), 137.43 (s), 131.43 (s), 91.18 (s), 71.24 (d, J = 108.1 Hz), 34.93 (d, J = 5.0 Hz).

31P NMR (162 MHz, D2O): δ = 27.81 (s).

MS (ESI): m/z [M + Na]+ = 334.

HRMS (ESI): m/z [M + Na]+ calcd for C8H10IO3PNa: 334.9304; found: 334.9297.


#

(2-(4-Cyanophenyl)-2-hydroxyethyl)phosphinic Acid (3m)

White solid; yield: 16.9 mg (40%); mp 225–227 °C; Rf = 0.4.

1H NMR (400 MHz, D2O): δ = 7.78 (d, J = 8.3 Hz, 2 H), 7.53 (d, J = 8.2 Hz, 2 H), 6.90 (d, J = 512.0 Hz, 1 H), 3.93–3.80 (m, 1 H), 3.29–3.10 (m, 1 H), 2.89 (ddd, J = 14.3, 11.3, 9.5 Hz, 1 H).

13C NMR (101 MHz, D2O): δ = 144.82 (d, J = 14.5 Hz), 132.46 (s), 130.09 (s), 119.95 (s), 108.94 (s), 71.04 (d, J = 108.0 Hz), 35.65 (d, J = 5.3 Hz).

31P NMR (162 MHz, D2O): δ = 27.53 (s).

MS (ESI): m/z [M + Na]+ = 234.

HRMS (ESI): m/z [M + Na]+ calcd for C9H10NO3PNa: 234.0291; found: 234.0282.


#

(2-Hydroxy-2-(4-(trifluoromethyl)phenyl)ethyl)phosphinic Acid (3n)

Light yellow solid; yield: 36.6 mg (72%); mp 213–215 °C; Rf = 0.4.

1H NMR (400 MHz, D2O): δ = 7.65 (d, J = 7.9 Hz, 2 H), 7.46 (d, J = 7.9 Hz, 2 H), 6.83 (d, J = 496.0 Hz, 1 H), 3.82 (d, J = 10.1 Hz, 1 H), 3.13 (d, J = 13.8 Hz, 1 H), 2.82 (dd, J = 22.3, 11.0 Hz, 1 H).

13C NMR (101 MHz, D2O): δ = 142.94 (d, J = 14.5 Hz), 129.72 (s), 128.59–127.24 (m), 127.94 (q, J = 32.1 Hz, CF3), 125.77 (s), 123.07 (s), 120.37 (s), 71.22 (d, J = 108.1 Hz), 35.32 (d, J = 5.3 Hz).

19F NMR (376 MHz, D2O): δ = –62.05 (s).

MS (ESI): m/z [M + Na]+ = 277.

HRMS (ESI): m/z [M + Na]+ calcd for C9H10F3O3PNa: 277.0212; found: 277.0207.


#

(2-Hydroxy-2-(4-(methoxycarbonyl)phenyl)ethyl)phosphinic Acid (3o)

White solid; yield: 43.4 mg (89%); mp 194–196 °C; Rf = 0.4.

1H NMR (400 MHz, D2O): δ = 7.73 (d, J = 8.0 Hz, 2 H), 7.26 (d, J = 8.0 Hz, 2 H), 6.77 (d, J = 508.0 Hz, 1 H), 3.73 (s, 4 H), 3.01 (d, J = 11.1 Hz, 1 H), 2.84–2.58 (m, 1 H).

13C NMR (101 MHz, D2O): δ = 169.12 (s), 144.70 (d, J = 14.4 Hz), 129.43 (s), 127.30 (s), 71.12 (d, J = 108.1 Hz), 52.40 (s), 35.40 (d, J = 5.0 Hz).

31P NMR (162 MHz, D2O): δ = 27.71 (s).

MS (ESI): m/z [M + Na]+ = 267.

HRMS (ESI): m/z [M + Na]+ calcd for C10H13O5PNa: 267.0393; found: 267.0381.


#

(2-Hydroxy-2-(naphthalen-1-yl)ethyl)phosphinic Acid (3p)

Yellow solid; yield: 27.4 mg (58%); mp 203–205 °C; Rf = 0.3.

1H NMR (400 MHz, MeOD): δ = 8.05 (d, J = 8.3 Hz, 1 H), 7.69 (d, J = 8.0 Hz, 1 H), 7.58 (d, J = 8.1 Hz, 1 H), 7.35 (dd, J = 11.2, 4.0 Hz, 1 H), 7.30 (t, J = 7.3 Hz, 2 H), 7.27–7.21 (m, 1 H), 6.86 (d, J = 500.0 Hz, 1 H), 3.70 (d, J = 10.4 Hz, 1 H), 3.57 (d, J = 13.4 Hz, 1 H), 3.03–2.86 (m, 1 H).

