Palladium catalytic system for inhibition of O-arylation type reaction and regioselective direct arylation at C2 of phenols

Abstract

The palladium-catalysed arylation of free OH phenol derivatives proceeds regioselectively either at C2 or at OH with a variety of electron-deficient aryl bromides or heteroaryl bromides. The nature of the base was found to be crucial to control the regioselectivity of the reaction. In the presence of potassium acetate, the direct arylation at C2 is favoured; whereas, under the same reaction conditions, the use of potassium carbonate gave selectively the O-arylation type products.

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Introduction

Biaryl derivatives display a set of bioactive or physical properties and their preparation constitutes an active field of research in organic chemistry.¹ Several methods for the preparation of those products have been described. The palladium-catalysed direct arylation of some aromatics via a C–H bond activation using aryl halides has led to successes in recent years.^2,3 For such direct coupling reactions, no preparation of an organometallic derivative is required, and this is a tremendous advantage as compared to the more classical cross-coupling procedures arising from more costly Suzuki–Miyaura, Stille, or Negishi reactions. Moreover, the direct arylation reaction provides only an acid (HX) associated to a required base as a by-product and therefore presents advantages both in terms of atom-economy and relatively inert wastes. However, if this procedure has been widely applied in recent years for the synthesis of biaryls bearing alkoxy, fluoro, or amide substituents,^2a on the other hand, relatively few biaryls bearing unprotected hydroxy as a substituent have been prepared by palladium-catalysed direct C–H bond functionalisation.^4–7 This might be due to the possible competitive palladium-catalysed reaction of aryl halides with phenols to form ethers.⁸ So far, most of the examples of direct arylation of phenols employ rhodium catalysts.⁹ A few examples of intramolecular reactions,⁵ and intermolecular palladium-catalysed reactions using protected phenols have also been described.¹⁰ The arylation at C2′ of a 2-hydroxybiphenyl using Cs₂CO₃ as the base has also been reported.⁷

We now report that the use of KOAc as the base controls the intermolecular direct palladium-catalysed arylation of phenols with aryl bromides at carbon C2 with inhibition of the O-arylation reaction; whereas, the use of K₂CO₃ as the base promotes selectively the O-arylation in high yield.

Results and discussion

As the nature of the base has been found in recent years to be a crucial factor to promote efficiently palladium-catalysed direct arylations,¹¹ we could expect a drastic influence of the nature of the base, associated with that of the ligand, on the selectivity for the palladium-catalysed reaction of aryl bromides with phenols.

First, we have considered the reaction of 3,5-dimethoxyphenol with 4-bromobenzonitrile to reach the formation of C2 arylated phenol 1a (Scheme 1). The formation of O-arylation type product 1c was also expected.

Scheme 1 Arylation of 3,5-dimethoxyphenol with 4-bromobenzonitrile.

We first explored the activity of several catalysts for this reaction. KOAc and DMAc were employed as the base and solvent, as we had previously observed that under these conditions the O-arylation of furfuryl alcohol^11a or the N-arylation of an aminothiophene^11b was inhibited to give regioselectively the direct arylation at C5 of the heteroaromatics. The assistance of carboxylate ligand on palladium for the direct arylation has been demonstrated by Fagnou.¹² In the presence of 4 mol% Pd(OAc)₂ as the catalyst, direct arylation product 1a was obtained in moderate yield and selectivity (Table 1, entry 1). The reaction was found to give 43% arylation at C2 and 50% homocoupling product 1d. Only traces of C4 arylated product 1b or O-arylation product 1c were detected. The use of 2 mol% Pd(OAc)₂, PdCl₂ or [PdCl(C₃H₅)]₂ led to 51–60% selectivities in 1a (Table 1, entries 2–4). The addition of the phosphine ligands dppe or PPh₃ was found to give low selectivities in 1a; whereas the use of dppb produced 1a in 61% selectivity, but only a partial conversion of 4-bromobenzonitrile was observed (Table 1, entries 5–7). Then, we explored the activity of PdCl(C₃H₅)(dppb), as we recently demonstrated it was one of the best catalysts for the direct arylation of some furans, thiophenes or thiazoles.¹³ Using 2 mol% of PdCl(C₃H₅)(dppb) as the catalyst precursor, DMAc as the solvent and KOAc as the base at 150 °C, the desired C2-arylation product 1a was obtained in 59% selectivity (Table 1, entry 8). Moreover, a complete conversion of the aryl bromide was observed. The O-arylation product 1c was also produced in 9% selectivity. We also evaluated the influence of the nature of the base. In the presence of the carbonates, K₂CO₃ or Cs₂CO₃, complete conversions of 4-bromobenzonitrile were observed, but only traces of product 1a were detected (Table 1, entries 11 and 12). With these two bases, the major product was the O-arylated phenol 1c which was obtained in 92% and 88% selectivities. Finally, it should be noted that the ratio of 3,5-dimethoxyphenol and 4-bromobenzonitrile has also an important influence on the selectivity of the reaction. A 4 : 1 ratio of these reactants gives much better results than a 1 : 1 ratio (Table 1, entries 8 and 16).

