An efficient catalytic method for hydrophosphination of heterocumulenes with diethylzinc as precatalyst without a solvent

Abstract

Commercially available compound ZnEt₂ acts as an efficient precatalyst for the solvent-free hydrophosphinations of heterocumulenes using Ph₂PH as reagent. As far as we knew, this has been not reported in group 12 metal catalyzing reactions. A suggested mechanism of this reaction is explored, and the intermediate [{Ph₂PC(NⁱPr)₂}ZnEt]₂ is obtained and characterized by a single-crystal X-ray structural analysis.

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Introduction

As group 12 metal, zinc has Lewis acidity similar to those main group metals, which makes it widely used in various catalytic reactions, especially enantioselective transformations.^1–4 As the earth-abundant first-row transition metal, zinc has high availability, low prices and low toxicity when compared with most of the traditional transition metals. Therefore, sustainable development awareness and the increasing risk of environmental pollution has motivated researchers to exploring the application of zinc complexes. Diethylzinc, with an accessible price is one of the simplest zinc complexes, which was firstly synthesized by E. Frankland in 1848 and structural defined by J. Bacsa et al. in 2011.^5,6 In recent years, ZnEt₂ has been extensively used in asymmetric addition of aldehydes and ketones,^7–10 Mannich reactions,^11,12 aldol reactions,^13,14 Henry reactions,^15,16etc. However, ZnEt₂ being used in the reaction without auxiliary ligands are rare.¹⁷

Organophosphorus compounds are becoming significant in modern industrial chemistry and academics as they are widely used in the organic modification of materials,¹⁸ syntheses of pesticides¹⁹ and catalysts,²⁰ and design of pharmaceuticals.²¹ The synthesis of organophosphorus compounds has become a hot research area.^22–25 Heterocumulenes with R–N=C=E (E = O, S, N–R) skeletons, containing a chain of two double bonds, are commercially available and widely used in the syntheses of phospha-guandidines, phosphaureas, and phosphathioureas. These organophosphorus compounds are widely used as stabilizing ligands for various metal compounds.^26–29 Hydrophosphination and Hydrophosphorylation, the addition of P–H or P(O)–H bonds to unsaturated substrates is a particularly attractive approach since its 100% atom economical yield. So far, many transition metal-catalyzed reactions have been reported, such as the addition of phosphine oxide to C=C and C≡C bonds.^30–36 Furthermore, a number of metal catalysts have been investigated and reported involving organic alkali metal compounds,³⁷ heavier group 2 complexes,³⁸ Rare-Earth-metal complexes,^39–41 and late transition metal compounds^42,43 to promote the addition of the phosphines P–H to carbodiimides, isocyanates, and isothiocyanates.

Previously, our group reported on LAlH₂ (L = HC(CMeNAr)₂, Ar = 2,6-Et₂C₆H₃) (1, Fig. 1) catalyzed hydrogenation of carbodiimides using alkyne and pinacolborane.⁴⁴ Inspired by those results, we have planned to carry out aluminum-catalyzed hydrophosphination of heterocumulenes. Recently, M. Itazaki et al. reported the catalyst-free hydrophosphination of isocyanates and isothiocyanates with diphenylphosphine under neat conditions, which limited to a range of small aromatic isocyanates and isothiocyanates.⁴⁵ In particular, cyclohexyl isocyanate and adamantylisocyanate exhibited no reactivity under the same conditions. Furthermore, they demonstrated the negative effect of solvents on hydrophosphination. Therefore, we limited the scope of our study to the catalysis of aliphatic and large aromatic heterocumulenes under solvent-free conditions. However, aluminum compounds failed to act as catalysts as expected. So we shifted 1 to the zinc compound LZnEt (2, Fig. 1),⁴⁶ which has a similar structure to 1, and successfully catalyzed the reaction of Ph₂PH with N,N′-diisopropyl carbodiimide (DIC). Then we shifted our research direction to zinc-catalyzed hydrophosphination of heterocumulenes, and its reaction mechanism.

