Non-Selective Reduction of P-Stereogenic Phosphinoylacetic Acid Esters and 3-Phosphorylated Coumarins to Phosphino-Boranes: Discovery of Unexpected 2,3-Dihydrobenzofuran Derivative

Abstract

This paper presents the efficient reduction of phosphinoylacetic acid esters and 3-phosphorylated coumarin to their corresponding phosphino-boranes using BH₃-THF complexes. Optimized conditions for the reduction of phosphinoylacetic acid esters resulted in high yields of phosphinoborates. The straightforwardness and efficiency of the process were demonstrated for diarylphosphinoylacetic acid ethyl esters, as well as P-stereogenic L-menthyl esters, where the simultaneous reduction of the strong P=O bond and the ester group was exclusively observed for the first time. The study also highlighted the significant influence of steric effects with bulky substituents, such as the menthol group or the 1-naphthyl substituent at phosphorus, on the reduction efficiency. However, the reduction of 3-phosphorylated coumarins produced an unexpected reaction product: a 2,3-dihydrobenzofuran derivative. The present findings provide valuable information on the direct reduction of phosphine oxides and related compounds, demonstrating the versatility of borane complexes in synthetic chemistry, and provide new perspectives for studying the problems of symmetry and asymmetry in the chemistry of such transformations.

1. Introduction

Phosphines and their related oxides have significant importance in the fields of organic synthesis, catalysis, and co-ordination chemistry. These compounds are extensively utilized as ligands in transition metal catalysts and as reagents in chemical processes due to their distinctive characteristics [1,2,3,4,5,6,7]. Phosphines play a crucial role as intermediates in various chemical reactions, including the Appel, Wittig, and Mitsunobu reactions [8,9,10,11,12,13]. The reduction of these compounds is significant not only from a synthetic standpoint, but also in an industrial context, where the selectivity and efficiency of the process are important.

The P=O bond is highly stable because of its elevated bond energy and the robust electronegativity of the oxygen atom. Converting this bond to phosphine is difficult and requires the application of potent reducing agents and suitable reaction conditions. This change can be accomplished using different approaches, each providing unique benefits and constraints [14,15,16,17]. Different approaches can be employed to make this modification, each with its own unique advantages and limits.

Traditional methods for reducing the P=O bond involve the use of metal hydrides such as lithium aluminium hydride (LiAlH₄) [18]. LiAlH₄ is a strong reducing agent that can effectively reduce phosphine oxides to free phosphines, offering a high productivity in reducing various phosphine oxides. However, it requires controlled conditions and is highly reactive, posing potential hazards during. More recent approaches employ silanes and siloxanes, which provide a high efficiency and selectivity under milder conditions [19]. Trichlorosilane (HSiCl₃), ref. [20], is widely used, either alone or in combination with triphenylphosphine (Ph₃P) to enhance reactivity [21]. Additionally, hexachlorodisilane (Si₂Cl₆) and hexamethyldisiloxane (Si₂Me₆), activated by cesium fluoride (CsF) or tetrabutylammonium fluoride (TBAF), are effective in these reductions [22,23,24]. The combination of triethoxysilane (HSi(OEt)₃) with titanium tetraisopropoxide (Ti(OiPr)₄), ref. [25], also demonstrates a high efficiency. Phenylsilane (PhSiH₃), ref. [26] and polymethylhydrosiloxane (PMHS) [27,28] are versatile reducing agents, often used in microwave-assisted, solvent-free conditions to improve reaction efficiency.

The direct reduction of the phosphorus–oxygen bond to phosphine–borane is beneficial in organophosphorus chemistry, since it eliminates the requirement to generate free phosphine. The reaction can be performed using reagents like borates, which serve as both reducing agents and form stable complexes with the resulting phosphine. Phosphine–boranes possess numerous benefits compared to free phosphines, rendering them highly valuable as intermediates and reagents in the field of organic chemistry [29,30,31,32]. Phosphine–boranes exhibit a greater stability and are more convenient to manage compared to free phosphines. Furthermore, the presence of the borane group serves to safeguard the phosphine compound from undergoing oxidation and other undesired chemical processes, thus preserving the inherent reactivity of the phosphine core for later transformations. Furthermore, phosphine–boranes can be readily eliminated to obtain liberated phosphine as required, offering a versatile instrument for synthetic applications. Complexation with borane enhances the solubility of phosphine in organic solvents, hence enabling its application in catalytic reactions or biological systems.

One effective method for obtaining phosphine–boranes was presented by Gilheany’s group. It involved using oxalyl chloride in the first step to convert phosphine oxides into chlorophosphonium salts and then treating them with sodium borohydride. Under mild reaction conditions, sodium borohydride acted in this reaction as both a source of hydride and borane, yielding phosphine–borane directly (Scheme 1a) [33].

In 2015, the same group described a two-step method for deoxygenating O-alkylphosphinates, phosphinothioates, and some phosphonamides to their corresponding P(III) borane adducts [34]. The reaction was based on the use of alkyl triflate to activate the phosphoryl bond, and then the reduction of the intermediate using lithium borohydride (Scheme 1b).

Boranes, such as the BH₃-THF complex, are known for their high reactivity and ability to reduce various functional groups. The literature describes numerous applications of boranes in the reduction reactions of ketones, aldehydes, esters, and P=O bonds. Their ability to form stable complexes with phosphine oxide and efficiently transfer hydrogen makes them ideal reagents for such transformations.

Reagents such as BH₃-THF and dimethyl sulfide-borane, BH₃-S(Me)₂, are effective in reducing phosphine oxides. They can be used to reduce different phosphine oxides to obtain the corresponding phosphino-boranes.

Keglevich’s group has been working on the reduction of cyclic phosphine oxides using BH₃-S(Me)₂, Scheme 2, [35,36,37]. Under mild conditions, the method they developed was effective in converting various cyclic phosphine oxides into phosphino-boranes, highlighting the versatility and usefulness of BH₃-S(Me)₂ as a suitable reducing reagent for such transformations.

