Nitrene-Mediated P–N Coupling Under Iron Catalysis

Abstract

Open AccessCCS ChemistryCOMMUNICATION14 Jul 2022Nitrene-Mediated P–N Coupling Under Iron Catalysis Ziqian Bai, Fangfang Song, Hao Wang, Wangxing Cheng, Shiyang Zhu, Yi Huang, Gang He and Gong Chen Ziqian Bai State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Fangfang Song State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Hao Wang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Wangxing Cheng State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Shiyang Zhu State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Yi Huang State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Gang He State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 and Gong Chen *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 https://doi.org/10.31635/ccschem.021.202101056 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail P–N and P=N bonds play important roles in the design and synthesis of functional molecules such as bioactive compounds and organic ligands for catalysis. Existing methods for P–N coupling mostly rely on Staudinger condensation or nucleophilic substitution between phosphorus electrophiles and amine nucleophiles. Herein, we report a nitrene-mediated intermolecular P–N coupling reaction between various phosphorus nucleophiles and dioxazolones under simple iron-catalyzed conditions. These reactions offer an efficient, versatile, and broadly applicable method for synthesis of a range of N–P compounds, including amidophosphines, iminophosphonamides, phosphinamides, aminophosphines, and iminophosphoranes, from readily available precursors under mild conditions. Download figure Download PowerPoint Introduction The unique electronic configuration, stereochemical arrangement, and bonding modes make phosphorus (P) an essential element in nature and the human-made world.1,2 Besides carbon and oxygen, P can form single or double bonds with nitrogen (N), enabling the design and synthesis of a wide range of functional molecules such as bioactive compounds and organic materials (Scheme 1a).3–8 In particular, the P–N motif has gained increasing popularity in the design of organic ligands for both organo- and metal catalysis.9–18 Despite its importance, the development of P–N coupling reactions has been relatively slow over the past few decades.19–29 The classical Staudinger condensation reaction between phosphines and azides and nucleophilic substitution reactions between phosphorus halides and amines remain the workhorse methods for constructing P–N bonds (Scheme 1b). While very useful, these methods typically require relatively forced conditions and use of hazardous or sensitive reagents. In principle, substitution reactions between phosphorus nucleophiles and N-based electrophiles provide an alternative disconnection strategy to make P–N bonds.29 However, this strategy has been underexplored due to the limited choice of suitable N partners. Herein, we report a nitrene-mediated P–N coupling reaction of various phosphorus nucleophiles and dioxazolones under simple iron catalysis (Scheme 1c).30–37,a Scheme 1 | Occurrence and synthesis of P–N containing compounds. Download figure Download PowerPoint Results and Discussion Early work by Sauer and Mayer38 showed that 1,4,2-dioxazol-5-ones, which can be readily prepared from carboxylic acids in two steps, can undergo decarboxylation under thermal or photochemical conditions to generate N-acyl nitrenes, which can react with dimethyl sulfoxide solvent to form N-acyl sulfoximines. Bolms demonstrated that both sulfides and sulfoxides can undergo efficient imidation reaction with dioxazolones via nitrene transfer under Ru catalysis and light irradiation at room temperature (rt).39 Work from Chang and others40–52 showed that these dioxazolone reagents can facilitate various metal-catalyzed C–H amidation and alkene functionalization reactions. Recently, we discovered that dioxazolones can undergo intermolecular N–N coupling with arylamines to make hydrazides under either iridium or iron catalysis.53–63 Mechanistic studies of the Ir-catalyzed system indicated an outer-sphere nucleophilic attack of the nitrogen group of Ir-nitrenoid intermediate by amine leads to the N–N coupling product. Encouraged by the S-imidation64–69 and N–N coupling reactions, we questioned whether a similar