Table 1 Influence of the reaction conditions for palladium catalysed coupling of 3,5-dimethoxyphenol with 4-bromobenzonitrile (Scheme 1)^a

Entry	[Pd] (mol%)	Ratio ArOH : ArBr	Base	Ratio 1a : 1b : 1c : 1d	Conv. (%)
a 4-Bromobenzonitrile (1 mmol), 3,5-dimethoxyphenol (1–4 mmol), base (2 mmol), 150 °C, 40 h, under argon, conversion of 4-bromobenzonitrile. b Isolated yield in 1a. c 130 °C.
1	Pd(OAc)2 (4)	4 : 1	KOAc	43 : 3 : 4 : 50	86
2	Pd(OAc)2 (2)	4 : 1	KOAc	55 : 2 : 3 : 40	78
3	PdCl2 (2)	4 : 1	KOAc	60 : 4 : 2 : 34	100
4	½ [PdCl(C3H5)]2 (2)	4 : 1	KOAc	51 : 4 : 1 : 44	100
5	Pd(OAc)2/dppe (2)	4 : 1	KOAc	30 : 1 : 48 : 21	45
6	Pd(OAc)2/dppb (2)	4 : 1	KOAc	61 : 1 : 9 : 29	74
7	Pd(OAc)2/2 PPh3 (2)	4 : 1	KOAc	31 : 6 : 32 : 31	54
8	PdCl(C3H5)(dppb) (2)	4 : 1	KOAc	59 : 3 : 9 : 29	100 (39)^b
9	PdCl(C3H5)(dppb) (2)	4 : 1	NaOAc	37 : 5 : 0 : 58	90
10	PdCl(C3H5)(dppb) (2)	4 : 1	CsOAc	30 : 8 : 26 : 36	90
11	PdCl(C3H5)(dppb) (2)	4 : 1	K2CO3	3 : 2 : 92 : 3	100
12	PdCl(C3H5)(dppb) (2)	4 : 1	Cs2CO3	6 : 5 : 88 : 1	100
13	PdCl(C3H5)(dppb) (2)	4 : 1	KF	0 : 0 : 13 : 87	60
14	PdCl(C3H5)(dppb) (2)	4 : 1	KOAc	65 : 6 : 9 : 20	40^c
15	PdCl(C3H5)(dppb) (2)	2 : 1	KOAc	34 : 2 : 7 : 57	92
16	PdCl(C3H5)(dppb) (2)	1 : 1	KOAc	20 : 2 : 12 : 66	65

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The scope of the coupling of phenols at C2 or O using other aryl bromides was then investigated using PdCl(C₃H₅)(dppb) catalyst and either KOAc (Table 2) or K₂CO₃ (Table 3) as the base (Scheme 2).

Table 2 Scope of the palladium-catalysed direct 2-arylation of 3,5-dimethoxyphenol^a

Entry	Product	Yield (%)
a PdCl(C3H5)(dppb) (0.02 mmol), aryl bromide (1 mmol), 3,5-dimethoxyphenol (4 mmol), KOAc (2 mmol), DMAc, 150 °C, 48 h, under argon, isolated yields. b 24 h. c 60 h.
1		34^b
2		35
3		38
4		32
5		37
6		32
7		33^b
8		54
9		41
10		42
11		37^c
12		43
13		44

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Table 3 Palladium-catalysed O-arylation of various phenols with aryl bromides in the presence of K₂CO₃ as the base (Scheme 2)^a

Entry	Phenol	Product	Yield (%)
a PdCl(C3H5)(dppb) (0.02 mmol), aryl bromide (1.2 mmol), phenol derivative (1 mmol), K2CO3 (2 mmol), DMAc, 150 °C, 40 h, under argon, isolated yields. b 24 h.
1			82
2			74^b
3			91^b
4			79^b
5			83
6			93
7			90
8			92

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Scheme 2 Palladium-catalysed C- or O-arylation of phenols.