Subsequently, Pietrusiewicz et al. showed that BH₃-S(Me)₂ can be used to reduce the P=O bond in secondary phosphine oxides, directly providing the corresponding secondary phosphine–boranes [38,39]. The reaction proceeds under mild conditions, and the addition of a small amount of water to the reaction mixture greatly increases the yield of the products (Scheme 3).

In 2015, Pietrusiewicz’s group demonstrated that the same effect could be achieved for tertiary phosphine oxides with a hydroxyl group in the carbon backbone at the α or β carbon atom [40]. This conversion involved the reduction of the strong P=O bond by BH₃-THF under mild conditions, facilitated by intramolecular P=O---B complexation directed by the proximal α- or β-hydroxyl groups present in the phosphine oxide structures. The process proceeded with a complete configuration inversion at the phosphine center. Extending this methodology further, in 2018, we presented a method for the reduction of tertiary sulfanylphosphine and aminoalkylphosphine oxides using borane complexes [41]. This approach used neighboring activating groups, such as SH and NH, to support the reduction process, achieving high yields and, thus, demonstrating the versatility and utility of the method for various functional groups.

Recently, the same group extended this methodology to the reduction of P=O bonds in phosphonate and phosphinate derivatives [42]. This reduction, without the simultaneous cleavage of ester and amide bonds, was made possible by using BH₃-THF and/or BH₃-S(Me)₂ complexes and allowed us to obtain the corresponding borane-protected P(III) phosphonate and phosphinate derivatives in a single step.

In this paper, we present a simple conversion of phosphinoylacetic acid esters to their corresponding phosphino-boranes using a commercially available BH₃-THF complex under comparatively mild conditions, without chemically harmful and troublesome-to-use additives. Although the conversion of phosphinoylacetic acid esters unselectively provides β-hydroxyphosphino-boranes, it directly leads to the simultaneous reduction of the strong P=O bond and, parallelly, the ester group to alcohol, which has previously been impossible in a single step under such conditions. This approach appears valuable, considering the potential applications of such compounds and the fact that functionalized β-hydroxyphosphino-boranes are currently obtained only by multistep transformations. Additionally, we investigated the reduction of 3-phosphorylated coumarin derivatives with borane complexes, which led to the unexpected formation of 2,3-dihydrobenzofuran derivatives.

The aim of our work is to provide a comprehensive understanding of the scope and limitations of the use of BH₃-THF for the reduction of phosphinoylacetic acid esters and to contribute to the development of more efficient synthesis methods for the future.

2. Materials and Methods

2.1. Instrumentation

2.1.1. General

All reactions were set up using standard Schlenk techniques and carried out under an argon atmosphere using anhydrous solvents, unless otherwise noted. Commercially available chemicals were obtained from Sigma-Aldrich and used as received. NMR spectra were recorded using a Bruker AV500 (¹H 500 MHz, ³¹P 202 MHz, ¹³C NMR 126 MHz) spectrometer (Bruker, Karlsruhe, Germany). All spectra were obtained in CDCl₃ solutions, and the chemical shifts (δ) were expressed in ppm using an internal reference to TMS and external reference to 85% H₃PO₄ in D₂O for ³¹P. Coupling constants (J) were given in Hz. The abbreviations of signal patterns were as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; and b, broad. Elemental analyses were measured on a Perkin-Elmer CHN 2400 system (PerkinElmer, Waltham, MA, USA). HPLC–HRMS was performed on a Shimazu LCMS-8030 LCMS System using a reverse-phase stationary phase with water/MeCN (65:35) as an eluent, electrospray ionization (ESI), and an IT-TOF detector (Shimadzu Europa, Duisburg, Germany). Melting points were determined on a Buchi 510 apparatus (Buchi, Flawil, Switzerland). Thin-layer chromatography (TLC) was performed on silica gel (Kieselgel 60, F254 on aluminum sheets, Merck) using UV light (254 nm). All column chromatographic separations and purifications were conducted using Merck silica gel 60 (230–400 mesh), (Merck, Darmstadt, Germany).

2.1.2. General Procedure for the Synthesis of Phosphinoylacetic Acid Ethyl Esters 1a–d

A solution of ethyl bromoacetate (1.0 g, 6 mmol) in anhydrous THF (2 mL) was added dropwise to a corresponding secondary phosphine oxide (6 mmol) suspended in anhydrous THF (5 mL), followed by the portion wise addition of a 60% dispersion of NaH in oil (6 mmol) under argon in a Schlenk-type flask. After addition, the reaction mixture was stirred at rt. for 22 h, then evaporated, and CH₂Cl₂ (10 mL) was added. The organic phase was washed with H₂O (2 × 10 mL), dried over anhydrous MgSO₄, filtered, and evaporated. The resulting oil was dissolved in warm solution hexane/CH₂Cl₂ (1:1) and slowly cooled to afford precipitate 1a–d.

Ethyl diphenylphosphinoylacetate (1a). The reaction of diphenylphosphine oxide (1.21 g 6 mmol) produced 1.59 g (92%) of a white solid. Mp. 72–73 °C. lit., ref. [43] 72–73 °C. HRMS (ESI-IT-TOF) m/z calcd for C16H17O3P [M+H]⁺: 289.0915; found: 288.0916. ¹H NMR (500 MHz, CDCl₃): δ 7.89–7.74 (m, 4H), 7.62–7.54 (m, 2H), 7.54–7.45 (m, 4H), 4.01 (q, J = 7.1 Hz, 2H), 3.50 (d, J = 14.9 Hz, 2H), 1.04 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 166.16 (d, J = 5.2 Hz), 132.26 (d, J = 2.9 Hz), 131.80 (d, J = 104.0 Hz), 131.13 (d, J = 9.9 Hz), 128.63 (d, J = 12.4 Hz), 61.55, 39.22 (d, J = 60.5 Hz), 13.82. ³¹P NMR (202 MHz, CDCl₃): δ 26.75.

