Synthesis of 2-pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters via nucleophilic aromatic substitution

Article abstract of DOI:10.1080/10426507.2016.1248763

In this study, we developed a method for the synthesis of 2-pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters using easily accessible starting materials, H-phosphinate and H-phosphonate esters and pyridine N-oxides. The H-phosphinate and

Full text of DOI:10.1080/10426507.2016.1248763

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2-Pyridylthiophosphinic acids and phosphonates
Synthesis of 2-pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters via
nucleophilic aromatic substitution
Natsuhisa Oka,* Kensuke Ori, and Kaori Ando*
Department of Chemistry and Biomolecular Science, Faculty of Engineering, Gifu University, 1-
1 Yanagido, Gifu 501-1193
oka@gifu-u.ac.jp
Abstract
In this study, we developed a method for the synthesis of 2-pyridylthiophosphinic acids and 2-
pyridylthiophosphonate monoesters using easily accessible starting materials, H-phosphinate and
H-phosphonate esters and pyridine N-oxides. The H-phosphinate and H-phosphonate esters were
sulfurized to give H-thiophosphinate and H-thiophosphonate esters. The pyridine N-oxides were
converted into N-methoxypyridinium sulfonates, which were then used for nucleophilic aromatic
substitution with the H-thiophosphinate/thiophosphonate esters to afford 2-
pyridylthiophosphinate monoesters and 2-pyridylthiophosphonate diesters. Finally, alkaline
hydrolysis and subsequent neutralization afforded various 2-pyridylthiophosphinic acids and 2-
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pyridylthiophosphonate monoesters in good yields. The structure of a 2-pyridylthiophosphonate
monoester was determined using X-ray crystallographic analysis.
Key words:
2-pyridyl, thiophosphinic acid, thiophosphinate, thiophosphonate, nucleophilic aromatic
substitution
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Introduction
2-Pyridylphosphine oxide, 2-pyridylphosphinate, and 2-pyridylphosphonate derivatives have
been used in coordination chemistry as bidentate ligands. Various applications such as selective
extraction of precious metal ions1 and syntheses of luminescent complexes2 and transition metal
catalysts3 have been reported. In particular, 2-pyridylphosphinic acids and 2-pyridylphosphonate
monoesters with free P–OH groups form very stable complexes with various kinds of metal ions4
and have very recently been successfully applied to the development of lanthanide complexes for
cellular optical imaging.2f h Herein, we describe our study on the synthesis of 2-
–
pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters wherein one of the
oxygen atoms on the phosphorus center is replaced by sulfur. Oxygen to sulfur exchange has
long been used in organophosphorus chemistry to alter coordination behavior.5 We expect that 2-
pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters will be novel bidentate
ligands with different coordination behavior from those of the parent 2-pyridylphosphinic acids
and 2-pyridylphosphonate monoesters. Despite such potential usefulness, the syntheses of 2-
pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters have not yet been
reported in the literature, to the best of our knowledge. Under these circumstances, we began our
study on the synthesis of these compounds and have reported the synthesis of some 2-
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pyridylthiophosphinate monoesters via the nucleophilic aromatic substitution (SNAr) reaction of
H-thiophosphinate esters in a previous communication.6 In this study, we report the complete
details and further extension of the study to the synthesis of various 2-pyridylthiophosphinic
acids and 2-pyridylthiophosphonate monoesters.
Results and Discussion
2-Pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters were synthesized
according to Scheme 1. First, H-phosphinate and H-phosphonate esters 1 were converted into H-
thiophosphinate and H-thiophosphonate esters 2 (Step 1). Various 4-substituted pyridine N-
oxides 3 were methylated at the 1-position by methyl sulfonates to afford N-methoxypyridinium
sulfonates 4 (Step 2), which were then used to introduce 2-pyridyl groups with R3 substituents
onto the phosphorus atoms of 2 by a DBU-promoted SNAr reaction,7 giving 2-
pyridylthiophosphinate and phosphonate esters 5 (Step 3). Finally, compounds 5 were
hydrolyzed to afford the 2-pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters
6 (Step 4).
Methyl phenylphosphinate 1a, diphenyl phosphonate 1b, and diisopropyl phosphonate 1c were
used as starting materials. The P=O to P=S conversion of 1a–c using Lawesson’s reagent8 is
summarized in Table 1. We previously reported that 1a was efficiently converted into 2a at room
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temperature (RT) using 0.5 equiv of Lawesson’s reagent, though some unidentified byproducts
with higher polarity than the desired 2a were generated as the reaction time was prolonged.6 As
in that report, the yield of 2a was maximized when the reaction was finished within 1.5 h (entries
1, 2). In contrast, the conversion of 1b did not progress at RT (entry 3). The reaction proceeded
under reflux conditions and the desired product 2b was obtained (entry 4), though the yield was
low due to the generation of some polar byproducts. The reaction was therefore conducted at 60
°C (entry 5) to suppress the generation of byproducts and 2b was obtained in good yield when
the amount of Lawesson’s reagent was increased to 0.7 equiv (entry 6). The same tendency was
observed for another H-phosphonate diester 1c; a large proportion of byproducts were observed
under reflux conditions, while the desired 2c was obtained in good yield when the reaction was
conducted at 60 °C (entries 7, 8).
Next, N-methoxypyridinium sulfonates 4a–e were synthesized (Table 2). Heating a mixture of
pyridine N-oxide 3a and methyl tosylate at 100 °C over 8 h without solvent completely
converted 3a into N-methoxypyridinium tosylate 4a, as reported in the literature;9 however, an
attempt to synthesize compound 4b under the same conditions resulted in decomposition of the
product (entry 2). We found that compound 3b was much more reactive than 3a due to the
electron-donating 4-propyl group and the reaction was complete within 10 min (entry 3).
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Prolonged heating caused decomposition of the resulting 4b, as shown in entry 2. Compound 4c
with a 4-methoxy group was even more sensitive to heat, resulting in the generation of a
complex mixture within 20 min (entry 4). Therefore, the reaction was conducted at RT using
CH2Cl2 as a solvent (entry 5). Compound 3d, with similar reactivity to 3c, was also methylated
under similar conditions (entry 6). In contrast, compound 3e with an electron-withdrawing 4-
chloro group was not methylated with methyl tosylate, even at 100 °C over 12 h (entries 7, 8).
The methylation of 3e was therefore carried out with more reactive methyl triflate to give 4e
(entry 10). Compounds 4a–e were thus obtained and used for the introduction of 2-pyridyl
groups without purification.
