Synthesis of Quinolizidine-Based 1,4-Azaphosphinines via Cyclization of Heteroarylmethyl(alkynyl)phosphinates

Abstract

Intramolecular hydroarylation of (phenylethynyl)­phosphinates represents a powerful strategy for constructing six-membered phosphorus heterocycles. In this study, we report a silver-catalyzed cyclization protocol that enables the efficient synthesis of 1,4-aza-phosphorus heterocycles under mild conditions. The approach demonstrates broad substrate tolerance, affording full conversion across more than 30 derivatives. Dearomatization of pyridine leads to the formation of previously unreported quinolizidine-based 1,4-azaphosphinine scaffolds. These novel phosphorus heterocycles expand the structural diversity of phosphorus-containing frameworks and open new opportunities in the chemistry of functional heterocycles.

Introduction

Phosphorus-containing compounds play a pivotal role in modern chemistry due to their versatile applications in catalysis, − materials science, − and drug discovery. − Among these, phosphorus hexacycles stand out as a unique class of compounds, characterized by their ambipolar redox properties, , luminescence properties, − and potential for postfunctionalization. , Therefore, the synthesis of phosphorus-containing heterocycles has evolved considerably over the past several years. Recent advancements in organophosphorus chemistry have introduced innovative strategies for constructing phosphorus-containing rings, including intra- or intermolecular cyclization of alkynes with phosphonates, phosphine oxides, phosphines, , and phosphonium salts, cyclization of ylides, or [2+2+2] cycloaddition of diynes with phosphaalkynes. − Recently, we reported the intramolecular acid-assisted cyclization of phosphinates bearing an acetylene moiety. , This method demonstrated the efficient conversion of diphenyl phosphinate I into cyclic product II in trifluoroacetic acid (Figure ). Encouraged by these results, we pursued the preparation of the aza analogue of cyclic phosphinate 5p, which could potentially be transformed into bidentate pyridyl-phosphinine ligands. However, we observed that under these conditions, the reaction is extremely slow and ineffective (see for details). Inspired by the work of Lee et al. on similar transformations involving carbophilic activation, , we explored the use of a gold/silver catalyst. Intriguingly, while phosphinate 1p exhibited high reactivity under these conditions, the cyclization occurred not at the phenyl but rather at the pyridyl, leading to the dearomatization of pyridine and the formation of 2p with an unprecedented 1,4-azaphosphinine scaffold. Although this transformation is documented for pyridines bearing an alkyne activated by a carbonyl group, − its application in phosphorus chemistry has remained unexplored. Motivated by this observation, we decided to study the reaction in detail.

1.

Results and Discussion

We began our study with the preparation of phosphinate 1a as a model compound via the Michaelis–Arbuzov reaction. The starting material, 2-bromomethylpyridine, is intrinsically unstable due to the presence of both electrophilic and nucleophilic moieties. Therefore, it is commercially available only as its hydrobromide. To obtain the free base, the salt was deprotonated by extraction between DCM and aqueous potassium carbonate. We observed that the resulting solution was relatively stable at room temperature but decomposed upon heating or solvent evaporation, as indicated by the change in color from transparent to deep red. Due to its instability, the solution of 2-bromomethylpyridine in DCM was reacted directly with phosphonite 6a. Refluxing this mixture resulted in only negligible formation of phosphinate 1a. To overcome this limitation, the reaction mixture was gradually heated to 100 °C, during which the solvent was distilled off while the starting material was converted almost completely. Nevertheless, this treatment inevitably caused decomposition of 2-bromomethylpyridine, resulting in a relatively low isolated yield of 1a.

Having 1a in hand, we proceeded to screen various π-acidic transition metal-based catalysts to optimize the reaction conditions (Table ). Copper­(I) and copper­(II) catalysts, as well as palladium­(II) acetate, showed no conversion (entries 1–3). A gold­(I) catalyst, Ph₃PAuNTf₂, exhibited low catalytic activity, providing a conversion of 12% (entry 4). Silver­(I) salts demonstrated more promising results, with AgNO₃ yielding 36% (entry 5), AgF 44% (entry 6), and AgBF₄ 54% conversion (entry 7). Remarkably, CH₃COOAg and CF₃COOAg both achieved complete conversion of 1a with excellent isolated yields (entries 8 and 9, respectively). Reducing the loading of CF₃COOAg from 0.1 to 0.02 equiv maintained full conversion (entry 10). Additionally, the reaction also proceeded with complete conversion in other chlorinated (CHCl₃ and DCE) and nonchlorinated (DMF, THF, and MeOH) solvents.

1. Catalyst Screening.

entry	catalyst (equiv)	conversion (%)
1	[(MeCN)4Cu]PF6 (0.1)	0
2	Cu(OTf)2 (0.1)	0
3	Pd(OAc)2 (0.1)	0
4	Ph3PAuNTf2 (0.1)	12
5	AgNO3 (0.1)	36
6	AgF (0.1)	44
7	AgBF4 (0.1)	54
8	CH3COOAg (0.1)	100 (80)
9	CF3COOAg (0.1)	100 (87)
10	CF3COOAg (0.02)	100

^aReactions were performed using 0.1 mmol of 1a.

^bThe conversion was calculated by measuring the ratio of starting material 1a to product 2a in the ³¹P NMR spectrum of the crude reaction mixture.

^cIsolated yield.

The proposed mechanism is depicted in Scheme . Initially, the triple bond in 1a is activated by the π-acidic silver­(I) catalyst, which promotes nucleophilic attack by the pyridine lone pair, leading to the formation of a pyridinium species. Deprotonation of the pyridinium intermediate at the acidic α-position of phosphinate then generates a vinyl silver species. Subsequent protodemetalation of this intermediate affords final 1,4-azaphosphinine product 2a and regenerates the silver­(I) catalyst.

1. Plausible Reaction Mechanism for Ag­(I)-Catalyzed Pyridine Dearomatization.

The scope of this transformation was examined by first evaluating the influence of the electronic and steric properties of the aryl group attached to the acetylene moiety (Scheme , colored green). For this purpose, a series of phosphinates 1a–o were synthesized from phosphonites 6a–o, respectively, which were in turn prepared from commercially available substituted phenylacetylenes (for details, see ). Due to the low stability of intermediates 6a–o, they were used in the transformation into 1a–o, respectively, without any purification. This two-step procedure afforded 1a–h in 30–40% yields. For substrates bearing strong electron-withdrawing substituents (1i–o), the yields decreased significantly, reaching 6% in the case of 2-trifluoromethyl-substituted phosphinate 1o. Cyclization of 1a–o proceeded successfully; all substituents were well tolerated, providing the desired products 2a–o, respectively, in good to excellent yields. Notably, methoxy- and dimethoxy-substituted phosphinates 1b–e exhibited exceptional reactivity, affording the corresponding products in excellent yields ranging from 90% to 96%. In the case of dimethoxy phosphinate 1d, the yield can be ascribed to its high reactivity, which even led to spontaneous cyclization of 1d to 2d during the purification. After the silica gel column, a few percent of cyclized product 2d was observed in the NMR spectra (see ). Similar behavior was also observed for other phosphinates in this study (e.g., isoquinoline derivative 3j (see )). On the other hand, substrates bearing electron-withdrawing groups such as fluoro, difluoro, cyano, or trifluoromethyl (2j–o) also exhibited good reactivity, although the yields were slightly lower than those of phosphinates with ED groups. The influence of sterically demanding ortho substituents was found to be negligible when comparing the cyclization of ortho-substituted (1c and 1o) and para-substituted (1b and 1n) phosphinates. However, the presence of ortho substitutions in products 2c and 2o resulted in hindered rotation and, consequently, in the formation of axial chirality, giving rise to two diastereomers observed in the NMR spectra (see ).

2. Reactivity of Phosphinates 1a–o Bearing Substituted Arylacetylenes.

^a Diastereomeric ratios (dr).

Next, the influence of an additional aromatic ring attached to the benzylic position was evaluated (Scheme , colored red). To investigate this effect, diarylmethyl bromides 8p–u were synthesized by the reaction of 2-lithiopyridine with the corresponding aldehydes, followed by bromination of resulting alcohols 7p–u, respectively, using the Appel reaction (for details, see ). Notably, the electronic properties of the attached aryl rings played a crucial role in determining the stability of bromomethylpyridines 8p–u. For instance, trifluoromethyl-substituted derivative 8r exhibited relatively high stability, allowing for successful isolation via column chromatography. In contrast, the presence of an electron-donating methoxy group significantly reduced the stability, causing the chromatographic isolation of 8q to be impossible. Thus, methoxy derivative 8q was obtained via bromination with PBr₃ and used directly in the next step without further purification. All phosphinates 1p–u were obtained as inseparable mixtures of diastereomers in yields of approximately 30%, except for methoxy-substituted 1q, which was isolated in only 8% yield due to the previously mentioned low stability of bromide 8q. The cyclization of all starting materials 1p–u proceeded smoothly, affording products 2p–u, respectively, in excellent yields (85–98%). No significant difference in reactivity was observed between electron-donating methoxy phosphinate 1q and electron-withdrawing trifluoromethyl phosphinate 1r, suggesting that the electronic effects of the attached aryl ring had minimal influence on the efficiency of the cyclization under the applied conditions. Moreover, ortho substitution in phosphinates 1s and 1u did not affect their reactivity.

3. Reactivity of Phosphinates 1p–u Bearing an Additional Aromatic Ring.

^a Diastereomeric ratios (dr).

^b Overall yield.

^c CCDC registration numbers are 2489828 for 2r, 2489827 for (S _a ,R)-2t, and 2489829 for (R _a ,R)-2t.

The reaction of 1-naphthyl phosphinate 1t led to the formation of a binaphthyl scaffold, resulting in the generation of two pairs of diastereomers: (S _a ,R)/(R _a ,S)-2t and (R _a ,R)/(S _a ,S)-2t. These diastereomers were successfully separated by column chromatography. Furthermore, single crystals of both diastereomeric pairs, suitable for X-ray crystallographic analysis, were obtained by slow cooling of their EtOAc solution, enabling the assignment of the absolute configuration of both isomers (Figure A). The aromatic character of the pyridine ring in 2t was investigated using DFT calculations at the B3LYP/6-311++G­(d,p) level of theory (Figure B). The N-heterocycle displayed a NICS(0) value of −0.66, which is consistent with the proposed dearomatization reaction. This finding is further supported by the alternation of bond lengths observed in the X-ray crystal structure, which reveals the 1,4-diene character of the pyridine moiety.

2.

(A) ORTEP projection of the crystal structure of diastereomers of 2t. Hydrogen atoms have been omitted for the sake of clarity. Thermal ellipsoids are shown with 50% probability. (B) NICS(0) values (blue) and bond lengths (angstroms, red).

Finally, the reactivity of phosphinates 3a–m bearing various nitrogen-containing heterocycles was evaluated (Scheme , colored blue). This investigation aimed to explore the influence of different heterocyclic frameworks on the cyclization process and the stability of the resulting products. Pyrazine (3a and 3b) and pyrimidine (3c) phosphinates, containing two nitrogen atoms, exhibited reactivity comparable to that of parent pyridine derivative 1a, affording 1,4-azaphosphinines 4a–c, respectively, in excellent yields (86–95%). A more intriguing difference was observed between the reactivities of quinoline 3h and isoquinoline 3j derivatives. While isoquinoline 3j underwent cyclization smoothly, yielding 4j overnight, the reaction of quinoline 3h proceeded much more slowly. Full conversion was eventually achieved after 13 days. Even lower reactivity was observed for quinoxaline derivative 3i, where only approximately 50% conversion was reached after 18 days. Furthermore, no reaction was observed in the case of even more sterically hindered dibenzo­[f,h]­quinoxaline derivative 3k. This trend suggested that substitution at the ortho position to nitrogen significantly diminishes reactivity. To verify this hypothesis, we synthesized and evaluated a series of phosphinates 3d–g bearing various substituents at the ortho, meta, and para positions to nitrogen. Indeed, derivatives 3d–g _ortho exhibited no reactivity, regardless of the electronic nature of the substituents, including both the electron-donating (3f _ortho ) and the electron-withdrawing (3g _ortho ) groups. In some cases (4d _meta and 4f _meta ), substitution at the meta position resulted in only slightly reduced reaction rates, in comparison with that of unsubstituted 1a, with no clear dependence on the electronic properties of the substituents. Finally, all para-substituted derivatives 3d–g _para underwent cyclization smoothly. These findings confirm that steric hindrance at the ortho position to nitrogen (see 4d–g _ortho and 4h, 4i, 4k, and 4m in Scheme ) plays a crucial role in suppressing reactivity, while electronic effects have a negligible influence on the cyclization outcome. Finally, the potential for double cyclization was examined using bis-phosphinates 3l and 3m. While pyrazine-based derivative 3l cyclized smoothly to afford the desired product 4l, no reaction was observed for quinoline derivative 3m, further emphasizing the sensitivity of the transformation to steric factors.

4. Reactivity of Phosphinates 3a–m Bearing Substituted Pyridines and Other Nitrogen Heterocycles.

^a Unless otherwise stated.

^b Full conversion was achieved after 3 days.

^c Full conversion was achieved after 5 days.

^d Full conversion was achieved after 13 days.

^e Approximately 50% conversion was reached after 18 days.

^f CCDC registration number 2489828.

For comparison of 1,4-azaphosphinine 2a and its derivative II containing a carbon atom in place of nitrogen, the electrostatic potentials, HOMO/LUMO energies, and band gaps (E _g) were calculated (using DFT calculations at the B3LYP/6-311G++(d,p) level of theory (Figure A,B)). The relative energies of the frontier MOs are shifted toward lower values in both the HOMO and the LUMO. The HOMO of derivative 2a is decreased by more than 0.89 eV in comparison to that of II. The changes in energy levels of the FMOs together contribute to the decrease in the energy gap (E _g) by almost 0.78 eV. More detailed analyses of the MOs are shown in . The attachment of additional π-systems, by annulation of extra benzene rings (4h–j and 4l), leads to a decrease in HOMO energy by up to 0.3 eV, while the LUMO energy remains practically unchanged.

3.

Illustration of the differences in the properties of carbo (II) and hetero (2a) analogues. (A) Electrostatic potentials mapped onto the electron density surface in the range from −0.03 (red) to 0.03 (blue). (B) Calculated HOMO/LUMO orbitals and energy gaps (E _g) (DFT, B3LYP/6-311G++(d,p)) and experimental values of optical gap energies (blue). (C) Normalized UV–vis spectra of compounds 2a and II.

The UV–vis absorption spectra of 1,4-azaphosphinine 2a showed a significant bathochromic shift (ca. 60–120 nm) of the 0–0 transition compared with that of derivative II (Figure C), resulting in notably lower ΔE ^opt values of up to 0.97 eV. The observed red-shift and experimentally given values of the optical band gap are consistent with the DFT-calculated HOMO–LUMO energy gap as well as the simulated absorption spectra (UV–vis spectra and theoretical absorption spectra are provided in the , respectively). summarizes the main spectral features of the selected compounds in comparison with those of their carbo analogue II.

It is noteworthy that in contrast with recently reported π-extended azaphosphinine-based TADF-active systems, the present 1,4-azaphosphinines did not exhibit any detectable emission. The absence of emission suggests that the molecules undergo rapid nonradiative decay, which is further supported by the absence of measurable excitation spectra (not shown). The only exception is bis-phospha derivative 4l, which likely benefits from conjugation involving both phosphinate moieties, partially restricting nonradiative relaxation. The excitation and emission spectra of 4l are provided in .

Conclusions

In summary, a series of intramolecular hydroarylation reactions of pyridyl phosphinates were developed, providing an efficient route to 1,4-azaphosphinines via catalytic dearomatization. Catalytic screening revealed that Ag­(I) salts, particularly CF₃COOAg, are highly effective, promoting full conversion even at low catalyst loadings. The transformation proceeded smoothly across a wide range of substrates, demonstrating excellent functional group tolerance. Both electron-donating and electron-withdrawing substituents on the arylacetylene moiety were well tolerated, furnishing 2a–o in excellent to very good yields. The reaction also performed well with additional aromatic rings (providing derivatives 2p–u) and various nitrogen-containing heterocycles (4a–m). However, steric hindrance at the ortho position to nitrogen significantly reduced or even completely suppressed reactivity (4h, 4i, 4k, 4m, and 4d–g _ortho ). Double cyclization was achieved for pyrazine-based bis-phosphinate 4l. Overall, this work provides a versatile and mild approach to so far unreported phosphorus heterocyclic frameworks, highlighting the crucial role of steric effects in controlling reactivity.

Experimental Section

Materials and Methods

¹H, ¹³C­{¹H}, ¹⁹F, ³¹P, and ³¹P­{¹H} NMR spectra were recorded using a Bruker Avance 400 MHz instrument. Chemical shifts are reported in parts per million (δ) relative to TMS, CFCl₃, and PPh₃ (−6 ppm) or referenced to residuals of CDCl₃ (δ = 7.26 and 77.16 ppm) or CD₂Cl₂ (δ = 5.30 and 54.00 ppm). The coupling constants (J) are given in hertz. The HMBC experiments were set up for J _C–H = 5 Hz. For the correct assignment of the ¹H and ¹³C NMR spectra of key compounds, COSY, HSQC, and HMBC experiments were performed. GC–MS analyses were performed on an Agilent 6890 gas chromatograph coupled to an Agilent 5973 mass spectrometer operating in 70 eV ionization mode. A DB-5MS column (30 m × 0.25 mm × 0.25 μm) was used with He as a carrier gas at a flow rate of 1.0 mL/min. The initial temperature of 50 °C was held for 3 min and increased at a rate of 10 °C/min to 290 or 310 °C. The injection port was set at 250, 300, or 310 °C, depending on the volatility of the sample, and the m/z values are given along with their relative intensities (percent). For exact mass measurement, the spectra were internally calibrated using Na formate or tuning mix APCI-TOF. ESI and APCI high-resolution mass spectra were measured in positive mode by a micrOTOF QIII mass spectrometer (Bruker) and determined by Compass Data Analysis software. TLC was performed on silica gel 60 F254-coated aluminum sheets, and compounds were visualized with UV light (254 and 366 nm). Column chromatography was performed on an HPFC Biotage Isolera One system with prepacked flash silica gel columns with KP-Sil silica cartridges (0.040–0.063 mm). Absorption spectra were recorded using a DSM172 spectrophotometer (Online Instrument Systems, Inc.) in the wavelength range of 190–650 nm. Data were acquired at 20 °C (using a Peltier cell), with a data interval of 0.5 nm, a bandwidth of 1 nm, and a DIT of 5 ms. Fluorescence spectra of 4l in excitation and emission modes were recorded in a quartz cuvette with a 1 cm optical path using a FP-8300 spectrofluorometer (JASCO) controlled by Spectra Manager II. Data were acquired at room temperature under a nitrogen (5.0) atmosphere using the following measurement conditions: excitation and emission bandwidths of 5 nm, scanning speed of 100 nm/min, and a data interval of 0.5 nm. The standard Schlenk technique was used for all reactions. Dichloromethane was freshly distilled from calcium hydride under an argon atmosphere. Other solvents were of HPLC quality. Commercially available reagents were purchased from Merck or Fluorochem and used as received.

General Procedure for the Preparation of Phosphonites 6a–o (GP1_A)

The corresponding phenylacetylene (1 equiv) was dissolved in tetrahydrofuran (0.17 M) under an argon atmosphere and cooled to −78 °C. A 2.5 M solution of n-butyllithium in hexane (1 equiv) was then added (LiHMDS was used as a base instead of n-BuLi in the synthesis of bromo- and cyano-substituted derivatives 6h and 6i, respectively), and the reaction mixture was stirred at −78 °C for 15 min. Subsequently, diethyl chlorophosphite (1 equiv) was introduced, and the reaction was allowed to proceed at 60 °C for 1 h. Following the completion of the reaction, tetrahydrofuran was evaporated, and the residue was dissolved in dichloromethane (10 mL). The resulting mixture was filtered to remove insoluble salts, and the solvent was evaporated to afford phosphonites 6a–o as a brown liquid. These crude products were obtained in approximately 80% purity, as determined by GC-MS analysis, and used in subsequent reactions without further purification.

General Procedure for the Preparation of Phosphinates 1a–o (GP2_A)

2-Bromomethylpyridine hydrobromide (1 equiv) was treated with a 10% aqueous solution of K₂CO₃ to achieve a basic pH. The resulting aqueous phase was extracted with dichloromethane (3 × 10 mL/mmol), and the combined organic layers were dried over anhydrous MgSO₄, filtered, and then mixed with phosphonites 6a–o (1 equiv). The solvent was subsequently distilled off at atmospheric pressure, and the resulting oily residue was heated at 100 °C in an oil bath for approximately 2 h. Upon consumption of the starting materials, as monitored by GC-MS, the crude mixture was purified by column chromatography to afford the desired phosphinates 1a–o.

General Procedure for the Preparation of 1,4-Azaphosphinines 2a–o (GP3_A)

A Schlenk flask was charged with phosphinate 1a–o (1 equiv), silver­(I) trifluoroacetate (0.02–0.05 equiv), and dry DCM (0.05–0.15 M) under an inert atmosphere. The resulting mixture was stirred overnight. Upon consumption of the starting material, as monitored by GC-MS or TLC, the crude product was purified by column chromatography to afford the desired 1,4-azaphosphinines 2a–o as an oil, which typically solidified over time or upon treatment with EtOAc.

