Synthesis of Symmetric and P-Stereogenic Self-Assembling Pyridone-Based Phosphorus Ligands

Dedication

Dedicated to Paul Knochel on the occasion of his 70th birthday.

Abstract

6-(Diphenylphosphino)pyridin-2(1H)-one (6-DPPon) is a unique ligand that can self-assemble in transition metal complexes. This self-assembly is achieved through hydrogen bonding interactions that mimic a bidentate coordination sphere. As a consequence, there is considerable interest in preparing derivatives of 6-DPPon and optimizing their synthesis. Herein, we present different methods for the preparation of self-assembling pyridone-based phosphorus ligands. Nineteen pyridone ligands were prepared using electrophilic and nucleophilic routes, including eleven P-stereogenic ligands.

Keywords

Ligand synthesis - Pyridone ligands - Self-assembly - P-stereogenic ligands - Phosphine chlorides - Bromine–lithium exchange - Crystal structure

Introduction

In a directional work, our group reported the surprisingly high activity and linear selectivity of the 6-(diphenyl-phosphino)pyridin-2(1H)-one (6-DPPon, L1, [Scheme 1a]) ligand in the rhodium-catalyzed hydroformylation of 1-octene ([Scheme 1b]).[1] Extensive mechanistic studies have revealed that the formation of hydrogen bonds in the backbone of the rhodium catalyst is responsible for this remarkable result.[1] [2] [3] [4] [5] [6] The free ligand forms a hydrogen-bridged dimer that links the pyridone units of two molecules. However, in transition metal complexes, the pyridone unit of the ligand can isomerize to its hydroxypyridine tautomer, which results in an intramolecular hydrogen bonding between the hydroxypyridine and its complementary pyridone form of two coordinated ligands. By this, 6-DPPon mimics a bidentate ligand with a comparatively wide bite angle, which results in high regioselectivity in the hydroformylation of terminal olefines. Additionally, the hydrogen bonding in the ligand backbone enables structural flexibility, allowing for an easy adoption of different coordination geometries within the catalytic cycle, which results in high catalytic activity. In hydroformylation of terminal alkenes using a 6-DPPon-based catalyst, a high functional group tolerance was observed even for substrates that could form hydrogen bonds themselves.[1] Notably, the catalyst’s high activity made it possible to perform the reaction under mild conditions, such as ambient pressure and temperature,[7] and even in water.[8] Since this makes hydroformylation available with a simple syngas balloon, this protocol can be used in many synthetic applications, even in biochemical systems.[9] [10] [11] The high robustness of the hydroformylation reaction catalyzed by 6-DPPon-based systems allows for its combination with many other chemical transformations. Using this method, we have developed catalytic systems that start with alkenes and synthesize valuable products such as alcohols,[12] cross aldol products,[13] diindolylmethanes,[14] and BODIPY dyes[15] [16] over (multi-)step tandem reaction sequences.[17]

Scheme 1 6-(Diphenylphosphino)pyridin-2(1H)-one (6-DPPon, L1) and examples of its application in catalysis.

6-DPPon and its derivatives could also be used successfully for the hydroformylation of more challenging substrates, such as alkynes and terminal allenes ([Scheme 1b]).[18] [19] Moreover, 6-DPPon-based ligands with a chiral substituent at the pyridone can form an axially chiral ligand backbone via twisted hydrogen bonds in transition metal complexes.[20] This property was successfully used in the asymmetric hydrogenation of alkenes. Furthermore, 6-DPPon ligands have been used in palladium catalysis, such as allylic substitution reactions.[21] [22] In one example, the ligand was proposed to serve as a directional group for the allylic alcohol substrate.[21]

These catalytic applications highlight the importance of efficiently synthesizing 6-DPPon and its derivatives. This article presents two strategies toward this goal ([Scheme 2]): (1) the electrophilic route, wherein a phosphine electrophile reacts with a lithiated pyridone precursor, and (2) the nucleophilic route, during which an anionic phosphine nucleophile reacts with a halogenated pyridone precursor in an S_NAr reaction. In both cases, the final step is the deprotection of the tert-butoxy group using formic acid. The following covers the synthesis of phosphine electrophiles and their use in the electrophilic route to 6-DPPon ligands. A short discussion of the nucleophilic route will complete the summary of the synthesis of this ligand class.

Scheme 2 Electrophilic and nucleophilic routes toward pyridone-based phosphorus ligands.

Results and Discussion

Synthesis of Electrophilic Phosphorus Reagents

For the preparation of pyridone phosphorus ligands, several P-electrophiles are required. As basic intermediates for more complex P-electrophiles, the phosphine chlorides Cl₂P(NEt₂) (1), ClP(NEt₂)₂ (3), and ClP(NEt₂)Ph (4) were synthesized ([Scheme 3]). 1 was accessible in moderate yield by allowing PCl₃ to react with HNEt₂ in the presence of NEt₃.[23] [24] However, since this reaction leads to the stoichiometric formation of ammonium salt that complicates distillation despite filtration, a modified procedure was followed for the synthesis of 3. In a previous literature report, TMS-NEt₂ (2) was used to convert PCl₃ into P(NEt₂)₃, which was then converted to 3 via disproportion with PCl₃.[25] [26] To our delight, 2 could be transformed directly into 3 in good yield and the by-product TMS-Cl was easily separable via distillation. It is important to use the correct stoichiometry of reagents to avoid difficult-to-separate mixtures of 1 and 3. This was controlled via ³¹P NMR spectroscopy. For unsymmetric phosphine chlorides, ClP(NEt₂)Ph (4) was synthesized as the key precursor in 83% yield from commercially available Cl₂PPh by reaction with two equivalents of HNEt₂.[27] For the synthesis of more complex phosphine electrophiles, different routes are feasible. The retrosynthetic analysis is depicted in [Scheme 4].

Scheme 3 Preparation of phosphine electrophiles 1, 3, and 4.

Scheme 4 Retrosynthetic analysis of phosphine electrophiles. ^a Diaryl(diethylamino)phosphines or diarylphosphine oxides can be transformed into the corresponding diarylphosphine chlorides using PCl₃, RCOCl, or HCl. Aryl(bis-diethylamino)phosphines can be transformed as well using this method.

Starting from the reaction of either 1 or commercially available diethyl phosphite with an aryl Grignard reagent, symmetric diaryl(diethylamino)phosphines ([Scheme 4a])[28] [29] or secondary diarylphosphine oxides ([Scheme 4b])[30] can be obtained. Different methods to convert the latter ones into the corresponding phosphine chlorides can be found in literature. The first two are the reaction with PCl₃ or HCl.[23] [31] [32] [33] [34] In these cases, removal of resulting side products Cl₂P(NEt₂) (1), HOPCl₂, or excess HCl is crucial; otherwise, unwanted side reactions or even termination of the subsequent reaction can occur. Another option is to use carboxylic acid chlorides, such as lauroyl chloride or AcCl.[35] [36] For chiral pyridone ligands bearing two different aryl or alkyl substituents on the phosphorus atom besides the pyridone group, a suitable precursor ClP(NEt₂)R₁ is required for the synthesis of more complex unsymmetric P-electrophiles ([Scheme 4c]). Due to its simple preparation, ClP(NEt₂)Ph (4) was used for the synthesis of most chiral pyridone ligands prepared in this work. The chloro substituent in 4 is significantly easier to exchange with a second alkyl or aryl moiety by reaction with metal organyls compared to the diethylamino group. This allows for monosubstitution on the phosphorus atom. Later on, the diethylamino group can be transformed into a chloro group using similar methods as described before. Another route is the reaction of 3 with an aryl-lithium compound to form a bis(diethylamino)phosphine intermediate, which can be converted into a phosphine dichloride ([Scheme 4d]).[37] [38] [39] [40]

Applying these strategies, a range of (diethylamino)phosphines (5–15) and secondary diarylphosphine oxides (16, 17) were synthesized ([Scheme 5a,b]). The diaryl(diethylamino)-phosphines 5 and 6 were prepared based on a literature report in good to very good yields using the respective Grignard reagent and 1.[41] A big advantage of this method is the simple purification of the products, which were obtained in sufficient purity for the subsequent step after filtration of the resulting magnesium salts and concentration of the filtrate under reduced pressure. For large-scale synthesis of these intermediates, bulb-to-bulb distillation can be used to increase product purity. Furthermore, precursor 4 was used to prepare nine different unsymmetric (diethylamino)phosphines (7–15) in yields up to 90%. In case of the mesityl-substituted derivative 8, t-BuLi was necessary for bromine–lithium exchange. Direct deprotonation of 1,3-dimethoxybenzene with n-BuLi/TMEDA provided 14 in excellent yield after treatment with 4. Interestingly, 4 reacts readily with n-BuLi itself, forming (diethylamino)phosphine 15, which carries both an aryl and an alkyl residue, in high yield. In agreement with the strategy described before ([Scheme 4b]), the diarylphosphine oxide 16 was obtained from the Grignard reagent and diethyl phosphite in high yield. The synthetic protocol was further optimized for the bis(m-CF₃) derivative 17 via the deprotonation of H(O)P(OEt)₂ using NaH prior to its addition to the Grignard reagent at 0 °C. This saves one equivalent of Grignard reagent and reduces the amount of magnesium salts that must be hydrolyzed after the reaction is complete. Unlike the (diethylamino)phosphines 5–15, the phosphine oxides are not sensitive toward oxidation and hydrolysis. This enables purification by flash column chromatography on one hand and a longer storage time on the other. Consequently, PCl₃ was used to obtain the symmetric diarylphosphine chlorides 18–21 in moderate to good yields of up to 88%, starting from the corresponding diaryl(diethylamino)phosphines (5, 6) and the secondary diarylphosphine oxides (16, 17, [Scheme 5c]). The unsymmetric phosphine chlorides on the other hand were prepared in situ from 7–15 using etheric HCl as the chloride source and were immediately utilized in the next step as a solution in anhydrous THF.

Scheme 5 Preparation of electrophilic phosphorus reagents used in the synthesis of symmetric and P-stereogenic pyridone ligands. ^a With 2.0 eq. t-BuLi; ^b With 1.05 eq. n-BuLi.

Electrophilic Routes toward Pyridone Ligands

Next, 2-bromo-6-(tert-butoxy)pyridine (22) and 2-(tert-butoxy)-6-chloropyridine (23) were synthesized in excellent yields via an S_NAr reaction, starting from the corresponding dihalopyridines and KOt-Bu ([Scheme 6]).[1] [6] Under the given reaction conditions, exclusive mono substitution was observed. Additionally, the yield depends considerably on the quality of the KOt-Bu used.

Scheme 6 Synthesis of tert-butoxy halopyridines 22 and 23.

According to [Scheme 2], the actual ligand synthesis required a suitable nucleophile to react with the P-electrophile. Therefore, the bromine–lithium exchange of 22 with n-BuLi was investigated ([Table 1]). After 30 min at −78 °C, full conversion was achieved in THF (entry 1). In contrast, hardly any formation of the lithiated pyridine was observed in Et₂O at −78 °C, even after 2 h reaction time (entry 2). To our delight, the lithiation proceeded smoothly in Et₂O at 0 °C over 30 min (entry 3). Hence, there are two viable routes toward the lithiated protected pyridone.

Table 1 Lithiation of 2-bromo-6-(tert-butoxy)pyridine (22) with n-BuLi

Entry	Solvent	T/°C	t/min	Conversion/%a
1	THF	−78	30	100
2	Et2O	−78	120	<10
3	Et 2 O	0	30	100

^a The conversion was determined by hydrolyzing an aliquot of the reaction mixture and analyzing it via ¹H NMR spectroscopy.

Based on these results, a reliable and robust route toward symmetric pyridone ligands L1–L5 was developed ([Scheme 7a]). As outlined before, 22 was lithiated with n-BuLi in Et₂O at 0 °C and then allowed to react with the corresponding freshly prepared symmetric diarylphosphine chloride. The crude tert-butoxy protected intermediates were dissolved directly in degassed formic acid or degassed solutions of formic acid in DCM to obtain the free pyridone ligands. Following this procedure, 6-DPPon (L1) was obtained in high yield of 75% over two steps.[6] It is worth noting that the yield is essentially the same whether the protected intermediate is isolated or not. To our delight, the fluorinated ligands L3–L5 were also obtained in good yields of 60 to 69%. For the para-methoxy substituted ligand 6-BpAnPon (L2), which was applied before in tandem hydroformylation–hydrogenation,[12] a lower yield of 30% was obtained. Based on the crude NMR of the protected ligand, this might be due to a less clean reaction of the aryl-lithium with the phosphine chloride compared to the other derivatives. Similarly, the chiral ligands L6–L14 were obtained in moderate to good yields as racemic mixtures ([Scheme 7b]). As a single modification, the bromine–lithium exchange was done in THF at −78 °C. The best yield of 63% was achieved for rac-L14, which carries an alkyl substituent in addition to the phenyl ring. This yield is remarkable because of the significantly higher sensitivity of this ligand toward oxidation compared to the other derivatives. The enantiomers of rac-L6, rac-L8, rac-L9, and rac-L13 were separated using preparative chiral HPLC. Both enantiomers were obtained with >99% ee and stored under inert atmosphere at −20 °C to exclude thermal racemization. The stability of the P-stereocenter of L9 was confirmed with 98% ee after 672 days at ambient temperature. For rac-L14, reversible protection of the phosphorus center as its borane adduct was necessary; otherwise, we could not avoid partial oxidation during the HPLC separation. Borane deprotection of the phosphorus with HNEt₂ is possible afterward under complete retention of configuration.[42] Additionally, the P-stereogenic bis-alkyl-phosphine ligand rac-L15 was synthesized by reacting lithiated 22 with ClP(t-Bu)Me, followed immediately by borane protection prior to isolation of rac-24. Then, the pyridone was deprotected in excellent yield using formic acid, followed by quantitative borane deprotection with HNEt₂. The total yield of rac-L15 was 21% over three steps.

Scheme 7 Synthesis of pyridone phosphorus ligands via electrophilic routes. ^a Enantiomers were separated using preparative chiral HPLC (Chiralpak AD-H), both enantiomers were obtained with >99% ee. ^b Synthesis of Racemic P-Stereogenic Pyridone Phosphorus Ligands.

Recent investigations in our group have shown that the 6-DPyPon ligand (L16), which features two N-pyrrolyl groups bound to the phosphorus atom, exhibited notably high catalytic activity and linear selectivity in both rhodium- and iridium-catalyzed hydroformylation of 1-octene.[39] It is remarkable that the electronic environment at the phosphorus center of L16 appears to enhance hydrogen bonding within the ligand backbone and thereby leads to the very high linear selectivity observed in iridium-catalyzed hydroformylation, even at elevated temperatures up to 140 °C. Due to the interesting properties of L16,[39] we improved its synthesis as outlined in [Scheme 8].

Scheme 8 Synthesis of 6-DPyPon (L16).

In contrast to the original publication, the bromine–lithium exchange in 22 was done in Et₂O at 0 °C. The resulting lithiated species was then trapped with ClP(NEt₂)₂ (3) and the desired intermediate 25 was obtained in 87% yield, which was a significant improvement to the initial procedure (45% yield, in THF at −78 °C). In the next step, PCl₃ was used to exchange the diethylamino groups with chloro substituents. Formation of the ArPCl₂ intermediate could be monitored by ³¹P NMR spectroscopy. Addition of an excess amount of lithium pyrrol-1-ide gave 26 in 52% yield. Similar yields were achieved using AcCl instead of PCl₃. Etheric HCl was unsuitable to generate the phosphine dichloride, since even traces of excess HCl led to hydrolysis of the formed intermediate 26 and polymerization of pyrrole. Finally, deprotection with formic acid in DCM furnished L16 in a surprisingly high yield of 76%, although phosphorus ligands with N-pyrrolyl groups are normally sensitive toward hydrolysis.[39] [43] Similar to the previously presented route, further experiments were conducted using bis(pyrrol-1-yl)phosphine chloride as a precursor for 6-DPyPon. However, intermediate 26 could not be obtained via this approach.

Taking a deeper look at the electrophilic route presented for P-stereogenic pyridone ligands starting from 4 clearly reveals one big limitation, since one of the aryl moieties is fixed to phenyl ([Scheme 7b]). To overcome this, we developed a reaction sequence, which provides access to P-stereogenic pyridone ligands with two functionalized aryl rings besides the pyridone. The rac-6-bmTFMPPyPon ( rac-L17) ligand was chosen as the synthetic target for this approach ([Scheme 9]). Starting by the lithiation of 1-bromo-3,5-bis(trifluoromethyl)benzene and reaction with ClP(NEt₂)₂ (3), intermediate 27 was formed. The obtained yield strongly depended on the used lithiation conditions ([Table 2]). Lithiation with n-BuLi in THF at −78 °C followed by addition of 3 gave 27 in 52% yield ([Table 2], entry 1). The yield decreased to 29% under similar conditions in Et₂O ([Table 2], entry 2). To our delight, 27 was obtained in almost quantitative yield at 0 °C in Et₂O ([Table 2], entry 3). The reaction in Et₂O not only led to an improved yield, but also to a significantly cleaner reaction in comparison to THF. As a result, the product was obtained with >95% purity and could be used in the next step without purification.

Scheme 9 Synthesis of racemic 6-bmTFMPPyPon ( rac-L17).

Table 2 Synthesis of bis(diethylamino)[3,5-bis(trifluoromethyl)phenyl]phosphine (27)

Entry	Solvent	T/°C	Yield 27/%
1	THF	−78	52
2	Et2O	−78	29
3	Et 2 O	0	94

One of the diethylamino substituents was then selectively exchanged with a chloro substituent. For this ligand AcCl was used, as the resulting N,N-diethylacetamide has no negative effect on the reaction and can later be removed by column chromatography. To directly analyze the formation of the ClArP(NEt₂) intermediate via ³¹P NMR spectroscopy, C₆D₆ was added to the reaction mixture (δ = 132.2 ppm, [Fig. 1]). After complete conversion, the ClArP(NEt₂) solution was slowly added to lithiated 22 to obtain rac-28 in 46% yield.

Fig. 1 ³¹P NMR spectra (122 MHz, C₆D₆) of the ClArP(NEt₂) intermediate formation (red: starting material 27; green: after 30 min; blue: after 70 min).

