Tandem Dehydrogenation/Oxidation/Oxidative Cyclization Approach to Wrightiadione and Its Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b01618

Wrightiadione contains a unique tetracyclic isoflavone moiety and has been shown to exhibit a broad range of biological activities. An efficient and straightforward synthetic method for generating the molecular complexity of wrightiadione was developed th

Full text of DOI:10.1021/acs.orglett.5b01618

Letter
pubs.acs.org/OrgLett
Tandem Dehydrogenation/Oxidation/Oxidative Cyclization
Approach to Wrightiadione and Its Derivatives
Yujeong Jeong,†,‡ Youngtaek Moon,†,‡ and Sungwoo Hong*,‡,†
†Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 305-701, Korea
‡Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 305-701, Korea
S
* Supporting Information
ABSTRACT: Wrightiadione contains a unique tetracyclic
isoflavone moiety and has been shown to exhibit a broad
range of biological activities. An efficient and straightforward
synthetic method for generating the molecular complexity of
wrightiadione was developed through three-step tandem
dehydrogenation/oxidation/oxidative cyclization reactions with
a Pd/Cu catalytic system. This unprecedented one-pot route
utilizes a broad range of substrates, providing a convenient and powerful synthetic tool for accessing naturally occurring
tetracyclic isoflavone wrightiadione and its nitrogen-containing derivatives.
intermediate 4, and then (iii) subsequent Pd-catalyzed oxidative
rightiadione (1a), isolated from dried bark of Wrightia
Wtomentosa is a unique tetracyclic isoflavone used cyclization via direct intramolecular C−C bond formation of 4.
The starting materials, 2-benzyl-substituted chromanones or
enaminones 2, can be readily prepared by 1,4-addition of
chromones using various organocuprates.3b The design of
tandem processes can provide an opportunity for the direct
construction of molecular complexity from simple starting
materials. In addition, one-pot procedures are synthetically and
environmentally advantageous for carrying out sequential
catalytic operations in a single reaction vessel, thereby reducing
synthesis time, undesired waste, and costs.4,5 Therefore, we were
interested in exploring one-pot sequential transformations that
would enable facile synthesis of wrightiadione scaffolds by
tandem catalysis. Herein, we present the first example of a
tandem dehydrogenation/oxidation/oxidative cyclization proc-
ess from readily available 2-benzylchromanones or dihydroqui-
nolinones, which provides an efficient and straightforward
protocol for the preparation of the tetracyclic isoflavones and
their nitrogen-containing derivatives.
medicinally in Thailand. This natural product exhibits a broad
range of biological activities, including cytotoxicity against
leukemia cell lines.1 Consequently, the development of efficient
methods for the synthesis of the wrightiadione scaffold is a topic
of considerable importance.2 Driven by the need for a more
efficient synthetic route to wrightiadione derivatives, we were
particularly interested in exploring an efficient, one-pot approach
starting from simple starting materials such as readily available
chromones and enaminones.3a
The transformations could be achieved via a multistep
sequence (Scheme 1): (i) Pd-catalyzed dehydrogenation of 2-
benzyl-substituted ketones 2 to α,β-unsaturated system 3, (ii)
Cu-catalyzed oxidation of the C−C bond at the γ-position of the
α,β-unsaturated carbonyl system of 3 to afford the ketone
Scheme 1. Approach to Wrightiadione Scaffold Involving
Tandem Dehydrogenation/Oxidation/Oxidative Cyclization
In line with our hypothesis, we studied the feasibility of each
step of the tandem process to determine the most compatible
conditions. We initially explored the possibility of applying our
recently reported Pd-catalyzed dehydrogenation reaction to this
process.6 Because Pd(II) catalyst, which promotes the
dehydrogenation of saturated ketones,7−9 could also be used to
catalyze oxidative C−C bond formation, it seems to be feasible to
conduct both types of reactions as one-pot reactions. We also
speculated that the intermediates 3 generated in situ from
Pd(II)-catalyzed dehydrogenation of 2 might undergo further
copper-catalyzed oxidation of the benzylic C−H bond with
molecular oxygen10−12 because of the increased acidity of the
Received: May 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01618
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Letter
resulting methylene γ-hydrogens of the α,β-enolone system. In
the overall tandem process, Cu(II) was employed not only as the
oxidative trigger to regenerate Pd(0) to Pd(II) but also as a
catalyst to promote the oxidation of the benzylic C−H bond.