Ethyl (2-metoxyphenyl)phenylphosphinoylacetate (1b). The reaction of (2-metoxyphenyl)phenylphosphine oxide (1.39 g 6 mmol) produced 1.81 g (95%) of a light yellow solid. Mp. 65–66 °C. HRMS (ESI-IT-TOF) m/z calcd for C₁₇H₁₉O₄P [M+H]⁺: 319.1021; found: 310.1024. ¹H NMR (500 MHz, CDCl₃): δ 7.97 (ddd, J = 13.5, 7.6, 1.8 Hz, 1H), 7.82 (ddd, J = 12.5, 8.3, 1.3 Hz, 2H), 7.58–7.46 (m, 2H), 7.46–7.39 (m, 2H), 7.14–7.05 (m, 1H), 6.93 (dd, J = 8.3, 5.7 Hz, 1H), 4.03 (q, J = 7.1 Hz, 2H), 3.80 (s, 3H), 3.61 (dd, J = 14.7, 1.0 Hz, 2H), 1.02 (t, J = 7.2 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 166.52 (d, J = 6.5 Hz), 159.77 (d, J = 4.2 Hz), 134.44 (d, J = 6.0 Hz), 134.36 (d, J = 2.2 Hz), 133.04 (d, J = 106.8 Hz), 131.76 (d, J = 2.9 Hz), 130.73 (d, J = 10.3 Hz), 128.26 (d, J = 12.6 Hz), 121.18 (d, J = 11.7 Hz), 119.54 (d, J = 103.2 Hz), 110.82 (d, J = 6.9 Hz), 61.24, 55.42, 38.45 (d, J = 63.3 Hz), 13.86. ³¹P NMR (202 MHz, CDCl₃): δ 25.33.

Ethyl benzylphenylphosphinoylacetate (1c). The reaction of benzylphenylphosphine oxide (1.3 g 6 mmol) produced 1.56 g (86%) of a white solid. Mp. 81–82 °C. HRMS (ESI-IT-TOF) m/z calcd for C₁₇H₁₉O₃P [M+H]⁺: 303.1072; found: 303.1072. ¹H NMR (500 MHz, CDCl₃): δ 7.72–7.63 (m, 2H), 7.59–7.52 (m, 1H), 7.47 (dddd, J = 8.2, 5.6, 3.1, 1.3 Hz, 2H), 7.32–7.20 (m, 6H), 4.17–4.04 (m, 2H), 3.75–3.45 (m, 2H), 3.27–2.99 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 166.75 (d, J = 4.0 Hz), 132.28 (d, J = 2.9 Hz), 131.07 (d, J = 44.0 Hz), 130.81 (d, J = 9.0 Hz), 130.47, 130.20 (d, J = 5.4 Hz), 128.69 (d, J = 2.8 Hz), 128.51 (d, J = 11.8 Hz), 127.15 (d, J = 3.2 Hz), 61.61, 42.21–32.01 (m), 13.98. ³¹P NMR (202 MHz, CDCl₃): δ 32.10.

Ethyl (1-naphtyl)phenylphosphinoylacetate (1d). The reaction of (1-naphtyl)phosphine oxide (1.51 g 6 mmol) produced 1.54 g (76%) of a yellow solid. Mp. 63–64 °C. HRMS (ESI-IT-TOF) m/z calcd for C₂₀H₁₉O₃P [M+H]⁺: 339.1072; found: 339.1071. ¹H NMR (500 MHz, CDCl₃): δ 8.60–8.53 (m, 1H), 8.05 (dq, J = 8.4, 1.4 Hz, 1H), 7.96 (ddd, J = 15.9, 7.2, 1.2 Hz, 1H), 7.90 (dt, J = 7.2, 2.0 Hz, 1H), 7.82 (ddd, J = 12.4, 8.3, 1.4 Hz, 2H), 7.60–7.39 (m, 6H), 3.93 (q, J = 7.1 Hz, 2H), 3.70 (dd, J = 15.0, 2.2 Hz, 2H), 0.94 (t, J = 7.1 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 166.32 (d, J = 5.3 Hz), 133.81 (d, J = 9.5 Hz), 133.66 (d, J = 3.0 Hz), 133.23 (d, J = 9.1 Hz), 132.58 (d, J = 10.9 Hz), 132.35 (d, J = 104.0 Hz), 132.27 (d, J = 3.0 Hz), 131.24 (d, J = 10.1 Hz), 129.05, 128.70 (d, J = 12.6 Hz), 127.56, 127.52 (d, J = 102.2 Hz), 126.61, 126.57, 124.37 (d, J = 14.4 Hz), 61.54, 39.55 (d, J = 60.9 Hz), 13.71. ³¹P NMR (202 MHz, CDCl₃) δ 30.12.

2.2. General Procedure for the Synthesis of Phosphinoylacetic Acid L-menthyl Esters 2a–c

A solution of L-menthyl bromoacetate (1.66 g, 0.006 mol) in anhydrous THF (20 mL) was added dropwise to secondary phosphine oxide (0.006 mol) suspended in anhydrous THF (40 mL), followed by the portion wise addition of a 60% dispersion of NaH in oil (0.006 mol) under argon in a Schlenk-type flask. After addition, the reaction mixture was stirred at rt. for 22 h, then evaporated, and CH₂Cl₂ (50 mL) was added. The organic phase was washed with H₂O (2 × 50 mL), dried over anhydrous MgSO₄, filtered, and evaporated. The resulting oil was dissolved in warm solution hexane/CH₂Cl₂ (2:1) and slowly cooled to afford crystalline precipitate 2a–c.

