Cross coupling of benzylammonium salts with boronic acids using a well-defined N-heterocyclic carbene–palladium(ii) precatalyst

Abstract

N-heterocyclic carbene–palladium(ii)-catalyzed cross-coupling of benzylammonium salts with arylboronic acids for the synthesis of diarylmethane derivatives via C–N bond activation has been developed. Notably, in the presence of the easily prepared and bench-stable Pd-PEPPSI precatalyst, the Csp³–N bond activation of the benzylammonium salt even proceeded smoothly in isopropanol at room temperature.

N-heterocyclic carbene–palladium(ii)-catalyzed cross-coupling of benzylammonium salts with arylboronic acids for the synthesis of diarylmethane derivatives via C–N bond activation has been developed.

Studies on synthetic methods of diarylmethane derivatives have attracted considerable attention because the compounds are important structural units in organic synthesis, materials science and pharmaceutical development.¹ Among the synthetic approaches explored, transition metal catalyzed Suzuki coupling is one of the most important and frequently used methods. Over the past decade, the most popular strategies for the cross coupling of benzyl halides² and benzyl sulfonates³ with aryl boric acid using Pd-catalysis have been reported. Disappointingly, some obvious drawbacks are involved with the use of benzyl halides and benzyl sulfonates as the electrophiles. These reagents are sometimes difficult in terms of substrate tolerance and storage. During recent years, the transition metal catalyzed Suzuki coupling reactions by the C–N bonds cleavage have been developed.⁴ Among them, the cross coupling of quaternary ammonium salts has been quite well explored because they are more easily available from amine precursors or benzyl halides and they are also stable to long-term storage. Since the pioneering work of MacMillan and co-workers in 2003,⁵ with aryltrimethylammonium salts as the electrophiles in various catalytic reactions such as cross-coupling,⁶ C–H arylation,⁷ borylation⁸ and reductive carboxylation reactions⁹ have been carried out. Although excellent results have been obtained, the optimization and development of cross-coupling reactions involving Csp³–N bond cleavage of benzylammonium salts under mild conditions, such as in aqueous media or at room temperature, are still worthwhile projects.¹⁰ In this present contribution, we have developed efficient catalytic systems^11–13 for the Suzuki–Miyaura coupling of benzyl chlorides with arylboronic acids, producing the corresponding diarylmethane derivatives in high yields. In a recent communication, the N-heterocyclic carbene–palladium(ii) complexes were also found to be active catalysts for the Suzuki–Miyaura cross-coupling of N-acylsuccinimides with arylboronic acids via C–N bond activation.¹⁴ Considering our successful experience with the applications of this complexes in the cross-coupling reaction, we then turned our recent interest to the coupling reaction between benzylammonium salt and arylboronic acids for the formation of diarylmethane derivatives. In such context, we herein report the first example of NHC–Pd-PEPPSI catalyzed coupling reactions of benzylammonium salts with arylboronic acids via Csp³–N bond activation under mild conditions (Scheme 1).

Scheme 1. NHC–Pd(ii) catalyzed coupling reactions of benzylammonium salts with arylboronic acids via Csp³–N bond activation.

It is initiated by investigating the crossing coupling of 4-methoxyphenyl boronic acid with benzyltrimethylammonium bromide 1a, which is readily prepared quantitatively via the reaction of trimethylamine and benzyl bromide. The details were shown in Table 1. The choice of base is crucial to the yield of the reaction (Table 1, entries 1–9).¹⁵ In the presence of the IPr–Pd-PEPPSI complex 4a as the catalyst, K₃PO₄·3H₂O as the base in isopropanol at 70 °C, we were delighted to observe that the reaction gave the corresponding diarylmethanes quantitatively. Several other solvents including THF, EtOH, 1,4-dioxane, toluene, CH₃CN and H₂O were tested, and the yield was not enhanced further (Table 1, entries 10–15). When 2.0 mol% of complex 4a was tested, the yield of cross coupling product was obtained in 82% yield (Table 1, entry 16). It is worth mentioning that the IPr–Pd-PEPPSI complex 4a still gave good yield at room temperature (Table 1, entry 18). Further screening of NHC–Pd(ii) catalysts demonstrates that the coordination environment of the NHC–Pd(ii) complexes had an obvious effect on the yield (Table 1, entries 18–23). When a solvent mixture of isopropanol and water was tested, the yield of the product reduced to 76% (Table 1, entry 24). In this case, heating to 50 °C was found to be necessary (Table 1, entry 25). Then the performance of the other five NHC–Pd(ii) complexes 4b–f in this reaction condition was examined, and IPr–Pd-PEPPSI complex 4a was found to be optimal (Table 1, entry 25 vs. entries 26–30).

