Carbon-Hydrogen Bond Functionalization Approach for the Synthesis of Fluorenones and ortho-Arylated Benzonitriles

Abstract

A palladium-catalyzed benzamide ortho-arylation/reaction with (CF₃CO)₂O sequence was developed allowing a convenient one-pot synthesis of ortho-arylated benzonitriles and fluorenone derivatives. The outcome of this transformation is dependent on the amide N-alkyl substituent. Dehydration of ortho-arylated N-cyclohexyl-benzamides by (CF₃CO)₂O results in efficient production of benzonitriles. In contrast, o-arylated N-propylbenzamides are converted to fluorenone derivatives.

ortho-Cyano substituted biaryls are valuable pharmaceutical intermediates and are widely used in organic synthesis.¹ The biaryl units can be obtained using well-developed cross-coupling methods.² However, this requires both coupling partners to be functionalized. Often, starting materials for these coupling reactions need to be synthesized lengthening the synthetic schemes. Coupling of a C-H bond with a carbon-leaving group bond would allow to use simple starting materials.³

The first transition-metal-catalyzed C-H/C-halogen bond couplings were developed by Tremont, Liebeskind, and Ohta in 1980’s.⁴ Recently many other examples utilizing this methodology have been reported. Both unfunctionalized and directing-group-containing substrates can be arylated by aryl halides, stannanes, boronates, or aryliodonium salts under palladium, rhodium, and ruthenium catalysis.⁵ Our group has previously developed a general method for coupling directing-group-containing substrates with aryl iodides.⁶ Anilides, benzamides, benzylamines, 2-arylpyridines, and benzoic acids can be efficiently arylated by employing this methodology.⁷ Good functional group tolerance is usually observed.

Unfortunately, this method can not be employed for benzonitrile ortho-arylation. Nitriles are known to slow down or even stop catalytic cycles due to strong binding of cyano group to transition metals.⁸ An alternative is to use another directing group that can be transformed into cyano group after the arylation step.⁹

It is known that amides can be converted to nitriles by using strong dehydrating agents, for example, phosphorus oxychloride or thionyl chloride.¹⁰ Catalytic dehydration of primary amides is known.¹¹ Mild conditions (trifluoroacetic anhydride, room temperature) can be employed to obtain a benzonitrile from a primary benzamide.¹²

We have shown that arylated anilides can be dehydrated to form phenanthridines by using trifluoroacetic anhydride reagent.^7f We decided to apply this approach to the synthesis of o-arylated benzonitriles. In preliminary experiments, isopropyl benzamides were subjected to the standard arylation conditions^7c followed by reaction mixture treatment with trifluoroacetic anhydride at 110 °C. This sequence resulted in the formation of fluorenone and benzonitrile mixture.¹³ The possible mechanism is presented in Scheme 1. After arylation and treatment of reaction mixture with trifluoroacetic anhydride, an equilibrium mixture of N-trifluoroacetylamide and its O-trifluoroacetyl isomer^7f,14 is formed. If R group is a secondary alkyl group that can form a stable carbocation, dealkylation of amide occurs and benzonitrile is formed as the major product (Scheme 1, path A). However, if amide possesses a primary alkyl substituent, stable carbocation can not be formed, and electrophilic aromatic substitution results in the formation of fluorenone imine. Hydrolysis to fluorenone occurs during work-up (Scheme 1, path B).

Scheme 1.

Proposed Reaction Path

According to the above analysis, selective formation of benzonitriles can be achieved if the amide substrate contains a group capable of forming a carbocation with greater stability. Unfortunately, t-butyl amides are not stable under the arylation conditions. It has been reported that cyclohexyl cation is substantially more stable than isopropyl cation.¹⁵ We were pleased to discover that cyclohexylamide derivatives formed nitriles selectively in most cases. Reaction of N-cyclohexyl-3-methylbenzamide with 4-chloroiodobenzene followed by treatment with trifluoroacetic anhydride resulted in 2-(4-chlorophenyl)-5-methylbenzonitrile formation in 65% yield (Table 1, entry 1). Other ortho-arylated benzonitriles can be obtained in moderate to good yields by employing the same conditions (Table 1). Electron-donating (entries 1-3) and - withdrawing (entries 4-6) groups can be present on benzamides. Both electron-rich (entry 2) and electron-poor (entries 1, 3-7) aryl iodides are reactive. However, when an electron-rich 3,5-dimethyliodobenzene was reacted with an electron-rich benzamide derivative, a fluorenone byproduct was isolated in 27% yield in addition to the desired nitrile. In all other cases, formation of fluorenone byproducts was not observed. N-Cyclohexylbenzamide can be diarylated and upon treatment with trifluoroacetic anhydride an ortho-diarylated benzonitrile is obtained in a good yield (Table 1, entry 7). Chloride, bromide, ester, and ether groups can be present on both coupling partners.

