Synthesis of phenanthrone derivatives from sec- alkyl aryl ketones and aryl halides via a palladium-catalyzed dual C-H bond activation and enolate cyclization

Article abstract of DOI:10.1021/ja1026248

A palladium-catalyzed chelation-assisted C-H activation of alkyl aryl ketones and their reaction with aryl iodides to afford ortho-arylated products is described. For sec-alkyl aryl ketones, the catalytic reaction proceeds further to give 10,10-dialkylphenanthrone derivatives. A possible reaction mechanism involving directed dual C-H bond activation and enolate cyclization for the formation of 10,10-dialkylphenanthrone derivatives is proposed.

Full text of DOI:10.1021/ja1026248

Published on Web 06/04/2010
Synthesis of Phenanthrone Derivatives from sec-Alkyl Aryl Ketones and Aryl
Halides via a Palladium-Catalyzed Dual C-H Bond Activation and Enolate
Cyclization
Parthasarathy Gandeepan, Kanniyappan Parthasarathy, and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua UniVersity, Hsinchu 30013, Taiwan
Received March 29, 2010; E-mail: chcheng@mx.nthu.edu.tw
Recently, palladium-catalyzed direct transformations of inacti-
vated C-H bonds into various functional groups has emerged as a
powerful method in organic synthesis. In particular, reactions
involving directing-group-assisted activation of sp2 or sp3 C-H
bonds of ortho aromatic or alkenyl C-H bonds have been
extensively investigated.1 In general, this type of ortho C-H bond
activation involves a five-membered cyclometalation reaction.2 The
directing groups frequently used in these C-H bond activation
reactions include aldehyde, oxime, imine, alcohol, amine, carboxylic
acid, phenol, and nitrile.1,2 The use of a ketone group as the
directing group in the ortho aromatic C-H bond activation is also
known. In this context, several examples of aromatic ketone-assisted
addition of ortho C-H bonds to alkynes,3a-c alkenes,3d-g and CO/
alkenes3h catalyzed by ruthenium complexes have been reported.
In addition, a palladium-catalyzed multiple arylation of benzyl
phenyl ketones with aryl bromides was reported by Miura and co-
workers,4 and a ruthenium-catalyzed ortho arylation of aromatic
ketones with aryl boronates was revealed by Kakiuchi et al.5 in
2003. Our continuous interest in metal-catalyzed dual C-H bond
activation reactions6 via both five- and seven-membered metalla-
cycles prompted us to explore the reaction of alkyl aromatic ketones
with aryl iodides. Herein, we report an interesting synthesis of
phenanthrone derivatives from sec-alkyl aryl ketones and aryl
halides by a palladium-catalyzed dual C-H activation and enolate
cyclization.
reaction, although there are two possible sites (C2 and C6 of 1d)
for C-H bond activation, the activation occurred only at C6, likely
as a result of the steric effect of the chloro group at C3. The reaction
of 4-chloroacetophenone (1e) with 2c also proceeded smoothly to
give the corresponding ortho-arylated product 3j in good yield (entry
10). Similarly, propiophenone (1f) reacted with 2f to give 3k in
68% yield (entry 11). Unlike the above results, benzophenone (1g)
reacted efficiently with 2f to provide ortho-diarylated product 3A
(Table 1 scheme) in 82% yield.
Table 1. Results of the Reaction of Aryl Ketones with Aryl Iodidesa
Since Pd(OAc)2/Ag2O is known to be an effective catalyst system
for ortho C-H functionalization,1d-g we employed this system for
the reaction of acetophenone (1a) with iodobenzene (2a) in
trifluoroacetic acid (TFA). The reaction at 120 °C for 20 h gave
ortho-arylated product 3a in 23% isolated yield (Table 1, entry 1).
Similarly, 4-methoxyiodobenzene (2b) gave 3b in 20% yield (Table
1, entry 2). Gratifyingly, the reaction of ethyl 4-iodobenzoate (2c)
with 1a gave the corresponding arylated product 3c in 78% yield
(Table 1, entry 3). Thus, it appears that aryl iodides with an electron-
withdrawing substituent give higher yields of ortho-arylated
products than those with an electron-donating group. The effects
of various silver salts, oxidants, and solvents on the product yield
were examined, and the results are shown in the Supporting
Information.
a Unless otherwise mentioned, all of the reactions were carried out
using ketone 1 (1.00 mmol), aryl iodide 2 (3.00 mmol), Pd(OAc)2 (10
mol %), Ag2O (1.0 mmol), and TFA (2.0 mL) at 120 °C for 20 h.
b Isolated yields.
Under the catalytic reaction conditions shown in Table 1,
4-methylacetophenone (1b) reacted smoothly with aryl iodides 2c-f
having an electron-withdrawing substituent to give the correspond-
ing ortho-arylated products 3d-g in 80, 71, 92 and 84% isolated
yield, respectively (Table 1, entries 4-7). The palladium-catalyzed