To test the feasibility of converting intermediate 3 to the
ketone intermediate 4, our efforts began by exploring possible
conditions for selective oxidation of enaminone 3a. Recent
advances in Cu-catalyzed oxidation provide useful starting points
for our investigation of reactions.12 Because the dehydrogenation
event is highly solvent dependent, enaminone 3a was subjected
to the various reaction conditions in pivalic acid.6a To our delight,
pivalic acid was found to be the optimal solvent in the oxidation
step. Among the Cu species screened, Cu(OAc)2 under 1 atm of
O2 was most effective, allowing the isolation of ketone
intermediate 4a in 65% yield (Table 1). Further screening
Table 2. Studies for Pd(II)-Catalyzed Intramolecular
Oxidative Coupling
a
b
entry cat. (10 mol %) additive (equiv) oxidant (equiv) yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NaOAc (0.5)
NaOAc (0.5)
NaOAc (0.5)
NaOAc (0.5)
NaOAc (0.5)
AlCl3 (3)
Ag2O (1.5)
AgOAc (1.5)
Ag2CO3 (1.5)
AgTFA (1.5)
Ag2O (1.5)
Ag2O (1.5)
86
76
75
68
0
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
12
53
35
Ag2O (1.5)
Ag2O (1.5)
Table 1. Cu-Catalyzed Oxidation
c
NaOAc (0.5)
a
Reaction conditions: 4a (0.05 mmol), Pd(OAc)2 (10 mol %),
Cu(OAc)2 (3 equiv), Ag2O (1.5 equiv), NaOAc (0.5 equiv), PivOH
b
(0.5 mL) under O at 120 °C for 8 h, Schlenk flask. 1H NMR yield.
c
Without Cu(OAc)2.
a
b
Table 3. Optimized Studies for Pd(II)-Catalyzed Tandem
Dehydrogenation/Oxidation/Oxidative Cyclization
Reactions of β-Substituted Cyclic Ketone
entry
Cu (5 mol %)
additive (equiv)
NaOAc (0.5)
yield (%)
1
2
3
4
5
6
7
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuI
65
85
79
69
80
75
84
a
Ag2O (1.5)
NaOAc (0.5)
CuBr2
NaOAc (0.5)
CuCl2
NaOAc (0.5)
Cu(OAc)2
NaOAc (0.5)/Ag2O (1.5)
b
a
entry
Cu (equiv)
Ag (equiv)
Ag2O (1.5)
base (equiv) yield (%) (4a/5a)
Reaction conditions: 3a (0.05 mmol), Cu (5 mol %), additive in
b
PivOH (0.5 mL) under O2 at 120 °C for 8 h. 1H NMR yield.
1
2
3
4
5
6
Cu(OAc)2 (3)
Cu(OAc)2 (3)
64 (40:60)
NaOAc (0.5)
NaOAc (0.5)
NaOAc (2)
61 (66:34)
7 (100:0)
60 (3:97)
60 (31:69)
78 (14:86)
83 (10:90)
70 (12:88)
Ag2O (1.5)
Ag2O (1.5)
Ag2O (1.5)
Ag2O (1.5)
Ag2O (1.5)
Ag2O (1.5)
studies revealed that the optimal result could be obtained with
the addition of NaOAc (0.5 equiv), producing 4a in the highest
yield (85%). NaOAc appears to facilitate the reaction by
removing a proton generated in the process of radical formation.
Next, we investigated direct intramolecular C−C bond
formation through Pd-catalyzed oxidative cyclization of the
resulting ketone intermediate 4a.13,14 After surveying some
potential catalytic systems, we found that the combination of
Pd(OAc)2, Cu(OAc)2, and NaOAc in PivOH, which were
employed in either the dehydrogenation or oxidation steps,
could enable the intramolecular oxidative coupling reaction, but
with only 15% yield of the desired product 5a. Further screening
studies revealed that the optimal result could be obtained with
the addition of Ag2O, indicating the important role of Ag2O in
the oxidative coupling reaction (Table 2, entry 1).13 Other silver
sources were less effective in this reaction (entries 2−4). Under
the optimized reaction conditions, the oxidative cyclization of 4a
proceeded to provide the best yield of 86%. Notably, control
experiments verified that no reaction occurred without Pd
catalyst, which indicated that Lewis acid catalyzed Nazarov-type
cyclization was unlikely to be operative in this system (entries 5
and 6).
