Site-selective Suzuki-Miyaura reactions of 2,3-dibromo-1H-inden-1-one

Article abstract of DOI:10.1016/j.tetlet.2010.10.101

The first transition metal-catalyzed cross-coupling reactions of 2,3-dibromo-1H-inden-1-one are reported. The Suzuki-Miyaura reaction of 2,3-dibromo-1H-inden-1-one with 2 equiv of arylboronic acid gave 2,3-diaryl-1H-inden-1-ones. The reaction with 1 equiv of arylboronic acid gave 2-bromo-3-aryl-1H-inden-1-ones with very good site-selectivity. The one-pot reaction of 2,3-dibromo-1H-inden-1-one with two different arylboronic acids afforded 2,3-diaryl-1H-inden-1-ones containing two different terminal aryl groups.

Full text of DOI:10.1016/j.tetlet.2010.10.101

Tetrahedron Letters 52 (2011) 184–187
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Site-selective Suzuki–Miyaura reactions of 2,3-dibromo-1H-inden-1-one
Munawar Hussain a, Nguyen Thai Hung a, Rasheed Ahmed Khera a, Alexander Villinger a, Peter Langer a,b,
⇑
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b 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:
The first transition metal-catalyzed cross-coupling reactions of 2,3-dibromo-1H-inden-1-one are
reported. The Suzuki–Miyaura reaction of 2,3-dibromo-1H-inden-1-one with 2 equiv of arylboronic acid
gave 2,3-diaryl-1H-inden-1-ones. The reaction with 1 equiv of arylboronic acid gave 2-bromo-3-aryl-1H-
inden-1-ones with very good site-selectivity. The one-pot reaction of 2,3-dibromo-1H-inden-1-one with
two different arylboronic acids afforded 2,3-diaryl-1H-inden-1-ones containing two different terminal
aryl groups.
Received 8 September 2010
Revised 15 October 2010
Accepted 19 October 2010
Available online 12 November 2010
Keywords:
Catalysis
Ó 2010 Elsevier Ltd. All rights reserved.
Palladium
Suzuki–Miyaura reaction
Site-selectivity
Indenones
2,3-Diaryl-1H-inden-1-ones are of considerable pharmacologi-
cal relevance.1 Classic syntheses of these molecules rely on intra-
molecular Friedel–Crafts acylation reactions,2 on the reaction of
3-(p-methoxybenzyl)phthalide with phenylmagnesium bromide
and subsequent rearrangement,3 and on the reaction of 2-phe-
nyl-1H-inden-1,3(2H)-dione with phenylmagnesium bromide and
subsequent extrusion of water.4 2,3-Diaryl-1H-inden-1-ones have
also been prepared from dibenzoylmethane5 and benzophenone
derivatives.6 Recent transition metal-catalyzed syntheses of 2,3-
diaryl-1H-inden-1-ones include the reaction of 1-methoxy-4-
(40-methoxyphenylethynyl)-benzene with 2-bromobenzaldehyde7
and the reaction of diphenyl acetylene with 2-bromobenzenebo-
ronic acid.8
time.12 Surprisingly, transition metal-catalyzed cross-coupling
reactions of 2,3-dibromo-1H-inden-1-one have, to the best of our
knowledge, not been reported to date. Herein, we report the syn-
thesis of 2,3-diaryl-1H-inden-1-ones by site-selective S–M reac-
tions of 2,3-dibromo-1H-inden-1-one. The products are not
readily available by other methods.
The S–M reaction of 2,3-dibromo-1H-inden-1-one (1)13 with
2 equivofarylboronicacids2a–e gavethe2,3-diaryl-1H-inden-1-ones
3a–e in excellent yields (Scheme 1, Table 1).
The best yields were obtained using 2.2 equiv of the arylboronic
acid, Pd(PPh3)4 (5 mol %) as the catalyst, and K2CO3 (2 M aqueous
solution) as the base (1,4-dioxane, 70 °C, 6 h).14,15 The employment
of Pd(PPh3)2Cl2 proved to be less efficient in terms of yield. The
reactions could be successfully carried out with both electron-rich
and electron-poor arylboronic acids.