The C2 arylation reactions were performed using DMAc, KOAc, 150 °C and 2 mol% catalyst as the reaction conditions. First, we studied the reactivity of para-substituted aryl bromides. In the presence of electron-deficient aryl bromides such as 4-bromonitrobenzene, 4-trifluoromethylbromobenzene, 4-bromobenzophenone or 4-bromopropiophenone, the products 2–5 were obtained in 32–38% yields (Table 2, entries 1–4). Similar yields were obtained in the presence of the meta- or ortho-substituted aryl bromides, 2- or 3-bromobenzonitriles, 3-bromonitrobenzene, 3-trifluoromethylbromobenzene and also with 2-bromonaphthalene (Table 2, entries 5–7, 9 and 10). An higher yield of 54% was obtained with 3,5-bis(trifluoromethyl)bromobenzene (Table 2, entry 8). N-containing heterocycles are very common motifs in pharmaceutically active compounds. Therefore, preparative methods of biheteroaryl derivatives containing pyridines or quinolines remain an essential research topic in organic synthesis. We observed that 4-bromopyridine or 3-bromoquinoline also gave regioselectively the desired coupling products 13 and 14 in 43% and 44% yields (Table 2, entries 12 and 13). For all these reactions, complete conversions of the aryl bromides were observed. However, in all cases, quite large amounts of the homocoupling products of the aryl bromides were formed as side-products lowering the yields.

With a phenol bearing a dimethylamino substituent at C3, the direct arylation proceeds regioselectively at C6 (Scheme 3). No arylation at C2 was detected. This regioselectivity might come from steric factors. Using 4-bromobenzonitrile or 3,5-bis(trifluoromethyl)bromobenzene 15 and 16 were obtained in 41% and 44% yields, respectively.

Scheme 3 Palladium-catalysed direct arylation of 3-dimethylaminophenol.

Then, we also extended the scope of the O-arylation of phenols using K₂CO₃ as the base and PdCl(C₃H₅)(dppb) catalyst (Table 3). Such simple coupling reaction conditions employing a cheaper base and a ligand than those usually employed (Cs₂CO₃ and electron-rich phosphanes) might be useful. Four aryl bromides, 2- or 4-bromobenzonitriles, 4-bromonitrobenzene or 4-bromopyridine, have been reacted with 3,5-dimethoxyphenol. In all cases, the desired arylation products 1c and 17–19 were obtained very selectively and in good yields of 74–91% (Table 3, entries 1–4). Four other phenol derivatives were also employed successfully. The coupling of 3-dimethylaminophenol, 4-methoxyphenol, 3,5-dimethylphenol or 2,6-dimethoxyphenol with 4-bromonitrobenzene gave 20–23 in 83–93% yields (Table 3, entries 5–8).

Conclusion

In summary, we have demonstrated that when appropriate reaction conditions are employed, the palladium-catalysed direct arylation of free OH phenol derivatives proceeds regioselectively either at C2 or at OH with a variety of electron-deficient aryl bromides and heteroaryl bromides. The regioselectivity of the coupling depends on the nature of the base. In the presence of K₂CO₃ selective O-arylations were observed. On the other hand, the use of KOAc as the base inhibits the O-arylation and promotes the arylation at C2. These regioselectivities are consistent with a concerted metallation deprotonation mechanism (CMD) demonstrated by Lapointe and Fagnou.^12b To our knowledge, this is the first method for palladium-catalysed direct mono-arylation at C2 of unprotected phenols. This procedure generally gives lower yields than the rhodium-catalysed direct arylation of phenols;⁹ on the other hand, lower catalyst and ligand loadings were employed, and a wider functional group tolerance on the aryl bromide was observed.

Experimental section

DMAc (N,N-dimethylacetamide) (99%) was purchased from Acros. KOAc (99%), K₂CO₃ (99%), [Pd(C₃H₅)Cl]₂ (56.5%) and dppb [1,4-bis(diphenylphosphino)butane] (98%) were purchased from Alfa Aesar. These compounds were not purified before use.

Preparation of the PdCl(C₃H₅)(dppb) catalyst¹⁴

An oven-dried 40 mL Schlenk tube equipped with a magnetic stirring bar under an argon atmosphere was charged with [Pd(C₃H₅)Cl]₂ (182 mg, 0.5 mmol) and dppb (426 mg, 1 mmol). 10 mL of anhydrous dichloromethane were added, then, the solution was stirred at room temperature for twenty minutes. The solvent was removed in vacuum. The yellow powder was used without purification. ³¹P NMR (81 MHz, CDCl₃) δ = 19.3 (s).