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
Cu(OAc)2 (3)
CsOAc (2)
NaOAc (0.5)
NaOAc (0.5)
NaOAc (0.5)
c
7
d
8
a
Reaction conditions: 2a (0.05 mmol), Cu(OAc)2 (3 equiv), catalyst
(20 mol %), base, Ag2O (1.5 equiv) in PivOH (0.5 mL) under O2 at
b
c
120 °C for 8 h. 1H NMR yield. t-BuOAc/PivOH = 1:10 (v/v).
d
Pd(OAc)2 (10 mol %).
predicted, optimization studies disclosed that the addition of
Ag2O was crucial for cyclizing the resulting intermediate 4a. The
solvent choice was also crucial, and other solvents including
acetic acid, trifluoroacetic acid, or organic solvent were less
effective. Among the bases screened, NaOAc (0.5 equiv) was
most effective in this process in terms of overall conversion
(entry 7). Notably, a lower isolated yield of product was obtained
with increased amounts of NaOAc, although the 4a/5a mixture
ratio was improved up to 3:97 (entry 4). The reaction of
substrate 2a was found to best proceed with the use of a tBuOAc/
PivOH (1:9 v/v) cosolvent system.
Encouraged by the above results, we next evaluated the
potential of the proposed tandem process by investigating the
reactivity of 2-benzyl-1-methyl-2,3-dihydroquinolin-4(1H)-one
(2a) as a model substrate for optimization (Table 3). After much
experimentation, we were pleased to find that the desired
product 5a was formed with the combined catalytic systems,
proving that the tandem process was indeed operating. As
To get more mechanistic insight, the overall tandem process of
2a was monitored under the standard reaction conditions
(Figure 1). Approximately 50% of intermediate 3a was produced
within 30 min and then disappeared quickly with concomitant
appearance of ketone 4a and tetracyclic product 5a, indicating
the intermediacy of 3a. Tetracyclic product 5a was observed after
the ketone intermediate 4a was produced, indicating Cu-
B
DOI: 10.1021/acs.orglett.5b01618
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Scheme 3. Substrate Scope of Tandem Dehydrogenation/
a
Oxidation/Oxidative Cyclization Reactions
Figure 1. Reaction profile of tandem process.
catalyzed oxidation is faster than Pd-catalyzed intramolecular
oxidative coupling of 3a.
On the basis of our observations, a mechanistic proposal for
the tandem process is outlined in Scheme 2. First, the enol form
Scheme 2. Proposed Mechanistic Pathways Underlying the
Present One-Pot Catalysis
of 2 is coordinated to Pd(II), followed by H-abstraction to
provide Pd(II) enolate I. Intermediate 3, generated by β-hydride
elimination, is oxidized with a copper catalyst and molecular
oxygen to afford the ketone intermediate 4. Next, the six-
membered palladacycle II is expected to be formed by initial
ortho-C−H bond activation of intermediate 4 via a concerted
metalation−deprotonation (CMD) process and subsequent
intramolecular C−H bond cleavage at the C3-position.13 In the
process, other mechanistic possibility involving initial electro-
philic palladation at the C3-position can also be conceived.15
Subsequent reductive elimination produces the desired product,
and oxidation of Pd(0) species to Pd(II) species completes the
catalytic cycle.
a
Reaction conditions: 2 (0.1−0.2 mmol), Pd(OAc)2 (20 mol %),
Cu(OAc)2 (3 equiv), Ag2O (1.5 equiv), NaOAc (0.5 equiv), PivOH (1
mL), O2, 120 °C, 8−24 h, Schlenk flask; isolated yields. t-BuOAc/
PivOH = 1:10 (v/v).
b
substituents including phenyl, benzyl, and ethyl formate groups
were all tolerable under the reaction conditions to afford the
desired products in modest to good yields (5n−q). In addition,
expanding the scope from dihydroquinolinones to a chromanone
system was also possible, giving rise to wrightiadione (1a) and its
derivatives (1b−e). The use of a tBuOAc/PivOH (1:9) cosolvent
system did not influence the efficiency of the reaction in most of
substrates, except 2a, 2o, and 2p. A mixture of isomers was
observed for substrates bearing a meta-substituent, and intra-
molecular oxidative coupling occurred at the more sterically
accessible C−H bond of the aryl group, thereby leading to the
The optimal conditions were then applied to a variety of
substrates to test the utility of the new method (Scheme 3). The
tetracyclic scaffold could be easily equipped with an additional
substituent, such as an alkyl, methoxy, hydroxyl, trifluoromethyl,
or chloro group, by this tandem catalytic process. A variety of N-
C
DOI: 10.1021/acs.orglett.5b01618
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Organic Letters
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure and characterization of new compounds
(1H and 13C NMR spectra). The Supporting Information is
available free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b01618.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hongorg@kaist.ac.kr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported financially by Institute for Basic
Science (IBS-R010-G1).
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