Regioselective synthesis of indenols by rhodium-catalyzed C-H activation and carbocyclization of aryl ketones and alkynes

Article abstract of DOI:10.1002/anie.201100229

Ketones and alkynes join together: The catalytic title reaction proceeds rapidly at 120 °C and requires only 1 hour for completion (see scheme). The reaction mechanism likely involves chelation-assisted ortho C-H activation, insertion of the alkyne moiety, carbocyclization, and protonation. Cp=pentamethylcyclopentadienyl. Copyright

Full text of DOI:10.1002/anie.201100229

DOI: 10.1002/anie.201100229
À
C H Activation
À
Regioselective Synthesis of Indenols by Rhodium-Catalyzed C H
Activation and Carbocyclization of Aryl Ketones and Alkynes**
Krishnamoorthy Muralirajan, Kanniyappan Parthasarathy, and Chien-Hong Cheng*
Substituted indenol moieties are an important structural unit
present in various biologically active compounds that possess
analgesic, insecticidal, and myorelaxation properties.[1,2]
Despite the high utility of indenols, only few synthetic
routes are reported in the literature.[2,3–6]
annulation reaction to give indenols using a ruthenium
complex as the catalyst.[8g] Very recently, Shibata and co-
À
workers reported a C H bond activation/carbocyclization
reaction of aromatic ketones and alkynes catalyzed by a
cationic iridium complex to afford benzofulvenes in which
indenols were obtained as minor products.[8h] Our continuous
Transition-metal-catalyzed carbocyclization is a powerful
method for the construction of indenol derivatives in organic
synthesis.[7] In this context, Liebeskind et al. reported a
stoichiometric reaction of alkynes with ortho-manganated
acetophenones to give indenols.[2a] Vicente et al. also de-
scribed the stoichiometric reaction of palladium(II) com-
plexes of 2-acylaryl with alkynes to afford indenol deriva-
tives.[3] Carbocyclization of o-haloaromatic ketones or alde-
hydes with alkynes to give substituted indenols were reported
by Yamamoto and co-workers[4] as well as our research
group.[5] Later, Murakami and co-workers described a regio-
selective rhodium-catalyzed carbocyclization reaction of o-
formylphenylboronic acid with alkynes to give substituted
inden-1-ol derivatives.[6] However, the above methods for
synthesizing indenol derivatives required halides or boronic
acids and sometimes harsh reaction conditions [Eq. (1)]. To
interest in metal-catalyzed C H activation[9] and carbocyliza-
À
tion reactions[6] prompted us to explore the reaction of aryl
ketones with alkynes. Herein, we report the synthesis of
substituted indenols from aryl ketones and alkynes through
À
rhodium-catalyzed
C H
activation/carbocyclization.
À
Recently, many C H activation reactions catalyzed by Rh–
Cp* complexes have been reported.[10]
Treatment of acetophenone 1a with diphenyl acetylene 2a
in the presence of 1.0 mol% of [{RhCp*Cl2}2], 5 mol% of
.
AgSbF6, and 2.0 equivalents of Cu(OAc)2 H2O in tert-amyl
alcohol at 1208C for 1 hour gave indenol product 3a in 91%
yield (Table 1, entry 1). The structure of 3a was confirmed by
its 1H and 13C NMR spectra and mass spectrometry data.
The choice of silver salt and oxidant were very crucial for
the success of the present catalytic reaction. A series of silver
salts and oxidants were examined for the reaction of 1a with
2a (for detailed studies, see the Supporting Information).[11]
Among them, the combination of AgSbF6 and Cu(OAc)2·H2O
gave the best results and afforded 3a in 91% yield. In the
absence of either the silver salt or an oxidant, the reaction of
1a with 2a afforded only a trace amount of 3a. The use of
oxygen or benzoquinone as the oxidant was ineffective. The
choice of solvent was also vital to the catalytic reaction. The
best solvent was tert-amyl alcohol in which 3a was obtained in
91% yield. 1,2-dichloroethane was also an effective solvent
and gave 3a in 61% yield. Other solvents such as tBuOH,
MeOH, EtOH, and acetic acid were less effective for the
catalytic reaction and gave 3a in 42, 16, 16, and 36% yield,
respectively.
the best of our knowledge, there is no effective method for the
À
synthesis of indenols using ketone-assisted C H activation/
carbocylization, although a limited number of examples are
À
available using a ketone as the directing group for the C H
