Synthesis of benzo[c]fluorenone through a one-pot cascade reaction using inden-1-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.11.081

A novel one-pot thermal cycloaddition of two indenones followed by a decarbonylation and dehydrogenation cascade afforded benzo[c]fluorenones regioselectively. Various substituted indenone derivatives were converted into their corresponding benzo[c]fluorenones in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2013.11.081

Accepted Manuscript
Synthesis of benzo[c]fluorenone through a one-pot cascade reaction using in-
den-1-one derivatives
Shuyan Zheng, Hongsheng Tan, Xiaoguang Zhang, Chunhui Yu, Zhengwu Shen
PII:
S0040-4039(13)02029-7
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.11.081
TETL 43877
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 September 2013
14 November 2013
21 November 2013
Please cite this article as: Zheng, S., Tan, H., Zhang, X., Yu, C., Shen, Z., Synthesis of benzo[c]fluorenone through
a one-pot cascade reaction using inden-1-one derivatives, Tetrahedron Letters (2013), doi: http://dx.doi.org/
10.1016/j.tetlet.2013.11.081
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Synthesis of benzo[c]fluorenone by one-pot
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cascade reaction of inden-1-one derivatives
Shuyan Zheng, Hongsheng Tan, Xiaoguang Zhang, Chunhui Yu, Zhengwu Shen
-CO
DMF, 130 o
C
- H2
One-pot
process
17 Samples
Up to 95% of yield

1
Tetrahedron Letters
jo u rn al ho me p ag e : w ww .e lse vie r .c om
Synthesis of benzo[c]fluorenone through a one-pot cascade reaction using inden-1-
one derivatives
Shuyan Zheng,a,1 Hongsheng Tan,a,1 Xiaoguang Zhang,a Chunhui Yu,a Zhengwu Shena,b,∗
a School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
b Basilea Pharmaceutical China Ltd., Haimen, Jiangsu 226100, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel one-pot thermal cycloaddition of two indenones followed by a decarbonylation and
dehydrogenation cascade afforded benzo[c]fluorenones regioselectively. Various substituted
indenone derivatives were converted into their corresponding benzo[c]fluorenones in good to
excellent yields.
Received in revised form
Accepted
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
Indenones
Cycloaddition
Decarbonylation
Diels-Alder reaction
Regioselectivity
The Diels-Alder reaction is a cycloaddition reaction between a
conjugated diene and a dienophile and is widely used to
synthesise various six-membered ring systems. This ubiquitous
[4+2] reaction often exhibits high regio- and stereo selectivity.
Theoretically, an exocyclic double bond conjugated with an
aromatic ring may act as diene moiety in a Diels-Alder reaction,
but examples are rarely reported in the literature. This is because
the electron delocalisation effect on the aromatic ring stabilises
the molecule, hindering the molecule’s ability to participate in
the cycloaddition under mild conditions.1 Indenones are useful
intermediates for synthesising various molecules because they
can participate in numerous types of reactions due to their unique
combination of functionalities,. These reactions include Michael
additions,2 1,3-dipolarcycloadditions,3 [2+2] photodimerisations,4
epoxidations5 and aziridinations.6 In addition, indenones are also
extensively used as dienophiles in [4+2] cycloadditions.7
However, to our knowledge, they have seldom been used as the
diene moiety in Diels-Alder reactions. One exception was
reported by Balci’s group during the synthesis of the
dehydrogenation cascade, even though indenones have been used
for many years in organic synthesis. This paper describes a
Diels-Alder reaction using indenone derivatives with subsequent
decarbonylation and dehydrogenation steps, generating a simple
route
to
benzo[c]fluorenones.10
Accessing
these
benzofluorenones will produce known flurostatin-based natural
compounds11 more efficiently and facilitate rapid exploration of
related chemical structures with a fused ring motif, such as the
Previous work
heating
( 1 )
no solvent
45%
This work
bromoindenones; side reactions (Scheme 1) occurred with 3-
9
bromoindenone
and
3-bromo-5-methoxyindenone.8,
80%
( 2 )
Interestingly, there have been no reports of a Diels-Alder reaction
involving indenone and a subsequent decarbonylation and
———
∗ Corresponding author. Tel.: 0086-513-8219-8001; fax: 0086-513-8219-8003; e-mail: jeff_shen_1999@yahoo.com
1 These authors contributed equally to this paper