The N-methoxypyridinium sulfonates 4a–e were then allowed to react with compounds 2a–c
in the presence of DBU in MeCN at −40 °C, the conditions optimized through the synthesis of 2-
pyridylphosphinates,6 giving 13 kinds of 2-pyridylthiophosphinate and 2-pyridylthiophosphonate
esters 5a–m in 54–93% yields (Table 3). The reactions were quenched after 2a–c were
completely consumed (TLC). The reactions of 2a were completed with 1.5 molar equiv of 4a–e
(entries 1–5), whereas 2 molar equiv of 4a–e were necessary to drive the reactions of 2b and 2c
to completion (entries 6–13). The reaction rate was dependent on the R3 substituent as follows:
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Cl > H > Pr > MeO, BuO, indicating that the reactivity of 4 increased with a decrease of the
electron density on the pyridine ring.
Finally, compounds 5a–f, h, j were subjected to alkaline hydrolysis and subsequent
neutralization with acid to synthesize 2-pyridylthiophosphinic acids and 2-
pyridylthiophosphonate monoesters 6a–f, h, j (Table 4). Compound 5a was hydrolyzed with a
solution of triethylamine in MeOH aq. to give 6a in 89% yield after neutralization with 1 M HCl
(entry 1). In contrast, the alkaline hydrolysis of 5b was not promoted by triethylamine (entry 2),
but required 1 M NaOH in MeOH aq., which afforded compound 6b in 84% yield (entry 3).
Compounds 5c–e were also hydrolyzed by 1 M NaOH in MeOH aq. to give 6c–e in 63–74%
yields (entries 4–6). The hydrolysis of diphenyl ester 5f with 1 M NaOH in MeOH aq. resulted in
the formation of the fully hydrolyzed 2-pyridylthiophosphonic acid (entry 7). Therefore, 5f was
hydrolyzed using triethylamine at 50 °C. In this case, the hydrolysis was conducted in THF aq. in
place of MeOH aq. to prevent an ester exchange reaction, giving the desired 6f in 62% yield after
cation-exchange using ion-exchange resin (entry 8). Ester 5h was also converted into 6h under
the same conditions used for 6f except for the prolonged reaction time (entry 9). Because the
hydrolysis of diisopropyl ester 5j was not promoted by triethylamine under reflux conditions or
with MW irradiation (entries 10, 11), 5j was hydrolyzed by 1 M NaOH. The desired 6j was
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obtained in 58% yield when the hydrolysis was conducted at 75 °C (entry 12); 6j was not
obtained due to overhydrolysis under reflux conditions (entry 13).
The structure of 2-pyridylthiophosphonate monoester 6h was unambiguously determined by X-
ray crystallographic analysis (Figure 1). The X-ray structure of 6h showed that the compound
was crystallized as a racemic compound, in which two pairs of the (R)- and (S)-isomers were
contained in a unit cell (Figure 2). Each pair was formed by two hydrogen bonds between the
OH groups on the phosphorus and the nitrogen atom of the pyridine ring (O–N distance = 2.660
Å, O–H–N angle = 169.28°). The hydrogen bonds might contribute to a small O1–P–C angle
(94.33°) and a large O2–P–S angle (119.59°) by pulling the oxygen and the pyridyl group closer
to each other. Tables S 1 and S 2 (Supplemental Materials) present the X-ray data collection
parameters and selected bond lengths and angles.
Conclusion
In conclusion, the study described herein has provided the first method for the synthesis of 2-
pyridylthiophosphinic acids and 2-pyridylthiophosphonate monoesters. An unambiguous
structural analysis of a 2-pyridylthiophosphonate monoester by X-ray crystallography was also
conducted for the first time. We consider that the 2-pyridylthiophosphinic acids and 2-
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pyridylthiophosphonate monoesters will be useful for the preparation of novel bidentate ligands
with unique coordination behaviors.
Experimental
General information
Commercially available reagents were used without purification. Dry organic solvents were
prepared by appropriate procedures prior to use. The other organic solvents were reagent grade
and used as received. All reactions in dry solvents were carried out under argon. Analytical thin-
layer chromatography (TLC) was performed on Merck TLC plates (No. 5715) precoated with
silica gel 60 F254. Silica gel column chromatography was carried out using Kanto silica gel 60N
(spherical, neutral, 40–50 or 63–210 m). The 1H, 13C and 31P NMR spectra (400, 100, 161.7
MHz) were recorded on a JNM-AL-400 or a JNM-ECS-400 spectrometer (JEOL).
Tetramethylsilane (TMS) was used as an internal standard for 1H NMR. CDCl3 (77.0 ppm) and
C5D5N (123.87 ppm, central peak on the right side) were used as internal standards for 13C NMR
in CDCl3 and C5D5N, respectively. 85% H3PO4 was used as an external standard (δ 0.0) for 31P
NMR. 1H NMR data are reported as follows: chemical shift (multiplicity, coupling constants,
integration). Multiplicity is indicated as follows: s (singlet); d (doublet); dd (doublet of doublets);
t (triplet); q (quartet); sext (sextet); dsept (doublet of septets); m (multiplet); br (broad). High-
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resolution mass spectra were recorded on a Waters Xevo Q-Tof mass spectrometer (ESI-TOF).
The Supplemental Materials contains sample 1H, 13C and 31P NMR for 5h and 6h as
representative examples (Figures S 1 – S 6).
Methyl phenylthiophosphinate 2a6,10
Lawesson’s reagent (4.05 g, 10.0 mmol) was added to a stirred solution of methyl phosphinate
1a (3.12 g, 20.0 mmol) in dry toluene (40 mL) at RT. The resultant mixture was further stirred
for 1.5 h at RT. Insoluble materials were removed by suction filtration. The filtrate was diluted
with toluene (30 mL) and washed with H2O (30 mL). The aqueous layer was extracted with
toluene (3 × 15 mL). The organic layers were combined, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (CH2Cl2) to afford 2a (2.63 g, 15.3 mmol, 76%) as a slightly yellowish liquid.
