Efficient synthesis of dibenzo[a,c]cyclohepten-5-ones via a sequential Suzuki-Miyaura coupling and aldol condensation reaction

Article abstract of DOI:10.1021/jo900508z

(Chemical Equation Presented) A common strategy for the synthesis of a 7-membered-ring system with a Suzuki-Miyaura coupling followed by an acid/base-promoted intramolecular aldol condensation reaction has been developed. The reaction of 2′-bromoacetophen

Full text of DOI:10.1021/jo900508z

Efficient Synthesis of
Dibenzo[a,c]cyclohepten-5-ones via a Sequential
Suzuki-Miyaura Coupling and Aldol
Condensation Reaction
Young Lok Choi,†,‡ Chan-Mo Yu,‡ Bum Tae Kim,† and
Jung-Nyoung Heo*,†
Bioorganic Science DiVision, Korea Research Institute of
Chemical Technology, Daejeon 305-600, Republic of Korea,
and Department of Chemistry, Sungkyunkwan UniVersity,
Suwon 440-746, Republic of Korea
heojn@krict.re.kr
ReceiVed March 07, 2009
FIGURE 1. Colchicine, allocolchicine analogues, metasequirine B, and
dibenzo[a,c]cyclohepten-5-one framework.
7-membered ring is generally known to play an important role
in both stereochemistry and bioactivity. Various approaches
toward the synthesis of allocolchicine analogues have been
developed, including the transformation of natural colchicines,4
the ring expansion of phenanthrene derivatives,5 Diels-Alder
reactions,6 nonphenolic or phenolic biaryl oxidative couplings,7
direct arylations,8 and Nicolas reactions.9 From a synthetic point
of view, dibenzo[a,c]cyclohepten-5-one 7 represents a key
intermediate en route to numerous allocolchicine analogues.
Among the routes, a C-C coupling reaction followed by an
aldol condensation would be the most attractive if high catalytic
activities were realized.
At the outset of our studies, Leonard and co-workers at
AstraZeneca had already published an elegant total synthesis
of ZD6126 (5) that employed an Ullmann biaryl coupling
reaction and aldol condensation sequence for the assembly of
the cycloheptenone core.10 Kocienski’s group subsequently
reported an enantioselective route to (-)-N-acetylcolchinol (3)
that exploited a Suzuki-Miyaura coupling reaction/aldol con-
densation sequence for the construction of the 7-membered-
A common strategy for the synthesis of a 7-membered-ring
system with a Suzuki-Miyaura coupling followed by an
acid/base-promoted intramolecular aldol condensation reac-
tion has been developed. The reaction of 2′-bromoacetophe-
nones with 2-formylphenylboronic acids in the presence of
Pd(OAc)2 and CataCXium PIntB L8 efficiently provided
biaryl compounds, which were transformed to a wide array
of dibenzo[a,c]cyclohepten-5-ones in excellent yields by a
sequential treatment with p-TsOH, followed by 10% aq
NaOH.
Colchicine (1), allocolchicine analogues (2-5), and metase-
quirine B (6) attract synthetic and medicinal chemists due to
their remarkably unique structural features and interesting
bioactive properties (Figure 1).1,2 Of note, N-acetylcolchinol (3)
and its prodrug ZD 6126 (5) exhibit highly potent anticancer
effects via inhibition of tubulin polymerization.3 The central
(4) (a) Nicholls, G. A.; Tarbell, D. S. J. Am. Chem. Soc. 1953, 75, 1104–
1107. (b) Cech, J.; Santavy, F. Collect. Czech. Chem. Commun. 1949, 4, 532–
539. (c) Santavy, F. HelV. Chim. Acta 1948, 31, 821–826. (d) Fernholz, H. Liebigs
Ann. Chem. 1950, 568, 63–72.
(5) Seganish, W. M.; DeShong, P. Org. Lett. 2006, 8, 3951–3954.
(6) (a) Boyer, F.-D.; Hanna, I. Org. Lett. 2007, 9, 715–718. (b) Vorogushin,
A. V.; Predeus, A. V.; Wulff, W. D.; Hansen, H.-J. J. Org. Chem. 2003, 68,
5826–5831.
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4842. (b) Wu, T. R.; Chong, J. M. Org. Lett. 2006, 8, 15–18. (c) Besong, G.;
Jarowicki, K.; Kocienski, P. J.; Sliwinski, E.; Boyle, F. T. Org. Biomol. Chem.