In recent years,
a number of site-selective palladium(0)-
catalyzed cross-coupling reactions of polyhalogenated heterocy-
cles have been developed. The site-selectivity of these reactions
is generally influenced by electronic and steric parameters.9 We
have reported site-selective Suzuki–Miyaura (S–M) reactions of
tetrabrominated thiophene, N-methylpyrrole, selenophene, and
of other polyhalogenated arenes and heteroarenes.10
The S–M reaction of
1 with arylboronic acids 2a–c,f,g
(1.0 equiv) afforded the 3-aryl-2-bromo-1H-inden-1-ones 4a–e in
excellent yields and with very good site-selectivity (Scheme 2,
Tables 2 and 3).14,16 The first attack occurred at position 3 of 1.
During the optimization (Table 3), carried out for derivatives 4b
Bellina and Sulikowski and their co-workers reported site-
selective transition metal-catalyzed reactions of several dibromof-
uranones.11 It occurred to us that 2,3-dibromo-1H-inden-1-one
might be a suitable starting material for the synthesis of 2,3-dia-
ryl-1H-inden-1-ones. The reactions of 2,3-dibromo-1H-inden-
1-one with amines and C-nucleophiles, such as Grignard reagents,
ethyl cyanoacetate, and ethyl acetoacetate, are known for a long
ArB(OH)2
Ar
O
Br
O
2a-e
i
Ar
Br
3a-e
1
⇑
Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
Scheme 1. Synthesis of 3a–e. Reagents and conditions: (i) 3a–e (2.2 equiv),
Pd(PPh3)4 (5 mol %), 2 M K2CO3 (aq), dioxane, 70 °C, 6 h.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.101

M. Hussain et al. / Tetrahedron Letters 52 (2011) 184–187
185
Table 1
Synthesis of 3a–e
1) Ar1B(OH)2
2) Ar2B(OH)2
Ar1
O
Br
% (3)a
Ar2
2,3
Ar
Br
a
b
c
d
e
4-MeC6H4
4-FC6H4
3-(MeO)C6H4
C6H5
100
95
98
97
93
i
O
5a-e
1
Scheme 3. Synthesis of 5a–e. Reagents and conditions: (i) (1) Ar1B(OH)2 2a,f,j
(1.0 equiv), Pd(PPh3)4 (3 mol %), 2 M K2CO3 (aq), dioxane, 45 °C, 4 h; (2) Ar2B(OH)2
2b,f,h,i (1.1 equiv), Pd(PPh3)4 (3 mol %), 70 °C, 6 h.
4-ClC6H4
a
Yield of isolated products.
Table 4
Synthesis of 5a–e
ArB(OH)2
2a-c,f,g
Ar
O
Br
Br
2
5
Ar1
Ar2
% (5)a
Br
i
a,h
a,i
f,b
j,h
a,f
a
b
c
d
e
4-MeC6H4
4-MeC6H4
2,6-(MeO)2C6H3
2-(MeO)C6H4
4-MeC6H4
4-(MeO)C6H4
3-ClC6H4
4-FC6H4
4-(MeO)C6H4
2,6-(MeO)2C6H3
93
O
89
86b
87b
90
4a-e
1
Scheme 2. Synthesis of 4a–e. Reagents and conditions: (i) 2a–c,f,g (1.0 equiv),
Pd(PPh3)4 (3 mol %), 2 M K2CO3 (aq), dioxane, 45 °C, 4 h.
a
Yields of isolated products.
Reaction temperature: 40 °C.
b
Table 2
Synthesis of 3-aryl-2-bromoinden-1-ones 4a–e
2
4
Ar
% (4)a
a
b
f
g
c
a
b
c
d
e
4-MeC6H4
4-FC6H4
2,6-(MeO)2C6H3
3,5-Me2C6H3
3-(MeO)C6H4
98
83
83b
88
95b
a
Yields of isolated products.