2
Tetrahedron letters
potentially therapeutic benfluron analogues.12
Scheme 3. Attempts at cross-coupling with various
dienophiles
Readily available 1-indenone 1b was chosen as the substrate to
optimise the reaction conditions. Various reaction conditions
were tested and some selected results are presented in Table 1.
Scheme 1 Synthesis of benzo[c]fluorenone derivatives
The reaction was discovered when we attempted to use 6-
methoxyindenone 1a as a dienophile for a Diels-Alder reaction in
an unrelated study. The compound had decomposed after one
month of storage in a refrigerator (approximately 4oC).
Fortunately, one of main products was isolated from the mixture,
and its structure was assigned to be dihydrobenzo[c]fluorenone
2aa based on the spectroscopic data (Scheme 2). Subsequent
oxidation with DDQ yielded bright-red crystals and an X-ray
crystal diffraction analysis confirmed the structure as
dimethoxybenzo[c]fluorenone 2ab. Further examination of this
reaction indicated that the benzo[c]fluorenone could be easily
produced after refluxing indenone 1a in toluene.
Table 1. Optimization of reaction conditions for
benzo[c]fluorenone formation
1b
2b
Yield
(%)d
Temp./ time
Entry
Solvent
Catalyst
1a
2a
3
Toluene
Toluene
40
32
68
42
0
120 ℃ / 30 h
120 ℃ /30 h
120 ℃ /20 h
150 ℃ / 30 h
Reflux 10 h
50 ℃/ 5 h
4 o
C
Et2AlCl
DDQ
THF
35 days
Toluene
Sc(OTf)3
1a
4a
5b
6b
7b
8
2aa
xylene
Xylene, 130 o
30 h, 50%
C
CH2Cl2
CH2Cl2
ZnI2
0
ClCH2CH2Cl
ClCH2CH2Cl
THF
0
80 ℃/ 10 h
80 ℃/ 10 h
80 ℃/ 10 h
140 ℃/ 5 h
80 ℃/ 8 h
Sc(OTf)3
70
28
62
45
85
2ab
9
Scheme 2. Reaction forming a benzo[c]fluorenone
10c
11c
12
13
HOCH2CH2OCH3
EtOH
This unexpected result caught our interest immediately
because indenone’s role as a diene moiety in the Diels-Alder
reaction was so unusual. In addition, the regioselectivity of the
reaction was quite interesting because the benzo[c]fluorenone
formed exclusively. Therefore, further investigations were
carried out to understand the scope and the limitations of this
reaction.
DMF
130 ℃/ 8 h
80 ℃/ 5 h
DMF
Sc(OTf)3
82
b
aThe conversion was low and the most of 1b was recovered.
No
reaction and 1b was recovered. c The by-product was the Michael adduct
between the alcohol and the indenone. d Isolated yield.
DMF
130 oC
In a nonpolar solvent, such as toluene or xylene, the reaction
proceeded very slowly, and the yields remained unsatisfactory
(entry 1 and 4). However, when Sc(OTf)3 was added as a
catalyst, the yield of the reaction improved significantly (entry
3). In DCM or 1,2-dichloroethane, no reaction was observed,
even the indenone was highly soluble in these two solvents.
Interestingly, when a large amount of Sc(OTf)3 (0.2 eq) was used
in 1,2-dichloroethane, the substrate was completely converted
(entry 8). THF could also be used as the solvent of this reaction,
however, due to the poor solubility of the indenone in THF, the