2006, 4, 2193–2207.
(8) Leblanc, M.; Fagnou, K. Org. Lett. 2005, 7, 2849–2852.
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(10) (a) Broady, S. D.; Golden, M. D.; Leonard, J.; Muir, J. C.; Maudet, M.
Tetrahedron Lett. 2007, 48, 4627–4630. (b) Lennon, I. C.; Ramsden, J. A.; Brear,
C. J.; Broady, S. D.; Muir, J. C. Tetrahedron Lett. 2007, 48, 4623–4626.
(11) Besong, G.; Billen, D.; Dager, I.; Kocienski, P.; Sliwinski, E.; Tai, L. R.;
Boyle, F. T. Tetrahedron 2008, 64, 4700–4710.
† Korea Research Institute of Chemical Technology.
‡ Sungkyunkwan University.
(1) For reviews, see: (a) Capraro, H. G.; Brossi; A. In The Alkaloids; Brossi,
A., Ed.; Academic Press: Orlando, FL, 1984; Vol. 23, Chapter 1. (b) Boyé, O.;
Brossi, A. In The Alkaloids; Brossi, A.; Cordell, G. A., Eds.; Academic Press:
San Diego, CA, 1992; Vol. 41, p 125. (c) Graening, T.; Schmalz, H.-G. Angew.
Chem., Int. Ed. 2004, 43, 3230–3256.
(2) (a) Sancéau, J.-Y.; Dhal, R.; Brown, E. Tetrahedron 1994, 50, 3363–
3380. (b) Sancéau, J.-Y.; Dhal, R.; Brown, E. Nat. Prod. Lett. 1992, 1, 221–
224.
(3) (a) Davis, P. D.; Dougherty, G. J.; Blakey, D. C.; Galbraith, S. M.; Tozer,
G. M.; Holder, A. L.; Naylor, M. A.; Nolan, J.; Stratford, M. R. L.; Chaplin,
D. J.; Hill, S. A. Cancer Res. 2002, 62, 7247–7253. (b) Boyé, O.; Brossi, A.;
Yeh, H. J. C.; Hamel, E.; Wegrzynski, B.; Toome, V. Can. J. Chem. 1992, 70,
1237–1249.
3948 J. Org. Chem. 2009, 74, 3948–3951
10.1021/jo900508z CCC: $40.75 2009 American Chemical Society
Published on Web 04/08/2009

SCHEME 1. Direct One-Pot Synthesis of
Dibenzo[a,c]cyclohepten-5-one
TABLE 1. Optimization of a Catalytic System for the
Suzuki-Miyaura Coupling Reactiona
FIGURE 2. Ligand effect on the Suzuki-Miyaura coupling reaction.
entry
Pd
ligand
base
KF
K3PO4
CsF
solvents time (h) yield (%)b
We first examined the Suzuki-Miyaura coupling reaction at
room temperature, following the procedure described by Buch-
wald et al.15 The results are illustrated in Table 1. The coupling
of aryl bromide 8a with boronic acid 9a in the presence of
JohnPhos L1 and KF in THF proceeded in 92% yield (entry
1). In contrast, coupling between 10 and 11 was fruitless in
giving biaryl 12a. With K3PO4 or CsF as a base, the couplings
were less effective and provided 12a in 84% or 81% yield,
respectively (entries 2 and 3). Surprisingly, the use of Cs2CO3
appeared to inhibit catalytic turnover (entry 4). Variations on
the palladium source (Pd(PPh3)4, PdCl2, Pd2(dba)3) gave inferior
yields, even with longer reaction times (entries 5-7). Changing
the solvent to dioxane led to the formation of 12a in 87% yield
(entry 8). After screening a variety of ligands16 while maintain-
ing the best combinations of reaction conditions (Pd(OAc)2, KF,
and THF), we found that only ligand L2 proved to be effective,
furnishing 12a in acceptable yield (entry 9). It is particularly
noteworthy that ligands L1 and L2, only possessing a di-tert-
butyl phosphinyl group, readily facilitate the Suzuki-Miyaura
coupling reaction, suggesting that the high catalytic activity may
result from their ability to inhibit the formation of palladacycles.