Ethyl (Phenylethynyl)­(pyridin-2-ylmethyl)­phosphinate (1a)

First, GP1_A was followed to generate crude phosphonite 6a by reacting ethynylbenzene (1.24 mL, 11.25 mmol) with n-butyllithium (4.50 mL, 2.5 M in n-hexane, 11.25 mmol), followed by the addition of diethyl chlorophosphite (1.62 mL, 11.25 mmol). In the second step, GP2_A was employed using crude 6a and 2-(bromomethyl)­pyridine hydrobromide (2.85 g, 11.25 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 1.284 g of phosphinate 1a (4.50 mmol, 40% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.62–8.53 (m, 1H), 7.66 (tdd, J = 7.6, 1.9, 0.8 Hz, 1H), 7.51–7.39 (m, 4H), 7.39–7.30 (m, 2H), 7.23–7.15 (m, 1H), 4.36–4.15 (m, 2H), 3.62 (d, J = 20.5 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.9 (d, J = 8.2 Hz), 149.7 (d, J = 2.9 Hz), 136.7 (d, J = 3.0 Hz), 132.7 (d, J = 2.1 Hz, 2C), 130.8, 128.6 (2C), 124.9 (d, J = 4.8 Hz), 122.2 (d, J = 3.3 Hz), 119.7 (d, J = 4.2 Hz), 101.7 (d, J = 37.1 Hz), 80.8 (d, J = 205.6 Hz), 62.7 (d, J = 7.4 Hz), 41.9 (d, J = 114.2 Hz), 16.4 (d, J = 6.6 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.84; R_f = 0.45 (93:7 CHCl₃/MeOH); EI MS 285 (5%, M⁺), 284 (16%), 241 (56%), 192 (100%), 165 (57%), 156 (30%), 123 (17%), 102 (34%), 93 (60%), 65 (23%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₇NO₂P]⁺ 286.0991, found 286.0991 (100%).

Ethyl ((4-Methoxyphenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1b)

First, GP1_A was followed to generate crude phosphonite 6b by reacting 1-ethynyl-4-methoxybenzene (0.49 mL, 3.79 mmol) with n-butyllithium (1.51 mL, 2.5 M in n-hexane, 3.79 mmol), followed by the addition of diethyl chlorophosphite (0.545 mL, 3.79 mmol). In the second step, GP2_A was employed using crude 6b and 2-(bromomethyl)­pyridine hydrobromide (0.958 g, 3.79 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 0.335 g of phosphinate 1b (1.06 mmol, 28% over two steps) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.61–8.54 (m, 1H), 7.65 (td, J = 7.5, 1.5 Hz, 1H), 7.48–7.38 (m, 3H), 7.19 (dddd, J = 7.4, 4.3, 2.2, 1.1 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 4.32–4.14 (m, 2H), 3.83 (s, 3H), 3.61 (d, J _P–H = 20.4 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 161.4, 152.0 (d, J = 8.3 Hz), 149.6 (d, J = 2.7 Hz), 136.4 (d, J = 3.1 Hz), 134.3 (d, J = 2.2 Hz), 124.7 (d, J = 4.9 Hz), 122.0 (d, J = 3.4 Hz), 114.2, 111.5 (d, J = 4.7 Hz), 102.3 (d, J = 37.9 Hz), 79.7 (d, J = 208.7 Hz), 62.4 (d, J = 7.2 Hz), 55.4, 41.9 (d, J = 113.3 Hz), 16.3 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.08; R_f = 0.13 (EtOAc); EI MS 315 (10%, M⁺), 224 (15%), 200 (100%), 195 (20%), 132 (50%), 123 (40%), 93 (40%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₃P]⁺ 316.1097, found 316.1091 (100%).

Ethyl ((2-Methoxyphenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1c)

First, GP1_A was followed to generate crude phosphonite 6c by reacting 1-ethynyl-2-methoxybenzene (1.00 mL, 7.73 mmol) with n-butyllithium (3.09 mL, 2.5 M in n-hexane, 7.73 mmol), followed by the addition of diethyl chlorophosphite (1.11 mL, 7.73 mmol). In the second step, GP2_A was employed using crude 6c and 2-(bromomethyl)­pyridine hydrobromide (1.96 g, 7.73 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 0.850 g of phosphinate 1c (2.70 mmol, 35% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.56 (dt, J = 5.1, 1.3 Hz, 1H), 7.64 (td, J = 7.7, 1.9 Hz, 1H), 7.49 (ddd, J = 7.8, 2.6, 1.3 Hz, 1H), 7.44–7.33 (m, 2H), 7.22–7.14 (m, 1H), 6.96–6.79 (m, 2H), 4.24 (dtt, J = 13.3, 9.5, 6.3 Hz, 2H), 3.85 (s, 3H), 3.63 (d, J = 20.4 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 161.5 (d, J = 1.5 Hz), 151.9 (d, J = 8.4 Hz), 149.6 (d, J = 2.6 Hz), 136.5 (d, J = 2.9 Hz), 134.4 (d, J = 2.2 Hz), 132.3, 124.8 (d, J = 4.7 Hz), 122.1 (d, J = 3.4 Hz), 120.5, 110.9, 109.0 (d, J = 4.5 Hz), 98.8 (d, J = 38.2 Hz), 84.6 (d, J = 207.3 Hz), 62.6 (d, J = 7.3 Hz), 55.8, 41.8 (d, J = 113.4 Hz), 16.2 (d, J = 6.6 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.68; R_f = 0.50 (92:8 CHCl₃/MeOH); EI MS 315 (4%, M⁺), 286 (45%), 222 (41%), 156 (30%), 131 (100%), 93 (66%), 65 (21%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₃P]⁺ 316.1097, found 316.1099 (100%).

Ethyl ((3,4-Dimethoxyphenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1d)

First, GP1_A was followed to generate crude phosphonite 6d by reacting 4-ethynyl-1,2-dimethoxybenzene (500 mg, 3.08 mmol) with n-butyllithium (1.23 mL, 2.5 M in n-hexane, 3.08 mmol), followed by the addition of diethyl chlorophosphite (0.443 mL, 3.08 mmol). In the second step, GP2_A was employed using crude 6d and 2-(bromomethyl)­pyridine hydrobromide (731 mg, 3.08 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 510 mg of phosphinate 1d (1.48 mmol, 48% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.60–8.51 (m, 1H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.49–7.40 (m, 1H), 7.18 (dddd, J = 7.4, 5.0, 2.3, 1.2 Hz, 1H), 7.09 (dd, J = 8.3, 1.9 Hz, 1H), 6.94 (d, J = 1.9 Hz, 1H), 6.80 (d, J = 8.3 Hz, 1H), 4.33–4.13 (m, 2H), 3.89 (s, 3H), 3.86 (s, 3H), 3.61 (d, J = 20.4 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.8 (d, J = 8.4 Hz), 151.3, 149.4 (d, J = 2.6 Hz), 148.5, 136.3 (d, J = 3.0 Hz), 126.4 (d, J = 2.1 Hz), 124.6 (d, J = 4.8 Hz), 121.9 (d, J = 3.4 Hz), 114.6 (d, J = 2.0 Hz), 111.3 (d, J = 4.5 Hz), 110.8, 102.2 (d, J = 37.9 Hz), 79.3 (d, J = 207.7 Hz), 62.3 (d, J = 7.3 Hz), 55.8, 55.8, 41.8 (d, J = 113.2 Hz), 16.1 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.04; R_f = 0.43 (93:7 CHCl₃/MeOH); EI MS 345 (24%, M⁺), 302 (37%), 254 (26%), 238 (31%), 225 (39%), 162 (46%), 154 (37%), 123 (67%), 93 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₂₁NO₄P]⁺ 346.1203, found 346.1204 (100%).

Ethyl ((3,5-Dimethoxyphenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1e)

First, GP1_A was followed to generate crude phosphonite 6e by reacting 1-ethynyl-3,5-dimethoxybenzene (2.00 g, 12.33 mmol) with n-butyllithium (4.93 mL, 2.5 M in n-hexane, 12.33 mmol), followed by the addition of diethyl chlorophosphite (1.77 mL, 12.33 mmol). In the second step, GP2_A was employed using crude 6e and 2-(bromomethyl)­pyridine hydrobromide (3.12 g, 12.33 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 1.60 g of phosphinate 1e (4.63 mmol, 38% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.57 (d, J = 4.0 Hz, 1H), 7.73–7.62 (m, 1H), 7.52–7.38 (m, 1H), 7.21–7.02 (m, 1H), 6.60 (d, J = 2.3 Hz, 2H), 6.52 (t, J = 2.3 Hz, 1H), 4.39–4.09 (m, 2H), 3.77 (s, 6H), 3.61 (d, J = 20.6 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 160.5, 151.8 (d, J = 8.3 Hz), 149.6 (d, J = 2.7 Hz), 136.5 (d, J = 3.0 Hz), 124.7 (d, J = 4.8 Hz), 122.1 (d, J = 3.4 Hz), 120.8 (d, J = 4.4 Hz), 110.2 (d, J = 2.1 Hz, 2C), 104.0, 101.5 (d, J = 37.0 Hz), 80.2 (d, J = 204.7 Hz), 62.6 (d, J = 7.3 Hz), 55.5 (2C), 41.8 (d, J = 113.3 Hz), 16.2 (d, J = 6.7 Hz) (the signals corresponding to the two equivalent quaternary carbons could not be assigned with certainty); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.86; R_f = 0.43 (93:7 CHCl₃/MeOH); EI MS 435 (44%, M⁺), 344 (100%), 301 (53%), 282 (39%), 254 (99%), 225 (70%), 210 (60%), 195 (37%), 156 (67%), 123 (54%), 93 (96%), 65 (34%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₂₁NO₄P]⁺ 346.1203, found 346.1204 (100%).

Ethyl ((4-Methylphenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1f)

First, GP1_A was followed to generate crude phosphonite 6f by reacting 1-ethynyl-4-methylbenzene (230 mg, 1.98 mmol) with n-butyllithium (0.791 mL, 2.5 M in n-hexane, 1.98 mmol), followed by the addition of diethyl chlorophosphite (0.284 mL, 1.98 mmol). In the second step, GP2_A was employed using crude 6f and 2-(bromomethyl)­pyridine hydrobromide (500 mg, 1.98 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 229 mg of phosphinate 1f (0.765 mmol, 39% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.59–8.53 (m, 1H), 7.65 (td, J = 7.6, 1.2 Hz, 1H), 7.48–7.41 (m, 1H), 7.35 (d, J = 8.2 Hz, 2H), 7.23–7.16 (m, 1H), 7.14 (d, J = 8.6 Hz, 2H), 4.31–4.13 (m, 2H), 3.61 (d, J = 20.4 Hz, 2H), 2.36 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.7 (d, J = 8.3 Hz), 149.4 (d, J = 2.6 Hz), 141.2, 136.5 (d, J = 3.0 Hz), 132.4 (d, J = 2.0 Hz, 2C), 129.2 (2C), 124.7 (d, J = 4.8 Hz), 122.1 (d, J = 3.4 Hz), 116.4 (d, J = 4.5 Hz), 102.2 (d, J = 37.6 Hz), 80.1 (d, J = 207.3 Hz), 62.5 (d, J = 7.3 Hz), 41.7 (d, J = 113.2 Hz), 21.6, 16.2 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.90; R_f = 0.69 (93:7 CHCl₃/MeOH); EI MS 299 (10%, M⁺) 255 (37%), 207 (100%), 179 (49%), 156 (31%), 115 (46%), 93 (58%), 65 (24%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₂P]⁺ 300.1148, found 300.1150 (100%).

Ethyl ((4-(tert-Butyl)­phenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1g)

First, GP1_A was followed to generate crude phosphonite 6g by reacting 1-(tert-butyl)-4-ethynylbenzene (313 mg, 1.98 mmol) with n-butyllithium (0.791 mL, 2.5 M in n-hexane, 1.98 mmol), followed by the addition of diethyl chlorophosphite (0.284 mL, 1.98 mmol). In the second step, GP2_A was employed using crude 6g and 2-(bromomethyl)­pyridine hydrobromide (500 mg, 1.98 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 236 mg of phosphinate 1g (0.692 mmol, 35% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.61–8.52 (m, 1H), 7.65 (tdd, J = 7.6, 1.9, 0.8 Hz, 1H), 7.46–7.34 (m, 5H), 7.22–7.15 (m, 1H), 4.31–4.13 (m, 2H), 3.61 (d, J = 20.5 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H), 1.30 (s, 9H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 154.4, 152.0 (d, J = 8.4 Hz), 149.7 (d, J = 2.6 Hz), 136.5 (d, J = 3.1 Hz), 132.4 (d, J = 1.9 Hz, 2C), 125.6 (2C), 124.8 (d, J = 4.8 Hz), 122.1 (d, J = 3.4 Hz), 116.6 (d, J = 4.4 Hz), 102.1 (d, J = 37.6 Hz), 80.2 (d, J = 206.9 Hz), 62.6 (d, J = 7.3 Hz), 41.9 (d, J = 113.3 Hz), 35.1, 31.1 (3C), 16.3 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.99; R_f = 0.52 (93:7 CHCl₃/MeOH); EI MS 341 (16%, M⁺), 297 (26%), 250 (42%), 234 (100%), 221 (24%), 156 (51%), 123 (44%), 93 (81%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₀H₂₅NO₂P]⁺ 342.1617, found 342.1618 (100%).

Ethyl ((4-Bromophenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1h)

First, GP1_A was followed to generate crude phosphonite 6h by reacting 1-bromo-4-ethynylbenzene (1.00 g, 5.52 mmol) with LiHMDS (5.52 mL, 1 M in THF, 5.52 mmol), followed by the addition of diethyl chlorophosphite (0.794 mL, 5.52 mmol). In the second step, GP2_A was employed using crude 6h and 2-(bromomethyl)­pyridine hydrobromide (1397 mg, 5.52 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 600 mg of phosphinate 1h (1.65 mmol, 30% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.62–8.47 (m, 1H), 7.66 (td, J = 7.7, 1.9 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.45–7.38 (m, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.19 (dddd, J = 7.4, 4.9, 2.4, 1.2 Hz, 1H), 4.33–4.12 (m, 2H), 3.61 (d, J = 20.6 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.7 (d, J = 8.4 Hz), 149.7 (d, J = 2.7 Hz), 136.6 (d, J = 3.0 Hz), 133.9 (d, J = 2.0 Hz, 2C), 132.0 (2C), 125.5, 124.8 (d, J = 4.9 Hz), 122.2 (d, J = 3.4 Hz), 118.6 (d, J = 4.5 Hz), 100.3 (d, J = 36.8 Hz), 82.0 (d, J = 203.2 Hz), 62.7 (d, J = 7.4 Hz), 41.8 (d, J = 113.5 Hz), 16.3 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.79; R_f = 0.62 (92:8 CHCl₃/MeOH); EI MS 363 (8%, M⁺) 319 (62%), 272 (81%), 245 (37%), 191 (100%), 180 (34%), 156 (44%), 123 (30%), 93 (99%), 65 (61%); HRMS (APCI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆ ⁷⁹BrNO₂P]⁺ 364.0097, found 364.0095 (100%).

Ethyl ((4-Chlorophenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1i)

First, GP1_A was followed to generate crude phosphonite 6i by reacting 1-chloro-4-ethynylbenzene (1.50 g, 10.9 mmol) with n-butyllithium (4.39 mL, 2.5 M in n-hexane, 10.9 mmol), followed by the addition of diethyl chlorophosphite (1.58 mL, 10.9 mmol). In the second step, GP2_A was employed using crude 6i and 2-(bromomethyl)­pyridine hydrobromide (2.78 g, 10.9 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 960 mg of phosphinate 1i (3.00 mmol, 27% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.62–8.50 (m, 1H), 7.66 (tdd, J = 7.7, 1.9, 0.8 Hz, 1H), 7.42 (ddd, J = 7.9, 2.5, 1.2 Hz, 1H), 7.39 (d, J = 8.6 Hz, 2H), 7.33 (d, J = 8.7 Hz, 2H), 7.19 (dddd, J = 7.4, 4.9, 2.3, 1.1 Hz, 1H), 4.30–4.14 (m, 2H), 3.61 (d, J = 20.6 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.6 (d, J = 8.3 Hz), 149.6 (d, J = 2.8 Hz), 136.9, 136.4 (d, J = 3.0 Hz), 133.6 (d, J = 2.1 Hz, 2C), 128.9 (2C), 124.6 (d, J = 4.9 Hz), 122.1 (d, J = 3.4 Hz), 118.0 (d, J = 4.6 Hz), 100.1 (d, J = 36.7 Hz), 81.8 (d, J = 203.2 Hz), 62.5 (d, J = 7.4 Hz), 41.7 (d, J = 113.4 Hz), 16.2 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.78; R_f = 0.65 (93:7 CHCl₃/MeOH); EI MS 319 (7%, M⁺), 275 (53%), 227 (100%), 191 (58%), 156 (38%), 136 (57%), 123 (37%), 93 (88%), 65 (40%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆ClNO₂P]⁺ 320.0602, found 320.0603 (100%).

Ethyl ((4-Fluorophenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1j)

First, GP1_A was followed to generate crude phosphonite 6j by reacting 1-ethynyl-4-fluorobenzene (0.48 mL, 4.16 mmol) with n-butyllithium (1.67 mL, 2.5 M in n-hexane, 4.16 mmol), followed by the addition of diethyl chlorophosphite (0.60 mL, 4.16 mmol). In the second step, GP2_A was employed using crude 6j and 2-(bromomethyl)­pyridine hydrobromide (1.053 g, 4.16 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 353 mg of phosphinate 1j (1.17 mmol, 28% over two steps) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.55 (dd, J = 4.9, 1.0 Hz, 1H), 7.65 (td, J = 7.7, 1.1 Hz, 1H), 7.50–7.39 (m, 3H), 7.22–7.15 (m, 1H), 7.08–6.99 (m, 2H), 4.31–4.11 (m, 2H), 3.60 (d, J _P–H = 20.6 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.0 (d, J = 253.7 Hz), 151.8 (d, J = 8.3 Hz), 149.7 (d, J = 2.7 Hz), 136.7 (d, J = 3.0 Hz), 134.9 (dd, J = 8.9, 2.1 Hz), 124.9 (d, J = 4.8 Hz), 122.3 (d, J = 3.4 Hz), 116.2 (d, J = 22.4 Hz), 115.9–115.8 (m), 100.6 (d, J = 37.3 Hz), 80.8 (dd, J = 205.0, 1.6 Hz), 62.7 (d, J = 7.4 Hz), 41.9 (d, J = 113.5 Hz), 16.4 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.86; ¹⁹F NMR (376 MHz, CDCl₃) δ −106.21; R_f = 0.15 (EtOAc); EI MS 303 (2%, M⁺), 302 (5%), 259 (50%), 211 (100%), 183 (50%), 156 (20%), 120 (45%), 93 (60%), 65 (40%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆FNO₂P]⁺ 304.0897, found 304.0896 (100%).

Ethyl ((3,4-Difluorophenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1k)

First, GP1_A was followed to generate crude phosphonite 6k by reacting 4-ethynyl-1,2-difluorobenzene (1.00 mL, 8.25 mmol) with n-butyllithium (3.30 mL, 2.5 M in n-hexane, 8.25 mmol), followed by the addition of diethyl chlorophosphite (1.19 mL, 8.25 mmol). In the second step, GP2_A was employed using crude 6k and 2-(bromomethyl)­pyridine hydrobromide (2.09 g, 8.25 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 567 mg of phosphinate 1k (1.77 mmol, 21% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) 8.57 (d, J = 4.2 Hz, 1H), 7.66 (td, J = 7.7, 2.4 Hz, 1H), 7.41 (dd, J = 7.9, 2.8 Hz, 1H), 7.30–7.10 (m, 4H), 4.34–4.10 (m, 2H), 3.60 (d, J = 20.7 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 152.4 (dd, J = 212.6, 13.0 Hz), 151.7 (d, J = 8.2 Hz), 149.9 (dd, J = 208.1, 13.0 Hz), 149.8 (d, J = 2.8 Hz), 136.7 (d, J = 3.0 Hz), 130.4–129.1 (m), 124.9 (d, J = 5.1 Hz), 122.4 (d, J = 3.6 Hz), 121.7 (d, J = 19.1 Hz), 118.1 (d, J = 18.3 Hz), 116.6 (d, J = 7.5 Hz), 99.0 (d, J = 36.5 Hz), 81.6 (d, J = 202.1 Hz), 62.8 (d, J = 7.4 Hz), 41.9 (d, J = 113.5 Hz), 16.4 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.69; ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −131.17 (d, J = 21.3 Hz), −135.66 (d, J = 21.2 Hz); R_f = 0.56 (92:8 CHCl₃/MeOH); EI MS 321 (2%, M⁺), 320 (8%), 277 (53%), 229 (100%), 201 (42%), 156 (21%), 138 (37%), 93 (58%), 65 (30%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₅F₂NO₂P]⁺ 322.0803, found 322.0803 (100%).

Ethyl ((3,5-Difluorophenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1l)

First, GP1_A was followed to generate crude phosphonite 6l by reacting 1-ethynyl-3,5-difluorobenzene (1.00 mL, 8.42 mmol) with n-butyllithium (3.37 mL, 2.5 M in n-hexane, 8.42 mmol), followed by the addition of diethyl chlorophosphite (1.21 mL, 8.42 mmol). In the second step, GP2_A was employed using crude 6l and 2-(bromomethyl)­pyridine hydrobromide (2.13 g, 8.42 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 435 mg of phosphinate 1l (1.35 mmol, 16% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (dd, J = 4.0, 0.9 Hz, 1H), 7.67 (tdd, J = 7.7, 1.9, 0.8 Hz, 1H), 7.47–7.36 (m, 1H), 7.25–7.16 (m, 1H), 7.01–6.94 (m, 2H), 6.90 (tt, J = 8.8, 2.3 Hz, 1H), 4.36–4.13 (m, 2H), 3.61 (d, J = 20.8 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 162.5 (dd, J = 250.8, 13.0 Hz, 2C), 151.4 (d, J = 8.4 Hz), 149.6 (d, J = 2.7 Hz), 136.7 (d, J = 3.1 Hz), 124.8 (d, J = 5.0 Hz), 122.3 (d, J = 3.5 Hz), 115.5 (dd, J = 11.5, 2.1 Hz), 115.5 (dd, J = 27.5, 2.1 Hz, 2C), 107.0 (t, J = 25.2 Hz), 98.1 (d, J = 35.9 Hz), 82.6 (d, J = 199.5 Hz), 62.8 (d, J = 7.4 Hz), 41.6 (d, J = 113.7 Hz), 16.2 (d, J = 6.6 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.54; ¹⁹F NMR (376 MHz, CDCl₃) δ −108.01; R_f = 0.58 (92:8 CHCl₃/MeOH); EI MS 321 (3%, M⁺), 320 (11%), 277 (59%), 229 (100%), 201 (43%), 156 (30%), 138 (34%), 93 (78%), 65 (40%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₅F₂NO₂P]⁺ 322.0803, found 322.0802 (100%).