Notably, rac-28 could also be obtained starting from 25 by selective exchange of one diethylamino group with a chloro group and reaction with one equivalent of (3,5-bis(trifluoromethyl)phenyl)lithium in comparable yield. Subsequent diarylphosphine chloride synthesis starting from rac-28 with AcCl followed by reaction with lithium pyrrol-1-ide resulted in 55% yield of rac-29. Moreover, it is possible to first incorporate the pyrrole substituent into 27 in excellent yield ( rac-30, 93%). However, numerous experiments to produce rac-29 from this intermediate failed. Last, rac-29 was deprotected with formic acid in benzene to yield rac-6-bmTFMPPyPon ( rac-L17). Although the overall yield was low with 7%, this product represents a quite challenging molecule due to the labile N-pyrrolyl substituent. This is underlined by the attempt to deprotect rac-29 in pure formic acid, which did not lead to the desired product but to decomposition and polymerization of the pyrrole leaving group.

At this point we wondered whether there is a possibility to perform a one-pot synthesis of 6-DPPon derivatives as well. To clarify this question, 2-bromo-6-(tert-butoxy)pyridine (22) and two equivalents of 5-bromo-1,3-di-tert-butyl-2-methoxybenzene were dissolved in an appropriate solvent. After lithiation with three equivalents of n-BuLi, PCl₃ was added to the reaction mixture ([Table 3]). Neither in Et₂O, nor in THF, the desired product was obtained at 0 °C ([Table 3], entries 1 and 4). Decreasing the temperature in Et₂O to −78 °C had no positive effect ([Table 3], entry 2), nor did separate lithiations of 22 and the corresponding aryl bromide ([Table 3], entry 3). To our delight, 25% of 6-BDTBMPPon (L18) could be isolated after deprotection, when the reaction was carried out in THF at −78 °C ([Table 3], entry 5). This result indicates that a one-pot synthesis of 6-DPPon derivatives is indeed possible, despite the moderate yield. Further optimization studies are currently ongoing in our laboratories. Crystals of L18 suitable for X-ray diffraction analysis were obtained from CD₂Cl₂ by slow evaporation of the solvent. The Ortep-3 plot, derived of the crystal structure of L18, shows a dimeric structure formed by hydrogen bonds between two ligand molecules in their tautomeric pyridone form, similar to the published structure of 6-DPPon (L1, [Fig. 2]).[1]

Table 3 One-pot synthesis of 6-BDTBMPPon (L18)

Entry	Solvent	T/°C	Yield L18/%
1	Et2O	0	−
2	Et2O	−78	−
3a	Et2O/THF	0/−78	−
4	THF	0	−
5	THF	−78	25

^a Separate lithiation of 22 in Et₂O at 0 °C and of the corresponding aryl bromide in THF at −78 °C.

Fig. 2 Ortep-3 plot obtained from the crystal structure of the 6-BDTBMPPon ligand (L18). Solvent molecules are omitted for clarity. For further information see SI.

Nucleophilic Route toward Pyridone Ligands

The so-far schemed electrophilic routes toward pyridone ligands require the handling of sensitive phosphorus and metalorganic reagents in most cases over multiple steps, which can limit the scale of the ligand synthesis. A viable alternative access toward pyridone ligands is presented in [Scheme 10]. Commercially available triaryl-phosphines can be transformed into a reactive phosphorus nucleophile under Birch conditions. Such a nucleophile reacts readily with tert-butoxy halopyridine 22 or 23 via an S_NAr reaction. After direct deprotection with formic acid, the targeted pyridone ligands can be achieved in good to high yields even in multigram scale.[1] The same phosphorus nucleophile can in principle be accessed via deprotonation of diarylphosphines. However, due to the oxidation sensitivity of these reagents, we chose the Birch conditions for the preparation of the phosphorus nucleophiles.

Scheme 10 Nucleophilic route toward 6-DPPon (L1) and 6-BmAnPon (L19).

Conclusion

In conclusion, electrophilic and nucleophilic routes were developed for the preparation of 19 pyridone-based self-assembling phosphorus ligands. The electrophilic route enabled the stepwise replacement of chloro or NEt₂ groups from suitable precursors with alkyl or aryl groups including the protected pyridone unit. Therefore, it is possible to design pyridone ligands with tailor-made electronic and steric properties. Notably, 11 of the prepared 6-DPPon derivatives are P-stereogenic. The enantiomers of six of those ligands were separated with excellent ee using chiral preparative HPLC. The thermal stability of this ligand class was demonstrated by almost unchanged high ee after storage at ambient temperature for 672 days. The multigram synthesis of 6-DPPon ligands was successfully demonstrated using a nucleophilic route under Birch conditions. The methods described herein for the synthesis of self-assembling pyridone ligands could lead to a more widespread application of this ligand class in transition metal catalysis.

All moisture- and oxygen-sensitive reactions were carried out in flame-dried glassware under an argon atmosphere using a standard Schlenk line apparatus. An overpressure of argon was maintained throughout the reaction time. Syringes and cannulas for the addition of anhydrous solvents and reagents were flushed with argon three times prior to use. “High vacuum” refers to an oil pump’s end pressure of 0.1 mbar. Technical-grade solvents for extraction and column chromatography (hexanes, CH, n-pentane, DCM, Et₂O, EtOAc) were distilled using a rotary evaporator before use. Solvents used for reactions were dried and purified following common methods (see supporting information (SI)).

Organometallic reagents: The molarity of organolithium reagents (n-BuLi, t-BuLi) was determined by direct titration of 2-(pivaloylamino)toluene.[44] The molarity of Grignard reagents was determined by direct titration of salicylaldehyde phenylhydrazone.[45]

All other chemicals were commercially available and used without further purification.

Flash column chromatography was accomplished using Machery-Nagel Silica Gel 60® (40−63 μm). The silica gel was deactivated with 5% NEt₃ when needed.

Thin layer chromatography was performed on aluminum plates precoated with SiO₂ (Merck, 60 F₂₅₄). The resulting spots were visualized under UV light at 254 nm and stained either with KMnO₄-, H₃[PMo₁₂O₄₀]-, or H₃[PMo₁₂O₄₀]/Ce(SO₄)₂ solution. The TLC plates were deactivated with NEt₃/hexanes (1:10 (v:v)) when needed.

A list of the instruments used for all analyses (NMR, MS, CHN analysis, melting points, and optical rotation) can be found in the SI.

NMR: All ¹H NMR spectra are reported in ppm relative to the residual solvent peaks at 7.26 ppm (CHCl₃), 7.16 ppm (C₆D₅H), or 5.32 ppm (CDHCl₂), as appropriate. All ¹³C NMR spectra are reported in ppm relative to the signals at 77.1 ppm (CDCl₃), 128.0 ppm (C₆D₆), or 53.8 ppm (CD₂Cl₂), respectively, and were obtained with ¹H decoupling. All ³¹P NMR spectra were obtained with ¹H decoupling.

Dichloro(diethylamino)phosphine (Cl₂P(NEt₂), 1)

NEt₃ (50.5 mL, 36.8 g, 364 mmol, 1.00 eq.) was added dropwise to a solution of PCl₃ (31.8 mL, 50.0 g, 364 mmol, 1.00 eq.) in Et₂O (500 mL) at 0 °C over 30 min. Subsequently, HNEt₂ (37.7 mL, 26.6 g, 364 mmol, 1.00 eq.) was added dropwise at 0 °C and the resulting suspension was stirred overnight at ambient temperature. The solids were filtered off, washed with Et₂O (200 mL), and the solvent of the combined organic layers was removed under reduced pressure. The crude product was purified by fractional distillation under reduced pressure (the distillation was carried out using a Vigreux column; bp 85 °C at 22 mbar) to obtain the title compound (26.3 mL, 31.5 g, 181 mmol, 50%) as a colorless liquid.

¹H NMR (300 MHz, C₆D₆): δ = 2.84 (dq, J = 13.1, 7.1 Hz, 4 H, H-1), 0.70 (t, J = 7.2 Hz, 6 H, H-2).

³¹P NMR (122 MHz, C₆D₆): δ = 162.3 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₄H₁₁ ³⁵Cl₂NP⁺: 174.0001; found: 173.9996.

The analytical data are consistent with those previously reported in literature.[46]

N,N-Diethyl(trimethylsilyl)amine (TMS-NEt₂, 2)

Based on a modified literature procedure,[25] TMS-Cl (65.6 mL, 56.0 g, 515 mmol, 1.00 equiv) was added dropwise to a solution of HNEt₂ (107 mL, 75.4 g, 1.03 mol, 2.00 equiv) in anhydrous Et₂O (500 mL) at 0 °C. The reaction mixture was then allowed to warm to ambient temperature and stirred for 1 h. The resulting precipitate was filtered off and washed with anhydrous Et₂O. After removal of the solvent, the residue was purified by fractional distillation under reduced pressure (bp 87–91 °C at 250 mbar) to afford the title compound as a colorless liquid (79.1 mL, 60.7 g, 418 mmol, 81%).

¹H NMR (300 MHz, CDCl₃): δ = 2.79 (q, J = 7.0 Hz, 4 H, H-1), 0.97 (t, J = 7.0 Hz, 6 H, H-2), 0.04 (s, 9 H, H-1′).

MS (CI, NH₃): m/z (%) = 146 (100) [M + H]⁺.

The analytical data are consistent with those previously reported in literature.[25]

Bis(diethylamino)chlorophosphine (ClP(NEt₂)₂, 3)

PCl₃ (1.71 mL, 2.68 g, 19.5 mmol, 1.00 eq.) was added to a solution of N,N-diethyl(trimethylsilyl)amine 2 (8.32 mL, 6.38 g, 43.9 mmol, 2.25 eq.) in anhydrous Et₂O (40 mL) at 0 °C. The reaction mixture was then allowed to warm to ambient temperature and stirred until complete consumption of the starting material, as confirmed by ³¹P NMR spectroscopy. After removal of the solvent under reduced pressure, TMS-Cl was distilled off at ambient pressure. The residue was purified by fractional distillation under reduced pressure (bp 82–84 °C at 2 mbar) to obtain the title compound (3.18 mL, 3.19 g, 15.1 mmol, 78%) as a colorless liquid.

¹H NMR (300 MHz, C₆D₆): δ = 3.14–2.88 (m, 8 H, H-1), 0.94 (t, J = 7.1 Hz, 12 H, H-2).

³¹P NMR (122 MHz, C₆D₆): δ = 153.5 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₈H₂₁ ³⁵ClN₂P⁺: 211.1125; found: 211.1119.

Chlorodiethylaminophenylphosphine (ClP(NEt₂)Ph, 4)

The reaction was performed according to a literature procedure.[27] Cl₂PPh (22.7 mL, 30.0 g, 168 mmol, 1.00 eq.) was dissolved in anhydrous Et₂O (300 mL) and cooled to 0 °C. A solution of HNEt₂ (34.5 mL, 24.5 g, 335 mmol, 2.00 eq.) in anhydrous Et₂O (50 mL) was then added dropwise over 3 h. The resulting suspension was warmed to ambient temperature and stirred overnight. The solids were filtered off under Ar, washed with anhydrous Et₂O (200 mL), and the filtrate was concentrated under reduced pressure. The crude product was purified by fractional distillation under reduced pressure (bp 75 °C at 0.1 mbar) to afford the title compound as a colorless oil (30.1 g, 140 mmol, 83%).

¹H NMR (400 MHz, C₆D₆): δ = 7.84–7.79 (m, 2 H, H-2), 7.26–7.20 (m, 2 H, H-3), 7.19–7.14 (m, 1 H, H-4), 2.97 (dq, J = 12.0, 7.0 Hz, 4 H, H-1′), 0.92 (t, J = 7.2 Hz, 6 H, H-2′).

¹³C NMR (101 MHz, C₆D₆): δ = 140.1 (d, J = 29.5 Hz, C-1), 131.0 (d, J = 20.4 Hz, 2 C, C-2), 129.7 (d, J = 1.4 Hz, C-4), 128.6 (d, J = 3.9 Hz, 2 C, C-3), 44.0 (d, J = 13.1 Hz, 2 C, C-1′), 14.1 (d, J = 6.2 Hz, 2 C, C-2′).

³¹P NMR (162 MHz, C₆D₆): δ = 140.9 (s).

MS (EI, 70 eV): m/z (%) = 216 (100) [M]⁺.

The analytical data are consistent with those previously reported in literature.[47]

General Procedure A (GP A): Synthesis of Diaryl(diethylamino)phosphines

Based on a literature procedure,[41] Mg turnings (2.0 eq.) were suspended in anhydrous Et₂O (10 mL). The Grignard reaction was started by the addition of 0.5 mL of the corresponding aryl bromide (heating under reflux if necessary). A solution of the aryl bromide (total of 2.2 eq.) in anhydrous Et₂O (20 mL) was then added dropwise and the reaction mixture was stirred until complete consumption of the magnesium (heating under reflux if necessary). After the dropwise addition of Cl₂P(NEt₂) 1 (1.0 eq.) at 0 °C, the reaction mixture was heated under reflux for 2 h. The mixture was then cooled to ambient temperature and the supernatant solution was collected using a syringe and filtered through Celite. The solvent was removed under reduced pressure and the residue was dried under high vacuum. The crude product was used directly in the following step without further purification.

Diethylamino-bis(4-methoxyphenyl)phosphine (5)

The reaction was performed according to GP A using Mg (1.18 g, 48.6 mmol), 4-bromoanisole (6.69 mL, 10.0 g, 53.5 mmol), and Cl₂P(NEt₂) (3.54 mL, 4.23 g, 24.3 mmol). The title compound (3.88 g, 12.2 mmol, 50%) was obtained as a yellow oil.

¹H NMR (300 MHz, C₆D₆): δ = 7.54–7.46 (m, 4 H, H-2′), 6.85–6.80 (m, 4 H, H-3′), 3.31 (s, 6 H, H-1″), 3.18–3.01 (m, 4 H, H-1), 0.93 (t, J = 7.1 Hz, 6 H, H-2).

³¹P NMR (122 MHz, C₆D₆): δ = 60.2 (s).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₂₅NO₂P⁺: 318.1617; found: 318.1623.

Diethylamino-bis(4-fluorophenyl)phosphine (6)

The reaction was performed according to GP A using Mg (1.26 g, 52.0 mmol), 1-bromo-4-fluorobenzene (6.28 mL, 10.0 g, 57.1 mmol), and Cl₂P(NEt₂) (3.78 mL, 4.52 g, 26.0 mmol) to afford the title compound (6.80 g, 23.2 mmol, 89%).

¹H NMR (300 MHz, CDCl₃): δ = 7.42–7.30 (m, 4 H, H-2′), 7.11–6.99 (m, 4 H, H-3′), 3.12–2.97 (m, 4 H, H-1), 0.94 (t, J = 7.0 Hz, 6 H, H-2).

³¹P NMR (121 MHz, CDCl₃): δ = 60.4 (t, J = 5.6 Hz).

General Procedure B (GP B): Synthesis of Aryl(diethylamino)-(phenyl)phosphines via Halogen–Metal Exchange

To a solution of the corresponding aryl bromide (1.0 eq.) in an anhydrous solvent, n-BuLi (1.0 eq.) was added dropwise at −78 °C. After stirring for 2 h, ClP(NEt₂)Ph 4 (1.0 eq.) was added slowly, the reaction mixture was warmed to ambient temperature, and stirred overnight. The solvent was removed under reduced pressure, and the residue was dissolved in anhydrous Et₂O and filtered under Ar. The filtrate was concentrated and the crude product was purified by bulb-to-bulb distillation under reduced pressure, affording the desired product as a colorless oil with sufficient purity for the following step.

Diethylamino(1-naphthyl)(phenyl)phosphine (7)

The reaction was performed according to GP B using 1-bromo-naphthalene (1.35 mL, 2.00 g, 9.66 mmol), anhydrous THF (20 mL), n-BuLi (1.60 m solution in n-hexane, 6.04 mL, 9.66 mmol), and ClP(NEt₂)Ph (2.08 g, 9.66 mmol). The title compound (1.92 g, 6.25 mmol, 65%) was obtained as a colorless oil.

Distillation: 185 °C, 0.02 mbar.

¹H NMR (400 MHz, C₆D₆): δ = 8.61–8.53 (m, 1 H, H-7), 7.70–7.60 (m, 3 H, Ar-H), 7.49–7.41 (m, 2 H, Ar-H), 7.29 (ddd, J = 8.0, 7.1, 0.8 Hz, 1 H, Ar-H), 7.25–7.18 (m, 2 H, Ar-H), 7.13–7.03 (m, 3 H, Ar-H), 3.18–2.99 (m, 4 H, H-1″), 0.80 (t, J = 7.1 Hz, 6 H, H-2″).

¹³C NMR (101 MHz, C₆D₆): δ = 140.8 (d, J = 12.3 Hz, C-1′), 138.1 (d, J = 21.8 Hz, C-1)*, 135.5 (d, J = 22.8 Hz, C-8a)*, 134.1 (d, J = 3.8 Hz, C-4a), 132.4 (d, J = 19.8 Hz, 2 C, C-2′), 130.1 (d, J = 2.5 Hz, Ar-C), 129.4 (C-4′), 128.9 (d, J = 1.8 Hz, Ar-C), 128.4 (d, J = 5.6 Hz, 2 C, C-3′), 128.3 (Ar-C), 126.6 (d, J = 24.9 Hz, C-2), 126.1 (d, J = 2.4 Hz, Ar-C), 126.0 (Ar-C), 125.6 (C-7), 45.1 (d, J = 16.1 Hz, 2 C, C-1″), 14.7 (d, J = 3.3 Hz, 2 C, C-2″).

*Assignment of signals eventually interchangeable.

³¹P NMR (162 MHz, C₆D₆): δ = 54.0 (s).

MS (EI, 70 eV): m/z (%) = 307 (100) [M]⁺.

The analytical data are consistent with those previously reported in literature.[48]

Diethylamino(mesityl)(phenyl)phosphine (8)

The reaction was performed according to a modified GP B using 2-bromo-1,3,5-trimethylbenzene (1.00 mL, 1.30 g, 6.53 mmol, 1.00 eq.), anhydrous THF (15 mL), t-BuLi (1.65 m solution in n-hexane, 7.93 mL, 13.1 mmol, 2.00 eq.), and ClP(NEt₂)Ph (1.41 g, 6.53 mmol, 1.00 eq.). The title compound (1.18 g, 3.94 mmol, 60%) was obtained as a colorless oil.