With this result in mind, we next examined a broad range of
Buchwald’s biaryl phosphine ligands L1-L5 and Beller’s
heteroarylphosphine ligands L6-L8, all bearing the di-tert-butyl
phosphine group (Figure 2). In the reaction of 8a with 9a (eq
1), all ligands provided 12a in excellent yields. For further
optimization of the ligand, the coupling of less reactive partners
such as aryl halide 8b and 9b was carried out (eq 2). As shown
in Figure 2, among the ligands tested (L1, L5, L7, and L8),
CataCXium PIntB L8 proved to be the most effective.17 We
believe that the efficacy of coupling reactions with ligand L8
depends not only on the steric bulkiness but also on the electron
richness. For example, ligands possessing the tert-butyl group
led to the best results, while cyclohexyl-substituted phosphine
ligands gave no or little desired coupling product.18
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
PdCl2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
L1
L1
L1
L1
L1
L1
L1
L1
L2
THF
THF
THF
2
2
2
92
84
81
0
Cs2CO3 THF
2
KF
KF
KF
KF
KF
THF
THF
THF
dioxane
THF
24
24
24
2
16
36
70
87
65
2
a Reaction conditions: 8a (0.5 mmol), 9a (0.75 mmol, 1.5 equiv), Pd
(2.0 mol %), base (1.5 mmol, 3 equiv), ligand (4.0 mol %), solvent (1.5
mL), rt. b Isolated yield.
ring moiety.11 However, the need remains for the development
of novel catalytic systems that enhance the reaction yields while
maintaining rapid access to a wide range of derivatives.
As part of our ongoing research into the chemistry of
polycycles, we recently reported a direct, one-pot method for
the synthesis of phenanthrenes via a Suzuki-Miyaura coupling/
aldol condensation cascade.12 In addition, the application of this
method to pharmacologically important aristolactam analogues
was explored.13 Herein, we have extended the scope of this
protocol to include the more formidable 7-membered-ring
systems, such as dibenzo[a,c]cyclohepten-5-one.
In the first instance, we employed a standard one-pot protocol,
which was explored by our laboratory.12,13 Initial attempts at
the one-pot reaction of bromoacetophenone 8a with formyl-
phenylboronic acid 9a were unsuccessful (Scheme 1). Alter-
natively, switching the coupling partners to aryl bromide 11
and boronic acid 10 led to the formation of the desired product,
7a, in 57% yield. With this promising result in hand, we
underwent considerable efforts to find a suitable catalytic system
for the one-pot Suzuki-Miyaura coupling/aldol condensation
reaction cascade. We, however, were faced with the inefficacy
of the one-pot procedure. At that point, we believed that the
challenge lie in the Suzuki-Miyaura coupling reaction, due to
the presence of the less tolerant o-acetyl moiety, presumably
via formation of a stable palladacyclic structure.14 Consequently,
our attention was turned to the stepwise reaction such that
relatively milder reaction conditions could be applied.
(12) Kim, Y. H.; Lee, H.; Kim, Y. J.; Kim, B. T.; Heo, J.-N. J. Org. Chem.
2008, 73, 495–501.
(13) Kim, J. K.; Kim, Y. H.; Nam, H. T.; Kim, B. T.; Heo, J.-N. Org. Lett.
2008, 10, 3543–3546.
Having established suitable conditions, the scope and limita-
tions of this protocol were explored. The results are summarized
(14) Cámpora, J.; Maya, C. M.; Palma, P.; Carmona, E.; Gutiérrez, E.; Ruiz,
C.; Graiff, C.; Tiripicchio, A. Chem. Eur. J. 2005, 11, 6889–6904.
(15) Wolfe, J. P.; Singer, R. A.; Yang, B. H.; Buchwald, S. L. J. Am. Chem.
Soc. 1999, 121, 9550–9561.
J. Org. Chem. Vol. 74, No. 10, 2009 3949

TABLE 2. Synthesis of Biaryl Keto-Aldehydesa
TABLE 4.
Synthesis of Dibenzo[a,c]cyclohepten-5-onesa
a Reaction conditions: 8 (0.5 mmol), 9 (0.75 mmol, 1.5 equiv),
Pd(OAc)2 (2.0 mol %), KF (1.5 mmol, 3 equiv), L8 (4.0 mol %), THF
(1.5 mL), rt. b Isolated yield. c Isolated yield of 13i. d The reaction was
run at 80 °C.
