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Keywords:

  • arylation;
  • catalysis;
  • C[BOND]C bond formation;
  • C[BOND]H activation;
  • ruthenium

Abstract

  1. Top of page
  2. Abstract
  3. Experimental Section
  4. Acknowledgements

Selective monoarylation of aryl 2-pyridyl ketones with a variety of arylbromides via arene sp2 C[BOND]H bond activation/functionalisation is achieved with a [RuCl2(p-cymene)]2/ p-CF3C6H4CO2H catalytic system. The reaction via a 6-membered ruthenacycle is more difficult to perform than via a 5-membered cyclometallate but the activation of only one ortho C[BOND]H bond is unprecedentedly highly selective. A variety of functional 2-pyridine derivatives are easily obtained. It is shown via H/D exchange that the carboxylic acid favours the reversible C[BOND]H bond activation.

Catalytic C[BOND]H bond activation has become an important method leading to various C[BOND]C bond cross-coupling reactions.1 Recently, non-expensive ruthenium(II) catalysts that are easy to prepare, often stable to air and water, have shown high efficiency for cross-coupling reactions from sp2 C[BOND]H bonds through arylation with (hetero)arylhalides or through oxidative dehydrogenative alkenylation.24 The diarylation of ortho C[BOND]H bonds of functional arenes has now become easy to perform with ruthenium(II) catalysts when the formation of a 5-membered ruthenacycle intermediate is possible (I in Scheme 1),2, 3, 5 especially with carboxylate-ruthenium catalysts,6, 7 even in water.4, 8 The selective monoarylation versus diarylation of functional arenes containing two non-protected ortho sp2 C[BOND]H bonds, has been shown difficult to achieve via a 5-membered cyclometallate intermediate,9 unless the [RuCl2(PPh3)(arene)] catalyst operating in water was used10 (I in Scheme 1).

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Scheme 1. N-containing cyclometallated intermediates arising from C[BOND]H bond activation.

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Compounds containing the aryl 2-pyridyl ketone moiety have shown bioactivity, such as in grossularines11 and non-planar β-carboline-based analogues.12 These unique properties of 2-pyridyl (hetero)aryl ketones and the potential of their derivatives as functional ligands motivate the search for selective aryl C[BOND]H bond activation for further functionalisation, but via a 6-membered metallacycle (II, in Scheme 1). In comparison to 5-membered metallacycles, the activation of sp2 C[BOND]H bond by deprotonation via a 6-membered metallacycle intermediate is relatively scarce.[13] Such a metallacycle was easily obtained from phenyl 2-pyridyl ketone on reaction with [Cp*IrCl2]214 (II, M=IrClCp*, in Scheme 1). By contrast, the same aryl ketone on reaction with [RuCl2(p-cymene)]2/NaBPh4 leads to the chelation of both N and O heteroatoms, thus favouring a 5-membered metallacycle but without C[BOND]H bond activation/cleavage and formation of the 6-membered ruthenacycle.15, 16

Here we report the first selective catalytic ortho monoarylation of aryl 2-pyridyl ketones in the presence of ruthenium(II) catalyst, via a 6-membered ruthenacycle, with the association to a catalytic amount of a carboxylate derivative of p-CF3C6H4CO2H as a proton shuttle [Eq. (1)]

  • equation image(1)

The first attempt to perform the catalytic arylation of phenyl 2-pyridyl ketone 1 a with 2 equiv of PhBr with [RuCl2(p-cymene)]2/4 KOAc catalyst system revealed that at 150 °C, NMP was the most efficient solvent with respect to water, AcOH or toluene. Only 67 % conversion was reached, preferentially leading to the monoarylation, showing that arylation of 1 a is possible, but difficult to reach (Table 1, entry 1), with respect to the arylation of phenyl pyridine.6ab, 8 Then various sources of carboxylate were evaluated and KOPiv did not lead to significant improvement (entries 2–4). Benzoic acid derivatives showed higher efficiency (entries 5–8), especially p-CF3C6H4CO2H allowed to decrease the reaction time to 20 h with excellent conversion and good selectivity in monoarylation product (entry 7) and appeared to be the best cocatalyst precursor for C[BOND]H bond activation leading to 6-membered metallacycle intermediate. After 36 h of reaction in the presence of p-CF3C6H4CO2H (30 mol %) with Na2CO3, the observed conversion of the ketone 1 a was 92 % and the monoarylated product 3 a was isolated in 68 % yield (entry 11).

Table 1. Ruthenium(II) catalysed arylation of phenyl 2-pyridyl ketone with bromobenzene—optimisation parameters.[a] inline image
EntryBaseAdditivetConv.[d]Ratio[d]
[mol %][h][%](3 a/4 a)
  1. [a] Phenyl 2-pyridyl ketone 1 a (0.5 mmol), PhBr 2 (1.0 mmol, 2 equiv), [RuCl2(p-cymene)]2 (5 mol %), base (1.5 mmol, 3 equiv), additive (30 mol %), NMP (2 mL), under argon; [b] 1.5 equiv of PhBr; [c] 2 equiv of K2CO3. [d] Determined by GC analysis. [e] in parenthesis, isolated yield of pure compound 3 a (%).