L-menthyl diphenylphosphinoylacetate (2a). The reaction of diphenylphosphine oxide (1.21 g 6 mmol) produced 2.3 g (96%) of a white solid. Mp. 64–65 °C, lit., ref. [44], 63–65 °C. HRMS (ESI-IT-TOF) m/z calcd for C₂₄H₃₁O₃P [M+H]⁺: 399.2011; found: 399.2012. ¹H NMR (500 MHz, CDCl₃): δ 7.87–7.74 (m, 4H), 7.57–7.52 (m, 2H), 7.48 (dt, J = 7.2, 3.3 Hz, 4H), 4.57 (td, J = 10.9, 4.4 Hz, 1H), 3.49 (dd, J = 14.7, 1.4 Hz, 2H), 1.71–1.63 (m, 1H), 1.59 (ddd, J = 13.2, 7.1, 3.4 Hz, 1H), 1.34 (tdp, J = 12.4, 6.4, 3.0 Hz, 1H), 1.22 (ddt, J = 14.2, 11.3, 3.1 Hz, 1H), 0.99–0.87 (m, 1H), 0.81 (d, J = 6.6 Hz, 3H), 0.78 (d, J = 7.1 Hz, 3H), 0.76–0.65 (m, 1H), 0.60 (dd, J = 7.0, 1.4 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 165.71 (d, J = 5.1 Hz), 132.35 (d, J = 3.0 Hz), 132.17 (d, J = 2.9 Hz), 131.53 (d, J = 2.9 Hz), 131.15 (d, J = 9.9 Hz), 128.61 (d, J = 12.3 Hz), 75.78, 46.51, 40.28, 39.35 (d, J = 61.0 Hz), 34.02, 31.27, 25.69, 23.00, 21.91, 20.81, 15.92. ³¹P NMR (202 MHz, CDCl₃) δ 26.33.

L-menthyl (2-metoxyphenyl)phenylphosphinoylacetate (2b). The reaction of (2-metoxyphenyl)phenylphosphine oxide (1.39 g 6 mmol) produced 2.36 g (91%) of alight yellow solid. Mp 98–99 °C lit., ref. [45] 97–98 °C. HRMS (ESI-IT-TOF) m/z calcd for C₂₅H₃₃O₄P [M+H]⁺: 429.2116; found: 429.2115. ¹H (500 MHz, CDCl₃): δ 7.98 (dd, J = 13.5, 7.6 Hz, 1H), 7.84 (dd, J = 12.5, 7.9 Hz, 2H), 7.58–7.40 (m, 4H), 7.15–7.07 (m, 1H), 6.97–6.90 (m, 1H), 4.58 (td, J = 10.9, 4.3 Hz, 1H), 3.83 (s, 3H), 3.70–3.53 (m, 2H), 1.79–1.66 (m, 2H), 1.64–1.54 (m, 2H), 1.40–1.29 (m, 1H), 1.16 (t, J = 11.6 Hz, 1H), 0.99–0.88 (m, 1H), 0.80 (dd, J = 11.4, 6.8 Hz, 6H), 0.76–0.65 (m, 2H), 0.62 (d, J = 6.9 Hz, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 166.02 (d, J = 6.7 Hz), 159.79 (d, J = 4.2 Hz), 134.55 (d, J = 5.9 Hz), 134.25 (d, J = 2.0 Hz), 133.08 (d, J = 106.4 Hz), 131.72 (d, J = 2.9 Hz), 130.75 (d, J = 10.2 Hz), 128.25 (d, J = 12.6 Hz), 121.17 (d, J = 11.6 Hz), 119.64 (d, J = 102.9 Hz), 110.74 (d, J = 7.0 Hz), 75.39 (s), 55.37 (s), 46.57 (s), 40.28 (s), 38.61 (d, J = 63.1 Hz), 34.09 (s), 31.26 (s), 25.69 (s), 23.03 (s), 21.92 (s), 20.84 (s), 15.96 (s). ³¹P NMR (202 MHz, CDCl₃) δ 25.11.

L-menthyl (1-naphtyl)phenylphosphinoylacetate (2c). The reaction of (1-naphtyl)phosphine oxide (1.51 g 6 mmol) produced 2.29 g (85%) of a yellow oil; mixture of diastereomers 1:1. ³¹P NMR (202 MHz, CDCl₃): δ 30.25 (s), 30.03 (s).

2.3. General Procedure for Synthesis of Phosphinoylacetic Acids 3a–b

To a stirred solution of the corresponding secondary phosphine oxide (2 mmol) and chloroacetic acid (0.24 g, 2.5 mmol) in DMSO (3 mL), a 56% aq KOH solution (0.55 mL, 5.5 mmol) was added dropwise at r.t. After heating for 1 h at 40–60 °C, the mixture was diluted with H₂O. The aqueous solution was acidified with diluted HCl and the crude mixture was extracted with CHCl₃. The combined CHCl₃ extracts were dried (MgSO₄), filtered, and evaporated under vacuum. The residue was crystallized from MeCN.

Diphenylphosphinylacetic Acid (3a). The reaction of diphenylphosphine oxide (404 mg, 2,5 mmol) produced a white solid of 3a (539 mg, 83%). Mp 144–145 °C lit., ref. [46] 145–146 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.75–7.68 (m, 4 H), 7.55–7.32 (m, 6 H), 6.81 (br s, 1 H), 3.46 (d, J = 14.2 Hz, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 167.31 (d, J = 5.6 Hz), 132.44 (d, J = 2.8 Hz), 131.07 (d, J = 10.3 Hz), 130.85 (d, J = 105.7 Hz), 128.75 (d, J = 12.6 Hz), 38.36 (d, J = 62.2 Hz). ³¹P NMR (202 MHz, CDCl₃): δ = 30.42.