nucleophilic attack of acyl nitrenoid intermediate by secondary phosphines might lead to the P–N coupling product. As shown in Table 1, mixing diphenylphosphine (PI) 1 (1 equiv), 3-methyl dioxazolone 2 (1 equiv), and 2.5 mol% of [Cp*IrCl2]2 in 1,2-dichloroethane (DCE) under nitrogen at rt for 12 h gave the desired acetamido phosphine (PIII) 3a in 5% yield along with a trace amount (∼2%) of phosphinamide 3c (entry 1, based on gas chromatography–mass spectrometry (GC-MS) analysis of the crude reaction mixture). The use of other Ir catalysts did not give significant improvement. To our delight, the use of a simple iron catalyst (5 mol % of FeCl2 •4H2O) under the same conditions gave 60% of 3a (entry 3). FeCl2, FeCl3, and FeBr2 gave comparable results (entries 4–6). In contrast, Fe(OAc)2 and Fe(acac)2 gave very little product (see Supporting Information Table S1 for details). Unlike hygroscopic FeCl2, FeCl2 •4H2O can be conveniently handled on the benchtop. Most halogenated hydrocarbon solvents worked well. Reaction of 2 equiv of 1 and 1 equiv of 2 gave 3a in excellent yields and chemoselectivity (entry 10). The reaction can be completed in 10 min (entry 11). Purification of 3a by silica gel chromatography was problematic as it can be partially oxidized to form 3c during the separation process. 1 also can be oxidized to form diphenylphosphine oxide 4 under air atmosphere. Table 1 | Fe-Catalyzed N–P Coupling Reaction of 1 and 2 Entry Change from the above Conditions Yield of 3a/ 3b/ 3c (%)a 1 1 (1 equiv), 2 (1 equiv), [Cp*IrCl2]2 (2.5 mol %) as cat., 12 h 5/ND/2 2 1 (1 equiv), 2 (1 equiv), [Cp*IrCl2]2 (2.5 mol %) as cat., 12 h, 4 M 10/1/6 3 1 (1 equiv), 2 (1 equiv), FeCl2•4H2O as cat. 60/ND/2 4 1 (1 equiv), 2 (1 equiv), FeCl2 as cat. 62/ND/2 5 1 (1 equiv), 2 (1 equiv), FeCl3 as cat. 55/ND/2 6 1 (1 equiv), 2 (1 equiv), FeBr2 as cat. 55/ND/3 7 1 (1 equiv), 2 (1 equiv), no cat. no reaction 8 1 (1 equiv), 2 (1 equiv), THF as sol. 35/2/5 9 1 (1 equiv), 2 (1 equiv), toluene as sol. 39/ND/4 10 1 (2 equiv), 2 (1 equiv) 93/ND/2 11 1 (2 equiv), 2 (1 equiv), 10 min 93/ND/2 12 1 (2 equiv), 2 (1 equiv), under air 86/ND/1 13 1 (2 equiv), 2 (1 equiv);treatment w/H2O2 (10 equiv), 10 min ND/ND/95b 14 1 (2 equiv), 2 (1 equiv);treatment w/BH3 -THF (2 equiv), 1 h 5/ND/ND+ 86 (76b) of 3d 15 1 (2 equiv), 2 (1 equiv);treatment w/BH3 -THF (5 equiv), 3 h ND/ND/ND+ 81b of 3e 16 1 (1 equiv), 2 (2.5 equiv) 1/85 (80b)/2 17 1 (2 equiv), 2 (1 equiv) w/0.1 mol % of Fe cat. on 10 mmol scale, 12 h; treatment w/BH3 -THF (2 equiv), 3 h 95b of 3d 18 1 (1 equiv), 2 (2.5 equiv) w/0.5 mol % of Fe cat. on 6 mmol scale, 3 h 94b of 3b aAll screening reactions were carried on a 0.4 mmol scale, yields are based on GC-MS analysis of crude reaction mixture unless otherwise specified. Fe catalysts of ≥99.99% purity were used. bIsolated yield. See Supporting Information Table S1 for more results under other conditions. ND, not detected. Treatment of the reaction mixture (entry 10) in the same pot with 10 equiv of aq. H2O2 for 10 min gave 3c in 95% isolated yield (entry 13). Treatment of the reaction mixture with 2 equiv of BH3-tetrahydrofuran (THF) led to the formation of stable borane complex 3d (entry 14). Moreover, treatment of the reaction mixture with excess BH3-THF (5 equiv) for 3 h gave reduced aminophosphine product 3e as a borane complex in excellent isolated yield (81%, entry 15). Finally, reaction of 1 (1 equiv) with an excess amount of 2 (2.5 equiv) under the same conditions gave double imidation product iminophosphonamide (PV) 3b in excellent yield and selectivity (entry 16). Compounds 3b, 3d, and 3e can be readily purified by silica gel chromatography. The structures of 3b and 3c were confirmed by X-ray crystallography. Notably, reaction of 1 and 2 on a gram scale using 0.1 mol % of FeCl2 •4H2O catalyst for 12 h gave 3d in 95% isolated yield after the BH3 -THF treatment (entry 17). 