Table 1.

Formal Arylation of Benzonitriles^a

Entry	R	FG	Benzonitrile	Yield
1	3-Me	4-Cl		65%
2b	3-Me	3,5-diMe		54%
3	3-Me	4-CO2Et		73%
4	3-Br	4-CO2Et		56%
5	3-Br	3-Cl		72%
6	2-Cl	4-CF3		84%
7	H	3-OCF3		63%

^aPd(OAc)₂ (5 mol%), AgOAc (1.3-2.3 equiv), ArI (3-4 equiv), benzamide (1 equiv), TFA (0.7 mL), 120 °C; then (CF₃CO)₂O (2-3 equiv), 90-110 °C. Yields are isolated yields.

^b1,3,7-Trimethylfluorenone byproduct was isolated in 27% yield.

As mentioned before, in preliminary experiments fluorenone side products were detected. Fluorenone is a key structure in some antitumor drugs,¹⁶ natural products,¹⁷ and compounds for organic electronics.¹⁸ There are two major synthetic approaches leading to fluorenones. First, Friedel-Crafts-type cyclizations (or their anionic equivalents) lead to fluorenones.^18a,c,19 Second methodology is based on carbon-carbon bond formation from benzophenone starting materials under Pschorr cyclization conditions or transition metal catalysis.²⁰ Other known methods for fluorenone synthesis require hazardous carbon monoxide²¹ and highly reactive intermediates, for example, benzyne.^21a,22

As discussed above, changing N-cyclohexyl group to N-propyl functionality should facilitate fluorenone core formation (Scheme 1, path B). Thus, 3-methyl-N-propylbenzamide was subjected to standard arylation conditions followed by reaction with trifluoroacetic anhydride at 110 °C. Fluorenone derivative was obtained as the only product in 79% yield (Table 2, entry 2). Other fluorenones can be synthesized in a similar fashion. Aryl iodides possessing electron-releasing (Table 2, entries 2, 5) or withdrawing (Table 2, entries 1, 3, 4, 6) substituents can be used in this transformation and fluorenones were isolated in 62-79% yields. Esters, ethers, and halogen atoms can be present on both coupling components. However, use of electron poor benzamides was unsuccessful in our hands. Poor conversions were observed either during arylation or cyclization step. If para-substituted benzamides are used, after diarylation and treatment of reaction mixture with trifluoroacetic anhydride 1-aryl substituted fluorenones can be obtained (Table 2, entry 6).

Table 2.

Fluorenone Synthesis^a

Entry	R	FG	Product	Yield
1	3-Me	4-CF3		75%
2	3-Me	3,5-diMe		79%
3	2-MeO	4-CO2Et		66%
4	2-MeO	4-Br		62%
5	2-MeO	4-t-Bu		62%
6	4-t-Bu	4-Cl		64%

^aPd(OAc)₂ (5 mol%), AgOAc (1.3-2.3 equiv), ArI (3-4 equiv), benzamide (1 equiv), TFA (0.7 mL), 120 °C; then (CF₃CO)₂O (2-3 equiv), 110 °C. Yields are isolated yields.

In conclusion, we have developed a useful and convenient method for the synthesis of ortho-arylated benzonitriles and fluorenones starting from simple benzamides. The product yield and reaction scope in most cases is limited by the arylation step. Changing alkyl substituent on amide functionality allows to fine-tune the reaction to obtain the desired product. Thus, N-propyl benzamides can be converted to fluorenones, while N-cyclohexyl benzamides afford benzonitrile derivatives. Good functional group tolerance is observed. Halogens, esters, and ethers are tolerated on benzamide and aryl iodide coupling components.

Experimental Section

General procedure for synthesis of benzonitriles

A 2-dram vial was charged with substrate, Pd(OAc)₂ (5 mol%), AgOAc (1.3-2.3 equiv), aryl iodide (3-4 equiv), and trifluoroacetic acid (TFA) (0.5 mL). The resulting solution was heated at 120 °C for 0.5-4h. Conversion was monitored by GC. After that, reaction mixture was cooled to room temperature and trifluoroacetic anhydride (2.0-3.0 equiv.) was added. The vial was placed in oil bath (90-110 °C) for 1-3h. The conversion was monitored by GC. After completion of reaction, ether was added to reaction mixture followed by filtration through a pad of Celite®. Filtrate was washed twice with aqueous NaHCO₃. Organic layer was dried over MgSO₄. Solvent was removed by evaporation under reduced pressure (aspirator) and residue was purified by flash chromatography.