1H and 31P NMR spectra were identical to those reported in the literature.6,10
Diphenyl thiophosphonate 2b
Lawesson’s reagent (8.49 g, 21.0 mmol) was added to a stirred solution of diphenyl
phosphonate 1b (7.03 g, 30.0 mmol) in dry toluene (60 mL) at RT. The resultant mixture was
then heated at 60 °C with stirring for 4 h. The mixture was allowed to cool to RT and insoluble
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materials were removed by suction filtration. The filtrate was diluted with toluene (30 mL) and
washed with H2O (30 mL). The aqueous layer was extracted with toluene (2 × 15 mL). The
organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography ((hexane–CH2Cl2 (1:1,
v/v)) to afford 2b (5.31 g, 21.2 mmol, 71%) as a slightly yellowish liquid, which solidified to
white crystals upon standing at –20 °C. 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 668.4 Hz,
1H), 7.37 (t, J = 8.0 Hz, 4H), 7.25–7.16 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 149.7 (d, JPC
10.7 Hz), 129.7, 125.7, 121.1 (d, JPC = 5.7 Hz). 31P NMR (161.7 MHz, CDCl3) δ 64.2. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C12H12O2PS+ 251.0290; Found 251.0301.
=
Diisopropyl thiophosphonate 2c
Lawesson’s reagent (8.50 g, 21.0 mmol) was added to a stirred solution of diisopropyl
phosphonate 3c (4.98 g, 30.0 mmol) in dry toluene (60 mL) at RT. The resultant mixture was
then heated at 60 °C with stirring for 3 h. The mixture was allowed to cool to RT and insoluble
materials were removed by suction filtration. The filtrate was diluted with toluene (30 mL) and
washed with H2O (30 mL). The aqueous layer was extracted with toluene (2 × 15 mL). The
organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography ((hexane–CH2Cl2 (7:3,
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v/v)) to afford 2c (4.29 g, 23.5 mmol, 78%) as a colorless liquid. 1H NMR (400 MHz, CDCl3) δ
7.77 (d, J = 644.8 Hz, 1H), 4.85 (dsept, J = 11.2, 6.4 Hz, 2H), 1.34 (dd, J = 6.4, 4.2 Hz, 12H).
13C NMR (100 MHz, CDCl3) δ 71.4 (d, JPC = 6.6 Hz), 23.7 (d, JPC = 4.2 Hz), 23.4 (d, JPC = 5.8
Hz). 31P NMR (161.7 MHz, CDCl3) δ 65.0. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for
C6H15NaO2PS+ 205.0423; Found 205.0441.
Methyl phenyl(2-pyridyl)thiophosphinate 5a
A mixture of pyridine N-oxide (1.43 g, 15.0 mmol) and methyl p-toluenesulfonate (2.79 g,
15.0 mmol) was heated at 100 °C for 8 h to afford N-methoxypyridinium tosylate 4a9 as a white
solid, which was used without purification. DBU (2.24 mL, 15.0 mmol) and a solution of the
thus obtained 4a in dry MeCN (20.0 mL) were subsequently added to a stirred solution of 2a
(1.72 g, 10.0 mmol) in dry MeCN (12.5 mL) at –40 °C, and the resultant mixture was further
stirred for 10 min at the same temperature. A 0.2 M NaH2PO4 aqueous solution (15 mL) was
added, and the mixture was allowed to warm to RT. The mixture was then extracted with AcOEt
(3 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel column chromatography
((CH2Cl2–MeOH (100:1 to 99:1, v/v)) to afford 5a (1.92 g, 7.70 mmol, 77%) as a slightly
yellowish oil. NMR spectra were identical to those in the literature.6.
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Methyl phenyl(4-propyl-2-pyridyl)thiophosphinate 5b
A mixture of 4-propylpyridine N-oxide (0.823 g, 6.00 mmol) and methyl p-toluenesulfonate
(1.12 g, 6.01 mmol) was heated at 100 °C for 10 min to afford N-methoxy-4-propylpyridinium
tosylate 4b as a white solid. 1H NMR (400 MHz, CDCl3) δ 9.42 (d, J = 7.0 Hz, 2H), 7.86 (d, J =
7.0 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.14 (d, J = 8.2 Hz, 2H), 4.41 (s, 3H), 2.74 (t, J = 7.6 Hz,
2H), 2.33 (s, 3H), 1.65 (sext, J = 7.6 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 162.0, 143.4, 140.3, 139.3, 129.1, 128.5, 125.7, 69.4, 37.3, 22.6, 21.0, 13.4. Compound
4b thus obtained was used without purification. DBU (0.898 mL, 6.00 mmol) and a solution of
4b in dry MeCN (15 mL) were subsequently added to a stirred solution of 2a (0.686 g, 4.00
mmol) in dry MeCN (5.0 mL) at –40 °C, and the resultant mixture was further stirred for 1 h at
the same temperature. A 0.2 M NaH2PO4 aqueous solution (30 mL) was added, and the mixture
was allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 20 mL). The
organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography ((hexane–AcOEt (8:1,
v/v)) to afford 5b (0.724 g, 2.48 mmol, 62%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ
8.62 (d, J = 5.2 Hz, 1H), 8.10–8.03 (m, 3H), 7.53–7.43 (m, 3H), 7.17 (t, J = 2.4 Hz, 1H), 3.76 (d,
J = 14.4 Hz, 3H), 2.63 (t, J = 7.6 Hz, 2H), 1.67 (sextet, J = 7.6 Hz, 2H), 0.95 (t, J = 7.6 Hz, 3H).
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13C NMR (100 MHz, CDCl3) δ 155.9 (d, JPC = 140.2 Hz), 152.2 (d, JPC = 11.4 Hz), 150.0 (d, JPC
= 20.0 Hz), 132.4 (d, JPC = 109.6 Hz), 132.1 (d, JPC = 2.9 Hz), 132.0 (d, JPC = 10.5 Hz), 128.3 (d,
JPC = 13.3 Hz), 128.1 (d, JPC = 26.7 Hz), 125.4 (d, JPC = 3.8 Hz), 51.7 (d, JPC = 5.7 Hz), 37.3,
23.4, 13.7. 31P NMR (161.7 MHz, CDCl3) δ 78.5. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C15H19NOPS+ 292.0919; Found 292.0907.
Methyl 4-methoxy-2-pyridyl(phenyl)thiosphosphinate 5c
A mixture of 4-methoxypyridine N-oxide (0.188 g, 1.50 mmol), methyl p-toluenesulfonate
(0.279 g, 1.50 mmol), and dry CH2Cl2 (2.0 mL) was stirred at RT for 6 h, and then concentrated
to dryness to give N-methoxy-4-methoxypyridinium tosylate 4c as a white solid. 1H NMR (400
MHz, CDCl3) δ 9.18 (d, J = 7.8 Hz, 2H), 7.78 (d, J = 7.8 Hz, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.15
(d, J = 7.8 Hz, 2H), 4.36 (s, 3H), 4.08 (s, 3H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
170.0, 143.4, 142.4, 139.2, 128.4, 125.5, 114.3, 69.2, 58.2, 20.9. Compound 4c thus obtained
was used without purification. DBU (0.224 mL, 1.50 mmol) and a solution of 4c in dry MeCN
(3.5 mL) were subsequently added to a stirred solution of 2a (0.174 g, 1.00 mmol) in dry MeCN
(1.5 mL) at –40 °C, and the resultant mixture was further stirred for 2 h at the same temperature.