13C NMR (101 MHz, MeOD): δ = 134.97 (d, J = 14.8 Hz), 134.11 (s), 132.12 (s), 128.32 (s), 127.36 (s), 126.58 (s), 125.42 (s), 125.02 (s), 124.98 (s), 123.64 (s), 71.29 (d, J = 107.8 Hz), 32.96 (s).

31P NMR (162 MHz, MeOD): δ = 27.68 (s).

MS (ESI): m/z [M + Na]+ = 259.

HRMS (ESI): m/z [M + Na]+ calcd for C12H13O3PNa: 259.0495; found: 259.0488.


#

(2-Hydroxy-2-(naphthalen-2-yl)ethyl)phosphinic Acid (3q)

Yellow solid; yield: 32.6 mg (69%); mp 195–197 °C; Rf = 0.3.

1H NMR (400 MHz, MeOD): δ = 7.72–7.60 (m, 4 H), 7.33 (dd, J = 8.4, 1.7 Hz, 1 H), 7.32–7.23 (m, 2 H), 6.81 (d, J = 500.0 Hz, 1 H), 3.64 (d, J = 11.2 Hz, 1 H), 3.13 (ddd, J = 14.2, 5.0, 2.4 Hz, 1 H), 2.78 (ddd, J = 14.2, 11.1, 8.5 Hz, 1 H).

13C NMR (101 MHz, MeOD): δ = 136.93 (d, J = 14.6 Hz), 133.68 (s), 132.31 (s), 127.54 (s), 127.39 (s), 127.29 (s), 127.14 (s), 127.12 (s), 125.40 (s), 124.78 (s), 72.12 (d, J = 108.8 Hz), 35.96 (d, J = 4.9 Hz).

31P NMR (162 MHz, MeOD): δ = 27.42 (s).

MS (ESI): m/z [M + Na]+ = 259.

HRMS (ESI): m/z [M + Na]+ calcd for C12H13O3PNa: 259.0495; found: 259.0485.


#

(1-Hydroxy-2,3-dihydro-1H-inden-2-yl)phosphinic Acid (3r)

Light yellow solid; yield: 13.9 mg (35%, dr >20:1); mp 237–239 °C; Rf  = 0.3.

1H NMR (400 MHz, D2O): δ = 7.36 (dt, J = 7.1, 3.5 Hz, 2 H), 7.31–7.23 (m, 2 H), 6.93 (d, J = 504.0 Hz, 1 H), 3.42 (dd, J = 17.1, 9.5 Hz, 2 H), 2.99 (d, J = 2.4 Hz, 1 H), 2.95 (d, J = 2.4 Hz, 1 H).

13C NMR (101 MHz, D2O): δ = 140.27 (d, J = 10.5 Hz), 126.93 (s), 125.09 (s), 80.14 (d, J = 116.5 Hz), 40.98 (d, J = 10.4 Hz).

31P NMR (162 MHz, D2O): δ = 28.49 (s).

MS (ESI): m/z [M + Na]+ = 221.

HRMS (ESI): m/z [M + Na]+ calcd for C9H11O3PNa: 221.0338; found: 221.0343.


#

(2-Hydroxy-2-((8S,9R,13R,14R)-13-methyl-17-oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenanthren-2-yl)ethyl)phosphinic Acid (3s)

White solid; yield: 37.6 mg (52%, dr >20:1); mp 285–287 °C; Rf = 0.3.

1H NMR (400 MHz, D2O): δ = 7.17 (d, J = 7.8 Hz, 1 H), 7.10–6.94 (m, 2 H), 6.80 (d, J = 508.0 Hz, 1 H), 3.73 (d, J = 10.3 Hz, 1 H), 2.96 (d, J = 13.3 Hz, 1 H), 2.78 (s, 2 H), 2.64 (dd, J = 23.2, 10.9 Hz, 1 H), 2.47 (dd, J = 19.4, 8.5 Hz, 1 H), 2.25 (s, 1 H), 2.09 (dd, J = 21.2, 11.2 Hz, 2 H), 1.95 (d, J = 22.3 Hz, 2 H), 1.75 (d, J = 8.1 Hz, 1 H), 1.61–1.48 (m, 1 H), 1.47–1.16 (m, 5 H), 0.78 (s, 3 H).
13C NMR (101 MHz, D2O): δ = 138.21 (s), 137.17 (s), 136.04 (s), 129.94 (s), 129.83 (s), 126.77 (d, J = 9.3 Hz), 125.53 (s), 71.56 (d, J = 107.9 Hz), 49.70 (s), 48.63 (s), 43.54 (s), 37.69 (s), 35.97 (s), 34.85 (s), 30.90 (s), 28.73 (s), 25.93 (s), 25.25 (s), 21.08 (s), 13.28 (s).
31P NMR (162 MHz, D2O): δ = 28.12 (s).