3
reaction’s results were unsatisfactory. Protic solvents, such as
EtOH and 2-methoxyethanol were unsuitable for this reaction
because they reacted with the 1-indenone to form Michael
adducts. Finally, DMF was identified as the most efficient
solvent for this reaction (entry 12), it facilitating the complete
conversion of the substrate and inducing the best yield. Although
Sc(OTf)3 could accelerate the reaction (entry 13), however, using
electron-withdrawing groups, such as chloro, bromo and acetyl,
were stable at room temperature and could even be stored as such
for several months. However, under our standard reaction
conditions, the benzo[c]fluorenones could only be obtained in
moderate yields. The indenones with methoxyl, methyl and
acetamido substituents (entry 1~7 and entry 12) were more
reactive and could form the desired benzo[c]fluorenones
smoothly. Interestingly, for 4-methoxyindenone (entry 7), the
aromatic isosteroid was the major product of this reaction. This
product may form because the steric hindrance of the group at the
4-position changed the [4+2] cycloaddition’s regioselectivity. In
fact, all other indenones without 4-substitution only form
o
DMF alone at 130 C was chosen for this reaction because it
already give satisfactory results.
Table 2. Coupling reactions between two indenones
benzo[c]fluorenones.
naphthalindenone
In
(entry
addition,
14),
while synthesizing
we observed only
R
O
dihydrobenzo[c]fluorenone 2oa; this compound could be
converted into benzo[c]fluorenone via DDQ oxidation. However,
the formation of dihydrobenzo[c]fluorenone clearly indicated that
the dehydrogenation is the last mechanism step in the reaction
cascade. For the reaction with 3-bromoindenone, 5-
bromobenzo[c]fluorenone 2l was generated in a much better
yield than what was previously reported (entry 11)8.
DMF
R
O
o
130
C
R
Entry
Indenone
Benzo[c]fluorenone
Entry
Indenone
Benzo[c]fluorenone
NO
2
O
O
O
N
2
1
O
8
O
N
O
2
2b
1b
2h
48%
1h
85%
OMe
O
Table 3. Coupling two different indenones
O
O
O
MeO
MeO
O
O
2
9
O
R2
2a
1a
80%
2i
O
O
1i
35%
DMF
MeO
+
R
R1
R2
130 oC
O
O
O
R1
O
3
10
O
MeO
R
MeO
2c
1j R = Cl
R
1c
82%
1k
R = Br
2j R = Cl 45%
2k R = Br 42%
Entry
Benzo[c]fluorenone
Indenone
O
O
O2N
4
O
O
11
O
R1
R2
Br
2d
1d
1l
84%
2l
Br
1
88%
O
OMe
O
MeO
NHAc
1h R1 = NO2
R2 = H
O
O
MeO
MeO
MeO
5
12
MeO
MeO
O
2p
NHAc
35%
R1= H
R2= OCH3
1c
1m
NHAc
1e
2m
42%
2e
76%
Br
O
O
OMe
O
OMe
O
OMe
2
O
6
13
O
R
O
O
O
2f
2n
1n
1f
72%
1k R = Br
1c
28%
MeO
R = OCH3
2q
28%
MeO
O
O
H
O
O
R1
7
14
O
H
2oa
2ga
35%
OMe
OMe
OMe
O
92%
1o
1g
O
R2
3
1b R1 = H
R2 = H
O
OMe
39% 2r
2gb
2ob
OMe
1f R1= OCH3
R2= CH3
52%
95%
Subsequently, various indenone derivatives were used to
further explore the scope and limitations of the reaction. The
results are depicted in Table 2. Generally, electron-rich
indenones furnished better results than electron-deficient
substrates. The electron-rich indenones have increased electron
density at the cyclopentadienone moiety, forming a 4-electron π
system and becoming a more reactive diene in the Diels-Alder
reaction. However, in the electron-deficient indenones, the
cyclopentadienone moiety tended to occupy a 2-electron π
system; this arrangement followed the [4n+2] rule and therefore
remained quite stable. For example, indenone derivatives with
Subsequently, cross coupling reactions using two different
indenones were examined, and the results are depicted in Table 3.
Unfortunately, the yields for these reactions were unsatisfactory
due to their limited chemoselectivity.
To continue exploring the use of indenone as a diene moiety
in Diels-Alder reactions, indenone was tested with other