A 0.2 M NaH2PO4 aqueous solution (8 mL) was added, and the mixture was allowed to warm to
RT. The mixture was then extracted with AcOEt (2 × 20 mL). The organic layers were
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combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography ((hexane–AcOEt–CH2Cl2 (6:2:2, v/v/v)) to
afford 5c (0.213 g, 0.762 mmol, 76%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.54
(d, J = 5.6 Hz, 1H), 8.08–8.02 (m, 2H), 7.81 (dd, J = 8.8, 2.4 Hz, 1H), 7.52–7.41 (m, 3H), 6.83
(ddd, J = 5.6, 2.4, 1.6 Hz, 1H), 3.86 (s, 3H), 3.75 (d, J = 14.4 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ 165.9 (d, JPC = 15.3 Hz), 157.9 (d, JPC = 140.1 Hz), 151.5 (d, JPC = 22.9 Hz), 132.2 (d,
JPC = 110.6 Hz), 132.2 (d, JPC = 2.8 Hz), 131.9 (d, JPC = 11.5 Hz), 128.3 (d, JPC = 13.3 Hz),
114.2 (d, JPC = 29.5 Hz), 111.4 (d, JPC = 2.9 Hz), 55.5, 51.8 (d, JPC = 5.7 Hz). 31P NMR (161.7
MHz, CDCl3) δ 79.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C13H15NO2PS+ 280.0556;
Found 280.0543.
Methyl 4-butoxy-2-pyridyl(phenyl)thiophosphinate 5d
A mixture of 4-buthoxypyridine N-oxide (0.502 g, 3.00 mmol), methyl p-toluenesulfonate
(0.559 g, 3.00 mmol), and dry CH2Cl2 (4.5 mL) was stirred at RT for 27 h, and then concentrated
to dryness to give N-methoxy-4-butoxypyridinium tosylate 4d as a white solid. 1H NMR (400
MHz, CDCl3) δ 9.14 (d, J = 6.6 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 6.6 Hz, 2H), 7.13
(d, J = 8.0 Hz, 2H), 4.31 (s, 3H), 4.20 (t, J = 6.4 Hz, 2H), 2.33 (s, 3H), 1.76 (m, 2H), 1.43 (sext,
J = 7.6 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 169.6, 143.5, 142.5,
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139.3, 128.5, 125.7, 114.7, 71.4, 69.3, 30.1, 21.1, 18.7, 13.4. Compound 4d thus obtained was
used without purification. DBU (0.450 mL, 3.01 mmol) and a solution of 4d in dry MeCN (6.00
mL) were subsequently added to a stirred solution of 2a (0.344 g, 2.00 mmol) in dry MeCN
(2.50 mL) at –40 °C, and the resultant mixture was further stirred for 2.5 h at the same
temperature. A 0.2 M NaH2PO4 aqueous solution (15 mL) was added, and the mixture was
allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 20 mL). The organic
layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography ((hexane–CH2Cl2 (3:7, v/v)) to afford
5d (0.471 g, 1.47 mmol, 74%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.53 (d, J =
5.6 Hz, 1H), 8.08–8.03 (m, 2H), 7.81 (dd, J = 9.0, 2.6 Hz, 1H), 7.53–7.42 (m, 3H), 6.81 (ddd, J =
5.8, 2.6, 1.8, 1H), 4.05 (dt, J = 6.4, 2.8 Hz, 2H), 3.76 (d, J = 13.6 Hz, 3H), 1.82–1.75 (m, 2H),
1.49 (sextet, J = 7.4 Hz, 2H), 0.98 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1 (d,
JPC = 15.2 Hz), 157.4 (d, JPC = 139.2 Hz), 151.3 (d, JPC = 22.9 Hz), 132.0 (d, JPC = 109.7 Hz),
132.0 (d, JPC = 2.9 Hz), 131.7 (d, JPC = 11.5 Hz), 128.0 (d, JPC = 13.4 Hz), 114.7 (d, JPC = 29.6
Hz), 111.3 (d, JPC = 1.9 Hz), 67.8, 51.5 (d, JPC = 5.7 Hz), 30.5, 18.8, 13.5. 31P NMR (161.7 MHz,
CDCl3) δ 79.9. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C16H21NO2PS+ 322.1025; Found
322.1030.
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Methyl 4-chloro-2-pyridyl(phenyl)thiophosphinate 5e
Methyl trifluoromethanesulfonate (0.328 mL, 3.00 mmol) was added dropwise to a stirred
solution of 4-chloropyridine N-oxide (0.389 g, 3.00 mmol) in dry CH2Cl2 (4.5 mL) at 0 °C. The
mixture was allowed to warm to RT, further stirred for 1 h, and concentrated under reduced
pressure to afford N-methoxy-4-chloropyridinium triflate 4e as a white solid. 1H NMR (400
MHz, CDCl3) δ 9.09 (d, J = 7.0 Hz, 2H), 8.04 (d, J = 7.0 Hz, 2H), 4.41 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 153.2, 141.7, 130.0, 120.3 (q, JCF = 318.0 Hz), 70.0. Compound 4e thus obtained
was used without purification. DBU (0.450 mL, 3.01 mmol) and a solution of 4e in dry MeCN
(7.5 mL) were subsequently added to a stirred solution of 2a (0.344 g, 2.00 mmol) in dry MeCN
(2.5 mL) at –40 °C, and the resultant mixture was further stirred for 30 min at the same
temperature. A 0.2 M NaH2PO4 aqueous solution (15 mL) was added, and the mixture was
allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 20 mL). The organic
layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography ((hexane–AcOEt (4:1, v/v)) to afford
5e (0.489 g, 1.72 mmol, 86%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J =
4.8 Hz, 1H), 8.25 (dd, J = 7.2, 1.2 Hz, 1H), 8.06 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H),
7.55–7.44 (m, 3H), 7.36–7.34 (m, 1H), 3.77 (d, J = 14.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
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158.3 (d, JPC = 139.2 Hz), 150.9 (d, JPC = 21.0 Hz), 145.0 (d, JPC = 16.2 Hz), 132.5 (d, JPC = 2.8
Hz), 132.0 (d, JPC = 11.4 Hz), 131.5 (d, JPC = 110.6 Hz), 128.4 (d, JPC = 14.3 Hz), 127.9 (d, JPC
27.7 Hz), 125.5 (d, JPC = 2.9 Hz), 51.8 (d, JPC = 5.8 Hz). 31P NMR (161.7 MHz, CDCl3) δ 77.1.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C12H12ClNOPS+ 284.0060; Found 284.0063.
