Synthesis of sterically encumbered biaryls based on a 'copper(I)-catalyzed arylation/[3+3] cyclocondensation' strategy

Article abstract of DOI:10.1016/j.tetlet.2008.10.093

Sterically encumbered biaryls are prepared in two steps by CuI-proline-catalyzed arylation of acetylacetone to give 3-arylpentane-2,4-diones and subsequent formal [3+3] cyclization of the latter with 1,3-bis(trimethylsilyloxy)-1,3-dienes.

Full text of DOI:10.1016/j.tetlet.2008.10.093

Tetrahedron Letters 50 (2009) 118–120
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of sterically encumbered biaryls based on a ‘copper(I)-catalyzed
arylation/[3+3] cyclocondensation’ strategy
Asad Ali a,b, Ihsan Ullah a,b, Muhammad Sher a,b, 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:
Sterically encumbered biaryls are prepared in two steps by CuI-proline-catalyzed arylation of acetyl-
acetone to give 3-arylpentane-2,4-diones and subsequent formal [3+3] cyclization of the latter with
1,3-bis(trimethylsilyloxy)-1,3-dienes.
Received 18 September 2008
Revised 18 October 2008
Accepted 21 October 2008
Available online 1 November 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Arenes
Catalysis
Cyclizations
Regioselectivity
Silyl enol ethers
Functionalized sterically encumbered biaryls, such as 3-aryl-
benzoates or 4-arylphenols, occur in many pharmacologically rele-
vant natural products. The simple biaryls cynandione A–C, isolated
from several plant sources, show activity against hepatocytes, hu-
man bladder carcinoma T-24 cells, epidermoid carcinoma KB cells,
and human hepatoma PLC/PRF/5 cells.1 3-Arylbenzoates are also
present in many flavones (e.g., 2,3-dihydroamentoflavone,2a bar-
tramiaflavone,2b robustaflavone,2c and dichamanetin).2d,e For some
derivatives, inhibition of the human liver cathepsins B and K has
been reported.2f,g The natural product anastatin A, which contains
difficult task. An alternative approach to sterically encumbered
and highly functionalized arenes relies on the application of suit-
able dienes in cyclization reactions (building block approach).
Some years ago, Chan et al. developed9 a convenient approach to
salicylates by formal [3+3] cyclizations10 of 1,3-bis(trimethylsilyl-
oxy)-1,3-dienes11 with 3-trimethylsilyloxy-2-en-1-ones. Herein,
O
O
O
O
Me
+
Me
R1
Me
Me
R1
1
a
hydroxylated dibenzofuran moiety, shows hepatoprotective
activity.3 Many pharmacologically active natural products, such
as picropodophyllone, contain a 3-alkyl-4-arylnaphth-1-ol moiety
and can be formally regarded as sterically encumbered 4-arylphe-
nols.4 Others, such as dioncophylleine A, contain a naphthalene
and an isoquinoline moiety.5 Flavidin can be regarded as a bridged
sterically encumbered biaryl derivative.6
I
i
R2
3a-d
R2
2a-d
ii
The most important synthetic approach to biaryls relies on pal-
ladium(0)-catalyzed cross-coupling reactions.7 Although these
reactions are broadly applicable, the synthesis of sterically encum-
bered and functionalized products can be sometimes difficult. In
recent years, a number of new ligands have been reported which
allow to address these problems.8 On the other hand, the regiose-
lective synthesis of the required starting materials, functionalized
and highly substituted aryl halides, or triflates, can be a very
Me3SiO
Me
O
Me
R1
R2
4a-d
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
Scheme 1. Synthesis of 4a–d. Reagents and conditions: (i) K2CO3, CuI 10 mol %,
-proline 20 mol %, DMSO, 90 °C, 6–12 h; (ii) Me3SiCl, NEt3, C6H6, 20 °C, 72 h.
L
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.093

