Cu(II)-catalyzed cross-dehydrogenative coupling reaction of N′-acyl arylhydrazines and phosphites

Abstract

A novel Cu(II)-catalyzed cross-dehydrogenative coupling reaction of N′-aryl acylhydrazines and dialkyl phosphites has been developed for the synthesis of phosphorylhydrazides by using NMO as an external oxidant and AgNO₃ as additive. Various N′-aryl acylhydrazines were mildly and regioselectively converted to corresponding phosphorylhydrazides with good to excellent yields.

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Introduction

Phosphoramidates are important building blocks that are widely present in natural bioactive products and pharmaceuticals, such as microcin C7,¹ phosmidosine,² agrocin 84 (ref. 3) and fosaprepitant,⁴ and display antifungal, antitumor, and antiemetic activities. Phosphoramidates are also frequently used as ligands or chiral catalysts in asymmetric synthesis,⁵ as flame retardants,⁶ and for efficient ionization and suppression of matrix-related ion effects in MALDI-TOF mass spectrometry.⁷ The synthesis of phosphoramidates is of great importance because of their wide range of applications. Conventional methods for this transformation normally involve treating amines with phosphorus halides in the presence of a base (Scheme 1a), or via reactions of amines with dibenzyl or dialkyl phosphites using CCl₄ as activating agent (Atherton–Todd reaction) (Scheme 1b).⁸ Although this protocol is widely followed, it involves tedious multistep syntheses, handling of toxic reagents, production of large amounts of toxic waste, and long reaction time. To circumvent these problems, several greener and more atom-economical procedures have been developed using phosphites as starting materials. For example, Prabhu et al. designed a metal- and solvent-free synthesis of phosphoramidates via I₂-catalyzed cross-dehydrogenative coupling (CDC) reaction of diethyl phosphate with amines in the presence of H₂O₂ (aq.).⁹ Under optimal conditions, various primary and secondary amines were smoothly and efficiently converted to their corresponding phosphoramidates. A similar transformation was documented by Singh and co-workers for the phosphorylation of primary aromatic amines using air as terminal oxidant (Scheme 1c).¹⁰ Recently, a Cu-catalyzed (or mediated) oxidative cross-coupling reaction was proven to be a highly efficient approach for the formation of C–C and C-heteroatom bonds.¹¹ Based on these findings, forming N–P bonds under Cu-catalyzed conditions were recently attempted. For example, Mizuno et al. developed an oxidative cross-coupling of phosphites and amides using Cu(II) acetate as catalyst and air as terminal oxidant (Scheme 1d).¹² Almost simultaneously, CuI and CuBr were proven to be excellent catalysts for similar CDC reactions.¹³

Scheme 1 The synthetic procedures for phosphoramidates.

The phosphorylation of amines, amides and sulfoximines has been intensively investigated in recent years. However, accessing phosphorylhydrazides has been relatively ignored. Owing to the broad utilizations of phosphamide derivatives in synthetic chemistry as well as in medicinal chemistry, phosphorylhydrazides might also be applied in these areas.¹⁴ As far as we know, only two examples have been reported regarding the preparation of phosphorylhydrazides. One route formed phosphorylhydrazides via the phosphorylation of N′-acyl arylhydrazines in the presence of PCl₅/POCl₃ (Scheme 2a).¹⁵ The other route involved the reaction of dialkyl phosphites with N′-acyl arylhydrazines under the catalysis of benzoic anhydride (Scheme 2b).¹⁴ However, the former involved the use of toxic reagents, such as PCl₅/POCl₃, and was sensitive to moist atmosphere. Meanwhile, the latter needed high reaction temperatures and special substrates to ensure good yield, which thereby limits its applications. Hence, a mild, efficient and practical access to phosphorylhydrazides is still highly desirable.

Scheme 2 Synthetic procedures for phosphorylhydrazides.

Our previous studies demonstrated that N′-aryl acylhydrazine is an efficient coupling partner that could undergo homo- and cross-coupling reactions in the presence of Cu(OAc)₂·H₂O.¹⁶ As we continued exploring the reaction profiles of N′-aryl acylhydrazines, we envisioned that the cross-dehydrogenative coupling of N′-aryl acylhydrazines and dialkyl phosphites could be performed mildly and regioselectively using Cu(II) species as a catalyst. Herein, we report our recent findings on the preparation of phosphorylhydrazides via CDC reaction.