Diphenyl 2-pyridylthiophosphonate 5f
=
N-Methoxypyridinium tosylate 4a was prepared from pyridine N-oxide (0.0951 g, 1.00 mmol)
and methyl p-toluenesulfonate (0.186 g, 1.00 mmol) as described in the synthesis of 5a, and used
without purification. DBU (0.150 mL, 1.00 mmol) and a solution of the thus prepared 4a in dry
MeCN (2.0 mL) were subsequently added to a stirred solution of 2b (0.126 g, 0.503 mmol) in
dry MeCN (0.50 mL) at –40 °C, and the resultant mixture was further stirred for 30 min at the
same temperature. A 0.2 M NaH2PO4 aqueous solution (4 mL) was added, and the mixture was
allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 10 mL). The organic
layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (CH2Cl2) to afford 5f (0.135 g, 0.412
mmol, 82%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.89 (d, J = 4.8 Hz, 1H), 8.23 (t,
J = 7.6 Hz, 1H), 7.82 (m, 1H), 7.44 (m, 1H), 7.32–7.28 (m, 4H), 7.20–7.14 (m, 6H). 13C NMR
(100 MHz, CDCl3) δ 154.2 (d, JPC = 192.6 Hz), 150.2 (d, JPC = 15.3 Hz), 150.1 (d, JPC = 17.2
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Hz), 136.5 (d, JPC = 12.4 Hz), 129.3, 127.8 (d, JPC = 30.5 Hz), 126.2 (d, JPC = 3.8 Hz), 125.3 (d,
JPC = 1.9 Hz), 121.7 (d, JPC = 4.8 Hz). 31P NMR (161.7 MHz, CDCl3) δ 73.7. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C17H15NO2PS+ 328.0556; Found 328.0576.
Diphenyl 4-propyl-2-pyridylthiophosphonate 5g
N-Methoxy-4-propylpyridinium tosylate 4b was prepared from 4-propylpyridine N-oxide
(0.274 g, 2.00 mmol) and methyl p-toluenesulfonate (0.372 g, 2.00 mmol) as described in the
synthesis of 5b, and used without purification. DBU (0.300 mL, 2.01 mmol) and a solution of the
thus prepared 4b in dry MeCN (3.0 mL) were subsequently added to a stirred solution of 2b
(0.250 g, 1.00 mmol) in dry MeCN (2.0 mL) at –40 °C, and the resultant mixture was further
stirred for 1 h at the same temperature. A 0.2 M NaH2PO4 aqueous solution (7 mL) was added,
and the mixture was allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 10
mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2) to
afford 5g (0.200 g, 0.541 mmol, 54%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.78
(dd, J = 4.8, 0.8 Hz, 1H), 8.06 (dd, J = 7.6, 0.8 Hz, 1H), 7.33–7.28 (m, 5H), 7.20–7.15 (m, 6H),
2.66 (t, J = 7.8 Hz, 2H), 1.68 (sextet, J = 7.6 Hz, 2H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3) δ 154.0 (d, JPC = 190.7 Hz), 152.5 (d, JPC = 13.4 Hz), 150.3 (d, JPC = 8.6 Hz),
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150.2 (d, JPC = 23.9 Hz), 129.4, 128.4 (d, JPC = 31.5 Hz), 126.4 (d, JPC = 3.8 Hz), 125.4 (d, JPC
=
1.9 Hz), 121.9 (d, JPC = 4.8 Hz), 37.2, 23.3, 13.6. 31P NMR (161.7 MHz, CDCl3) δ 74.8. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C20H21NO2PS+ 370.1025; Found 370.1024.
Diphenyl 4-methoxy-2-pyridylthiophosphonate 5h
N-Methoxy-4-methoxypyridinium tosylate 4c was prepared from 4-methoxypyridine N-oxide
(0.125 g, 1.00 mmol) and methyl p-toluenesulfonate (0.186 g, 1.00 mmol) as described in the
synthesis of 5c, and used without purification. DBU (0.150 mL, 1.00 mmol) and a solution of the
thus prepared 4c in dry MeCN (2.0 mL) were subsequently added to a stirred solution of 2b
(0.125 g, 0.500 mmol) in dry MeCN (0.50 mL) at –40 °C, and the resultant mixture was further
stirred for 2 h at the same temperature. A 0.2 M NaH2PO4 aqueous solution (4 mL) was added,
and the mixture was allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 10
mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2) to
afford 5h (0.155 g, 0.434 mmol, 87%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.72
(d, J = 5.6 Hz, 1H), 7.80 (dd, J = 9.9, 2.6 Hz, 1H), 7.34–7.30 (m, 4H), 7.20–7.16 (m, 6H), 6.98–
6.96 (m, 1H), 3.90 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 165.8 (d, JPC = 18.1 Hz), 155.9 (d, JPC
= 192.7 Hz), 151.8 (d, JPC = 26.7 Hz), 150.3 (d, JPC = 8.5 Hz), 129.4, 125.4, 121.9 (d, JPC = 3.8
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Hz), 114.8 (d, JPC = 33.3 Hz), 112.0 (d, JPC = 3.8 Hz), 55.5. 31P NMR (161.7 MHz, CDCl3) δ
74.6. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C18H17NO3PS+ 358.0661; Found 358.0677.
Diphenyl 4-chloro-2-pyridythiophosphonate 5i
N-Methoxy-4-chloropyridinium triflate 4e was prepared from 4-chloropyridine N-oxide (0.130
g, 1.00 mmol) and methyl trifluoromethanesulfonate (0.109 mL, 1.00 mmol) as described in the
synthesis of 5e, and used without purification. DBU (0.150 mL, 1.00 mmol) and a solution of the
thus prepared 4e n dry MeCN (2.0 mL) were subsequently added to a stirred solution of 2b
(0.125 g, 0.500 mmol) in dry MeCN (0.50 mL) at –40 °C, and the resultant mixture was further
stirred for 10 min at the same temperature. A 0.2 M NaH2PO4 aqueous solution (4 mL) was
added, and the mixture was allowed to warm to RT and extracted with AcOEt (2 × 10 mL). The
organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column chromatography (CH2Cl2) to afford 5i
(0.168 g, 0.464 mmol, 93%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.74 (d, J = 5.2
Hz, 1H), 8.23 (dd, J = 7.8, 2.0 Hz, 1H), 7.42 (dt, J = 5.2, 2.0 Hz, 1H), 7.30 (t, J = 8.0 Hz, 4H),
7.20–7.14 (m, 6H). 13C NMR (100 MHz, CDCl3) δ 156.1 (d, JPC = 193.6 Hz), 151.2 (d, JPC
=
25.8 Hz), 150.1 (d, JPC = 8.6 Hz), 145.1 (d, JPC = 18.1 Hz), 129.5, 128.2 (d, JPC = 31.5 Hz), 126.4
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(d, JPC = 2.8 Hz), 125.6, 121.8 (d, JPC = 3.8 Hz). 31P NMR (161.7 MHz, CDCl3) δ 71.4. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C17H14ClNO2PS+ 362.0166; Found 362.0176.