3b was obtained in 94% isolated yield on a gram scale using 0.5 mol % of FeCl2•4H2O catalyst for 3 h (entry 18). A range of secondary phosphines and dioxazolones reacted to give the corresponding acetamido phosphine borane complex, aminophosphine borane complex, and iminophosphonamide in good to excellent yields and selectivity under the optimized protocols A– C (Scheme 2). Functional groups such as alkyl bromide ( 5d), terminal alkyne ( 6d), N-Phth ( 7d), and alkene ( 8d) were tolerated. Besides diaryl phosphines ( 11d and 12d), dialkyl ( 14d), or mixed arylalkyl phosphine ( 13d) also worked well. Sterics strongly influence reactivity. For example, di-imidation product 10b was obtained in moderate yield even under more concentrated conditions. The reaction of bulky di-tert-butyl phosphine with 2 only gave monoimidation product 15d. In comparison with secondary phosphines, their phosphine oxide derivatives such as 4 show significantly lower reactivity under the same conditions. Reaction of diethyl phosphite 16 did not form the corresponding phosphoramide 17. Scheme 2 | Scope of secondary phosphines and dioxazolones. Isolated yield on a 0.2 mmol scale. aComplex mixture. bOverreduction. c[P]: 2 M. dFollowed by treatment with 5 equiv of BH3-THF. ND, not detected. Download figure Download PowerPoint As shown in Scheme 3a, treatment of acetamido phosphine borane complex 3d with NEt3 in DCE at 55 °C followed by concentration in vacuo cleanly gave 3a. Reaction of 3a with 3-phenyldioxazolone gave the mixed imonophosphoamide 18 in near quantitative yield via a one-pot operation. As shown in Scheme 3b, reaction of imonophosphoamide 3b with [Cp*RhCl2]2 in the presence of K2CO3 at rt cleanly gave Cp*(PN2) Rh complex 19.13,14,18 Mixing acetamido phosphine 3a with [Cp*MCl2]2 (M: Ir, Rh) and K2CO3 gave a mixture of 20-M and its iminolate derivative 21-M in varied ratios.b Structures of 19, 20-Ir, and 20-Rh were confirmed by X-ray crystallography. Scheme 3 | (a) Synthesis of mixed iminophosphonamide. (b) Formation of metal complexes of 3a and 3b. Download figure Download PowerPoint As shown in Scheme 4, aryl and alkyl tertiary phosphines can also react with dioxazolones to give N-acyl iminophosphoranes in good to excellent yields under the standard Fe-catalyzed conditions. Most of these compounds are stable and can be purified by silica gel chromatography. Reaction of PPh3 with 2 gave 22 in 95% yield. Notably, reaction of sterically demanding tri-tert-butylphosphine with 2 gave 24 in excellent yield. Reactions of various diphosphine ligands such as 2,2'-Bis(diphenylphosphino)biphenyl (BIPHEP) ( 26), 1,3-Bis(diphenylphosphino)propane (DPPP) ( 27), 1,4-Bis(diphenylphosphino)-2,3-O-isopropylidene-2,3-butanediol (DIOP) ( 28), and 1,1'-Bis(diphenylphosphino)ferrocene (DPPF) ( 29) gave the corresponding bis-imidation products in high yields using 3 equiv of dioxazolones. Reaction of Xantphos bearing two closely positioned P atoms primarily gave the monoimidation product 25. Reaction of PPh3 with sterically less demanding dioxazolones ( 30 and 31) proceeded smoothly. In comparison, reaction with dioxazolone derived from leucine did not give product 32. Reaction of triethylphosphite gave triethyliminophosphate 33 in high yield whereas the reaction of tris(1-pyrrolidinyl)phosphine failed to give tris(1-pyrrolidinyl) iminophosphorane. Scheme 4 | Synthesis of N-acyl iminophosphoranes. Isolated yield on a 0.2 mmol scale. a3 equiv of dioxazolone was used. b50 °C, 3 h. c10 h. Download figure Download PowerPoint Control experiments showed that dioxazolone 2 did not react with the FeCl2 •4H2O catalyst in the absence of PPh3 under the same conditions. FeCl2(PPh3)2 was also an excellent catalyst for the reaction of 2 and PPh3 (Scheme 5a).70,c Density functional theory (DFT) calculations were performed to probe the mechanism and estimate the energetics of the P–N coupling of 2 and PPh3 under the catalysis of FeCl2.d Pathways via the quintet energy surface are most energetically favorable (see Supporting Information Figures S8–S9 for detailed analysis of pathways via singlet and triplet energy surfaces for this reaction). Scheme 5 | Mechanistic studies of P–N coupling of 2 and PPh3. DFT calculations were performed using Gaussian-16, A03 programs at the (U)PBE0-D3(BJ)/Def2-TZVPP (SMD-DCE)//(U)PBE0-D3(BJ)/Def2-SVP (gas) level of theory. (a) FeCl2(PPh3)2 as catalyst. (b) Favored pathway via P–N RE of pentacoordinated Fe-nitrenoid intermediate. (c) Alternative pathway via P–N RE of tetra coordinated nitrenoid intermediate. (d) Other intermediate and TS. aSmall fractions of spin population are on Cl (∼0.2α), acyl O (∼0.1α) and P (∼0.2β) (isovalue = 0.05). bΔG of this TS equals that of FeCl2 (0.0 kcal/mol) by coincidence. 