Reaction temperature: 40 °C, the other reactions were carried out at 45 °C.
b
and 4e, it proved to be very important to use exactly 1.0 equiv of
the arylboronic acid and Pd(PPh3)4 (3 mol %) as the catalyst. The
employment of Pd(PPh3)2Cl2 resulted in a significant decrease of
the yield and of the site-selectivity. The temperature played an
important role. A good selectivity was achieved only when the
reaction was carried out at 45 °C for 4b (derived from the less reac-
tive, electron poor arylboronic acid 2b) or at 40 °C for 4e (derived
from the electron rich arylboronic acid 2c) because the second
cross-coupling was slow at this temperature. The formation of a
mixture of starting material, mono- and di-substituted products
was generally observed when the reaction was carried out at tem-
peratures between 45 and 70 °C. In the case of highly reactive
methoxy-substituted arylboronic acids (2f,c), the temperature
had to be further decreased to 40 °C to achieve a good site-selectiv-
ity. The reactions were successful for both electron-rich and elec-
tron-poor arylboronic acids.
Figure 1. Crystal structure of 3d.
proved to be important that the first step was carried out at
45 °C (or at 40 °C in case of 2f,j) to achieve a good site-selectivity
in favor of position 3 of the substrate. The second step had to be
carried out at 70 °C to guarantee a complete reaction of position
2. All reactions proceeded in excellent yields. It was important to
add the catalyst again when the second boronic acid was added.
Otherwise, the yields decreased, more products are formed, and
the products could not be isolated in pure form.
The one-pot reaction of 1 with two different arylboronic acids,
which were sequentially added, afforded the unsymmetrical 2,3-
diaryl-1H-inden-1-ones 5a–e containing two different terminal
aryl groups (Scheme 3, Table 4).17,18 During the optimization, it
Table 3
Optimization of the synthesis of 4b and 4e
a
a
Entry
Conditions
T (°C)
%
(4b+3b)
% (4e+3c)
1
2
3
4
5
6
Pd(PPh3)2Cl2 (3 mol %), 2 M K2CO3 (aq.)
Pd(PPh3)2Cl2 (3 mol %), K3PO4
Pd(PPh3)4 (3 mol %), 2 M K2CO3 (aq.)
Pd(PPh3)4 (3 mol %), 2 M K2CO3 (aq)
Pd(PPh3)4 (3 mol %), 2 M K2CO3 (aq)
Pd(PPh3)4 (3 mol %), 2 M K2CO3 (aq)
45
45
20
40
45
60
55+0
47+0
36+9
51+10
13+0b
95+0
Traces+0b
67+0b
83+0
22+29b
19+39b
28+25b
a
Yields of isolated products.
no complete conversion.
b

186
M. Hussain et al. / Tetrahedron Letters 52 (2011) 184–187
2. Weitz, E.; Scheffer, A. Chem. Ber. 1921, 54, 2343.
3. Bergmann, E. D. J. Org. Chem. 1956, 21, 461.
4. Frank, R. L.; Eklund, H.; Richter, J. W.; Vanneman, C. R.; Wennerberg, A. N. J. Am.
Chem. Soc. 1944, 66, 1.
5. Beringer, F. M.; Forgione, P. S.; Yudis, M. D. Tetrahedron 1960, 8, 49.
6. Koelsch, F. J. Am. Chem. Soc. 1932, 54, 2487.
7. Jeffrey, J. L.; Sarpong, R. Org. Lett. 2009, 11, 5450.
8. (a) Morimoto, T.; Yamasaki, K.; Hirano, A.; Tsutsumi, K.; Kagawa, N.; Kakiuchi,
K.; Harada, Y.; Fukumoto, Y.; Chatani, N.; Nishioka, T. Org. Lett. 2009, 11, 1777;
For a classic synthesis of 2,3-diphenyl-1H-inden-1-one starting with diphenyl
acetylene, see: (b) Eisch, J. J.; Kaska, W. C. J. Am. Chem. Soc. 1966, 88, 2976.