Optimization of the cross-coupling reaction on substrate 1a^a.

Entry	Cat.	Base	Solvent	Temp (°C)	Yieldc (%)
1	4a	KOtBu	iPrOH	70	89
2	4a	Na2CO3	iPrOH	70	Trace
3	4a	K2CO3	iPrOH	70	91
4	4a	NaHCO3	iPrOH	70	Trace
5	4a	K3PO4	iPrOH	70	70
6	4a	K3PO4·3H2O	iPrOH	70	>99
7	4a	NaOAc	iPrOH	70	Trace
8	4a	NaOH	iPrOH	70	90
9	4a	KOH	iPrOH	70	98
10	4a	K3PO4·3H2O	THF	70	47
11	4a	K3PO4·3H2O	1,4-Dioxane	70	98
12	4a	K3PO4·3H2O	EtOH	70	88
13	4a	K3PO4·3H2O	Toluene	70	30
14	4a	K3PO4·3H2O	CH3CN	70	59
15	4a	K3PO4·3H2O	H2O	70	54
b16	4a	K3PO4·3H2O	iPrOH	70	82
17	4a	K3PO4·3H2O	iPrOH	50	99
18	4a	K 3 PO 4 ·3H 2 O	i PrOH	rt	96
19	4b	K3PO4·3H2O	iPrOH	rt	92
20	4c	K3PO4·3H2O	iPrOH	rt	90
21	4d	K3PO4·3H2O	iPrOH	rt	22
22	4e	K3PO4·3H2O	iPrOH	rt	42
23	4f	K3PO4·3H2O	iPrOH	rt	16
24	4a	K3PO4·3H2O	iPrOH : H2O (1 : 1)	rt	75
25	4a	K 3 PO 4 ·3H 2 O	i PrOH : H 2 O (1 : 1)	50	97
26	4b	K3PO4·3H2O	iPrOH : H2O (1 : 1)	50	91
27	4c	K3PO4·3H2O	iPrOH : H2O (1 : 1)	50	90
28	4d	K3PO4·3H2O	iPrOH : H2O (1 : 1)	50	86
29	4e	K3PO4·3H2O	iPrOH : H2O (1 : 1)	50	6
30	4f	K3PO4·3H2O	iPrOH : H2O (1 : 1)	50	Trace

^aAll reactions were carried out using 1a (0.20 mmol), 2a (0.40 mmol), base (2.0 equiv.), cat. (5.0 mol%) in solvent (0.1 M) for 15 h.

^bCat. (2.0 mol%).

^cIsolated yields.

Since the reaction was performed in isopropanol at room temperature as well as in a solvent mixture consisting of isopropanol (1.0 mL) and water (1.0 mL) at 50 °C rather well, they were both applied as the reaction conditions in the following experiments to explore the scope of the cross coupling. As shown in Table 2, a series of aromatic boronic acids with benzyltrimethylammonium bromide were investigated in ⁱPrOH in the presence of 5.0 mol% complex 4a and 2.0 equiv. K₃PO₄·3H₂O at room temperature for 15 h. Gratifyingly, most of the coupling reaction proceeded rapidly and efficiently to provide the corresponding diarylmethane derivatives in excellent yields. It seems that the electronic effect and the steric effect of the substituents on the aromatic boronic acids have little effect on the reaction efficiency. No matter electron-donating (3aa–3ah) or -withdrawing (3ai–3aj) groups on the phenyl ring of boronic acids, good to excellent yields were obtained. The reaction was quite feasible with benzyltrimethylammonium bromide when the ortho-substituted aryl boronic acid was used (3ac and 3ag). In addition, in the case of 1-naphthylboronic acid or 2-naphthylboronic acid afforded in high reaction efficiency under the present reaction conditions (3ak–3al). Particularly, when heteroaromatic boronic acid, such as thienyl, was used as the substrate, high yield of the corresponding product was always observed (3am). Subsequently, a series of aromatic boronic acids with benzyltrimethylammonium bromide were investigated in ⁱPrOH–H₂O in the presence of 5.0 mol% complex 4a and 2.0 equiv. K₃PO₄·3H₂O at 50 °C for 15 h. All of the above substrates still worked well to afford the desired products in good to almost quantitative yields.