MS (ESI): m/z [M + Na]+ = 385.

HRMS (ESI): m/z [M + Na]+ calcd for C20H21O4PNa: 385.1539; found: 385.1536.


#

(3-Hydroxy-1,2-diphenylethyl)phosphinic Acid (3t)

White solid; yield: 46.6 mg (89%, dr >20:1); mp 202–205 °C; Rf = 0.4.

1H NMR (400 MHz, D2O): δ = 7.47 (d, J = 7.7 Hz, 2 H), 7.42 (d, J = 7.6 Hz, 2 H), 7.32 (d, J = 7.5 Hz, 2 H), 7.29 (s, 1 H), 7.26 (d, J = 9.7 Hz, 1 H), 7.24–7.17 (m, 2 H), 6.65 (d, J = 560.0 Hz, 1 H), 4.50 (dd, J = 10.4, 2.8 Hz, 1 H), 4.41–4.22 (m, 1 H).

13C NMR (101 MHz, D2O): δ = 141.94 (d, J = 10.9 Hz), 141.00 (d, J = 3.1 Hz), 128.85 (d, J = 1.9 Hz), 128.41 (d, J = 2.6 Hz), 126.97 (d, J = 16.4 Hz), 71.72 (d, J = 108.1 Hz), 52.81 (d, J = 6.3 Hz).

31P NMR (162 MHz, D2O): δ = 22.83 (s).

MS (ESI): m/z [M + Na]+ = 285.

HRMS (ESI): m/z [M + Na]+ calcd for C14H15O3PNa: 285.0651; found: 285.0647.


#

(2-Hydroxy-1,2-di-o-tolylethyl)phosphinic Acid (3u)

Light yellow solid; yield: 45.2 mg (78%, dr >20:1); mp 192–194 °C; Rf  = 0.4.

1H NMR (400 MHz, MeOD): δ = 7.57 (d, J = 7.7 Hz, 1 H), 7.12–7.01 (m, 1 H), 7.00–6.90 (m, 2 H), 6.91–6.79 (m, 4 H), 6.62 (d, J = 512.0 Hz, 1 H), 4.62 (t, J = 6.0 Hz, 1 H), 4.00–3.83 (m, 1 H), 2.25 (s, 3 H), 2.10 (s, 3 H).

13C NMR (101 MHz, MeOD): δ = 139.92 (t, J = 8.3 Hz), 137.11 (s), 135.93 (s), 130.02 (s), 129.80 (s), 129.21 (s), 129.18 (s), 125.84 (s), 125.72 (s), 125.22 (s), 124.98 (s), 73.86 (d, J = 107.6 Hz), 43.80 (d, J = 6.2 Hz), 18.95 (d, J = 39.1 Hz).

31P NMR (162 MHz, MeOD): δ = 23.99 (s).

MS (ESI): m/z [M + Na]+ = 313.

HRMS (ESI): m/z [M + Na]+ calcd for C16H19O3PNa: 313.0964; found: 313.0973.


#

(1,2-Bis(3-chlorophenyl)-2-hydroxyethyl)phosphinic Acid (3v)

Light yellow solid; yield: 60.0 mg (91%, dr >20:1); mp 230–233 °C; Rf  = 0.4.

1H NMR (400 MHz, MeOD): δ = 7.49 (s, 1 H), 7.42 (s, 1 H), 7.39 (d, J = 7.6 Hz, 1 H), 7.32 (d, J = 7.7 Hz, 1 H), 7.26–7.21 (m, 2 H), 7.21–7.15 (m, 2 H), 6.61 (d, J = 520.0 Hz, 1 H), 4.41 (t, J = 6.1 Hz, 1 H), 4.16 (t, J = 6.4 Hz, 1 H).

13C NMR (101 MHz, MeOD): δ = 144.63 (d, J = 7.7 Hz), 143.43 (d, J = 7.5 Hz), 133.80 (s), 133.54 (s), 129.51 (s), 129.32 (s), 129.22 (s),128.41 (s), 127.79 (s), 126.81 (s), 126.26 (d, J = 6.4 Hz), 72.59 (d, J = 107.9 Hz), 51.76 (d, J = 6.2 Hz).

31P NMR (162 MHz, MeOD): δ = 23.33 (s).

MS (ESI): m/z [M + Na]+ = 352.

HRMS (ESI): m/z [M + Na]+ calcd for C14H13Cl2O3PNa: 352.9872; found: 352.9864.


#

(R)-(2-Hydroxy-2-(thiophen-3-yl)ethyl)phosphinic Acid (3w)

Brown solid; yield: 23.0 mg (60%); mp 219–221 °C; Rf = 0.3.