9. For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
(a) Schröter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245; (b) Schnürch, M.;
Flasik, R.; Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur. J. Org. Chem.
2006, 3283; (c) Wang, R.; Manabe, K. Synthesis 2009, 1405.
10. (a) Dang, T. T.; Dang, T. T.; Ahmad, R.; Reinke, H.; Langer, P. Tetrahedron Lett.
2008, 49, 1698; (b) Dang, T. T.; Villinger, A.; Langer, P. Adv. Synth. Catal. 2008,
350, 2109; (c) Hussain, M.; Nguyen, T. H.; Langer, P. Tetrahedron Lett. 2009, 50,
3929; (d) Tengho Toguem, S.-M.; Hussain, M.; Malik, I.; Villinger, A.; Langer, P.
Tetrahedron Lett. 2009, 50, 4962; (e) Hussain, M.; Malik, I.; Langer, P. Synlett
2009, 2691; (f) Dang, T. T.; Dang, T. T.; Rasool, N.; Villinger, A.; Langer, P. Adv.
Synth. Catal. 2009, 351, 1595; (g) Ullah, I.; Khera, R. A.; Hussain, M.; Langer, P.
Tetrahedron Lett. 2009, 50, 4651; (h) Nawaz, M.; Farooq, M. I.; Obaid-Ur-
Rahman, A.; Khera, R. A.; Villinger, A.; Langer, P. Synlett 2010, 150.
Figure 2. Crystal structure of 4c.
11. (a) Sulikowski, G. A.; Agnelli, F.; Corbett, R. M. J. Org. Chem. 2000, 65, 337; (b)
Bellina, F.; Anselmi, C.; Viel, S.; Mannina, L.; Rossi, R. Tetrahedron 2001, 57,
9997; (c) Bellina, F.; Anselmi, C.; Rossi, R. Tetrahedron Lett. 2001, 42, 3851.
12. (a) Liebermann, C. Chem. Ber. 1898, 31, 2083; (b) Liebermann, C. 1899, 32, 261.;
(c) Liebermann, C. Chem. Ber. 1899, 32, 920; (d) Liebermann, C. Chem. Ber. 1900,
33, 569; (e) Simonis, H.; Kirschten, C. Chem. Ber. 1912, 45, 567.
More electron deficient
Br
13. Basurto, S.; Garcia, S.; Neo, A. G.; Torroba, T.; Marcos, C. F.; Miguel, D.; Barbera,
J.; Blanca Ros, M.; de la Fuente, M. R. Chem. Eur. J. 2005, 11, 5362.
Br
14. General procedure for the synthesis of 3a–e and 4a–e: The reaction was carried
out in a pressure tube. To a suspension of 1 (144 mg, 0.5 mmol), Pd(PPh3)4
(2.5–3.0 mol % per cross-coupling), and boronic acid 2 (0.5–0.55 mmol per
cross-coupling) in dioxane (5 mL) was added a 2 M solution of K2CO3 (aq)
(1 mL). The mixture was heated at the indicated temperature (40–70 °C) under
Argon atmosphere for 4–6 h. The reaction was diluted with water and
extracted with CH2Cl2 (3 ꢀ 25 mL). The combined organic layers were dried
(Na2SO4), filtered, and the filtrate was concentrated in vacuo. The resulting
residue was purified by column chromatography (silica gel, EtOAc/heptanes).
15. 2,3-Diphenyl-1H-inden-1-one (3d). Starting with 1 (144 mg, 0.5 mmol) and
phenylboronic acid (135 mg, 1.1 mmol), 3d was isolated as a colorless solid
(137 mg, 97%). Reaction temperature: 70 °C. 1H NMR (300 MHz, CDCl3):
d = 7.04–7.07 (m, 1H, ArH), 7.16–7.22 (m, 6H, ArH), 7.30–7.34 (m, 6H, ArH),
7.45–7.51 (m, 1H, ArH). 13C NMR (62.9 MHz, CDCl3): d = 121.3, 123.0, 127.7,
128.1, 128.5, 128.8, 129.0, 129.3, 130.0 (CH), 130.8, 132.4, 132.7 (C), 133.4
Less electron deficient
O
1
Scheme 4. Possible explanation for the site-selectivity of cross-coupling reactions
of 1.