2-(4-Ethoxycarbonylphenyl)-5-methylbenzonitrile (Table 1, entry 3)

N-Cyclohexyl-3-methylbenzamide (152 mg, 0.7 mmol), Pd(OAc)₂ (7.8 mg, 0.035 mmol), AgOAc (152 mg, 0.91 mmol), and ethyl 4-iodobenzoate (580 mg, 2.1 mmol) were dissolved in TFA (0.5 mL). Resulting solution was heated for 40 min at 120 °C. After cooling to room temperature, trifluoroacetic anhydride (300 μL, 2.1 mmol) was added and reaction mixture was heated for 1.5h at 90 °C. After completion, ether (5 mL) was added to the reaction mixture followed by filtration through the pad of Celite®. Basic extraction and purification by flash chromatography (EtOAc/hexanes 1/9 to 1/7) gave 135 mg (73%) of a crystalline material, mp 133-134 °C (EtOAc/hexanes), R_f=0.42 (EtOAc/hexanes 1/4). ¹H NMR (300 MHz, CDCl₃, ppm) δ 8.18-8.13 (m, 2H) 7.64-7.58 (m, 3H) 7.51-7.40 (m, 2H) 4.14 (q, 2H, J=7.2 Hz) 2.45 (s, 3H) 1.42 (t, 3H, J= 7.2 Hz). ¹³C NMR (75 MHz, CDCl₃, ppm) δ 166.3, 142.6, 141.8, 138.7, 134.3, 134.0, 130.8, 130.14, 130.08, 129.0, 118.6, 111.4, 61.3, 20.9, 14.5. FT-IR (neat, cm^-1) ν 2224, 1716. Anal. calcd. for C₁₇H₁₅NO₂: C 76.96, H 5.70, N 5.28. Found: C 77.10, H 5.72, N 5.26.

General procedure for synthesis of fluorenones

A 2-dram vial was charged with substrate, Pd(OAc)₂ (5 mol%), AgOAc (1.3-2.3 equiv), and aryl iodide (3-4 equiv). Trifluoroacetic acid (0.5 mL) was added and resulting solution was heated at 120 °C for 0.5-1h. After completion of reaction (monitored by GC) the mixture was cooled to room temperature and trifluoroacetic anhydride (TFAA) (2.0-3.0 equiv.) was added. The vial was placed in oil bath (110 °C) for 1-4.5h. The conversion was monitored by GC. After completion of reaction, ether or dichloromethane was added to reaction mixture followed by filtration through a pad of Celite®. Filtrate was washed twice with aqueous NaHCO₃. Organic layer was dried over MgSO₄. Solvent was removed by evaporation in vacuum and residue was purified by flash chromatography.

7-Methyl-2-trifluoromethylfluoren-9-one (Table 2, entry 1)

3-Methyl-N-propylbenzamide (124 mg, 0.7 mmol), Pd(OAc)₂ (7.8 mg, 0.035 mmol), AgOAc (140 mg, 0.84 mmol), and 4-trifluoromethyliodobenzene (571 mg, 2.1 mmol) were dissolved in TFA (0.5 mL). Resulting solution was heated for 40 min at 120 °C. After cooling to room temperature, trifluoroacetic anhydride (300 μL, 2.1 mmol) was added and reaction mixture was heated for 4.5h at 110 °C. After completion, ether (5 mL) was added to the reaction mixture followed by filtration through a pad of Celite®. Basic extraction and purification by flash chromatography (EtOAc/hexanes 1/17 to 1/13) gave 137 mg (75%) of yellow crystalline material, mp 125-126 °C (EtOAc/hexanes), R_f=0.41 (EtOAc/hexanes 1/10). ¹H NMR (300 MHz, CDCl₃, ppm) δ 7.89 (s, 1H) 7.73 (d, 1H, J=7.9 Hz) 7.57 (d, 1H, J=7.9 Hz) 7.52 (s, 1H) 7.47 (d, 1H, J=7.7 Hz) 7.34 (d, 1H, J=7.7 Hz) 2.41 (s, 3H). ¹³C NMR (75 MHz, CDCl₃, ppm) δ 192.5, 147.9, 140.9, 140.7, 135.8, 134.9, 131.7 (q, J_C-F=5.3 Hz) 131.1 (q, J_C-F=32.8 Hz) 125.6, 124.0 (q, J_C-F=271.5Hz) 121.35, 121.28, 121.1, 120.3, 21.6. FT-IR (neat, cm^-1) ν 1715. Anal. calcd. for C₁₅H₉F₃O: C 68.70, H 3.46. Found: C 68.44, H 3.41.