Synthesis of 2,3-diarylfluorenones by domino 'twofold Heck/ electrocyclization/dehydrogenation' reactions of 2,3-dibromoindenone

Article abstract of DOI:10.1016/j.tetlet.2013.03.011

Abstract Domino double Heck/electrocyclization/dehydrogenation reactions of 2,3-dibromo-1H-inden-1-one with styrenes provide a convenient synthesis of 2,3-diarylfluorenones.

Full text of DOI:10.1016/j.tetlet.2013.03.011

Tetrahedron Letters xxx (2013) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 2,3-diarylfluorenones by domino ‘twofold
Heck/electrocyclization/dehydrogenation’ reactions of 2,3-dibromoindenone
Omer A. Akrawi a, Afsar Khan a,b, Munawar Hussain a, Hamid H. Mohammed a,c, Alexander Villinger a,
Peter Langer a,d,
⇑
a Institut für Chemie, Universität Rostock, Albert- Einstein-Str. 3a, 18059 Rostock, Germany
b Department of Chemistry, COMSATS Institute of Information Technology, Abbottabad, Pakistan
c Department of Chemistry, College of Science, University of Al-Mustansiryah, Baghdad, Iraq
d Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Domino double Heck/electrocyclization/dehydrogenation reactions of 2,3-dibromo-1H-inden-1-one with
styrenes provide a convenient synthesis of 2,3-diarylfluorenones.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 7 February 2013
Revised 28 February 2013
Accepted 4 March 2013
Available online xxxx
Keywords:
Catalysis
Palladium
Heck reaction
Domino reactions
Indenones
Fluorenones are an important structural scaffold found in many
natural products, such as dengibsin, dengibsinin, and dendroflorin
which have been isolated from Asiatic orchid Dendrobium gibsonii
Lindley.1 Fluorenones constitute the central core of a variety of
compounds which exhibit important biomedical activity as well
as optical and electronic properties. For example, they act as virus
and enzyme inhibitors,2,3 organic light emitting devices (OLED),4
photosensitizers,5 and liquid crystals (Fig. 1).6,7 Because of the mul-
tifold applications of fluorenone derivatives, several synthetic
methodologies have been developed which include, for example,
Friedel–Crafts type cyclizations of biarylcarboxylic acids,8 oxida-
tions of fluorenol and fluorenes,9,10 intramolecular Diels–Alder
reactions of conjugated enynes or diarylacetylene systems,11a,b for-
mal 3+3 cyclocondensations of 1,3-bis(silyloxy)-1,3-buatdienes,11c
and remote metalation of 2-biphenylcarboxamides or 2-
biphenyloxazolines.12
phenyl-(2-phenyl-benzylidene)-amines,17 and reactions of aro-
matic amides with aryl halides.18 Fluorenones have been recently
prepared by Pd-catalyzed C–H activation of aryl aldoxime ethers
with arenes19 or with aryl iodides followed by oxidative Heck cycli-
zation,20 by sequential reaction of 2-bromobenzaldehydes with
arylboronic acids,21,22 by double CH-activation of diarylketones,23
and by decarboxylative C–H arylation of benzoic acids under radical
conditions.24 The synthesis of arylated fluorenones has only scarcely
been reported so far.18,22–25 In recent years, we have studied the syn-
thesis of benzoannulated heterocycles by domino double Heck elec-
trocyclization reactions.26,27 Herein, we wish to report the first
application of this methodology to indenones. The domino double
Heck electrocyclization reactions of 2,3-dibromoindenone with sty-
renes provides a convenient approach to 2,3-diarylfluorenones
which are not readily available by other methods.
The palladium catalyzed reaction of 2,3-dibromoindenone (1),
which was prepared according to the literature,28 with styrene
2a afforded fluorenone 3a by a domino double Heck electrocycliza-
tion reaction in up to 95% yield (Scheme 1, Table 1).29,30 The reac-
tion had to be thoroughly optimized because the yields were,
under standard conditions, very low. The best yields were obtained
when Pd(OAc)2 (5 mol %) in the presence of t-Butyl-X-Phos
(10 mol %) was used as the catalyst (Table 1, entry 4, Fig. 2). The
reaction was carried out in DMF at 65 °C and was completed al-
ready in 5 h. The yields dropped when other catalysts and ligands
In the last decade palladium catalyzed cross-coupling reactions
have been applied to the preparation of the fluorenone moiety.
Examples include Pd-catalyzed cyclizations of ortho-iodobenzophe-
nones,13 the Pd-catalyzed cyclocarbonylation of ortho-halobiaryls,14
the annulation of arynes to 2-haloarenecarbaldehydes,15 sequential
coupling of aryl halides, alkynes, and arynes,16 reactions of 2-iodo-
⇑
Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.03.011
Please cite this article in press as: Akrawi, O. A.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.011

