Ru-Catalyzed C–H Arylation of Fluoroarenes with Aryl Halides

Although the ruthenium-catalyzed C–H arylation of arenes bearing directing groups with haloarenes is well-known, this process has never been achieved in the absence of directing groups. We report the first example of such a process and show that unexpectedly the reaction only takes place in the presence of catalytic amounts of a benzoic acid. Furthermore, contrary to other transition metals, the arylation site selectivity is governed by both electronic and steric factors. Stoichiometric and NMR mechanistic studies support a catalytic cycle that involves a well-defined η6-arene-ligand-free Ru(II) catalyst. Indeed, upon initial pivalate-assisted C–H activation, the aryl-Ru(II) intermediate generated is able to react with an aryl bromide coupling partner only in the presence of a benzoate additive. In contrast, directing-group-containing substrates (such as 2-phenylpyridine) do not require a benzoate additive. Deuterium labeling and kinetic isotope effect experiments indicate that C–H activation is both reversible and kinetically significant. Computational studies support a concerted metalation–deprotonation (CMD)-type ruthenation mode and shed light on the unusual arylation regioselectivity.

. D/H scrambling of d 1
The reaction vessel was capped, evacuated and backfilled with N 2 three times, then left under vacuum for 30 min. The vial was then backfilled with N 2 and 1.0 mL of a 0.5 M solution of a 98:2 mixture of d 1 -1a : 1a (1.0 equiv, 0.50 mmol) in 1,4-dioxane was then added via syringe. The vial was resealed with a new cap under a stream of N 2 and the mixture was heated to 90 ºC for 16 h.
Upon completion, the reaction mixture was cooled to room temperature diluted with 3 mL of Et 2 O, filtered through a cotton plug and evaporated in vacuo to give a residue, to which 1,3,5trimethoxybenzene (0.33 equiv, 0.167 mmol) was added as internal standard in CDCl 3 .

entry
[Ru] (mol %) d 1 -1a:1a (initial ratio)  1) 1 H-NMR expansion of p-cymene and O-CH 2 C 3 H 7 region for independently isolated Ru1a. 1#) 19 F-NMR expansion for independently isolated Ru1a. 2) 1 H-NMR expansion of the reaction described in Table S1 entry 2, showing: pcymene and O-CH 2 C 3 H 7 regions for Ru1a, and aromatic singlet for internal standard 1,3,5-trimethoxybenzene; relative integration of signals corresponding to Ru1a with respect to the standard gives the yield of Ru1a. 2#) 19 F-NMR expansion of reaction described in Table S1 entry 2, showing Ru1a. 3) 1 H-NMR expansion of reaction described in Table S1 entry 2, showing the aromatic proton for 1a and O-CH 2 C 3 H 7 protons for d 1 -1a and 1a; relative integration of the aromatic proton of 1a with respect to O-CH 2 C 3 H 7 protons gives the ratio between for d 1 -1a and for 1a. 3#) 19 F-NMR expansion of the reaction described in Table S1 entry 2, showing d 1 -1a and 1a. 4) 1 H-NMR expansion of reaction described in Table S1 entry 2, showing the aromatic proton of 1a and O-CH 2 C 3 H 7 protons for d 1 -1a and 1a; relative integration of the aromatic proton of 1a with respect to O-CH 2 C 3 H 7 protons gives the ratio between d 1 -1a and 1a.

