Palladium-catalyzed direct intramolecular double α-C-H arylation of 1,5-diketone: A strategy for synthesis of Tro?ger's base analogues

Article abstract of DOI:10.1016/j.tetlet.2014.04.069

9-Aryl-2,3:6,7-dibenzobicyclo[3.3.1]nona-2,6-diene-4,8-diones were straightforwardly prepared via a tandem reaction of easily available ortho-chloroacetophenone and ortho-chlorochalcone catalyzed by PdCl ₂(PCy₃)₂.

Full text of DOI:10.1016/j.tetlet.2014.04.069

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed direct intramolecular double
a-C–H arylation
of 1,5-diketone: a strategy for synthesis of Tröger’s base analogues
Jia Ju a,b, Lei Zhang a, Ruimao Hua a,
⇑
a Department of Chemistry, Tsinghua University, Beijing 100084, China
b Institute of Chemical Materials, CAEP, Mianyang 621900, China
a r t i c l e i n f o
a b s t r a c t
Article history:
9-Aryl-2,3:6,7-dibenzobicyclo[3.3.1]nona-2,6-diene-4,8-diones were straightforwardly prepared via a
tandem reaction of easily available ortho-chloroacetophenone and ortho-chlorochalcone catalyzed by
PdCl2(PCy3)2.
Received 28 January 2014
Revised 14 April 2014
Accepted 17 April 2014
Available online xxxx
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
C–H arylation
C–Cl activation
1,5-Diketone
Palladium-catalyzed
Tröger’s base analogues
Tröger’s base (TB, Scheme 1) was first synthesized in 1887,1 and
its structure was finally confirmed in 1935.2 From the 1980s, stud-
ies on the design and synthesis of TB derivatives have been greatly
increased, and it was disclosed that these compounds due to their
unique structural features could be applied in many fields as chiral
reagents and ligands,3 molecular recognition,4 and supramolecular
chemistry.5 In addition, the synthesis and application of TB’s ana-
logues such as TB-C,6 TB-O,6 and TB-CO (2,3:6,7-dibenzobicy-
clo[3.3.1]nona-2,6-diene-4,8-dione)6,7 are also interesting to
organic chemists (Scheme 1). In particular, TB-CO has been well
studied since it can be easily modified via the transformation of
carbonyl groups by traditional reactions.7
N
R
R
R
N
O
O
R
R
R
O
Scheme 1. TB’s structure and examples of its analogue.
On the other hand, we have recently been interested in develop-
ment of high atom-economic reactions by using aryl chlorides as
reactants in the Sonogashira coupling,8 Heck coupling,9 and syn-
thesis of quinolines.10 Because palladium-catalyzed intramolecular
arylation of ketones has become a general synthetic method for the
synthesis of cyclic compounds,11 and in continuation of our inter-
est in the development of high atom-economic reaction using aryl
chloride as reaction partner, we examined the intramolecular dou-
4,8-dione (2a), to develop an efficient and simple procedure for
the synthesis of 9-substituted derivatives of TB-CO. Fortunately,
as shown in Eq. 1 the desired product was obtained in 47% isolated
yield,12 and its structure was confirmed by its spectroscopic data
and X-ray crystallography (Fig. 1).13
Encouraged by the initial results, we therefore designed a tan-
dem reaction of easily available ortho-chloroacetophenone and
ortho-chlorochalcone for the formation of 9-aryl-2,3:6,7-dibenzo-
bicyclo[3.3.1]nona-2,6-diene-4,8-diones involving the sequential
ble
a-arylation of 1,5-di(2-chlorophenyl)-3-phenyl-1,5-dione (1)
under the similar reaction conditions reported in our previous
report,9 with the purpose of establishing a simple synthetic route
to access 9-aryl-2,3:6,7-dibenzobicyclo[3.3.1]-nona-2,6-diene-
intermolecular Michael addition and intramolecular double
a-C–
H arylation in the presence of PdCl2(PCy3)2/Cs2CO3 as shown in
Scheme 2. Thus we studied the reaction of 20-chloroacetophenone
(3) with 1-(20-chlorophenyl)-3-phenylprop-2-en-1-one (4a) under
different conditions to optimize the reaction conditions for the for-
mation of 2a, and the obtained results are summarized in Table 1.
⇑
Corresponding author. Tel.: +86 10 62792596; fax: +86 10 62771149.
