HOTf mediated cascade reactions of 1-arenoylcyclopropanecarboxylic acids with arenes

Article abstract of DOI:10.1039/c2cc17581a

The cascade reactions of 1-arenoylcyclopropanecarboxylic acids with arenes proceed smoothly in freshly distilled HOTf to give the corresponding tetrahydro-5H-benzo[c]fluorene derivatives in good yields along with high stereoselectivities under mild conditions. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2cc17581a

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COMMUNICATION
HOTf mediated cascade reactions of 1-arenoylcyclopropanecarboxylic
acids with arenesw
Gen-Qiang Chen, Xiang-Ying Tang and Min Shi*
Received 5th December 2011, Accepted 10th January 2012
DOI: 10.1039/c2cc17581a
The cascade reactions of 1-arenoylcyclopropanecarboxylic acids
with arenes proceed smoothly in freshly distilled HOTf to give
the corresponding tetrahydro-5H-benzo[c]fluorene derivatives
in good yields along with high stereoselectivities under mild
conditions.
Table 1 Optimization of the reaction conditions
Yieldd (%)
2a
It has been well known that transition metal or Lewis acid
(or Brønsted acid) catalyzed/mediated ring-opening reaction
of cyclopropane is a powerful synthetic approach for the rapid
construction of molecular complexity in organic synthesis.1
A number of pharmaceutically interesting substances and
biologically active natural products have been synthesized by
this synthetic approach.2 In this communication, we wish to
present an interesting trifluoromethanesulfonic acid CF3SO3H
(HOTf) mediated cascade reaction of 1-arenoylcyclopropane-
carboxylic acid with arenes in the rapid generation of tetra-
hydro-5H-benzo[c]fluorene derivatives in good yields along
with high stereoselectivities under mild conditions.
Entry Lewis acids or Brønsted acids Time/h Solvent
1a
2b
3b
4c
5c
BF3ÁOEt2
Sc(OTf)3
HOTf
HOTf
TFA
12
12
12
0.5
12
—
—
—
Complex
84
Trace
DCE
DCE
—
—
The reaction was performed in a 25 mL flame and vacuum dried
a
Schlenk tube. 0.3 mmol of 1a, 0.2 mL of benzene and 0.8 mL of
b
BF3ÁOEt2. 0.3 mmol of 1a, 0.2 mL of benzene and 0.3 mmol of
c
Sc(OTf)3 or HOTf, 0.8 mL DCE. 0.3 mmol of 1a, 0.2 mL of benzene
d
and 0.8 mL of HOTf (entry 4) or TFA (entry 5). Isolated yields.
We initiated our investigations by seeking the optimal
conditions for the cascade reaction of 1-benzoylcyclopropane-
carboxylic acid 1a with benzene. After screening of Lewis acids
such as BF3ÁOEt2 and Sc(OTf)3 as well as freshly distilled Brønsted
acids such as HOTf and trifluoroacetic acid (TFA), we found that
1a could react with benzene smoothly in HOTf at 60 1C to give
a novel tetrahydro-5H-benzo[c]fluorene derivative, (6aS,11bR)-
11b-phenyl-6,6a-dihydro-5H-benzo[c]fluoren-7(11bH)-one 2a, as a
single diastereoisomer in 84% yield within 0.5 h (Table 1, entry 4)
and other catalysts are totally ineffective in this reaction (entries
1–3 and 5).3 The structure of 2a has been unambiguously deter-
mined by X-ray diffraction and its ORTEP drawing and the CIF
data have been presented in the ESI.w4
Table 2 HOTf mediated cascade reactions of substrates 1 and benzene
Yieldb (%)
Entrya
R
t/h
2
3
1
2
3
4
5
6
p-Br, 1b
p-CH3, 1c
p-Cl, 1d
p-F, 1e
m-Cl, 1f
m-Br, 1g
1.0
0.5
1.0
2.0
2.0
2.0
2b, 83
2c, 72
2d, 92
2e, 88
—
—
—
—
—
3f, 67
3g, 73
With these optimal reaction conditions in hand, we sub-
sequently turned our attention to examine the substrate scope of
this interesting cascade reaction with respect to a variety of
1-arenoylcyclopropanecarboxylic acids 1 with benzene. The results
are summarized in Table 2. As can be seen from Table 2, all
—
a
Reaction conditions: 0.3 mmol of 1, 0.2 mL of benzene and 0.8 mL
b
of HOTf. Isolated yields.
the reactions proceeded smoothly to give the corresponding
tetrahydro-5H-benzo[c]fluorene derivatives 2b–2e and 3f and 3g
as a single diastereoisomer in good to high yields for the substrates
1b–1g bearing different substituents at the benzene ring (Table 2,
entries 1–6).
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 354 Fenglin Road, Shanghai 200032, P. R. China.
E-mail: mshi@mail.sioc.ac.cn; Fax: +86-21-64166128
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data of new compounds. CCDC
834559, 837266, 844935, 848746, 855051. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c2cc17581a
Moreover, using p-xylene as the nucleophile instead of
benzene, we found that the reactions also proceeded efficiently
c
2340 Chem. Commun., 2012, 48, 2340–2342
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Table 3 HOTf mediated cascade reactions of substrates 1 and p-xylene