2
O. A. Akrawi et al. / Tetrahedron Letters xxx (2013) xxx–xxx
O
O
PCy2
OH
PCy2
O
PCy2
O
OMe
O
O
OH OMe
OH
OH OMe
Dengibsin in
Dengibsin
X-Phos
P
S-Phos
Ru-Phos
O
H
N
H
N
P(tBu)2
HBF4
N
N
P
O
O
I
Me
Me
I
HO
OH
P(tBu)3 HBF4
P(Cy)3
tert-Butyl X-Phos
Human Telomerase inhbitor
Figure 2. Structures of ligands.
O
O
HO
Table 2
Synthesis of 3a–n
OH
RO
OR
2,3
Ar
Yielda (%)
a
b
c
d
e
f
g
h
j
i
k
l
m
n
4-(tBuO)C6H4
4-tBuC6H4
4-(MeO)C6H4
4-(EtO)C6H4
4-MeC6H4
3-MeC6H4
Ph
4-BrC6H4
3-BrC6H4
4-ClC6H4
95
92
81
85
77
89
80
75
71
70
73
72
68
65
OH OMe
Dedroflorin
R=n-CnH(n+1), n=1-16.
LC(Liquid Crystal)
Figure 1. Important natural and synthetic fluorenones.
Ar
Ar
Br
Ar
2a-n
3-ClC6H4
4-FC6H4
3-FC6H4
4-(MeCO)C6H4
Br
Ar
i
O
O
3a-n
1
a
Isolated yields.
Ar
65 °C while other substrates, such as 2,3-dialkenylthiophenes,26 re-
quire temperatures of up to 200 °C.
Ar
Ar
Having the optimized conditions in hand, we next focused on
the preparative scope. The reaction of 1 with styrenes 2a–n affor-
ded fluorenones 3a–n in 65–95% yields (Table 2). The yields of
products 3a–g, derived from styrenes containing electron donating
substituents, were higher than the yields of the other products
which are derived from styrenes containing electron withdrawing
substituents. It is noteworthy, that brominated styrenes 2h,j could
be successfully employed without competing side reactions. This
might be explained by the fact that carbon atoms C-2 and C-3 of
indenone 1 are rather electron poor and more rapidly undergo
the oxidative addition with the Pd catalyst than the respective car-
bon atom of the styrene. The acetyl substituted styrene 2n also
underwent the reaction in good yield.
O
O
B
A
Scheme 1. Synthesis of 3a–n. Reagents and condition: (a) 2a–n (2.3 equiv),
Pd(OAc)2 (5 mol %), X-Phos (10 mol %), NEt3 (8 equiv), DMF, 65 °C, 5 h.
or other solvents and higher temperatures were employed. It is
interesting to note that the novel, more sterically hindered ligand
tButyl-X-Phos gave a considerable better yield thanparent X-Phos.
It is noteworthy, that the electrocyclization proceeded already at
Table 1
Optimization of the reaction conditions for 3a
No.
Catalysis
Ligand
Solvent
Base
T (°C)
t (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
—
DMF
Toluene
DMF
DMF
DMF
Toluene
DMF
Toluene
DMF
NEt3
iPr2NEt
NEt3
NEt3
NEt3
iPr2NEt
NEt3
NEt3
50
80
65
65
50
80
65
80
50
48
24
5
20
43
68
95
34
52
63
75
30
Ru-Phos
t-Butyl-X-Phos
P(Cy)3
5
48
24
5
5
48
P(Cy)3
S-Phos
X-Phos
P(tBu)3ꢀHBF4
Na2CO3
a
Isolated yields.
Please cite this article in press as: Akrawi, O. A.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.011