E-mail address: ruimao@mail.tsinghua.edu.cn (R. Hua).
http://dx.doi.org/10.1016/j.tetlet.2014.04.069
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Ju, J.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.069

2
J. Ju et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Pd(PPh3)4, and Pd2(dba)3 did not show any catalytic activity for
the formation of 2a (entries 7–10).
O
Cl
H
PdCl2(PCy3)2 (5 mol%)
Cs2CO3 (3.0 equiv)
O
Under the reaction conditions indicated in entry 1 of Table 1, we
then investigated the generality of the present procedure by the
reaction of 3 with ortho-chlorochalcone derivatives 4, and the
results concluded in Table 2 are disclosed: (1) The corresponding
diones 2 could be obtained in fair to moderate yields with the
use of various substituents on aryl rings in 4. (2) The reactions with
the use of 4 bearing either electron-donating groups (4b–d) or
electron-withdrawing groups (4f, 4i, and 4l) at para-position on
aryl rings afforded the corresponding products in moderate yields
(38–51%), and the cases at meta- (4e, 4j) or ortho-position (4k),
gave relatively low yields, probably due to steric hindrance. An
exception was the reaction of 4m, which has a cyano group at
para-position, but the yield of 2m was low, probably due to the
coordinative ability of the cyano group to obstruct the reaction;
(3) in the reaction of 4g and 4h, the former with the substituted
O
(1)
Ph
1,4-dioxane
120 oC, 24 h, N2
Ph
H
O
Cl
2a 47 %
1
O
O
Figure 1. X-ray structure of compound 2a.
position at b-position was significantly more reactive than at
a-
position. (4) The heterocyclic groups of thiophenyl (4n) and furyl
(4o) could be also introduced to the 9-position of 2 for further
transformation. The limit of the present catalytic reaction appears
to be the unsatisfactory yields of the desired diones 2, since the for-
mation of 2 requires a high selective process of intramolecular
Cl
H
O
O
Ar
Ar
Michael addition
O
O
+
H
Cl
Cl
Cl
double a-C–H arylation simultaneously.
O
intramolecular
double α−C-H
arylation
In addition, under the optimized conditions, the reactions of 3
with 4 bearing alkyl group such as 1-(20-chlorophenyl)-2-penten-
1-one (4p) and 1-(20-chlorophenyl)-4,4-dimethyl-2-penten-1-one
(4q), as well as 1-(20-chlorophenyl)propen-1-one (4r, without sub-
stituent) have also been examined. Unfortunately, the reactions did
not afford the corresponding desirable cyclic dione derivative 2 at
all. On the basis of GC and GC–MS analyses of the reaction mixture,
it was found that 3 and 4q were almost recovered, 4p was recov-
ered in 46%, and 4r was completely consumed. No by-product(s)
could be identified, and only small amount of acetophenone could
be confirmed resulting possibly from the dechlorination of 3.
Ar
HCl
HCl
O
Scheme 2. A strategy for the synthesis of Tröger’s base analogue.
Table 1
Optimizing the reaction conditionsa
O
O
O
Pd catalyst (5 mol%)
Cs2CO3 (3 equiv)
solvent, temp.
24 h, N2
Ph
+
Ph
2a
O
O
O
Cl
Cl
3
4a
O
Et
t-Bu
1.2 equiv
Cl
4p
Cl
4q
Cl
Entry
Catalyst
Solvent
Temp (°C)
Yieldb (%)
4r
1
2
3
4
5
6
7
8
9
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PCy3)2
PdCl2(PPh3)2
PdCl2
1,4-Dioxane
1,4-Dioxane
Toluene
THF
DMSO
120
100
120
120
120
120
120
120
120
120
45
<5
27
<5
0
0
0
0
0
In summary, we have developed a one-pot synthetic reaction to
construct 9-aryl-2,3:6,7-dibenzobicyclo[3.3.1]nona-2,6-diene-4,
8-diones via a palladium-catalyzed tandem reaction of ortho-
chloroacetophenone and ortho-chlorochalcone derivatives includ-
ing intermolecular Michael addition and intramolecular double
DMF
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
Pd(PPh3)4
Pd2(dba)3
10
0
a
Unless otherwise noted, reactions were carried out using 1.2 mmol of 3,
1.0 mmol of 4a, 0.05 mmol of catalyst, and 3.0 mmol of Cs2CO3 in 3.0 mL of solvent
under nitrogen atmosphere in a sealed tube for 24 h.