The structures of the products were established by 2D NMR
experiments (NOESY, HMBC). The structures of 3d and 4c were
independently confirmed by X-ray crystal structure analyses (Figs.
1 and 2).19
The site-selective formation of 4a–e and 5a–e can be explained
by electronic reasons (Scheme 4). The first attack of palladium(0)
catalyzed cross-coupling reactions generally occurs at the more
electron deficient and sterically less hindered position.9,20 Position
3 of 2,3-dibromo-1H-inden-1-one (1) is considerably more elec-
tron-deficient than position 2. Handy and Zhang reported a simple
guide for the prediction of the site-selectivity of palladium(0) cat-
alyzed cross-coupling reactions of polyhalogenated substrates
based on the 1H NMR chemical shift values of the non-halogenated
analogs.20 In fact, the 1H NMR signal of proton H-3 of inden-1-one
is shifted downfield compared to proton H-2.
In conclusion, we have reported site-selective Suzuki–Miyaura
reactions of 2,3-dibromo-1H-inden-1-one which provide a conve-
nient and site-selective approach to 2,3-diaryl-1H-inden-1-ones
and 3-aryl-2-bromo-1H-inden-1-ones. The scope and applications
of the methodology outlined herein is currently under investiga-
tion in our laboratories.
(CH), 145.2, 155.3 (C), 196.0 (CO). IR (KBr):
m = 3380, 3070 (w), 1700, 1604,
1455, 1444, 1348, 1178, 1157, 1149, 1081, 1065 (m), 1027, 1010, 999, 929, 918,
858, 840, 807 (w), 780, 760, 751, 723, 699, 675 (s), 637, 612, 587, 549 (s), 1205,
1183, 1156, 1065, 1042 (m), 818, 742, 701 (s), 617, 610, 587, 562, 537 (m)
cmꢁ1. GC–MS (EI, 70 eV): m/z (%) = 282 ([M]+, 100), 265 (16), 252 (47), 239 (03),
176 (06), 126 (12). HRMS (EI, 70 eV): calcd for C21H14O [M]+: 282.10392;
found: 282.10341.
16. 2-Bromo-3-(2,6-dimethoxyphenyl)-1H-inden-1-one (4c). Starting with
(144 mg, 0.5 mmol), Pd(PPh3)4 (18 mg, 3 mol %) and
1
2,6-
dimethoxyphenylboronic acid (91 mg, 0.5 mmol), 4c was isolated as
a
colorless crystalline solid (143 mg, 83%). Reaction temperature: 40 °C. 1H
NMR (250 MHz, CDCl3): d = 3.71 (s, 6H, 2OCH3), 6.58–6.68 (m, 3H, ArH), 7.05–
7.18 (m, 2H, ArH), 7.22–7.34 (m, 2H, ArH). 13C NMR (62.9 MHz, CDCl3): d = 54.8
(OCH3), 103.0 (CH), 107.8 (C), 120.1 (CH), 120.6 (C), 121.8, 127.1 (CH), 128.3
(C), 129.8, 132.7 (CH), 144.3, 153.3, 156.7 (C), 189.1 (CO). IR (KBr):
m = 3009,
2965, 2934, 2836 (w), 1729, 1594, 1583, 1470, 1457, 1441, 1423 (s), 1358,
1300 (w), 1290 (m), 1249 (s), 1189, 1169, 1151 (w), 1101, 1078, 1028 (s), 952,
942, 918, 903, 873, 845 (w), 817, 800, 771, 756, 729, 721 (m), 703 (s), 667, 650,
633, 614, 595, 577, 544 (w) cmꢁ1. GC–MS (EI, 70 eV): m/z (%) = 344 ([M]+, 79Br,
43), 265 (13), 250 (100), 234 (16), 207 (14), 165 (14). HRMS (EI, 70 eV): calcd
for C17H13O379Br [M]+: 344.00481; found: 344.00480.
