Palladium-Catalyzed N-Alkenylation of N-Aryl Phosphoramidates with Alkenes

Versatile and concise Pd-catalyzed oxidative N-alkenylation of N-aryl phosphoramidates with alkenes is described in this study, a reaction that is of great significance but surprisingly unexploited. The transformation proceeds under mild reaction conditions, using O2 as a green oxidant and TBAB as an effective additive. An efficient catalytic system allows a variety of drug-related substrates to participate in these transformations, which is of great interest in the drug discovery and development of phosphoramidates.


Introduction
Multi-functionalized phosphoramidates represent a promising class of phosphorous compounds and have fascinating applications in the pharmaceutical industry, as flame retardants, and in asymmetric catalysis [1,2]. In medicinal chemistry, the late-stage modification of phosphoramidates skeletons led to the discovery of plentiful FDA-approved drugs [3,4], such as Tenofovir Alafenamide (for HBV), Sofosbuvir (a blockbuster drug for HCV) and Thymectacin (for cancer therapy). Recently established, Redesivir is a new broad-spectrum antiviral drug developed by Gilead, which has been effectively used to treat COVID-19 [5]. However, accessible synthetic approaches for N-modification of N-aryl phosphoramidates have surprisingly not been developed. To date, only alkylation with α, β-unsaturated ketones [6], allenylation with propargyl alcohols [7], intramolecular allylation reaction [8], and alkynylation with alkynyl bromides [9] have been reported to remould these privileged organophosphorus compounds. Therefore, the development of novel and ingenious methods to realize N-diversification of phosphoramidates based on an atom-economic strategy is still highly desirable.
In recent years, palladium-catalyzed intermolecular oxidative amination of alkenes with anilines has been used to synthesize complex enamines [10][11][12][13], but it is unsuitable for electron-deficient aniline. Metal-catalyzed direct alkenylation of N-aryl phosphoramidates with alkenes represents a significant but challenging assignment, mainly due to the special structural characteristics of the N-aryl phosphoramidates. (1) The phosphoryl could function as a directing group, which easily gives rise to achieving the ortho functionalization of the aniline moiety, as demonstrated by palladium-catalyzed ortho-arylation of aniline with di(aryl)iodium triflate (Scheme 1a) [14]. (2) There is a large steric hindrance between the adjacent phosphoryl and aniline, which would weaken the N-H activation of N-aryl phosphoramidates with transition-metal catalysts. (3) The good affinity between phosphoramidates and the transition-metal centre would reduce the catalyst's Lewis acidity [15,16], thus inhibiting the activation of alkenes. According to the theory of soft and hard acid-base, we envisioned that excessive soft ligands could occupy the coordination space of transition metal ions, thus reducing the chance of chelating phosphoramidate with the transition metal. In that case, it is expected to overcome the use of phosphoramidate as a directing group for the inevitable ortho C-H alkenylation of the aniline moiety [17,18] and to avoid the deactivation of the catalyst. Based on our long-term interest in alkene functionalization [19][20][21], herein, we describe a concise palladium-catalyzed oxidative coupling of N-aryl phosphoramidates with alkenes with excellent regio-and stereoselectivity, in which it was found that appropriate LiOAc and TBAB are essential for the successful transformation (Scheme 1b).
Molecules 2023, 28, x FOR PEER REVIEW 2 of 15 catalyst's Lewis acidity [15,16], thus inhibiting the activation of alkenes. According to the theory of soft and hard acid-base, we envisioned that excessive soft ligands could occupy the coordination space of transition metal ions, thus reducing the chance of chelating phosphoramidate with the transition metal. In that case, it is expected to overcome the use of phosphoramidate as a directing group for the inevitable ortho C-H alkenylation of the aniline moiety [17,18] and to avoid the deactivation of the catalyst. Based on our long-term interest in alkene functionalization [19][20][21], herein, we describe a concise palladium catalyzed oxidative coupling of N-aryl phosphoramidates with alkenes with excellen regio-and stereoselectivity, in which it was found that appropriate LiOAc and TBAB are essential for the successful transformation (Scheme 1b).