(2-Methoxyphenyl)phenylphosphinylacetic Acid (3b). The reaction of (2-methoxyphenyl)phenylphosphine oxide (464 mg, 2,5 mmol) produced a white solid of 3a (573 mg, 79%). Mp 173–174 °C lit., ref. [46] 173–174 °C. ¹H NMR (500 MHz, CDCl₃): δ = 7.66 (ddd, J = 13.7, 7.6, 1.7 Hz, 1 H), 7.61–7.50 (m, 2 H), 7.36–7.25 (m, 2 H), 7.21 (tdd, J = 8.2, 3.2, 1.2 Hz, 2 H), 6.85 (tdd, J = 7.5, 2.1, 0.9 Hz, 1 H), 6.77 (br s, 1 H), 6.71 (dd, J = 8.3, 5.8 Hz, 1 H), 3.56 (s, 3 H), 3.39 (dd, J = 14.1, 5.5 Hz, 2 H). ¹³C NMR (126 MHz, CDCl₃): δ = 167.51 (d, J = 6.2 Hz), 159.91 (d, J = 4.6 Hz), 134.78 (d, J = 2.1 Hz), 134.25 (d, J = 6.2 Hz), 132.14 (d, J = 2.9 Hz), 131.81 (d, J = 108.2 Hz), 130.70 (d, J = 10.8 Hz), 128.47 (d, J = 12.8 Hz), 121.35 (d, J = 11.7 Hz), 118.26 (d, J = 105.7 Hz), 110.99 (d, J = 7.0 Hz), 55.45, 37.46 (d, J = 63.2 Hz). ³¹P NMR (202 MHz, CDCl₃): δ = 30.11.

2.4. General Procedure for Synthesis of Phosphino-Borane Complexes 4a–d from Phosphinoylacetic Acid Ethyl Esters 1a–d

A 1.0 M solution of borane in THF was added to the solution of the corresponding phosphinoylacetic acid esters (1 mmol) in dry THF (2 mL) under argon flow. The mixture was heated to 80 °C and stirred. After a specified time, the reaction was cooled down to r.t. and the solvent was removed in vacuum to afford a crude product. The solid products were simply washed with 25 mL of 10% HCl of dried over anhydrous MgSO₄. The crude residue was purified by column chromatography on silica gel (eluent: hexane/CHCl₃) with a gradient mixture ratio from 1:4 to 1:2.

(2-Hydroxyethyl)diphenylphosphino-borane (4a)). The reaction of 1a (288 mg, 1 mmol) refluxed with 1M BH₃-THF (10.0 equiv.) for 72 h produced a white oil of 4a (222 mg, 91%). HRMS (ESI-IT-TOF) m/z calcd for C₁₄H₁₈BOP [M+H]+: 245.1188; found: 245.1187. ¹H NMR (500 MHz, CDCl₃): δ 7.77–7.64 (m, 4H), 7.49 (dddd, J = 16.2, 8.3, 5.4, 1.8Hz, 6H), 3.94 (dt, J = 15.5, 6.5 Hz, 2H), 2.58 (dt, J = 11.7, 6.5 Hz, 2H), 2.09 (s, 1H), 1.45–0.72 (m, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 132.09 (d, J = 9.2 Hz), 131.45 (d, J = 2.6 Hz), 129.02 (d, J = 56.3 Hz), 128.98 (d, J = 10.2 Hz), 57.61 (d, J = 2.5 Hz), 29.36 (d, J = 36.2 Hz). ³¹P NMR (202 MHz, CDCl₃): δ 10.60 (d, J = 69.5 Hz).

(2-Hydroxyethyl)(2-metoxyphenyl)phenylphosphino-Borane (4b)

The reaction of 1b (318 mg, 1 mmol) refluxed with 1M BH₃-THF (10.0 equiv.) for 72 h produced a white oil of 4b (232 mg, 85%). HRMS (ESI-IT-TOF) m/z calcd for C₁₅H₂₀BO₂P [M+H]+: 275.1274; found: 275.1274. ¹H NMR (500 MHz, CDCl₃): δ 7.93 (ddd, J = 13.8, 7.7, 1.7 Hz, 1H), 7.76–7.61 (m, 2H), 7.53 (t, J = 7.9 Hz, 1H), 7.43 (ddt, J = 16.5, 8.5, 4.0 Hz, 3H), 7.10 (td, J = 7.5, 2.0 Hz, 1H), 6.91 (dd, J = 8.4, 3.5 Hz, 1H), 3.99–3.78 (m, 2H), 3.73 (s, 3H), 2.87 (tt, J = 13.2, 6.3 Hz, 1H), 2.74–2.61 (m, 1H), 2.16 (s, 1H), 0.85–0.64 (m, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 161.28 (d, J = 1.8 Hz), 136.29 (d, J = 14.7 Hz), 134.04 (d, J = 2.2 Hz), 131.47 (d, J = 9.5 Hz), 129.89 (d, J = 59.8 Hz), 128.43 (d, J = 10.4 Hz), 121.30 (d, J = 12.3 Hz), 115.79 (d, J = 54.1 Hz), 111.23 (d, J = 4.2 Hz), 58.00 (d, J = 2.6 Hz), 55.39, 27.69 (d, J = 37.8 Hz). ³¹P NMR (202 MHz, CDCl₃): δ 11.02 (d, J = 79.4 Hz).

(2-Hydroxyethyl)benzylphenylphosphino-borane (4c). The reaction of 1c (302 mg, 1 mmol) refluxed with 1M BH₃-THF (10.0 equiv.) for 72 h produced a white oil of 4c (174 mg, 68%). HRMS (ESI-IT-TOF) m/z calcd for C₁₅H₂₀BOP [M+H]+: 259.1345; found: 259.1346. ¹H NMR (500 MHz, CDCl₃): δ 7.63–7.51 (m, 3H), 7.49–7.38 (m, 2H), 7.29–7.18 (m, 3H), 6.95 (ddd, J = 4.9, 4.1, 2.1 Hz, 2H), 4.06–3.74 (m, 2H), 3.48–3.08 (m, 2H), 2.34–2.01 (m, 2H), 1.28 (bs, 1H), 1.08–0.48 (m, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 132.30 (d, J = 8.9 Hz), 131.90 (d, J = 7.3 Hz), 131.71 (d, J = 2.5 Hz), 129.94 (d, J = 4.1 Hz), 128.72 (d, J = 9.9 Hz), 128.36 (d, J = 2.7 Hz), 127.19 (d, J = 52.7 Hz), 127.12 (d, J = 3.1 Hz), 57.53, 35.19 (d, J = 31.6 Hz), 26.81 (d, J = 35.0 Hz). ³¹P NMR (202 MHz, CDCl₃): δ 12.44 (d, J = 79.6 Hz).