Ethyl ((4-Cyanophenyl)­ethynyl)­(pyridin-2-ylmethyl)­phosphinate (1m)

First, GP1_A was followed to generate crude phosphonite 6m by reacting 4-ethynylbenzonitrile (1.50 g, 11.8 mmol) with LiHMDS (11.8 mL, 1 M in THF, 11.8 mmol), followed by the addition of diethyl chlorophosphite (1.70 mL, 11.8 mmol). In the second step, GP2_A was employed using crude 6m and 2-(bromomethyl)­pyridine hydrobromide (2.98 g, 11.8 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 725 mg of phosphinate 1m (2.34 mmol, 20%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.62–8.50 (m, 1H), 7.71–7.60 (m, 3H), 7.55 (d, J = 8.4 Hz, 2H), 7.41 (dd, J = 7.7, 2.5 Hz, 1H), 7.25–7.16 (m, 1H), 4.40–4.05 (m, 2H), 3.62 (d, J = 20.7 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.5 (d, J = 8.3 Hz), 149.8 (d, J = 2.7 Hz), 136.8 (d, J = 3.0 Hz), 133.1 (d, J = 2.1 Hz, 2C), 132.3 (2C), 124.9 (d, J = 5.0 Hz), 125.0 (d, J = 4.3 Hz), 122.4 (d, J = 3.6 Hz), 117.9, 114.2, 98.7 (d, J = 35.6 Hz), 84.8 (d, J = 198.5 Hz), 63.0 (d, J = 7.4 Hz), 41.8 (d, J = 113.9 Hz), 16.4 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.52; R_f = 0.75 (93:7 CHCl₃/MeOH); EI MS 310 (5%, M⁺), 309 (8%), 266 (64%), 247 (16%), 218 (100%), 190 (40%), 127 (26%), 93 (55%), 65 (32%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₆N₂O₂P]⁺ 311.0944, found 311.0949 (100%).

Ethyl (Pyridin-2-ylmethyl)­((4-(trifluoromethyl)­phenyl)­ethynyl)­phosphinate (1n)

First, GP1_A was followed to generate crude phosphonite 6n by reacting 1-ethynyl-4-(trifluoromethyl)­benzene (500 mg, 2.94 mmol) with n-butyllithium (1.17 mL, 2.5 M in n-hexane, 2.94 mmol), followed by the addition of diethyl chlorophosphite (0.422 mL, 2.94 mmol). In the second step, GP2_A was employed using crude 6n and 2-(bromomethyl)­pyridine hydrobromide (743 mg, 2.94 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 85.0 mg of phosphinate 1n (0.241 mmol, 8% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.56 (d, J = 4.3 Hz, 1H), 7.66 (td, J = 7.8, 1.9 Hz, 1H), 7.60 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 8.3 Hz, 2H), 7.42 (ddd, J = 7.9, 2.6, 1.2 Hz, 1H), 7.24–7.15 (m, 1H), 4.33–4.14 (m, 2H), 3.62 (d, J = 20.7 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.6 (d, J = 8.3 Hz), 149.8 (d, J = 2.8 Hz), 136.7 (d, J = 3.1 Hz), 132.9 (d, J = 2.1 Hz, 2C), 132.3 (d, J = 33.0 Hz), 125.6 (q, J = 3.8 Hz, 2C), 124.9 (d, J = 5.0 Hz), 123.5, 122.4 (d, J = 3.4 Hz), 99.4 (d, J = 35.9 Hz), 83.1 (d, J = 200.6 Hz), 62.9 (d, J = 7.4 Hz), 41.8 (d, J = 113.6 Hz), 16.4 (d, J = 6.6 Hz) (the signal of the CF₃ group could not be unambiguously assigned due to its low intensity and overlap with other signals); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.84; ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −63.19; R_f = 0.55 (93:7 CHCl₃/MeOH); EI MS 353 (7%, M⁺), 352 (14%), 334 (13%), 309 (70%), 290 (21%), 261 (100%), 233 (31%), 191 (19%), 170 (19%), 156 (19%), 93 (57%), 65 (23%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₆F₃NO₂P]⁺ 354.0865, found 354.0866 (100%).

Ethyl (Pyridin-2-ylmethyl)­((2-(trifluoromethyl)­phenyl)­ethynyl)­phosphinate (1o)

First, GP1_A was followed to generate crude phosphonite 6o by reacting 1-ethynyl-2-(trifluoromethyl)­benzene (500 mg, 2.94 mmol) with n-butyllithium (1.17 mL, 2.5 M in n-hexane, 2.94 mmol), followed by the addition of diethyl chlorophosphite (0.422 mL, 2.94 mmol). In the second step, GP2_A was employed using crude 6o and 2-(bromomethyl)­pyridine hydrobromide (743 mg, 2.94 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 63.0 mg of phosphinate 1o (0.178 mmol, 6% over two steps) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.61–8.52 (m, 1H), 7.73–7.61 (m, 3H), 7.59–7.51 (m, 2H), 7.47–7.41 (m, 1H), 7.19 (dddd, J = 7.4, 5.0, 2.3, 1.1 Hz, 1H), 4.33–4.18 (m, 2H), 3.63 (d, J = 20.5 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.4 (d, J = 8.4 Hz), 149.7 (d, J = 2.6 Hz), 136.6 (d, J = 2.9 Hz), 135.2 (d, J = 2.2 Hz), 132.5 (q, J = 31.3 Hz), 131.7, 130.5, 126.1 (q, J = 5.0 Hz), 124.8 (d, J = 5.0 Hz), 123.0 (q, J = 273.6 Hz) 122.2 (d, J = 3.3 Hz), 117.9–117.7 (m), 96.4 (d, J = 36.0 Hz), 86.2 (d, J = 199.1 Hz), 62.9 (d, J = 7.5 Hz), 41.6 (d, J = 114.2 Hz), 16.2 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.22; ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −61.90; R_f = 0.51 (92:8 CHCl₃/MeOH); EI MS 353 (8%, M⁺), 309 (68%), 290 (23%), 261 (100%), 240 (65%), 222 (43%), 185 (40%), 157 (15%), 93 (71%), 65 (26%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₆F₃NO₂P]⁺ 354.0865, found 354.0869 (100%).

2-Ethoxy-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2a)

GP3_A was followed with 1a (2.00 g, 7.01 mmol), CF₃COOAg (31.0 mg, 0.140 mmol), and 35 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 1.74 g of 1,4-azaphosphinine 2a (6.10 mmol, 87%) as a pale-yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.41 (m, 3H), 7.41–7.29 (m, 2H), 7.01 (d, J = 7.6 Hz, 1H), 6.73 (d, J = 9.2 Hz, 1H), 6.64–6.43 (m, 1H), 5.82 (ddd, J = 7.8, 6.1, 1.6 Hz, 1H), 5.77–5.68 (m, 1H), 5.21 (d, J = 4.2 Hz, 1H), 3.98 (p, J = 7.4 Hz, 2H), 1.31 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.2 (d, J = 2.0 Hz), 148.8 (d, J = 4.0 Hz), 136.8 (d, J = 12.2 Hz), 131.2, 129.7, 129.4 (2C), 128.7 (2C), 127.0 (d, J = 2.5 Hz), 126.8, 107.4, 105.9 (d, J = 124.3 Hz), 86.9 (d, J = 145.9 Hz), 61.7 (d, J = 6.1 Hz), 17.0 (d, J = 6.4 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.57; R_f = 0.41 (93:7 CHCl₃/MeOH); EI MS 285 (<3%, M⁺), 193 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₇NO₂P]⁺ 286.0991, found 286.0990 (100%); mp 67.2–73.6 °C (Et₂O).

2-Ethoxy-4-(4-methoxyphenyl)­pyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2b)

GP3_A was followed with 1b (82 mg, 0.26 mmol), CF₃COOAg (3.0 mg, 15 μmol), and 2 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 74 mg of 1,4-azaphosphinine 2b (0.23 mmol, 90%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.28 (d, J = 8.6 Hz, 2H), 7.10 (dq, J = 7.6, 1.0 Hz, 1H), 7.02–6.95 (m, 2H), 6.77–6.70 (m, 1H), 6.64–6.56 (m, 1H), 5.83 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.73 (dd, J = 4.2, 1.5 Hz, 1H), 5.21 (dd, J = 4.3, 1.8 Hz, 1H), 4.04–3.94 (m, 2H), 3.86 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 160.5, 151.0 (d, J = 2.2 Hz), 148.8 (d, J = 4.0 Hz), 131.1, 130.0, 128.9 (d, J = 12.4 Hz), 126.8 (d, J = 1.3 Hz), 126.7 (d, J = 14.6 Hz), 114.6, 107.2, 105.6 (d, J = 124.1 Hz), 86.7 (d, J = 145.8 Hz), 61.6 (d, J = 6.0 Hz), 55.4, 16.9 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.98; R_f = 0.50 (93:7 CHCl₃/MeOH); EI MS 315 (<1%, M⁺), 223 (100%), 208 (80%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₈NO₃P]⁺ 316.1097, found 316.1098 (100%).

2-Ethoxy-4-(2-methoxyphenyl)­pyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2c)

GP3_A was followed with 1c (200 mg, 0.634 mmol), CF₃COOAg (2.8 mg, 0.013 mmol), and 2.3 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 180 mg of a 60:40 diastereomeric mixture of 1,4-azaphosphinines 2c (0.571 mmol, 90%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.44–7.34 (m, 1H), 7.20 (ddd, J = 15.5, 7.5, 1.7 Hz, 1H), 6.98 (tdd, J = 7.5, 3.0, 1.0 Hz, 1H), 6.93–6.86 (m, 1H), 6.83 (ddd, J = 7.7, 3.0, 1.1 Hz, 1H), 6.65 (ddd, J = 9.6, 4.8, 1.4 Hz, 1H), 6.54 (ddd, J = 8.8, 5.9, 3.5 Hz, 1H), 5.75 (ddd, J = 7.7, 6.3, 1.5 Hz, 1H), 5.62 (ddd, J = 6.1, 4.2, 1.8 Hz, 1H), 5.08 (dd, J = 4.5, 2.0 Hz, 1H), 3.88–3.73 (m, 2H), 3.66 (s, 3H, OCH₃ of the major diastereomer), 3.63 (s, 3H, OCH₃ of the minor diastereomer), 1.24 (t, J = 7.1 Hz, 3H, CH₂–CH₃ of the minor diastereomer), 1.20 (t, J = 7.0 Hz, 3H, CH₂–CH₃ of the major diastereomer) (in the ¹H NMR spectrum, the signals of both diastereomers overlap significantly, except for those corresponding to the CH₃ groups, which appear as distinct resonances); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 156.0, 155.9, 149.1 (d, J = 2.3 Hz), 148.9 (d, J = 2.4 Hz), 148.6 (d, J = 4.2 Hz), 148.5 (d, J = 4.1 Hz), 131.5, 131.4, 130.8, 130.7, 130.5, 130.3, 126.9 (d, J = 3.0 Hz), 126.5, 126.5, 126.4, 126.4, 125.3 (d, J = 12.2 Hz), 121.4, 121.1, 110.9, 110.8, 107.2, 107.1, 105.4 (d, J = 122.5 Hz), 105.4 (d, J = 123.2 Hz), 85.5 (d, J = 145.9 Hz), 85.4 (d, J = 144.9 Hz), 61.7 (d, J = 5.9 Hz), 61.2 (d, J = 6.1 Hz), 55.5, 55.4, 16.8 (d, J = 6.4 Hz), 16.5 (d, J = 6.5 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.62, 18.48; R_f = 0.50 (92:8 CHCl₃/MeOH); EI MS 315 (4%, M⁺), 286 (45%), 222 (41%), 156 (30%), 131 (100%), 93 (66%), 65 (21%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₃P]⁺ 316.1097, found 316.1099 (100%).

4-(3,4-Dimethoxyphenyl)-2-ethoxypyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2d)

GP3_A was followed with 1d (190 mg, 0.550 mmol), CF₃COOAg (2.43 mg, 0.011 mmol), and 11 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 183 mg of 1,4-azaphosphinine 2d (0.530 mmol, 96%) as an orange solid: ¹H NMR (400 MHz, CDCl₃) δ 7.09 (d, J = 7.6 Hz, 1H), 7.00–6.89 (m, 2H), 6.83 (s, 1H), 6.73 (d, J = 8.1 Hz, 1H), 6.64–6.56 (m, 1H), 5.83 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.77 (dd, J = 4.2, 1.5 Hz, 1H), 5.22 (dd, J = 4.3, 1.8 Hz, 1H), 4.06–3.95 (m, 2H), 3.93 (s, 3H), 3.87 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 150.9 (d, J = 2.1 Hz), 149.9, 149.3, 148.6 (d, J = 4.1 Hz), 131.0, 128.9 (d, J = 12.5 Hz), 126.8 (d, J = 3.1 Hz), 126.6, 126.5, 121.2, 111.4, 107.2, 105.4 (d, J = 123.8 Hz), 86.6 (d, J = 145.6 Hz), 61.5 (d, J = 6.0 Hz), 56.0, 55.9, 16.8 (d, J = 6.4 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.87; R_f = 0.43 (93:7 CHCl₃/MeOH); EI MS 345 (5%, M⁺), 253 (100%), 238 (41%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₂₁NO₄P]⁺ 346.1203, found 346.1213 (100%); mp 156.0–158.0 °C (EtOAc).

4-(3,5-Dimethoxyphenyl)-2-ethoxypyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2e)

GP3_A was followed with 1e (800 mg, 2.32 mmol), CF₃COOAg (10 mg, 0.046 mmol), and 15 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 760 mg of 1,4-azaphosphinine 2e (2.20 mmol, 95%) as a yellow-orange amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.06 (dd, J = 7.6, 1.1 Hz, 1H), 6.72 (dd, J = 9.6, 1.4 Hz, 1H), 6.65–6.56 (m, 1H), 6.56–6.37 (m, 3H), 5.83 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.77 (dd, J = 4.2, 1.6 Hz, 1H), 5.21 (dd, J = 4.4, 1.9 Hz, 1H), 4.09–3.90 (m, 2H), 3.79 (s, 6H), 1.32 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 161.0, 150.7 (d, J = 1.9 Hz), 148.4 (d, J = 4.0 Hz), 138.0 (d, J = 12.2 Hz), 130.8, 126.7 (d, J = 3.0 Hz), 126.3 (d, J = 16.1 Hz), 107.2, 106.2 (2C), 104.8 (d, J = 123.7 Hz), 101.2, 86.3 (d, J = 145.7 Hz), 61.4 (d, J = 6.1 Hz), 55.3 (2C), 16.6 (d, J = 6.4 Hz) (the signals corresponding to the two equivalent quaternary carbons could not be assigned with certainty); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.83; R_f = 0.43 (93:7 CHCl₃/MeOH); EI MS 345 (<5%, M⁺), 253 (100%), 238 (41%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₂₁NO₄P]⁺ 346.1203, found 346.1205 (100%).

2-Ethoxy-4-(p-tolyl)­pyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2f)

GP3_A was followed with 1f (135 mg, 0.451 mmol), CF₃COOAg (1.9 mg, 9.0 μmol), and 3 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 130 mg of 1,4-azaphosphinine 2f (0.434 mmol, 96%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.31–7.20 (m, 4H), 7.06 (dd, J = 7.6, 1.1 Hz, 1H), 6.73 (d, J = 10.0 Hz, 1H), 6.63–6.54 (m, 1H), 5.81 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.73 (dd, J = 4.2, 1.5 Hz, 1H), 5.21 (dd, J = 4.4, 1.9 Hz, 1H), 4.08–3.85 (m, 2H), 2.41 (s, 3H), 1.32 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.3 (d, J = 2.0 Hz), 148.9 (d, J = 4.1 Hz), 139.9, 133.9 (d, J = 12.2 Hz), 131.2, 130.0 (2C), 128.6 (2C), 126.9, 126.9, 126.7, 107.3, 105.7 (d, J = 124.1 Hz), 86.8 (d, J = 145.8 Hz), 61.7 (d, J = 6.1 Hz), 21.4, 17.0 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.54; R_f = 0.69 (93:7 CHCl₃/MeOH); EI MS 299 (<1%, M⁺), 207 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₂P]⁺ 300.1148, found 300.1148 (100%); mp 158.6–160.9 °C (EtOAc).

4-(4-(tert-Butyl)­phenyl)-2-ethoxypyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2g)

GP3_A was followed with 1g (60.0 mg, 0.176 mmol), CF₃COOAg (1.94 mg, 8.79 μmol), and 4 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 53.0 mg of 1,4-azaphosphinine 2g (0.155 mmol, 88%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.47 (d, J = 8.7 Hz, 2H), 7.31–7.21 (m, 2H), 7.09 (dt, J = 7.6, 1.0 Hz, 1H), 6.73 (d, J = 9.2 Hz, 1H), 6.64–6.50 (m, 1H), 5.83 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.74 (dd, J = 4.2, 1.6 Hz, 1H), 5.20 (dd, J = 4.4, 1.9 Hz, 1H), 4.05–3.89 (m, 2H), 1.35 (s, 9H), 1.31 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 153.0, 151.4 (d, J = 1.9 Hz), 148.9 (d, J = 4.1 Hz), 133.7 (d, J = 12.2 Hz), 131.3, 128.3 (2C), 127.0 (d, J = 3.2 Hz), 126.8, 126.7, 126.2 (2C), 107.3, 105.6 (d, J = 124.1 Hz), 86.6 (d, J = 145.8 Hz), 61.7 (d, J = 6.1 Hz), 34.9, 31.3, 16.9 (d, J = 6.5 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.88; R_f = 0.52 (93:7 CHCl₃/MeOH); EI MS 341 (1%, M⁺), 249 (100%), 234 (77%), 219 (23%), 103 (17%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₀H₂₅NO₂P]⁺ 342.1617, found 342.1615 (100%).

4-(4-Bromophenyl)-2-ethoxypyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2h)

GP3_A was followed with 1h (200 mg, 0.549 mmol), CF₃COOAg (2.42 mg, 10.9 μmol), and 3.6 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 168 mg of 1,4-azaphosphinine 2h (0.461 mmol, 84%) as a pale-yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.62 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 6.97 (dd, J = 7.6, 1.1 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 6.61 (ddt, J = 10.0, 6.7, 1.9 Hz, 1H), 5.85 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.73 (dd, J = 4.2, 1.8 Hz, 1H), 5.23 (dd, J = 4.4, 1.9 Hz, 1H), 4.01 (dq, J = 9.1, 7.0 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR δ 149.9 (d, J = 2.2 Hz), 148.8 (d, J = 4.0 Hz), 135.6 (d, J = 12.4 Hz), 132.7, 130.9, 130.3, 127.0 (d, J = 13.3 Hz), 127.0, 124.3, 107.8, 106.3 (d, J = 124.0 Hz), 87.3 (d, J = 146.5 Hz), 61.9 (d, J = 6.2 Hz), 17.0 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.13; R_f = 0.57 (92:8 CHCl₃/MeOH); EI MS 363 (<2%, M⁺), 273 (97%) 271 (100%), 191 (42%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆ ⁷⁹BrNO₂P]⁺ 364.0097, found 364.0099 (100%).

4-(4-Chlorophenyl)-2-ethoxypyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2i)

GP3_A was followed with 1i (600 mg, 1.88 mmol), CF₃COOAg (8.3 mg, 0.038 mmol), and 12.5 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 553 mg of 1,4-azaphosphinine 2i (1.73 mmol, 92%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.46 (d, J = 8.8 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 6.97 (dd, J = 7.6, 1.0 Hz, 1H), 6.77–6.69 (m, 1H), 6.65–6.54 (m, 1H), 5.84 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.72 (dd, J = 4.2, 1.7 Hz, 1H), 5.27–5.18 (m, 1H), 4.00 (dq, J = 9.2, 7.1 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR δ 149.7 (d, J = 2.2 Hz), 148.6 (d, J = 4.0 Hz), 135.9, 135.0 (d, J = 12.4 Hz), 130.7, 129.9 (2C), 129.6 (2C), 126.9 (d, J = 1.7 Hz), 126.8 (d, J = 11.5 Hz), 107.6, 106.1 (d, J = 123.6 Hz), 87.1 (d, J = 146.1 Hz), 61.6 (d, J = 6.0 Hz), 16.9 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.07; R_f = 0.65 (93:7 CHCl₃/MeOH); EI MS 319 (<2%, M⁺), 229 (35%), 227 (100%), 191 (18%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆ClNO₂P]⁺ 320.0602, found 320.0601 (100%); mp 157.1–161.3 °C (EtOAc).

2-Ethoxy-4-(4-fluorophenyl)­pyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2j)

GP3_A was followed with 1j (0.105 g, 0.35 mmol), CF₃COOAg (4 mg, 0.02 mmol), and 3 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 0.86 g of 1,4-azaphosphinine 2j (0.28 mmol, 82%) as an orange amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.40–7.32 (m, 2H), 7.20–7.15 (m, 2H), 6.99 (dd, J = 7.7, 1.1 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 6.65–6.56 (m, 1H), 5.85 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.74 (dd, J = 4.2, 1.7 Hz, 1H), 5.24 (dd, J = 4.5, 1.9 Hz, 1H), 4.02 (dq, J = 9.1, 7.1 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR δ 163.2 (d, J = 250.8 Hz), 149.8 (d, J = 2.2 Hz), 148.6 (d, J = 4.0 Hz), 132.7 (dd, J = 12.5, 3.7 Hz), 130.8, 126.9, 126.78 (d, J = 1 Hz), 126.76, 116.5 (d, J = 21.7 Hz), 107.5, 106.3 (d, J = 124.1 Hz), 87.2 (d, J = 146.2 Hz), 61.7 (d, J = 6.1 Hz), 16.9 (d, J = 6.3 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −110.34; ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.23; R_f = 0.37 (93:7 CHCl₃/MeOH); EI MS 303 (<1%, M⁺), 211 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆FNO₂P]⁺ 304.0897, found 304.0892 (100%).