General procedure for the direct ortho-arylation of phenols 1a and 2–16

In a typical experiment, the aryl bromide (1 mmol), phenol derivative (4 mmol), KOAc (196 mg, 2 mmol) and PdCl(C₃H₅)(dppb) (13.6 mg, 0.02 mmol) were dissolved in DMAc (10 mL) under an argon atmosphere. The reaction mixture was stirred at 150 °C for 24–60 h (see Table 2). Then, the solvent was evaporated and the product was purified by silica gel column chromatography.

6′-Hydroxy-2′,4′-dimethoxybiphenyl-4-carbonitrile (1a). From 4-bromobenzonitrile (0.182 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 1a was obtained in 39% (0.099 g) yield. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.75 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.4 Hz, 2H), 6.21 (m, 2H), 5.03 (s, 1H), 3.84 (s, 3H), 3.73 (s, 3H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 161.8, 158.4, 154.4, 138.7, 132.7, 132.4, 119.3, 111.3, 108.9, 93.8, 92.1, 56.1, 55.8. Elemental analysis: calcd (%) for C₁₅H₁₃NO₃ (255.27): C 70.58, H 5.13; found: C 70.47, H 5.10%. 4′-Hydroxy-2′,6′-dimethoxybiphenyl-4-carbonitrile (1b) was also isolated in low yield ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.66 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 8.4 Hz, 2H), 6.18 (s, 2H), 5.12 (bs, 1H), 3.73 (s, 6H).

4,6-Dimethoxy-4′-nitrobiphenyl-2-ol (2). From 4-bromonitrobenzene (0.202 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 2 was obtained in 34% (0.093 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 8.32 (d, J = 8.7 Hz, 2H), 7.58 (d, J = 8.7 Hz, 2H), 6.23–6.19 (m, 2H), 3.85 (s, 3H), 3.75 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 161.6, 158.1, 154.0, 146.8, 140.4, 132.1, 123.7, 108.2, 93.5, 91.8, 55.7, 55.4. Elemental analysis: calcd (%) for C₁₄H₁₃NO₅ (275.26): C 61.09, H 4.76; found: C 61.15, H 4.58%.

4,6-Dimethoxy-4′-trifluoromethylbiphenyl-2-ol (3). From 4-trifluoromethylbromobenzene (0.225 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 3 was obtained in 35% (0.104 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 7.71 (d, J = 8.1 Hz, 2H), 7.51 (d, J = 8.1 Hz, 2H), 6.24 (d, J = 2.2, 1H), 6.22 (d, J = 2.2 Hz, 1H), 3.83 (s, 3H), 3.73 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 161.0, 158.2, 154.2, 136.9, 131.6, 129.5 (q, J = 32.0 Hz), 125.6 (q, J = 3.7 Hz), 124.3 (q, J = 272.2 Hz), 109.2, 93.5, 91.8, 55.8, 55.5. Elemental analysis: calcd (%) for C₁₅H₁₃F₃O₃ (298.26): C 60.40, H 4.39; found: C 60.49, H 4.21%.

(6′-Hydroxy-2′,4′-dimethoxybiphenyl-4-yl)-phenylmethanone (4). From 4-bromobenzophenone (0.261 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 4 was obtained in 38% (0.127 g) yield. ¹H NMR (200 MHz, CDCl₃, 25 °C): δ = 7.94 (d, J = 8.0 Hz, 2H), 7.88 (d, J = 8.1 Hz, 2H), 7.70–7.45 (m, 5H), 6.25 (d, J = 2.1 Hz, 1H), 6.21 (d, J = 2.1 Hz, 1H), 5.24 (s, 1H), 3.85 (s, 3H), 3.76 (s, 3H). ¹³C NMR (50 MHz, CDCl₃, 25 °C): δ = 196.3, 161.2, 158.1, 154.3, 137.6, 137.5, 136.5, 132.4, 131.1, 130.7, 130.0, 128.4, 109.1, 93.2, 91.7, 55.7, 55.4. Elemental analysis: calcd (%) for C₂₁H₁₈O₄ (334.37): C 75.43, H 5.43; found: C 75.50, H 5.57%.