Fig. 1 The structures of aluminum hydride (1) and zinc ethyl (2).

Herein, we report on the unprecedented example of ZnEt₂ without auxiliary ligands used as a catalyst for catalytic hydro-phosphination of aliphatic and large aromatic heterocumulenes, producing phospha-guanidines, phosphaureas and phosphathioureas with moderate conditions and high efficiency.

Results and discussion

At first, we examined the catalytic performance of different metallic compounds including LAlH₂ (L = HC(CMeNAr)₂, Ar = 2,6-Et₂C₆H₃) 1, LZnEt 2, AlMe₃3, HAl(ⁱBu)₂4, CuCl₂5, ZnCl₂6, Zn(OAc)₂7, and ZnEt₂8 for the hydrophosphination of DIC with Ph₂PH in a 1 : 1 molar ratio at 60 °C under neat conditions (Table 1, entries 1–8). In the presence of 5 mol% of organoaluminum compounds 1, 3, 4, and Lewis acid 5 no reactions were observed to yield any products after 24 h. The results indicated that organoaluminum compounds and CuCl₂ did not contribute to the hydrophosphination of carbodiimide (Table 1, entries 1–4). Then we attempted to use Inorganic and organic zinc compounds 2, 6, 7, and 8 as pre-catalysts, under the same condition. We found, that the desired P–H addition product ⁱPrN=C(PPh₂)(NHⁱPr) 9a was generated, and the catalytic performance of inorganic zinc compounds was significantly inferior to that of organic zinc compounds (entries 5–8). Besides, reactions catalyzed by organozinc compounds reached a yield of 99% in 5 min (entries 7 and 8). Therefore, we thought that the high temperature might not be necessary to reach a level like that in the case of rare earth metals.^39,41 Indeed, we showed that this reaction proceeds at room temperature (entries 9 and 10). Moreover, the reaction of DIC with Ph₂PH proceeds at room temperature without solvent. After 5 min, the reaction catalyzed by 8 was substantially completed (entry 9), while the reaction catalyzed by 2 was only converted to 73% within 12 h (entry 10). Decreasing the catalyst loading to 3 mol%, the reaction afforded the product only in a yield of 52% within 15 min (entry 11). Hence, 5 mol% of catalyst 8 at ambient temperature in neat condition was chosen to be the optimum reaction condition for the hydrophosphination of heterocumulenes.

Table 1 Optimization of the reaction conditions^a

Entry	Catayst (mol%)	T [°C]	Time	Yield^b
a Reactions carried out using 1.0 mmol of DIC, 1.0 mmol of Ph2PH in 10 mL Schlenk flask without solvent under nitrogen atmosphere. b Yield determined by ^31P NMR.
1	1 (5%)	60	24 h	0%
2	3 (5%)	60	24 h	0%
3	4 (5%)	60	24 h	0%
4	5 (5%)	60	24 h	0%
5	6 (5%)	60	24 h	75%
6	7 (5%)	60	24 h	87%
7	2 (5%)	60	5 min	>99%
8	8 (5%)	60	5 min	>99%
9	8 (5%)	25	5 min	>99%
10	2 (5%)	25	12 h	73%
11	8 (3%)	25	15 min	52%