4-(3,4-Difluorophenyl)-2-ethoxypyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2k)

GP3_A was followed with 1k (460 mg, 1.43 mmol), CF₃COOAg (6.3 mg, 0.029 mmol), and 9.5 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 382 mg of 1,4-azaphosphinine 2k (1.19 mmol, 83%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.29 (q, J = 8.7 Hz, 1H), 7.20 (t, J = 9.4 Hz, 1H), 7.12 (d, J = 8.6 Hz, 1H), 6.94 (dd, J = 7.6, 1.1 Hz, 1H), 6.74 (d, J = 9.2 Hz, 1H), 6.66–6.52 (m, 1H), 5.87 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.73 (dd, J = 4.1, 1.9 Hz, 1H), 5.24 (dd, J = 4.4, 1.9 Hz, 1H), 4.01 (dq, J = 9.1, 7.0 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CHCl₃) δ 150.9 (dd, J = 240.6, 14.5 Hz), 150.3 (dd, J = 239.2, 14.6 Hz), 148.6–148.3 (m), 133.1 (dt, J = 12.5, 5.1 Hz), 130.3, 126.8, 126.8, 126.6, 125.1, 118.4 (d, J = 17.5 Hz), 117.9 (d, J = 17.7 Hz), 107.8, 106.3 (d, J = 123.6 Hz), 87.0 (d, J = 146.3 Hz), 61.6 (d, J = 6.1 Hz), 16.6 (d, J = 6.4 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.74; ¹⁹F NMR (376 MHz, CDCl₃) δ −134.85, −134.90; R_f = 0.49 (92:8 CHCl₃/MeOH); EI MS 321 (<3%, M⁺), 229 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₅F₂NO₂P]⁺ 322.0803, found 322.0804 (100%).

4-(3,5-Difluorophenyl)-2-ethoxypyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2l)

GP3_A was followed with 1l (80 mg, 0.25 mmol), CF₃COOAg (2.7 mg, 12 μmol), and 2.5 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 60 mg of 1,4-azaphosphinine 2l (0.19 mmol, 76%) as a yellow-orange amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.00–6.90 (m, 4H), 6.75 (ddd, J = 9.3, 1.5, 0.8 Hz, 1H), 6.62 (dddd, J = 10.8, 6.3, 2.4, 0.9 Hz, 1H), 5.90 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.76 (dd, J = 4.1, 2.1 Hz, 1H), 5.32–5.10 (m, 1H), 4.03 (dq, J = 9.1, 7.0 Hz, 2H), 1.33 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR δ 163.3 (dd, J = 252.0, 12.1 Hz), 148.6 (d, J = 4.0 Hz), 148.3 (q, J = 2.4 Hz), 139.3 (dt, J = 12.6, 9.6 Hz), 130.4, 127.0 (d, J = 9.3 Hz), 126.9 (d, J = 3.7 Hz), 112.1 (d, J = 22.8 Hz, 2C), 108.1, 106.4 (d, J = 123.9 Hz), 105.5, 87.4 (d, J = 146.9 Hz), 61.8 (d, J = 6.2 Hz), 16.9 (d, J = 6.4 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.50; ¹⁹F NMR (376 MHz, CDCl₃) δ −106.37, −106.91; R_f = 0.58 (92:8 CHCl₃/MeOH); EI MS 321 (2%, M⁺), 229 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₅F₂NO₂P]⁺ 322.0803, found 322.0803 (100%).

4-(2-Ethoxy-2-oxidopyrido­[1,2-a]­[1,4]­azaphosphinin-4-yl)­benzonitrile (2m)

GP3_A was followed with 1m (150.0 mg, 0.483 mmol), CF₃COOAg (4.3 mg, 19 μmol), and 3.2 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 115.0 mg of 1,4-azaphosphinine 2m (0.371 mmol, 77%) as a pale-yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.79 (d, J = 8.5 Hz, 2H), 7.51 (d, J = 7.7 Hz, 2H), 6.84 (dd, J = 7.6, 1.1 Hz, 1H), 6.76 (dd, J = 9.1, 1.3 Hz, 1H), 6.62 (ddt, J = 10.2, 6.8, 1.7 Hz, 1H), 5.87 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.73 (dd, J = 4.2, 2.1 Hz, 1H), 5.27 (dd, J = 4.3, 1.9 Hz, 1H), 4.03 (dq, J = 9.1, 7.0 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 148.8 (d, J = 2.0 Hz), 148.6 (d, J = 3.8 Hz), 141.0 (d, J = 12.4 Hz), 133.3 (2C), 130.5, 129.6 (2C), 127.2 (d, J = 16.1 Hz), 127.0 (d, J = 3.1 Hz), 117.9, 114.0, 108.2, 107.0 (d, J = 123.9 Hz), 87.8 (d, J = 146.9 Hz), 62.0 (d, J = 6.0 Hz), 17.0 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.33; R_f = 0.72 (93:7 CHCl₃/MeOH); EI MS 310 (<3%, M⁺), 218 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₆N₂O₂P]⁺ 311.0944, found 311.0940 (100%); mp 149.5–152.0 °C (EtOAc).

2-Ethoxy-4-(4-(trifluoromethyl)­phenyl)­pyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2n)

GP3_A was followed with 1n (40.0 mg, 0.113 mmol), CF₃COOAg (1.2 mg, 5.6 μmol), and 2 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 32.0 mg of 1,4-azaphosphinine 2n (0.091 mmol, 80%) as a pale-yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 7.8 Hz, 2H), 6.90 (dd, J = 7.6, 1.0 Hz, 1H), 6.81–6.71 (m, 1H), 6.68–6.58 (m, 1H), 5.87 (ddd, J = 7.7, 6.2, 1.5 Hz, 1H), 5.76 (dd, J = 4.1, 2.0 Hz, 1H), 5.27 (dd, J = 4.4, 1.9 Hz, 1H), 4.03 (dq, J = 9.1, 7.0 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 149.4 (d, J = 2.1 Hz), 148.7 (d, J = 4.0 Hz), 140.2 (d, J = 12.6 Hz), 132.0 (q, J = 33.0 Hz), 130.7, 129.3 (2C), 127.2, 127.0, 126.5 (2C), 123.7 (q, J = 272.7 Hz), 108.0, 106.6 (d, J = 124.0 Hz), 87.5 (d, J = 146.7 Hz), 61.9 (d, J = 6.1 Hz), 17.0 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.82; ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −62.92; R_f = 0.55 (93:7 CHCl₃/MeOH); EI MS 353 (<2%, M⁺), 261 (100%), 191 (7%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₆F₃NO₂P]⁺ 354.0865, found 354.0868 (100%); mp 192.8–195.0 °C (EtOAc).

2-Ethoxy-4-(2-(trifluoromethyl)­phenyl)­pyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2o)

GP3_A was followed with 1o (50.0 mg, 0.142 mmol), CF₃COOAg (1.5 mg, 7.1 μmol), and 2.8 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 36.0 mg of a 92:8 diastereomeric mixture of 1,4-azaphosphinines 2o (0.102 mmol, 72%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.81 (dd, J = 7.8, 1.5 Hz, 1H), 7.68 (td, J = 7.6, 1.5 Hz, 1H), 7.63 (td, J = 8.0, 1.5 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 6.81–6.66 (m, 1H), 6.66–6.52 (m, 2H), 5.82 (ddd, J = 7.7, 6.2, 1.6 Hz, 1H), 5.69 (dd, J = 4.2, 2.3 Hz, 1H), 5.19 (dd, J = 4.3, 2.1 Hz, 1H), 3.88–3.71 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 148.8 (d, J = 3.8 Hz), 147.4 (d, J = 2.1 Hz), 134.2 (dd, J = 12.3, 2.1 Hz), 133.1, 131.1, 130.6, 130.2, 128.5 (q, J = 30.8 Hz), 127.2–127.1 (m), 127.0, 126.9–126.8 (m), 123.5 (q, J = 274.0 Hz), 107.7, 106.7 (d, J = 120.3 Hz), 86.4 (d, J = 145.0 Hz), 62.0 (d, J = 6.2 Hz), 16.6 (d, J = 7.0 Hz) (the signals corresponding to the minor diastereomer in the ¹³C and ¹H NMR spectra were not assigned); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.51, 16.10; ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −59.65, −59.71; R_f = 0.45 (92:8 CHCl₃/MeOH); EI MS 353 (5%, M⁺), 261 (100%), 240 (10%), 222 (5%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₆F₃NO₂P]⁺ 354.0865, found 354.0862 (100%).

General Procedure for the Preparation of Alcohols 7p–u (GP1_B)

A Schlenk flask was charged with the appropriate 2-bromopyridine (1 equiv) and dry tetrahydrofuran (THF) to achieve a 0.2 M solution under an inert atmosphere. The reaction mixture was cooled to −78 °C, and a solution of n-butyllithium (1 equiv, 2.5 M in n-hexane) was added dropwise. After the mixture had been stirred for 15 min, the appropriate aldehyde (1 equiv) was added dropwise. The mixture was stirred for 1 h at −78 °C and then slowly warmed to room temperature. A saturated aqueous solution of ammonium chloride (NH₄Cl) was added, and the mixture was extracted with diethyl ether (Et₂O, 3 × 20 mL). The combined organic layers were dried over anhydrous magnesium sulfate (MgSO₄). After solvent evaporation, the residue was purified by column chromatography.

General Procedure for the Preparation of Bromides 8p and 8r–u (GP2_B)

A Schlenk flask was charged with the appropriate alcohol 7p or 7r–u (1 equiv), triphenylphosphine (1.8 equiv), tetrabromomethane (1.5 equiv), and dry tetrahydrofuran (THF) to achieve a 0.15 M solution under an inert atmosphere. After the mixture had been stirred at room temperature for 1 h, the precipitate was filtered through a pad of Celite, and the solid was washed with cold diethyl ether. The combined filtrate was collected. After removal of the solvents under reduced pressure, the residue was purified by column chromatography.

General Procedure for the Preparation of Phosphinates 1p and 1r–u (GP3_B)

A round-bottom flask was charged with the appropriate bromomethyl azaaromatic 8p or 8r–u (1 equiv) and phosphonite 6a (1 equiv). The resulting reaction mixture was heated at 100 °C in an oil bath for approximately 2 h. Upon consumption of the starting materials, as monitored by GC-MS, the crude mixture was purified by column chromatography to afford the desired phosphinates 1p or 1r–u.

General Procedure for the Preparation of 1,4-Azaphosphinines 2p–u (GP4_B)

A Schlenk flask was charged with phosphinate 1p–u (1 equiv), silver­(I) trifluoroacetate (0.02–0.05 equiv), and dry DCM (0.05–0.15 M) under an inert atmosphere. The resulting mixture was stirred overnight. Upon consumption of the starting material, as monitored by GC-MS or TLC, the crude product was purified by column chromatography to afford the desired 1,4-azaphosphinines 1p–u as an oil, which typically solidified over time or upon treatment with EtOAc.

Phenyl­(pyridin-2-yl)­methanol (7p)

A round-bottom flask was charged with phenyl­(pyridin-2-yl)­methanone (1.00 g, 5.46 mmol), sodium borohydride (103 mg, 2.73 mmol), and 27 mL of MeOH. After the mixture had been stirred at room temperature for 1 h, the reaction was quenched with water. The mixture was concentrated under vacuum and extracted with dichloromethane (DCM, 3 × 15 mL). The combined organic layers were dried over anhydrous magnesium sulfate. After solvent evaporation, 0.988 g of alcohol 7p (5.33 mmol, 98%) was obtained as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 6.0 Hz, 2H), 7.36–7.28 (m, 7H), 5.77 (s, 3H). The NMR spectrum is in accordance with published literature data.

(4-Methoxyphenyl)­(pyridin-2-yl)­methanol (7q)

GP1_B was followed with 2.00 mL of 2-bromopyridine (20.5 mmol), 103 mL of THF, 8.2 mL of a solution of n-BuLi (20.5 mmol, 2.5 M in n-hexane), and 2.49 mL of 4-methoxybenzaldehyde (20.5 mmol). Crystallization from ethanol provided 2.4 g of alcohol 7q (11.2 mmol, 54%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.65–8.48 (m, 1H), 7.61 (td, J = 7.7, 1.8 Hz, 1H), 7.28 (d, J = 8.7 Hz, 2H), 7.23–7.16 (m, 1H), 7.13 (dd, J = 7.9, 1.0 Hz, 1H), 6.87 (d, J = 8.7 Hz, 2H), 5.71 (d, J = 3.2 Hz, 1H), 5.26–5.10 (m, 1H), 3.79 (s, 3H). The NMR spectrum is in accordance with published literature data.

(4-Trifluoromethylphenyl)­(pyridin-2-yl)­methanol (7r)

GP1_B was followed with 2.00 mL of 2-bromopyridine (20.5 mmol), 103 mL of THF, 8.2 mL of a solution of n-BuLi (20.5 mmol, 2.5 M in n-hexane), and 2.80 mL of 4-trifluoromethylbenzaldehyde (20.5 mmol). The resulting product was purified by column chromatography (90:10 PE/EtOAc), yielding 4.11 g of alcohol 7r (16.2 mmol, 79%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J = 5.1 Hz, 1H), 7.65 (td, J = 7.7, 1.8 Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 8.1 Hz, 2H), 7.23 (ddd, J = 7.0, 4.6, 0.9 Hz, 1H), 7.14 (dd, J = 7.9, 0.9 Hz, 1H), 5.80 (s, 1H), 5.34 (s, 1H). The NMR spectrum is in accordance with published literature data.

(2,5-Dimethylphenyl)­(pyridin-2-yl)­methanol (7s)

GP1_B was followed with 1.16 mL of 2-bromopyridine (11.9 mmol), 60 mL of THF, 4.8 mL of a solution of n-BuLi (11.9 mmol, 2.5 M in n-hexane), and 1.60 g of 2,5-dimethylbenzaldehyde (11.9 mmol). The resulting product was purified by column chromatography (PE/EtOAc, gradient from 100:0 to 75:25), yielding 2.1 g of alcohol 7s (9.85 mmol, 83%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.59 (d, J = 5.0 Hz, 1H), 7.60 (td, J = 7.7, 1.7 Hz, 1H), 7.24–7.17 (m, 1H), 7.09–6.98 (m, 4H), 5.94 (s, 1H), 5.14 (s, 1H), 2.30 (s, 3H), 2.27 (s, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 161.2, 147.9, 140.5, 136.9, 135.7, 133.1, 130.7, 128.7, 128.6, 122.4, 121.3, 72.8, 21.1, 19.1; R_f = 0.34 (75:25 PE/EtOAc); EI MS 213 (19%, M⁺), 194 (100%), 182 (14%), 93 (21%), 80 (25%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₄H₁₆NO]⁺ 214.1226, found 214.1218 (17%).

Naphthalen-1-yl­(pyridin-2-yl)­methanol (7t)

GP1_B was followed with 1.00 mL of 2-bromopyridine (10.3 mmol), 51 mL of THF, 4.1 mL of a solution of n-BuLi (10.3 mmol, 2.5 M in n-hexane), and 1.39 mL of 1-naphthaldehyde (10.3 mmol). The resulting product was purified by column chromatography (PE/EtOAc, gradient from 75:25 to 55:45), yielding 1.63 g of alcohol 7t (6.93 mmol, 67%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 4.9 Hz, 1H), 8.14–8.09 (m, 1H), 7.89–7.80 (m, 2H), 7.55 (td, J = 7.7, 1.8 Hz, 1H), 7.51–7.40 (m, 4H), 7.24–7.18 (m, 1H), 7.05 (dd, J = 7.9, 1.0 Hz, 1H), 6.42 (s, 1H), 5.40 (s, 1H). The NMR spectrum is in accordance with published literature data.

(Mesityl)­(pyridin-2-yl)­methanol (7u)

GP1_B was followed with 1.00 mL of 2-bromopyridine (10.3 mmol), 51 mL of THF, 4.1 mL of a solution of n-BuLi (10.3 mmol, 2.5 M in n-hexane), and 1.49 mL of 2,4,6-trimethylbenzaldehyde (10.3 mmol). The resulting product was purified by column chromatography (PE/EtOAc, gradient from 88:12 to 80:20), yielding 1.79 g of alcohol 7u (7.88 mmol, 77%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ 8.59 (dt, J = 4.9, 1.4 Hz, 1H), 7.57 (td, J = 7.7, 1.7 Hz, 1H), 7.19 (ddt, J = 7.3, 5.0, 1.0 Hz, 1H), 6.90 (dd, J = 7.9, 1.1 Hz, 1H), 6.83 (s, 2H), 6.19 (s, 1H), 5.38 (d, J = 1.8 Hz, 1H), 2.26 (s, 3H), 2.18 (s, 6H). The NMR spectrum is in accordance with published literature data.

2-(Bromo­(phenyl)­methyl)­pyridine (8p)

GP2_B was followed with 7p (560 mg, 3.02 mmol), triphenylphosphine, (1.43 g, 5.44 mmol), tetrabromomethane (1.50 g, 4.54 mmol), and 21 mL of THF. The resulting product was purified by column chromatography (PE/EtOAc, gradient from 88:12 to 80:20), yielding 570 mg of bromide 8p (2.30 mmol, 76%) as a pink amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 8.60 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 7.68 (td, J = 7.7, 1.8 Hz, 1H), 7.59–7.50 (m, 3H), 7.39–7.31 (m, 2H), 7.31–7.26 (m, 1H), 7.19 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 6.26 (s, 1H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 159.5, 149.3, 139.8, 137.0, 128.7 (2C), 128.6 (2C), 128.4, 122.9, 122.8, 55.1; R_f = 0.44 (83:17 PE/EtOAc); EI MS 168 (100%, [M – Br]⁺); HRMS (ESI) m/z [M + H]⁺ calcd for [C₁₂H₁₁ ⁷⁹BrN]⁺ 248.0069, found 248.0071 (43%).

2-(Bromo­(4-(trifluoromethyl)­phenyl)­methyl)­pyridine (8r)

GP2_B was followed with 7r (750 mg, 3.52 mmol), triphenylphosphine (1.66 g, 6.33 mmol), tetrabromomethane (1.96 g, 5.92 mmol), and 26 mL of THF. The resulting product was purified by column chromatography (PE/EtOAc, gradient from 100:0 to 82:18), yielding 1.01 g of bromide 8r (3.20 mmol, 81%) as a slightly pink oil: ¹H NMR (400 MHz, CDCl₃) δ 8.61 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 7.75–7.65 (m, 3H), 7.60 (d, J = 8.2 Hz, 2H), 7.54 (dt, J = 7.9, 1.1 Hz, 1H), 7.22 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H), 6.25 (s, 1H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 158.8, 149.7, 143.9 (d, J = 1.5 Hz), 137.4, 130.5 (q, J = 32.6 Hz), 129.2 (2C), 125.7 (q, J = 3.7 Hz, 2C), 12.0 (q, J = 272.3 Hz), 123.2, 123.0, 53.6; ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −62.71; R_f = 0.67 (83:17 PE/EtOAc); EI MS 236 (100%, [M – Br]⁺), 167 (51%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₃H₉ ⁷⁹BrF₃N]⁺ 315.9945, found 315.9945 (100%).

2-(Bromo­(2,5-dimethylphenyl)­methyl)­pyridine (8s)

GP2_B was followed with 7s (1.00 g, 3.95 mmol), triphenylphosphine (1.86 g, 7.11 mmol), tetrabromomethane (1.75 g, 5.27 mmol), and 23 mL of THF. The resulting product was purified by column chromatography (PE/EtOAc, gradient from 100:0 to 90:10), yielding 670 mg of bromide 8s (2.42 mmol, 69%) as a pink amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 8.60 (ddd, J = 4.9, 1.9, 0.9 Hz, 1H), 7.70 (td, J = 7.7, 1.8 Hz, 1H), 7.55 (dt, J = 7.9, 1.1 Hz, 1H), 7.39–7.32 (m, 1H), 7.20 (ddd, J = 7.5, 4.8, 1.2 Hz, 1H), 7.08–6.96 (m, 2H), 6.47 (s, 1H), 2.35 (s, 3H), 2.30 (s, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 159.1, 148.8, 137.6, 137.5, 136.1, 132.8, 130.8, 130.0, 129.4, 123.6, 122.9, 52.3, 21.2, 19.2; R_f = 0.8 (75:25 PE/EtOAc); EI MS 196 (100%, [M – Br]⁺), 181 (64%); HRMS (ESI/QTOF) m/z [M – Br]⁺ calcd for [C₁₄H₁₄N]⁺ 196.1121, found 196.1124 (100%).

2-(Bromo­(naphthalen-1-yl)­methyl)­pyridine (8t)

GP2_B was followed with 7t (1.60 g, 6.80 mmol), triphenylphosphine (3.21 g, 12.24 mmol), tetrabromomethane (3.38 g, 10.20 mmol), and 45 mL of THF. The resulting product was purified by column chromatography (PE/EtOAc, gradient from 100:0 to 75:25), yielding 1.61 g of bromide 8t (5.41 mmol, 80%) as a pink amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 8.64 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 8.16 (d, J = 9.0 Hz, 1H), 7.88 (dd, J = 8.0, 1.6 Hz, 1H), 7.84 (d, J = 8.2 Hz, 1H), 7.77 (dd, J = 7.2, 1.2 Hz, 1H), 7.68 (td, J = 7.7, 1.8 Hz, 1H), 7.59–7.42 (m, 4H), 7.22 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.08 (s, 1H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 159.5, 149.3, 137.2, 135.1, 134.0, 130.5, 129.5, 129.0, 127.9, 126.7, 126.1, 125.5, 123.8, 123.5, 122.9, 52.9; R_f = 0.82 (75:25 PE/EtOAc); EI MS 218 (100%, [M – Br]⁺), 189 (10%), 108 (16%); HRMS (ESI/QTOF) m/z [M – Br]⁺ calcd for [C₁₆H₁₂N]⁺ 218.0964, found 218.0966 (100%).