1-(6′-Hydroxy-2′,4′-dimethoxybiphenyl-4-yl)-propan-1-one (5). From 4-bromopropiophenone (0.213 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 5 was obtained in 32% (0.092 g) yield. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 8.08 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 6.24 (d, J = 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 5.05 (s, 1H), 3.85 (s, 3H), 3.74 (s, 3H), 3.05 (q, J = 7.2 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 200.3, 161.2, 158.0, 154.1, 137.8, 135.9, 131.3, 128.7, 109.1, 93.1, 91.7, 55.7, 55.3, 31.8, 8.2. Elemental analysis: calcd (%) for C₁₇H₁₈O₄ (286.32): C 71.31, H 6.34; found: C 71.40, H 6.19%.

6′-Hydroxy-2′,4′-dimethoxybiphenyl-3-carbonitrile (6). From 3-bromobenzonitrile (0.182 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 6 was obtained in 37% (0.094 g) yield. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.69 (s, 1H), 7.68–7.60 (m, 2H), 7.55 (t, J = 7.8 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 4.93 (s, 1H), 3.84 (s, 3H), 3.73 (s, 3H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 161.3, 158.1, 154.1, 135.7, 135.0, 134.4, 130.8, 129.4, 118.8, 112.5, 108.0, 93.4, 91.7, 55.7, 55.4. Elemental analysis: calcd (%) for C₁₅H₁₃NO₃ (255.27): C 70.58, H 5.13; found: C 70.59, H 5.21%.

4,6-Dimethoxy-3′-nitrobiphenyl-2-ol (7). From 3-bromonitrobenzene (0.202 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 7 was obtained in 32% (0.088 g) yield. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 8.18 (s, 1H), 8.12 (d, J = 8.1 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.9 Hz, 1H), 6.11 (s, 2H), 4.85 (s, 1H), 3.76 (s, 3H), 3.65 (s, 3H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 161.4, 158.2, 154.1, 148.5, 137.4, 134.8, 129.3, 126.4, 122.2, 107.9, 93.4, 91.7, 55.7, 55.4. Elemental analysis: calcd (%) for C₁₄H₁₃NO₅ (275.26): C 61.09, H 4.76; found: C 61.01, H 4.80%.

4,6-Dimethoxy-3′-trifluoromethylbiphenyl-2-ol (8). From 3-trifluoromethylbromobenzene (0.225 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 8 was obtained in 33% (0.098 g) yield. ¹H NMR (3 MHz, CDCl₃, 25 °C): δ = 7.66–7.52 (m, 4H), 6.23 (d, J = 2.2 Hz, 1H), 6.20 (d, J = 2.2 Hz, 1H), 5.26 (s, 1H), 3.83 (s, 3H), 3.72 (s, 3H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 161.1, 158.2, 154.2, 134.5 (m), 133.7, 131.2 (q, J = 32.2 Hz), 129.2, 128.1 (q, J = 3.8 Hz), 124.3 (q, J = 3.8 Hz), 124.1 (q, J = 273.5 Hz), 109.0, 93.4, 91.8, 55.7, 55.4. Elemental analysis: calcd (%) for C₁₅H₁₃F₃O₃ (298.26): C 60.40, H 4.39; found: C 60.32, H 4.51%.

4,6-Dimethoxy-3′,5′-bistrifluoromethylbiphenyl-2-ol (9). From 3,5-bis(trifluoromethyl)bromobenzene (0.293 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 9 was obtained in 54% (0.198 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 7.89 (s, 2H), 7.83 (s, 1H), 6.2 (d, J = 2.2 Hz, 1H), 6.17 (d, J = 2.2 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 161.2, 158.2, 154.2, 135.5, 131.5, 131.1 (q, J = 33.0 Hz), 123.2 (q, J = 272.6 Hz), 120.5 (m), 107.7, 93.7, 91.5, 55.6, 55.3. Elemental analysis: calcd (%) for C₁₆H₁₂F₆O₃ (366.26): C 52.47, H 3.30; found: C 52.54, H 3.21%.

3,5-Dimethoxy-2-naphthalen-2-ylphenol (10). From 2-bromonaphthalene (0.207 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 10 was obtained in 41% (0.115 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 7.97 (d, J = 8.4 Hz, 1H), 7.91 (m, 1H), 7.88 (m, 1H), 7.85 (s, 1H), 7.57–7.52 (m, 2H), 7.49 (d, J = 8.4 Hz, 1H), 6.30 (d, J = 2.3 Hz, 1H), 6.23 (d, J = 2.3 Hz, 1H), 5.27 (s, 1H), 3.88 (s, 3H), 3.75 (s, 3H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 160.9, 158.2, 154.4, 133.6, 132.7, 130.1, 129.4, 129.3, 128.7, 127.9, 127.7, 126.3, 126.2, 109.7, 92.7, 91.6, 55.7, 55.4. Elemental analysis: calcd (%) for C₁₈H₁₆O₃ (280.32): C 77.12, H 5.75; found: C 77.05, H 5.80%.