1K2CO3KOAc (30)606782:18
2K2CO3KOPiv (20)606589:11
3K2CO3KOPiv (30)607380:20
4K2CO3KOAc (30),607684:16
HOAc (0.001)
5K2CO3PhCO2H (30)609378:22
6[b]K2CO3PhCO2H (30)208486:14
7[b]K2CO3p-CF3C6H4CO2H (30)209375:25(49)[e]
8[b]K2CO3p-tBuC6H4CO2H (30)207983:17
9[b]K2CO3[c]p-CF3C6H4CO2H (30)201080:20
10[b]Na2CO3p-CF3C6H4CO2H (30)208390:10
11[b]Na2CO3p-CF3C6H4CO2H (30)369290:10(68)[e]

Under the optimised conditions (Table 1, entry 11), a variety of arylbromides could lead successfully to arylation of 1 a and monoarylated products 3 ak were selectively formed and isolated (Table 2). Electron-rich aryl bromides led to slightly higher yields with good selectivity in monoarylation products (entries 3–5) than electron-withdrawing groups (F, CF3) (entries 6–7 and 10–11).

Table 2. Ruthenium(II) catalysed arylation of phenyl 2-pyridyl ketone with aryl bromide.[a] inline image
EntryProduct Conv.[b]Ratio[b]Yield[c]
[%](3/4)[%]
  1. [a] Phenyl 2-pyridyl ketone 1 a (0.5 mmol), arylbromide (0.75 mmol, 1.5 equiv), [RuCl2(p-cymene)]2 (5 mol %), Na2CO3 (1.5 mmol, 3 equiv), p-CF3C6H4CO2H (30 mol %), NMP (2 mL), under argon, 150 °C, 36 h; [b] determined by GC; [c] Isolated yield after purification by flash chromatography. [d] 2 mmol scale reaction in 4 mL of NMP. [e] A mixture of products 3 c/4 c was obtained in a ratio 90/10.

1
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R=H, 3 a9390:1068
2R=H, 3 a8891:958[d]
3R=Me, 3 b9096:463
4R=OMe, 3 c9090:1072[e]
5R=tBu, 3 d9295:570
6R=F, 3 e8793:756
7R=CF3, 3 h8887:1351
8R=Ph, 3 i7695:556
9R=CO2Me, 3 l7599:161
10
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3 f8789:1159
11
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3 g5693:737
12
Thumbnail image of
3 j7899:163
13
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3 k7799:156

Arylation of 1 a with p-MeO2CC6H4Br produced the monoarylated compound 3 l with excellent selectivity and 61 % isolated yield (entry 9). However attempts to perform arylation of 1 a with p-MeCO-C6H4Br was unsuccessful (conv. 20 %).

This reaction allowed us to prepare substituted PyCOPh derivatives, containing as ortho substituent a p-biphenyl group for ketone 3 i (56 %), and a naphtyl group for ketone 3 j (63 %). Importantly, the use of p-bromostyrene shows that the alkenyl group does not affect the reaction and no Heck-type product formation was observed as the compound (2-(p-styryl)phenyl)(2-pyridyl)ketone 3 k with a free vinyl group was isolated with 56 % yield.

The arylation of various aryl 2-pyridylketones with bromo-benzene was then performed (Table 3). The monoarylation of 2-pyridyl ketones 5 a5 c bearing a para-substituent (F, OMe, Me) on the benzene ring led to monoarylated products 6 a6 c isolated in 50–68 % yields (entries 1–3). Surprisingly the ortho tolyl isomer 5 e led to the arylated compound 6 e with a poor yield (15 %), likely attributable to steric inhibition of the formation of the planar 6-membered intermediate of type II (M=RuLn+ in Scheme 1), with respect to m-Me (54 %) and p-Me (68 %) isomers (entries 3–5).

Table 3. Ruthenium(II) catalysed arylation of substituted aryl 2-pyridyl ketone with bromobenzene.[a] inline image
Entryproduct Conv.[b]Ratio[b]Yield of 6[c]
[%](mono/di)[%]
  1. [a] Aryl 2-pyridyl ketone (0.5 mmol), bromobenzene (0.75 mmol, 1.5 equiv), [RuCl2(p-cymene)]2 (5 mol %), Na2CO3 (1.5 mmol, 3 equiv), p-CF3C6H4CO2H (30 mol %), NMP (2 mL), under argon, 150 °C, 36 h; [b] determined by GC; [c] Isolated yield.