2-(Bromo­(mesityl)­methyl)­pyridine (8u)

GP2_B was followed with 7u (1.50 g, 6.60 mmol), triphenylphosphine (3.12 g, 11.88 mmol), tetrabromomethane (3.28 g, 9.90 mmol), and 44 mL of THF. The resulting product was purified by column chromatography (PE/EtOAc, gradient from 100:0 to 85:15), yielding 1.35 g of bromide 8u (4.65 mmol, 71%) as a pink amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 8.64–8.52 (m, 1H), 7.63 (dtd, J = 15.5, 8.0, 1.5 Hz, 2H), 7.16 (ddt, J = 7.2, 4.9, 1.2 Hz, 1H), 6.86 (s, 2H), 6.79 (s, 1H), 2.27 (s, 3H), 2.19 (s, 6H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 158.6, 149.3, 138.4, 137.4, 136.7, 134.4, 130.4, 122.6, 121.9, 52.0, 21.1, 20.8; R_f = 0.3 (91:9 PE/EtOAc); EI MS 210 (100%, [M – Br]⁺), 195 (86%), 180 (14%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₅H₁₇ ⁷⁹BrN]⁺ 290.0539, found 290.0530 (5%).

Ethyl (Phenyl­(pyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (1p)

GP3_B was followed with phosphonite 6a (385 mg, 1.73 mmol) and bromide 8p (430 mg, 1.73 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 249 mg of phosphinate 1p (0.689 mmol, 40%) as a brown oil, obtained as a diastereomeric mixture: ¹H NMR (400 MHz, CDCl₃) δ 8.53 (dt, J = 4.9, 1.9 Hz, 1H), 7.71–7.53 (m, 4H), 7.37–7.21 (m, 8H), 7.12 (dddt, J = 6.4, 5.0, 3.0, 1.7 Hz, 1H), 4.78 (dd, J = 20.9, 3.0 Hz, 1H), 4.21–4.00 (m, 2H), 1.21 (td, J = 7.1, 1.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 156.0, 149.5, 137.2–136.3 (m), 134.7 (dd, J = 20.5, 5.9 Hz), 132.3 (2C), 130.5, 130.04, 129.97, 128.5 (2C), 128.4 (2C), 127.5, 124.3 (dd, J = 5.2, 3.4 Hz), 122.2 (d, J = 2.0 Hz), 119.6 (d, J = 4.4 Hz), 101.8 (dd, J = 36.1, 18.1 Hz), 81.1 (dd, J = 206.9, 21.6 Hz), 62.8 (d, J = 7.7 Hz), 58.0 (dd, J = 113.4, 23.4 Hz), 16.2 (d, J = 6.4 Hz) (some proton and carbon signals were split due to phosphorus coupling and the presence of two diastereomers, hindering unambiguous spectral interpretation); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.80, 17.13; R_f = 0.81 (EtOAc); EI MS 361 (24%, M⁺), 298 (24%), 268 (76%), 167 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₂H₂₁NO₂P]⁺ 362.1304, found 362.1304 (100%).

Ethyl ((4-Methoxyphenyl)­(pyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (1q)

A Schlenk flask was charged with alcohol 7q (1.00 g, 4.65 mmol), phosphorus tribromide (0.219 mL, 2.32 mmol), and 23 mL of dry DCM. The reaction mixture was stirred at room temperature for 1 h. Subsequently, the reaction was quenched by adding a 10% aqueous solution of K₂CO₃. The aqueous phase was extracted with DCM (3 × 10 mL), and the combined organic layers were dried over anhydrous MgSO₄, filtered, and then mixed with phosphonite 6a (1.03 g, 4.65 mmol). The solvent was subsequently distilled off at atmospheric pressure, and the resulting oily residue was heated at 100 °C in an oil bath for 2 h. The resulting product was purified by column chromatography (PE/EtOAc, gradient from 50:50 to 100:0), yielding 146 mg of phosphinate 1q (0.373 mmol, 8%) as a brown oil, obtained as a diastereomeric mixture: ¹H NMR (400 MHz, CDCl₃) δ 8.65–8.45 (m, 1H), 7.71 (ddd, J = 8.9, 7.8, 1.5 Hz, 1H), 7.69–7.63 (m, 1H), 7.57 (ddd, J = 11.0, 8.8, 2.2 Hz, 2H), 7.45–7.27 (m, 5H), 7.22–7.14 (m, 1H), 6.88 (d, J = 8.2 Hz, 2H), 4.79 (dd, J = 20.9, 2.9 Hz, 1H), 4.33–4.12 (m, 2H), 3.78 (s, 3H), 1.32–1.24 (m, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 159.2 (d, J = 2.7 Hz), 156.7–156.3 (m), 149.7, 136.8 (d, J = 5.8 Hz), 132.6 (2C), 131.3 (dd, J = 7.6, 1.5 Hz, 2C), 130.6, 128.6 (d, J = 2.2 Hz, 2C), 127.2–126.6 (m), 124.4 (dd, J = 5.2, 1.8 Hz), 122.3, 120.0 (dd, J = 4.3, 2.0 Hz), 114.2 (2C), 101.9 (dd, J = 35.6, 6.2 Hz), 81.4 (dd, J = 205.6, 19.0 Hz), 63.0 (d, J = 7.7 Hz), 57.3 (dd, J = 113.8, 24.1 Hz), 55.4, 16.4 (dd, J = 6.5, 2.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.02, 17.38; R_f = 0.56 (EtOAc); EI MS 391 (20%, M⁺), 299 (16%), 198 (100%), 182 (16%), 167 (34%), 154 (16%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₃H₂₃NO₃P]⁺ 392.1410, found 392.1408 (100%).

Ethyl (Phenylethynyl)­(pyridin-2-yl­(4-(trifluoromethyl)­phenyl)­methyl)­phosphinate (1r)

GP3_B was followed with phosphonite 6a (668 mg, 3.01 mmol) and bromide 8r (950 mg, 3.01 mmol). The resulting product was purified by column chromatography (PE/EtOAc, gradient from 100:0 to 50:50), yielding 515 mg of phosphinate 1r (1.20 mmol, 40%) as a brown oil, obtained as a diastereomeric mixture: ¹H NMR (400 MHz, CDCl₃) δ 8.62 (ddd, J = 4.8, 2.8, 1.3 Hz, 1H), 7.80 (ddd, J = 11.0, 8.2, 2.2 Hz, 2H), 7.73–7.63 (m, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.46–7.38 (m, 1H), 7.37–7.29 (m, 4H), 7.25–7.18 (m, 1H), 4.89 (dd, J = 21.0, 2.4 Hz, 1H), 4.20 (tt, J = 8.5, 6.4 Hz, 2H), 1.29 (td, J = 7.1, 2.5 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 156.4–154.0 (m), 149.8, 139.3–138.6 (m), 137.0 (d, J = 5.0 Hz), 132.5 (t, J = 1.9 Hz, 2C), 130.8 (d, J = 3.4 Hz), 130.6 (dd, J = 7.2, 2.6 Hz, 2C), 130.1–129.5 (m), 128.6 (d, J = 3.1 Hz, 2C), 126.3–125.2 (m, 2C), 124.6 (d, J = 5.2 Hz), 122.7 (d, J = 1.9 Hz), 119.5 (dd, J = 4.5, 2.4 Hz), 102.5 (dd, J = 36.7, 18.7 Hz), 80.7 (dd, J = 209.5, 14.5 Hz), 63.1 (dd, J = 7.6, 5.3 Hz), 57.8 (dd, J = 113.3, 10.6 Hz), 16.2 (d, J = 6.5 Hz) (the signal of the CF₃ group could not be unambiguously assigned due to its low intensity and overlap with other signals); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.52, 16.02; ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −62.59, −62.59; R_f = 0.22 (50:50 PE/EtOAc); EI MS 429 (25%, M⁺), 400 (18%), 385 (13%), 366 (37%), 336 (100%), 235 (75%), 216 (29%), 165 (96%), 102 (32%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₃H₂₀F₃NO₂P]⁺ 430.1178, found 430.1179 (100%).

Ethyl ((2,5-Dimethylphenyl)­(pyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (1s)

GP3_B was followed with phosphonite 6a (483 mg, 2.17 mmol) and bromide 8s (600 mg, 2.17 mmol). The resulting product was purified by column chromatography (PE/EtOAc, gradient from 50:50 to 25:75), yielding 306 mg of a 55:45 diastereomeric mixture of phosphinate 1s (0.786 mmol, 36%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.58 (d, J = 4.7 Hz, 2H), 7.83 (d, J = 2.1 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.69–7.56 (m, 4H), 7.43–7.28 (m, 10H), 7.20–7.13 (m, 2H), 7.07 (d, J = 7.4 Hz, 2H), 6.98 (d, J = 7.7 Hz, 2H), 5.16 (d, J = 1.9 Hz, 1H), 5.11 (d, J = 1.6 Hz, 1H), 4.25–4.10 (m, 4H), 2.42 (s, 6H), 2.32 (s, 6H), 1.28 (t, J = 7.0 Hz, 6H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 156.7, 156.5 (d, J = 5.3 Hz), 149.5 (2C), 136.8 (d, J = 4.3 Hz, 2C), 135.8 (d, J = 2.4 Hz), 135.7 (d, J = 2.2 Hz), 134.2 (dd, J = 10.0, 6.7 Hz, 2C), 133.5 (d, J = 3.6 Hz), 133.4 (d, J = 5.9 Hz), 132.7–132.3 (m, 4C), 130.9–130.3 (m, 6C), 128.6 (d, J = 2.6 Hz, 4C), 128.5 (t, J = 2.5 Hz, 2C), 124.7 (dd, J = 5.4, 3.1 Hz, 2C), 122.3 (2C), 120.0 (d, J = 4.4 Hz, 2C), 101.4 (d, J = 36.2 Hz, 2C), 81.6 (d, J = 205.3 Hz, 2C), 62.9 (d, J = 3.5 Hz), 62.8 (d, J = 3.6 Hz), 53.4 (dd, J = 115.1, 20.0 Hz, 2C), 21.4 (2C), 20.0 (d, J = 3.6 Hz, 2C), 16.3 (d, J = 6.5 Hz, 2C); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.07, 17.84; R_f = 0.69 (EtOAc); EI MS 389 (27%, M⁺), 360 (15%), 297 (93%), 220 (32%), 206 (50%), 194 (82%), 181 (100%), 165 (27%), 102 (23%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₄H₂₅NO₂P]⁺ 390.1617, found 390.1618 (100%).

Ethyl (Naphthalen-1-yl­(pyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (1t)

GP3_B was followed with phosphonite 6a (1.19 g, 5.37 mmol) and bromide 8t (1.60 g, 5.37 mmol). The resulting product was purified by column chromatography (PE/EtOAc, gradient from 75:25 to 30:70), yielding 740 mg of a 51:49 diastereomeric mixture of phosphinate 1t (1.80 mmol, 34%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.66–8.56 (m, 2H), 8.41 (ddd, J = 7.3, 2.4, 1.2 Hz, 1H), 8.35 (ddd, J = 7.3, 2.5, 1.2 Hz, 1H), 8.31 (d, J = 8.4 Hz, 2H), 7.88–7.77 (m, 4H), 7.73–7.66 (m, 1H), 7.64–7.42 (m, 9H), 7.42–7.36 (m, 1H), 7.36–7.27 (m, 5H), 7.25–7.19 (m, 2H), 7.19–7.08 (m, 4H), 5.74 (dd, J = 21.8, 2.2 Hz, 2H), 4.20 (dqd, J = 8.8, 7.1, 5.7 Hz, 4H), 1.28 (t, J = 7.0 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 156.5 (d, J = 3.2 Hz), 156.3 (d, J = 6.2 Hz), 149.4, 149.4, 136.8 (d, J = 1.8 Hz), 136.8 (d, J = 1.8 Hz), 134.3, 132.6 (d, J = 2.1 Hz, 2C), 132.5 (d, J = 1.9 Hz, 2C), 132.4, 132.3, 131.6 (d, J = 2.6 Hz), 131.5 (d, J = 5.2 Hz), 130.5 (d, J = 9.3 Hz, 2C), 129.0 (2C), 128.5 (2C), 128.4 (d, J = 1.9 Hz, 2C), 128.4 (2C), 128.1 (d, J = 8.0 Hz), 128.0 (d, J = 7.4 Hz), 126.6 (2C), 125.7 (2C), 125.6 (d, J = 2.0 Hz), 125.6 (d, J = 1.9 Hz), 124.8 (d, J = 2.9 Hz), 124.8 (d, J = 2.5 Hz), 123.8 (2C), 122.3 (d, J = 2.4 Hz, 2C), 119.6 (d, J = 4.4 Hz), 119.7 (d, J = 4.4 Hz), 102.0 (d, J = 21.8 Hz), 101.6 (d, J = 21.8 Hz), 81.5 (dd, J = 207.7, 3.6 Hz, 2C), 63.0 (d, J = 7.6 Hz), 62.9 (d, J = 7.6 Hz), 52.9 (d, J = 115.3 Hz, 2C), 16.3 (d, J = 2.9 Hz), 16.3 (d, J = 3.1 Hz) (one signal could not be unambiguously assigned due to spectral overlap); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.82, 17.42; R_f = 0.19 (50:50 PE/EtOAc); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₆H₂₃NO₂P]⁺ 412.1461, found 412.1460 (100%).

Ethyl (Mesityl­(pyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (1u)

GP3_B was followed with phosphonite 6a (766 mg, 3.45 mmol) and bromide 8u (1.00 g, 3.45 mmol). The resulting product was purified by column chromatography (PE/EtOAc, gradient from 75:25 to 25:75), yielding 380 mg of a 54:46 diastereomeric mixture of phosphinate 1u (0.942 mmol, 27%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.65–8.57 (m, 2H), 7.59–7.50 (m, 2H), 7.42–7.33 (m, 3H), 7.33–7.21 (m, 8H), 7.11 (dd, J = 7.5, 4.9 Hz, 2H), 6.99–6.76 (m, 4H), 5.41 (d, J = 25.7 Hz, 1H), 5.36 (d, J = 27.0 Hz, 1H), 4.56–4.28 (m, 2H), 4.24–4.01 (m, 3H), 2.52 (s, 6H), 2.24 (d, J = 2.2 Hz, 6H), 2.10 (s, 3H), 2.02 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 157.9 (d, J = 1.5 Hz), 157.5 (d, J = 3.8 Hz), 149.0, 148.8, 139.2 (2C), 138.3 (2C), 137.1 (d, J = 3.6 Hz), 136.9 (d, J = 3.3 Hz), 136.2, 136.1 (d, J = 1.4 Hz), 132.3 (d, J = 2.0 Hz, 2C), 132.2 (d, J = 2.0 Hz, 2C), 131.0 (2C), 130.2, 130.1, 129.7 (d, J = 4.4 Hz), 129.5 (d, J = 7.6 Hz), 129.1 (2C), 128.34 (2C), 128.29 (2C), 123.4 (d, J = 8.6 Hz), 123.3 (d, J = 7.8 Hz), 121.4 (2C), 120.2 (d, J = 4.2 Hz), 120.0 (d, J = 4.4 Hz), 99.8 (d, J = 35.0 Hz), 99.4 (d, J = 36.1 Hz), 83.9 (d, J = 105.0 Hz), 81.9 (d, J = 106.7 Hz), 62.6 (d, J = 7.4 Hz), 62.0 (d, J = 7.2 Hz), 52.7 (d, J = 120.4 Hz), 52.0 (d, J = 119.2 Hz), 22.0–21.4 (m, 5C), 20.8, 16.3 (d, J = 6.6 Hz), 16.2 (d, J = 6.9 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.69, 17.54; R_f = 0.43–0.47 (67:33 PE/EtOAc); EI MS 403 (22%, M⁺), 374 (19%), 311 (100%), 234 (20%), 220 (32%), 208 (65%), 195 (58%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₅H₂₇NO₂P]⁺ 404.1774, found 404.1774 (100%).

2-Ethoxy-1,4-diphenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2p)

GP4_B was followed with 1p (240 mg, 0.664 mmol), CF₃COOAg (2.9 mg, 13 μmol), and 35 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 228 mg of 1,4-azaphosphinine 2p (0.631 mmol, 95%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.74–7.30 (m, 10H), 7.09 (d, J = 7.6 Hz, 1H), 6.83–6.75 (m, 1H), 6.49 (dddd, J = 9.9, 6.2, 2.7, 1.3 Hz, 1H), 5.86–5.76 (m, 2H), 3.89 (ddq, J = 10.4, 9.2, 7.0 Hz, 1H), 3.82–3.65 (m, 1H), 1.02 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR δ 150.9 (d, J = 2.3 Hz), 145.0 (d, J = 7.8 Hz), 137.1 (d, J = 12.4 Hz), 134.2, 131.7, 129.6, 129.2, 128.9, 128.5, 127.3 (d, J = 1.5 Hz), 126.5 (d, J = 1.6 Hz), 123.0 (d, J = 11.1 Hz), 106.9, 104.6 (d, J = 125.7 Hz), 102.7 (d, J = 139.3 Hz), 62.3 (d, J = 6.4 Hz), 16.5 (d, J = 6.2 Hz) (two signals were not observed, most likely due to broadening caused by phenyl group rotation); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 14.94; R_f = 0.18 (EtOAc); EI MS 361 (<3%, M⁺), 269 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₂H₂₁NO₂P]⁺ 362.1304, found 362.1303 (100%).

2-Ethoxy-1-(4-methoxyphenyl)-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2q)

GP4_B was followed with 1q (60.0 mg, 0.153 mmol), CF₃COOAg (3.4 mg, 15 μmol), and 3 mL of DCM. The resulting product was purified by column chromatography (EtOAc/MeOH, gradient from 100:0 to 97:3), yielding 55.0 mg of 1,4-azaphosphinine 2q (0.141 mmol, 92%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.36 (m, 7H), 7.07 (d, J = 7.6 Hz, 1H), 6.98 (d, J = 9.1 Hz, 2H), 6.82–6.76 (m, 1H), 6.48 (dddd, J = 9.8, 6.2, 2.8, 1.3 Hz, 1H), 5.84–5.74 (m, 2H), 3.95–3.86 (m, 1H), 3.84 (s, 3H), 3.79–3.71 (m, 1H), 1.05 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR δ 159.1 (d, J = 1.7 Hz), 151.2 (d, J = 2.5 Hz), 145.4 (d, J = 8.7 Hz), 137.3 (d, J = 12.5 Hz), 132.7 (2C), 131.8, 129.7, 129.4 (2C), 128.7 (2C), 126.5 (d, J = 1.7 Hz), 126.1, 123.2 (d, J = 11.1 Hz), 114.5 (2C), 107.0, 104.4 (d, J = 125.1 Hz), 102.1 (d, J = 140.5 Hz), 62.4 (d, J = 6.5 Hz), 55.4, 16.7 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.18; R_f = 0.23 (EtOAc); EI MS 391 (6%, M⁺), 299 (100%), 284 (57%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₃H₂₃NO₃P]⁺ 392.1410, found 392.1412 (100%).

2-Ethoxy-4-phenyl-1-(4-(trifluoromethyl)­phenyl)­pyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2r)

GP4_B was followed with 1r (100 mg, 0.233 mmol), CF₃COOAg (2.6 mg, 12 μmol), and 1.5 mL of DCM. The resulting product was purified by column chromatography (EtOAc/MeOH, gradient from 100:0 to 96:4), yielding 89.0 mg of 1,4-azaphosphinine 2r (0.207 mmol, 89%) as a yellow solid. Single crystals suitable for X-ray analysis were obtained by slowly cooling its EtOAc solution: ¹H NMR (400 MHz, CDCl₃) 7.88–7.46 (m, 7H), 7.46–7.35 (m, 2H), 7.13 (dt, J = 7.7, 1.2 Hz, 1H), 6.74 (dd, J = 9.8, 1.4 Hz, 1H), 6.60–6.51 (m, 1H), 5.92–5.80 (m, 2H), 3.90 (ddq, J = 10.4, 8.8, 7.1 Hz, 1H), 3.84–3.65 (m, 1H), 1.05 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.2 (d, J = 2.2 Hz), 145.4 (d, J = 7.1 Hz), 138.6, 137.1 (d, J = 12.5 Hz), 132.1 (3C), 129.9, 129.5 (2C), 128.7 (2C), 127.5 (d, J = 1.7 Hz), 125.9 (2C), 124.4 (q, J = 271.9 Hz), 122.7 (d, J = 11.1 Hz), 107.3, 105.4 (d, J = 126.2 Hz), 101.2 (d, J = 139.4 Hz), 62.5 (d, J = 6.4 Hz), 16.7 (d, J = 6.1 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 14.50; ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −62.47; R_f = 0.33 (EtOAc); EI MS 429 (<2%, M⁺), 337 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₃H₂₀F₃NO₂P]⁺ 430.1178, found 430.1176 (100%); mp 155.4–156.9 °C (EtOAc).

1-(2,5-Dimethylphenyl)-2-ethoxy-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2s)

GP4_B was followed with 1s (100 mg, 0.257 mmol), CF₃COOAg (2.8 mg, 13 μmol), and 5 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 94.0 mg of a 1:1.1 diastereomeric mixture of 1,4-azaphosphinine 2s (0.241 mmol, 94%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.39 (m, 10H), 7.34 (d, J = 2.2 Hz, 1H), 7.18 (dd, J = 10.3, 7.6 Hz, 2H), 7.12–6.99 (m, 5H), 6.52–6.43 (m, 2H), 6.42–6.34 (m, 2H), 5.86–5.73 (m, 4H), 4.03–3.79 (m, 3H), 3.72 (ddq, J = 10.3, 8.8, 7.1 Hz, 1H), 2.36 (s, 3H), 2.34 (s, 3H), 2.33 (s, 3H), 2.20 (s, 3H), 1.16 (t, J = 7.0 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 150.9 (dd, J = 19.0, 2.6 Hz), 144.3 (dd, J = 34.0, 8.3 Hz), 137.3 (d, J = 5.7 Hz), 137.2 (d, J = 5.6 Hz), 137.0 (d, J = 3.6 Hz), 135.7 (d, J = 1.9 Hz), 135.3 (d, J = 1.8 Hz), 134.8 (d, J = 4.1 Hz), 133.8 (d, J = 3.0 Hz), 132.8, 132.4, 132.4 (d, J = 3.3 Hz), 131.8, 131.7, 130.5 (d, J = 1.6 Hz), 130.1 (d, J = 1.5 Hz), 129.6, 129.3, 128.7, 128.6, 126.6 (dd, J = 6.3, 1.7 Hz), 122.9 (t, J = 12.1 Hz), 106.6 (d, J = 2.2 Hz), 105.6 (d, J = 2.8 Hz), 104.4, 102.4 (d, J = 140.8 Hz), 102.3 (d, J = 140.8 Hz), 62.1 (d, J = 3.6 Hz), 62.1 (d, J = 3.6 Hz), 21.1, 20.9, 19.7, 19.3, 16.8 (d, J = 6.4 Hz), 16.6 (d, J = 5.6 Hz) (some proton and carbon signals were split due to phosphorus coupling and the presence of two diastereomers, hindering unambiguous spectral interpretation); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.06, 14.41; R_f = 0.38 (EtOAc); EI MS 389 (3%, M⁺), 297 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₄H₂₅NO₂P]⁺ 390.1617, found 390.1620 (100%).