Scope of the coupling reaction with respect to the arylboric acid.

^aAll reactions were carried out using 1a (0.20 mmol), 2 (0.40 mmol), K₃PO₄·3H₂O (2.0 equiv.), cat. 4a (5.0 mol%) in ⁱPrOH (0.1 M) at room temperature for 15 h.

^bAll reactions were carried out using 1a (0.20 mmol), 2 (0.40 mmol), K₃PO₄·3H₂O (2.0 equiv), cat. 4a (5.0 mol%) in mixture solvent (ⁱPrOH : H₂O [v / v] = 1 : 1, 0.1 M) at 50 °C for 15 h.

Inspired by these results and our attention was next turned to the cross coupling reaction of benzylammonium salts with 4-methoxyphenyl boronic acid. As shown in Table 3, the reactions proceed smoothly to afford diarylmethanes in excellent yields. Roughly, the electron-donating group in the phenyl ring of benzylammonium salts showed some beneficial effect on the yields of the catalysis products. Benzylammonium salts bearing fluorine substituent showed good reactivity in this transformation (3be). Substrate 1 having naphthalene ring substituent was also suitable for such transformation to afford products 3bg and 3bh in good yields under appropriate conditions. In addition, when benzyltrimethylammonium triflate was used as the substrate, high yield of the corresponding product was always observed (3bi).

Scope of the coupling reaction with respect to the benzylammonium salts.

^aAll reactions were carried out using 1 (0.20 mmol), 2a (0.40 mmol), K₃PO₄·3H₂O (2.0 equiv.), cat. 4a (5.0 mol%) in ⁱPrOH (0.1 M) at room temperature for 15 h.

^bAll reactions were carried out using 1 (0.20 mmol), 2a (0.40 mmol), K₃PO₄·3H₂O (2.0 equiv.), cat. 4a (5.0 mol%) in mixture solvent (ⁱPrOH : H₂O [v / v] = 1 : 1, (0.1 M)) at 50 °C for 15 h.

On the basis of the mechanism of previous reports^10b and our results, a putative reaction mechanism was then proposed in Scheme 2. First, oxidative addition of Pd(0) I produced in situ, with benzyltrimethylammonium salt 1 formed intermediate II with the release of trimethylamine. Then a transmetalation reaction of the intermediate II with aryl boronic acid converted to intermediate IV, which followed by reductive elimination to the product 3 with simultaneous regeneration of the Pd(0) catalyst.

Scheme 2. Proposed reaction mechanism.

Conclusions

In summary, we have developed the first example of NHC–Pd(ii) catalyzed cross-coupling of benzylammonium salts with arylboronic acids to form diarylmethane derivatives, a very important skeleton in synthetic chemistry. The current process tolerates broad scope with respect to both the boronic acid and benzylammonium salts under mild conditions. Further exploration of these N-heterocyclic carbene–palladium(ii) complexes and their catalytic applications in other reactions is in progress.

Experimental

General remarks

The catalytic reactions were carried out under a nitrogen atmosphere. Benzylammonium salts were prepared according to the literature method.¹⁶ The N-heterocyclic carbene–palladium(ii) complexes were synthesized according to our previous report.^11b Solvents were dried by standard methods and freshly distilled prior to use. All other chemicals were used as purchased. ¹H and ¹³C NMR spectra were recorded on a Bruker DPX 400 instrument using TMS as an internal standard.

General procedure for the cross-coupling of benzylammonium salts with arylboronic acids

A Schlenk flask was charged with the required benzylammonium salts 1a (0.20 mmol, 46.0 mg), (4-methoxyphenyl)boronic acid (0.40 mmol, 60.8 mg), N-heterocyclic carbene–palladium(ii) complex 4a (5 mol%, 6.8 mg), K₃PO₄·3H₂O (2.0 equiv., 106.5 mg), and ⁱPrOH (0.1 M) [or ⁱPrOH : H₂O [v / v] = 1 : 1, 0.1 M]. The mixture was stirred at room temperature [or 50 °C] for 15 h under N₂. After cooling, the mixture was evaporated and the product was isolated by by preparative TLC on silica gel plates eluting with CH₂Cl₂/petroleum ether to afford the diarylmethane. The purified products were identified by NMR spectra and their analytical data are given in the ESI.†

Conflicts of interest

There are no conflicts to declare.