Diisopropyl 2-pyridylthiophosphonate 5j
N-Methoxypyridinium tosylate 4a was prepared from pyridine N-oxide (0.951 g, 10.0 mmol)
and methyl p-toluenesulfonate (1.86 g, 10.0 mmol) as described in the synthesis of 5a, and used
without purification. DBU (1.50 mL, 10.0 mmol) and a solution of the thus prepared 4a in dry
MeCN (20.0 mL) were subsequently added to a stirred solution of 2c (0.912 g, 5.00 mmol) in dry
MeCN (5.0 mL) at –40 °C, and the resultant mixture was further stirred for 30 min at the same
temperature. A 0.2 M NaH2PO4 aqueous solution (30 mL) was added, and the mixture was
allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 20 mL). The organic
layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (CH2Cl2) to afford 5j (1.13 g, 4.36
mmol, 87%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 4.4 Hz, 1H), 8.04
(m, 1H), 7.77 (m, 1H), 7.37 (m, 1H), 4.98 (dsept, J = 10.4, 6.2 Hz, 2H), 1.39 (d, J = 6.2 Hz, 6H),
1.27 (d, J = 6.2 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ 156.7 (d, JPC = 193.5 Hz), 150.0 (d, JPC
= 23.1 Hz), 135.9 (d, JPC = 12.3 Hz), 126.3 (d, JPC = 28.0 Hz), 125.2 (d, JPC = 4.1 Hz), 72.2 (d,
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JPC = 6.6 Hz), 23.7 (d, JPC = 4.1 Hz), 23.3 (d, JPC = 5.7 Hz). 31P NMR (161.7 MHz, CDCl3) δ
74.8. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C11H19NO2PS+ 260.0869; Found 260.0870.
Diisopropyl 4-propyl-2-pyridylthiophosphonate 5k
N-Methoxy-4-propylpyridinium tosylate 4b was prepared from 4-propylpyridine N-oxide
(0.137 g, 1.00 mmol) and methyl p-toluenesulfonate (0.186 g, 1.00 mmol) as described in the
synthesis of 5b, and used without purification. DBU (0.150 mL, 1.00 mmol) and a solution of the
thus prepared 4b in dry MeCN (2.0 mL) were subsequently added to a stirred solution of 2c
(0.0909 g, 0.499 mmol) in dry MeCN (0.50 mL) at –40 °C, and the resultant mixture was further
stirred for 1 h at the same temperature. A 0.2 M NaH2PO4 aqueous solution (4 mL) was added,
and the mixture was allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 10
mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (hexane–
AcOEt–CH2Cl2 (8:1:1, v/v/v)) to afford 5k (0.117 g, 0.388 mmol, 78%) as a pale yellow oil. 1H
NMR (400 MHz, CDCl3) δ 8.65 (d, J = 4.8 Hz, 1H), 7.88 (dd, J = 7.6, 0.8 Hz, 1H), 7.18 (m, 1H),
4.96 (dsept, J = 10.4, 6.2 Hz, 2H), 2.64 (t, J = 7.8 Hz, 2H), 1.68 (sextet, J = 7.4 Hz, 2H), 1.39 (d,
J = 6.2 Hz, 6H), 1.27 (d, J = 6.2 Hz, 6H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3)
δ 156.3 (d, JPC = 189.7 Hz), 151.7 (d, JPC = 12.4 Hz), 149.9 (d, JPC = 23.9 Hz), 126.8 (d, JPC
=
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28.7 Hz), 125.4 (d, JPC = 2.8 Hz), 72.3 (d, JPC = 5.7 Hz), 37.3, 23.8 (d, JPC = 3.9 Hz), 23.5 (d, JPC
= 5.7 Hz), 23.3, 13.6. 31P NMR (161.7 MHz, CDCl3) δ 75.7. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C14H25NO2PS+ 302.1338; Found 302.1326.
Diisopropyl 4-methoxy-2-pyridylthiophosphonate 5l
N-Methoxy-4-methoxypyridinium tosylate 4c was prepared from 4-methoxypyridine N-oxide
(0.100 g, 0.799 mmol) and methyl p-toluenesulfonate (0.149 g, 0.800 mmol) as described in the
synthesis of 5c, and used without purification. DBU (0.119 mL, 0.797 mmol) and a solution of
the thus prepared 4c in dry MeCN (2.0 mL) were subsequently added to a stirred solution of 2c
(0.0732 g, 0.402 mmol) in dry MeCN (0.50 mL) at –40 °C, and the resultant mixture was further
stirred for 3 h at the same temperature. A 0.2 M NaH2PO4 aqueous solution (4 mL) was added,
and the mixture was allowed to warm to RT. The mixture was then extracted with AcOEt (2 × 10
mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2) to
afford 5l (0.0930 g, 0.321 mmol, 80%) as a pale yellow oil. 1H NMR (400 MHz, CDCl3) δ 8.59
(d, J = 5.2 Hz, 1H), 7.62 (dd, J = 9.0, 2.2 Hz, 1H), 6.86 (ddd, J = 5.2, 2.6, 2.2 Hz, 1H), 4.96
(dsept, J = 10.4, 6.4 Hz, 2H), 3.90 (s, 3H), 1.39 (d, J = 6.4 Hz, 6H), 1.27 (d, J = 6.4 Hz, 6H). 13C
NMR (100 MHz, CDCl3) δ 165.5 (d, JPC = 17.2 Hz), 158.1 (d, JPC = 190.7 Hz), 151.4 (d, JPC
=
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25.8 Hz), 113.2 (d, JPC = 30.5 Hz), 111.1 (d, JPC = 2.9 Hz), 72.4 (d, JPC = 6.6 Hz), 55.3, 23.8 (d,
JPC = 3.8 Hz), 23.5 (d, JPC = 4.8 Hz). 31P NMR (161.7 MHz, CDCl3) δ 75.3. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C12H21NO3PS+ 290.0974; Found 290.0983.