2-Ethoxy-1-(naphthalen-1-yl)-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2t)

GP4_B was followed with 1t (250 mg, 0.608 mmol), CF₃COOAg (2.7 mg, 12 μmol), and 4 mL of DCM. The resulting product was purified by column chromatography (EtOAc/MeOH, gradient from 100:0 to 97:3), yielding 80 mg of 1,4-azaphosphinine (R _a ,R)/(S _a ,S)-2t (0.194 mmol, 32%) as a yellow solid and 130 mg of 1,4-azaphosphinine (S _a ,R)/(R _a ,S)-2t (0.316 mmol, 52%) as a yellow amorphous solid. Single crystals of both diastereomers suitable for X-ray analysis were obtained by slowly cooling their EtOAc solution.

(R_a,R)/(S_a,S)-2t

¹H NMR (400 MHz, CDCl₃) δ 8.14 (dd, J = 6.2, 3.6 Hz, 1H), 7.87 (dd, J = 6.2, 3.5 Hz, 2H), 7.57–7.43 (m, 9H), 7.13 (d, J = 7.6 Hz, 1H), 6.36 (dddd, J = 8.8, 6.1, 2.7, 1.3 Hz, 1H), 6.22 (dt, J = 9.6, 1.2 Hz, 1H), 5.89 (d, J = 1.1 Hz, 1H), 5.79 (ddd, J = 7.6, 6.0, 1.6 Hz, 1H), 3.96 (ddq, J = 10.3, 8.5, 7.0 Hz, 1H), 3.81 (ddq, J = 10.3, 8.8, 7.1 Hz, 1H), 1.14 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.0 (d, J = 2.2 Hz), 145.6 (d, J = 8.1 Hz), 137.1 (d, J = 12.5 Hz), 134.2, 134.2, 131.6, 131.5, 129.7, 129.3, 129.3, 128.7, 128.4 (d, J = 2.1 Hz), 128.1, 126.71, 126.67 (d, J = 1.8 Hz), 126.6, 126.2, 125.6 (d, J = 2.1 Hz), 123.2 (d, J = 11.4 Hz), 106.7, 105.2 (d, J = 125.1 Hz), 100.3 (d, J = 141.0 Hz), 62.1 (d, J = 6.3 Hz), 16.9 (d, J = 6.2 Hz) (two signals are missing due to overlapping); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 14.31; R_f = 0.28 (EtOAc); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₆H₂₃NO₂P]⁺ 412.1461, found 412.1462 (100%); mp 196.1–197.2 °C (EtOAc).

(S_a,R)/(R_a,S)-2t

¹H NMR (400 MHz, CDCl₃) δ 7.95–7.84 (m, 3H), 7.80 (ddd, J = 7.1, 2.2, 1.2 Hz, 1H), 7.64–7.40 (m, 8H), 7.15 (dt, J = 7.6, 1.1 Hz, 1H), 6.39 (dddd, J = 9.9, 6.1, 2.7, 1.3 Hz, 1H), 6.26 (dt, J = 9.5, 1.3 Hz, 1H), 5.91 (d, J = 1.1 Hz, 1H), 5.81 (ddd, J = 7.7, 6.1, 1.6 Hz, 1H), 3.71 (ddq, J = 10.3, 9.2, 7.0 Hz, 1H), 3.43 (ddq, J = 10.2, 8.7, 7.1 Hz, 1H), 0.62 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.2 (d, J = 2.6 Hz), 145.2 (d, J = 8.0 Hz), 137.2 (d, J = 12.5 Hz), 134.2, 132.6 (d, J = 3.7 Hz), 131.8, 131.1 (d, J = 3.9 Hz), 130.4, 129.8, 129.4, 128.8, 128.6, 128.2 (d, J = 2.0 Hz), 126.8 (d, J = 1.8 Hz), 126.3 (d, J = 2.2 Hz), 126.2, 126.0, 125.8, 123.5 (d, J = 11.6 Hz), 106.9, 105.0 (d, J = 127.3 Hz), 100.2 (d, J = 140.2 Hz), 62.4 (d, J = 6.5 Hz), 16.3 (d, J = 5.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 14.90; R_f = 0.16 (EtOAc); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₆H₂₃NO₂P]⁺ 412.1461, found 412.1464 (100%).

2-Ethoxy-1-mesityl-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (2u)

GP4_B was followed with 1u (130 mg, 0.322 mmol), CF₃COOAg (3.6 mg, 16 μmol), and 6.4 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 110 mg of 1,4-azaphosphinine 2u (0.273 mmol, 85%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.39 (m, 5H), 7.08 (d, J = 7.5 Hz, 1H), 6.96 (d, J = 14.9 Hz, 2H), 6.46 (dddd, J = 10.2, 6.1, 2.8, 1.3 Hz, 1H), 6.35–6.27 (m, 1H), 5.83–5.71 (m, 2H), 3.96 (ddq, J = 10.3, 8.6, 7.1 Hz, 1H), 3.75 (ddq, J = 10.3, 8.4, 7.0 Hz, 1H), 2.38 (s, 3H), 2.31 (s, 3H), 2.21 (s, 3H), 1.07 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 150.9 (d, J = 2.6 Hz), 144.1 (d, J = 8.7 Hz), 140.5 (d, J = 3.0 Hz), 138.5 (d, J = 3.6 Hz), 137.4 (d, J = 12.5 Hz), 137.2 (d, J = 2.1 Hz), 132.0, 129.7, 129.3 (2C), 129.1 (d, J = 1.8 Hz), 128.9 (2C), 128.6, 126.7, 122.4 (d, J = 11.9 Hz), 106.5, 105.2 (d, J = 125.8 Hz), 101.3 (d, J = 142.1 Hz), 62.0 (d, J = 6.4 Hz), 21.2, 21.0, 20.2, 16.8 (d, J = 5.8 Hz) (the signals corresponding to the two equivalent quaternary carbons could not be assigned with certainty); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 14.89; R_f = 0.33 (EtOAc); EI MS 403 (7%, M⁺), 311 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₅H₂₇NO₂P]⁺ 404.1774, found 404.1778 (100%); mp 145.1–150.3 °C (EtOAc).

General Procedure for the Preparation of Phosphinates 3a–m (GP2_c)

A round-bottom flask was charged with the appropriate bromomethyl azaaromatic (1 equiv) and phosphonite 6a (1 equiv). The resulting reaction mixture was heated at 100 °C in an oil bath for approximately 2 h. Upon consumption of the starting materials, as monitored by GC-MS, the crude mixture was purified by column chromatography to afford the desired phosphinates 3a–m.

General Procedure for the Preparation of 1,4-Azaphosphinines 4a–m (GP3_c)

A Schlenk flask was charged with phosphinates 3a–m (1 equiv), silver­(I) trifluoroacetate (0.02–0.05 equiv), and dry DCM (0.05–0.15 M) under an inert atmosphere. The resulting mixture was stirred overnight. Upon consumption of the starting material, as monitored by GC-MS or TLC, the crude product was purified by column chromatography to afford the desired 1,4-azaphosphinines 4a–m as an oil, which typically solidified over time or upon treatment with EtOAc.

Ethyl (Phenylethynyl)­(pyrazin-2-ylmethyl)­phosphinate (3a)

GP2_C was followed with 2-(bromomethyl)­pyrazine (150 mg, 0.867 mmol) and phosphonite 6a (193 mg, 0.867 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 86 mg of phosphinate 3a (0.30 mmol, 35%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.73–8.65 (m, 1H), 8.55 (d, J = 2.2 Hz, 1H), 8.52–8.44 (m, 1H), 7.52–7.40 (m, 3H), 7.40–7.31 (m, 2H), 4.34–4.15 (m, 2H), 3.63 (dd, J = 20.8, 1.5 Hz, 2H), 1.37 (td, J = 7.1, 1.9 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 148.5 (d, J = 8.7 Hz), 146.0 (d, J = 5.2 Hz), 144.5 (d, J = 2.9 Hz), 143.2 (d, J = 3.8 Hz), 132.7 (d, J = 2.1 Hz, 2C), 131.0, 128.7 (2C), 119.4 (d, J = 4.5 Hz), 102.4 (d, J = 37.9 Hz), 80.3 (d, J = 208.7 Hz), 63.0 (d, J = 7.2 Hz), 39.5 (d, J = 113.8 Hz), 16.4 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.07; R_f = 0.56 (93:7 CHCl₃/MeOH); EI MS 286 (5%, M⁺), 194 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₅H₁₆N₂O₂P]⁺ 287.0944, found 287.0943 (100%).

Ethyl ((3-Methylpyrazin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3b)

GP2_C was followed with 2-(bromomethyl)-3-methylpyrazine (490 mg, 2.62 mmol) and phosphonite 6a (582 mg, 2.62 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 310 mg of phosphinate 3b (1.03 mmol, 39%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.43–8.28 (m, 2H), 7.58–7.45 (m, 2H), 7.45–7.41 (m, 1H), 7.40–7.31 (m, 2H), 4.42–4.01 (m, 2H), 3.67 (d, J = 21.1 Hz, 3H), 2.72 (d, J = 1.6 Hz, 3H), 1.37 (t, J = 7.1 Hz, 2H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 153.9 (d, J = 5.7 Hz), 147.0 (d, J = 9.9 Hz), 142.4 (d, J = 4.1 Hz), 141.8 (d, J = 3.3 Hz), 132.6 (d, J = 2.1 Hz, 2C), 130.9, 128.6 (2C), 119.4 (d, J = 4.4 Hz), 101.9 (d, J = 37.6 Hz), 80.7 (d, J = 207.0 Hz), 62.8 (d, J = 7.3 Hz), 39.0 (d, J = 114.0 Hz), 22.4, 16.3 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.57; R_f = 0.67 (93:7 CHCl₃/MeOH); EI MS 300 (8%, M⁺), 256 (43%), 207 (100%), 165 (53%), 108 (25%), 102 (34%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₈N₂O₂P]⁺ 301.1100, found 301.1100 (100%).

Ethyl (Phenylethynyl)­(pyrimidin-2-ylmethyl)­phosphinate (3c)

GP2_C was followed with 2-(bromomethyl)­pyrimidine (1.00 g, 5.78 mmol) and phosphonite 6a (1.28 g, 5.78 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 873 mg of phosphinate 3c (3.05 mmol, 53%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.74 (dd, J = 4.9, 0.8 Hz, 2H), 7.53–7.47 (m, 2H), 7.47–7.41 (m, 1H), 7.40–7.32 (m, 2H), 7.20 (td, J = 5.0, 2.1 Hz, 1H), 4.38–4.18 (m, 2H), 3.83 (d, J = 20.9 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 162.9 (d, J = 9.4 Hz), 157.5 (d, J = 2.5 Hz), 132.6 (2C), 130.7, 128.6 (2C), 119.7 (d, J = 4.4 Hz), 119.3 (d, J = 3.1 Hz), 101.5 (d, J = 38.5 Hz), 81.0 (d, J = 211.2 Hz), 62.7 (d, J = 7.1 Hz), 43.5 (d, J = 112.6 Hz), 16.3 (d, J = 6.6 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) 15.03; R_f = 0.41 (92:8 CHCl₃/MeOH); EI MS 286 (8%, M⁺), 285 (17%), 242 (49%), 194 (100%), 165 (81%), 154 (27%), 124 (54%), 94 (66%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₅H₁₆N₂O₂P]⁺ 287.0944, found 287.0940 (100%).

Ethyl ((6-Fluoropyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3d _ortho )

GP2_C was followed with 2-(bromomethyl)-6-fluoropyridine (500 mg, 2.63 mmol) and phosphonite 6a (585 mg, 2.63 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 425 mg of phosphinate 3d _ortho (1.40 mmol, 53%) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.80–7.71 (m, 1H), 7.53–7.48 (m, 2H), 7.47–7.41 (m, 1H), 7.39–7.30 (m, 3H), 6.84 (dt, J = 8.2, 2.7 Hz, 1H), 4.33–4.16 (m, 2H), 3.55 (d, J = 20.8 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 150.7 (dd, J = 13.8, 8.2 Hz), 141.4 (dd, J = 7.6, 3.2 Hz), 132.6 (d, J = 2.1 Hz), 130.7, 128.5, 122.1 (d, J = 4.5 Hz), 122.1 (d, J = 4.5 Hz), 119.5 (d, J = 4.6 Hz), 107.8 (dd, J = 36.6, 3.7 Hz), 102.0 (d, J = 38.0 Hz), 80.4 (d, J = 208.3 Hz), 62.7 (d, J = 7.3 Hz), 41.1 (d, J = 113.5 Hz), 16.2 (d, J = 6.8 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −67.07; ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.78; R_f = 0.46 (EtOAc); EI MS 303 (2%, M⁺), 302 (5%), 259 (50%), 211 (100%), 183 (50%), 156 (20%), 120 (45%), 93 (60%), 65 (40%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆FNO₂P]⁺ 304.0897, found 304.0911 (100%).

Ethyl ((6-Methylpyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3e _ortho )

GP2_C was followed with 2-(bromomethyl)-6-methylpyridine (500 mg, 2.69 mmol) and phosphonite 6a (597 mg, 2.69 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 353 mg of phosphinate 3e _ortho (1.18 mmol, 44%) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.54 (t, J = 7.7 Hz, 1H), 7.50–7.42 (m, 4H), 7.44–7.40 (m, 1H), 7.37–7.31 (m, 2H), 7.24 (dd, J = 7.9, 2.3 Hz 1H), 7.04 (dd, J = 7.6, 2.3 Hz, 1H), 4.31–4.15 (m, 2H), 3.58 (d, J _P–H = 20.5 Hz, 2H), 2.51 (s, 3H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 158.3 (d, J = 2.6 Hz), 150.9 (d, J = 8.1 Hz), 136.7 (d, J = 3.1 Hz), 132.5 (d, J = 2.0 Hz), 130.6, 128.5, 121.64 (d, J = 2.0 Hz), 121.59, 119.7 (d, J = 4.4 Hz), 101.4 (d, J = 37.1 Hz), 80.9 (d, J = 205.3 Hz), 62.5 (d, J = 7.3 Hz), 41.8 (d, J = 113.3 Hz), 24.4, 16.2 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.25; R_f = 0.26 (EtOAc); EI MS 299 (1%, M⁺), 298 (5%), 207 (25%), 206 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₂P]⁺ 300.1148, found 300.1154 (100%).

Ethyl ((6-Methoxypyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3f _ortho )

GP2_C was followed with 2-(bromomethyl)-6-methoxypyridine (399 mg, 1.98 mmol) and phosphonite 6a (439 mg, 1.98 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 396 mg of phosphinate 3f _ortho (1.26 mmol, 64%) as an orange oil: ¹H NMR (400 MHz, CDCl₃) δ 7.52 (ddd, J = 8.3, 7.3, 0.9 Hz, 1H), 7.48–7.40 (m, 3H), 7.39–7.32 (m, 2H), 6.95 (dd, J = 7.3, 2.9 Hz, 1H), 6.63 (dd, J = 8.2, 2.5 Hz, 1H), 4.34–4.17 (m, 2H), 3.87 (s, 3H), 3.51 (d, J = 20.7 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 163.7 (d, J = 2.6 Hz), 149.2 (d, J = 8.7 Hz), 138.9 (d, J = 3.2 Hz), 132.4 (d, J = 1.9 Hz), 130.6, 128.5, 119.8 (d, J = 4.4 Hz), 117.3 (d, J = 6.2 Hz), 109.0 (d, J = 3.8 Hz), 101.2 (d, J = 37.0 Hz), 81.1 (d, J = 205.5 Hz), 62.3 (d, J = 7.3 Hz), 53.3, 41.3 (d, J = 114.1 Hz), 16.3 (d, J = 7.0 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.54; R_f = 0.50 (EtOAc); EI MS 315 (10%, M⁺), 222 (10%), 208 (40%), 165 (60%), 123 (20%), 102 (30%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₃P]⁺ 316.1097, found 316.1099 (100%).

Methyl 6-((Ethoxy­(phenylethynyl)­phosphoryl)­methyl)­picolinate (3g _ortho )

GP2_C was followed with methyl 6-(bromomethyl)­picolinate (200 mg, 0.869 mmol) and phosphonite 6a (193 mg, 0.869 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 221 mg of phosphinate 3g _ortho (0.644 mmol, 74%) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 8.04 (ddd, J = 7.7, 2.1, 1.1 Hz, 1H), 7.82 (td, J = 7.8, 0.7 Hz, 1H), 7.67 (ddd, J = 7.8, 2.4, 1.1 Hz, 1H), 7.50–7.40 (m, 3H), 7.37–7.30 (m, 2H), 4.33–4.15 (m, 2H), 3.94 (s, 3H), 3.74 (d, J = 20.7 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.6, 152.4 (d, J = 7.7 Hz), 147.9 (d, J = 2.4 Hz), 137.4 (d, J = 2.8 Hz), 132.6 (d, J = 2.2 Hz), 130.7, 128.5, 128.1 (d, J = 4.3 Hz), 123.7 (d, J = 3.1 Hz), 119.5 (d, J = 4.4 Hz), 102.0 (d, J = 37.8 Hz), 80.5 (d, J = 207.9 Hz), 62.7 (d, J = 7.3 Hz), 52.9, 41.7 (d, J = 113.1 Hz), 16.2 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.18; R_f = 0.30 (EtOAc); EI MS 343 (1%, M⁺), 328 (100%), 300 (90%), 165 (20%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₁₉NO₄P]⁺ 344.1046, found 344.1032 (100%).

Ethyl ((5-Fluoropyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3d _meta )

GP2_C was followed with 2-(bromomethyl)-5-fluoropyridine (747 mg, 3.93 mmol) and phosphonite 6a (873 mg, 3.93 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc, gradient from 100:0 to 50:50), yielding 487 mg of phosphinate 3d _meta (1.61 mmol, 41%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 2.9 Hz, 1H), 7.52–7.41 (m, 4H), 7.41–7.31 (m, 3H), 4.31–4.15 (m, 2H), 3.60 (d, J = 20.3 Hz, 2H), 1.36 (td, J = 7.1, 1.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 158.8 (dd, J = 255.7, 3.8 Hz), 147.8 (dd, J = 8.4, 4.0 Hz), 137.8 (dd, J = 23.6, 2.6 Hz), 132.6 (d, J = 2.1 Hz), 130.8, 128.6, 125.6 (t, J = 4.5 Hz), 123.4 (dd, J = 18.6, 3.2 Hz), 119.6 (d, J = 4.4 Hz), 101.8 (d, J = 37.1 Hz), 80.7 (d, J = 205.7 Hz), 62.7 (d, J = 7.3 Hz), 41.0 (dd, J = 114.1, 1.5 Hz), 16.3 (d, J = 6.6 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.35 (d, J = 5.9 Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −129.46 (d, J = 6.1 Hz); R_f = 0.64 (92:8 CHCl₃/MeOH); EI MS 303 (9%, M⁺), 302 (21%), 259 (57%), 211 (82%), 174 (28%), 165 (100%), 141 (34%), 111 (51%), 102 (50%), 83 (26%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆FNO₂P]⁺ 304.0897, found 304.0899 (100%).

Ethyl ((5-Methylpyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3e _meta )

GP2_C was followed with 2-(bromomethyl)-5-methylpyridine (755 mg, 4.06 mmol) and phosphonite 6a (902 mg, 4.06 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 310 mg of phosphinate 3e _meta (1.04 mmol, 26%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J = 1.3 Hz, 1H), 7.51–7.39 (m, 4H), 7.39–7.29 (m, 3H), 4.32–4.13 (m, 2H), 3.58 (d, J = 20.3 Hz, 2H), 2.31 (d, J = 2.4 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 150.1 (d, J = 2.6 Hz), 148.7 (d, J = 8.5 Hz), 137.2 (d, J = 3.2 Hz), 132.6 (d, J = 2.0 Hz, 2C), 131.7 (d, J = 3.7 Hz), 130.7, 128.6 (2C), 124.2 (d, J = 4.9 Hz), 119.8 (d, J = 4.4 Hz), 101.5 (d, J = 36.9 Hz), 81.0 (d, J = 204.2 Hz), 62.6 (d, J = 7.3 Hz), 41.40 (d, J = 113.7 Hz), 18.2, 16.4 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.24; R_f = 0.50 (92:8 CHCl₃/MeOH); EI MS 299 (10%, M⁺), 298 (15%), 255 (47%), 236 (23%), 206 (100%), 191 (18%), 165 (43%), 137 (18%), 107 (72%), 77 (30%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₂P]⁺ 300.1148, found 300.1148 (100%).

Ethyl ((5-Methoxypyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3f _meta )

GP2_C was followed with 2-(bromomethyl)-5-methoxypyridine (290 mg, 1.437 mmol) and phosphonite 6a (319 mg, 1.437 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 171 mg of phosphinate 3f _meta (0.542 mmol, 38%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J = 3.0 Hz, 1H), 7.46–7.41 (m, 2H), 7.41–7.35 (m, 1H), 7.33–7.27 (m, 3H), 7.13 (ddd, J = 8.6, 3.0, 0.8 Hz, 1H), 4.28–4.06 (m, 2H), 3.79 (s, 3H), 3.52 (d, J = 20.0 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 154.7 (d, J = 3.2 Hz), 143.4 (d, J = 8.6 Hz), 137.1 (d, J = 2.5 Hz), 132.5 (d, J = 2.0 Hz, 2C), 130.6, 128.5 (2C), 124.9 (d, J = 4.8 Hz), 121.2 (d, J = 3.2 Hz), 119.7 (d, J = 4.4 Hz), 101.5 (d, J = 36.7 Hz), 80.9 (d, J = 204.0 Hz), 62.5 (d, J = 7.4 Hz), 55.6, 40.7 (d, J = 114.4 Hz), 16.27 (d, J = 6.6 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.42; R_f = 0.64 (92:8 CHCl₃/MeOH); EI MS 315 (21%, M⁺), 271 (64%), 252 (31%), 224 (100%), 208 (58%), 186 (38%), 180 (68%), 165 (67%), 153 (22%), 123 (75%), 102 (48%), 80 (28%), 52 (25%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₃P]⁺ 316.1097, found 316.1096 (100%).