Distillation: 220 °C, 0.05 mbar.

¹H NMR (400 MHz, C₆D₆): δ = 7.46–7.39 (m, 2 H, H-2′), 7.18–7.13 (m, 2 H (integration too large due to overlap with C₆D₅H signal), H-3′), 7.07–7.02 (m, 1 H, H-4′), 6.78 (d, J = 2.8 Hz, 2 H, H-3), 3.19–3.04 (m, 4 H, H-1″), 2.39 (s, 6 H, H-5), 2.11 (s, 3 H, H-6), 0.91 (t, J = 7.0 Hz, 6 H, H-2″).

¹³C NMR (101 MHz, C₆D₆): δ = 145.2 (d, J = 17.5 Hz, C-1 or C-1′), 143.1 (d, J = 17.2 Hz, 2 C, C-2), 138.7 (C-4), 133.0 (d, J = 24.5 Hz, C-1 or C-1′), 130.5 (d, J = 2.9 Hz, 2 C, C-3), 129.5 (d, J = 20.4 Hz, 2 C, C-2′), 128.7 (d, J = 4.4 Hz, 2 C, C-3′), 127.0 (d, J = 1.7 Hz, C-4′), 46.3 (d, J = 17.0 Hz, 2 C, C-1″), 23.6 (d, J = 17.8 Hz, 2 C, C-5), 20.9 (C-6), 15.0 (d, J = 3.4 Hz, 2 C, C-2″).

³¹P NMR (162 MHz, C₆D₆): δ = 51.9 (s).

MS (EI, 70 eV): m/z (%) = 299 (33) [M]⁺.

Diethylamino(2-trifluoromethylphenyl)(phenyl)phosphine (9)

The reaction was performed according to a slightly modified GP B using 1-bromo-2-(trifluoromethyl)benzene (5.22 g, 23.2 mmol, 1.00 eq.), anhydrous Et₂O (20 mL), n-BuLi (1.56 m solution in n-hexane, 15.6 mL, 24.4 mmol, 1.05 eq.), and ClP(NEt₂)Ph (5.00 g, 23.2 mmol, 1.00 eq.). The title compound (4.80 g, 14.8 mmol, 64%) was obtained as a colorless oil.

Distillation: 185 °C, 0.05 mbar.

¹H NMR (400 MHz, C₆D₆): δ = 7.59 (dd, J = 7.7, 3.7 Hz, 1 H, Ar-H), 7.49 (dd, J = 7.9, 3.1 Hz, 1 H, Ar-H), 7.34–7.26 (m, 2 H, Ar-H), 7.20–7.03 (m, 5 H, Ar-H), 3.16–2.96 (m, 4 H, H-1″), 0.79 (t, J = 7.1 Hz, 6 H, H-2″).

³¹P NMR (121 MHz, C₆D₆): δ = 55.4 (q, J = 56.5 Hz).

MS (EI, 70 eV): m/z (%) = 326 (28) [(M=O)−CH₃]⁺.

The analytical data are consistent with those previously reported in literature. [49]

Diethylamino(3-trifluoromethylphenyl)(phenyl)phosphine (10)

The reaction was performed according to a slightly modified GP B using 1-bromo-3-(trifluoromethyl)benzene (3.13 g, 13.9 mmol, 1.00 eq.), anhydrous Et₂O (20 mL), n-BuLi (1.56 m solution in n-hexane, 9.36 mL, 14.6 mmol, 1.05 eq.), and ClP(NEt₂)Ph (3.00 g, 13.9 mmol, 1.00 eq.). The crude product was directly purified by bulb-to-bulb distillation under reduced pressure (185 °C, 0.05 mbar) without filtration to afford the title compound (3.35 g, 10.3 mmol, 74%) as a colorless oil.

¹H NMR (300 MHz, C₆D₆): δ = 7.95–7.88 (m, 1 H, Ar-H), 7.42–7.28 (m, 4 H, Ar-H), 7.18–7.08 (m, 3 H, Ar-H), 7.01–6.91 (m, 1 H, Ar-H), 3.00–2.84 (m, 4 H, H-1″), 0.80 (t, J = 7.1 Hz, 6 H, H-2″).

³¹P NMR (121 MHz, C₆D₆): δ = 62.2 (s).

MS (EI, 70 eV): m/z (%) = 326 (24) [(M=O)−CH₃]⁺.

The analytical data are consistent with those previously reported in literature.[49]

General Procedure C (GP C): Synthesis of Aryl(diethylamino)-(phenyl)phosphines via the Corresponding Grignard Reagent

The corresponding aryl bromide (1.00 eq.) was added dropwise to a suspension of Mg turnings (1.05 eq.) in anhydrous Et₂O. After complete addition, the reaction mixture was heated under reflux for 1 h, then cooled to 0 °C and treated with ClP(NEt₂)Ph 4 (0.80 eq.). The mixture was then warmed to ambient temperature and stirred for another 2 h. The resulting solids were filtered off under Ar and the filtrate was concentrated under reduced pressure. Purification by bulb-to-bulb distillation under reduced pressure afforded the desired product as a colorless oil with sufficient purity for the following step.

Diethylamino(2-methylphenyl)(phenyl)phosphine (11)

The reaction was performed according to GP C using 1-bromo-2-methylbenzene (2.39 mL, 3.42 g, 20.0 mmol), anhydrous Et₂O (20 mL), Mg (0.51 g, 21.0 mmol), and ClP(NEt₂)Ph (3.45 g, 16.0 mmol). The title compound (2.24 g, 8.26 mmol, 52%) was obtained as a colorless oil.

Distillation: 165 °C, 0.05 mbar.

¹H NMR (400 MHz, C₆D₆): δ = 7.50–7.38 (m, 3 H, Ar-H), 7.17–7.01 (m, 6 H, Ar-H), 3.13–2.96 (m, 4 H, H-1″), 2.36 (s, 3 H, H-7), 0.82 (t, J = 7.0 Hz, 6 H, H-2″).

¹³C NMR (101 MHz, C₆D₆): δ = 141.4 (d, J = 26.1 Hz, C-2), 140.6 (d, J = 13.8 Hz, C-1′), 139.6 (d, J = 17.4 Hz, C-1), 132.1 (d, J = 20.0 Hz, 2 C, C-2′), 131.3 (d, J = 2.7 Hz, C-3 or C-5), 130.5 (d, J = 3.8 Hz, C-3 or C-5), 128.6 (C-4′), 128.4 (d, J = 5.7 Hz, 2 C, C-3′), 128.2 (C-6 (superimposed by solvent signal)), 126.0 (C-4), 45.2 (d, J = 16.0 Hz, 2 C, C-1″), 21.1 (d, J = 20.3 Hz, C-7), 14.7 (d, J = 3.3 Hz, 2 C, C-2″).

³¹P NMR (162 MHz, C₆D₆): δ = 53.8 (s).

MS (EI, 70 eV): m/z (%) = 271 (100) [M]⁺.

The analytical data are consistent with those previously reported in literature.[49]

Diethylamino(3-methylphenyl)(phenyl)phosphine (12)

The reaction was performed according to GP C using 1-bromo-3-methylbenzene (2.43 mL, 3.42 g, 20.0 mmol), anhydrous Et₂O (20 mL), Mg (0.51 g, 21.0 mmol), and ClP(NEt₂)Ph (3.45 g, 16.0 mmol). The title compound (2.28 g, 8.40 mmol, 53%) was obtained as a colorless oil.

Distillation: 180 °C, 0.7 mbar.

¹H NMR (300 MHz, C₆D₆): δ = 7.62–7.48 (m, 2 H, Ar-H), 7.42–7.29 (m, 2 H, Ar-H), 7.24–7.07 (m, 4 H, Ar-H), 7.03–6.94 (m, 1 H, Ar-H), 3.06 (dq, J = 9.6, 7.1 Hz, 4 H, H-1″), 2.12 (s, 3 H, H-7), 0.89 (t, J = 7.1 Hz, 6 H, H-2″).

³¹P NMR (121 MHz, C₆D₆): δ = 62.9 (s).

MS (EI, 70 eV): m/z (%) = 271 (100) [M]⁺.

The analytical data are consistent with those previously reported in literature. [49]

Diethylamino(3,5-dimethylphenyl)(phenyl)phosphine (13)

The reaction was performed according to GP C using 1-bromo-3,5-dimethylbenzene (2.72 mL, 3.70 g, 20.0 mmol), anhydrous Et₂O (20 mL), Mg (0.51 g, 21.0 mmol), and ClP(NEt₂)Ph (3.45 g, 16.0 mmol). The title compound (1.82 g, 6.38 mmol, 40%) was obtained as a colorless oil.

Distillation: 230 °C, 0.06 mbar.

¹H NMR (400 MHz, C₆D₆): δ = 7.60–7.54 (m, 2 H, Ar-H), 7.25 (d, J = 7.3 Hz, 2 H, H-2), 7.21–7.07 (m, 3 H, Ar-H), 6.79 (s, 1 H, H-4), 3.16–3.02 (m, 4 H, H-1″), 2.11 (d, J = 0.7 Hz, 6 H, H-5), 0.90 (t, J = 7.1 Hz, 6 H, H-2″).

¹³C NMR (101 MHz, C₆D₆): δ = 141.6 (d, J = 16.0 Hz, C-1 or C-1′), 140.9 (d, J = 15.4 Hz, C-1 or C-1′), 137.6 (d, J = 6.2 Hz, 2 C, C-3), 132.4 (d, J = 19.9 Hz, 2 C, C-2 or C-2′), 130.3 (d, J = 20.3 Hz, 2 C, C-2 or C-2′), 130.3 (C-4), 128.4 (d, J = 5.6 Hz, 2 C, C-3′), 128.3 (C-4′), 44.8 (d, J = 15.8 Hz, 2 C, C-1″), 21.4 (2 C, C-5), 14.7 (d, J = 3.4 Hz, 2 C, C-2″).

³¹P NMR (162 MHz, C₆D₆): δ = 62.2 (s).

MS (EI, 70 eV): m/z (%) = 285 (100) [M]⁺.

Diethylamino(2,6-dimethoxyphenyl)(phenyl)phosphine (14)

1,3-Dimethoxybenzene (2.42 mL, 2.56 g, 18.5 mmol, 1.00 eq.) and TMEDA (0.1 mL) were dissolved in anhydrous Et₂O (15 mL) and cooled to 0 °C. Subsequently, n-BuLi (1.56 m solution in n-hexane, 12.5 mL, 19.5 mmol, 1.05 eq.) was added dropwise, the reaction mixture was warmed to ambient temperature, and stirred for 2 h. The resulting colorless suspension was then treated with ClP(NEt₂)Ph 4 (4.00 g, 18.5 mmol, 1.00 eq.) at −78 °C, slowly warmed to ambient temperature, and stirred overnight. The solids were filtered off under Ar and the solvent was removed under reduced pressure. The crude product was purified by bulb-to-bulb distillation under reduced pressure (200 °C, 0.05 mbar) to afford the title compound (5.31 g, 16.7 mmol, 90%) as a colorless oil.

¹H NMR (300 MHz, C₆D₆): δ = 7.56–7.46 (m, 2 H, H-2′), 7.22–7.00 (m, 4 H (integration too large due to overlap with C₆D₅H signal), H-4, H-4′ and H-3′), 6.33 (dd, J = 8.3, 2.2 Hz, 2 H, H-3), 3.34–3.14 (m, 10 H, H-1″ and H-5), 1.01 (t, J = 7.1 Hz, 6 H, H-2″).

¹³C NMR (75 MHz, C₆D₆): δ = 163.1 (d, J = 9.4 Hz, 2 C, C-2), 144.6 (d, J = 7.9 Hz, C-1′), 131.2 (C-4)*, 129.9 (d, J = 19.8 Hz, 2 C, C-2′), 127.8 (d, J = 4.6 Hz, 2 C, C-3′), 126.5 (d, J = 1.7 Hz, C-4′)*, 117.0 (d, J = 42.7 Hz, C-1), 104.7 (2 C, C-3), 55.2 (d, J = 0.9 Hz, 2 C, C-5), 46.3 (d, J = 16.7 Hz, 2 C, C-1″), 15.2 (d, J = 4.0 Hz, 2 C, C-2″).

*Assignment of signals eventually interchangeable.

³¹P NMR (121 MHz, C₆D₆): δ = 45.6 (s).

MS (EI, 70 eV): m/z (%) = 317 (100) [M]⁺.

Diethylamino(n-butyl)(phenyl)phosphine (15)

ClP(NEt₂)Ph 4 (2.50 g, 11.6 mmol, 1.00 eq.) was added slowly to a solution of n-BuLi (1.56 m solution in n-hexane, 7.82 mL, 12.2 mmol, 1.05 eq.) in anhydrous Et₂O (20 mL) at 0 °C. The reaction mixture was warmed to ambient temperature, the resulting solids were filtered off under Ar, and the filtrate was concentrated. The crude product was purified by bulb-to-bulb distillation under reduced pressure (120 °C, 0.01 mbar) to afford the title compound (2.20 g, 9.27 mmol, 80%) as a colorless oil.

¹H NMR (400 MHz, C₆D₆): δ = 7.46–7.41 (m, 2 H, H-2′), 7.24–7.18 (m, 2 H, H-3′), 7.13–7.07 (m, 1 H, H-4′), 2.99–2.82 (m, 4 H, H-1″), 1.96–1.82 (m, 1 H, H-1, H-2 or H-3), 1.71–1.38 (m, 5 H, H-1, H-2 and H-3), 0.95 (t, J = 6.9 Hz, 6 H, H-2″), 0.93 (t, J = 7.3 Hz, 3 H, H-4).

¹³C NMR (101 MHz, C₆D₆): δ = 144.1 (d, J = 19.3 Hz, C-1′), 130.5 (d, J = 16.8 Hz, 2 C, C-2′), 128.3 (d, J = 4.1 Hz, 2 C, C-3′), 127.6 (C-4′), 44.5 (d, J = 14.6 Hz, 2 C, C-1″), 28.6 (d, J = 15.0 Hz, C-1, C-2 or C-3), 28.2 (d, J = 18.2 Hz, C-1, C-2 or C-3), 24.7 (d, J = 13.5 Hz, C-1, C-2 or C-3), 15.5 (d, J = 3.1 Hz, 2 C, C-2″), 14.2 (C-4).

³¹P NMR (162 MHz, C₆D₆): δ = 57.2 (s).

MS (EI, 70 eV): m/z (%) = 237 (78) [M]⁺.

General Procedure D (GP D): Synthesis of Secondary Diarylphosphine Oxides

Mg turnings (3.0 eq.) were suspended in anhydrous Et₂O (10 mL). The Grignard reaction was started by the addition of 0.5 mL of the corresponding aryl bromide (heating under reflux if necessary). A solution of aryl bromide (total of 3.0 eq.) in anhydrous Et₂O was then added dropwise and the reaction mixture was stirred until complete consumption of the magnesium (heating under reflux if necessary). After dropwise addition of diethyl phosphite (1.0 eq.) at 0 °C, the reaction mixture was heated under reflux for 2 h. The mixture was then cooled to 0 °C and the magnesium salts carefully dissolved with 10% aqueous HCl. H₂O was added and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over MgSO₄ and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography.

Bis(4-fluorophenyl)phosphine Oxide

The reaction was performed according to a slightly modified GP D using Mg (2.50 g, 103 mmol, 3.00 eq.), 1-bromo-4-fluorobenzene (12.4 mL, 19.8 g, 113 mmol, 3.30 eq.), diethyl phosphite (4.42 mL, 4.74 g, 34.3 mmol, 1.00 eq.), and anhydrous Et₂O (75 mL). The crude product was purified by flash column chromatography (SiO₂, EtOAc–DCM) to afford the title compound (4.49 g, 18.9 mmol, 55%) as a colorless, viscous oil.

R_f = 0.28 (DCM–EtOAc, 3:1).

¹H NMR (300 MHz, CDCl₃): δ = 8.07 (d, J = 485.9 Hz, 1 H, P-H), 7.74–7.62 (m, 4 H, H-2), 7.24–7.15 (m, 4 H, H-3).

³¹P NMR (122 MHz, CDCl₃): δ = 18.9 (s).

¹⁹F NMR (282 MHz, CDCl₃): δ = −104.9 (m).

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₂H₁₀F₂OP⁺: 239.0432; found: 239.0430.

The analytical data are consistent with those previously reported in literature. ⁵⁰

Bis(4-trifluoromethylphenyl)phosphine Oxide (16)

The reaction was performed according to GP D using Mg (0.75 g, 30.9 mmol), 1-bromo-4-(trifluoromethyl)benzene (4.33 mL, 6.94 g, 30.9 mmol), diethyl phosphite (1.32 mL, 1.42 g, 10.3 mmol), and anhydrous Et₂O (35 mL). The crude product was purified by flash column chromatography (SiO₂, DCM–EtOAc, 3:1) to afford the title compound (2.67 g, 7.90 mmol, 77%) as a colorless solid.

R_f = 0.47 (DCM–EtOAc, 3:1).

¹H NMR (300 MHz, CDCl₃): δ = 8.19 (d, J = 490.9 Hz, 1 H, P-H), 7.91–7.76 (m, 8 H, Ar-H).

³¹P NMR (122 MHz, CDCl₃): δ = 17.8 (s).

¹⁹F NMR (282 MHz, CDCl₃): δ = −63.4 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₄H₁₀F₆OP⁺: 339.0368; found: 339.0375.

The analytical data are consistent with those previously reported in literature. ⁵¹

Bis[3,5-bis(trifluoromethyl)phenyl]phosphine Oxide (17)

Mg turnings (1.35 g, 55.7 mmol, 2.20 eq.) were suspended in anhydrous Et₂O (10 mL). The Grignard reaction was started by addition of 0.5 mL 1-bromo-3,5-bis(trifluoromethyl)benzene (heated under reflux if necessary). A solution of 1-bromo-3,5-bis(trifluoromethyl)benzene (total of 8.73 mL, 14.8 g, 50.6 mmol, 2.00 eq.) in anhydrous Et₂O (30 mL) was then added dropwise and the reaction mixture was stirred for another 30 min.