O. A. Akrawi et al. / Tetrahedron Letters xxx (2013) xxx–xxx
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Figure 3. Ortep plot of 3b.
The structures of all products were analyzed by spectroscopic
methods. The structure of 3b was independently confirmed by X-
ray crystal structure analysis (Fig. 3).31
In conclusion, we have reported a new and convenient synthe-
sis of 2,3-diarylfluorenones by domino double Heck/electrocycliza-
tion/dehydrogenation reactions of 2,3-dibromo-1H-inden-1-one.
29. General procedure for the synthesis of fluorenones 3a–n. In a pressure tube
(glass bomb) a suspension of Pd(OAc)2 (6 mg, 0.025 mmol) and t-Butyl-X-Phos
[2-di-tert-butylphosphino-20,40,60-triisopropylbiphenyl] (21 mg, 0.05 mmol) in
DMF (3 mL) was flushed with Ar and stirred at 20 °C to give a brownish
transparent solution. To the stirred solution were added 1,2-dibromoindanone
1 (143 mg, 0.5 mmol), the styrene (2.3 equiv 1.15 mmol) and NEt3 (8.0 equiv,
0.6 mL, 4.0 mmol). The reaction mixture was stirred at 65 °C for 5 h. The
solution was cooled to 20 °C, poured into a mixture of brine and CH2Cl2 (25 mL
each), and the organic and the aqueous layer were separated. The latter was
extracted with CH2Cl2 (3 ꢁ 25 mL). The combined organic layers were washed
with H2O (3 ꢁ 20 mL), dried (Na2SO4), concentrated in vacuo, and passed
through a column (flash silica gel, heptanes–EtOAc) to yield the product.
30. 2,3-Bis[4-(tert-butoxy)phenyl]-9H-fluoren-9-one (3a). Compound 3a was
Acknowledgments
Financial support by the DAAD (scholarships for O.A.A. and
A.K.), by the Ministry of Higher Education and Scientific Research
Iraq (support of H.H.M.), and by the State of Mecklenburg-Vor-
pommern (scholarship for M.H.) is gratefully acknowledged.
References and notes
isolated as
a
yellow solid (226 mg, 95%), mp: 139–141 °C: 1H NMR
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(300 MHz, CDCl3): d = 1.24 (s, 9H, OC(CH3)3), 1.25 (s, 9H, OC(CH3)3), 6.72–
6.80 (m, 4H, ArH), 6.92 (d, 2H, J = 8.7 Hz, ArH), 6.97 (d, 2H, J = 8.5 Hz, ArH), 7.21
(td, 1H, J = 7.3, 1.1 Hz, ArH), 7.40 (td, 1H, J = 7.4, 1.0 Hz, ArH), 7.45–7.47 (m, 2H,
ArH), 7.60 (br d, 1H, J = 7.2 Hz, ArH), 7.63 (s, 1H, ArH). 13C NMR (75.5 MHz,
CDCl3): d = 28.8, 28.9 (3CH3), 78.5, 78.6 (C), 120.3, 122.5 (CH), 123.6 (2CH),
124.3, 126.4, 129.0 (CH), 130.2 (2CH), 133.1 (C), 134.7 (CH), 134.8, 135.6, 135.9,
141.3, 143.1, 144.2, 146.7, 154.5, 154.9 (C), 193.4 (CO). IR (KBr): v = 3093, 3054,
3030, 2972, 2931, 2873 (w), 1711 (s), 1681, 1674, 1668, 1651, 1645, 1633 (w),
1613, 1601 (m), 1574, 1567, 1557, 1538, 1532 (w), 1506 (m), 1478, 1471 (w),
1453 (m), 1416, 1389 (w), 1363 (m), 1308, 1298 (w), 1159 (s), 1125, 1099,
1088, 1026, 1012, 944, 922, 914 (w), 890, 854, 843 (s), 769, 728 (m), 684, 666,
646, 640, 626, 602, 599, 547, 532 (w) cmꢂ1. GC–MS (EI, 70 eV): m/z (%) = 476
([M]+, 4), 365 (27), 364 (100), 318 (4), 305 (6), 276 (5). HRMS (ESI–TOF/MS):
calcd for C33H33O3 [M+H]+: 477.24242; found: 477.24221.
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31. CCDC-929181 contains all crystallographic details of this publication and is
available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or can be
ordered from the following address: Cambridge Crystallographic Data Centre,
12 Union Road, GB-Cambridge CB21EZ; Fax: +44 1223 336 033; or
deposit@ccdc.cam.ac.uk.
Please cite this article in press as: Akrawi, O. A.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.03.011