Methyl 6-((Ethoxy­(phenylethynyl)­phosphoryl)­methyl)­nicotinate (3g _meta )

GP2_C was followed with methyl 6-(bromomethyl)­nicotinate (500 mg, 2.17 mmol) and phosphonite 6a (500 mg, 2.17 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc, gradient from 100:0 to 50:50), yielding 284 mg of phosphinate 3g _meta (0.827 mmol, 38%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 9.21–9.11 (m, 1H), 8.26 (ddd, J = 8.1, 2.3, 0.7 Hz, 1H), 7.53 (ddd, J = 8.1, 2.5, 0.9 Hz, 1H), 7.51–7.41 (m, 3H), 7.39–7.31 (m, 2H), 4.35–4.16 (m, 2H), 3.95 (s, 3H), 3.69 (d, J = 21.0 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.6 (d, J = 1.6 Hz), 156.3 (d, J = 8.4 Hz), 150.7 (d, J = 2.9 Hz), 137.5 (d, J = 2.9 Hz), 132.5 (d, J = 2.0 Hz), 130.8, 128.6, 124.5 (d, J = 3.4 Hz), 124.3 (d, J = 4.7 Hz), 119.3 (d, J = 4.5 Hz), 101.9 (d, J = 37.8 Hz), 80.4 (d, J = 207.9 Hz), 62.7 (d, J = 7.2 Hz), 52.4, 42.1 (d, J = 112.6 Hz), 16.2 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.38; R_f = 0.65 (92:8 CHCl₃/MeOH); EI MS 343 (15%, M⁺), 342 (25%), 299 (67%), 280 (28%), 252 (100%), 214 (43%), 191 (52%), 181 (30%), 165 (81%), 151 (68%), 120 (28%), 102 (43%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₁₉NO₄P]⁺ 344.1046, found 344.1047 (100%).

Ethyl ((4-Fluoropyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3d _para )

GP2_C was followed with 2-(bromomethyl)-4-fluoropyridine (306 mg, 1.61 mmol) and phosphonite 6a (358 mg, 1.61 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 220 mg of phosphinate 3d _para (0.725 mmol, 45%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.52 (dd, J = 8.7, 5.7 Hz, 1H), 7.50–7.39 (m, 3H), 7.38–7.31 (m, 2H), 7.19 (dt, J = 9.5, 2.5 Hz, 1H), 6.94 (ddt, J = 8.2, 5.7, 2.3 Hz, 1H), 4.34–4.15 (m, 2H), 3.61 (d, J = 20.6 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 168.8 (dd, J = 262.5, 3.4 Hz), 155.1 (t, J = 7.7 Hz), 151.9 (dd, J = 7.2, 2.7 Hz), 132.6 (d, J = 2.1 Hz, 2C), 130.9, 128.7 (2C), 119.6 (d, J = 4.6 Hz), 112.7 (dd, J = 17.5, 4.7 Hz), 110.4 (dd, J = 16.3, 3.2 Hz), 101.9 (d, J = 37.5 Hz), 80.6 (d, J = 207.3 Hz), 62.8 (d, J = 7.3 Hz), 41.9 (dd, J = 113.5, 3.2 Hz), 16.3 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.69 (d, J = 3.2 Hz); ¹⁹F­{¹H} NMR (376 MHz, CDCl₃) δ −102.27; R_f = 0.70 (92:8 CHCl₃/MeOH); EI MS 303 (9%, M⁺), 302 (19%), 259 (36%), 240 (23%), 211 (100%), 174 (34%), 165 (83%), 141 (24%), 120 (36%), 111 (89%), 102 (59%), 83 (53%); HRMS (APCI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆FNO₂P]⁺ 304.0897, found 304.0900 (100%).

Ethyl ((4-Methylpyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3e _para )

GP2_C was followed with 2-(bromomethyl)-4-methylpyridine (452 mg, 2.43 mmol) and phosphonite 6a (540 mg, 2.43 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 196 mg of phosphinate 3e _para (0.656 mmol, 27%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.41 (d, J = 5.1 Hz, 1H), 7.50–7.45 (m, 2H), 7.45–7.40 (m, 1H), 7.38–7.32 (m, 2H), 7.28–7.26 (m, 1H), 7.01 (dd, J = 4.9, 2.3 Hz, 1H), 4.33–4.17 (m, 2H), 3.57 (d, J = 20.5 Hz, 2H), 2.33 (d, J = 0.8 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.5 (d, J = 8.3 Hz), 149.3 (d, J = 2.6 Hz), 147.7 (d, J = 3.0 Hz), 132.6 (d, J = 2.0 Hz, 2C), 130.6, 128.5 (2C), 125.7 (d, J = 4.8 Hz), 123.2 (d, J = 3.4 Hz), 119.7 (d, J = 4.3 Hz), 101.5 (d, J = 37.0 Hz), 80.9 (d, J = 205.0 Hz), 62.6 (d, J = 7.4 Hz), 41.7 (d, J = 113.3 Hz), 21.0, 16.3 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.18; R_f = 0.55 (92:8 CHCl₃/MeOH); EI MS 299 (6%, M⁺), 298 (11%), 255 (29%), 236 (23%), 206 (100%), 165 (23%), 107 (51%), 77 (20%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₂P]⁺ 300.1148, found 300.1152 (100%).

Ethyl ((4-Methoxypyridin-2-yl)­methyl)­(phenylethynyl)­phosphinate (3f _para )

GP2_C was followed with 2-(bromomethyl)-4-methoxypyridine (1.40 g, 6.93 mmol) and phosphonite 6a (1.54 g, 6.93 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 250 mg of phosphinate 3f _para (0.793 mmol, 11%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, J = 5.8 Hz, 1H), 7.53–7.48 (m, 2H), 7.47–7.43 (m, 1H), 7.40–7.34 (m, 2H), 7.00 (t, J = 2.6 Hz, 1H), 6.75 (dt, J = 5.9, 2.3 Hz, 1H), 4.37–4.18 (m, 2H), 3.85 (s, 3H), 3.59 (d, J = 20.4 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 166.1 (d, J = 2.8 Hz), 153.3 (d, J = 8.0 Hz), 150.7 (d, J = 2.5 Hz), 132.6 (d, J = 2.1 Hz, 2C), 130.7, 128.6 (2C), 119.7 (d, J = 4.4 Hz), 110.5 (d, J = 4.8 Hz), 108.9 (d, J = 3.0 Hz), 101.6 (d, J = 37.3 Hz), 80.8 (d, J = 205.5 Hz), 62.6 (d, J = 7.3 Hz), 55.2, 41.9 (d, J = 113.3 Hz), 16.3 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.96; R_f = 0.50 (92:8 CHCl₃/MeOH); EI MS 315 (11%, M⁺), 314 (17%), 271 (29%), 252 (44%), 224 (100%), 208 (66%), 180 (81%), 165 (31%), 123 (67%), 10 (36%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₃P]⁺ 316.1097, found 316.1100 (100%).

Methyl 6-((Ethoxy­(phenylethynyl)­phosphoryl)­methyl)­isonicotinate (3g _para )

GP2_C was followed with methyl 6-(bromomethyl)­isonicotinate (413 mg, 1.795 mmol) and phosphonite 6a (399 mg, 1.795 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc, gradient from 100:0 to 50:50), yielding 294 mg of phosphinate 3g _para (0.856 mmol, 48%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.73 (d, J = 5.1 Hz, 1H), 8.05–7.94 (m, 1H), 7.75 (ddd, J = 5.1, 2.3, 1.6 Hz, 1H), 7.52–7.46 (m, 2H), 7.43 (d, J = 7.6 Hz, 1H), 7.39–7.31 (m, 2H), 4.34–4.17 (m, 2H), 3.92 (s, 3H), 3.69 (d, J = 20.8 Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 165.5, 153.2 (d, J = 8.5 Hz), 150.5 (d, J = 2.9 Hz), 138.0 (d, J = 3.2 Hz), 132.7 (d, J = 2.0 Hz), 130.8, 128.6, 124.0 (d, J = 4.9 Hz), 121.4 (d, J = 3.5 Hz), 119.6 (d, J = 4.5 Hz), 102.1 (d, J = 37.5 Hz), 80.6 (d, J = 207.1 Hz), 62.8 (d, J = 7.4 Hz), 52.8, 41.9 (d, J = 113.1 Hz), 16.3 (d, J = 6.7 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.06; R_f = 0.70 (92:8 CHCl₃/MeOH); EI MS 343 (13%, M⁺), 342 (20%), 299 (86%), 252 (100%), 214 (36%), 192 (48%), 181 (28%), 165 (86%), 151 (77%), 102 (54%), 64 (21%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₁₉NO₄P]⁺ 344.1046, found 344.1049 (100%).

Ethyl (Phenylethynyl)­(quinolin-2-ylmethyl)­phosphinate (3h)

GP2_C was followed with 2-(bromomethyl)­quinoline (750 mg, 3.38 mmol) and phosphonite 6a (750 mg, 3.38 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 330 mg of phosphinate 3h (0.984 mmol, 29%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.14 (d, J = 8.5 Hz, 1H), 8.05 (dt, J = 8.4, 1.0 Hz, 1H), 7.82 (dd, J = 7.9, 1.2 Hz, 1H), 7.70 (ddd, J = 8.4, 6.9, 1.5 Hz, 1H), 7.58 (dd, J = 8.5, 1.6 Hz, 1H), 7.53 (ddt, J = 8.0, 6.9, 1.1 Hz, 2H), 7.42–7.37 (m, 3H), 7.35–7.26 (m, 3H), 4.34–4.16 (m, 2H), 3.82 (d, J = 20.7 Hz, 2H), 1.36 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 152.4 (d, J = 8.1 Hz), 148.2 (d, J = 2.6 Hz), 136.6 (d, J = 2.4 Hz), 132.6 (d, J = 2.1 Hz), 130.7 (2C), 129.7, 129.1 (d, J = 1.2 Hz), 128.5 (2C), 127.7 (d, J = 1.7 Hz), 127.1 (d, J = 2.3 Hz), 126.5 (d, J = 1.7 Hz), 122.6 (d, J = 3.3 Hz), 119.6 (d, J = 4.5 Hz), 101.9 (d, J = 37.4 Hz), 80.9 (d, J = 206.6 Hz), 62.7 (d, J = 7.4 Hz), 42.9 (d, J = 112.1 Hz), 16.3 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.58; R_f = 0.71 (92:8 CHCl₃/MeOH); EI MS 335 (<2%, M⁺), 243 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₀H₁₉NO₂P]⁺ 336.1148, found 336.1147 (100%).

Ethyl (Phenylethynyl)­(quinoxalin-2-ylmethyl)­phosphinate (3i)

GP2_C was followed with 2-(bromomethyl)­quinoxaline (240 mg, 1.07 mmol) and phosphonite 6a (750 mg, 3.38 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 185 mg of phosphinate 3i (0.550 mmol, 51%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.96 (d, J = 1.4 Hz, 1H), 8.17–8.08 (m, 1H), 8.10–8.03 (m, 1H), 7.82–7.70 (m, 2H), 7.47–7.39 (m, 3H), 7.33 (dd, J = 8.1, 7.0 Hz, 2H), 4.45–4.17 (m, 2H), 3.85 (d, J = 21.0 Hz, 2H), 1.37 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 147.9 (d, J = 8.7 Hz), 146.2 (d, J = 3.3 Hz), 142.5 (d, J = 2.9 Hz), 141.5 (d, J = 2.6 Hz), 132.7 (d, J = 2.1 Hz, 2C), 131.0, 130.4 (d, J = 1.4 Hz), 129.9 (d, J = 1.7 Hz), 129.4 (d, J = 1.8 Hz), 129.2 (d, J = 1.4 Hz), 128.7 (2C), 119.3 (d, J = 4.5 Hz), 102.7 (d, J = 38.1 Hz), 80.4 (d, J = 209.7 Hz), 63.0 (d, J = 7.3 Hz), 40.4 (d, J = 112.6 Hz), 16.3 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 14.81; R_f = 0.65 (93:7 CHCl₃/MeOH); EI MS 336 (<3%, M⁺), 307 (7%), 244 (100%), 102 (9%); HRMS (ESI) m/z [M + H]⁺ calcd for [C₁₉H₁₈N₂O₂P]⁺ 337.1100, found 337.1102 (100%).

Ethyl (Isoquinolin-1-ylmethyl)­(phenylethynyl)­phosphinate (3j)

GP2_C was followed with 1-(bromomethyl)­isoquinoline (250 mg, 1.13 mmol) and phosphonite 6a (250 mg, 1.13 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 192 mg of phosphinate 3j (0.573 mmol, 51%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 8.50 (dd, J = 5.6, 0.9 Hz, 1H), 8.32 (dd, J = 8.6, 1.3 Hz, 1H), 7.85–7.79 (m, 1H), 7.67 (ddd, J = 8.2, 6.9, 1.3 Hz, 1H), 7.64–7.56 (m, 2H), 7.42–7.37 (m, 1H), 7.34–7.28 (m, 4H), 4.30–4.11 (m, 4H), 1.31 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 152.4 (d, J = 9.6 Hz), 142.2 (d, J = 3.9 Hz), 136.6 (d, J = 2.6 Hz), 132.6 (d, J = 2.1 Hz, 2C), 130.7, 130.3, 128.5 (2C), 128.0 (d, J = 4.0 Hz), 127.5, 127.3, 126.5 (d, J = 1.8 Hz), 120.5 (d, J = 3.9 Hz), 119.7 (d, J = 4.5 Hz), 101.9 (d, J = 37.4 Hz), 81.1 (d, J = 206.9 Hz), 62.8 (d, J = 7.4 Hz), 39.8 (d, J = 113.1 Hz), 16.3 (d, J = 6.8 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.24; R_f = 0.33 (95:5 CHCl₃/MeOH); EI MS 335 (16%, M⁺), 291 (23%), 272 (31%), 243 (100%), 206 (36%), 165 (25%), 143 (70%), 115 (60%), 102 (29%); HRMS (ESI) m/z [M + H]⁺ calcd for [C₂₀H₁₉NO₂P]⁺ 336.1148, found 336.1146 (100%).

Ethyl (Dibenzo­[f,h]­quinoxalin-2-ylmethyl)­(phenylethynyl)­phosphinate (3k)

GP2_C was followed with 2-(bromomethyl)­dibenzo­[f,h]­quinoxaline (170 mg, 0.526 mmol) and phosphonite 6a (117 mg, 0.526 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 150 mg of phosphinate 3k (0.344 mmol, 65%) as a brown oil: ¹H NMR (400 MHz, CDCl₃) δ 9.24 (dd, J = 8.1, 1.4 Hz, 1H), 9.21 (dd, J = 7.9, 1.7 Hz, 1H), 8.96 (d, J = 2.0 Hz, 1H), 8.68–8.55 (m, 2H), 7.84–7.69 (m, 3H), 7.60 (ddd, J = 8.2, 7.0, 1.1 Hz, 1H), 7.45–7.33 (m, 3H), 7.30–7.18 (m, 2H), 4.51–4.15 (m, 2H), 3.92 (d, J = 20.9 Hz, 2H), 1.38 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 146.7 (d, J = 9.0 Hz), 144.5 (d, J = 4.8 Hz), 140.8 (d, J = 2.8 Hz), 139.8 (d, J = 3.3 Hz), 132.8 (d, J = 2.1 Hz, 2C), 131.7, 131.4, 130.8, 129.9 (d, J = 1.6 Hz), 129.8, 129.7, 129.6, 128.6 (2C), 127.9, 127.6, 125.8, 125.5, 122.9, 122.8, 119.5 (d, J = 4.4 Hz), 102.6 (d, J = 37.9 Hz), 80.6 (d, J = 209.2 Hz), 62.9 (d, J = 7.3 Hz), 39.9 (d, J = 113.7 Hz), 16.4 (d, J = 6.9 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.93; R_f = 0.53 (50:50 CHCl₃/EtOAc); EI MS 436 (48%, M⁺), 435 (92%), 407 (100%), 389 (18%), 343 (21%), 244 (26%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₇H₂₂N₂O₂P]⁺ 437.1413, found 437.1411 (100%).

Diethyl (Pyrazine-2,3-diylbis­(methylene))­bis­((phenylethynyl)­phosphinate) (3l)

GP2_C was followed with 2,3-bis­(bromomethyl)­pyrazine (120 mg, 0.451 mmol) and phosphonite 6a (201 mg, 0.902 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 95 mg of phosphinate 3l (0.193 mmol, 43%) as a brown oil, obtained as a 1:1 mixture of two diastereomers: ¹H NMR (400 MHz, CDCl₃) δ 8.45 (s, 2H), 7.53–7.41 (m, 6H), 7.40–7.30 (m, 4H), 4.35–4.16 (m, 4H), 4.16–3.88 (m, 4H), 1.37 (td, J = 7.1, 4.7 Hz, 6H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 148.4 (2C), 142.8 (2C), 132.7 (4C), 130.9 (d, J = 1.8 Hz, 2C), 128.7 (4C), 119.5 (2C), 102.2 (d, J = 44.5 Hz, 2C), 80.7 (d, J = 207.3 Hz, 2C), 62.9 (2C), 39.0 (d, J = 112.8 Hz, 2C), 16.4 (2C) (signals of some carbons were split due to the presence of two diastereomers); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.65, 15.50; R_f = 0.68 (93:7 CHCl₃/MeOH); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₆H₂₇N₂O₄P₂]⁺ 493.1441, found 493.1436 (100%).

Diethyl (Quinoxaline-2,3-diylbis­(methylene))­bis­((phenylethynyl)­phosphinate) (3m)

GP2_C was followed with 2,3-bis­(bromomethyl)­quinoxaline (250 mg, 0.791 mmol) and phosphonite 6a (352 mg, 1.58 mmol). The resulting product was purified by column chromatography (CHCl₃/EtOAc/MeOH, gradient from 50:50:0 to 48:48:4), yielding 290 mg of phosphinate 3m (0.535 mmol, 68%) as a brown oil, identified as a 1:1 mixture of two diastereomers. Upon standing, the mixture solidified. The resulting solid was treated with diethyl ether and filtered. ³¹P NMR analysis indicated that this procedure afforded one diastereomer in approximately 90% purity: ¹H NMR (400 MHz, CDCl₃) δ 8.03 (dd, J = 6.3, 3.5 Hz, 2H), 7.74–7.68 (m, 2H), 7.48–7.38 (m, 6H), 7.33 (ddt, J = 8.7, 6.9, 1.0 Hz, 4H), 4.36–4.06 (m, 8H), 1.36 (t, J = 7.0 Hz, 6H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 149.2–147.1 (m, 2C), 141.4 (2C), 132.7 (4C), 130.9 (2C), 130.0 (2C), 128.9 (2C), 128.6 (4C), 120.2–118.2 (m, 2C), 102.4 (d, J = 38.5 Hz, 2C), 80.7 (d, J = 208.7 Hz, 2C), 64.5–61.7 (m, 2C), 40.0 (d, J = 111.2 Hz, 2C), 17.9–14.6 (m, 2C); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.93, 15.66; R_f = 0.53 (93:7 CHCl₃/MeOH); HRMS (APCI/QTOF) m/z [M + H]⁺ calcd for [C₃₀H₂₉N₂O₄P₂]⁺ 543.1597, found 543.1603 (100%).

8-Ethoxy-6-phenylpyrazino­[1,2-a]­[1,4]­azaphosphinine 8-Oxide (4a)

GP3_A was followed with 3a (50.0 mg, 0.175 mmol), CF₃COOAg (1.93 mg, 8.73 μmol), and 3.5 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 45.0 mg of 1,4-azaphosphinine 4a (0.157 mmol, 90%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 8.20 (s, 1H), 7.69–7.47 (m, 3H), 7.42–7.30 (m, 2H), 6.81 (d, J = 5.4 Hz, 1H), 6.77 (d, J = 4.5 Hz, 0H), 5.95–5.79 (m, 1H), 5.61 (ddd, J = 4.2, 1.7, 0.8 Hz, 1H), 4.16–3.98 (m, 3H), 1.35 (td, J = 7.1, 0.7 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 154.5 (d, J = 16.7 Hz), 150.1 (d, J = 1.6 Hz), 141.5 (d, J = 3.4 Hz), 134.8 (d, J = 11.9 Hz), 130.3, 129.5 (2C), 128.7 (2C), 123.0, 121.0, 106.6 (d, J = 126.8 Hz), 92.6 (d, J = 141.0 Hz), 62.1 (d, J = 6.0 Hz), 17.0 (d, J = 6.1 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.15; R_f = 0.49 (93:7 CHCl₃/MeOH); EI MS 286 (5%, M⁺), 194 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₅H₁₆N₂O₂P]⁺ 287.0944, found 287.0945 (100%).

8-Ethoxy-1-methyl-6-phenylpyrazino­[1,2-a]­[1,4]­azaphosphinine 8-Oxide (4b)

GP3_A was followed with 3b (85.0 mg, 0.0283 mmol), CF₃COOAg (3.13 mg, 14.0 μmol), and 5.6 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 73.0 mg of 1,4-azaphosphinine 4b (0.243 mmol, 86%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.49 (dt, J = 5.4, 2.9 Hz, 3H), 7.40–7.32 (m, 2H), 6.81–6.73 (m, 2H), 5.84 (dd, J = 4.0, 1.0 Hz, 1H), 5.75–5.67 (m, 1H), 4.08 (dq, J = 9.2, 7.1 Hz, 2H), 2.52 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) ¹³C NMR δ 158.9 (d, J = 13.6 Hz), 150.9 (d, J = 1.9 Hz), 141.4 (d, J = 3.0 Hz), 135.8 (d, J = 12.2 Hz), 130.2, 129.5 (2C), 128.8 (2C), 121.6, 120.5, 106.5 (d, J = 126.1 Hz), 89.9 (d, J = 139.7 Hz), 62.1 (d, J = 6.1 Hz), 23.7, 17.1 (d, J = 6.0 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.65; R_f = 0.59 (93:7 CHCl₃/MeOH); EI MS 300 (3%, M⁺), 208 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₈N₂O₂P]⁺ 301.1100, found 301.1105 (100%).