In a second flask, a solution of diethyl phosphite (3.26 mL, 3.49 g, 25.3 mmol, 1.00 eq.) in anhydrous THF (5 mL) was deprotonated by portionwise addition of NaH (60% in mineral oil, 1.01 g, 25.3 mmol, 1.00 eq.). The resulting sodium salt was then added dropwise to the Grignard at 0 °C. The reaction mixture was heated under reflux for 2 h, then cooled to 0 °C, and the magnesium salts carefully dissolved with 10% aqueous HCl. H₂O was added and the aqueous layer was extracted with DCM (3x). The combined organic layers were dried over MgSO₄ and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, EtOAc–DCM) to afford the title compound (7.77 g, 16.4 mmol, 65%) as a colorless solid.

R_f = 0.92 (DCM–EtOAc, 3:1).

¹H NMR (300 MHz, CDCl₃): δ = 8.31 (d, J = 504.3 Hz, 1 H, P-H), 8.20 (d, J = 13.4 Hz, 4 H, H-2), 8.15 (s, 2 H, H-4).

³¹P NMR (122 MHz, CDCl₃): δ = 14.3 (s).

¹⁹F NMR (282 MHz, CDCl₃): δ = −63.1 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₆H₈F₁₂OP⁺: 475.0116; found: 475.0118.

The analytical data are consistent with those previously reported in literature. [33]

General Procedure E (GP E): Synthesis of Symmetric Diarylphosphine Chlorides

The corresponding diaryl(diethylamino)phosphine or secondary diarylphosphine oxide (1.0 eq.) was dissolved in anhydrous DCM and treated with PCl₃ (1.5 to 3.0 eq.). The reaction mixture was stirred at ambient temperature for 1 h. All volatiles were removed under high vacuum using a cooling trap (liquid N₂). The residue was dissolved in a minimum amount of anhydrous Et₂O and quickly filtered through Celite. The solvent was removed and the residue dried under high vacuum. The formation of the diarylphosphine chloride was confirmed by ³¹P NMR spectroscopy and it was directly used in the following step without further purification.

Bis(4-methoxyphenyl)chlorophosphine (18)

The reaction was performed according to a slightly modified GP E using diethylamino-bis(4-methoxyphenyl)phosphine 5 (3.40 g, 10.7 mmol, 1.00 eq.), PCl₃ (2.81 mL, 4.41 g, 32.1 mmol, 3.00 eq.), and anhydrous DCM (25 mL). The reaction was stirred at ambient temperature for 30 min. The title compound (1.83 g, 6.52 mmol, 61%) was obtained as a yellow oil.

³¹P NMR (121 MHz, CDCl₃): δ = 85.4 (s).

The analytical data are consistent with those previously reported in literature. [33]

Bis(4-fluorophenyl)chlorophosphine (19)

The reaction was performed according to GP E using diethylamino-bis(4-fluorophenyl)phosphine 6 (11.4 g, 39.0 mmol, 1.00 eq.), PCl₃ (5.12 mL, 8.03 g, 58.5 mmol, 1.50 eq.), and anhydrous DCM (100 mL) to afford the title compound (5.93 g, 23.1 mmol, 59%).

³¹P NMR (121 MHz, CDCl₃): δ = 80.6 (t, J = 4.7 Hz).

The analytical data are consistent with those previously reported in literature.[33]

Bis(4-trifluoromethylphenyl)chlorophosphine (20)

The reaction was performed according to GP E using bis(4-trifluoro-methylphenyl)phosphine oxide 16 (2.00 g, 5.91 mmol, 1.00 eq.), PCl₃ (1.55 mL, 2.44 g, 17.7 mmol, 3.00 eq.), and anhydrous DCM (10 mL). The title compound (1.85 g, 5.19 mmol, 88%) was obtained as a yellow oil.

³¹P NMR (101 MHz, CDCl₃): δ = 75.3 (s).

The analytical data are consistent with those previously reported in literature.[33]

Bis[3,5-bis(trifluoromethyl)phenyl]chlorophosphine (21)

The reaction was performed according to GP E using bis[3,5-bis(trifluoromethyl)phenyl]phosphine oxide 17 (7.68 g, 16.2 mmol, 1.00 eq.), PCl₃ (2.74 mL, 4.30 g, 31.3 mmol, 1.93 eq.), and anhydrous DCM (35 mL) to yield the title compound (5.22 g, 10.6 mmol, 65%).

³¹P NMR (121 MHz, CDCl₃): δ = 71.7 (s).

The analytical data are consistent with those previously reported in literature.[33]

2-Bromo-6-(tert-butoxy)pyridine (22)

2,6-Dibromopyridine (4.74 g, 20.0 mmol, 1.00 eq.) was dissolved in anhydrous toluene (75 mL). KOt-Bu (3.14 g, 28.0 mmol, 1.40 eq.) was added and the resulting suspension was stirred at 80 °C for 2 h under exclusion of moisture. After cooling to ambient temperature, the reaction mixture was filtered through Celite, the solids were washed with DCM, and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, hexanes–EtOAc, 10:1), yielding the title compound (4.10 g, 17.8 mmol, 89%) as a colorless liquid.

R_f = 0.79 (hexanes–EtOAc, 9:1).

¹H NMR (400 MHz, CDCl₃): δ = 7.34 (dd, J = 8.1, 7.5 Hz, 1 H, H-4), 6.97 (dd, J = 7.5, 0.7 Hz, 1 H, H-3), 6.57 (dd, J = 8.2, 0.7 Hz, 1 H, H-5), 1.58 (s, 9 H, H-2′).

¹³C NMR (101 MHz, CDCl₃): δ = 163.1 (C-6), 140.1 (C-4), 137.7 (C-2), 119.5 (C-3), 111.5 (C-5), 81.0 (C-1′), 28.5 (3 C, C-2′).

HRMS (APCI): m/z [M + H]⁺ calcd for C₉H₁₃ ⁷⁹BrNO⁺: 230.0175; found: 230.0172.

The analytical data are consistent with those previously reported in literature. [6]

2-(tert-Butoxy)-6-chloropyridine (23)

2,6-Dichloropyridine (10.0 g, 67.6 mmol, 1.00 eq.) was dissolved in anhydrous toluene (150 mL). KOt-Bu (9.10 g, 81.1 mmol, 1.20 eq.) was added and the resulting suspension was stirred at 80 °C for 6 h under exclusion of moisture. After cooling to ambient temperature, the reaction mixture was filtered through SiO₂ (5 × 5 cm) and the filtrate was concentrated under reduced pressure. The crude product was purified by bulb-to-bulb distillation under reduced pressure (200 °C, 0.1 mbar), yielding the title compound (12.0 g, 64.6 mmol, 96%) as a colorless liquid.

R_f = 0.85 (hexanes–EtOAc, 9:1).

¹H NMR (500 MHz, CDCl₃): δ = 7.44 (dd, J = 8.2, 7.5 Hz, 1 H, H-4), 6.82 (dd, J = 7.5, 0.7 Hz, 1 H, H-5), 6.54 (dd, J = 8.2, 0.7 Hz, 1 H, H-3), 1.58 (s, 9 H, H-2′).

¹³C NMR (126 MHz, CDCl₃): δ = 163.3 (C-2), 147.6 (C-6), 140.2 (C-4), 115.7 (C-5), 111.3 (C-3), 80.9 (C-1′), 28.6 (3 C, C-2′).

HRMS (APCI): m/z [M]⁺ calcd for C₉H₁₂ ³⁵ClNO⁺: 185.0602; found: 185.0606.

The analytical data are consistent with those previously reported in literature.[1]

6-(Diphenylphosphino)pyridin-2(1H)-one (6-DPPon, L1)

Method A: Electrophilic Route

2-Bromo-6-(tert-butoxy)pyridine 22 (100 mg, 0.43 mmol, 1.00 eq.) was dissolved in anhydrous Et₂O (3 mL) and cooled to 0 °C. Subsequently,

n-BuLi (1.56 m solution in n-hexane, 0.28 mL, 0.43 mmol, 1.00 eq.) was added dropwise and the resulting yellow solution was stirred at 0 °C for 1 h. ClPPh₂ (95.0 mg, 0.43 mmol, 1.00 eq.) was then added, the reaction mixture was allowed to warm to ambient temperature and stirred for an additional hour. After addition of H₂O (1 drop), the solvent was removed under reduced pressure and the residue was purified by flash column chromatography (SiO₂, DCM) to afford 2-(tert-butoxy)-6-(diphenyl-phosphino)pyridine (125 mg, 0.34 mmol, 77%) as a colorless solid.

(mp 77 °C).

Method B: Nucleophilic Route – Multigram Scale

In a 1000-mL three-necked flask, Na (5.40 g, 235 mmol, 2.03 eq.) was dissolved in liquid NH₃ (ca. 500 mL) over 10 min at −78 °C. After 15 min, the deep blue solution was treated portionwise with triphenylphosphine (30.4 g, 116 mmol, 1.00 eq.) and stirred at −78 °C for 2 h, resulting in an orange suspension. After addition of 2-(tert-butoxy)-6-chloropyridine 23 (21.5 g, 116 mmol, 1.00 eq.) and anhydrous THF (175 mL), the reaction mixture was slowly warmed to ambient temperature and stirred overnight. The reaction was quenched with H₂O (200 mL) and the aqueous layer was extracted with Et₂O (3 × 150 mL). The combined organic layers were dried over Na₂SO₄ and the solvent was removed under reduced pressure. The residual oil was triturated with MeOH, leading to crystallization of the desired product. 2-(tert-Butoxy)-6-(diphenylphosphino)pyridine (34.2 g, 102 mmol, 88%) was obtained as a colorless solid (mp 77 °C) and was used directly in the next step without further purification.

Deprotection

2-(tert-Butoxy)-6-(diphenylphosphino)pyridine (27.5 g, 82.0 mmol, 1.00 eq.) was dissolved in degassed, concentrated formic acid (280 mL). After stirring at ambient temperature for 2 h, the reaction mixture was diluted with H₂O (340 mL). The precipitate was collected by filtration, washed with aqueous formic acid (HCO₂H:H₂O = 1:2 (v/v), 80 mL), and dried under high vacuum. 6-DPPon (15.9 g, 56.9 mmol, 69%) was obtained as a colorless solid. The combined aqueous layers were concentrated under reduced pressure, yielding additional 6.7 g 6-DPPon (24.0 mmol, 29%) after flash column chromatography (SiO₂, DCM ➔ EtOAc–DCM, 2:1).

Note: The obtained precipitate after addition of H₂O is usually quite pure. To further increase its purity, it can be digerated with Et₂O.

Mp 187 °C; R_f = 0.33 (EtOAc–DCM, 1:1).

¹H NMR (700 MHz, CDCl₃): δ = 9.54 (br. s, 1 H, N-H), 7.43–7.34 (m, 10 H, H-2′, H-3′ and H-4′), 7.28 (ddd, J = 9.2, 6.7, 2.1 Hz, 1 H, H-4), 6.45 (dd, J = 9.3, 1.1 Hz, 1 H, H-3), 6.15 (ddd, J = 6.5, 5.3, 1.1 Hz, 1 H, H-5).

¹³C NMR (176 MHz, CDCl₃): δ = 163.9 (d, J = 1.5 Hz, C-2), 146.3 (d, J = 25.2 Hz, C-6), 140.2 (d, J = 6.9 Hz, C-4), 133.9 (d, J = 20.3 Hz, 4 C, C-2′), 132.8 (d, J = 10.0 Hz, 2 C, C-1′), 130.1 (2 C, C-4′), 129.2 (d, J = 7.4 Hz, 4 C, C-3′), 121.0 (C-3), 113.4 (d, J = 20.5 Hz, C-5).

³¹P NMR (283 MHz, CDCl₃): δ = −9.4 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₇H₁₅NOP⁺: 280.0886; found: 280.0887.

Anal. calcd for C₁₇H₁₄NOP: C, 73.11; H, 5.05; N, 5.02. Found: C, 72.97;

H, 5.18; N, 4.73.

The analytical data are consistent with those previously reported in literature.[6]

6-[Bis(4-methoxyphenyl)phosphino]pyridin-2(1H)-one (6-BpAnPon, L2)

To a solution of 2-bromo-6-(tert-butoxy)pyridine 22 (1.48 g, 6.41 mmol, 1.00 eq.) in anhydrous Et₂O (40 mL), n-BuLi (2.5 m solution in hexanes, 2.57 mL, 6.41 mmol, 1.00 eq.) was added dropwise at 0 °C and the resulting yellow solution was stirred for 1 h. Then a solution of bis(4-methoxyphenyl)chlorophosphine 18 (1.80 g, 6.41 mmol, 1.00 eq.) in anhydrous Et₂O (3 mL) was added slowly. The mixture was warmed to ambient temperature and stirred for another hour. The reaction was quenched by addition of stoichiometric amounts of H₂O (0.12 mL) and the solvent was removed under reduced pressure. The residue was dissolved in H₂O/DCM (1:1, 40 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The residue was filtered through a short plug of deactivated silica (2 × 5 cm, hexanes ➔ hexanes–DCM, 1:1) and concentrated under reduced pressure to obtain the protected ligand (1.73 g, 4.37 mmol), which was directly used in the next step without further purification.

The protected ligand was dissolved in degassed, concentrated formic acid (8 mL) and stirred at ambient temperature for 1 h. The reaction mixture was then diluted with H₂O (75 mL), leading to precipitation of the desired product. The precipitate was collected by filtration, dissolved in DCM (75 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was dissolved in EtOAc (30 mL), filtered through a short silica plug, and the filtrate was concentrated again. Final precipitation with Et₂O afforded 6-BpAnPon (662 mg, 1.95 mmol, 30% over two steps) as a colorless solid.

Note: Residual formic acid could be removed by drying under vacuum over P₂O₅ (in a desiccator).

Mp 163-165 °C; R_f = 0.39 (EtOAc).

¹H NMR (700 MHz, CD₂Cl₂): δ = 9.62 (br. s, 1 H, N-H), 7.35–7.31 (m, 4 H, H-2′), 7.26 (ddd, J = 9.0, 6.7, 2.1 Hz, 1 H, H-4), 6.97–6.92 (m, 4 H, H-3′), 6.31 (dd, J = 9.2, 1.1 Hz, 1 H, H-3), 5.99 (ddd, J = 6.8, 4.3, 1.1 Hz, 1 H, H-5), 3.81 (s, 6 H, H-1″).

¹³C NMR (176 MHz, CD₂Cl₂): δ = 164.0 (C-2), 161.7 (2 C, C-4′), 148.6 (d, J = 23.2 Hz, C-6), 140.3 (d, J = 5.4 Hz, C-4), 136.0 (d, J = 22.2 Hz, 4 C, C-2′), 124.2 (d, J = 6.9 Hz, 2 C, C-1′), 120.3 (C-3), 115.1 (d, J = 8.5 Hz, 4 C, C-3′), 112.4 (d, J = 16.7 Hz, C-5), 55.7 (2 C, C-1″).

³¹P NMR (283 MHz, CD₂Cl₂): δ = −12.1 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₉H₁₉NO₃P⁺: 340.1097; found: 340.1103.

6-[Bis(4-fluorophenyl)phosphino]pyridin-2(1H)-one (6-BpFPPon, L3)

To a solution of 2-bromo-6-(tert-butoxy)pyridine 22 (2.00 g, 8.70 mmol, 1.00 eq.) in anhydrous Et₂O (50 mL), n-BuLi (1.3 m solution in n-hexane, 6.69 mL, 8.70 mmol, 1.00 eq.) was added dropwise at 0 °C and the resulting yellow solution was stirred for 1 h. Bis(4-fluorophenyl)-chlorophosphine 19 (2.46 g, 9.57 mmol, 1.10 eq.) was added, the mixture was warmed to ambient temperature and stirred for another hour. The reaction was quenched by addition of stoichiometric amounts of H₂O (0.16 mL) and the solvent was removed under reduced pressure. The residue was dissolved in H₂O/DCM (1:1, 100 mL) and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure.

The resulting protected ligand was directly dissolved in degassed, concentrated formic acid (20 mL) and stirred at ambient temperature for 1 h. The reaction mixture was then diluted with H₂O (40 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, DCM ➔ DCM–EtOAc, 9:1) and digerated with Et₂O to afford 6-BpFPPon (1.89 g, 6.00 mmol, 69% over two steps) as a colorless solid.

Mp 185 °C; R_f = 0.10 (DCM–EtOAc, 9:1).

¹H NMR (400 MHz, CDCl₃): δ = 9.63 (br. s, 1 H, N-H), 7.41–7.30 (m, 4 H, H-2′), 7.30 (ddd, J = 8.9, 6.8, 2.1 Hz, H-4), 7.16–7.09 (m, 4 H, H-3′), 6.46 (d, J = 9.2 Hz, 1 H, H-3), 6.06 (dd, J = 6.1, 5.1 Hz, 1 H, H-5).

¹³C NMR (126 MHz, CDCl₃): δ = 164.2 (C-2), 164.2 (d, J = 251.8 Hz, 2 C, C-4′), 146.6 (d, J = 23.2 Hz, C-6), 140.3 (d, J = 5.7 Hz, C-4), 136.1 (dd, J = 22.1, 8.3 Hz, 4 C, C-2′), 128.2 (dd, J = 9.6, 3.5 Hz, 2 C, C-1′), 121.0 (C-3), 116.7 (dd, J = 21.2, 8.3 Hz, 4 C, C-3′), 113.3 (d, J = 17.0 Hz, C-5).

³¹P NMR (121 MHz, CDCl₃, calib. with H₃PO₄): δ = −10.9 (t, J = 4.3 Hz).

Anal. calcd for C₁₇H₁₂F₂NOP: C, 64.77; H, 3.84; N, 4.44. Found: C, 64.58;

H, 3.90; N, 4.53.