17. General procedure for the one-pot synthesis of 5a–e: The reaction was carried out
in a pressure tube. To a suspension of 1 (288 mg, 1.0 mmol), Pd(PPh3)4 (35 mg,
Acknowledgments
3 mol %), and Ar1B(OH)2 (1.0 mmol) in dioxane (5 mL) was added
a 2 M
solution of K2CO3 (aq) (1 mL). The mixture was heated at 40–45 °C under Argon
atmosphere for 6 h. The reaction mixture was cooled to 20 °C and Ar2B(OH)2
(1.1 mmol) and an additional amount of Pd(PPh3)4 (35 mg, 3 mol %) was added.
The reaction mixture was heated under Argon atmosphere for 6 h at 70 °C.
After cooling to 20 °C, the mixture was diluted with water and extracted with
CH2Cl2 (3 ꢀ 25 mL). The combined organic layers were dried (Na2SO4) and
concentrated in vacuo. The residue was purified by column chromatography
(EtOAc/heptanes).
Financial support by the State of Vietnam (MOET scholarship for
N.T.H.), by the State of Pakistan (HEC scholarship for R.A.K.), by the
DAAD (scholarship for R.A.K.) and by the State of Mecklenburg-
Vorpommern (scholarships for M.H. and N.T.H.) is gratefully
acknowledged.
18. 2-(4-Methoxyphenyl)-3-(p-tolyl)-1H-inden-1-one (5a). Starting with 1 (288 mg,
References and notes
1.0 mmol),
p-tolylboronic
acid
(136 mg,
1.0 mmol),
and
4-
a
methoxyphenylboronic acid (167 mg, 1.1 mmol), 5a was isolated as
1. (a) Anstead, G. M.; Wilson, S. R.; Katzenellenbogen, J. A. J. Med. Chem. 1989, 32,
2163; (b) Hajela, K.; Kapil, R. S. Ind. J. Chem., Sect. B 1995, 34, 361; (c) McDevitt,
R. E.; Malamas, M. S.; Manas, E. S.; Unwalla, R. J.; Xu, Z. B.; Miller, C. P.; Harris,
H. A. Bioorg. Med. Chem. Lett. 2005, 15, 3137.
colorless crystalline solid (303 mg, 93%). Reaction temperature: 45 °C (first
step), 70 °C (second step). 1H NMR (250 MHz, CDCl3): d = 2.41 (s, 3H, CH3), 3.80
(s, 3H, OCH3), 6.81 (d, J = 8.5 Hz, 2H, ArH), 7.12–7.21 (m, 1H), ArH), 7.14–7.28
(m, 8H, ArH), 7.52–57 (m, 1H, ArH). 13C NMR (62.9 MHz, CDCl3): d = 21.5 (CH3),

M. Hussain et al. / Tetrahedron Letters 52 (2011) 184–187
187
55.2 (OCH3), 113.6, 121.0, 127.7 (CH), 123.3 (C), 128.5, 128.6, 129.5 (CH), 130.0,
130.9 (C), 131.3 (CH), 131.6 (C) 133.3 (CH), 139.3, 145.6, 154.0, 159.1 (C), 197.0
19. CCDC 797044 (3d) and 797045 (4c) contain 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.
(CO). IR (KBr):
m = 3031, 2997, 2917, 2832 (w), 1606, 1591, 1574, 1511, 1484
(m), 1451 (s), 1426, 1369, 1314, 1282 (m), 1246, 1234 (s), 1205, 1183, 1156,
1065, 1042 (m), 818, 742, 701 (s), 617, 610, 587, 562, 537 (w) cmꢁ1. GC–MS (EI,
70 eV): m/z (%) = 326 ([M]+, 100), 311 (20), 268 (11), 239 (19), 163 (06). HRMS
(EI, 70 eV): calcd for C23H18O2 [M]+: 326.13019; found: 326.13013.
20. Handy, S. T.; Zhang, Y. Chem. Commun. 2006, 299.