TABLE 3. Optimization of Intramolecular Aldol Condensation
Reaction
yield
entry
1
conditions
(%)a
trace
Cs2CO3 (3 equiv), toluene/EtOH ) 2:1,
microwave 150 °C, 10 min
2
3
4
5
p-TsONa (“old”, 20 mol %, pH 10.38c),
H2O/EtOH ) 1:1, 70 °C, 2 h
p-TsONa (“new”, 20 mol %, pH 9.00c),
H2O/EtOH ) 1:1, 70 °C, 24 h
p-TsNa (20 mol %), H2O/EtOH ) 1:1, 70
°C, 24 h
87
NRb
NRb
94
(i) p-TsOH (20 mol %), H2O/EtOH ) 1:1,
1 min, and then (ii) 10% NaOH (40 mol
%), 70 °C, 10 min
6
7
premixed p-TsOH (20 mol %) and 10%
NaOH (40 mol %), H2O/EtOH ) 1:1, 70
°C, 1 h
10% NaOH (40 mol %), H2O/EtOH ) 1:1,
70 °C, 1 h
70
65
a Isolated yield. b No reaction. c pH value measured by a pH meter.
in Table 2. Couplings of 8a with a wide variety of o-
formylarylboronic acids 9a,c-g smoothly proceeded to give the
corresponding biaryl products 12a,c-g, regardless of the nature
of substituents on the aryl ring (entries 1 and 3-7). Heteroaryl-
a Reaction conditions: 12 (0.45 mmol), p-TsOH (20 mol %), H2O/
EtOH ) 1 mL:1 mL, rt, 1 min, and then 10% aq NaOH (40 mol %), 70
°C, 10 min. b Isolated yield.
boronic acids 9h-j also proved feasible, leading to the
heteroaryl-aryl systems 12h-j in reasonable to good yields
(16) Other ligands (DavePhos, S-Phos, X-Phos, rac-BINAP, DPPF, DPEphos,
and 2-(dicyclohexylphosphino)biphenyl) provided no or little desired product.
3950 J. Org. Chem. Vol. 74, No. 10, 2009

(entries 8-10). Interestingly, in the case of 9i, the desired
product 12i was obtained in only 34% yield, along with an
advanced aldol intermediate 13i in 21% yield (entry 9). Reaction
of the p-methoxy-substituted acetophenone 8b proved difficult,
presumably because of an increase in the electron density at
the acetyl moiety favoring formation of the palladacycle.
However, simply employing a longer reaction time afforded the
desired products in good to excellent yields (entries 2, 11, and
12). When using p-fluoro-substituted acetophenone 8c as the
substrate, as expected, the reaction provided the coupling
products in excellent yields (entries 13-16). In addition, the
doubly deactivated substrate 8d was also effective and afforded
12q in 96% yield,2 simply by heating the mixture at 80 °C for
1 h (entry 17).
Our next goal was the cyclization of biaryl keto-aldehydes
via an aldol condensation under typical base-promoted condi-
tions. However, it turned out to be difficult to obtain a
satisfactory yield in this reaction. Following the literature
method,19 the addition of sodium p-toluenesulfonate led to the
formation of the aldol adduct in high yield. During optimization
of reaction conditions, however, a lack of reproducibility was
observed. Through careful scrutiny as illustrated in Table 3,
we realized that “old” sodium p-toluenesulfonate (which had
been stored on a benchtop for quite a long period and changed
to wet solid) afforded the desired product, whereas the “new”
one provided no desired product (entry 2 vs. entry 3).20 With
sodium p-toluenesulfinate, no reaction was observed (entry 4).
After a screening of a variety of conditions, we were pleased
to find that the sequential treatment of keto-aldehyde 12a with
p-TsOH (20 mol %) and then 10% aq NaOH solution (40 mol
%) at 70 °C for 10 min furnished the dibenzo[a,c]cyclohepten-
5-one 7a in 94% yield (entry 5). In this case, we reasoned that
each of the aldol counterparts would be first activated by acid,
and then dehydration of intermediate 13a would be promoted
by base.
affording the 7-membered-ring systems (7h-j) in a range of
91-93% yields (entries 8-10).
In summary, we have developed an efficient catalytic system
for the synthesis of dibenzo[a,c]cyclohepten-5-ones via a
Suzuki-Miyaura coupling in the presence of Pd(OAc)2 and
CataCXium PIntB L8, followed by an acid/base-promoted
intramolecualr aldol condensation. Further study is now in
progress for applications of this protocol toward the total
synthesis of natural products as well as pharmaceuticals.