The analytical data are consistent with those previously reported in literature.[19]

6-[Bis(4-trifluoromethylphenyl)phosphino]pyridin-2(1H)-one (6-BpTFMPPon, L4)

To a solution of 2-bromo-6-(tert-butoxy)pyridine 22 (2.00 g, 8.70 mmol, 1.00 eq.) in anhydrous Et₂O (50 mL), n-BuLi (2.5 m solution in hexanes, 3.48 mL, 8.70 mmol, 1.00 eq.) was added dropwise at 0 °C and the resulting yellow solution was stirred for 1 h. Bis(4-trifluoromethyl-phenyl)chlorophosphine 20 (3.57 g, 10.0 mmol, 1.15 eq.) was added, the mixture was warmed to ambient temperature and stirred for another hour. The reaction was quenched by addition of stoichiometric amounts of H₂O (0.16 mL) and the solvent was removed under reduced pressure. The residue was dissolved in H₂O/DCM (1:1, 100 mL) and the aqueous layer was extracted with DCM (2 × 50 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (SiO₂, n-pentane–EtOAc, 9:1).

Degassed, concentrated formic acid (20 mL) was added to a solution of the protected ligand in anhydrous DCM (20 mL), the mixture was stirred at ambient temperature for 1 h, diluted with H₂O (40 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, DCM–EtOAc, 10:1). To achieve sufficient purity of the desired product, the resulting solid was dissolved in Et₂O (100 mL) under heating and subsequently precipitated by addition of n-pentane (100 mL). 6-BpTFMPPon (2.17 g, 5.22 mmol, 60% over two steps) was obtained as a colorless solid.

Mp 166–169 °C; R_f = 0.50 (DCM–EtOAc, 9:1).

¹H NMR (700 MHz, CD₂Cl₂/DMSO-d₆ (5:1)): δ = 11.36 (br. s, 1 H, N-H), 7.65–7.56 (m, 4 H, H-3′), 7.49–7.42 (m, 4 H, H-2′), 7.23–7.18 (m, 1 H, H-4), 6.31 (d, J = 9.2 Hz, 1 H, H-3), 5.80 (dd, J = 6.9, 3.5 Hz, 1 H, H-5).

¹³C NMR (176 MHz, CD₂Cl₂/DMSO-d₆ (5:1)): δ = 164.0 (d, J = 5.3 Hz, C-2), 146.5 (C-6), 139.7 (d, J = 4.1 Hz, C-4), 138.6 (d, J = 13.0 Hz, 2 C, C-1′), 134.5 (d, J = 20.6 Hz, 4 C, C-2′), 131.5 (q, J = 32.4 Hz, 2 C, C-4′), 125.7 (dq,

J = 7.6, 3.6 Hz, 4 C, C-3′), 124.1 (q, J = 272.4 Hz, 2 C, C-1″), 120.5 (C-3), 113.4 (d, J = 9.7 Hz, C-5).

³¹P NMR (283 MHz, CD₂Cl₂/DMSO-d₆ (5:1)): δ = −9.9 (s).

¹⁹F NMR (659 MHz, CD₂Cl₂/DMSO-d₆ (5:1)): δ = −63.0 (s).

Note: Due to solubility issues, the NMR spectra were recorded in a 5:1 mixture of CD₂Cl₂ and DMSO-d₆ and chemical shifts were referenced to residual CHDCl₂ for ¹H (δ = 5.32 ppm) and CD₂Cl₂ for ¹³C (δ = 53.8 ppm).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₉H₁₃F₆NOP⁺: 416.0633; found: 416.0640.

The analytical data are consistent with those previously reported in literature.[19]

6-[Bis(3,5-bis(trifluoromethyl)phenyl)phosphino]pyridin-2(1H)-one (6-BbmTFMPPon, L5)

To a solution of 2-bromo-6-(tert-butoxy)pyridine 22 (400 mg, 1.74 mmol, 1.00 eq.) in anhydrous Et₂O (12 mL), n-BuLi (1.65 m solution in n-hexane, 1.13 mL, 1.87 mmol, 1.07 eq.) was added dropwise at 0 °C and the resulting yellow solution was stirred for 1 h. Bis[3,5-bis(trifluoro-methyl)phenyl]chlorophosphine 21 (0.99 g, 2.00 mmol, 1.15 eq.) was added, the mixture was warmed to ambient temperature and stirred for another hour. The reaction was quenched by addition of stoichiometric amounts of H₂O (0.04 mL) and the solvent was removed under reduced pressure. The resulting oil was directly dissolved in degassed, concentrated formic acid (10 mL) and stirred at ambient temperature for 1 h. The reaction mixture was then diluted with H₂O (20 mL) and extracted with EtOAc (2 × 50 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, DCM–EtOAc, 40:1 ➔ 10:1) and digerated with hexanes to afford 6-BbmTFMPPon (584 mg, 1.06 mmol, 61% over two steps) as a colorless solid.

Mp 213 °C; R_f = 0.30 (DCM–EtOAc, 10:1).

¹H NMR (700 MHz, CD₂Cl₂): δ = 12.59 (br. s, 1 H, N-H), 7.97 (dd, J = 7.0, 2.2 Hz, 4 H, H-2′), 7.93 (t, J = 2.3 Hz, 2 H, H-4′), 7.35 (ddd, J = 9.1, 6.7, 2.3 Hz, 1 H, H-4), 6.48 (ddd, J = 9.0, 6.7, 1.1 Hz, 1 H, H-5), 6.21 (ddd, J = 9.3, 1.1, 1.1 Hz, 1 H, H-3).

¹³C NMR (176 MHz, CD₂Cl₂): δ = 165.6 (d, J = 1.4 Hz, C-2), 142.8 (d, J = 25.4 Hz, C-6), 140.7 (d, J = 11.6 Hz, C-4), 136.7 (d, J = 15.2 Hz, 2 C, C-1′), 134.1 (dq, J = 21.3, 3.9 Hz, 4 C, C-2′), 132.5 (qd, J = 33.6, 6.7 Hz, 4 C, C-3′), 124.4 (dq, J = 3.8, 3.8 Hz, 2 C, C-4′), 123.4 (q, J = 272.9 Hz, 4 C, C-1″), 123.1 (C-3), 117.2 (d, J = 32.8 Hz, C-5).

³¹P NMR (283 MHz, CD₂Cl₂): δ = −6.7 (s).

¹⁹F NMR (659 MHz, CD₂Cl₂): δ = −63.5 (s).

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₁H₁₁F₁₂NOP⁺: 552.0381; found: 552.0394.

The analytical data are consistent with those previously reported in literature.[19]

General Procedure F (GP F): Synthesis of Chiral Phosphine Chlorides

HCl (in Et₂O, 2.0 eq.) was slowly added to a solution of the corresponding aryl(diethylamino)(phenyl)phosphine or diethylamino(n-butyl)(phenyl)-phosphine (1.0 eq.) in anhydrous Et₂O (1.0 M) at 0 °C. The reaction mixture was stirred at 0 °C until complete conversion of the starting material, as confirmed by ³¹P NMR spectroscopy (approximately 30 min to 1 h). The resulting suspension was warmed to ambient temperature, filtered through Celite under Ar, and the solids were washed several times with anhydrous Et₂O. The filtrate was carefully concentrated and the residue was dried under vacuum for 30 min at slightly elevated temperature to remove traces of excess HCl. The phosphine chloride obtained was dissolved in anhydrous THF and used in the following step without further purification.

General Procedure G (GP G): Racemic Synthesis of P-stereogenic 6-DPPon Derivatives

To a solution of 2-bromo-6-(tert-butoxy)pyridine 22 (1.0 to 1.4 eq.) in anhydrous THF, n-BuLi (1.0 to 1.4 eq.) was added dropwise at −78 °C and the resulting yellow solution was stirred for 1 h. A solution of the corresponding unsymmetric phosphine chloride (1.0 eq.) in anhydrous THF (for preparation see GP F) was then added at −78 °C, the reaction mixture was slowly warmed to ambient temperature and stirred overnight. The reaction was quenched with H₂O (5 mL) and the aqueous layer was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with aqueous sat. NaHCO₃ (1 × 20 mL), dried over MgSO₄, and concentrated under reduced pressure. The resulting protected ligand was directly dissolved in degassed, concentrated formic acid (10 mL) and stirred at ambient temperature until complete conversion of the starting material (followed by TLC). The acid was then removed under vacuum and the crude product was either purified by flash column chromatography or recrystallization.

rac-6-[1-Naphthyl(phenyl)phosphino]pyridin-2(1H)-one (rac-L6)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (0.90 g, 3.91 mmol, 1.20 eq.), anhydrous THF (10 mL), n-BuLi (1.60 m solution in n-hexane, 2.45 mL, 3.91 mmol, 1.20 eq.), and chloro(1-naphthyl)(phenyl)phosphine (0.88 g, 3.26 mmol, 1.00 eq.). The crude product was purified by flash column chromatography (SiO₂, CH–EtOAc, 1:4) to afford the title compound (378 mg, 1.15 mmol, 35% over two steps) as a colorless solid.

Mp 193–195 °C; R_f = 0.30 (hexanes–EtOAc; 1:10).

¹H NMR (400 MHz, CDCl₃): δ = 9.35 (br. s, 1 H, N-H), 8.35–8.28 (m, 1 H,

Ar-H), 7.94–7.85 (m, 2 H, Ar-H), 7.55–7.47 (m, 2 H, Ar-H), 7.45–7.34 (m,

6 H, Ar-H), 7.28 (ddd, J = 9.3, 6.7, 2.2 Hz, 1 H, H-4), 7.15 (ddd, J = 7.0, 5.3, 1.2 Hz, 1 H, Ar-H), 6.45 (dd, J = 9.3, 1.1 Hz, 1 H, H-3), 6.23 (ddd, J = 6.7, 5.7, 1.1 Hz, 1 H, H-5).

¹³C NMR (101 MHz, CDCl₃): δ = 163.9 (C-2), 145.3 (d, J = 24.5 Hz, C-6), 140.3 (d, J = 7.7 Hz, C-4), 135.2 (d, J = 23.2 Hz, C-8a′), 134.2 (d, J = 20.7 Hz, 2 C, C-2″), 133.7 (d, J = 4.8 Hz, C-4a′), 132.5 (Ar-C), 132.1 (d, J = 8.9 Hz, C-1′ or C-1″), 130.9 (Ar-C), 130.3 (Ar-C), 130.0 (d, J = 12.5 Hz, C-1′ or C-1″), 129.4 (d, J = 7.7 Hz, 2 C, C-3″), 129.0 (d, J = 1.9 Hz, Ar-C), 127.0 (d, J = 2.4 Hz, Ar-C), 126.6 (Ar-C), 125.8 (d, J = 1.9 Hz, Ar-C), 125.4 (d, J = 26.6 Hz, Ar-C), 121.3 (C-3), 114.1 (d, J = 22.3 Hz, C-5).

³¹P NMR (162 MHz, CDCl₃): δ = −16.9 (s).

MS (EI, 70 eV): m/z (%) = 329 (100) [M]⁺.

Anal. calcd for C₂₁H₁₆NOP: C, 75.55; H, 4.98; N, 4.20. Found: C, 75.54; H, 5.02; N, 3.97.

Chiral HPLC (Chiralpak AD-H, λ = 311 nm, n-heptane:EtOH = 80:20, 0.8 mL min⁻¹, rt):

(+)-enantiomer: t_R = 12.7 min: [α]_D ²¹ +67.6 (c 0.55, CHCl₃);

(−)-enantiomer: t_R = 15.1 min: [α]_D ²¹ −68.8 (c 0.50, CHCl₃).

Totally, 35 mg of rac-L6 were separated via preparative chiral HPLC (Chiralpak AD-H, λ = 311 nm, n-heptane:EtOH = 80:20, 11.0 mL min⁻¹, 24 °C). Both enantiomers were obtained with >99% ee and the analytical data were consistent with those of the racemate. The products were stored under Ar at −20 °C to prevent thermal racemization.

rac-6-[2-Methylphenyl(phenyl)phosphino]pyridin-2(1H)-one (rac-L7)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (1.27 g, 5.53 mmol, 1.00 eq.), anhydrous THF (16 mL), n-BuLi (1.56 m solution in n-hexane, 3.72 mL, 5.81 mmol, 1.05 eq.), and chloro(2-methylphenyl)(phenyl)phosphine (1.30 g, 5.53 mmol, 1.00 eq.). The crude product was purified by flash column chromatography (SiO₂, hexanes–EtOAc, 1:8) to afford the title compound (465 mg, 1.59 mmol, 29% over two steps) as a colorless solid.

Decomposition >188 °C; R_f = 0.55 (hexanes–EtOAc, 1:8).

¹H NMR (300 MHz, CDCl₃): δ = 8.98 (br. s, 1 H, N-H), 7.45–7.22 (m, 8 H, H-4 and Ar-H), 7.20–7.12 (m, 1 H, Ar-H), 6.93–6.86 (m, 1 H, Ar-H), 6.50 (ddd, J = 9.2, 1.1, 0.5 Hz, 1 H, H-3), 6.23 (ddd, J = 6.8, 5.8, 1.1 Hz, 1 H, H-5), 2.41 (d, J = 1.5 Hz, 3 H, H-7′).

¹³C NMR (101 MHz, CDCl₃): δ = 163.9 (C-2), 145.5 (d, J = 24.7 Hz, C-6)*, 142.7 (d, J = 27.6 Hz, C-2′)*, 140.4 (d, J = 7.3 Hz, C-4), 134.1 (d, J = 21.8 Hz, 2 C, C-2″), 132.8 (Ar-C), 132.0 (d, J = 8.7 Hz, C-1′ or C-1″), 131.5 (d, J = 10.2 Hz, C-1′ or C-1″), 130.9 (d, J = 5.8 Hz, Ar-C), 130.3 (Ar-C), 130.2 (Ar-C), 129.4 (d, J = 7.3 Hz, 2 C, C-3″), 126.8 (Ar-C), 121.1 (C-3), 114.0 (d, J = 23.2 Hz, C-5), 21.2 (d, J = 21.8 Hz, C-7′).

*Assignment of signals eventually interchangeable.

³¹P NMR (121 MHz, CDCl₃): δ = −15.1 (s).

MS (EI, 70 eV): m/z (%) = 293 (100) [M]⁺.

Anal. calcd for C₁₈H₁₆NOP: C, 73.71; H, 5.50; N, 4.78. Found: C, 73.51; H, 5.89; N, 4.29.

rac-6-[3-Methylphenyl(phenyl)phosphino]pyridin-2(1H)-one (rac-L8)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (1.36 g, 5.90 mmol, 1.00 eq.), anhydrous THF (20 mL), n-BuLi (1.56 m solution in n-hexane, 3.97 mL, 6.20 mmol, 1.05 eq.), and chloro(3-methylphenyl)(phenyl)phosphine (1.38 g, 5.90 mmol, 1.00 eq.). The crude product was purified by flash column chromatography (SiO₂, hexanes–EtOAc, 1:8) and digerated with hexanes:i-PrOH = 3:1 to afford the title compound (696 mg, 2.37 mmol, 40% over two steps) as a colorless solid.

Decomposition >190 °C; R_f = 0.24 (hexanes–EtOAc, 1:8).

¹H NMR (300 MHz, CDCl₃): δ = 8.79 (br. s, 1 H, N-H), 7.47–7.09 (m, 10 H (integration too large due to overlap with CHCl₃ signal), H-4 and Ar-H), 6.51 (d, J = 9.1 Hz, 1 H, H-3), 6.28 (ddd, J = 6.6, 6.6, 1.7 Hz, 1 H, H-5), 2.34 (s, 3 H, H-7′).

¹³C NMR (101 MHz, CDCl₃): δ = 163.8 (C-2), 146.2 (d, J = 27.4 Hz, C-6), 140.2 (d, J = 7.6 Hz, C-4), 139.1 (d, J = 8.7 Hz, C-3′), 134.5 (d, J = 21.8 Hz, C-2′ or C-6′), 133.8 (d, J = 20.3 Hz, 2 C, C-2″), 132.9 (d, J = 10.2 Hz, C-1′ or C-1″), 132.4 (d, J = 8.8 Hz, C-1′ or C-1″), 131.1 (C-4′ or C-4″), 130.9 (d, J = 18.8 Hz, C-2′ or C-6′), 130.1 (C-4′ or C-4″), 129.2 (d, J = 7.3 Hz, 2 C, C-3″), 129.2 (d, J = 7.0 Hz, C-5′), 121.0 (C-3), 113.6 (d, J = 23.1 Hz, C-5), 21.5 (C-7′).

³¹P NMR (121 MHz, CDCl₃): δ = −7.9 (s).

MS (EI, 70 eV): m/z (%) = 293 (100) [M]⁺.

Anal. calcd for C₁₈H₁₆NOP: C, 73.71; H, 5.50; N, 4.78. Found: C, 73.43; H, 5.77; N, 4.60.

Chiral HPLC (Chiralpak AD-H, λ = 319 nm, n-heptane:EtOH = 90:10, 0.8 mL min⁻¹, rt):

(−)-enantiomer: t_R = 14.0 min: [α]_D ²¹ −7.3 (c 0.51, CHCl₃);

(+)-enantiomer: t_R = 15.2 min: [α]_D ²¹ +7.6 (c 0.55, CHCl₃).

Totally, 53 mg of rac-L8 was separated via preparative chiral HPLC (Chiralpak AD-H, λ = 319 nm, n-heptane:EtOH = 90:10, 11.0 mL min⁻¹, 24 °C). Both enantiomers were obtained with >99% ee and the analytical data were consistent with those of the racemate. The products were stored under Ar at −20 °C to prevent thermal racemization.

rac-6-[3,5-Dimethylphenyl(phenyl)phosphino]pyridin-2(1H)-one (rac-L9)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (1.21 g, 5.26 mmol, 1.00 eq.), anhydrous THF (15 mL), n-BuLi (1.56 m solution in n-hexane, 3.37 mL, 5.26 mmol, 1.00 eq.), and chloro(3,5-dimethylphenyl)(phenyl)phosphine (1.31 g, 5.26 mmol, 1.00 eq.). The crude product was purified by flash column chromatography (SiO₂, CH–EtOAc, 1:3) to afford the title compound (621 mg, 2.02 mmol, 38% over two steps) as a colorless solid.

Mp 128–130 °C; R_f = 0.77 (CH–EtOAc, 1:3).