C-H activation is also compatible with acetophenones 1 having a
chloro substituent on the aromatic ring. Treatment of 2-chloroac-
etophenone (1c) with 2f gave 3h in 52% yield (entry 8). The
reaction of 3-chloroacetophenone (1d) with 2f proceeded in a
regioselective manner to give 3i in 66% yield (entry 9). In this
Surprisingly, the reaction of isopropyl phenyl ketone (1h) with
ethyl 3-iodobenzoate (2d) under the same conditions as for the
Pd(OAc)2-catalyzed arylation of aryl ketones gave phenanthrone
derivative 4a in 68% yield (see Table 2). This arylation and
cyclization reaction was successfully extended to other sec-alkyl
aryl ketones and aryl halides, and the results are shown in Table 2.
Thus, the reaction of 1h with 3- and 4-nitro-1-iodobenzene (2e and
2f, respectively) afforded 10,10-dimethylphenanthrones 4b and 4c
in 78 and 69% yield, respectively. The reaction of cyclic alkyl aryl
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C O M M U N I C A T I O N S
ketones with aryl iodides also proceeded smoothly to give the
corresponding spirophenanthrone derivative. Accordingly, cyclo-
pentyl phenyl ketone (1i) reacted with 2f to give spirophenanthrone
4d in 76% yield. In a similar manner, various six- and seven-
membered cyclic alkyl aryl ketones 1j-m reacted with aryl iodides
efficiently under the same catalytic conditions to give the corre-
sponding spirophenanthrones 4e-i in good yields. The structure
of 4i was further confirmed by X-ray diffraction.
weaker than primary C-H and because the enolate from a sec-
alkyl ketone is stabilized to a greater extent by electron-withdrawing
Pd(II) than that from a methyl ketone. Finally, reductive elimination
of 10 affords product 4 and Pd(0). The latter is oxidized by silver
ion to regenerate the active Pd(II) species.7
Scheme 1
Table 2. Results of the Reaction of sec-Alkyl Aryl Ketones with
Aryl Iodidesa
To further support the proposed mechanism in Scheme 1, we
prepared arylation intermediates 3m and 3n separately and exam-
ined their behavior under various conditions. Thus, treatment of
3m and 3n with 10 mol % Pd(OAc)2 and 1 equiv of Ag2O in TFA
at 120 °C for 15 h gave the corresponding cyclization products 4j
and 4k in 94-92% isolated yield (eq 2):
When the same reaction was carried out in the absence of Ag2O,
4j was obtained in 9% yield (see the Supporting Information). It is
important to mention that methyl phenyl ketone 3a did not give
the expected cyclization product under the same catalytic conditions.
These observations are in agreement with the results in Tables 1
and 2 that primary alkyl aryl ketones do not undergo further
cyclization to give product 4. The role of Ag2O in the catalytic
reaction is not entirely clear, but it likely acts as a halide scavenger,
a base,7a and an oxidant as observed previously.7b,c
In conclusion, we have successfully developed a new and
mechanistically interesting method for the synthesis of phenanthrone
derivatives from sec-alkyl aryl ketones and aryl iodides catalyzed
by palladium acetate in trifluoroacetic acid. The catalytic reaction
appears to proceed via a dual C-H activation and enolate
cyclization. Further studies directed toward the synthesis of various
biaryl phenanthrone compounds and a detailed mechanistic inves-
tigation are in progress.
a Unless otherwise mentioned, all of the reactions were carried out
using ketone 1 (1.00 mmol), aryl iodide 2 (3.00 mmol), Pd(OAc)2 (10
mol %), Ag2O (1.0 mmol), and TFA (2.0 mL) at 120 °C for 20 h.
To account for the present catalytic reaction, a possible mech-
anism involving a palladium-catalyzed dual C-H activation and
enolate cyclization is proposed (Scheme 1). The first step likely
involves coordination of 1 to the Pd(II) species followed by ortho
C-H activation to form five-membered palladacycle 5. Oxidative
addition of aryl iodide to 5 to give Pd(IV) intermediate 66c,d,7d
followed by reductive elimination affords 3-Pd. These two steps
are evidenced by the isolation of palladacycle dimers 5a and 5k
from the reactions of Pd(OAc)2 with aryl ketones 1a and 1k,
respectively, in TFA. The structure of 5k was determined by single-
crystal X-ray diffraction (see the Supporting Information). More-
over, 5a reacted with 2f to afford ortho-arylation product 3l in 83%
yield, while 5k reacted with 2f to give cyclization product 4f in
86% yield (eq 1):
Acknowledgment. We thank the National Science Council of
the Republic of China (NSC-96-2113-M-007-020-MY3) for support
of this research.
Supporting Information Available: General experimental proce-
dures and characterization details. This material is available free of
charge via the Internet at http://pubs.acs.org.
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