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In order to see the scope and limitation of ZnEt₂-catalyzed hydrophosphination of heterocumulenes, we examined reactions with several heterocumulenes under the optimized conditions in hand. It was found that Ph₂PH worked well with N,N′-dicyclohexylcarbodiimide, and similarly to isopropyl N,N′-diisopropylcarbodiimide, producing the corresponding final product CyN=C(PPh₂)(NHCy) 9b in almost quantitative yields in 5 min (Table 2, entry 1). In the past, no successful reaction of N,N′-di-tert-butylcarbodiimide with Ph₂PH was ever reported, owing to the steric blocking.^38,41 Similarly, we also failed to catalyze this reaction (Table 2, entry 2). It turned out that the bulky hindrance of the substrate has a significant impact on the reaction. Then, the hydrophosphination also worked well with the aliphatic isocyanates as isopropyl and cyclohexyl isocyanates were converted to Ph₂PC(O)NH(ⁱPr) 9c and Ph₂PC(O)NHCy 9d in 2 min (Table 2, entries 3 and 4). The hydrophosphination of aliphatic isocyanates was also affected by steric hindrance, as tert-butyl isocyanate was converted to Ph₂PC(O)NH(^tBu) 9e in only 44% within 1 hour (Table 2, entry 5). Again, it is found that the increase in steric demands of the isothiocyanate N-substituents also affects the yield of the hydrophosphination, producing the corresponding product of tert-butyl 9h in a yield of 62% at 60 °C in 24 hours. The corresponding products of isopropyl 9f and cyclohexyl 9g groups are formed in good to quantitative yields within 2 hours (entries 6–8). The influence on the hydrophosphination of heterocumulenes performance might be attributable to the electron-withdrawing ability of E (E = N–R, O, S) which favors the attack of Ph₂P–. Furthermore, the reactions of large aromatic heterocumulenes and Ph₂PH might be due to a completely different phenomenon. N,N′-(2,6-Diisopropylphenyl)carbodiimide failed to obtain the corresponding product in 24 hours, even though heating to 60 °C (entry 9). This may be explained, that the steric effect of diisopropylphenyl is greater than the electron-donating effect. 2,6-Diisopropylphenyl isocyanate was almost totally reduced to the single insertion product Ph₂PC(O)NH(2,6-ⁱPr₂C₆H₃) 9i within 15 min (entry 10). This demonstrates that ZnEt₂-catalyzed hydrophosphination of isocyanates has similar addition selectivity to copper-catalyzed reactions.⁴³ What is surprising is that 2,6-diisopropylphenyl isothiocyanate only obtained products in a 69% yield. The single insertion product Ph₂PC(O)NH(2,6-ⁱPr₂C₆H₃) 9j and the double insertion product Ph₂PC(O)N(2,6-ⁱPr₂C₆H₃)C(O)NH(2,6-ⁱPr₂C₆H₃) 9k was observed in a ratio of 27 : 73 (entry 11). To investigate the addition selectivity of this reaction, the ratio of 2,6-ⁱPr₂C₆H₃/S/Ph₂PH was changed from 1 : 1 to 2 : 1 and 3 : 1. More surprisingly, the reaction results were different from the previously investigated regularity, in which the proportion of double insertion product decreased, while the ratios of ⁱPr₂C₆H₃/S increased (entries 12 and 13). Finally, we explored the influences of hydrophosphination reagents on the reaction, using Cy₂PH as a reactant with carbodiimide, isocyanate, and isothiocyanate. However, no corresponding products were obtained (entries 14–16). It might be explained by the reduced acidity of the hydrophosphination reagent, which is consistent with the findings of M. R. Crimmin et al.³⁸

Table 2 Hydrophosphination of heterocumulenes catalyzed by 8 ^a

Entry	R/E/R′	RNCE/R′2PH	Time	Yield	I : II^c
a Conditions: 1.0 mmol of RNCE, 1.0 R′2PH, 5 mol% catalyst 8 are charged in a screw-capped vial under nitrogen atmosphere, and the reaction mixture is carried out at room temperature. Chemical yields determined using ^31P NMR spectroscopy. b Reaction condition: 60 °C. c Ratio of single insertion to double insertion products.
1	Cy/N–Cy/Ph	1 : 1	5 min	99%	100 : 0
2^b	^tBu/N–^tBu/Ph	1 : 1	24 h	0%	0 : 0
3	^iPr/O/Ph	1 : 1	2 min	99%	100 : 0
4	Cy/O/Ph	1 : 1	2 min	99%	100 : 0
5	^tBu/O/Ph	1 : 1	1 h	44%	100 : 0
6	^iPr/S/Ph	1 : 1	2 h	98%	100 : 0
7	Cy/S/Ph	1 : 1	2 h	97%	100 : 0
8	^tBu/S/Ph	1 : 1	24 h	62%	100 : 0
9^b	2,6-^iPr2C6H3/N–2,6-^iPr2C6H3/Ph	1 : 1	24 h	0%	0 : 0
10	2,6-^iPr2C6H3/O/Ph	1 : 1	15 min	99%	100 : 0
11	2,6-^iPr2C6H3/S/Ph	1 : 1	24 h	69%	27 : 73
12	2,6-^iPr2C6H3/S/Ph	2 : 1	24 h	76%	38 : 62
13	2,6-^iPr2C6H3/S/Ph	3 : 1	24 h	84%	83 : 17
14^b	^iPr/N–^iPr/Cy	1 : 1	24 h	0%	0 : 0
15^b	^iPr/O/Cy	1 : 1	24 h	0%	0 : 0
16^b	^iPr/S/Cy	1 : 1	24 h	0%	0 : 0