¹H NMR (400 MHz, CDCl₃): δ = 8.98 (br. s, 1 H, N-H), 7.43–7.34 (m, 5 H, Ar-H), 7.32 (ddd, J = 9.0, 6.7, 2.2 Hz, 1 H, H-4), 7.05 (s, 1 H, H-4′), 6.96 (d, J = 8.7 Hz, 2 H, H-2′), 6.48 (dd, J = 9.2, 1.1 Hz, 1 H, H-3), 6.24 (ddd, J = 6.8, 5.9, 1.1 Hz, 1 H, H-5), 2.28 (d, J = 0.7 Hz, 6 H, H-5′).

¹³C NMR (101 MHz, CDCl₃): δ = 163.8 (C-2), 146.2 (d, J = 26.9 Hz, C-6), 140.3 (d, J = 8.1 Hz, C-4), 139.0 (d, J = 7.8 Hz, 2 C, C-3′), 133.8 (d, J = 20.2 Hz, 2 C, C-2″), 133.0 (d, J = 10.4 Hz, C-1′ or C-1″), 132.2 (C-4′), 132.0 (d, J = 9.6 Hz, C-1′ or C-1″), 131.5 (d, J = 20.6 Hz, 2 C, C-2′), 130.1 (C-4″), 129.2 (d, J = 7.3 Hz, 2 C, C-3″), 121.0 (C-3), 113.6 (d, J = 23.8 Hz, C-5), 21.4 (2 C, C-5′).

³¹P NMR (162 MHz, CDCl₃): δ = −9.2 (s).

MS (EI, 70 eV): m/z (%) = 307 (100) [M]⁺.

Anal. calcd for C₁₉H₁₈NOP: C, 73.39; H, 5.96; N, 4.50. Found: C, 73.47; H, 6.08; N, 4.40.

Chiral HPLC (Chiralpak AD-H, λ = 311 nm, n-heptane:EtOH = 90:10, 0.8 mL min⁻¹, rt):

(+)-enantiomer: t_R = 12.0 min: [α]_D ²¹ +19.9 (c 1.00, CHCl₃);

(−)-enantiomer: t_R = 13.5 min: [α]_D ²¹ −20.5 (c 0.99, CHCl₃).

Totally, 70 mg of rac-L9 was separated via preparative chiral HPLC (Chiralpak AD-H, λ = 311 nm, n-heptane:EtOH = 90:10, 11.0 mL min⁻¹, rt). Both enantiomers were obtained with >99% ee and the analytical data were consistent with those of the racemate. The products were stored under Ar at −20 °C to prevent thermal racemization.

rac-6-[Mesityl(phenyl)phosphino]pyridin-2(1H)-one (rac-L10)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (1.10 g, 4.80 mmol, 1.40 eq.), anhydrous THF (19 mL), n-BuLi (1.56 m solution in n-hexane, 3.08 mL, 4.80 mmol, 1.40 eq.), and chloro(mesityl)(phenyl)phosphine (0.90 g, 3.43 mmol, 1.00 eq.). The crude product was purified by flash column chromatography (SiO₂, hexanes–EtOAc, 1:9) to afford the title compound (325 mg, 1.01 mmol, 29% over two steps) as a colorless solid.

Mp 138–141 °C; R_f = 0.45 (hexanes–EtOAc, 1:10).

¹H NMR (400 MHz, C₆D₆): δ = 12.95 (br. s, 1 H, N-H), 7.36–7.28 (m, 2 H,

H-2″), 7.05–6.97 (m, 3 H, H-3″ and H-4″), 6.73 (dq, J = 2.9, 0.6 Hz, 2 H,

H-3′), 6.58 (ddd, J = 9.1, 6.8, 2.2 Hz, 1 H, H-4), 6.15 (ddd, J = 9.1, 0.9, 0.9 Hz, 1 H, H-3), 5.94 (ddd, J = 6.8, 1.2, 1.2 Hz, 1 H, H-5), 2.34 (q, J = 0.7 Hz, 6 H, H-5′), 2.03 (s, 3 H, H-6′).

¹³C NMR (101 MHz, C₆D₆): δ = 165.4 (d, J = 3.4 Hz, C-2), 149.9 (d,

J = 23.6 Hz, C-6), 146.3 (d, J = 17.0 Hz, 2 C, C-2′), 140.6 (d, J = 1.3 Hz, C-4′), 139.4 (d, J = 1.8 Hz, C-4), 133.2 (d, J = 12.5 Hz, C-1′ or C-1″), 132.7 (d,

J = 18.6 Hz, 2 C, C-2″), 130.4 (d, J = 4.9 Hz, 2 C, C-3′), 128.9 (d, J = 5.8 Hz,

2 C, C-3″), 128.5 (C-4″), 125.7 (d, J = 13.1 Hz, C-1′ or C-1″), 118.8 (d,

J = 2.7 Hz, C-3), 109.0 (d, J = 8.4 Hz, C-5), 23.6 (d, J = 17.7 Hz, 2 C, C-5′), 21.0 (C-6′).

³¹P NMR (162 MHz, C₆D₆): δ = −20.4 (s).

MS (EI, 70 eV): m/z (%) = 321 (89) [M]⁺.

Anal. calcd for C₂₀H₂₀NOP: C, 74.75; H, 6.27; N, 4.36. Found: C, 74.63;

H, 6.55; N, 3.97.

rac-6-[2,6-Dimethoxyphenyl(phenyl)phosphino]pyridin-2(1H)-one (rac-L11)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (0.70 g, 3.04 mmol, 1.40 eq.), anhydrous THF (12 mL),

n-BuLi (1.56 m solution in n-hexane, 1.88 mL, 2.93 mmol, 1.35 eq.), and chloro(2,6-dimethoxyphenyl)(phenyl)phosphine (0.61 g, 2.17 mmol, 1.00 eq.). The crude product was dissolved in t-BuOMe, and the resulting precipitate was collected by filtration and dried under high vacuum. The title compound (263 mg, 0.78 mmol, 36% over two steps) was obtained as a colorless solid.

Mp 187–189 °C.

¹H NMR (400 MHz, C₆D₆): δ = 10.11 (br. s, 1 H, N-H), 7.29–7.22 (m, 2 H,

H-2″), 7.02 (t, J = 8.3 Hz, 1 H, H-4′), 6.99–6.92 (m, 3 H, H-3″ and H-4″), 6.63 (ddd, J = 9.2, 6.5, 2.6 Hz, 1 H, H-4), 6.43 (ddd, J = 9.3, 1.0, 1.0 Hz, 1 H, H-3), 6.31 (ddd, J = 9.6, 6.5, 1.1 Hz, 1 H, H-5), 6.16 (dd, J = 8.3, 2.7 Hz, 2 H, H-3′), 3.13 (s, 6 H, H-5′).

¹³C NMR (101 MHz, C₆D₆): δ = 163.7 (d, J = 8.6 Hz, 2 C, C-2′), 163.4 (C-2), 146.9 (d, J = 33.7 Hz, C-6), 139.4 (d, J = 13.5 Hz, C-4), 135.8 (d, J = 11.2 Hz, C-1″), 133.3 (C-4′), 131.4 (d, J = 18.9 Hz, 2 C, C-2″), 128.7 (d, J = 5.3 Hz,

2 C, C-3″), 128.1 (C-4″ (superimposed by solvent signal)), 121.9 (C-3), 113.8 (d, J = 41.5 Hz, C-5), 109.8 (d, J = 22.6 Hz, C-1′), 105.2 (2 C, C-3′), 55.6 (2 C, C-5′).

³¹P NMR (162 MHz, C₆D₆): δ = −29.4 (s).

MS (EI, 70 eV): m/z (%) = 339 (100) [M]⁺.

Anal. calcd for C₁₉H₁₈NO₃P: C, 66.37; H, 5.42; N, 4.07. Found: C, 66.65;

H, 5.44; N, 4.04.

rac-6-[2-Trifluoromethylphenyl(phenyl)phosphino]pyridin-2(1H)-one (rac-L12)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (1.45 g, 6.31 mmol, 1.30 eq.), anhydrous THF (20 mL), n-BuLi (1.56 m solution in n-hexane, 4.04 mL, 6.31 mmol, 1.30 eq.), and chloro(2-trifluoromethylphenyl)(phenyl)phosphine (1.40 g, 4.85 mmol, 1.00 eq.). The crude product was dissolved in t-BuOMe, the resulting precipitate was filtered off and washed with t-BuOMe. The solvent of the combined organic layers was removed under reduced pressure and the solid residue was recrystallized from i-PrOH (1 mL). To achieve sufficient purity, the product was washed with t-BuOMe in an ultrasonic bath, affording the title compound (499 mg, 1.44 mmol, 30% over two steps) as a colorless solid.

Mp 171–174 °C.

¹H NMR (300 MHz, CDCl₃): δ = 7.86–7.78 (m, 1 H, Ar-H), 7.61–7.50 (m,

2 H, Ar-H), 7.47–7.27 (m, 7 H, H-4 and Ar-H), 6.53 (dd, J = 9.3, 1.0 Hz, 1 H, H-3), 6.20 (ddd, J = 6.6, 5.6, 1.0 Hz, 1 H, H-5).*

*Signal for N-H not detectable.

³¹P NMR (121 MHz, CDCl₃): δ = −12.3 (q, J = 53.4 Hz).

¹⁹F NMR (470 MHz, C₆D₆, calib. with CFCl₃): δ = −57.4 (d, J = 53.4 Hz).

MS (EI, 70 eV): m/z (%) = 347 (100) [M]⁺.

Anal. calcd for C₁₈H₁₃F₃NOP: C, 62.25; H, 3.77; N, 4.03. Found: C, 62.44;

H, 3.88; N, 3.81.

rac-6-[3-Trifluoromethylphenyl(phenyl)phosphino]pyridin-2(1H)-one (rac-L13)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (1.38 g, 6.02 mmol, 1.10 eq.), anhydrous THF (20 mL),

n-BuLi (1.56 m solution in n-hexane, 3.86 mL, 6.02 mmol, 1.10 eq.), and chloro(3-trifluoromethylphenyl)(phenyl)phosphine (1.58 g, 5.47 mmol, 1.00 eq.). The crude product was purified by flash column chromatography (SiO₂, hexanes–EtOAc, 1:8) to afford the title compound (927 mg, 2.67 mmol, 49% over two steps) as a colorless solid.

Mp 150–154 °C; R_f = 0.62 (hexanes–EtOAc, 1:10).

¹H NMR (300 MHz, CDCl₃): δ = 10.01 (br. s, 1 H, N-H), 7.67–7.64 (m, 2 H, Ar-H), 7.54–7.48 (m, 2 H, Ar-H), 7.46–7.33 (m, 5 H, Ar-H), 7.29 (ddd,

J = 9.3, 6.7, 2.1 Hz, 1 H, H-4), 6.45 (dd, J = 9.2, 1.0 Hz, 1 H, H-3), 6.08 (ddd, J = 6.6, 4.7, 1.1 Hz, 1 H, H-5).

³¹P NMR (121 MHz, CDCl₃): δ = −8.4 (s).

¹⁹F NMR (470 MHz, C₆D₆, calib. with CFCl₃): δ = −63.3 (s).

MS (EI, 70 eV): m/z (%) = 347 (100) [M]⁺.

Anal. calcd for C₁₈H₁₃F₃NOP: C, 62.25; H, 3.77; N, 4.03. Found: C, 62.38;

H, 3.53; N, 3.70.

Chiral HPLC (Chiralpak AD-H, λ = 322 nm, n-heptane:i-PrOH = 95:5, 0.8 mL min⁻¹, rt):

(+)-enantiomer: t_R = 27.3 min: [α]_D ²¹ +24.6 (c 0.68, CHCl₃);

(−)-enantiomer: t_R = 29.5 min: [α]_D ²¹ −25.0 (c 0.70, CHCl₃).

Totally, 45 mg of rac-L13 was separated via preparative chiral HPLC (Chiralpak AD-H, λ = 322 nm, n-heptane:i-PrOH = 95:5, 11.0 mL min⁻¹, 24 °C). Both enantiomers were obtained with >99% ee and the analytical data were consistent with those of the racemate. The products were stored under Ar at −20 °C to prevent thermal racemization.

rac-6-[n-Butyl(phenyl)phosphino]pyridin-2(1H)-one (rac-L14)

The reaction was performed according to GP G using 2-bromo-6-(tert-butoxy)pyridine (1.39 g, 6.03 mmol, 1.30 eq.), anhydrous THF (20 mL), n-BuLi (1.56 m solution in n-hexane, 3.87 mL, 6.03 mmol, 1.30 eq.), and chloro(n-butyl)(phenyl)phosphine (0.93 g, 4.64 mmol, 1.00 eq.). The crude product was purified by flash column chromatography (SiO₂, CH–EtOAc; 1:5) to afford the title compound (758 mg, 2.92 mmol, 63% over two steps) as a colorless oil.

R_f = 0.58 (CH–EtOAc, 1:5).

¹H NMR (400 MHz, C₆D₆): δ = 13.36 (br. s, 1 H, N-H), 7.62–7.56 (m, 2 H, H-2″), 7.10–7.00 (m, 3 H, H-3″ and H-4″), 6.66 (ddd, J = 9.2, 6.7, 1.8 Hz, 1 H, H-4), 6.38 (ddd, J = 9.1, 1.1, 0.5 Hz, 1 H, H-3), 5.95 (ddd, J = 6.6, 5.3, 1.1 Hz, 1 H, H-5), 2.55–2.44 (m, 1 H, H-1′)*, 2.16–2.03 (m, 1 H, H-1′)*, 1.50–1.31 (m, 4 H, H-2′ and H-3′)*, 0.79 (t, J = 7.1 Hz, 3 H, H-4′).

*Assignment of signals eventually interchangeable.

¹³C NMR (101 MHz, C₆D₆): δ = 166.0 (d, J = 1.6 Hz, C-2), 150.6 (d, J = 29.2 Hz, C-6), 140.0 (d, J = 6.8 Hz, C-4), 135.3 (d, J = 13.0 Hz, C-1″), 133.9 (d, J = 20.0 Hz, 2 C, C-2″), 129.6 (C-4″), 128.8 (d, J = 7.1 Hz, 2 C, C-3″), 120.3 (C-3), 112.3 (d, J = 20.3 Hz, C-5), 28.3 (d, J = 16.7 Hz, C-2′)*, 24.7 (d, J = 11.1 Hz, C-1′)*, 24.3 (d, J = 13.8 Hz, C-3′)*, 13.8 (C-4′).

*Assignment of signals eventually interchangeable.

³¹P NMR (162 MHz, C₆D₆): δ = −17.0 (s).

MS (EI, 70 eV): m/z (%) = 259 (100) [M]⁺.

rac-2-(tert-Butoxy)-6-[tert-butyl(methyl)phosphino]pyridine Borane Adduct (rac-24)

To a solution of 2-bromo-6-(tert-butoxy)pyridine 22 (1.77 g, 7.70 mmol, 1.00 eq.) in anhydrous THF (20 mL), n-BuLi (1.42 m solution in n-hexane, 5.42 mL, 7.70 mmol, 1.00 eq.) was added dropwise at −78 °C and the resulting yellow solution was stirred for 1 h. A solution of tert-butyl-chloro(methyl)phosphine (1.07 g, 7.70 mmol, 1.00 eq.) in anhydrous THF (5 mL) was then added at −78 °C, the reaction mixture was warmed to ambient temperature and treated with BH₃ ∙SMe₂ (1.00 m solution in DCM, 7.70 mL, 7.70 mmol, 1.00 eq.). After stirring for further 3 h, the reaction was quenched with H₂O (30 mL). The aqueous layer was extracted with EtOAc (3 × 20 mL), the combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, hexanes–EtOAc, 40:1) to afford the title compound (485 mg, 1.82 mmol, 24%) as a colorless oil.

R_f = 0.35 (hexanes–EtOAc, 40:1).

¹H NMR (400 MHz, CDCl₃): δ = 7.56 (ddd, J = 8.1, 7.1, 4.1 Hz, 1 H, H-4), 7.52–7.48 (m, 1 H, H-5), 6.70 (ddd, J = 8.3, 1.4, 1.4 Hz, 1 H, H-3), 1.59 (s, 9 H, H-2′), 1.59 (d, J = 10.3 Hz, 3 H, H-1″), 1.14 (d, J = 13.8 Hz, 9 H, H-2″′), 0.69 (br. q, J = 91.0 Hz, 3 H, B-H ₃).

¹³C NMR (101 MHz, CDCl₃): δ = 163.4 (C-2), 149.4 (d, J = 66.5 Hz, C-6), 138.0 (d, J = 10.9 Hz, C-4), 123.6 (d, J = 24.8 Hz, C-5), 115.5 (C-3), 79.9 (C-1′), 28.8 (d, J = 32.0 Hz, C-1″′), 28.8 (3 C, C-2′), 25.6 (d, J = 2.9 Hz, 3 C, C-2″′), 4.8 (d, J = 39.2 Hz, C-1″).

³¹P NMR (121 MHz, CDCl₃): δ = 31.1 (q, J = 62.2 Hz).

Anal. calcd for C₁₄H₂₇BNOP: C, 62.94; H, 10.19; N, 5.24. Found: C, 63.27;

H, 10.42; N, 5.23.

rac-6-[tert-Butyl(methyl)phosphino]pyridin-2(1H)-one Borane Adduct (rac-L15∙BH₃)

rac-2-(tert-Butoxy)-6-[tert-butyl(methyl)phosphino]pyridine borane adduct rac-24 (441 mg, 1.65 mmol, 1.00 eq.) was dissolved in degassed, concentrated formic acid (10 mL) and stirred at ambient temperature until complete conversion of the starting material (followed by TLC). The acid was then removed under vacuum and the crude product was purified by flash column chromatography (SiO₂, hexanes–EtOAc, 1:8) to afford the title compound (298 mg, 1.41 mmol, 86%) as a colorless solid.

Mp 140 °C; R_f = 0.51 (hexanes–EtOAc, 1:10).

¹H NMR (400 MHz, CDCl₃): δ = 7.45 (ddd, J = 9.3, 6.6, 2.8 Hz, 1 H, H-4), 6.74 (ddd, J = 8.0, 6.7, 1.1 Hz, 1 H, H-5), 6.66 (ddd, J = 9.3, 1.4, 1.4 Hz, 1 H, H-3), 1.72 (d, J = 10.0 Hz, 3 H, H-1′), 1.19 (d, J = 14.9 Hz, 9 H, H-2″), 0.65 (br. q, J = 114.2 Hz, 3 H, B-H ₃).*

*Signal for N-H not detectable.