Results and Discussion
To assess the N-alkenylation of N-aryl phosphoramidates, diphenyl p tolylphosphoramidate 1a, and ethyl acrylate 2a were chosen as substrates to explore the optimal reaction conditions, as summarized in Table 1 (see more details in Supporting  Information). Initially, some additives, such as Cu(OAc)2, CuCl2, BQ, pyridine and LiBr were evaluated. These additives are usually used in palladium-catalyzed alkene oxidative amination reactions but did not respond to this transformation (Entries 1-5). Fortunately when the reaction was conducted using Pd(OAc)2 as a catalyst, TBAB as an additive and LiOAc as a suitable base, 3a was obtained in a 65% yield in DME at 80 °C under an O atmosphere (Entry 6). Then, we further examined the common phase transfer catalysts However, the addition of TBAF, TBAC and TBAI completely inhibited the reactions (Entries 7-9). Various ether solvents were screened. Using TMBE instead of DME could improve the yield of the desired product to 80% (Entry 10). The examination of differen palladium salts showed that Pd(TFA)2 has higher catalytic activity than Pd(OAc)2 (entry 13), and the yield of 3a is raised to 89%. Whereafter, examination of different ligands (such as pyridine and phthalimide), previously proved in palladium-catalyzed aza-Wacke reactions [22][23][24][25], which not only failed to improve the reaction efficiency but it was also detrimental for this transformation (Entries 11, 12). Other Pd(II) catalysts, such as PdCl2 Pd(CH3CN)2Cl2, and Pd(PhCN)2Cl2, can not trigger the transformation, likely to be the difficulty in ligand exchange between the chloride ion and N-aryl phosphoramidates Finally, when the reaction was performed under an N2 atmosphere (Entry 14), 3a was isolated in only 7% of the yield, and the formation of palladium black indicated that O was used as an oxidant to regenerate the active palladium catalyst. Scheme 1. Tuning the reactivity of N-aryl phosphoramidates.

Results and Discussion
To assess the N-alkenylation of N-aryl phosphoramidates, diphenyl p-tolylphosphoramidate 1a, and ethyl acrylate 2a were chosen as substrates to explore the optimal reaction conditions, as summarized in Table 1 (see more details in Supporting Information). Initially, some additives, such as Cu(OAc) 2 , CuCl 2 , BQ, pyridine and LiBr, were evaluated. These additives are usually used in palladium-catalyzed alkene oxidative amination reactions but did not respond to this transformation (Entries 1-5). Fortunately, when the reaction was conducted using Pd(OAc) 2 as a catalyst, TBAB as an additive and LiOAc as a suitable base, 3a was obtained in a 65% yield in DME at 80 • C under an O 2 atmosphere (Entry 6). Then, we further examined the common phase transfer catalysts. However, the addition of TBAF, TBAC and TBAI completely inhibited the reactions (Entries 7-9). Various ether solvents were screened. Using TMBE instead of DME could improve the yield of the desired product to 80% (Entry 10). The examination of different palladium salts showed that Pd(TFA) 2 has higher catalytic activity than Pd(OAc) 2 (entry 13), and the yield of 3a is raised to 89%. Whereafter, examination of different ligands (such as pyridine and phthalimide), previously proved in palladium-catalyzed aza-Wacker reactions [22][23][24][25], which not only failed to improve the reaction efficiency but it was also detrimental for this transformation (Entries 11, 12). Other Pd(II) catalysts, such as PdCl 2 , Pd(CH 3 CN) 2 Cl 2 , and Pd(PhCN) 2 Cl 2, can not trigger the transformation, likely to be the difficulty in ligand exchange between the chloride ion and N-aryl phosphoramidates. Finally, when the reaction was performed under an N 2 atmosphere (Entry 14), 3a was isolated in only 7% of the yield, and the formation of palladium black indicated that O 2 was used as an oxidant to regenerate the active palladium catalyst.