Table 2
b
Isolated yield is based on 4a.
The synthesis of 9-aryl-2,3:6,7-dibenzobicyclo[3.3.1]-nona-2,6-diene-4,8-diones
O
O
O
PdCl2(PCy3)2 (5 mol%)
Cs2CO3 (3.0 equiv)
When
a mixture of 3 (1.2 mmol), 4a (1.0 mmol), Cs2CO3
Ar
Ar
+
(3.0 mmol), and PdCl2(PCy3)2 (0.05 mmol) in 1,4-dioxane (3.0 mL)
in a sealed tube was heated at 120 °C with stirring under nitrogen
atmosphere for 24 h, 2a was isolated from the reaction mixture in
45% yield (entry 1), accompanied with the formation of dechlori-
nated by-products of starting materials. Decreasing the reaction
temperature to 100 °C resulted in a very low yield of the desired
product (entry 2). The screening of solvents disclosed that when
the reaction was carried out in toluene, 2a was isolated in 27%
yield (entry 3), and however, the use of THF, DMSO, and DMF
resulted in a very low yield or no formation of 2a (entries 4–6).
In addition, other palladium catalysts such as PdCl2(PPh3)2, PdCl2,
1,4-dioxane
Cl
120 oC, 24 h, N2
Cl
3
4
O
2
1.2 mmol
1.0 mmol
Ar
Yield (%)
Ar
Yield (%)
p-Tolyl 4b
p-tBuC6H4 4c
2b
2c
2d
2e
2f
43
43
38
23
36
48
14
p-FC6H4 4i
m-FC6H4 4j
o-FC6H4 4k
p-F3CC6H4
p-NCC6H4 4m
2-Thiophenyl 4n
2-Furyl 4o
2i
2j
2k
2l
51
35
26
41
10
22
20
p-MeOC6H4 4d
m-MeOC6H4 4e
p-PhC6H4 4f
2-Naphthyl 4g
1-Naphthyl 4h
4
2m
2n
2o
2g
2h
Please cite this article in press as: Ju, J.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.069

J. Ju et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
a-C–H arylation. Although the yields of products remain to be
Supplementary data
improved, the present method provides an alternative, efficient,
and simple procedure for the synthesis of 9-substituted derivatives
of TB-CO compared to traditional methods which often need long
synthetic steps and harsh reaction conditions. Also the synthesized
9-substituted derivatives of TB-CO (polycyclic diones) have high
potential application in supramolecular chemistry via further
transformation.
Supplementary data (general method, characterization data,
charts of 1H, 13C NMR for all products, and the data of X-ray crystal
structure of 2a) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2014.04.069.
References and notes
A typical experimental procedure (Table 1, entry 1): a mixture
of 20-chloroacetophenone (3) (185.0 mg, 1.2 mmol), 1-(20-chloro-
phenyl)-3-phenylprop-2-en-1-one (242.0 mg, 1.0 mmol) (4a),
PdCl2(PCy3)2 (36.8 mg, 0.05 mmol), and Cs2CO3 (977.5 mg,
3.0 mmol) in 1,4-dioxane (3 mL) in a thick-walled screw-capped
Pyrex tube was heated with stirring at 120 °C (oil bath tempera-
ture) for 24 h under nitrogen atmosphere. After the reaction mix-
ture was cooled to room temperature, CH2Cl2 (5.0 mL) was
added, and the GCMS analysis was performed. After removal of vol-
atiles under reduced pressure, the residue was subjected to column
chromatography isolation (silica gel, eluted with a mixture solvent
of petroleum ether and ethyl acetate (50:1)) to give 2a as a yellow
solid (145.9 mg, 0.45 mmol, 45%). Data for 2a: yellow solid, mp
170–172 °C; 1H NMR (300 MHz, CDCl3) d 7.91 (1H, d, J = 7.9 Hz),
7.75 (1H, d, J = 7.9 Hz), 7.45–7.37 (3H, m), 7.36–7.33 (2H, m),
7.29–7.23 (2H, m), 7.12–7.08 (4H, m), 4.32 (2H, s), 4.25 (1H, s);
13C NMR (75 MHz, CDCl3) d 194.4, 193.8, 140.5, 139.1, 137.3,
135.2, 134.7, 129.4, 129.1, 128.9, 128.9, 128.8, 128.7, 128.6,
127.7, 127.3, 127.2, 54.4, 54.3, 46.3; GC–MS m/z (% rel inten.)