Results and discussions

Our study began with an initial catalyst screen (Table 1) using N′-phenylbenzohydrazide (1a) and diisopropyl phosphite (2a) as model substrates. In the presence of 0.1 equiv. Cu(OAc)₂·H₂O, the reaction proceeded smoothly to afford the desired CDC reaction product 3a with 35% yield and without an external oxidant or additive (Table 1, entry 1). The yield was greatly improved by the introduction of Ag₂CO₃ (1.0 equiv.) as an additive (from 35% to 70%, entry 2). Considering that external oxidants are usually essential in CDC reactions,¹⁷ we also tested NMO and found that it could improve the yield significantly (from 70% to 95%, entry 3). A detailed investigation on the molar ratio of Cu(OAc)₂·H₂O revealed that 0.1 equiv. was optimal for this catalytic system. Next, several conventional Cu salts such as CuCl₂, CuBr₂, CuCl, CuBr and CuI were also evaluated (Table 1, entries 5–9). In general, the catalytic abilities of Cu(I) species were better than those of Cu(II) salts in the presence of NMO, and only moderate yields were obtained from the Cu(II)-catalyzed process (entries 5–9). We concluded that Cu(I) species might more readily coordinate with phosphite in the catalytic cycle under oxidative conditions. Notably, NMO played a central role in this CDC reaction, and its absence dramatically reduced the yield (entries 7 and 8).

Table 1 Optimization of the reaction conditions^a

Entry	Catalyst	Additive	Solvent	Yield^b (%)
a 1a (0.3 mmol), 2a (0.6 mmol), NMO (0.6 mmol), MS 4 Å (30 mg), DMSO (2.0 mL), rt, 12–24 h.b Isolated yields.c No additive was added.d No NMO was added.e NMO (1.0 equiv.).
1	Cu(OAc)2·H2O (0.1 equiv.)	—	DMSO	35^c^,^d
2	Cu(OAc)2·H2O (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	DMSO	70^d
3	Cu(OAc)2·H2O (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	DMSO	95
4	Cu(OAc)2·H2O (0.05 equiv.)	Ag2CO3 (1.0 equiv.)	DMSO	88
5	CuCl2 (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	DMSO	73
6	CuBr2 (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	DMSO	54
7	CuCl (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	DMSO	39^d
8	CuCl (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	DMSO	90
9	CuI (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	DMSO	81
10	Cu(OAc)2·H2O (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	Dioxane	71
11	Cu(OAc)2·H2O (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	THF	75
12	Cu(OAc)2·H2O (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	Toluene	45
13	Cu(OAc)2·H2O (0.1 equiv.)	Ag2CO3 (1.0 equiv.)	CH2Cl2	53
14	Cu(OAc)2·H2O (0.1 equiv.)	K2CO3 (1.0 equiv.)	DMSO	74
15	Cu(OAc)2·H2O (0.1 equiv.)	TEA (1.0 equiv.)	DMSO	67
16	Cu(OAc)2·H2O (0.1 equiv.)	AgOAc (1.0 equiv.)	DMSO	97
17	Cu(OAc)2·H2O (0.1 equiv.)	AgNO3 (1.0 equiv.)	DMSO	97
18	Cu(OAc)2·H2O (0.1 equiv.)	AgNO3 (0.2 equiv.)	DMSO	99
19	Cu(OAc)2·H2O (0.1 equiv.)	AgNO3 (0.2 equiv.)	DMSO	88^e
20	—	AgNO3 (0.2 equiv.)	DMSO	Trace^d
21	—	—	DMSO	Trace^c

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Subsequently, we focused on the effect of the solvent in the process. As shown in Table 1, polar solvents such as dioxane, THF, CH₂Cl₂ as well as the non-polar toluene were not compatible with the process (entries 10–13). To evaluate the additive effect, several bases were screened (entries 14–15). Unfortunately, both inorganic and organic bases did not improve the yield, which indicated that Ag salt might be crucial in regulating the catalytic cycle. Thus, two other Ag salts AgOAc, and AgNO₃ were assessed (Table 1, entries 16–17), both of which promoted the reaction efficiently (97%). Further investigations on reducing the molar ratio of Ag salts showed that 0.2 equiv. of AgNO₃ was optimal and promoted the CDC reaction quantitatively (entry 18). Accordingly, reducing the amount of NMO used caused a slight drop in yield (entry 19). Control experiments showed that Cu(OAc)₂ is essential for the phosphorylation reaction (entries 20–21), and silver black can be observed in most cases.