bond activation.[8,9e]
Under the optimal reaction conditions described above,
various substituted acetophenones (1b–f) were treated with
diphenyl acetylene 2a and gave the corresponding indenol
derivatives. Thus, 4-methylacetophenone 1b afforded 3b in
89% yield (entry 2). Electron-rich 3,4-dimethoxyacetophe-
none 1c reacted nicely with 2a and gave 3c in 76% yield
In 1999, Woodgate and co-workers reported the first
À
example of a ketone-assisted C H activation/cyclopenta-
[*] K. Muralirajan, Dr. K. Parthasarathy, Prof. Dr. C.-H. Cheng
Department of Chemistry
À
(entry 3). In the reaction, there are two possible C H bond
National Tsing Hua University
Hsinchu 30013, Taiwan (China)
Fax: (+886)3572-4698
E-mail: chcheng@mx.nthu.edu.tw
Homepage: http://mx.nthu.edu.tw/%7Echcheng
activation sites at C2 and C6 of 1c, but the reaction occurred
only at C6 and is likely a result of the steric bulk of the
methoxy group at C3. Electron-withdrawing 4-fluoroaceto-
phenone 1d provided functionalized indenol 3d in 80% yield
(entry 4). The present catalytic reaction is also compatible
with halo substituents on the aromatic ring of acetophenone
1. Thus, the reaction of 4-chloro-, 4-bromo-, and 4-iodoace-
tophenones 1e–g with 2a gave the corresponding indenol 3e,
[**] We thank the National Science Council of China (NSC-99-2811M-
007-089) for support of this research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201100229.
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Communications
[a]
À
Table 1: Results of rhodium-catalyzed C H activation and carbocylization of aryl ketones with alkynes.
3 f, and 3g in 77, 79 and 93% yield,
respectively (entries 5–7). The
phenyl substituent in acetophenone
1h provided 3h in 78% yield
(entry 8). The effect of changing
the methyl group in acetophenone
1a to another substituents was also
investigated. Thus, propiophenone
1i and isobutyrophenone 1j reacted
effectively with 2a and provided 3i
and 3j in 76 and 83% yield, respec-
tively (entries 9 and 10). Finally, the
reaction of bulkier benzophenone
1k with 2a also proceeded smoothly
and afforded product 3k in good
yield (entry 11).
In addition to 2a, other sym-
metrical alkynes (2b–d) were also
tested for the present reaction.
Thus, methyl- (2b), methoxy- (2c),
and bromo- (2d) substituted diphe-
Entry
Ketone
Alkyne
Product
Yield [%][b]
1
2
1a
1b
2a
2a
3a: R1 =H
91
89
3b: R1 =Me
À
nylacetylenes underwent C H acti-
vation and carbocylization with 1a
and afforded the corresponding
indenols 3l–n in good yields
(entries 12–14). The present cata-
lytic reaction was successfully
extended to the aliphatic alkyne
2e and gave 3o in 73% yield
(entry 15).
To understand the regioselectiv-
ity of the present reaction, unsym-
metrical alkynes were used as the
substrates for the reaction with 1a.
Thus, 1-phenyl-1-propyne (2 f) and
1-phenyl-1-butyne (2g) gave the
single regioisomeric products 3p
and 3q in 77 and 73% yield, respec-
tively (entries 16 and 17). Similarly,
3
1c
2a
3c
76[c]
4
5
6
7
8
1d
1e
1 f
1g
1h
2a
2a
2a
2a
2a
3d: R1 =F
3e: R1 =Cl
3 f: R1 =Br
3g: R1 =I
80
77
79
93
78
3h: R1 =Ph
9
10
11
1i
1j
1k
2a
2a
2a
3i: R2 =Et
76
83
81
3j: R2 =CH(CH3)2
3k: R2 =Ph
12
13
14
15
1a
1a
1a
1a
2b
2c
2d
2e
3l: R3,R4 =4-MeC6H4
3m: R3,R4 =4-OMeC6H4
3n: R3,R4 =4-BrC6H4
3o: R3,R4 =CH2OMe
84
79
86
73
excellent
regioselectivity
was
observed in the reaction of phenyl-
cyclopropylacteylene 2h and prop-
argylic ether 2i with 1a, and
afforded 3r and 3s in 61 and 78%
yield, respectively (entries 18 and
19). Encouraged by the above
results, we further examined the
reaction of 4-bromoacetophenone
1 f with 2 f, 2h, and 2i and these
reactions afforded highly regio-
selective indenols 3t, 3u, and 3v in
74, 62, and 81% yield, respectively
(entries 20–22). Similarly, 4-iodo-
acetophenone 1g and isobutyro-
phenone 1j reacted with 2i and 2 f
in a highly regioselective manner
and gave indenol derivatives 3w
and 3x in 84 and 79% yield, respec-
tively (entries 23 and 24).
16
17
18
19
1a
1a
1a
1a
2 f
2g
2h
2i
3p: R3 =Me
3q: R3 =Et
77
73
61
78
3r: R3 =Cpr
3s: R3 =CH2OMe
20
21
22
1 f
1 f
1 f
2 f
2h
2i
3t: R3 =Me
74
62
81
3u: R3 =Cpr
3v: R3 =CH2OMe
23
1g
2i
3w
84
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Angew. Chem. Int. Ed. 2011, 50, 4169 –4172