3,5-Dimethoxy-2-(6-methoxynaphthalen-2-yl)-phenol (11). From 6-methoxy-2-bromonaphthalene (0.237 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 11 was obtained in 42% (0.130 g) yield. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.86–7.82 (m, 1H), 7.80–7.70 (m, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.23–7.16 (m, 2H), 6.31 (d, J = 2.2 Hz, 1H), 6.25 (d, J = 2.2 Hz, 1H), 5.60 (s, 1H), 3.96 (s, 3H), 3.86 (s, 3H), 3.74 (s, 3H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 160.6, 158.4, 157.9, 154.4, 134.0, 129.8, 129.5, 129.4, 129.2, 127.7. 127.6, 119.0, 110.2, 105.9, 93.1, 91.8, 55.8, 55.5, 55.4. Elemental analysis: calcd (%) for C₁₉H₁₈O₄ (310.34): C 73.53, H 5.85; found: C 73.59, H 5.94%.

6′-Hydroxy-2′,4′-dimethoxybiphenyl-2-carbonitrile (12). From 2-bromobenzonitrile (0.182 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 12 was obtained in 37% (0.094 g) yield. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 8.90 (d, J = 7.9 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.78 (t, J = 8.4 Hz, 1H), 7.51 (t, J = 8.2 Hz, 1H), 6.57 (d, J = 2.4 Hz, 1H), 6.48 (d, J = 2.4 Hz, 1H), 4.04 (s, 3H), 3.90 (s, 3H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 161.7, 161.1, 159.3, 153.8, 135.1, 134.7, 130.1, 126.9, 126.4, 119.6, 102.1, 96.0, 94.0, 55.9, 55.6. Elemental analysis: calcd (%) for C₁₅H₁₃NO₃ (255.27): C 70.58, H 5.13; found: C 70.69, H 5.17%.

3,5-Dimethoxy-2-pyridin-4-ylphenol (13). From 4-bromopyridine hydrochloride (0.194 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 13 was obtained in 43% (0.099 g) yield. ¹H NMR (200 MHz, CDCl₃, 25 °C): δ = 8.6 (d, J = 5.2 Hz, 2H), 7.4 (d, J = 5.6 Hz, 2H), 6.24 (d, J = 2.2 Hz, 1H), 6.18 (d, J = 2.2 Hz, 1H), 3.82 (s, 3H), 3.74 (s, 3H). ¹³C NMR (50 MHz, CDCl₃, 25 °C): δ = 161.5, 158.1, 154.9, 149.3, 142.6, 126.4, 107.4, 93.8, 91.4, 55.7, 55.4. Elemental analysis: calcd (%) for C₁₃H₁₃NO₃ (231.25): C 67.52, H 5.67; found: C 67.47, H 5.51%.

3,5-Dimethoxy-2-quinolin-3-ylphenol (14). From 3-bromoquinoline (0.208 g, 1 mmol) and 3,5-dimethoxyphenol (0.616 g, 4 mmol), 14 was obtained in 44% (0.124 g) yield. ¹H NMR (200 MHz, CDCl₃, 25 °C): δ = 8.88 (s, 1H), 8.20 (s, 1H), 8.04 (d, J = 8.2 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.62 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.4 Hz, 1H), 6.34 (d, J = 2.1 Hz, 1H), 6.19 (d, J = 2.1 Hz, 1H), 3.8 (s, 3H), 3.72 (s, 3H). ¹³C NMR (50 MHz, CDCl₃, 25 °C): δ = 161.7, 159.1, 156.5, 153.8, 146.0, 138.0, 129.8, 128.5, 128.4, 128.3, 127.8, 127.0, 107.2, 94.6, 91.5, 56.1, 55.8. Elemental analysis: calcd (%) for C₁₇H₁₅NO₃ (281.31): C 72.58, H 5.37; found: C 72.64, H 5.21%.

4′-Dimethylamino-2′-hydroxybiphenyl-4-carbonitrile (15). From 4-bromobenzonitrile (0.182 g, 1 mmol) and 3-dimethylaminophenol (0.548 g, 4 mmol), 15 was obtained in 41% (0.098 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 7.71 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.20 (d, J = 8.5 Hz, 1H), 6.44 (dd, J = 8.5 Hz, J = 2.4 Hz, 1H), 6.27 (d, J = 2.4 Hz, 1H), 5.02 (s, 1H), 3.01 (s, 6H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 153.3, 152.1, 143.1, 132.4, 130.9, 129.2, 119.2, 114.5, 109.5, 105.9, 99.6, 40.3. Elemental analysis: calcd (%) for C₁₅H₁₄N₂O (238.28): C 75.61, H 5.92; found: C 75.42, H 5.99%.