As illustrated in Scheme 2, palladium-catalyzed direct cross-coupling of N-aryl phosphoramidates with ethyl acrylate displayed spectral functional group compatibility. Various anilines of phosphoramidates bearing electron-donating substituents, such as methyl (3a), methoxy (3b, 3q), trifluoromethoxy (3c), phenoxy (3d), and tertiary butyl (3e), and smoothly participated in these transformations to obtain the target products in excellent yields. Phosphoramidates with electron-withdrawing groups on aniline, such as trifluoromethyl (3j), acetyl (3k) and ester (3l), could be efficiently converted into the corresponding N-vinyl phosphoramidates with useful yields. Generally, N-aryl phosphoramidates bearing electron-donating substituents show much higher reactivity than that with electron-withdrawing counterparts. The current catalytic system could be compatible with important halogen functional groups (3f-3h), which provides an important synthetic tool for further derivatization. Remarkably, methylthio (3i) is sensitive to palladium catalysts because of its strong coordination ability and small steric hindrance, and it is also feasible under standard reaction conditions. As expected, the position of the substituent in the aniline ring of N-aryl phosphoramidates affected the efficiency of transformation, in the cases of diphenyl o-tolylphosphoramidate (3n) and diphenyl mesitylphosphoramidate (3o). Diphenyl naphthalen-1-ylphosphoramidate (3m) also worked in the same way and exhibited wonderful reaction efficiency. Naphthalen-2-yl phenyl N-phenyl phosphoramidate (3r) was subjected to the N-vinylation coupling reaction, which had predictable regioselectivity and good yield. However, the use of diphenyl (4-methylbenzyl)phosphoramidate (3s) and P,P-diphenyl-N-(p-tolyl)phosphinic amide (3t) as substrates failed to give the corresponding N-alkenylation product. These experimental results show that aryloxy on the P atom and aryl group on the N atom of phosphoramidate are indispensable for reaction efficiency. Importantly, the 5 mmol scale reaction progressed smoothly, and a satisfactory yield of 3a could be obtained. As illustrated in Scheme 2, palladium-catalyzed direct cross-coupling of N phosphoramidates with ethyl acrylate displayed spectral functional group compati Various anilines of phosphoramidates bearing electron-donating substituents, su methyl (3a), methoxy (3b, 3q), trifluoromethoxy (3c), phenoxy (3d), and tertiary buty and smoothly participated in these transformations to obtain the target produ excellent yields. Phosphoramidates with electron-withdrawing groups on aniline, s trifluoromethyl (3j), acetyl (3k) and ester (3l), could be efficiently converted in corresponding N-vinyl phosphoramidates with useful yields. Generally, N phosphoramidates bearing electron-donating substituents show much higher rea than that with electron-withdrawing counterparts. The current catalytic system cou compatible with important halogen functional groups (3f-3h), which provid important synthetic tool for further derivatization. Remarkably, methylthio ( sensitive to palladium catalysts because of its strong coordination ability and small hindrance, and it is also feasible under standard reaction conditions. As expecte position of the substituent in the aniline ring of N-aryl phosphoramidates affecte efficiency of transformation, in the cases of diphenyl o-tolylphosphoramidate (3n Pd(OAc) 2 pyridine DME 0 5 Pd ( Subsequently, we turned our attention to the scope of acrylate. As shown in Scheme 3, various functionalized acrylates show good reactivity. Trifluoromethyl (4b), methoxyl (4c), halogen (4d) and tetrahydrofuran-2-yl (4e) could be well accommodated and afforded the respective products. The compound 2-methoxyethyl acrylate, mainly used as an adhesive, could undergo selective amination to gain 4c in a good yield. Isobornyl acrylate, a monomer of acrylic resins, was easily transformed into the anticipated product 4h. Furthermore, this N-alkenylation of N-phenyl phosphoramidate could also be applied for the late-stage modification of important medical agents. Acrylate alkenes derived from 2,6-dimethylphenol (4f, food spices), Chloroxylenol (4g, disinfector), Carvacrol (4i, local anaesthetic) and D-Menthol (4j, excitants) all worked well in the abovementioned protocols. It is undeniable that ethyl methacrylate and ethyl crotonate did not work at all under the present catalytic systems, suggesting that a substituent on a carbon carbon