8-Ethoxy-6-phenylpyrimido­[1,2-a]­[1,4]­azaphosphinine 8-Oxide (4c)

GP3_A was followed with 3c (200 mg, 0.699 mmol), CF₃COOAg (3.09 mg, 14.0 μmol), and 4.6 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 189 mg of 1,4-azaphosphinine 4c (0.660 mmol, 95%) as an orange solid: ¹H NMR (400 MHz, CDCl₃) δ 8.08–7.98 (m, 1H), 7.49 (dd, J = 4.9, 1.9 Hz, 3H), 7.39–7.33 (m, 2H), 7.31 (ddd, J = 7.5, 2.0, 0.8 Hz, 1H), 5.87 (dd, J = 7.5, 3.4 Hz, 1H), 5.83 (dd, J = 3.9, 1.0 Hz, 1H), 5.65 (d, J = 3.9 Hz, 1H), 4.05 (dq, J = 9.2, 7.0 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 155.4 (d, J = 4.4 Hz), 152.0 (d, J = 12.1 Hz), 149.2 (d, J = 3.0 Hz), 138.9, 135.2 (d, J = 13.1 Hz), 130.3, 129.6 (2C), 128.7 (2C), 107.4 (d, J = 124.1 Hz), 103.7, 89.3 (d, J = 143.9 Hz), 61.9 (d, J = 6.2 Hz), 16.9 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 19.39; R_f = 0.36 (92:8 CHCl₃/MeOH); EI MS 286 (<2%, M⁺), 194 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₅H₁₆N₂O₂P]⁺ 287.0944, found 287.0947 (100%); mp 132.6–140.2 °C (EtOAc).

2-Ethoxy-7-fluoro-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (4d _meta )

GP3_A was followed with 3d _meta (230 mg, 0.758 mmol), CF₃COOAg (8.4 mg, 38 μmol), and 5 mL of DCM. The reaction mixture was stirred at rt for 3 days. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 210 mg of 1,4-azaphosphinine 4d _meta (0.692 mmol, 91%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) 7.57–7.43 (m, 3H), 7.42–7.29 (m, 2H), 7.03–6.93 (m, 1H), 6.76 (dd, J = 10.1, 6.1 Hz, 1H), 6.68–6.55 (m, 1H), 5.76 (dd, J = 4.2, 1.7 Hz, 1H), 5.32 (dd, J = 4.4, 2.3 Hz, 1H), 4.01 (dq, J = 9.2, 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 150.8, 148.6 (d, J = 236.0 Hz), 146.7 (d, J = 4.3 Hz), 136.3 (d, J = 12.2 Hz), 130.0, 129.6 (2C), 128.6 (dd, J = 16.3, 7.3 Hz, 2C), 121.4 (d, J = 27.6 Hz), 121.4 (d, J = 27.5 Hz), 116.4 (d, J = 42.7 Hz), 105.5 (d, J = 125.4 Hz), 88.8 (d, J = 145.0 Hz), 61.9 (d, J = 6.1 Hz), 17.0 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.30; ¹⁹F NMR (376 MHz, CDCl₃) δ −144.87; R_f = 0.54 (92:8 CHCl₃/MeOH); EI MS 303 (3%, M⁺), 211 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆FNO₂P]⁺ 304.0897, found 304.0896 (100%).

2-Ethoxy-7-methyl-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (4e _meta )

GP3_A was followed with 3e _meta (130 mg, 0.434 mmol), CF₃COOAg (4.8 mg, 22 μmol), and 2.9 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 118 mg of 1,4-azaphosphinine 4e _meta (0.394 mmol, 91%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.41 (m, 3H), 7.41–7.29 (m, 2H), 6.79 (s, 1H), 6.71 (d, J = 9.3 Hz, 1H), 6.49 (dt, J = 9.3, 2.0 Hz, 1H), 5.68 (dd, J = 4.2, 1.7 Hz, 1H), 5.19 (dd, J = 4.3, 1.9 Hz, 1H), 4.03–3.87 (m, 2H), 1.82 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.0 (d, J = 2.0 Hz), 147.9 (d, J = 4.1 Hz), 137.0 (d, J = 12.2 Hz), 130.4 (d, J = 3.0 Hz), 129.6, 129.3 (2C), 128.6 (2C), 127.5, 126.5 (d, J = 16.2 Hz), 116.3, 105.1 (d, J = 124.5 Hz), 86.1 (d, J = 146.0 Hz), 61.6 (d, J = 6.1 Hz), 17.8, 16.9 (d, J = 6.5 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.46; R_f = 0.50 (92:8 CHCl₃/MeOH); EI MS 299 (3%, M⁺), 207 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₂P]⁺ 300.1148, found 300.1149 (100%).

2-Ethoxy-7-methoxy-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (4f _meta )

GP3_A was followed with 3f _meta (80.0 mg, 0.254 mmol), CF₃COOAg (2.8 mg, 13 μmol), and 1.7 mL of DCM. The reaction mixture was stirred at rt for 5 days. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 71.0 mg of 1,4-azaphosphinine 4f _meta (0.225 mmol, 89%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.44 (m, 3H), 7.43–7.31 (m, 2H), 6.72 (d, J = 9.9 Hz, 1H), 6.53 (dtd, J = 9.8, 2.3, 0.6 Hz, 1H), 6.50–6.43 (m, 1H), 5.69 (dd, J = 4.2, 1.7 Hz, 1H), 5.23 (dd, J = 4.5, 1.9 Hz, 1H), 3.98 (dq, J = 9.2, 7.0 Hz, 2H), 3.31 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.0 (d, J = 2.1 Hz), 146.5 (d, J = 4.1 Hz), 143.9, 136.9 (d, J = 12.3 Hz), 129.7, 129.2 (2C), 128.5 (2C), 127.8 (d, J = 16.2 Hz), 124.3 (d, J = 2.9 Hz), 111.1, 104.2 (d, J = 125.3 Hz), 87.0 (d, J = 145.3 Hz), 61.6 (d, J = 6.2 Hz), 55.3, 16.9 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.65; R_f = 0.58 (92:8 CHCl₃/MeOH); EI MS 315 (7%, M⁺), 223 (100%), 208 (22%), 180 (18%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₃P]⁺ 316.1097, found 316.1095 (100%).

Methyl 2-Ethoxy-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine-7-carboxylate 2-Oxide (4g _meta )

GP3_A was followed with 3g _meta (210 mg, 0.612 mmol), CF₃COOAg (6.7 mg, 31 μmol), and 4 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 198 mg of 1,4-azaphosphinine 4g _meta (0.577 mmol, 94%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.98–7.90 (m, 1H), 7.55–7.48 (m, 3H), 7.40–7.33 (m, 2H), 7.10–7.03 (m, 1H), 6.72 (d, J = 9.6 Hz, 1H), 5.88 (dd, J = 4.1, 1.7 Hz, 1H), 5.36 (dd, J = 4.4, 2.0 Hz, 1H), 4.05 (dq, J = 9.1, 7.0 Hz, 2H), 3.71 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.6, 151.4 (d, J = 1.7 Hz), 148.0 (d, J = 3.4 Hz), 137.2, 135.9 (d, J = 12.0 Hz), 130.3, 129.6 (2C), 128.7 (2C), 126.2 (d, J = 16.1 Hz), 125.3 (d, J = 2.8 Hz), 111.5, 108.0 (d, J = 124.2 Hz), 90.1 (d, J = 144.5 Hz), 61.9 (d, J = 6.2 Hz), 52.3, 17.0 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 15.23; R_f = 0.56 (92:8 CHCl₃/MeOH); EI MS 343 (2%, M⁺), 251 (100%), 191 (21%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₁₉NO₄P]⁺ 344.1046, found 344.1044 (100%); mp 167.6–169.3 °C (EtOAc).

2-Ethoxy-8-fluoro-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (4d _para )

GP3_A was followed with 3d _para (100 mg, 0.33 mmol), CF₃COOAg (3.6 mg, 16 μmol), and 6.5 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 88.0 mg of 1,4-azaphosphinine 4d _para (0.290 mmol, 88%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.55–7.44 (m, 3H), 7.43–7.31 (m, 2H), 7.09 (dd, J = 8.3, 5.8 Hz, 1H), 6.35 (dd, J = 9.8, 2.9 Hz, 1H), 5.85–5.68 (m, 2H), 5.23–5.10 (m, 1H), 4.02 (dq, J = 9.1, 7.0 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 160.0 (d, J = 266.0 Hz), 150.8, 149.6 (dd, J = 11.5, 4.3 Hz), 136.6 (d, J = 12.1 Hz), 134.9 (d, J = 10.8 Hz), 130.1, 129.6 (2C), 128.6 (2C), 107.0 (dd, J = 21.7, 16.9 Hz), 106.7 (d, J = 124.1 Hz), 101.5 (d, J = 30.5 Hz), 86.9 (dd, J = 147.5, 6.7 Hz), 61.9 (d, J = 6.0 Hz), 17.0 (d, J = 6.2 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.01; ¹⁹F NMR (376 MHz, CDCl₃) δ −110.91; R_f = 0.63 (92:8 CHCl₃/MeOH); EI MS 303 (<3%, M⁺), 211 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₆H₁₆FNO₂P]⁺ 304.0897, found 304.0894 (100%).

2-Ethoxy-8-methyl-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (4e _para )

GP3_A was followed with 3e _para (100 mg, 0.334 mmol), CF₃COOAg (3.7 mg, 3.2 μmol), and 2.2 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 95.0 mg of 1,4-azaphosphinine 4e _para (0.317 mmol, 95%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.52–7.43 (m, 3H), 7.34 (d, J = 5.7 Hz, 2H), 6.95 (d, J = 7.7 Hz, 1H), 6.55–6.47 (m, 1H), 5.71 (dd, J = 4.2, 1.6 Hz, 1H), 5.67 (dd, J = 7.7, 2.1 Hz, 1H), 5.10 (dd, J = 4.5, 1.9 Hz, 1H), 4.05–3.90 (m, 2H), 2.05 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 151.1 (d, J = 2.0 Hz), 149.2 (d, J = 4.3 Hz), 137.5 (d, J = 3.2 Hz), 136.7 (d, J = 12.2 Hz), 130.5, 129.7, 129.3 (2C), 128.6 (2C), 123.8 (d, J = 16.2 Hz), 110.5, 105.3 (d, J = 123.9 Hz), 84.4 (d, J = 147.1 Hz), 61.6 (d, J = 6.1 Hz), 20.5, 16.9 (d, J = 6.5 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.27; R_f = 0.52 (92:8 CHCl₃/MeOH); EI MS 299 (3%, M⁺), 207 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₂P]⁺ 300.1148, found 300.1148 (100%).

2-Ethoxy-8-methoxy-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine 2-Oxide (4f _para )

GP3_A was followed with 3f _para (70 mg, 0.22 mmol), CF₃COOAg (2.5 mg, 11 μmol), and 1.5 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 63 mg of 1,4-azaphosphinine 4f _para (0.20 mmol, 90%) as a yellow oil: ¹H NMR (400 MHz, CDCl₃) δ 7.51–7.40 (m, 3H), 7.39–7.29 (m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 5.93 (dd, J = 2.9, 1.3 Hz, 1H), 5.67 (dd, J = 4.1, 1.6 Hz, 1H), 5.63 (dd, J = 8.1, 2.8 Hz, 1H), 5.03 (dd, J = 4.2, 2.4 Hz, 1H), 3.96 (dqd, J = 9.2, 7.0, 0.9 Hz, 2H), 3.75 (s, 3H), 1.31 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 157.4 (d, J = 4.7 Hz), 150.8 (d, J = 4.8 Hz), 136.9 (d, J = 12.2 Hz), 132.8, 129.7, 129.4 (2C), 128.7 (2C), 105.6 (d, J = 123.5 Hz), 104.3, 99.8 (d, J = 17.2 Hz), 83.2 (d, J = 149.2 Hz), 61.6 (d, J = 6.1 Hz), 55.5, 17.0 (d, J = 6.4 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.00; R_f = 0.50 (92:8 CHCl₃/MeOH); EI MS 315 (2%, M⁺), 223 (100%), 208 (33%), 180 (20%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₇H₁₉NO₃P]⁺ 316.1097, found 316.1102 (100%).

Methyl 2-Ethoxy-4-phenylpyrido­[1,2-a]­[1,4]­azaphosphinine-8-carboxylate 2-Oxide (4g _para )

GP3_A was followed with 3g _para (190 mg, 0.553 mmol), CF₃COOAg (6.1 mg, 28 μmol), and 3.7 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 172 mg of 1,4-azaphosphinine 4g _para (0.501 mmol, 91%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.54–7.44 (m, 4H), 7.40–7.30 (m, 2H), 7.06 (d, J = 7.8 Hz, 1H), 6.26 (dd, J = 7.9, 2.0 Hz, 1H), 5.79 (dd, J = 4.2, 1.5 Hz, 1H), 5.50 (dd, J = 4.3, 1.9 Hz, 1H), 4.04 (dq, J = 9.2, 7.0 Hz, 2H), 3.88 (s, 3H), 1.34 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 164.3 (d, J = 1.7 Hz), 151.2 (d, J = 2.1 Hz), 147.1 (d, J = 4.0 Hz), 136.2 (d, J = 12.2 Hz), 131.5, 130.8 (d, J = 16.6 Hz), 129.9, 129.4 (2C), 128.48, 128.46 (2C), 105.9 (d, J = 125.5 Hz), 105.2, 91.9 (d, J = 142.7 Hz), 61.8 (d, J = 6.1 Hz), 52.7, 16.8 (d, J = 6.3 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.13; R_f = 0.65 (92:8 CHCl₃/MeOH); EI MS 343 (<2%, M⁺), 251 (100%), 192 (18%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₈H₁₉NO₄P]⁺ 344.1046, found 344.1048 (100%).

3-Ethoxy-1-phenyl-[1,4]­azaphosphinino­[1,2-a]­quinoline 3-Oxide (4h)

GP3_A was followed with 3h (50.0 mg, 0.149 mmol), CF₃COOAg (1.65 mg, 7.46 μmol), and 2.9 mL of DCM. The reaction mixture was stirred at room temperature for 13 days to achieve full conversion of the starting material, as monitored by NMR. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 29 mg of 1,4-azaphosphinine 4h (0.086 mmol, 58%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 7.29 (dd, J = 7.7, 1.6 Hz, 1H), 7.26–7.15 (m, 5H), 7.05–6.96 (m, 2H), 6.86 (ddd, J = 8.8, 7.3, 1.6 Hz, 1H), 6.77 (d, J = 9.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 5.86 (dd, J = 3.1, 2.2 Hz, 1H), 5.40 (t, J = 2.9 Hz, 1H), 4.04 (dqd, J = 8.4, 7.0, 1.3 Hz, 2H), 1.32 (t, J = 7.0 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 153.3, 149.9 (d, J = 2.6 Hz), 138.5 (d, J = 12.3 Hz), 137.5, 129.2, 128.9, 128.8 (d, J = 2.6 Hz, 2C), 127.7 (2C), 127.6, 127.3, 126.4 (d, J = 15.4 Hz), 124.7, 123.8, 123.7, 108.2 (d, J = 127.7 Hz), 94.0 (d, J = 140.7 Hz), 61.1 (d, J = 6.1 Hz), 16.9 (d, J = 6.5 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 18.54; R_f = 0.62 (92:8 CHCl₃/MeOH); EI MS 335 (<1%, M⁺), 243 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₂₀H₁₉NO₂P]⁺ 336.1148, found 336.1147 (100%).

3-Ethoxy-1-phenyl-[1,4]­azaphosphinino­[1,2-a]­quinoxaline 3-Oxide (4i)

GP3_A was followed with 3i (100 mg, 0.149 mmol), CF₃COOAg (3.3 mg, 15 μmol), and 6 mL of DCM. The reaction mixture was stirred at room temperature for 18 days to achieve approximately 50% conversion of the starting material, as monitored by NMR. The resulting product was purified by column chromatography (EtOAc/MeOH, gradient from 100:0 to 94:6), yielding 30 mg of 1,4-azaphosphinine 4i (0.089 mmol, 30%) as a yellow amorphous solid: ¹H NMR (400 MHz, CDCl₃) δ 8.31 (s, 1H), 7.62 (dd, J = 7.9, 1.6 Hz, 1H), 7.37–7.27 (m, 3H), 7.25–7.20 (m, 2H), 7.10 (td, J = 7.6, 1.2 Hz, 1H), 6.89 (ddd, J = 8.8, 7.3, 1.6 Hz, 1H), 6.54 (dd, J = 8.3, 1.2 Hz, 1H), 5.89 (dd, J = 3.3, 1.8 Hz, 1H), 5.81–5.73 (m, 1H), 4.18–4.05 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 154.2 (d, J = 16.0 Hz), 151.7, 142.5 (d, J = 2.3 Hz), 137.1 (d, J = 12.0 Hz), 136.2, 130.1, 129.9, 129.2 (2C), 129.1, 127.9, 127.8 (2C), 124.8, 122.4, 108.7 (d, J = 130.0 Hz), 98.9 (d, J = 136.2 Hz), 61.7 (d, J = 6.0 Hz), 16.9 (d, J = 6.4 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 16.65; R_f = 0.54 (93:7 CHCl₃/MeOH); EI MS 336 (<1%, M⁺), 244 (100%); HRMS (ESI/QTOF) m/z [M + H]⁺ calcd for [C₁₉H₁₈N₂O₂P]⁺ 337.1100, found 337.1106 (100%).

2-Ethoxy-4-phenyl-[1,4]­azaphosphinino­[2,1-a]­isoquinoline 2-Oxide (4j)

GP3_A was followed with 3j (150 mg, 0.447 mmol), CF₃COOAg (2.0 mg, 8.9 μmol), and 3 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 126 mg of 1,4-azaphosphinine 4j (0.376 mmol, 84%) as a white solid. Single crystals suitable for X-ray analysis were obtained by slowly cooling its EtOAc solution: ¹H NMR (400 MHz, CDCl₃) δ 8.01 (d, J = 7.9 Hz, 1H), 7.51–7.42 (m, 5H), 7.41–7.36 (m, 2H), 7.30 (dd, J = 7.4, 1.6 Hz, 1H), 6.85 (d, J = 7.8 Hz, 1H), 6.18 (t, J = 4.1 Hz, 1H), 6.12 (d, J = 7.8 Hz, 1H), 5.73 (d, J = 3.9 Hz, 1H), 4.04 (dq, J = 9.0, 7.0 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 153.0 (d, J = 2.5 Hz), 148.0 (d, J = 3.7 Hz), 137.4 (d, J = 12.7 Hz), 130.7, 130.1 (d, J = 2.2 Hz), 129.8, 129.3 (2C), 128.8 (2C), 128.4, 128.3, 127.3 (d, J = 13.2 Hz), 126.4, 124.8, 107.6, 103.7 (d, J = 126.9 Hz), 88.4 (d, J = 141.9 Hz), 61.7 (d, J = 6.0 Hz), 17.0 (d, J = 6.5 Hz); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.84; R_f = 0.33 (95:5 CHCl₃/MeOH); EI MS 335 (<1%, M⁺), 243 (100%); HRMS (ESI) m/z [M + H]⁺ calcd for [C₂₀H₁₉NO₂P]⁺ 336.1148, found 336.1149 (100%).

2,11-Diethoxy-4,9-diphenylpyrazino­[1,2-a:4,3-a′]­bis­([1,4]­azaphosphinine) 2,11-Dioxide (4l)

GP3_A was followed with 3l (30 mg, 0.061 mmol), CF₃COOAg (1.3 mg, 6.1 μmol), and 1.2 mL of DCM. The resulting product was purified by column chromatography (CHCl₃/MeOH, gradient from 100:0 to 96:4), yielding 28 mg of 1,4-azaphosphinine 4l (0.057 mmol, 93%) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ 7.49–7.39 (m, 6H), 7.38–7.30 (m, 4H), 6.29 (t, J = 3.6 Hz, 2H), 5.74 (s, 2H), 5.65 (d, J = 3.7 Hz, 2H), 4.10 (dq, J = 9.2, 7.0 Hz, 4H), 1.38 (t, J = 7.1 Hz, 6H); ¹³C­{¹H} NMR (101 MHz, CDCl₃) δ 152.2 (d, J = 2.6 Hz, 2C), 142.3 (dd, J = 16.2, 4.7 Hz, 2C), 135.4 (d, J = 12.8 Hz, 2C), 130.3 (2C), 129.2 (4C), 128.8 (4C), 110.1 (2C), 102.0 (d, J = 131.0 Hz, 2C), 97.2 (d, J = 133.5 Hz, 2C), 62.2 (d, J = 6.1 Hz, 2C), 17.0 (d, J = 6.3 Hz, 2C); ³¹P­{¹H} NMR (162 MHz, CDCl₃) δ 17.03; R_f = 0.55 (93:7 CHCl₃/MeOH); HRMS (ESI) m/z [M + H]⁺ calcd for [C₂₆H₂₇N₂O₄P₂]⁺ 493.1441, found 493.1439 (100%); mp 111.0–113.2 °C (EtOAc).

The data underlying this study are available in the published article and its . Additional primary research data have been uploaded to a compliant third-party repository and are publicly available at 10.5281/zenodo.17302225.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.joc.5c02870.

• ¹H, ¹³C, ³¹P, and ¹⁹F NMR spectra, computational data, and UV–vis data (PDF)

• FAIR data, including the primary NMR FID files, for compounds 1a–u, 2a–u, 3a–m, 4a–l, 7r–u, and 8p–u (ZIP)

The authors declare no competing financial interest.