(2-Hydroxyethyl)(1-naphtyl)phenylphosphino-borane (4d). The reaction of 1d (338 mg, 1 mmol) refluxed with 1M BH₃-THF (10.0 equiv.) for 72 h produced a white oil of 4c (144 mg, 49%). HRMS (ESI-IT-TOF) m/z calcd for C₁₈H₂₀BO₂P [M+H]+: 295.1345; found: 295.1345. ¹H NMR (500 MHz, CDCl₃): δ 8.18 (ddd, J = 14.5, 7.1, 1.2 Hz, 1H), 8.08 (dd, J = 8.3, 1.2 Hz, 1H), 7.96–7.84 (m, 2H), 7.67–7.59 (m, 3H), 7.50 (dtd, J = 8.9, 7.1, 1.3 Hz, 2H), 7.46–7.35 (m, 3H), 3.95 (dtd, J = 15.7, 6.5, 4.4 Hz, 2H), 2.86 (ddt, J = 14.4, 11.3, 6.4 Hz, 1H), 2.74 (ddt, J = 14.4, 10.4, 6.5 Hz, 1H), 1.28 (bs, 1H), 1.22–0.80 (m, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 134.71 (d, J = 12.5 Hz), 134.10, 133.28 (d, J = 2.7 Hz), 132.85, 131.46 (d, J = 9.2 Hz), 131.10 (d, J = 2.7 Hz), 130.24 (d, J = 56.5 Hz), 129.51, 129.09 (d, J = 10.3 Hz), 126.99, 126.37, 126.25 (d, J = 6.1 Hz), 125.02 (d, J = 12.6 Hz), 124.00, 57.81 (d, J = 2.8 Hz), 29.38 (d, J = 35.7 Hz). ³¹P NMR (202 MHz, CDCl₃): δ 12.51 (d, J = 64.7 Hz).

2.5. General Procedure for Synthesis of Phosphino-Borane Complexes 4a–b from Phosphinoylacetic Acid L-menthyl Esters 2a–b

A 1.0 M solution of borane in THF was added to the solution of corresponding phosphinoylacetic acid esters (1 mmol) in dry THF (2 mL) under argon flow. The mixture was heated to 80 °C and stirred. After a specified time, the reaction was cooled down to r.t. and the solvent was removed in vacuum to afford a crude product. The solid products were simply washed with 25 mL of 10% HCl of dried over anhydrous MgSO₄. The crude residue was purified by column chromatography on silica gel (eluent: hexane/CHCl₃) with a gradient mixture ratio from 1:2 to 1:4.

2.6. Procedure for Synthesis of 3-(Diphenylphosphinyl)-2H-Chromen-2-One (5)

3-(Diphenylphosphinyl)-2H-Chromen-2-One (5)

3-(Diphenylphosphinyl)-2H-chromen-2-one was obtained according to the previously described procedure [47].

¹H NMR (500 MHz, CDCl₃): δ 8.93 (d, J = 14.0 Hz, 1H), 7.95–7.88 (m, 4H), 7.69 (dd, J = 8.0, 1.6 Hz, 1H), 7.64 (ddd, J = 8.7, 7.5, 1.6 Hz, 1H), 7.61–7.55 (m, 2H), 7.54–7.46 (m, 4H), 7.40–7.30 (m, 2H). ¹³C NMR (126 MHz, CDCl₃): δ 159.12 (d, J = 13.6 Hz), 155.40, 153.99 (d, J = 4.8 Hz), 134.14, 132.47 (d, J = 2.8 Hz), 132.07 (d, J = 10.6 Hz), 130.54 (d, J = 110.4 Hz), 129.47, 128.52 (d, J = 13.0 Hz), 125.00, 121.64 (d, J = 102.1 Hz), 118.53 (d, J = 10.4 Hz), 116.81. ³¹P NMR (202 MHz, CDCl₃): δ 23.35.

2.7. Procedure for Synthesis of (2-methyl-tetrahydro-[2]furyl)-diphenylphosphine-borane (6)

A 1.0. M solution of borane in THF was added to the solution of corresponding coumarin 5 (1 mmol) in dry THF (2 mL) under argon flow. The mixture was heated to 80 °C and stirred. After a specified time, the reaction was cooled down to r.t. and the solvent was removed in vacuum to afford a crude product. The solid products were simply washed with 25 mL of 10% HCl of dried over anhydrous MgSO₄. The crude residue was purified by column chromatography on silica gel (eluent: hexane/CHCl₃) with a gradient mixture ratio from 1:3 to 1:5.

(2-methyl-tetrahydro-[2]furyl)-diphenylphosphine-borane (6). The reaction of 5 (346 mg, 1 mmol) refluxed with 1M BH₃-THF (10.0 equiv.) for 72 h produced a white oil of 4b (200 mg, 89%). HRMS (ESI-IT-TOF) m/z calcd for C₂₁H₂₂BOP [M+H]+: 333.1579; found: 333.1579. ¹H NMR (500 MHz, CDCl₃): δ 7.78–7.64 (m, 4H), 7.62–7.56 (m, 1H), 7.54–7.42 (m, 5H), 7.23–7.14 (m, 1H), 7.03–6.89 (m, 3H), 3.45 (dd, J = 15.9, 8.2 Hz, 1H), 2.35 (dd, J = 15.9, 6.6 Hz, 1H), 1.27 (d, J = 17.8 Hz, 3H), 1.24–0.82 (m, 3H). ¹³C NMR (126 MHz, CDCl₃): δ 151.24, 134.59 (d, J = 8.6 Hz), 132.88 (d, J = 8.1 Hz), 131.73 (d, J = 2.6 Hz), 131.08 (d, J = 2.5 Hz), 129.48, 129.06 (d, J = 9.9 Hz), 128.50 (d, J = 10.0 Hz), 128.26, 127.70 (d, J = 56.9 Hz), 125.41 (d, J = 54.2 Hz), 123.10, 122.80 (d, J = 7.6 Hz), 118.17, 34.68 (d, J = 3.5 Hz), 17.31. ³¹P NMR (202 MHz, CDCl₃): δ 32.87 (dd, J = 73.0, 16.6 Hz).