double bond had an obvious steric hindrance effect on alkene amination. Pleasingly, the treatment of α, β-unsaturated ketone also gave a good yield of the anticipated product (4k). Having extended the scope of electron-deficient alkenes with N-aryl phosphoramidates, we further examined styrene oxidative amination. Through systematic optimization of the reaction conditions, it was found that the direct cross-coupling of styrene with diphenyl N-phenyl phosphoramidate could be realized with the combination of Pd(TFA) 2 with catalytic amounts of Cu(OAc) 2 and 20 mol% LiOAc as the base, which is an important route for the preparation of 1,1-disubstituted alkenes. In addition, the anti-Markovniknov product originates from the possibility that the palladium centre coordinates with styrene to give a relatively stable benzyl carbocation intermediate. Subsequently, we turned our attention to the scope of acrylate. As shown in Scheme 3, various functionalized acrylates show good reactivity. Trifluoromethyl (4b), methoxyl (4c), halogen (4d) and tetrahydrofuran-2-yl (4e) could be well accommodated and afforded the respective products. The compound 2-methoxyethyl acrylate, mainly used as an adhesive, could undergo selective amination to gain 4c in a good yield. Isobornyl acrylate, a monomer of acrylic resins, was easily transformed into the anticipated product 4h. we further examined styrene oxidative amination. Through systematic optimization of the reaction conditions, it was found that the direct cross-coupling of styrene with diphenyl N-phenyl phosphoramidate could be realized with the combination of Pd(TFA)2 with catalytic amounts of Cu(OAc)2 and 20 mol% LiOAc as the base, which is an important route for the preparation of 1,1-disubstituted alkenes. In addition, the anti-Markovniknov product originates from the possibility that the palladium centre coordinates with styrene to give a relatively stable benzyl carbocation intermediate. The synthetic strategy was demonstrated in the incorporation of pharmaceutical molecules into N-alkenyl-N-aryl phosphoramidates (Scheme 4). N-aryl phosphoramidates derived from Cumidine (herbicide) and Benzocaine (local anaesthetics) were chosen as representative cases and treated with ethyl acrylate to provide the desired 5a and 5b, respectively. Furthermore, a vitamin E-derived electron-deficient alkene (5c) was also prepared and subjected to region-selective amination, providing the corresponding product with high reaction efficiency. The synthetic strategy was demonstrated in the incorporation of pharmaceutical molecules into N-alkenyl-N-aryl phosphoramidates (Scheme 4). N-aryl phosphoramidates derived from Cumidine (herbicide) and Benzocaine (local anaesthetics) were chosen as representative cases and treated with ethyl acrylate to provide the desired 5a and 5b, respectively. Furthermore, a vitamin E-derived electron-deficient alkene (5c) was also prepared and subjected to region-selective amination, providing the corresponding product with high reaction efficiency. Some experiments were performed to elucidate the oxidative cross-coupling reaction pathway between N-aryl phosphoramidates and alkenes (Scheme 5). Firstly, 1.0 equivalent TEMPO was added into the optimal reaction conditions, and the 4k was obtained in an 85% yield (Equation (1)), which suggests that a radical pathway could be ruled out. Some experiments were performed to elucidate the oxidative cross-coupling reaction pathway between N-aryl phosphoramidates and alkenes (Scheme 5). Firstly, 1.0 equivalent TEMPO was added into the optimal reaction conditions, and the 4k was obtained in an 85% yield (Equation (1)), which suggests that a radical pathway could be ruled out. Secondly, we did not observe any H/D exchange product (Equation (2)), which further excludes the first N-H activation of N-aryl phosphoramidates with a palladium catalyst. Finally, the formation of palladium black was observed in the absence of TBAB, whereas the reaction solution was always bright yellow in its presence. This result suggests that TBAB plays a role in stabilizing and assisting the oxidization of Pd (0) [26,27]. According to these experimental results and previous reports, a typical mechanism of palladium-catalyzed alkene chemistry is proposed in Scheme 4. Initially, the coordination of palladium salt with alkenes forms palladium-alkene adducts A, following the nucleophilic attack of Naryl phosphoramidates to produce the alkylpalladium complex B.

