Transition Metal-Catalyzed, “Ligand Free” P–C Coupling Reactions under MW Conditions ^†

Abstract

A method for “P-ligand free”, Pd(OAc)₂-catalyzed P–C coupling reactions under MW conditions was investigated in our group. In our latest work, this procedure was extended to dihalogenobenzenes. Copper-promoted reactions were studied experimentally and using quantum chemical calculations.

1. Introduction

The transition metal-catalyzed, P–C cross coupling reactions between vinyl halides and dialkyl phosphites were described 40 years ago by Hirao. The first reactions were carried out between vinyl/aryl halides and dialkyl phosphites in the presence of Pd(PPh₃)₄ catalyst [1,2]. Then, more phosphorus compounds, e.g., aryl phosphonates, -phosphinates, and tertiary phosphine oxides were also prepared effectively [3,4,5,6]. Later on, several Pd compounds in combination with different types of P-ligands were applied [3,4,5,6]. In these reactions, the active catalyst was formed in situ. In the past years, microwave (MW) technology was also applied in organic chemistry, which resulted in excellent yields during shorter reaction times [3,4,5,6]. Some nickel and copper salt catalyzed coupling reactions with added P- or N-ligands were also published [3,4,5,6].

2. Pd(OAc)₂ and NiCl₂-Catalyzed, Directly Added “P-ligand Free” P–C Coupling Reactions

Our group suggested a new Pd(OAc)₂-catalyzed, MW-assisted method for the P–C coupling reactions in 2013. These reactions were named “P-ligand free” Hirao reactions because of the lack of typically applied mono- or bidentate P-ligands [7]. They studied the coupling reactions between aryl derivatives and different >P(O)H-reagents, when the P-reagents were applied in some excess (Scheme 1) [7,8].

It is known that the catalytic cycle of the P–C coupling reactions is very similar to C–C couplings; the main steps are oxidative addition, ligand exchange and reductive elimination [9,10]. However, by our group, the entire, detailed catalytic cycle was calculated on the model reaction of the Pd(OAc)₂-promoted coupling of bromobenzene (PhBr) and diethyl phosphite (DEP) or diphenylphosphine oxide (DPPO) [11,12,13]. It was found that the necessary quantity of the >P(O)H-reagent’s excess is three times the catalyst precursor’s amount. The P-reagent served as a reduction agent and as the catalyst ligands via its trivalent tautomeric form (>POH). It all means that, if 10% of Pd(OAc)₂ is applied, 30% of the >P(O)H-reagent is needed, with all together 1.3 equivalents [11,12,13]. We also studied the kinetics of the coupling reactions, and an induction period was found (Figure 1) [14]. In the first ~22 min, the active catalyst (1) may be formed in situ from the Pd-precursor and the tautomeric form of the P-compound. We confirmed the reactivity order of the aryl halides: iodobenzene (PhI) was the most, PhBr was less, and chlorobenzene (PhCl) was the least reactive. We successfully promoted the PhBr and DPPO coupling reaction with potassium iodide (KI) at 100 °C [14].

After the previous results, we extended this Pd(OAc)-catalyzed, “P-ligand free”, MW-assisted method to different bromo-halogenobenzenes, namely 1,4-, 1,3-. Additionally, 1,2-dibromobenzenes and the analogous bromo-iodo or bromo-chloro derivatives were reacted with DEP and DPPO too (Scheme 2.) [15]. We found that, in most cases, the costly bromo-iodobenzenes could be replaced by the cheaper dibromo derivatives. The bis(>P(O)-benzene) species were synthesized directly or from the isolated mono(>P(O)-bromophenyl) derivatives. Three new products were prepared and characterized.

As a variation, “ligand free” nickel-catalyzed (e.g., NiCl₂), MW-assisted methods were also published earlier by our group [13,16,17,18]. The mechanism was calculated and, unexpectedly, a Ni(II)→Ni(IV) transition was observed instead of the earlier assumed Ni(0)→Ni(II) formation.

3. Cu-Catalyzed Hirao Reactions

After the Pd- and Ni-catalyzed accomplishments, we investigated the use of copper catalysts, which could be a cheaper option. Due to the copper’s lower reactivity, the most reactive aryl halide PhI had to be used. The first experiments were carried out in the presence of Cu(I)-salts (e.g., CuI, CuCl and CuBr) at 165 °C under MW conditions [19]. Using 20% of CuBr as the catalyst precursor and 2 equiv. of NEt₃ as the base seemed to be the best (Scheme 3). The mechanism of the reaction was also studied using quantum chemical calculations.

The three different ways of possible ligations of Cu(I) may be seen in Figure 2. The calculation results suggested that complexes 2 and 6 may catalyze the coupling reaction, but complex 6 is more dominant according to the experiments. It can be seen that Cu(I) → Cu(III) oxidation happens in the oxidative addition step [19].

Later on, Cu(II)-salts (e.g., CuSO₄, Cu(OAc)₂xH₂O, CuCl₂x2H₂O, and CuSO₄x5H₂O) were studied in the coupling reactions (Scheme 3) [20]. It was concluded that applying 20% of CuSO₄ or Cu(OAc)₂xH₂O as catalysts, together with two equivalents of NEt₃ is the best combination.

The earlier mentioned Cu(I) analogous reaction mechanism was assumed also in the Cu(II) case: in the oxidative addition step, the Cu²⁺ would be oxidized formally to Cu⁴⁺. However, this step was not feasible, between intermediates 15 and 17, no real TS (16) was found on the potential energy surface (Figure 3) [20].

Searching for a valid mechanism for the Cu(II)-precursors-catalyzed reactions, we looked for an alternative interpretation: a Cu(II) → Cu(I) reduction was assumed by the secondary phosphine oxide, accompanied by the P(III) → P(V) oxidization (Scheme 4) [20].

4. Conclusions

The “ligand free”, Pd(OAc)₂-catalyzed method was successfully used for synthesis of bromophenylphosphine oxides and phosphonates. The neglected Cu(I) and Cu(II)-salts catalyzed the P–C coupling reaction of iodobenzene with secondary phosphine oxides (diarylphosphine oxides) and was elaborated under MW irradiation. The investigated reactions were the most efficient when the P-reagent and NEt₃ were used in a 1:2 molar ratio. The mechanisms were studied using quantum chemical calculations.