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To investigate the mechanism of these reactions, we carried out the reaction of 8 with one equivalent of Ph₂PH at room temperature. It resulted in a zinc compound of composition EtZnPPh₂A, which was first synthesized in 1965.^47,48 On the basis of reaction previously reported in the literature,⁴⁹ the reaction of 8 with DIC yielded [{EtC(NⁱPr)₂}ZnEt]₂A′ for 70 h at 90 °C. Thus, it was reasonable to presume that Ph₂PH was the first to react with ZnEt₂ at the beginning of the reaction, and generated the active species. Then, the stoichiometric reaction of compound 9a with one equivalent of 4 in diethylether was carried out, to explore the step2 intermediate in this process. It resulted in the zinc compound [{Ph₂PC(NⁱPr)₂}ZnEt]₂C, which was characterized by single-crystal X-ray diffraction analysis (Fig. 2). Formation of compound C maybe helpful in binary polymerization of {Ph₂PC(NⁱPr)₂}ZnEt B, which is consistent with previously published literature.^17,37,39 Unfortunately, our attempts to isolate Bvia various synthetic routes have not been successful. Besides, we carried out the stoichiometric reaction of compound C with one equivalent of DIC, in which the emergence of a new doublet resonance (N–H) at δ 3.41 ppm and δ 3.39 ppm in the ¹H NMR spectrum proved compound C was an effective intermediate product.

Fig. 2 X-ray single-crystal structure of C. Themal ellipsoids are set at 50% probability level. All hydrogen atomsare omitted for clarity.

According to those results discussed and previous research, the proposed catalytic cycle is shown in Scheme 1. The first step is deprotonation of Ph₂PH, which generates the intermediate A and starts the cycle. The second step of the catalytic cycle is the insertion of the heteroalkenes into a Zn–PPh₂ bond, which produces the intermediate B. The last step via protonolysis of Ph₂PH with C, formed by dimerization of B, to yield the hydrophosphination product and regenerate the active species.

Scheme 1 The proposed mechanism of hydrophosphination of heteroalkenes catalyzed by 8.

Conclusions

In conclusion, the highly efficient and 100% atom-productive catalytic hydrophosphination of heteroalkenes has been elucidated by using the low-cost and commercially available zinc compound ZnEt₂. This is the first time that group 12 organometallic compound as catalysts for these reactions, and is a green and highly selective method to afford phospha-guanidines, phosphaureas and phosphathioureas. Under ambient temperature in neat condition, the electronic effect and steric hindrance of ligands on catalytic reactions were discussed, and several unreported hydrophosphinations were synthesized. Finally, a reliable mechanism for the catalytic cycle has been proposed by carrying out a series of stoichiometric reactions, and a constant intermediate product [{Ph₂PC(NⁱPr)₂}ZnEt]₂ has been synthesized. These results indicate ZnEt₂-catalyzed hydrophosphinations of heterocumulenes are environmentally sustainable.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We gratefully acknowledge financial support of this work by the National Nature Science Foundation of China (21872005, 21671018). H. W. R. thanks the DFG for financial support (RO 224/71-1).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental section, all spectroscopic data and spectra for all compounds. CCDC 2097921. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1dt02706a

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