Diisopropyl 4-chloro-2-pyridylthiophosphonate 5m
N-Methoxy-4-chloropyridinium triflate 4e was prepared from 4-chloropyridine N-oxide (0.104
g, 0.803 mmol) and methyl trifluoromethanesulfonate (0.0875 mL, 0.800 mmol) as described in
the synthesis of 5e, and used without purification. DBU (0.119 mL, 0.797 mmol) and a solution
of the thus prepared 4e in dry MeCN (2.0 mL) were subsequently added to a stirred solution of
2c (0.0727 g, 0.399 mmol) in dry MeCN (0.50 mL) at –40 °C, and the resultant mixture was
further stirred for 10 min at the same temperature. A 0.2 M NaH2PO4 aqueous solution (4 mL)
was added and the mixture was allowed to warm to RT. The mixture was then extracted with
AcOEt (2 × 10 mL). The organic layers were combined, dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by silica gel column
chromatography (CH2Cl2) to afford 5l (0.108 g, 0.368 mmol, 92%) as a pale yellow oil. 1H NMR
(400 MHz, CDCl3) δ 8.67 (d, J = 5.2 Hz, 1H), 8.02 (dd, J = 7.4, 2.0 Hz, 1H), 7.38 (dt, J = 5.2,
2.0 Hz, 1H), 4.98 (dsept, J = 10.8, 6.4 Hz, 2H), 1.40 (d, J = 6.4 Hz, 6H), 1.29 (d, J = 6.4 Hz,
6H). 13C NMR (100 MHz, CDCl3) δ 158.4 (d, JPC = 191.6 Hz), 150.9 (d, JPC = 24.8 Hz), 144.6
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(d, JPC = 17.2 Hz), 126.7 (d, JPC = 29.6 Hz), 125.5 (d, JPC = 3.8 Hz), 72.8 (d, JPC = 6.7 Hz), 23.8
(d, JPC = 3.8 Hz), 23.5 (d, JPC = 5.7 Hz). 31P NMR (161.7 MHz, CDCl3) δ 72.8. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C11H18ClNO2PS+ 294.0479; Found 294.0474.
Phenyl(2-pyridyl)thiophosphinic acid 6a
A mixture of 5a (1.81 g, 7.27 mmol), triethylamine (10.7 mL, 76.8 mmol), methanol (24 mL),
and water (51 mL) was heated to reflux for 8 h. The mixture was then allowed to cool to RT,
concentrated to some extend under reduced pressure, and lyophilized. The residue was dissolved
in water (20 mL), and subsequent addition of 1 M HCl aq. (7.27 mL) precipitated a white solid,
which was collected by suction filtration and dried in vacuo to give 6a (1.52 g, 6.49 mmol, 89%)
as a white solid. 1H NMR (400 MHz, pyridine-d5) δ 14.2 (br, 1H), 8.70 (d, J = 4.8 Hz, 1H),
8.66–8.58 (m, 3H), 7.68–7.63 (m, 1H), 7.48–7.38 (m, 3H), 7.15–7.11 (m, 1H). 13C NMR (100
MHz, pyridine-d5) δ 164.1 (d, JPC = 134.5 Hz), 150.1 (d, JPC = 19.0 Hz), 140.8 (d, JPC = 106.8
Hz), 136.2 (d, JPC = 9.5 Hz), 132.7 (d, JPC = 10.5 Hz), 131.1 (d, JPC = 2.9 Hz), 128.4 (d, JPC
=
12.4 Hz), 126.6 (d, JPC = 24.8 Hz), 124.5 (d, JPC = 2.9 Hz). 31P NMR (161.7 MHz, pyridine-d5) δ
58.6. ESI-HRMS: m/z calcd for C11H9NOPS– [(M – H)–] 234.0148, found 234.0124.
Phenyl(4-propyl-2-pyridyl)thiophosphinic acid 6b
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A mixture of 5b (0.724 g, 2.48 mmol), methanol (12 mL), and 1 M NaOH aq. (24 mL) was
heated to reflux for 3 h. The mixture was then allowed to cool to RT and concentrated under
reduced pressure. The residue was dissolved in water (10 mL), cooled to 0 °C, and 1 M HCl aq.
(24 mL) was added. The resultant precipitate was collected by suction filtration at RT, and dried
in vacuo to afford 6b (0.579 g, 2.09 mmol, 84%) as a white solid. 1H NMR (400 MHz, CDCl3) δ
8.72 (d, J = 6.0 Hz, 1H), 8.27–8.21 (m, 2H), 7.98 (d, J = 7.6 Hz, 1H), 7.45–7.44 (m, 4H), 2.72 (t,
J = 7.8 Hz, 2H), 1.71–1.62 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
161.5 (d, JPC = 6.7 Hz), 160.0 (d, JPC = 84.8 Hz), 140.4 (d, JPC = 5.7 Hz), 138.5 (d, JPC = 112.5
Hz), 131.8 (d, JPC = 11.5 Hz), 131.1 (d, JPC = 2.8 Hz), 129.8 (d, JPC = 13.3 Hz), 128.2 (d, JPC
=
13.3 Hz), 125.4, 37.9, 22.9, 13.5. 31P NMR (161.7 MHz, CDCl3) δ 47.3. ESI-HRMS: m/z calcd
for C14H15NOPS– [(M – H)–] 276.0617, found 276.0621.
4-Methoxy-2-pyridyl(phenyl)thiophosphinic acid 6c
 A mixture of 5c (0.213 g, 0.763 mmol), methanol (3.0 mL), and 1 M NaOH aq. (6.0 mL) was
stirred for 1.5 h at RT and concentrated under reduced pressure. The residue was dissolved in
water (3.0 mL), cooled to 0 °C, and 1 M HCl aq. (6.0 mL) was added. The mixture was then
allowed to warm to RT, concentrated under reduced pressure, and lyophilized. The residue was
washed with H2O (8 mL) and dried in vacuo to afford 6c (0.140 g, 0.528 mmol, 69%) as a white
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solid. 1H NMR (400 MHz, CDCl3) δ 8.63 (d, J = 6.8 Hz, 1H), 8.25–8.20 (m, 2H), 7.60 (d, J = 8.4
Hz, 1H), 7.44 (s, 3H), 7.01 (d, J = 6.8 Hz, 1H), 3.98 (s, 3H). 13C NMR (100 MHz, pyridine-d5) δ
167.0 (d, JPC = 13.2 Hz), 165.3 (d, JPC = 126.9 Hz), 150.5 (d, JPC = 20.0 Hz), 141.1 (d, JPC
=
108.8 Hz), 132.8 (d, JPC = 9.8 Hz), 131.1, 128.5 (d, JPC = 12.4 Hz), 113.8 (d, JPC = 24.7 Hz),
110.6, 55.7. 31P NMR (161.7 MHz, CDCl3) δ 48.2. ESI-HRMS: m/z calcd for C12H11NO2PS– [(M
– H)–] 264.0254, found 264.0250.