Table 1: (Continued)
Based on the stoichiometry of
the reaction, there should be no
redox reaction involved. However,
during the catalytic reaction the
solvent or substrates appear to
reduce the active RhIII species. As
Entry
Ketone
Alkyne
Product
Yield [%][b]
79
24
1j
2 f
3x
a
result, the catalytic reaction
[a] Unless otherwise mentioned, all reactions were carried out using aryl ketone 1 (1.00 mmol), alkyne 2
(1.20 mmol), [{RhCp*Cl2}2] (1.0 mol%), AgSbF6 (5.0 mol%), Cu(OAc)2·H2O (2.0 mmol), and tert-amyl
alcohol (2.5 mL) at 1208C for 1 h. [b] Yield of isolated product. [c] Reaction time was 30 min. Cpr=
cyclopropyl.
requires the presence of Cu-
(OAc)2·H2O to achieve higher
product yields. An evidence for
the involvement of solvent as a
reducing agent for the RhIII species
On the basis of known metal-catalyzed, directing-group-
is the observation that [{RhCp*Cl2}2] in the presence of
AgSbF6 (5 equiv) readily reacted with the solvent tert-amyl
alcohol to give a black metal-like precipitate and unknown
organic compounds. Thus, an important role of Cu-
(OAc)2·H2O likely involves oxidation of the reduced rhodium
species to regenerate the active RhIII species.[12e] In addition,
Cu(OAc)2·H2O also possibly provides the OAcÀ source for
the active rhodium species.[10d,e]
À
assisted C H bond activation/carbocyclization reac-
tions,[5–10,12] a possible mechanism is proposed to account for
the present catalytic reaction (Scheme 1). The catalytic cycle
In conclusion, we have developed a rhodium-catalyzed,
À
chelating-assisted C H activation of aryl ketones and the
reaction with alkynes to afford substituted indenols in good to
excellent yields. The catalytic reaction is highly regioselective
with unsymmetrical alkynes. In addition, this appears to be
À
the effective method to describe C H activation/carbocycli-
À
zation using ketone as a directing group for C H activation.
Further applications of this method in natural product
synthesis and a detailed mechanistic investigation are in
progress.
Scheme 1. Proposed mechanistic pathway for the formation of indenol
Experimental Section
derivatives.
General procedure for the rhodium-catalyzed synthesis of indenol
derivatives: A sealed tube containing [{RhCp*Cl2}2] (1.0 mol%),
AgSbF6 (5.0 mol%), and Cu(OAc)2·H2O (2.0 mmol) was evacuated
and purged with nitrogen three times. Then, t-amyl alcohol (2.5 mL),
aryl ketone 1 (1.00 mmol), and alkyne 2 (1.20 mmol) were sequen-
tially added to the system by syringe under nitrogen and the reaction
mixture was stirred at 1208C for 1 h. When the reaction was complete,
the mixture was cooled and diluted with CH2Cl2 (10 mL). The mixture
was filtered through a pad of Celite and the Celite was washed with
CH2Cl2 (50 mL). The filtrate was concentrated and the residue was
purified by column chromatography on silica gel (eluent: n-hexane/
EtOAc 10:4) to give the corresponding pure product 3.
is likely initiated by the removal of chloride by Ag+ in
[{RhCp*Cl2}2]. Coordination of 1a to the rhodium species and
À
subsequent ortho C H bond activation forms a five-mem-
bered rhodacycle I. Regioselective insertion of alkyne 2 f into
the rhodium–carbon bond of intermediate II gives seven-
membered rhodacycle III with the keto group p-bonded to
the rhodium center.[10k] Subsequent intramolecular insertion
=
of the C O group into the rhodium–alkenyl bond affords
rhodium alkoxide intermediate IV. Protonation of this
alkoxide provides the final product 3p and regenerates the
active RhIII species.
Received: January 11, 2011
Published online: March 29, 2011
The role of AgSbF6 probably involves removal of the
chloride ligands from the [{RhCp*Cl2}2] complex to generate
a more active rhodium complex which likely contains acetate
or solvent as ligands in addition to Cp*. The catalytic activity
of the rhodium catalyst system increases as the amount of
AgSbF6 relative to the rhodium dimer [{RhCp*Cl2}2]
increases from 1.0 to 5.0 equivalents (see the Supporting
Information).[11] These results suggest that as one of the
chloride ligands in the dimer is removed by Ag+, the rhodium
system starts to show catalytic activity. Based on the amount
of Ag+ used, it is likely that the highest catalytic activity is
reached as the four chloride atoms of the dimer are all
removed.
À
Keywords: alkynes · aryl ketones · C H activation · indenols ·
rhodium
.
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