and dehydration of intermediate D affords intermediate E or
F. The Friedel–Crafts reaction of intermediate E with benzene
gives product 2a and the hydride transfer between intermediate
F and p-xylene produces product 4a, respectively (Scheme 1).
The different reaction pathways in the formation of 2a and 4a are
presumably due to the different steric hindrance of benzene and
p-xylene. On the other hand, using o-xylene to replace p-xylene in
the above cascade reaction, the corresponding product 6 was
obtained as a regioisomeric mixture in 65% yield, further
suggesting that the steric effect of xylene is crucial in the reaction
outcome (Scheme 2).
Yieldb (%)
Entrya
R
t/h
4
5
1
2
3
4
5
6
7
H, 1a
0.5
1.5
1.0
1.0
2.0
2.0
2.0
4a, 80
4b, 68
4c, 94
4d, 69
4e, 74
—
—
—
—
—
—
5f, 67
5g, 67
p-Br, 1b
p-CH3, 1c
p-Cl, 1d
p-F, 1e
m-Cl, 1f
m-Br, 1g
To verify the key reaction intermediate, two control experi-
ments have been carried out under the standard conditions.
We found that the authentically prepared compound 76 gave
2a in 90% yield and another possible intermediate 8 afforded
complex product mixtures, suggesting that 7 might be the key
intermediate in the above cascade reaction (Scheme 3).
Another significant verification of the mechanism is that
when the cascade reaction of 1b was carried out in HOTf
containing a trace of water, the reaction product was rather
complex, but 9, derived from intermediate F, can be obtained
in 31% yield after recrystallization from DCM and PE (1 : 1).
Its structure has been further determined by X-ray diffraction
(Scheme 4).7
The hydride transfer between intermediate F and p-xylene8
can be verified by the formation of the by-product G during
the reaction of 1 with p-xylene under the standard conditions.
Obviously, compound G was derived from the intermolecular
Friedel–Crafts reaction of p-xylene with the generated cationic
intermediate, which has been identified by 1H NMR spectro-
scopic data and mass spectrum (Scheme 5, also see ESIw). On the
other hand, it should be also noted that complex product
mixtures derived from the further intermolecular Friedel–Crafts
reaction of compound G with the generated cationic intermediate
—
a
Reaction conditions: 0.3 mmol of 1, 0.2 mL of p-xylene and 0.8 mL
b
of HOTf. Isolated yields.
to produce the corresponding tetrahydro-5H-benzo[c]fluorene
derivatives 4a–4e and 5f and 5g in good to high yields as a
single diastereoisomer at room temperature (25 1C) under the
standard conditions (Table 3, entries 1–7). When the aromatic
group in 1 was replaced by a heteroaromatic moiety, complex
product mixtures were formed under the standard conditions
(for some other unsuccessful examples, please see Table SI in
the ESIw).
Their structures have been determined by spectroscopic
data, Mass and HR-Mass. Furthermore, the structures of 2c,
3g, and 4a have been further confirmed by X-ray diffraction.
Their ORTEP drawings and CIF data are presented in the
ESI.w5
A combined plausible reaction mechanism is shown in
Scheme 1 using 1a as a model. 1a first produces compound 8
through an intramolecular Friedel–Crafts reaction mediated by
HOTf via intermediate A. The reaction of 8 with an arene gives
ring-opened intermediate B, which undergoes intramolecular
cyclization in the presence of HOTf to afford intermediate C.
Deprotonation of intermediate C produces intermediate D
Scheme 2 Reaction of 1a with o-xylene.
Scheme 3 Control experiments.
Scheme 1 A proposed reaction mechanism for the formation of 2a
and 4a.
Scheme 4 Formation of product 9.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2340–2342 2341

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Scheme 5 Intermolecular Friedel–Crafts reaction of p-xylene.
could be formed in the above cascade reaction as well, giving
rather complex product mixtures (Scheme 5).
In summary, we have developed a novel and highly stereo-
selective cascade reaction of 1-arenoylcyclopropanecarboxylic
acids with arenes mediated by freshly distilled HOTf, affording
the corresponding tetrahydro-5H-benzo[c]fluorene derivatives
in good yields under mild conditions. A plausible reaction
mechanism has been also proposed on the basis of control
experiments.
We thank the Shanghai Municipal Committee of Science and
Technology (11JC1402600), National Basic Research Program
of China (973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (21072206, 20472096,
20872162, 20672127, 20821002 and 20732008).
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c
2342 Chem. Commun., 2012, 48, 2340–2342
This journal is The Royal Society of Chemistry 2012