General Procedure 3: C−H activation of fluoroarenes with complex C2
Ru(OPiv) 2 (p-cymene) (C2) (1.0 equiv) and the appropriate base (if any, see Table S2) were weighed in the open air and placed in a crimp-cap Schlenk microwave vial (10 mL) with a magnetic stirrer bar. The reaction vessel was capped, evacuated and backfilled with Ar three times, then left under vacuum for 30 min. The vial was then backfilled with Ar and the appropriate perfluoroarene and 1,4-dioxane (see Table S2) were added via syringe. The vial was resealed with a new cap under a stream of Ar and the reaction was heated at the stated temperature (see Table S2) for 16 h. Upon completion, the reaction mixture was cooled to room temperature and a given amount of 1,3,5trimethoxybenzene was added as internal standard in CDCl 3 . The crude mixture was then filtered through a cotton plug directly to an NMR tube. If purification was needed after NMR analysis, the crude was evaporated, dissolved in hexane and loaded on a silica column. The column was flushed with a 0-15% Et 2 O-hexane gradient using N 2 in replacement of compressed air. The yellow band observed was eluted and evaporated in vacuo to give the desired aryl ruthenium complex as a yellow/orange solid. The final complexes are stable under air for a few days, but decompose if exposed to oxygen for longer. Storage in a desiccator under vacuum or in a glove box is needed.
Suitable crystals of Ru1c for X-ray crystallography (see crystallographic section) were grown by slow evaporation from a concentrated solution of the complex in CDCl 3 . a Reaction conditions: C2 (1.0 equiv, 0.05 mmol), 1a (5.0 equiv), base and the solvent (see above) were stirred under Ar in a closed vessel at the specified temperature for 16 h; yield is evaluated by 1 H-NMR using 1,3,5trimethoxybenzene as internal standard. b C2 (0.20 mmol, 1.0 equiv). Yield in parenthesis refers to isolated material. Table S2. Optimization of the C−H activation of fluoroarenes with complex C2. S11 Figure S2. 1 H-NMR expansion of p-cymene ruthenium complexes region of reactions described in Table S2: 1) entry 4; 2) entry 5; 3) entry 6; 4) entry 7.

Characterization data of Ru1a, Ru1b and Ru1c
The General Procedure 3 was applied with Ru(OPiv) 2 (p-cymene) (C2)   Table S3). Upon completion, the vial was quickly cooled in a dry ice/acetone bath and a given amount of 1,3,5-trimethoxybenzene was added as internal standard in CDCl 3 . The crude was then filtered through a cotton plug directly into an NMR tube for analysis.

General Procedure 5: C−H arylation of 1a with catalysts C2-C4
The appropriate ruthenium catalyst (C2-C4) (10 mol), base and additive(s) (if any, see Table S4) were weighed in a crimp-cap Schlenk microwave vial (10 mL) with a magnetic stirrer bar. The reaction vessel was capped, evacuated and backfilled with N 2 three times, then left under vacuum for 30 min. The vial was backfilled with N 2 then 1a (111.1 mg, 0.5 mmol, 5.0 equiv), 2a or 2b (0.1 mmol, 1.0 equiv, 12.6 μL or 10.5 μL) and the appropriate solvent (see Table S4, concentration or equivalents with respect to the limiting reagent 2a or 2b) were added via syringe. The vial was resealed with a new cap under a stream of N 2 and the reaction was heated at 120 °C for 16 h. Upon completion, the reaction mixture was cooled to room temperature and a given amount of 1,3dinitrobenzene was added as internal standard in CDCl 3 . The crude was then filtered through a cotton plug directly into an NMR tube.     Table S6) were weighed in a crimp-cap Schlenk microwave vial (10 mL) with a magnetic stirrer bar. The reaction vessel was capped, evacuated and backfilled with N 2 three times, then left under vacuum for 30 min. The vial was backfilled with N 2 then 1a (5.0 or 3.0 equiv), 2a or 2b (1.0 equiv, 0.1 mmol or 0.5 mmol) and pivalonitrile (3.0 or 5.0 equiv) were added via syringe. The vial was resealed with a new cap under a stream of N 2 and the reaction was stirred at the specified temperature (see Table S6) for 16 h. Upon completion, the reaction mixture was cooled to room temperature and a given amount of 1,3-dinitrobenzene was added as internal standard in CDCl 3 . The crude was then filtered through a cotton plug directly into an NMR tube. If purification was needed after NMR analysis, the crude was evaporated, dissolved in hexane and loaded on a silica column for flash chromatography to afford the corresponding biaryls.  Table S6).  given amount of 1,3,5-trimethoxybenzene was added as internal standard in CDCl 3 . The crude was then filtered through a cotton plug directly to an NMR tube for analysis (see Table S7).  were stirred under N 2 in a closed vessel at 120 °C for the appropriate time; yield is evaluated by 1 H-NMR using 1,3,5-trimethoxybenzene as internal standard; % of free (η 6 -arene) is based on the loading of C2. and the reaction was heated at 120 °C for the appropriate time. Upon completion, the vial was quickly cooled in a dry ice/acetone bath and a given amount of 1,3,5-trimethoxybenzene (and C 6 F 6 , if needed, 0.5 equiv, 0.05 mmol, 5.8 L) was added as internal standard in CDCl 3 . The crude was then filtered through a cotton plug directly to an NMR tube for analysis (see Table S8).  S22 Figure S3. 19 F-NMR expansion of the reactions illustrated in Table S8 entry 6 displaying 1a, 3aa and Ru2a with relative integrations with respect to the internal standard C 6 F 6 .