1
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6 a9870:3064
2
Thumbnail image of
6 b6389:1150
3
Thumbnail image of
6 c9286:1468
4
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6 d65100:054
5
Thumbnail image of
6 e15100:015[b]

The carbonyl and the pyridyl groups of compounds 1 are essential for this arylation reaction to take place. Indeed, the arylation of the 2-benzyl pyridine only led to 15 % conversion under the same conditions. Furthermore, when the reaction was performed with benzophenone instead of phenyl 2-pyridyl ketone 1 a, only 13 % conversion into the corresponding o-biphenyl phenyl ketone was observed. This reaction shows the crucial role of the 2-pyridyl moiety as a coordinating and directing group. It is likely that the higher flexibility of the benzyl group does not facilitate the interaction of the RuII centre with the C[BOND]H bond and the 6-membered intermediate formation. However, the selective arylation of aryl 2-pyridyl ethers with ruthenium(II) catalyst has recently been successfully performed.17 Thus, the use of cheap and easy to make ruthenium(II) catalysts present advantages for the arylation of aryl 2-pyridyl ketone with respect to previous different functionalisations using Pd and Rh catalysts.13

The ease and reversibility of the ortho C[BOND]H bond cleavage were studied by H/D exchange NMR analysis. First, the reaction of 1 a in the presence of p-CF3C6H4CO2H (30 mol %)/Na2CO3 (100 mol %) and D2O (0.2 mL) was performed under the previous reaction conditions at 150 °C for 20 h. Only 13 % of H/D exchange took place at the ortho C[BOND]H bond (Scheme 2). The same reaction performed without Na2CO3 led to an extensive H/D exchange at ortho position (86 %) at 150 °C for only 20 h.

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Scheme 2. H/D exchange experiments in phenyl 2-pyridyl ketone 1 a.

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The H/D exchange at ortho C[BOND]H position is consistent with a cleavage of C[BOND]H bonds with a reversible protonation of the 6-membered metallacycle assisted by the free p-CF3C6H4CO2H(D) and thus retarded by Na2CO3. However this process is much less easily performed than via the formation of 5-membered metallacycles such as from 2-pyridylbenzene18, 19 or from aryl amides containing a N,N-chelating group.20

Competitive experiments show that electron-donating or electron-withdrawing groups on the arylbromide lead the similar arylation reactions of 1 a (Scheme 3). This arylation contrasts with that of arylamides with N,N-chelating group involving a nucleophilic substitution by the ruthenium(II) 5-membered ruthenacycle.20

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Scheme 3. Competitive arylation reactions with p-R-C6H4Br.

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A catalytic cycle, as shown in Scheme 4, can be proposed. [RuCl2(p-cymene)]2 in the presence of carboxylic acid and a base leads to Ru(O2CR)2(arene) complex.6ab, 18 The easy dissociation of a RuII-O2CR bond18 facilitates the coordination of 1 a leading to the formation of cyclometallate A, through a SEAr reaction.18 The electron-rich arylbromide should coordinate first to the cationic, 16 electron, 6-membered RuII ruthenacycle B, as for 5-membered metallacycles.18 Its oxidative addition followed by bromide substitution with the carboxylate may lead easily to reductive elimination into 3 a.

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Scheme 4. Proposed mechanism for monoarylation via 6-membered ruthenacycles.

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In summary, the above results show that the selective ortho monoarylation of 2-pyridyl arylketones with a variety of arylbromides can be performed using a ruthenium(II) catalytic system [RuCl2(p-cymene)]2/p-CF3C6H4COOH in the presence of Na2CO3 as a base. This reaction via a 6-membered cyclometallated intermediate is much more difficult to perform than through the previous examples of C[BOND]H bond cleavage/functionalisation involving a 5-membered ruthenacycle, but selectively favours monoarylation. H/D exchange at ortho C[BOND]H bonds are also more difficult to perform that those involving a 5-membered ruthenacycle but they occur more easily in the presence of D2O/p-CF3C6H4CO2H without the presence of base. These results show that for a difficult to perform C[BOND]H bond cleavage/functionalisation, it is necessary to search for the most effective carboxylate partner of the ruthenium(II) catalyst.

Experimental Section

  1. Top of page
  2. Abstract
  3. Experimental Section
  4. Acknowledgements

General procedure for [RuCl2(p-cymene)]2 catalysed arylation of aryl 2-pyridyl ketone with arylbromides: [RuCl2(p-cymene)]2 (0.025 mmol, 15.3 mg), arylbromide (0.75 mmol), aryl 2-pyridylketone (0.5 mmol), Na2CO3 (1.5 mmol, 159 mg), 4-trifluoromethylbenzoic acid (0.15 mmol, 28.5 mg) and NMP (2 mL) were introduced in a Schlenk tube under argon, equipped with a magnetic stirring bar and was stirred at 150 °C for 36 h. When the reaction was completed, the conversion of the reaction was analysed by gas chromatography. The solvent was then evaporated under vacuum and the desired product was purified by silica gel chromatography column and a mixture of petrol ether/ethyl acetate as the eluent.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Experimental Section
  4. Acknowledgements

The authors are grateful to CNRS, the French Ministry for Research, the Institut Universitaire de France (P.H.D.), the ANR program 09-Blanc-0101-01, and the Chinese Scholarship Council for a Ph.D. grant to B.L.