3. Results and Discussion

Strong binding between phosphorus and oxygen atoms hinders the reduction of phosphine oxides to phosphino-boranes. So far, few examples of such transformations have been recorded in the literature using BH₃ complexes, and they concern only a narrow substrate group, i.e., cyclic phosphine oxides with high structural ring strain. It has also been shown that the direct reduction of tertiary phosphine oxides to corresponding boranes by the BH₃-THF complex is possible when the structure of the molecule contains activating groups such as OH, SH, or NH (Scheme 4a). For these reasons, we tested a new group of substrates containing a carbonyl group in a molecule to determine the limitations and scope of the direct reduction of phosphine oxides. We selected simple phosphinoylacetic acids and their esters as model substrates (Scheme 4b). Phosphinoylacetic acids and their esters are readily available synthetically and have a carbonyl group in the β-position, which, in the presence of BH₃-THF, should facilitate the reduction of the P=O bond to the corresponding phosphine–borane.

3.1. Synthesis and Borane Reduction of Phosphinoylacetic Esters and Acids

In order to synthesize the esters, we followed the specified method [45], which entails the alkylation of secondary phosphine oxides using either ethyl 2-bromoacetate or menthyl 2-chloroacetate. The reactions were carried out in anhydrous THF with the addition of a 60% dispersion of sodium hydride (NaH) in oil at room temperature for 22 h. The ethyl esters 1a–d and menthyl esters 2a–c were obtained in yields of up to 96% (Scheme 5). Ester 2b was obtained as a single diastereoisomer, while 2c unfortunately remained a mixture of two diastereoisomers (1:1).

On the other hand, the corresponding phosphinoylacetic acids can be readily generated by reacting secondary phosphine oxides and chloroacetic acid in the presence of an aqueous solution of KOH in dimethylsulfoxide as a solvent [46,48]. Their reaction yields are up to 83% (Scheme 6).

We conducted a reduction of the model esters 1a–d and 2a–c and phosphinoylacetic acids 3a and 3b with various substituents at the phosphorus atom in order to thoroughly study the reducing properties of the BH₃-THF. We began our preliminary studies by reacting diphenylphosphinoylacetic acid ethyl ester 1a with 5 equiv. BH₃-THF. We were pleased to find that, at 80 °C and after 24 h, the ester was reduced and directly provided the corresponding phosphino-borane. Column chromatography isolation of the reaction product revealed a non-selective reduction process, which also reduced the ester group to yield the final hydroxyl derivative 4a with a yield of 32% (

Table 1. Reduction reactions of phosphinoylacetic acids and esters with BH₃-THF.

Entry	R1	R2	BH₃-THF (equiv.)	Time, h	Conv., % [a] (Yield), % [b]
1	Ph	Et	5	24	4a; 40 (32)
2	Ph	Et	10	72	4a; 98 (91)
3	o-An	Et	10	24	4b; 44
4	o-An	Et	10	72	4b; 90 (85)
5	Bn	Et	10	72	4c; 76 (68)
6	1-Naphthyl	Et	10	72	4d; 55 (49)
7	Ph	Menthyl	10	72	4a; 66 (58)
8	o-An	Menthyl	10	72	4b; 79 (73)
9	1-Naphthyl	Menthyl	10	72	ND
10 [c]	1-Naphthyl	Menthyl	10	72	ND
11	Ph	H	10	72	4a; 66 (60)
12	o-An	H	10	72	4b; 64 (54)

Reaction conditions: 1–3 (1.0 mmol), 1M BH₃-THF (5.0–10.0 equiv.), 80 °C, reaction time 24–72 h [a] reaction conversion calculated from the ³¹PNMR spectrum; [b] isolated yield; [c] reaction temp. 100 °C, toluene; ND = not detected.

, entry 1). We were surprised by the unexpected reduction of the ester group using BH₃-THF. This was contrary to what the literature suggests, as functional groups such acid chlorides, esters, carboxylic acid salts, or epoxides are often unreactive or exhibit a delayed reactivity relative to carboxylic acids upon reduction [49]. Increasing the amount of BH₃ twofold did not noticeably improve the conversion of the reaction; it was necessary to extend the reduction time with borane to 72 h. We obtained a pure product 4a with a yield of 91% under these conditions and a 98% reaction conversion (Table 1, entry 2). The data collected in Table 1 show that other ethyl esters of diarylphosphinoylacetic acid ethyl esters 1a–b and alkylarylphosphinoylacetic acids ethyl ester 1c were also sufficiently reactive to be reduced by BH₃-THF and yielded phosphino-boranes 4a–c, respectively, although it was still necessary to extend the reaction time to 72 h and a reaction temperature of 80 °C for efficient conversion.

Next, we checked the efficiency of the reduction reaction of the menthyl esters of diarylphosphinoylacetic acid (2a, 2b). These esters were of particular interest to us, because, like 2b, they can be easily obtained in enantiomerically pure form. Under standard reaction conditions, we examined the reduction with 10 equiv. of BH₃-THF and found that these esters were equally easily reduced to the appropriate phosphine-boranes 4a and 4b, with the simultaneous reduction of the ester group. However, under these conditions, no reaction occurred in the case of the menthyl ester of phosphonoylacetic acid bearing phenyl and naphthyl groups on the phosphorus atom, 2c, (Table 1, entry 9, 10). Increasing the reduction temp. to 100 °C and switching the solvent to toluene also did not yield the intended reaction product. Only the replacement of the menthyl ester with an ethyl ester enabled the reduction and yielded the final borane 4d in a poor 49% yield (Table 1, entry 6). It is likely that steric effects played a significant role here, and the bulky naphthyl and menthyl groups hindered the approach of the borane reagent, thus preventing reduction. This observation underscores the importance of considering steric effects when designing further reduction protocols with BH₃-THF complex.