Having established the optimal reaction conditions, the scope of this Cu-catalyzed CDC reaction was investigated. Various N′-aryl benzoylhydrazides with both electron-donating and electron-withdrawing groups attached to the aromatic ring were all good partners in this transformation, providing the corresponding phosphorylhydrazides with good to excellent yields (Table 2). In general, various halide substituents on Ar¹ rings were well tolerated (Table 2, entries 2–5), and electron-donating groups such as OMe on the Ar¹ ring were more effective than electron-withdrawing groups (entries 7 and 8). Ortho-substituted N′-aryl benzohydrazide as 1f only resulted in moderate yields, indicating that the reaction was sensitive to the steric hindrance of the Ar¹ group (entry 6). Di-substituted substrate 1i was also compatible with the catalytic system (entry 9). It should be noted that the regioselectivity of the phosphorylation might be influenced by the electronic cloud density of the Ar¹ group. Strong electron-withdrawing groups such as NO₂ on the Ar¹ group or pyridyl substituent led to comparable ratios of N-2 phosphorylating products (entries 8 and 10). N′-Benzyl benzohydrazide 1k was also tested under optimized conditions, but no desired product was obtained (entry 11).

Table 2 Substrate scope of N′-aryl acylhydrazides^a

Entry	R^1	Ar^1	Product	Yield^b (%)
a 1 (0.3 mmol), 2a (0.6 mmol), Cu(OAc)2·H2O (0.1 equiv.), NMO (0.6 mmol), AgNO3 (20 mol%), MS 4 Å (30 mg), DMSO (2.0 mL), rt, 12–24 h.b Isolated yields.c 33% N-2 phosphorylation product (3h′) was isolated.d 32% N-2 phosphorylation product (3j′) was isolated.e No reaction.
1	Ph (1a)	Ph	3a	99
2	Ph (1b)	4-FC6H4	3b	88
3	Ph (1c)	4-ClC6H4	3c	84
4	Ph (1d)	4-BrC6H4	3d	90
5	Ph (1e)	3-ClC6H4	3e	88
6	Ph (1f)	2-ClC6H4	3f	57
7	Ph (1g)	4-OMeC6H4	3g	97
8	Ph (1h)	4-NO2C6H4	3h	42 (33)^c
9	Ph (1i)	3,5-Di-MeC6H3	3i	74
10	Ph (1j)		3j	57 (32)^d
11	Ph (1k)	Benzyl	3k	NR^e
12	4-OMeC6H4 (1l)	Ph	3l	92
13	4-OHC6H4 (1m)	Ph	3m	81
14	4-BrC6H4 (1n)	Ph	3n	76
15	4-NH2C6H4 (1o)	Ph	3o	85
16	4-NO2C6H4 (1p)	Ph	3p	82
17	3-NO2C6H4 (1q)	Ph	3q	85
18	2-BrC6H4 (1r)	Ph	3r	83
19	Me (1s)	Ph	3s	85

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The reaction scope was further expanded to various N′-acyl phenylhydrazines. Most substituted aryl acyl groups with both electron-rich and electron-deficient substituents resulted in good to excellent yields (Table 2, entries 12–18). Unprotected hydroxyl and amino substituents were also tolerant in this reaction and showed good yields (entries 14 and 15). Simple alkanoyl substituted 1s could also couple with diisopropyl phosphite in high yield (entry 19).