5[Fe]NP-TS: TS for N–P RE of 5[Fe]NP. 5[Fe]NP-TS': TS for P–N coupling via outer-sphere attack of 5[Fe]NP by PPh3. Download figure Download PowerPoint As outlined in Scheme 5b, DFT calculations show that PPh3 and 2 can bind with FeCl2 to form a penta-coordinated complex 5 [Fe]DPP (S = 2). 5 [Fe]DPP then undergoes decarboxylation via transition state 5 [Fe]DPP-TS with an 8.9 kcal/mol energy barrier to generate Fe-nitrenoid intermediate 5 [Fe]NPP. Mulliken spin populations analysis indicated that most of the unpaired electrons of 5 [Fe]NPP are located on Fe (∼3.18α, 80%) and N (∼0.82α, 20%). 5 [Fe]NPP is probably best viewed as a Fe(III)-bound iminyl complex.71–77,e 5 [Fe]NPP can readily undergo reductive elimination (RE) via transition state 5 [Fe]NPP-TS with a very small energy barrier of 1.2 kcal/mol to form 5 [Fe]NPP-pdt. Notably, a strong O···P interaction with a bond distance of 3.00 Å was identified in 5 [Fe]NPP-TS.f Dissociation of 5 [Fe]NPP-pdt gives iminophosphorane product 22 and FeCl2PPh3. Overall, DFT calculations indicate that PPh3 is involved in the initial formation of Fe-acylnitrenoid and then migrates via an inner-sphere mechanism. The analogous formation and P–N RE of tetra-coordinated nitrenoid intermediate 5 [Fe]NP proceeds with a slightly less favored but comparable energy profile to that of 5 [Fe]NPP, providing a viable alternative reaction pathway (Scheme 5c, see Supporting Information Figure S9 for details). As outlined in Scheme 5d, the formation of tricoordinated nitrenoid intermediate 5 [Fe]N in the absence of PPh3 is much more difficult with a barrier of 28.6 Kcal/mol. In comparison with the inner-sphere P–N RE of 5 [Fe]NPP, forming a P–N bond via the outer-sphere attack of 5 [Fe]NP by PPh3 requires considerably higher activation energy. Conclusion We have developed a nitrene-mediated P–N coupling reaction of phosphines and dioxazolones under iron catalysis. These reactions offer an efficient, versatile, flexible, and broadly applicable method for synthesis of a variety of P–N and P=N compounds from readily available precursors under mild conditions. Mechanistic studies indicate that the RE of Fe-acylnitrenoid intermediate forms the P–N bond. Footnotes a During the review process of this manuscript, we became aware that a related work was reported by Yu and co-workers in a Chinese patent (CN 109762017, 2019). In that system, the reaction of dioxazolones and phosphines under the catalysis of FeCl2 and light irradiation at varied temperatures gave the corresponding N-acyl iminophosphoranes in good yield. Subsequently, a related paper on iron-catalyzed nitrene formation and transformation with dioxazolones was published.78 b More 21-Rh was formed at higher temperatures. 20-Rh/ 21-Rh: 1/1.6 (35 °C), 1/9 (55 °C). Compound 21-Rh has been isolated and characterized by NMR and HRMS, which matches with a bidentate P,O-phosphanyl iminolate complex with O replacing one of the Cl ligands in 20-Rh. Its structure has not been confirmed by X-ray crystallography. Co and Ni complexes with similar coordination modes are reported in ref 16. c Addition of 2 equiv of TEMPO had negligible impact on the Fe-catalyzed reaction of PPh3 and 2. However, TEMPO reacts with diphenylphosphine 1 to give an O–P adduct in the absence of Fe catalyst. d FeCl2 gave similar results to FeCl2•4H2O for this reaction. e Bond order analysis showed that the Fe–P bond in 5 [Fe]NPP has a Mayer bond order (MBO) of 0.73(Fe–P)/0.68(Fe–P), and the Fe–N bond has an MBO of 0.90, indicating a single bond character of the Fe–N bond. Evaluation of the oxidation state (OS) with the LOBA method using the Multiwfn package79 showed that the OS of Fe and NAc is 3 and −1, respectively. f N–P RE without the involvement of the O–P bonding interaction proceeds with a higher energy barrier (ΔΔG = 6.9 kcal/mol). See Supporting Information Figure S10 for independent gradient model analysis of both 5 [Fe]NPP and 5 [Fe]NPP-TS and other details. 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Google Scholar Chen A Google Scholar Information Chinese authors gratefully acknowledge the Natural Science Foundation of China (nos. 21421062 and 21901127), the China Postdoctoral Science Foundation (nos. 2018M640225 and 2019T120179), and Nankai-Cangzhou Green Chemistry Institute (no. NCC2020FH02) for financial support of this work. G.C. dedicates this work to the 100th anniversary of chemistry at Nankai University.