4
Tetrahedron letters
Organometallic Chem. 1994, 464, 171. (b) Vasil'ev, A. V.;
Walspurger, S.; Pale, P.; Sommer, J. Russ. J. Org. Chem.
2005, 41, 618.
Patra, A.; Bandyopadhyay, M.; Ghorai, S. K.; Mal, D. Org.
Prep. Proced. Int. 2003, 35, 515.
Melchiorre, P.; De Vincentiis, F.; Bencivenni, G.;
Pesciaioli, F.; Mazzanti, A.; Bartoli, G.; Galzerano, P.
Chem-Asian J. 2010, 5, 1652.
(a) Patra, A.; Ghorai, S. K.; De, S. R.; Mal, D.
Synthesis 2006, 15, 2556. (b) O'Sullivan, T. P.; Zhang, H.
B.; Mander, L. N. Org. Biomol. Chem., 2007, 5, 2627. (c)
Lin, Y. Q.; Jones, G. B.; Hwang, G. S.; Kappen, L.;
Goldberg, I. H. Org. Lett. 2005, 7, 71. (d) Mander, L. N.;
O'Sullivan, T. P. Synlett 2003, 9, 1367.
dienophiles (Scheme 3), such as p-benozquinone, maleric
anhydride, N-phenylmaleimide and chalcone; unfortunately, no
desired products were observed. The reasons of the failure of
these cross couplings remain unclear.
(5)
(6)
Based on the above results, a reaction mechanism was
proposed, as described in Scheme 4. First, a thermal Diels-Alder
cycloaddition between two indenone molecules broke aromaticity
(7)
to generate intermediate
aromatisation drove the decarbonylation process, forming
A
regioselectively. Next, re-
B.Subsequently, the final dehydrogenation was driven by the
completion of the completed large
(8)
(9)
Tutar, A.; Cakmak, O.; Balci, M. Tetrahedron 2001,
57, 9759.
Tutar, A.; Berkil, K.; Hark, R. R.; Balci, M. Syn.
Commun. 2008, 38, 1333.
π system, producing
benzo[c]fluorenone. The isolation of the intermediate B in some
reaction (entry 14, table 2) further confirmed the proposed
mechanism.
(10) For some important contributions on synthesis of
benzo[c]fluorenones, please to see: (a) Minuti, L.;
Taticchi, A.; Gacs-Baitz, E.; Marrocchi, A. Tetrahedron
R2
1998, 54, 10891. (b) Rodrıguez, D.; Navarro-Vázquez, A.;
́
Castedo, L.; Domınguez, D.; Saá, C. Tetrahedron Lett.
́
O
O
2002, 43, 2717. (c) ) Rodrıguez, D.; Navarro-Vázquez, A.;
Castedo, L.; Domınguez, D.; Saá, C. J. Org. Chem. 2003,
68, 1938. (d) Rodrıguez, D.; Martínez-Esperón, M.;
Navarro-Vázquez, A.; Castedo, L.; Domınguez, D.; Saá,
́
O
́
D-A Reaction
R1
R2
+
́
R1
́
O
C. J. Org. Chem. 2004, 69, 3842.
(11) (a) Lycka, A.; Jirman, J.; Nobilis, M.; Kvasnickova, E.;
Hais, I. M. Magn. Reson. Chem. 1987, 25, 1054. (b)
Kawazoe, K.; Yutani, A.; Tamemoto, K.; Yuasa, S.;
Shibata, H.; Higuti, T.; Takaishi, Y. J. Nat.
A
R2
R2
Prod. 2001, 64, 588.
- CO
- H2
O
(12) (a) Skalova, L.; Nobilis, M.; Szotakova, B.; Kondrova, E.;
Savlik, M.; Wsol, V.; Pichard-Garcia, L.; Maser, E.
Biochem Pharmacol. 2002, 64, 297. (b) Becker, F. F.;
Mukhopadhyay, C.; Hackfeld, L.; Banik, I.; Banik, B. K.
Bioorg. Med. Chem. 2000, 8, 2693.
O
R1
R1
B
C
Scheme 4. Proposed reaction mechanism
Supplementary Material
In summary, a one-pot cascade reaction that involves the
cycloaddition of two indenones, followed by decarbonylation and
dehydrogenation was discovered to form benzo[c]fluorenones
regioselectively. This method is the most convenient way to
synthesise benzo[c]fluorenone derivatives. Further research
remains on-going to expand the scope of the reaction.
The supplementary data (detailed experiment
procedures, compound characterisation, and copies of
spectra data) associated with this article can be found
online.
Acknowledgments
SYZ would like to thank Basilea Pharmaceutica China for
supporting these studies through its ADT program.
References and notes
(1)
(2)
(a) Padias, A. B.; Tien, T. P.; Hall Jr. H. K. J. Org. Chem.
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(a) Norager, N. G.; Lorentz-Petersen, L. L. R.; Kehler, J.;
Juhl, K.; Lyngso, L. O. Synlett 2011, 12, 1753. (b)
Nishimura, T.; Guo, X. X.; Uchiyama, N.; Katoh, T.;
Hayashi, T. J. Am. Chem. Soc. 2008, 130, 1576.
(a) Nugiel, D. A. Tetrahedron Lett. 2001, 42, 3545. (b)
Glass, A. C.; Morris, B. B.; Zakharov, L. N.; Liu, S. Y.
Org. Lett. 2008, 10, 4855.
(3)
(4)
(a) Davis, B. R.; Johnson, S. J.; Woodgate, P. D. Cambie,
R. C.; Mui, L. C. M.; Rutledge, P. S.; Woodgate, P. D. J.

5
Synthesis of benzo[c]fluorenone by one-pot
cascade reaction of inden-1-one derivatives
Shuyan Zheng, Hongsheng Tan, Xiaoguang Zhang, Chunhui Yu, Zhengwu Shen
-CO
- H2
DMF, 130 oC
One-pot
process
17 Samples
Up to 95% of yield