¹³C NMR (101 MHz, CDCl₃): δ = 163.8 (d, J = 4.2 Hz, C-2), 139.8 (d, J = 10.2 Hz, C-4), 137.9 (d, J = 43.4 Hz, C-6), 123.8 (C-3), 115.2 (d, J = 10.1 Hz, C-5), 29.5 (d, J = 30.5 Hz, C-1″), 25.5 (d, J = 2.9 Hz, 3 C, C-2″), 4.4 (d, J = 36.4 Hz, C-1′).

³¹P NMR (121 MHz, CDCl₃): δ = 31.7 (br. m).

MS (EI, 70 eV): m/z (%) = 211 (7) [M]⁺.

Anal. calcd for C₁₀H₁₉BNOP: C, 56.91; H, 9.07; N, 6.64. Found: C, 57.12; H, 9.22; N, 6.52.

Chiral HPLC (Chiralpak AD-H, λ = 313 nm, EtOH, 0.5 mL min⁻¹, rt):

(+)-enantiomer: t_R = 7.6 min: [α]_D ²² +3.7 (c 0.65, CH₂Cl₂);

(−)-enantiomer: t_R = 11.9 min: [α]_D ²² −3.7 (c 0.65, CH₂Cl₂).

Totally, 135 mg of rac-L15∙BH ₃ was separated via preparative chiral HPLC (Chiralpak AD-H, λ = 313 nm, EtOH, 11.0 mL min⁻¹, rt). Both enantiomers were obtained with >99% ee and the analytical data were consistent with those of the racemate. The products were stored under Ar at −20 °C to prevent thermal racemization.

Deprotection of rac-L15∙BH₃ (rac-L15)

rac-L15∙BH ₃ (218 mg, 1.03 mmol, 1.00 eq.) was dissolved in degassed HNEt₂ (10 mL) and heated under reflux for 6 h. All volatiles were then removed and the crude product was dried under high vacuum to afford rac-6-[tert-butyl(methyl)phosphino]pyridin-2(1H)-one ( rac-L15) (203 mg, 1.03 mmol, 100%) as a colorless oil.

¹H NMR (300 MHz, C₆D₆): δ = 12.08 (br. s, 1 H, N-H), 6.73 (ddd, J = 9.1, 6.6, 1.5 Hz, 1 H, H-4), 6.47 (ddd, J = 9.1, 1.0, 1.0 Hz, 1 H, H-3), 6.00 (ddd, J = 6.9, 5.9, 1.1 Hz, 1 H, H-5), 1.19 (d, J = 4.6 Hz, 3 H, H-1′), 0.96 (d, J = 12.4 Hz, 9 H, H-2″).

³¹P NMR (121 MHz, C₆D₆): δ = −6.0 (s).

Due to the lability of the ligand toward oxygen, only a ¹H and ³¹P NMR could be obtained.

2-(tert-Butoxy)-6-[bis(diethylamino)phosphino]pyridine (25)

To a solution of 2-bromo-6-(tert-butoxy)pyridine 22 (1.64 g, 7.12 mmol, 1.00 eq.) in anhydrous Et₂O (40 mL), n-BuLi (2.5 m solution in hexanes, 2.85 mL, 7.12 mmol, 1.00 eq.) was added dropwise at 0 °C and the resulting yellow solution was stirred for 1 h. Subsequently, ClP(NEt₂)₂ 3 (1.50 mL, 1.50 g, 7.12 mmol, 1.00 eq.) was added slowly and the reaction mixture was stirred at 0 °C for another hour. The reaction was quenched by addition of H₂O (0.13 mL) and the solvent was removed under reduced pressure. The residue was dissolved in H₂O/DCM (1:1, 40 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was filtered through a short plug of deactivated silica (hexanes) to afford the title compound (2.02 g, 6.21 mmol, 87%) as a pale yellow oil.

R_f = 0.90 (deactivated SiO₂, hexanes).

¹H NMR (700 MHz, C₆D₆): δ = 7.16 (ddd, J = 7.2, 3.6, 1.2 Hz, 1 H (integration too large due to overlap with C₆D₅H signal), H-5), 7.13 (ddd, J = 7.9, 7.3, 3.2 Hz, 1 H, H-4), 6.52 (ddd, J = 7.9, 1.2, 1.2 Hz, 1 H, H-3), 3.17 (ddq, J = 14.1, 8.2, 7.1 Hz, 4 H, H-1_B″), 3.10 (ddq, J = 14.0, 11.0, 7.1 Hz, 4 H, H-1_A″), 1.67 (s, 9 H, H-2′), 1.09 (t, J = 7.1 Hz, 12 H, H-2″).

¹³C NMR (176 MHz, C₆D₆): δ = 164.7 (d, J = 9.2 Hz, C-2), 163.3 (d, J = 13.7 Hz, C-6), 137.7 (d, J = 1.9 Hz, C-4), 119.6 (d, J = 21.7 Hz, C-5), 111.4 (d, J = 2.8 Hz, C-3), 79.0 (C-1′), 44.0 (d, J = 17.2 Hz, 4 C, C-1″), 28.9 (3 C, C-2′), 15.0 (d, J = 3.1 Hz, 4 C, C-2″).

³¹P NMR (283 MHz, C₆D₆): δ = 94.3 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₇H₃₃N₃OP⁺: 326.2356; found: 326.2354.

The analytical data are consistent with those previously reported in literature.[39]

2-(tert-Butoxy)-6-[bis(pyrrol-1-yl)phosphino]pyridine (26)

2-(tert-Butoxy)-6-[bis(diethylamino)phosphino]pyridine 25 (728 mg, 2.24 mmol, 1.00 eq.) was dissolved in a mixture of anhydrous THF (25 mL) and C₆D₆ (2.5 mL) and treated with PCl₃ (0.69 mL, 1.08 g, 7.84 mmol, 3.50 eq.) at ambient temperature. The formation of the ArPCl₂ intermediate was followed by ³¹P NMR spectroscopy (δ(ArPCl₂) = 144 ppm, solution A).

In a second flask, a solution of pyrrole (2.33 mL, 2.25 g, 33.6 mmol, 15.0 eq.) in anhydrous THF (25 mL) was deprotonated with n-BuLi (2.5 m solution in hexanes, 13.4 mL, 33.6 mmol, 15.0 eq.) at 0 °C. The mixture was stirred at 0 °C for 30 min (solution B).

After complete formation of the ArPCl₂ intermediate, solution B was added to solution A at 0 °C. The reaction mixture was warmed to ambient temperature and stirred for 2 h. The reaction was then quenched with H₂O (0.5 mL) and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (deactivated SiO₂, hexanes) to afford the title compound (363 mg, 1.16 mmol, 52%) as a colorless oil.

R_f = 0.60 (deactivated SiO₂, hexanes).

Note: Runtime on column is significantly longer than expected by R_f value.

¹H NMR (400 MHz, C₆D₆): δ = 6.91–6.88 (m, 4 H, H-2″), 6.82 (ddd, J = 8.4, 7.2, 3.4 Hz, 1 H, H-4), 6.41 (dd, J = 8.4, 0.8 Hz, 1 H, H-3), 6.40 (ddd, J = 7.2, 0.8, 0.8 Hz, 1 H, H-5), 6.32–6.28 (m, 4 H, H-3″), 1.41 (s, 9 H, H-2′).

¹³C NMR (101 MHz, C₆D₆): δ = 164.1 (d, J = 12.6 Hz, C-2 or C-6), 157.2 (d, J = 13.7 Hz, C-2 or C-6), 138.4 (d, J = 2.8 Hz, C-4), 125.1 (d, J = 14.8 Hz, 4 C, C-2″), 119.0 (d, J = 21.4 Hz, C-5), 114.0 (d, J = 1.4 Hz, C-3), 112.6 (d, J = 4.4 Hz, 4 C, C-3″), 80.4 (C-1′), 28.5 (3 C, C-2′).

³¹P NMR (162 MHz, C₆D₆): δ = 59.0 (s).

HRMS: m/z [M + H]⁺ calcd for C₁₇H₂₁N₃OP⁺: 314.1417; found: 314.1422.

The analytical data are consistent with those previously reported in literature.[39]

6-[Bis(pyrrol-1-yl)phosphino]pyridin-2(1H)-one (6-DPyPon, L16)

Degassed, concentrated formic acid (8.00 mL, 9.76 g, 212 mmol, 137 eq.) was added to a solution of 2-(tert-Butoxy)-6-[bis(pyrrol-1-yl)phosphino]-pyridine 26 (485 mg, 1.55 mmol, 1.00 eq.) in anhydrous DCM (40 mL) and the reaction mixture was stirred at ambient temperature for 15 min. The volume of the mixture was halved under reduced pressure (water bath of rotary evaporator at 20 °C). H₂O (20 mL) was then added and the aqueous layer was extracted with DCM (1 × 20 mL). The combined organic layers were washed with H₂O (2 × 20 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The resulting solid residue was digerated with a small amount of Et₂O and dried under vacuum over P₂O₅ for two days to afford 6-DPyPon (302 mg, 1.17 mmol, 76%) as a colorless solid.

Mp 201 °C.

¹H NMR (400 MHz, CD₂Cl₂): δ = 9.10 (br. s, 1 H, N-H), 7.34 (ddd, J = 9.3, 6.7, 3.0 Hz, 1 H, H-4), 7.01–6.97 (m, 4 H, H-2′), 6.49 (ddd, J = 9.3, 0.9, 0.9 Hz, 1 H, H-3), 6.41–6.38 (m, 4 H, H-3′), 5.96 (ddd, J = 6.8, 3.0, 1.0 Hz, 1 H, H-5).

¹³C NMR (101 MHz, CD₂Cl₂): δ = 163.2 (C-2), 144.6 (d, J = 11.3 Hz, C-6), 140.2 (d, J = 3.9 Hz, C-4), 125.3 (d, J = 15.5 Hz, 4 C, C-2′), 122.5 (d, J = 2.4 Hz, C-3), 114.0 (d, J = 5.1 Hz, 4 C, C-3′), 111.8 (d, J = 16.7 Hz, C-5).

³¹P NMR (162 MHz, CD₂Cl₂): δ = 53.5 (s).

HRMS: m/z [M + Na]⁺ calcd for C₁₃H₁₂N₃OPNa⁺: 280.0610; found: 280.0611.

The analytical data are consistent with those previously reported in literature.[39]

Bis(diethylamino)[3,5-bis(trifluoromethyl)phenyl]phosphine (27)

1-Bromo-3,5-bis(trifluoromethyl)benzene (1.23 mL, 2.09 g, 7.12 mmol, 1.00 eq.) was dissolved in anhydrous Et₂O (40 mL) and cooled to 0 °C. Subsequently, n-BuLi (2.5 m solution in hexanes, 2.85 mL, 7.12 mmol, 1.00 eq.) was added slowly. After 1 h, the deep red solution was treated with ClP(NEt₂)₂ 3 (1.50 mL, 1.50 g, 7.12 mmol, 1.00 eq.) and stirred for another hour at 0 °C. The reaction was quenched with H₂O (0.13 mL) and the solvent was removed under reduced pressure. The residue was dissolved in H₂O/DCM (1,1, 40 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over Na₂SO₄, and concentrated under reduced pressure to afford the title compound (2.59 g, 6.67 mmol, 94%) as a yellow oil. The crude product was directly used in the next step without further purification.

¹H NMR (400 MHz, C₆D₆): δ = 7.99–7.95 (m, 2 H, H-2′), 7.73–7.69 (m, 1 H, H-4′), 2.80 (dq, J = 10.0, 7.1 Hz, 8 H, H-1), 0.92 (t, J = 7.1 Hz, 12 H, H-2).

¹³C NMR (101 MHz, C₆D₆): δ = 146.9 (d, J = 5.3 Hz, C-1′), 131.6 (qd, J = 32.6, 2.2 Hz, 2 C, C-3′), 131.5 (dq, J = 16.8, 4.4 Hz, 2 C, C-2′), 124.3 (q, J = 272.5 Hz, 2 C, C-1″), 121.2 (dq, J = 7.5, 3.8 Hz, C-4′), 43.0 (d, J = 17.2 Hz, 4 C, C-1), 14.5 (d, J = 3.3 Hz, 4 C, C-2).

³¹P NMR (162 MHz, C₆D₆): δ = 94.8 (s).

¹⁹F NMR (377 MHz, C₆D₆): δ = −62.7 (s).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₆H₂₄F₆N₂P⁺: 389.1576; found: 389.1581.

rac-2-(tert-Butoxy)-6-[diethylamino(3,5-bis(trifluoromethyl)-phenyl)phosphino]pyridine (rac-28)

A solution of bis(diethylamino)[3,5-bis(trifluoromethyl)phenyl]phosphine 27 (986 mg, 2.54 mmol, 1.00 eq.) in anhydrous Et₂O (10 mL) and C₆D₆ (1 mL) was treated with AcCl (190 μL, 209 mg, 2.67 mmol, 1.05 eq.) and stirred at ambient temperature until complete consumption of the starting material, as confirmed by ³¹P NMR spectroscopy (δ(ArPCl(NEt₂)) = 132 ppm, ArPCl(NEt₂)-solution).

In a separate flask, 2-bromo-6-(tert-butoxy)pyridine 22 (613 mg, 2.67 mmol, 1.05 eq.) was dissolved in anhydrous Et₂O (10 mL) and cooled to 0 °C. n-BuLi (2.5 m solution in hexanes, 1.07 mL, 2.67 mmol, 1.05 eq.) was added and the mixture was stirred for 30 min, resulting in a yellow solution. The freshly prepared ArPCl(NEt₂) solution was then added dropwise, and the reaction mixture was allowed to warm to ambient temperature and stirred for another 30 min before being quenched with H₂O (10 mL). The aqueous layer was extracted with Et₂O (2 × 20 mL), and the combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography (deactivated SiO₂, hexanes) to afford the title compound (540 mg, 1.16 mmol, 46%) as a colorless oil.

R_f = 0.79 (deactivated SiO₂, hexanes).

¹H NMR (300 MHz, C₆D₆): δ = 7.98–7.92 (m, 2 H, H-2″′), 7.79–7.74 (m, 1 H, H-4″′), 7.00–6.97 (m, 2 H, Ar-H), 6.50–6.44 (m, 1 H, Ar-H), 3.04–2.85 (m, 4 H, H-1″), 1.32 (s, 9 H, H-2′), 0.78 (t, J = 7.1 Hz, 6 H, H-2″).

³¹P NMR (122 MHz, C₆D₆): δ = 60.2 (s).

¹⁹F NMR (282 MHz, C₆D₆): δ = −62.6 (s).

rac-2-(tert-Butoxy)-6-[3,5-bis(trifluoromethyl)phenyl(pyrrol-1-yl)-phosphino]pyridine (rac-29)

A solution of rac-2-(tert-butoxy)-6-[diethylamino(3,5-bis(trifluoro-methyl)phenyl)phosphino]pyridine rac-28 (540 mg, 1.16 mmol, 1.00 eq.) in anhydrous Et₂O (10 mL) and C₆D₆ (1 mL) was treated with AcCl (95 μL, 104 mg, 1.33 mmol, 1.15 eq.) and stirred at ambient temperature until complete consumption of the starting material, as confirmed by ³¹P NMR spectroscopy (δ(Ar₁Ar₂PCl) = 64 ppm, Ar₁Ar₂PCl-solution).

In a separate flask, pyrrole (0.80 mL, 0.78 g, 11.6 mmol, 10.0 eq.) was dissolved in anhydrous THF (10 mL) and cooled to 0 °C. n-BuLi (2.5 m solution in hexanes, 4.64 mL, 11.6 mmol, 10.0 eq.) was added and the mixture was stirred for 30 min. This solution was then added dropwise to the freshly prepared Ar₁Ar₂PCl solution and stirred for another hour at ambient temperature. The reaction was quenched with H₂O (10 mL). The aqueous layer was extracted with Et₂O (2 × 20 mL), and the combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The residue was dissolved in hexanes:DCM = 10:1 and filtered through a plug of deactivated SiO₂ (hexanes) to afford the title compound (296 mg, 0.64 mmol, 55%) as a colorless solid.

R_f = 0.50 (deactivated SiO₂, hexanes).

¹H NMR (700 MHz, C₆D₆): δ = 7.70–7.68 (m, 1 H, H-4″′), 7.67–7.65 (m, 2 H, H-2″′), 6.84–6.82 (m, 2 H, H-2″), 6.78 (ddd, J = 8.4, 7.2, 3.2 Hz, 1 H, H-4), 6.61 (ddd, J = 7.1, 4.3, 0.9 Hz, 1 H, H-5), 6.37 (ddd, J = 8.4, 0.7, 0.7 Hz, 1 H, H-3), 6.35–6.33 (m, 2 H, H-3″), 1.28 (s, 9 H, H-2′).

¹³C NMR (176 MHz, C₆D₆): δ = 164.2 (d, J = 9.3 Hz, C-2), 156.2 (d, J = 2.4 Hz, C-6), 142.4 (d, J = 19.8 Hz, C-1″′), 138.7 (d, J = 7.7 Hz, C-4), 131.9 (qd, J = 33.2, 5.6 Hz, 2 C, C-3″′), 131.5 (dq, J = 20.3, 3.9 Hz, 2 C, C-2″′), 125.8 (d, J = 13.0 Hz, 2 C, C-2″), 123.7 (q, J = 273.1 Hz, 2 C, C-1″″), 123.0 (dq, J = 3.8, 3.6 Hz, C-4″′), 121.6 (d, J = 33.5 Hz, C-5), 114.6 (C-3), 113.3 (d, J = 4.0 Hz, 2 C, C-3″), 80.1 (C-1′), 28.2 (3 C, C-2′).

³¹P NMR (122 MHz, C₆D₆): δ = 41.9 (s).