We also applied this reaction to diarylphosphinoylacetic acids 3a and 3b, yielding the corresponding products 4a and 4b with moderate yields of 60% and 54%, respectively.

Our findings demonstrated the efficient application of the reduction reaction with BH₃-THF to both esters and phosphinoylacetic acids. Such a reduction can be of value synthetically, since it directly and without additional transformations allows for the simultaneous preparation of phosphine–boranes containing hydroxyl groups in the beta position. In turn, such β-hydroxyethylphosphine-boranes can be valuable for further chemical transformations (e.g., the elimination of the OH from the vinyl group, the synthesis of bisphosphine ligands), ref. [50,51,52].

In the study, a 1M solution of BH₃-THF was used, which, at 80 °C, allowed for significant reaction conversion, up to 98%, and the production of valuable phosphino-borane structures in yields up to 91%. Taking into account the previous reports of our group, showing that the reduction of the P=O bond to the corresponding phosphine–borane is only possible due to the presence of neighboring OH, NH, or SH, we can suppose that, in our case, we observed an activating effect of the C=O group on the process.

3.2. Study on the Reduction of 3-Phosphorylated Coumarin

The observation that, using the BH₃-THF complex, it is possible to reduce the P=O bond to the corresponding phosphine–borane when there is a carbonyl group in the β-position to the phosphoryl group led us to hypothesize that the reduction methodology might also be applicable to 3-phosphorylated coumarins. Coumarins, known for their various chemical and biological properties and ready availability, were a tempting target for this study.

Coumarin is an aromatic compound with a bicyclic structure containing a lactone carbonyl group. Its structural similarity to previously studied phosphinoylacetic acid esters (1–3), related to the presence of a carbonyl group in the β-position to the phosphorus, suggested that a reduction of the P=O bond to phosphino-borane might be feasible (Figure 1). We considered the potential synthetic utility of this type of transformation, which could offer a new route for the synthesis of valuable phosphino-borane coumarin derivatives.

In this section of our study, we selected a model 3-phosphorylated coumarin, 3-(diphenylphosphinyl)-2H-chromen-2-one (5), to test the reduction potential of BH₃-THF and BH₃-S(Me)₂.

In the presence of 5.0 equiv. of the BH₃-TFH complex, at 80 °C and after 24 h, a complex mixture was obtained from which no pure compound was isolated (

Table 2. Reduction of 3-(diphenylphosphinyl)-2H-chromen-2-one with borane complexes.

Entry	Borane Complexes (equiv.)	Time, h	Conv., % [a]	Yield, % [b]
1	BH3-THF (5.0)	24	35	complex mixture
2	BH3-THF (10.0)	24	70	62
3	BH3-THF (10.0)	72	100	89
4	BH₃-S(Me)₂ (5.0)	24	100	90

Reaction conditions: 5 (1.0 mmol), 1M BH₃-THF or BH₃-S(Me)₂ (5.0–10.0 equiv.), 80 °C, reaction time 24–72 h [a] reaction conversion calculated from the ³¹PNMR spectrum; [b] isolated yield.

). By increasing the amount of boron complex to 10 equiv. and the reaction time to 72 h on the ³¹PNMR spectrum, a complete conversion of the substrate to a phosphino-borane derivative with a chemical shift = δ 32.87 (dd, J = 73.0, 16.6 Hz) was observed. After purifying the compound by column chromatography, ¹H NMR and ¹³CNMR analyses and detailed 2D-NMR (¹H−¹³HSQC and ¹H−¹³C HMBC) showed that the reduction of 3-phosphorylated coumarin 5 by BH₃-THF led to an unexpected 2,3-dihydrobenzofuran -based product 6 with a yield of 89%.

A complete conversion of 3-phosphorylated coumarin to product 6 can also be obtained in a shorter time, i.e., after 24 h using 5.0 equiv. of BH₃-S(Me)₂ complex. The yield of the isolated product was 90%.

This puzzling result of reduction by borane complexes suggests that the reaction conditions and the unsaturated bond in the coumarin backbone may have promoted the hydroboration reaction and subsequent intramolecular cyclization, transforming the coumarin structure into the 2,3-dihydrobenzofuran backbone, along with the reduction of the P=O group. At this preliminary stage of work, we are unable to propose the exact mechanism of the reaction. Our future research will focus on clarifying the intricate mechanism of this change and investigating its potential for use in synthesis.

4. Conclusions

In conclusion, the present study successfully demonstrated the efficient reduction of phosphinylacetic acid esters using BH₃-THF complexes, providing a simple method for the direct preparation of phosphino-borates with the simultaneous reduction of the ester group. The optimization of the reaction conditions resulted in high yields of up to 91%, especially under conditions of 10 equivalents of BH₃-THF at 80 °C for 72 h. The study also highlighted the influence of steric effects on the reduction process, with bulky substituents such as the 1-naphthyl group hindering the reaction. The application of this reduction methodology to 3-phosphorylated coumarins revealed unexpected results, in particular the formation of a 2,3-dihydrobenzofuran-based product. This suggests that the reaction conditions and the presence of an unsaturated bond in the coumarin backbone likely promote hydroboration and intramolecular cyclization, transforming the coumarin backbone. This discovery underscores the unique reactivity of 3-phosphorylated coumarins under borane-mediated reduction conditions and opens up new opportunities for the synthesis of 2,3-dihydrobenzofuran-based phosphino-borane derivatives. Future research will aim to elucidate the detailed mechanism of this transformation and explore its potential synthetic applications.

In summary, the findings provide valuable information on the reduction of phosphine oxides and related compounds, highlighting the versatility and potential of borane complexes in synthetic organic chemistry and laying the groundwork for future research and optimization in this area.