4-Butoxy-2-pyridyl(phenyl)thiophosphinic acid 6d
A mixture of 5d (0.322 g, 1.00 mmol), methanol (3.0 mL), and 1 M NaOH aq. (6.0 mL) was
heated to 50 °C for 1.5 h. The mixture was then allowed to cool to RT and concentrated under
reduced pressure. The residue was dissolved in water (3.0 mL), cooled to 0 °C, and 1 M HCl aq.
(6.0 mL) was added. The resultant precipitate was collected by suction filtration at RT and dried
in vacuo to afford 6d (0.227 g, 0.739 mmol, 74%) as a pale yellow solid. 1H NMR (400 MHz,
CDCl3) δ 8.60 (d, J = 6.8 Hz, 1H), 8.25–8.19 (m, 2H), 7.58 (dd, J = 8.6, 2.4 Hz, 1H), 7.43–7.40
(m, 3H), 6.98 (dd, J = 6.8, 2.4 Hz, 1H), 4.13 (m, 2H), 1.81–1.74 (m, 2H), 1.45 (sextet, J = 7.4
Hz, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 170.1 (d, JPC = 9.5 Hz), 162.5
(d, JPC = 83.9 Hz), 142.3 (d, JPC = 5.8 Hz), 138.6 (d, JPC = 111.6 Hz), 131.8 (d, JPC = 11.4 Hz),
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131.1 (d, JPC = 2.9 Hz), 128.2 (d, JPC = 12.3 Hz), 114.7 (d, JPC = 14.3 Hz), 112.1, 70.1, 30.4,
18.8, 13.6. 31P NMR (161.7 MHz, CDCl3) δ 48.1. ESI-HRMS: m/z calcd for C15H17NO2PS– [(M
– H)–] 306.0723, found 306.0712.
4-Chloro-2-pyridyl(phenyl)thiophosphinic acid 6e
A mixture of 5e (0.489 g, 1.72 mmol), methanol (7.5 mL), and 1 M NaOH aq. (15 mL) was
heated to reflux for 2 h. The mixture was then allowed to cool to RT and concentrated under
reduced pressure. The residue was dissolved in water (10 mL) and 1 M HCl aq. (24 mL) was
added. The resultant precipitate was collected by suction filtration and dried in vacuo to afford 6e
(0.291 g, 1.08 mmol, 63%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.76 (d, J = 5.6 Hz,
1H), 8.25–8.19 (m, 2H), 8.09 (dd, J = 7.4, 1.8 Hz, 1H), 7.62 (dt, J = 6.4, 1.0 Hz, 1H), 7.53–7.45
(m, 3H). 13C NMR (100 MHz, CDCl3) δ 162.4 (d, JPC = 83.9 Hz), 152.7 (d, JPC = 10.5 Hz), 142.3
(d, JPC = 6.6 Hz), 137.0 (d, JPC = 115.4 Hz), 132.0 (d, JPC = 11.5 Hz), 131.7 (d, JPC = 1.9 Hz),
130.1 (d, JPC = 14.3 Hz), 128.5 (d, JPC = 13.3 Hz), 126.2. 31P NMR (161.7 MHz, CDCl3) δ 49.2.
ESI-HRMS: m/z calcd for C11H8ClNOPS– [(M – H)–] 267.9758, found 267.9753.
Phenyl 2-pyridylthiophosphonate 6f
A mixture of 5f (0.164 g, 0.501 mmol), triethylamine (0.350 mL, 2.51 mmol), and THF–H2O
(1:2, v/v) (4.0 mL) was heated at 50 °C for 3 h, allowed to cool to RT, and concentrated under
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reduced pressure. The residue was dissolved in water (2 mL) and passed through a column of
Amberlite IR-120 (H+ form) (7 g). The eluent was lyophilized to give 6f (0.0777 g, 0.309 mmol,
62%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.67 (d, J = 5.6 Hz, 1H), 8.47 (t, J = 7.4
Hz, 1H), 8.33 (m, 1H), 7.77 (m, 1H), 7.22–7.17 (m, 4H), 7.06–7.01 (m, 1H). 13C NMR (100
MHz, pyridine-d5) δ 162.9 (d, JPC = 173.6 Hz), 154.1 (d, JPC = 8.6 Hz), 149.7 (d, JPC = 21.0 Hz),
136.5 (d, JPC = 10.5 Hz), 129.7, 127.5 (d, JPC = 26.7 Hz), 124.8 (d, JPC = 2.8 Hz), 124.0, 122.9
(d, JPC = 3.8 Hz). 31P NMR (161.7 MHz, CDCl3) δ 48.3. ESI-HRMS: m/z calcd for C11H9NO2PS–
[(M – H)–] 250.0097, found 250.0087.
Phenyl 4-methoxy-2-pyridylthiophosphonate 6h
A mixture of 5h (0.155 g, 0.434 mmol), triethylamine (0.600 mL, 4.30 mmol), and THF–H2O
(1:2, v/v) (4.0 mL) was heated at 50 °C for 23 h, allowed to cool to RT, and concentrated under
reduced pressure. The residue was dissolved in water (2 mL) and passed through a column of
Amberlite IR-120 (H+ form) (7 g). The eluent was lyophilized to give 6h (0.0746 g, 0.265 mmol,
61%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.44 (dd, J = 6.6, 1.4 Hz, 1H), 7.85 (dd, J =
9.6, 2.8 Hz, 1H), 7.20 (m, 4H), 7.09–7.01 (m, 2H), 4.05 (s, 3H). 13C NMR (100 MHz, CDCl3) δ
170.8 (d, JPC = 11.5 Hz), 158.3 (d, JPC = 130.7 Hz), 151.7 (d, JPC = 9.5 Hz), 142.1 (d, JPC = 8.6
Hz), 129.3, 124.2, 121.5 (d, JPC = 4.7 Hz), 114.3 (d, JPC = 15.3 Hz), 112.8, 57.3. 31P NMR (161.7
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