324 (M+, 94), 281 (36), 253 (30), 207 (100), 73 (84); IR (neat)
1. Tröger, J. J. Prakt. Chem. 1887, 36, 225–245.
2. Spielman, M. A. J. Am. Chem. Soc. 1935, 57, 583–585.
3. Selected reports, see: (a) Wilen, S. H.; Qi, J. Z.; Willard, P. G. J. Org. Chem. 1991,
56, 485–487; (b) Harmata, M.; Kahraman, M. Tetrahedron: Asymmetry 2000, 11,
2875–2879; (c) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006, 39, 221–229;
(d) Harmata, M.; Rayanil, K.-O.; Barnes, C. L. Supramol. Chem. 2006, 18, 581–
586.
4. (a) Goswami, S.; Ghosh, K. Tetrahedron Lett. 1997, 38, 4503–4506; (b) Goswami,
S.; Ghosh, K.; Dasgupta, S. J. Org. Chem. 2000, 65, 1907–1914.
5. Selected reviews, see: (a) Valík, M.; Strongin, R. M.; Král, V. Supramol. Chem.
2005, 17, 347–367; (b) Sergeyev, S. Helv. Chim. Acta 2009, 92, 415–444.
6. Turner, J. J.; Harding, M. M. Supramol. Chem. 2005, 17, 369–375.
7. Selected reports, see: (a) Tatemitsu, H.; Ogura, F.; Nakagawa, Y.; Nakagawa, M.;
Naemura, K.; Nakazaki, M. Bull. Chem. Soc. Jpn. 1975, 48, 2473–2483; (b) Try, A.
C.; Painter, L.; Harding, M. M. Tetrahedron Lett. 1998, 39, 9809–9812; (c)
Kimber, M. C.; Try, A. C.; Painter, L.; Harding, M. M.; Turner, P. J. Org. Chem.
2000, 65, 3042–3046; (d) Field, J. D.; Turner, P.; Harding, M. M.; Hatzikominos,
T.; Kim, L. New J. Chem. 2002, 26, 720–725; (e) Muthyala, R. S.; Carlson, K. E.;
Katzenellenbogen, J. A. Bioorg. Med. Chem. Lett. 2003, 13, 4485–4488; (f)
Stoncius, S.; Orentas, E.; Butkus, E.; Öhrström, L.; Wendt, O. F.; Wärnmark, K. J.
Am. Chem. Soc. 2006, 128, 8272–8285.
8. (a) Yi, C.; Hua, R. J. Org. Chem. 2006, 71, 2535–2537; (b) Yi, C.; Hua, R. Adv. Synth.
Catal. 2007, 349, 1738–1742.
9. Yi, C.; Hua, R. Tetrahedron Lett. 2006, 47, 2573–2576.
10. Qi, C.; Zheng, Q.; Hua, R. Tetrahedron 2009, 65, 1316–1320.
11. Selected reports, see: (a) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997, 38,
7581–7582; (b) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402–3415; (c)
Honda, T.; Namiki, H.; Satoh, F. Org. Lett. 2001, 3, 631–633; (d) Gaertzen, O.;
Buchwald, S. L. J. Org. Chem. 2002, 67, 465–475; (e) MacKay, J. A.; Bishop, R. L.;
Rawal, V. H. Org. Lett. 2005, 7, 3421–3424; (f) Khartulyari, A. S.; Maier, M. E.
Eur. J. Org. Chem. 2007, 317–324; (g) Marsden, S. P.; Watson, E. L.; Raw, S. A.
Org. Lett. 2008, 10, 2905–2908.
1691, 1678 cmꢀ1 CO); HRMS (ESI) calcd for C23H17O2 [M+H]+:
(m
325.1223, found: 325.1223.
Acknowledgments
This project was supported by the National Natural Science
Foundation of China (21032004, 20972084), the Specialized
Research Fund for the Doctoral Program of Higher Education
(20110002110051), and the Bilateral Scientific Cooperation
between Tsinghua University & K.U. Leuven.
12. It should be noted that when aryl bromides or aryl iodides were used, the
desirable product 2 could not be obtained. The main side-reaction is the
intramolecular Heck coupling reaction of 4.
13. Crystals for X-ray diffraction analysis were obtained by recrystallization from a
mixture of CH2Cl2 and cyclohexane. CCDC 936765 contains supplementary
crystallographic data for compound 2a.
Please cite this article in press as: Ju, J.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.069