A. Ali et al. / Tetrahedron Letters 50 (2009) 118–120
119
Table 1
Synthesis of 3a–d and 4a–d
3,4
R1
R2
% (3)a
% (4)a
a
b
c
H
H
H
CF3
H
76
82
72
65
90
88
80
86
Me
CO2Et
H
d
a
Isolated yields.
we report, for the first time, the synthesis of sterically encumbered
biaryls by combined CuI-proline-catalyzed arylation/[3+3]
a
cyclization approach. The products reported herein are not readily
available by other methods.
The CuI-proline-catalyzed arylation12 of acetylacetone (1) with
aryl iodides 2a–d, following conditions reported by He and co-
workers,13 afforded the 3-arylacetylacetones 3a–d in very good
yields (Scheme 1, Table 1). The silylation of 3a–d afforded the
3-silyloxy-2-en-1-ones 4a–d. The TiCl4-mediated formal [3+3]
cyclocondensation of 4a–d with 1,3-bis(silyloxy)-1,3-dienes 5a–i,
available from the corresponding 1,3-dicarbonyl compounds in
one or two steps,9 afforded the biaryls 6a–s (Scheme 2, Table 2).
During the optimization, it proved to be important to carry out
the reactions in a highly concentrated solution.14 The nature of
the aryl group of enones 4 does not seem to have a major influence
on the yield of the cyclization reactions. The best yields were ob-
tained for products 6a,h,l derived from non-substituted diene 5a.
Relatively low yields were obtained for biaryls 6d,g,k,o,s derived
Figure 1. Ortep plot of 6i (50% probability level).
from 5d, 5g, and 5h. Preliminary results show that 1,3-diketones
other than acetylacetone can be successfully employed in the
reactions.
Me3SiO OSiMe3
R3
The structure of 6i was independently confirmed by X-ray crys-
tal structure analysis (Fig. 1).15
R4
OH
O
R3
5a-i
Me3SiO
In conclusion, a variety of functionalized and sterically encum-
bered biaryls were prepared by combination of CuI-proline-cata-
lyzed arylations of 1,3-diketones and formal [3+3] cyclization
reactions. The products are not readily available by other methods.
The application of our methodology to the synthesis of 2,20,6-tri-
and 2,20,6,60-tetrasubstituted biaryls is currently being studied.
R4
O
Me
Me
i
Me
+
Me
R1
R1
R2
R2
4a-d
Acknowledgments
6a-s
Financial support from the State of Pakistan (HEC scholarship
for I.U.) and from the Friedrich-Irmgard-Harms-Stiftung (scholar-
ship for A.A.) is gratefully acknowledged.
Scheme 2. Synthesis of 6a–s. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢀ78?20 °C, 20 h.
References and notes
Table 2
Synthesis of biaryls 6a–s
1. Cynandiones A–C: (a) Lin, Y.-L.; Wu, Y.-M.; Kuo, Y.-H. Phytochemistry 1997, 45,
1057; (b) Huang, P.-L.; Won, S.-J.; Day, S.-H.; Lin, C.-N. Helv. Chim. Acta 1999, 82,
1716; (c) Lin, Y.-L.; Lin, T.-C.; Kuo, Y.-H. J. Nat. Prod. 1997, 60, 368; (d)
Buchanan, M. S.; Gill, M.; Yu, J. J. Chem. Soc., Perkin Trans. 1 1997, 919.
2. 2,3-Dihydroamentoflavone: (a) Das, B.; Mahender, G.; Rao, Y. K.; Prabhakar, A.;
Jagadeesh, B. Chem. Pharm. Bull. 2005, 53, 135. Bartramiaflavone: (b) Basile, A.;
Sorbo, S.; Lopez-Saez, J. A.; Cobianchi, R. C. Phytochemistry 2003, 62, 1145.
Robustaflavone: (c) Chen, J.-J.; Duh, C.-Y.; Chen, J.-F. Planta Med. 2005, 71, 659.
Dichamanetin: (d) Anam, E. M.; Ekpa, O. D.; Gariboldi, P. V.; Morah, F. N. I.;
Dosunmu, M. I. Indian J. Chem., Sect. B 1993, 32, 1051; (e) Dasgupta, B.; Burke, B.
A.; Stuartt, K. L. Phytochemistry 1981, 20, 153; (f) Zeng, G.-Z.; Tan, N.-H.; Hao,
X.-J.; Mu, Q.-Z.; Li, R.-T. Bioorg. Med. Chem. Lett. 2006, 16, 6178; (g) Zeng, G.-Z.;
Pan, X.-L.; Tan, N.-H.; Xiong, J.; Zhang, Y.-M. Eur. J. Med. Chem. Chim. Ther. 2006,
41, 1247.
4
5
6
R1
R2
R3
R4
% (6)a
a
a
a
a
a
a
a
b
b
b
b
c
c
c
c
d
d
d
d
a
b
c
d
e
f
g
a
b
c
h
a
b
c
h
a
i
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
Me
Me
CO2Et
CO2Et
CO2Et
CO2Et
H
H
H
Me
Bn
OMe
OEt
61
40
48
32
46
48
37
54
40
41
36
60
45
43
35
43
37
44
32
OMe
OMe
OMe
OMe
OMe
OMe
OEt
OMe
OMe
OMe
OEt
OMe
OMe
OMe
OEt
OMe
OMe
nHex
(CH2)2CH@CH2
Cl
H
H
Me
(CH2)2Ph
H
H
Me
(CH2)2Ph
H
3. Anastatin, A.; Yoshikawa, M.; Xu, F.; Morikawa, T.; Ninomiya, K.; Matsuda, H.
Bioorg. Med. Chem. Lett. 2003, 13, 1045.
4. (a) Tanoguchi, M.; Arimoto, M.; Saika, H.; Yamaguchi, H. Chem. Pharm. Bull.
1987, 35, 4162; (b) Plaumann, H. P.; Smith, J. G.; Rodrigo, R. J. Chem. Soc., Chem.
Commun. 1980, 354; (c) Wang, C.-L. J.; Ripka, W. C. J. Org. Chem. 1983, 48, 2555;
(d) Tuchinda, P.; Kumkao, A.; Pohmakotr, M.; Sophasan, S.; Santisuk, T.;
Reutrakul, V. Planta Med. 2006, 72, 60.
5. (a) Bringmann, G.; Dreyer, M.; Kopff, H.; Rischer, H.; Wohlfarth, M.; Hadi, H. A.;
Brun, R.; Meimberg, H.; Heubl, G. J. Nat. Prod. 2005, 68, 686; (b) Ponte-Sucre, A.;
Faber, J. H.; Guider, T.; Kajahn, I.; Pedersen, S. E. H.; Schultheis, M.; Bringmann,
G.; Moll, H. Antimicrob. Agents Chemother. 2007, 51, 188.
CF3
CF3
CF3
CF3
H
H
H
Me
f
g
(CH2)2CH@CH2
Cl
s
a
Isolated yields.