4-Dimethylamino-3′,5′-bistrifluoromethylbiphenyl-2-ol (16). From 3,5-bis(trifluoromethyl)bromobenzene (0.293 g, 1 mmol) and 3-dimethylaminophenol (0.548 g, 4 mmol), 16 was obtained in 44% (0.154 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 8.01, (s, 2H), 7.77 (s, 1H), 7.23 (d, J = 8.6 Hz, 1H), 6.45 (dd, J = 8.6 Hz, J = 2.4 Hz, 1H), 6.25 (d, J = 2.4 Hz, 1H), 4.94 (s, 1H), 3.02 (s, 6H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 153.2, 152.1, 140.3, 131.6 (q, J = 33.0 Hz), 131.0, 128.8, 123.5 (q, J = 272.6 Hz), 119.5 (m), 113.5, 106.0, 99.5, 40.3. Elemental analysis: calcd (%) for C₁₆H₁₃F₆NO (349.27): C 55.02, H 3.75; found: C 55.14, H 3.87%.

General procedure for the formation of ethers 1c and 17–23

In a typical experiment, the aryl bromide (1.2 mmol), phenol derivative (1 mmol), K₂CO₃ (276 mg, 2 mmol) and PdCl(C₃H₅)(dppb) (13.6 mg, 0.02 mmol) were dissolved in DMAc (10 mL) under an argon atmosphere. The reaction mixture was stirred at 150 °C for 24–40 h (see Table 3). Then, the solvent was evaporated and the product was purified by silica gel column chromatography.

4-(3,5-Dimethoxyphenoxy)-benzonitrile (1c). From 4-bromobenzonitrile (0.218 g, 1.2 mmol) and 3,5-dimethoxyphenol (0.154 g, 1 mmol), 1c was obtained in 82% (0.209 g) yield. ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 7.62 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 6.40 (t, J = 2.1 Hz, 1H), 6.23 (d, J = 2.1 Hz, 2H), 3.79 (s, 6H). ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 161.9, 161.2, 156.5, 134.1, 118.8, 118.1, 106.0, 98.7, 97.1, 55.5. Elemental analysis: calcd (%) for C₁₅H₁₃NO₃ (255.27): C 70.58, H 5.13; found: C 70.69, H 5.24%.

4-(3,5-Dimethoxyphenoxy)-nitrobenzene (17). From 4-bromonitrobenzene (0.242 g, 1.2 mmol) and 3,5-dimethoxyphenol (0.154 g, 1 mmol), 17 was obtained in 74% (0.204 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 8.22 (d, J = 9.1 Hz, 2H), 7.08 (d, J = 9.1 Hz, 2H), 6.37 (t, J = 2.2 Hz, 1H), 6.26 (d, J = 2.2 Hz, 2H), 3.80 (s, 6H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 163.4, 162.3, 156.8, 143.1, 126.3, 117.7, 99.3, 97.8, 55.9. Elemental analysis: calcd (%) for C₁₄H₁₃NO₅ (275.26): C 61.09, H 4.76; found: C 61.08, H 4.84%.

2-(3,5-Dimethoxyphenoxy)-benzonitrile (18). From 2-bromobenzonitrile (0.218 g, 1.2 mmol) and 3,5-dimethoxyphenol (0.154 g, 1 mmol), 18 was obtained in 91% (0.232 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 7.64 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 6.97 (d, J = 8.5 Hz, 1H), 6.32 (t, J = 2.2 Hz, 1H), 6.24 (d, J = 2.2 Hz, 2H), 3.77 (s, 6H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 161.6, 159.1, 156.6, 134.1, 133.5, 122.9, 117.3, 115.7, 103.5, 96.9, 94.0, 55.3. Elemental analysis: calcd (%) for C₁₅H₁₃NO₃ (255.27): C 70.58, H 5.13; found: C 70.69, H 5.24%.