Experimental Section
General Procedure for the Suzuki-Miyaura Coupling
Reaction. Acetophenone 8 (0.5 mmol), boronic acid 9 (0.75 mmol),
Pd(OAc)2 (2.2 mg, 2.0 mol %), KF (87 mg, 1.5 mmol), and L8
(6.7 mg, 4.0 mol %) were sequentially added to an oven-dried
microwave vial. The mixture was suspended in THF (1.5 mL) and
stirred for 2 h at rt. The reaction mixture was directly purified by
silica gel column chromatography (10% EtOAc/hexanes) to provide
the corresponding biaryl keto-aldehyde 12. Data for 12b: 1H NMR
(300 MHz, CDCl3) δ 9.65 (s, 1H), 7.83 (d, 1H, J ) 8.7 Hz), 7.51
(s, 1H), 7.00 (dd, 1H, J ) 8.7, 2.6 Hz), 6.78 (d, 1H, J ) 2.6 Hz),
6.69 (s, 1H), 3.99 (s, 3H), 3.92 (s, 3H), 3.88 (s, 3H), 2.21 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 199.1, 190.1, 161.4, 153.4, 149.0,
140.4, 139.5, 132.2, 131.6, 127.1, 117.8, 112.2, 108.5, 56.3, 56.1,
55.6, 29.3; HRMS (EI) calcd for C18H18O5 [M+] 314.1157, found
314.1157.
General Procedure for the Intramolecular Aldol
Condensation. To a solution of biaryl keto-aldehyde 12 (0.446
mmol) in H2O/EtOH (1 mL/1 mL) was added p-TsOH (17 mg,
0.089 mmol). The mixture was stirred at room temperature for 1
min, and then 10% aq NaOH solution (71 mg, 0.178 mmol) was
added. After being stirred at 70 °C for 10 min, the resulting mixture
was cooled to rt and diluted with water (10 mL). The aqueous layer
was extracted with EtOAc (3 × 10 mL). The combined organic
extracts were washed with brine, dried over MgSO4, and concen-
trated in vacuo. The residue was purified by silica gel column
chromatography (10% EtOAc/hexanes) to provide dibenzo[a,c]cy-
1
clohepten-5-one 7. Data for 7b: H NMR (300 MHz, CDCl3) δ
Finally, biaryl keto-aldehydes can be further elaborated to
dibenzo[a,c]cyclohepten-5-ones by using an acid/base-promoted
intramolecualr aldol condensation. The results are illustrated in
Table 4. All substrates possessing electron-donating or electron-
withdrawing groups efficiently proceeded to provide the cor-
responding aldol adducts in excellent yields. It is notable that
heteroaryl-aryl compounds 12h-j also proved effective in
8.03 (d, 1H, J ) 8.8 Hz), 7.35 (s, 1H), 7.34 (d, 1H, J ) 3.9 Hz),
7.25 (d, 1H, J ) 12.2 Hz), 7.11 (dd, 1H, J ) 8.9, 2.4 Hz), 6.98 (s,
1H), 6.60 (d, 1H, J ) 12.2 Hz), 4.02 (s, 3H), 3.99 (s, 3H), 3.95 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 190.7, 161.8, 149.8, 149.0,
139.1, 139.0, 134.5, 132.1, 131.8, 131.6, 127.5, 114.9, 113.5, 113.4,
113.3, 56.2, 56.1, 55.5; HRMS (EI) calcd for C18H16O4 [M+]
296.1049, found 296.1045.
Acknowledgment. We thank the KRICT and the Center for
Biological Modulators, Korea (KN-0807), for financial support.
(17) (a) Rataboul, F.; Zapf, A.; Jackstell, R.; Harkal, S.; Riermeier, T.;
Monsees, A.; Dingerdissen, U.; Beller, M. Chem. Eur. J. 2004, 10, 2983–2990.
(b) Zapf, A.; Jackstell, R.; Rataboul, F.; Riermeier, T.; Monsees, A.; Fuhrmann,
C.; Shaikh, N.; Dingerdissen, U.; Beller, M. Chem. Commun. 2004, 38–39.
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(19) Verma, A. K.; Koul, S.; Pannu, A. P. S.; Razdan, T. K. Tetrahedron
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(20) On the basis of the observed pH values, we reasoned that the increased
basic strength of the “old” p-TsONa (pH 10.38) would more facilitate the aldol
condensation compared with the “new” one (pH 9.00). For 1H NMR comparison,
see the Supporting Information.
Supporting Information Available: Detailed experimental
procedures, characterization data, and NMR spectra of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO900508Z
J. Org. Chem. Vol. 74, No. 10, 2009 3951