Various N′-aryl alkanoylhydrazines were also evaluated under the optimal conditions (Table 3, entries 1–5), and the corresponding phosphorylhydrazides were obtained with good to excellent yields. The structure of 3t was determined by crystal X-ray diffraction, which verified the reacting site unambiguously (see ESI†). Notably, the Boc group of tert-butyl 2-(diisopropoxyphosphoryl)-2-phenyl hydrazinecarboxylate (3t) can be easily removed under TFA/CH₂Cl₂ to obtain 95% yield of diisopropyl (1-phenylhydrazinyl)phosphonate (4) (Scheme 3), which could be used as a practical structure motif in organic transformations. In addition, two other phosphites 2b and 2c were also investigated under standard conditions. 2b could smoothly couple with 1a to give 73% yield of 3y (Table 3, entry 6). The reaction hardly occurred when diphenyl phosphite used as P source (entry 7), while dialkyl phosphonates could be utilized as coupling partners.

Table 3 Further exploration of substrate scope^a

Entry	Ar^1	R^1	R^2	Product	Yield^b (%)
a 1 (0.3 mmol), 2 (0.6 mmol), Cu(OAc)2·H2O (0.1 equiv.), NMO (0.6 mmol), AgNO3 (20 mol%), MS 4 Å (30 mg), DMSO (2.0 mL), rt, 12–24 h.b Isolated yields.
1	Ph (1t)	t-BuO	i-Pr (2a)	3t	96
2	4-FC6H4 (1u)	t-BuO	i-Pr (2a)	3u	86
3	4-ClC6H4 (1v)	t-BuO	i-Pr (2a)	3v	95
4	4-BrC6H4 (1w)	t-BuO	i-Pr (2a)	3w	85
5	3,5-Di-MeC6H3 (1x)	t-BuO	i-Pr (2a)	3x	75
6	Ph (1a)	Ph	OEt (2b)	3y	73
7	Ph (1a)	Ph	OPh (2c)	3z	Trace

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Scheme 3 Synthesis of diisopropyl (1-phenylhydrazinyl)phosphonate.

Moreover, an additional scaled-up experiment showed that this CDC reaction could be performed on the gram scale without any loss in yield (Scheme 4).

Scheme 4 Gram scale preparation of 3t.

To further explore the mechanism of the reaction process, we carried out several additional experiments. First, we used N-1-protected acylhydrazine (1y) and diisopropyl phosphite (2a) as substrates and subjected them to the standard reaction conditions (Scheme 5). We found that no desired product was generated, indicating that phosphorylation occurred on the N-1 position. Then, a control experiment was also conducted. Under standard conditions, tert-butyl 2-phenyldiazene carboxylate 5 was isolated in quantitative yield for 0.5 h, and was converted to 3t with the addition of 2a in 93% yield (Scheme 6).

Scheme 5 Coupling reaction of 1y and 2a.

Scheme 6 Control experiments.

Based on these experiments and literatures,^{12,13,16,18,19} we proposed a possible mechanism for this CDC reaction (Fig. 1). N′-Aryl acylhydrazine (A) was oxidized by Cu(II) (B) to yield azo intermediate C and release reductive Cu(I) species (D) at the same time. Diisopropyl phosphite (E) was converted to its isomer (F), and the latter coordinated with D to form the metal complex G. The transient intermediate H can be formed either by the interaction of G with azo intermediate C or through the direct reaction of G with A under the oxidation of NMO. The desired product I was obtained via the reductive elimination of H along with the release of Cu(I)X, which was oxidized to Cu(II) in the presence of AgNO₃.

Fig. 1 Cu(II)-catalyzed CDC reaction of N′-acyl arylhydrazines and phosphites.

Conclusions

In summary, we have developed a mild and regioselective phosphorylation procedure for the synthesis of N-aryl-N′-acylphosphorylhydrazides via Cu(II)-catalyzed CDC reaction. A broad substrate scope that can tolerate diverse functional groups and result in good to excellent yields was realized. This novel protocol is simple and environmentally friendly, which makes it applicable in practical organic synthesis.

Acknowledgements

This work was financially supported by the National High-tech R&D Program of China (863 Program, No. 2013AA092903) and the Guangdong Province Natural Science Foundation (No. 2015A030313184).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: ¹H, ¹³C and ³¹P NMR spectra. X-ray structure of 3t. CCDC 1482374. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra13931k

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