General Procedure 12: arylation of Ru2c with bromoarene 2c
All solid reagents, except Ru2c, were dried at 70 °C in a vacuum oven over night. All liquid reagents were dried over 4 Å molecular sieves and degassed with 3 freeze-pump-thaw cycles. In a glove box, Ru2c (0.03 mmol, 22.6 mg), additive (if any, see Table S9), 2c (12.2 μL, 0.09 mmol) and pivalonitrile (100 μL, 0.3 M) were loaded in a crimp-cap microwave vial with a stirrer bar. The vial was sealed and the mixture was stirred at 115 °C for 16 h. On completion, the mixture was filtered through a plug of silica with Et 2 O, the solvent was evaporated and octafluorotoluene (8.5 μL, 0.06 mmol, 2.0 equiv) was added as internal standard in CDCl 3 for quantitative 19 5   Table S9. Arylation of Ru2c with bromoarene 2c. Figure S4. 19 F-NMR expansion of the reaction described in entry 4 of Table S9, displaying 3cc and 3cc' with relative integration with respect to the internal standard octafluorotoluene.

Ru2c
S24 General Procedure 13: arylation of fluoroarene 1d with catalyst Ru2c or Ru1c with bromoarene 2c All solid reagents, except for Ru2c and Ru1c, were dried at 70 °C in a vacuum oven over night. All liquid reagents were dried over 4Å molecular sieves and degassed with 3 freeze-pump-thaw cycles.

Procedure 14: D/H -H/D scrambling experiment with fluoroarenes d 1 -1a and 1b under arylation conditions with bromobenzene 2b
All solid reagents, except C5, were dried at 70 °C in a vacuum oven over night. All liquid reagents were dried over 4Å molecular sieves and degassed with 3 freeze-pump-thaw cycles. In a glove box, loaded in a crimp-cap microwave vial with a stirrer bar. The vial was sealed, taken outside the box and the mixture was stirred at 115 °C for 10 min. On completion, the vial was quickly cooled in a dry ice/acetone bath and octafluorotoluene (17.7 μL, 0.125 mmol, 0.5 equiv) was added as internal standard in CDCl 3 . The crude mixture was then filtered through a cotton plug directly into an NMR tube for quantitative 19 F-NMR analysis.  Figure S6. 19 F-NMR expansion of the reaction illustrated in Scheme S1, displaying 1a, d 1 -1a, 1b, d 1 -1b, 7 3aa, 3ba with relative integrations with respect to the internal standard octafluorotoluene.

Procedure 15: KIE experiment of fluoroarenes d 1 -1a and 1y with bromobenzene 2b
All solid reagents, except C5, were dried at 70 °C in a vacuum oven over night. All liquid reagents were dried over 4Å molecular sieves and degassed with 3 freeze-pump-thaw cycles. In a glove box,
Spectroscopic data matched those previously reported.
Column chromatography (hexane 100%) afforded the title product as a colorless oil (94.0 mg, 74%).                  Figure S8. 19 F-NMR expansion of the reaction illustrated in Table S12

Crystallographic data of C5
The crystal structure was deposit at the Cambridge Crystallographic Data Centre.

Crystallographic data of C5'
The crystal structure was deposit at the Cambridge Crystallographic Data Centre.

Crystallographic data of Ru1c
The crystal structure was deposit at the Cambridge Crystallographic Data Centre.

Crystallographic data of Ru2c
The crystal structure was deposit at the Cambridge Crystallographic Data Centre.            Table 7 Torsion Angles for Ru2c