1H NMR (400 MHz, D2O): δ = 7.39 (dd, J = 4.9, 3.0 Hz, 1 H), 7.19 (d, J = 2.5 Hz, 1 H), 7.08 (dd, J = 4.9, 1.1 Hz, 1 H), 6.79 (d, J = 512.0 Hz, 1 H), 3.85–3.72 (m, 1 H), 3.03 (ddd, J = 14.8, 5.2, 3.0 Hz, 1 H), 2.89–2.74 (m, 1 H).

13C NMR (101 MHz, D2O): δ = 138.43 (d, J = 14.8 Hz), 128.59 (s), 126.10 (s), 122.45 (s), 70.92 (d, J = 109.2 Hz), 29.97 (d, J = 5.3 Hz).

31P NMR (162 MHz, D2O): δ = 27.92 (s).

MS (ESI): m/z [M + Na]+ = 214.

HRMS (ESI): m/z [M + Na]+ calcd for C6H9SO3PNa: 214.9902; found: 214.9893.


#

(R)-(2-((4-Methylphenyl)sulfonamido)-2-phenylethyl)phosphinic Acid (3x)

White solid; yield: 38.6 mg (57%); mp 205–208 °C; Rf = 0.4.

1H NMR (400 MHz, MeOD): δ = 7.29 (d, J = 8.2 Hz, 2 H), 6.99 (d, J = 8.1 Hz, 3 H), 6.95 (d, J = 4.1 Hz, 4 H), 6.92 (d, J = 524.0 Hz, 1 H), 3.38 (dd, J = 9.0, 5.3 Hz, 1 H), 3.08–2.94 (m, 1 H), 2.51 (ddd, J = 14.1, 11.3, 7.3 Hz, 1 H), 2.30 (s, 3 H).

13C NMR (101 MHz, MeOD): δ = 142.43 (s), 138.20 (s), 129.04 (s), 128.92 (s), 127.80 (s), 126.23 (s), 125.56 (s), 100.00 (s), 32.21 (s), 20.05 (s).

31P NMR (162 MHz, MeOD): δ = 25.49 (s).

MS (ESI): m/z [M + Na]+ = 362.

HRMS (ESI): m/z [M + Na]+ calcd for C15H15NO3PNa: 362.0586; found: 362.0584.


#

Synthesis of (2-Hydroxy-2-phenylethyl)phosphonic Acid (4) from 3a

A solution of (2-hydroxy-2-phenylethyl)phosphinic acid (3a; 0.58 mmol), DMSO (44 mg, 0.58 mmol, 1 equiv), and I2 (1.5 mg, 0.01 equiv) in THF (1 mL) was stirred under heating at 60 °C for 5 h. The solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (eluent: MeOH) to afford the desired product; white solid; yield: 112.5 mg (96%); mp 295–297 °C; Rf = 0.2.

1H NMR (400 MHz, D2O): δ = 7.26–7.20 (m, 2 H), 7.16 (dd, J = 12.9, 7.0 Hz, 3 H), 3.96 (ddd, J = 10.5, 7.4, 2.8 Hz, 1 H), 3.01 (dd, J = 10.9, 3.4 Hz, 1 H), 2.69 (ddd, J = 14.1, 11.3, 9.7 Hz, 1 H).

13C NMR (101 MHz, D2O): δ = 137.82 (d, J = 16.2 Hz), 129.17 (s), 128.59 (s), 126.72 (s), 68.57 (d, J = 159.6 Hz), 36.84 (d, J = 3.7 Hz).

31P NMR (162 MHz, D2O): δ = 19.45 (s).

MS (ESI): m/z [M + Na]+ = 225.

HRMS (ESI): m/z [M + Na]+ calcd for C8H11O4PNa: 225.0287; found: 225.0290.


#
#

Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2133-1963.
  • Supporting Information

Corresponding Author

Shang-Dong Yang
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University
222 South Tianshui Road, Lanzhou 730000
P. R. of China   

Publication History

Received: 12 June 2023

Accepted after revision: 19 July 2023

Accepted Manuscript online:
19 July 2023

Article published online:
13 September 2023

© 2023. Thieme. All rights reserved

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Scheme 1 Representatives of important β-hydroxyhydrophosphonic acid derivatives and different strategies for their synthesis
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Scheme 2 Substrate cope examinations. Reagents and conditions: NaH2PO2 (0.2 mmol), epoxy compound (0.6 mmol), catalyst (5 mol%), ligand (10 mol%), anhydrous solvent (1.0 mL) at the corresponding temperature under argon for 36 h. Isolated yields are shown. a Reaction conducted at 130 °C for 60 h.
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Scheme 3 Synthesis of β-hydroxyphosphonic acid compounds
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Scheme 4 Possible reaction mechanism