General Information
Phosphoramidates and acrylates were prepared according to the reported procedures. The 1 H and 13 C spectra of known compounds were in accordance with those described in the literature. All other reagents were purchased from TCI (Shanghai, China), Sigma-Aldrich (Shanghai, China), Alfa Aesar (Shanghai, China), Acros (Shanghai, China), and Meryer (Shanghai, China) and used without further purification. The 1 H NMR (500 MHz), 13 C NMR (125 MHz) and 19 F NMR (470 MHz) spectra were recorded in CDCl3 and DMSO-D6 solutions using a Burker AVANCE 500 spectrometer. High-resolution mass spectra were recorded on an ESI-Q-TOF mass spectrometer. Analysis of the crude reaction mixture was conducted on the Varian 4000 GC/MS and 1200 LC. All reactions were conducted using standard Schlenk techniques. Column chromatography was performed us- In summary, the versatile palladium-catalyzed oxidative cross-coupling of N-aryl phosphoramidates with alkenes has been discovered, providing a concise avenue by which to access structurally rich N-aryl-N-vinyl phosphoramidates. The outstanding attractions of these transformations are the use of O 2 as a green oxidant, a cocatalyst-free catalytic system, and late-stage functionalization of important pharmaceuticals as well as readily accessible starting materials. In view of the wide application of phosphoramidates in medical chemistry, this concise synthetic method provides a practical tool for accelerating the discovery of phosphoramidates drugs.

General Information
Phosphoramidates and acrylates were prepared according to the reported procedures. The 1 H and 13 C spectra of known compounds were in accordance with those described in the literature. All other reagents were purchased from TCI (Shanghai, China), Sigma-Aldrich (Shanghai, China), Alfa Aesar (Shanghai, China), Acros (Shanghai, China), and Meryer (Shanghai, China) and used without further purification. The 1 H NMR (500 MHz), 13 C NMR (125 MHz) and 19 F NMR (470 MHz) spectra were recorded in CDCl 3 and DMSO-D6 solutions using a Burker AVANCE 500 spectrometer. High-resolution mass spectra were recorded on an ESI-Q-TOF mass spectrometer. Analysis of the crude reaction mixture was conducted on the Varian 4000 GC/MS and 1200 LC. All reactions were conducted using standard Schlenk techniques. Column chromatography was performed using EM silica gel 60 (300-400 m).

General Procedure of Palladium-Catalyzed N-Alkenylation of Phosphoramidates with Alkenes
A 25 mL Schlenk tube equipped with a stir bar was charged with phosphoramidates (0.2 mmol), alkenes (0.6 mmol), Pd(TFA) 2 (0.02 mmol), TBAT (0.2 mmol) and TBME (0.06 mmol). The tube was fitted with a rubber septum, and then it was evacuated and refilled with dioxygen three times; then, the septum was replaced with a Teflon screwcap under oxygen flow. The reaction mixture was stirred at 80 • C for 24 h. After cooling down, the reaction mixture was diluted with 10 mL of ethyl ether, filtered through a pad of silica gel, followed by washing the pad of the silica gel with the same solvent (20 mL), concentrated under reduced pressure. The residue was then purified by flash chromatography on silica gel to provide the corresponding product.