120
A. Ali et al. / Tetrahedron Letters 50 (2009) 118–120
6. Jayaprakasha, G. K.; Rao, L. J.; Sakariah, K. K. Bioorg. Med. Chem. 2004, 12, 5141.
7. Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 2004.
8. Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. R. J. Am. Chem. Soc.
2005, 127, 4685.
9. (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534; (b)
Brownbridge, P.; Chan, T.-H.; Brook, M. A.; Kang, G. J. Can. J. Chem. 1983, 61,
688.
10. Review of [3+3] cyclizations: Feist, H.; Langer, P. Synthesis 2007, 327.
11. Review of 1,3-bis(trimethylsilyloxy)-1,3-dienes: Langer, P. Synthesis 2002, 441.
12. For a review of copper-assisted nucleophilic substitution reactions of aryl
halides, see: (a) Lindley, J. Tetrahedron 1984, 40, 1433. For selected examples,
see: (b) Okuro, K.; Furuune, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58,
7606; (c) Wolter, M.; Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803.
13. Jiang, Y.; Wu, N.; Wu, H.; He, M. Synlett 2005, 2731.
14. Typical procedure: synthesis of methyl 4-hydroxy-2,6-dimethoxybiphenyl-3-
carboxylate (6a): To a CH2Cl2 solution (5 mL) of 5a (500 mg, 1.9 mmol) and
4a (474 mg, 1.9 mmol) was dropwise added TiCl4 (0.21 mL, 1.91 mmol) at
ꢀ78 °C. The reaction mixture was allowed to warm to 20 °C for 6–12 h. After
stirring for additional 2–6 h at 20 °C, a saturated aqueous solution of NaHCO3
(20 mL) was added. The organic and the aqueous layers were separated, and
the latter was extracted with diethyl ether (3 ꢁ 25 mL). The combined organic
layers were dried (Na2SO4), filtered, and the filtrate was concentrated in vacuo.
The residue was purified by chromatography (silica gel, heptanes/ethyl
acetate) to give 6a as a colorless solid (300 mg, 61%). 1H NMR (300 MHz,
CDCl3): d = 1.86 (s, 3H, CH3), 2.17 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 6.76 (s, 1H,
ArH), 7.04–7.41 (m, 5H, Ph), 11.01 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
d = 20.7, 24.0 (CH3), 51.97 (OCH3), 110.7 (C), 116.1, 126.7, 128.4, 128.7, 129.6,
~
131.0 (CHAr), 135.0, 138.4, 140.8, 143.9, 160.9, 172.2 (C); IR (KBr):
m ¼ 2953
(w), 1653 (s), 1597 (s), 1441 (s), 1353 (m), 1318 (s), 1228 (s), 1092 (m), 990
(w), 810 (m) 701 (s) cmꢀ1. EI-MS (EI, 70 eV): m/z (%) = 256 (M+, 45), 224 (100),
196 (18), 167 (6); HRMS (EI): calcd for C16H16O3 [M]+: 256.108773; found:
256.10940.
15. CCDC-706287 contains all crystallographic details of this publication which are
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.