4-(3,5-Dimethoxyphenoxy)-pyridine (19). From 4-bromopyridine hydrochloride (0.233 g, 1.2 mmol) and 3,5-dimethoxyphenol (0.154 g, 1 mmol), 19 was obtained in 79% (0.182 g) yield. ¹H NMR (500 MHz, CDCl₃, 25 °C): δ = 8.50 (d, J = 4.6 Hz, 2H), 7.65 (d, J = 4.6 Hz, 2H), 6.3 (t, J = 2.2 Hz, 1H), 6.27 (d, J = 2.2 Hz, 2H), 3.80 (s, 6H). ¹³C NMR (125 MHz, CDCl₃, 25 °C): δ = 161.8, 155.7, 151.3, 135.8, 125.5, 99.2, 97.6, 55.5. Elemental analysis: calcd (%) for C₁₃H₁₃NO₃ (231.25): C 67.52, H 5.67; found: C 67.39, H 5.54%.

Dimethyl-[3-(4-nitrophenoxy)-phenyl]-amine (20). From 4-bromonitrobenzene (0.242 g, 1.2 mmol) and 3-dimethylaminophenol (0.137 g, 1 mmol), 20 was obtained in 83% (0.214 g) yield. ¹H NMR (200 MHz, CDCl₃, 25 °C): δ = 8.22 (d, J = 9.2 Hz, 2H), 7.28 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 9.2 Hz, 2H), 6.61 (d, J = 7.8 Hz, 1H), 6.44 (s, 1H), 6.41 (d, J = 8.0 Hz, 1H), 2.98 (s, 6H). ¹³C NMR (50 MHz, CDCl₃, 25 °C): δ = 163.8, 155.6, 152.3, 142.2, 130.5, 125.8, 116.8, 109.3, 107.8, 104.3, 40.4. Elemental analysis: calcd (%) for C₁₄H₁₄N₂O₃ (258.27): C 65.11, H 5.46; found: C 65.24, H 5.57%.

4-(4-Nitrophenoxy)-anisole (21). From 4-bromonitrobenzene (0.242 g, 1.2 mmol) and 4-methoxyphenol (0.124 g, 1 mmol), 21 was obtained in 93% (0.228 g) yield. ¹H NMR (200 MHz, CDCl₃, 25 °C): δ = 8.16 (d, J = 9.2 Hz, 2H), 7.10–6.92 (m, 6H), 3.84 (s, 3H). ¹³C NMR (50 MHz, CDCl₃, 25 °C): δ = 164.1, 157.1, 147.8, 142.2, 125.8, 121.8, 116.3, 115.2, 55.6. Elemental analysis: calcd (%) for C₁₃H₁₁NO₄ (245.23): C 63.67, H 4.52; found: C 63.80, H 4.47%.

3,5-Dimethyl-1-(4-nitrophenoxy)-benzene (22). From 4-bromonitrobenzene (0.242 g, 1.2 mmol) and 3,5-dimethylphenol (0.122 g, 1 mmol), 22 was obtained in 90% (0.219 g) yield. ¹H NMR (200 MHz, CDCl₃, 25 °C): δ = 8.20 (d, J = 9.2 Hz, 2H), 7.01 (d, J = 9.2 Hz, 2H), 6.91 (s, 1H), 6.73 (s, 2H), 2.35 (s, 6H). ¹³C NMR (50 MHz, CDCl₃, 25 °C): δ = 164.0, 155.0, 142.8, 140.7, 127.5, 126.3, 118.5, 117.4, 21.7. Elemental analysis: calcd (%) for C₁₄H₁₃NO₃ (243.26): C 69.12, H 5.39; found: C 69.02, H 5.24%.

2,6-Dimethoxy-1-(4-nitrophenoxy)-benzene (23). From 4-bromonitrobenzene (0.242 g, 1.2 mmol) and 2,6-dimethoxyphenol (0.154 g, 1 mmol), 23 was obtained in 92% (0.253 g) yield. ¹H NMR (200 MHz, CDCl₃, 25 °C): δ = 8.15 (d, J = 9.2 Hz, 2H), 7.21 (t, J = 8.4 Hz, 1H), 6.93 (d, J = 9.2 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 3.78 (s, 6H). ¹³C NMR (50 MHz, CDCl₃, 25 °C): δ = 163.4, 152.8, 147.1, 142.0, 126.4, 125.6, 114.9, 105.1, 56.0. Elemental analysis: calcd (%) for C₁₄H₁₃NO₅ (275.26): C 61.09, H 4.76; found: C 61.21, H 4.59%.

Acknowledgements

K.B. is grateful to CNRS and “Conseil regional de Bretagne” for a grant. We thank the CNRS and “Rennes Metropole” for providing financial support.

Notes and references

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