Carbon-hydrogen bond functionalization approach for the synthesis of fluorenones and ortho-arylated benzonitriles

Article abstract of DOI:10.1021/jo801300y

(Chemical Equation Presented) A sequence consisting of palladium-catalyzed benzamide ortho-arylation/reaction with (CF₃CO)₂O was developed allowing a convenient one-pot synthesis of ortho-arylated benzonitriles and fluorenone derivat

Full text of DOI:10.1021/jo801300y

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, ben-
zamides, 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 cannot be employed for benzoni-
trile ortho-arylation. Nitriles are known to slow down or even
stop catalytic cycles as a result of 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
Carbon-Hydrogen Bond Functionalization
Approach for the Synthesis of Fluorenones and
ortho-Arylated Benzonitriles
Dmitry Shabashov, Jesu´s R. Molina Maldonado, and
Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston,
Texas 77204-5003
olafs@uh.edu
ReceiVed June 17, 2008
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 ortho-arylated benzonitriles. In preliminary experiments,
isopropyl benzamides were subjected to the standard arylation
conditions7c followed by reaction mixture treatment with
A sequence consisting of palladium-catalyzed benzamide
ortho-arylation/reaction with (CF3CO)2O 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.
(4) (a) Tremont, S. J.; Rahman, H. U. J. Am. Chem. Soc. 1984, 106, 5759.
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Tetrahedron Lett. 1989, 30, 4085. (c) Akita, Y.; Inoue, A.; Yamamoto, K.; Ohta,
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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 the use of simple starting materials.3
The first transition-metal-catalyzed C-H/C-halogen bond
couplings were developed by Tremont, Liebeskind, and Ohta
in the 1980s.4 Recently many other examples utilizing this
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7818 J. Org. Chem. 2008, 73, 7818–7821
10.1021/jo801300y CCC: $40.75 2008 American Chemical Society
Published on Web 09/03/2008

TABLE 1. Formal Arylation of Benzonitrilesa
SCHEME 1. Proposed Reaction Path
trifluoroacetic anhydride at 110 °C. This sequence resulted in
the formation of a fluorenone and benzonitrile mixture.13 The
possible mechanism is presented in Scheme 1. After arylation
and treatment of the reaction mixture with trifluoroacetic
anhydride, an equilibrium mixture of N-trifluoroacetylamide and
its O-trifluoroacetyl isomer7f,14 is formed. If the 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 the amide
possesses a primary alkyl substituent, a stable carbocation cannot
be formed, and electrophilic aromatic substitution results in the
formation of fluorenone imine. Hydrolysis to fluorenone occurs
during workup (Scheme 1, path B).
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 treat-
ment 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 benz-
amide 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.
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
a Pd(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. b 1,3,7-Trimethylfluorenone byprod-
uct was isolated in 27% yield.
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 The
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 a N-cyclohexyl group to a
N-propyl functionality should facilitate fluorenone core forma-
tion (Scheme 1, path B). Thus, 3-methyl-N-propylbenzamide
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Bioorg. Med. Chem. Lett. 2006, 16, 5148.
(13) Arylation of N-isopropyl-3-methylbenzamide with 4-chloroiodobenzene
followed by treatment with trifluoroacetic anhydride resulted in formation of an
8:1 mixture of 2-(4-chlorophenyl)-5-methylbenzonitrile and 2-chloro-7-meth-
ylfluorenone (NMR analysis of crude reaction mixture). In contrast, arylation of
the corresponding cyclohexylamide followed by reaction with trifluoroacetic
anhydride afforded the nitrile exclusively (Table 1, entry 1). See the Supporting
information for details.
(14) Bourne, E. J.; Henry, S. H.; Tatlow, C. E. M.; Tatlow, J. C. J. Chem.
Soc. 1952, 4014.
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4711.
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J. Org. Chem. Vol. 73, No. 19, 2008 7819

TABLE 2. Fluorenone Synthesisa
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).
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 the alkyl substituent on the amide functionality makes
it possible to fine-tune the reaction to obtain the desired product.
Thus, N-propyl benzamides can be converted to fluorenones,
whereas N-cyclohexyl benzamides afford benzonitrile deriva-
tives. 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
0.5-4 h. Conversion was monitored by GC. After that, the 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 1-3 h. The conversion was monitored by
GC. After completion of the reaction, ether was added to the
reaction mixture followed by filtration through a pad of Celite.
Filtrate was washed twice with aqueous NaHCO3. The organic layer
was dried over MgSO4. Solvent was removed by evaporation under
reduced pressure (aspirator), and the residue was purified by flash
chromatography.
a Pd(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.
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). The 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 the reaction mixture was heated
for 1.5 h at 90 °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 1:9 to 1:7) gave 135 mg (73%) of a crystalline material,
mp 133-134 °C (EtOAc/hexanes), Rf ) 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) υ 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.
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 and 5) or electron-withdrawing (Table 2, entries 1, 3,
4, and 6) substituents can be used in this transformation, and
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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 the resulting solution was heated at 120
°C for 0.5-1 h. After completion of reaction (monitored by GC),
the mixture was cooled to room temperature, and trifluoroacetic
(21) (a) Chatani, N.; Kamitani, A.; Oshita, M.; Fukumoto, Y.; Murai, S. J. Am.
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7820 J. Org. Chem. Vol. 73, No. 19, 2008

1
anhydride (TFAA) (2.0-3.0 equiv) was added. The vial was placed
in oil bath (110 °C) for 1-4.5 h. The conversion was monitored
by GC. After completion of reaction, ether or dichloromethane was
added to the reaction mixture followed by filtration through a pad
of Celite. The filtrate was washed twice with aqueous NaHCO3.
The organic layer was dried over MgSO4. Solvent was removed
by evaporation in vacuum, and the residue was purified by flash
chromatography.
1/10). H 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, JC-F ) 5.3 Hz) 131.1 (q, JC-F ) 32.8 Hz) 125.6, 124.0
(q, JC-F ) 271.5 Hz) 121.35, 121.28, 121.1, 120.3, 21.6. FT-IR
(neat, cm-1) υ 1715. Anal. Calcd for C15H9F3O: C 68.70, H 3.46.
Found: C 68.44, H 3.41.
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-trifluo-
romethyliodobenzene (571 mg, 2.1 mmol) were dissolved in TFA
(0.5 mL). The 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 the reaction mixture was heated for
4.5 h 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), Rf ) 0.41 (EtOAc/hexanes
Acknowledgment. We thank the Welch Foundation (Grant
E-1571), NIH-NIGMS (Grant R01GM077635), A. P. Sloan
Foundation, and Camille and Henry Dreyfus Foundation for
supporting this research.
Supporting Information Available: Detailed experimental
procedures, characterization data for new compounds, and
complete ref 12. This material is available free of charge via
the Internet at http://pubs.acs.org.
JO801300Y
J. Org. Chem. Vol. 73, No. 19, 2008 7821