¹⁹F NMR (659 MHz, C₆D₆): δ = −62.8 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₂₁H₂₀F₆N₂OP⁺: 461.1212; found: 461.1210.

rac-1-(3,5-Bis(trifluoromethyl)phenyl)-N,N-diethyl-1-(1H-pyrrol-1-yl)phosphanamine (rac-30)

A solution of bis(diethylamino)[3,5-bis(trifluoromethyl)phenyl]phos-phine 27 (1.40 g, 3.61 mmol, 1.00 eq.) in anhydrous Et₂O (14 mL) was treated with AcCl (0.27 mL, 0.30 g, 3.79 mmol, 1.05 eq.) and stirred at ambient temperature until complete consumption of the starting material, as confirmed by ³¹P NMR spectroscopy (δ(ArPCl(NEt₂)) = 132 ppm ArPCl(NEt₂)-solution).

In a separate flask, pyrrole (0.75 mL, 0.73 g, 10.8 mmol, 3.00 eq.) was dissolved in anhydrous THF (14 mL) and cooled to 0 °C. n-BuLi (2.5 m solution in hexanes, 4.33 mL, 10.8 mmol, 3.00 eq.) was added and the mixture was stirred for 1 h. The freshly prepared ArPCl(NEt₂) solution was then added slowly, the reaction mixture was allowed to warm to ambient temperature and stirred for another hour, before being quenched with H₂O (0.19 mL). The solvent was removed under reduced pressure. The residue was dissolved in H₂O/DCM (1:1, 40 mL), and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were washed with brine (1 × 30 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was filtered through deactivated silica (hexanes) to afford the title compound (1.28 g, 3.35 mmol, 93%) as a yellow oil.

R_f = 0.85 (deactivated SiO₂, hexanes).

¹H NMR (400 MHz, C₆D₆): δ = 7.70–7.68 (m, 1 H, H-4′), 7.62–7.59 (m, 2 H, H-2′), 6.70–6.67 (m, 2 H, H-2″′), 6.37–6.35 (m, 2 H, H-3″′), 2.80–2.68 (m, 4 H, H-1), 0.67 (t, J = 7.1 Hz, 6 H, H-2).

¹³C NMR (101 MHz, C₆D₆): δ = 143.9 (d, J = 7.9 Hz, C-1′), 131.9 (qd, J = 33.1, 2.7 Hz, 2 C, C-3′), 130.9 (dq, J = 17.1, 4.1 Hz, 2 C, C-2′), 124.3 (d, J = 15.0 Hz, 2 C, C-2″′), 123.8 (q, J = 273.4 Hz, 2 C, C-1″), 122.5 (dq, J = 7.2, 3.6 Hz, C-4′), 112.4 (d, J = 3.6 Hz, 2 C, C-3″′), 43.4 (d, J = 16.7 Hz, 2 C, C-1), 13.7 (d, J = 4.0 Hz, 2 C, C-2).

³¹P NMR (162 MHz, C₆D₆): δ = 82.9 (s).

¹⁹F NMR (377 MHz, C₆D₆): δ = −62.9 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₆H₁₈F₆N₂P⁺: 383.1106; found: 383.1114.

rac-6-[3,5-Bis(trifluoromethyl)phenyl(pyrrol-1-yl)phosphino]-pyridine-2(1H)-one (rac-6-bmTFMPPyPon, rac-L17)

Degassed, concentrated formic acid (2.5 mL) was added to a solution of rac-2-(tert-butoxy)-6-[3,5-bis(trifluoromethyl)phenyl(pyrrol-1-yl)phos-phino]pyridine rac-29 (290 mg, 630 μmol, 1.00 eq.) in anhydrous benzene (10 mL). The reaction mixture was stirred at ambient temperature for 1 h. H₂O (2 mL) was added and the layers were separated. The organic layer was washed with H₂O (2 × 10 mL) and dried over Na₂SO₄. The solvent was removed under reduced pressure and the solid residue was first digerated with n-pentane and then with MeOH. rac-6-bmTFMPPyPon (71.0 mg, 176 μmol, 28%) was obtained as a colorless solid.

Mp 191 °C.

¹H NMR (400 MHz, C₆D₆): δ = 12.84 (br. s, 1 H, N-H), 7.65 (s, 1 H, H-4″), 7.56 (d, J = 6.1 Hz, 2 H, H-2″), 6.99–6.96 (m, 2 H, H-2′), 6.39 (ddd, J = 9.1, 6.7, 2.4 Hz, 1 H, H-4), 6.27–6.25 (m, 2 H, H-3′), 6.00 (ddd, J = 9.2, 0.9, 0.9 Hz, 1 H, H-3), 5.83 (ddd, J = 8.1, 6.6, 1.1 Hz, 1 H, H-5).

¹³C NMR (101 MHz, C₆D₆): δ = 165.1 (d, J = 1.9 Hz, C-2), 144.3 (d, J = 26.6 Hz, C-6), 139.8 (d, J = 10.4 Hz, C-4), 139.3 (d, J = 14.6 Hz, C-1″), 132.0 (qd, J = 33.3, 4.9 Hz, 2 C, C-3″), 131.6–131.1 (m, 2 C, C-2″), 126.0 (d, J = 14.5 Hz, 2 C, C-2′), 123.6 (q, J = 273.4 Hz, 2 C, C-1″′), 123.7–123.4 (m, C-4″), 122.5 (C-3), 115.9 (d, J = 33.0 Hz, C-5), 114.0 (d, J = 4.7 Hz, 2 C, C-3′).

³¹P NMR (162 MHz, C₆D₆): δ = 36.9 (s).

¹⁹F NMR (377 MHz, C₆D₆): δ = −62.9 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₁₇H₁₂F₆N₂OP⁺: 405.0586; found: 405.0591.

6-[Bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]pyridin-2(1H)-one (6-BDTBMPPon, L18)

2-Bromo-6-(tert-butoxy)pyridine 22 (300 mg, 1.30 mmol, 1.00 eq.) and 5-bromo-1,3-di-tert-butyl-2-methoxybenzene (780 mg, 2.60 mmol, 2.00 eq.) were dissolved in anhydrous THF (10 mL) and cooled to −78 °C. At this temperature, n-BuLi (2.5 M solution in hexanes, 1.56 mL, 3.90 mmol, 3.00 eq.) was added dropwise and the resulting solution was stirred for 1 h. PCl₃ (120 μL, 189 mg, 1.38 mmol, 1.06 eq.) was then added dropwise. The reaction mixture was first stirred at −78 °C for 2 h and then another hour at ambient temperature, before being quenched with stoichiometric amounts of H₂O (0.07 mL). The mixture was extracted with Et₂O (3 × 10 mL), the combined organic layers were dried over Na₂SO₄, and the solvent was removed under reduced pressure. The residue was purified by flash column chromatography (SiO₂, n-pentane–DCM, 4:1) to afford the protected ligand (222 mg, 358 μmol), which was used directly in the next step.

Degassed, concentrated formic acid (5 mL) was added to a solution of the protected ligand in anhydrous DCM (5 mL) and stirred at ambient temperature for 1 h. The reaction mixture was then diluted with H₂O and extracted with DCM (3 × 20 mL). The combined organic layers were dried over Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, DCM–EtOAc, 9:1 ➔ 4:1) to afford 6-BDTBMPPon (183 mg, 325 μmol, 25% over two steps) as a colorless solid.

Mp 221 °C; R_f = 0.41 (DCM–EtOAc, 4:1).

¹H NMR (500 MHz, CD₂Cl₂): δ = 9.00 (br. s, 1 H, N-H), 7.32 (ddd, J = 9.1, 6.7, 2.1 Hz, 1 H, H-4), 7.24 (d, J = 8.6 Hz, 4 H, H-2′), 6.37 (dd, J = 9.2, 1.1 Hz, 1 H, H-3), 6.09 (ddd, J = 6.7, 4.5, 1.1 Hz, 1 H, H-5), 3.69 (s, 6 H, H-1″), 1.36 (s, 36 H, H-3″).

¹³C NMR (126 MHz, CD₂Cl₂): δ = 163.6 (C-2), 161.8 (2 C, C-4′), 148.7 (d, J = 25.1 Hz, C-6), 145.0 (d, J = 7.7 Hz, 4 C, C-3′), 140.5 (d, J = 5.9 Hz, C-4), 132.9 (d, J = 22.3 Hz, 4 C, C-2′), 126.8 (d, J = 7.1 Hz, 2 C, C-1′), 120.2 (C-3), 112.4 (d, J = 18.0 Hz, C-5), 64.8 (2 C, C-1″), 36.2 (4 C, C-2″), 32.1 (12 C, C-3″).

³¹P NMR (202 MHz, CD₂Cl₂): δ = −8.1 (s).

HRMS (APCI): m/z [M + H]⁺ calcd for C₃₅H₅₁NO₃P⁺: 564.3601; found: 564.3608.

Slow evaporation of CD₂Cl₂ yielded crystals of sufficient quality for X-ray diffraction analysis.

6-[Bis(3-methoxyphenyl)phosphino]pyridin-2(1H)-one (6-BmAnPon, L19)

Na (306 mg, 13 mmol, 2.0 eq.) was dissolved in liquid NH₃ (ca. 20 mL) at −78 °C. After 15 min, the deep blue solution was treated with tris(3-methoxyphenyl)phosphine (2.3 g, 6.5 mmol, 1.0 eq.) and stirred at −78 °C for 2 h, resulting in an orange suspension. After addition of 2-bromo-6-(tert-butoxy)pyridine 22 (1.5 g, 6.5 mmol, 1.0 eq.) and anhydrous THF (20 mL), the reaction mixture was slowly warmed to ambient temperature over 1 h and stirred overnight. The reaction was quenched with H₂O (20 mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organic layers were dried over MgSO₄, filtered through a short silica plug (2 × 5 cm), and concentrated under reduced pressure. The resulting protected ligand (2.1 g, 5.3 mmol) was used directly in the next step without further purification.

The protected ligand was dissolved in degassed, concentrated formic acid (10 mL) and stirred at ambient temperature for 1 h. The reaction mixture was then diluted with H₂O (50 mL) and DCM (50 mL) and the aqueous layer was extracted with DCM (2 × 30 mL). The combined organic layers were dried over MgSO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography (SiO₂, DCM ➔ EtOAc) to afford 6-BmAnPon (925 mg, 2.7 mmol, 42% over two steps) as a colorless solid.

Mp 191 °C; R_f = 0.30 (EtOAc).

¹H NMR (300 MHz, CDCl₃): δ = 8.83 (br. s, 1 H, N-H), 7.40–7.28 (m, 3 H, H-5′ and H-4), 7.00–6.85 (m, 6 H, H-2′, H-4′ and H-6′), 6.51 (dd, J = 9.3, 1.1 Hz, 1 H, H-3), 6.31 (ddd, J = 7.0, 6.2, 1.1 Hz, 1 H, H-5), 3.77 (s, 6 H, H-1″).

¹³C NMR (75 MHz, CDCl₃): δ = 163.6 (C-2), 160.1 (d, J = 9.2 Hz, 2 C, C-3′), 145.7 (d, J = 27.3 Hz, C-6), 140.4 (d, J = 8.1 Hz, C-4), 133.9 (d, J = 10.6 Hz, 2 C, C-1′), 130.5 (d, J = 8.0 Hz, 2 C, C-5′), 125.9 (d, J = 19.0 Hz, 2 C, C-2′), 121.1 (C-3), 119.4 (d, J = 22.9 Hz, 2 C, C-6′), 115.8 (2 C, C-4′), 114.1 (d, J = 24.5 Hz, C-5), 55.4 (2 C, C-1″).

³¹P NMR (121 MHz, CDCl₃): δ = −6.8 (s).

Anal. calcd for C₁₉H₁₈NO₃P: C, 67.25; H, 5.35; N, 4.13. Found: C, 66.95; H, 5.46; N, 4.01.

Conflict of Interest

The authors declare that they have no conflict of interest.

Acknowledgement

We thank Jürgen Leonhardt, Günter Leonhardt-Lutterbeck, and Monika Lutterbeck for their technical assistance. We thank the analytical department of the Organic Institute of the Albert-Ludwigs Universität for their support. We thank Dr. Burkhard Butschke for crystal structure refinement.

• References

• 1 Breit B, Seiche W. J Am Chem Soc 2003; 125: 6608-6609
• 2 Gellrich U, Koslowski T, Breit B. Catal Sci Technol 2015; 5: 129-133
• 3 Gellrich U, Himmel D, Meuwly M, Breit B. Chem Eur J 2013; 19: 16272-16281
• 4 Gellrich U, Seiche W, Keller M, Breit B. Angew Chem Int Ed 2012; 51: 11033-11038
• 5 Huang J, Häussinger D, Gellrich U, Seiche W, Breit B, Meuwly M. J Phys Chem B 2012; 116: 14406-14415
• 6 Gellrich U, Huang J, Seiche W, Keller M, Meuwly M, Breit B. J Am Chem Soc 2011; 133: 964-975
• 7 Seiche W, Schuschkowski A, Breit B. Adv Synth Catal 2005; 347: 1488-1494
• 8 Straub AT, Otto M, Usui I, Breit B. Adv Synth Catal 2013; 355: 2071-2075
• 9 Spang J, Bork H, Belov F, Langermann J v, Vorholt AJ, Gröger H. Org Biomol Chem 2025; 23: 688-692
• 10 Manske JL, Nicolai J, Bloomer BJ, Clark DS, Hartwig JF. ACS Catal 2024; 14: 14356-14362
• 11 Bork H, Naße KE, Vorholt AJ, Gröger H. Angew Chem Int Ed 2024; 63: e202401989
• 12 Fuchs D, Rousseau G, Diab L, Gellrich U, Breit B. Angew Chem Int Ed 2012; 51: 2178-2182
• 13 Abillard O, Breit B. Adv Synth Catal 2007; 349: 1891-1895
• 14 Miller L, Bauer F, Breit B. Chem Eur J 2024; 30: e202400188
• 15 Miller L, Bauer F, Breit B. Eur J Org Chem 2025; 28: e202401089
• 16 Miller L, Impelmann A, Bauer F, Breit B. Chem Eur J 2024; 30: e202303752
• 17 Kemme ST, Smejkal T, Breit B. Chem Eur J 2010; 16: 3423-3433
• 18 Köpfer A, Breit B. Angew Chem Int Ed 2015; 54: 6913-6917
• 19 Agabekov V, Seiche W, Breit B. Chem Sci 2013; 4: 2418-2422
• 20 Wenz KM, Leonhardt-Lutterbeck G, Breit B. Angew Chem Int Ed 2018; 57: 5100-5104
• 21 Usui I, Schmidt S, Keller M, Breit B. Org Lett 2008; 10: 1207-1210
• 22a Birkholz M-N, Dubrovina NV, Shuklov IA. et al. Tetrahedron Asymmetry 2007; 18: 2055-2060
• 22b The synthesis of 1 is also possible using only HNEt₂. See the following reference Issleib K, Seidel W. Chem Ber 1959; 92: 2681-2694
• 22c For the positive effects of tertiary amine bases in the addition of secondary amines to phosphorus chlorides see: Moloy KG, Petersen JL. J Am Chem Soc 1995; 117: 7696-7710
• 22d Amigues EJ, Hardacre C, Keane G, Migaud ME. Green Chem 2008; 10: 660-669
• 23 Kraushaar K, Herbig M, Schmidt D, Wagler J, Böhme U, Kroke E. Z Naturforsch B 2017; 72: 909-921
• 24 Dellinger DJ, Sheehan DM, Christensen NK, Lindberg JG, Caruthers MH. J Am Chem Soc 2003; 125: 940-950
• 25 Bestmann HJ, Lienert J, Heid E. Chem Ber 1982; 115: 3875-3879
• 26 Burg AB, Slota PJ. J Am Chem Soc 1958; 80 (05) 1107-1109
• 27 Chantrell PG, Pearce CA, Toyer CR, Twaits R. J Appl Chem 1964; 14: 563-564
• 28 Hunt BB, Saunders BC. J Chem Soc 1957; 2413-2432
• 29 Nöth H, Vetter H-J. Chem Ber 1963; 96: 1109-1118
• 30 Montgomery RE, Quin LD. J Org Chem 1965; 30: 2393-2395
• 31 Casalnuovo AL, RajanBabu TV, Ayers TA, Warren TH. J Am Chem Soc 1994; 116: 9869-9882
• 32 Trost BM, Marschner C. Bull Soc Chim Fr 1997; 263-274
• 33 Zhang J-Q, Yang S, Han L-B. Tetrahedron Lett 2020; 61: 151556
• 34 Fogh AA, Belazregue S, Ashley AE, Chadwick FM. Organometallics 2025; 44: 665-671
• 35 Allmendinger S, Kinuta H, Breit B. Adv Synth Catal 2015; 357: 41-45
• 36 Reiter SA, Nogai SD, Schmidbaur H. Dalton Trans 2005; 247-255
• 37 Bauer F, Dierenbach N, Breit B, Asian J. Org Chem 2023; 12: e202300244
• 38 Pudovik MAZ. Obshch Khim 1981; 51: 518-526
• 39 Prikoszovich W, Schindlbauer H. Chem Ber 1969; 102 (09) 2922-2929
• 40 Imamoto T, Oshiki T, Onozawa T, Kusumoto T, Sato K. J Am Chem Soc 1990; 112: 5244-5252
• 41 Diebolt O, Tricas H, Freixa Z, van Leeuwen PWNM. ACS Catal 2013; 3: 128-137
• 42 Suffert J. J Org Chem 1989; 54: 509-510
• 43 Love BE, Jones EG. J Org Chem 1999; 64: 3755-3756
• 44 Landis MS, Turro NJ, Bhanthumnavin W, Bentrude WG. J Organomet Chem 2002; 646: 239-246
• 45 Czauderna CF, Slawin AMZ, Cordes DB, van der Vlugt JI, Kamer PCJ. Tetrahedron 2019; 75: 47-56
• 46 Stoop RM, Mezzetti A, Spindler F. Organometallics 1998; 17 (04) 668-675
• 47 Lee H, Hong SH. Appl Catal A Gen 2018; 560: 21-27
• 48 Kapoor PN, Pathak DD, Gaur G, Kutty M. J Organomet Chem 1984; 276: 167-170
• 49 Lhermet R, Moser E, Jeanneau E, Olivier-Bourbigou H, Breuil P-AR. Chem Eur J 2017; 23: 7433-7437

Publication History

Received: 17 June 2025

Accepted after revision: 03 August 2025

Accepted Manuscript online:
03 August 2025

Article published online:
12 September 2025