Palladium(II)-Catalyzed C-H Bond Activation/C-C Coupling/Intramolecular Tsuji-Trost Reaction Cascade: Facile Access to 2 H -Pyranonaphthoquinones

Article abstract of DOI:10.1021/acs.orglett.5b01304

An efficient one-pot synthesis of 2H-pyranonaphthoquinone was achieved via a palladium-catalyzed C-H bond activation/C-C bond formation/intramolecular Tsuji-Trost reaction cascade. The unprecedented procedure exhibits excellent functional group tolerance, giving the target naphthoquinones in moderate to good isolated yields (40-88%) under mild reaction conditions. Scalable production of the product can make this reaction a method of choice for the synthesis of 2H-pyranonaphthoquinones.

Full text of DOI:10.1021/acs.orglett.5b01304

Letter
pubs.acs.org/OrgLett
Palladium(II)-Catalyzed C−H Bond Activation/C−C Coupling/
Intramolecular Tsuji−Trost Reaction Cascade: Facile Access to
2H‑Pyranonaphthoquinones
Jinlei Bian,† Xue Qian,† Nan Wang,† Tong Mu,† Xiang Li,† Haopeng Sun,† Lianshan Zhang,‡
Qidong You,*,†,§ and Xiaojin Zhang*,†,∥
†Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China
‡National Engineering and Research Center for Target Drugs, Lianyungang, 222000, China
§State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
∥Department of Organic Chemistry, School of Science, China Pharmaceutical University, Nanjing 210009, China
S
* Supporting Information
ABSTRACT: An efficient one-pot synthesis of 2H-pyrano-
naphthoquinone was achieved via a palladium-catalyzed C−H
bond activation/C−C bond formation/intramolecular Tsuji−
Trost reaction cascade. The unprecedented procedure exhibits
excellent functional group tolerance, giving the target
naphthoquinones in moderate to good isolated yields (40−
88%) under mild reaction conditions. Scalable production of the product can make this reaction a method of choice for the
synthesis of 2H-pyranonaphthoquinones.
2H-Pyranonaphthoquinone is a special class of quinone-
containing compounds with important biological activities,
including anti-inflammatory, antitumor, and antimicrobial
activity.1 Many compounds of this class are found in natural
products such as α-xiloidone (1a), 7-methyldehydro-α-
lapachone (2), α-caryopterone (3), and pyranokunthone B
(4) (Figure 1).2 In general, these 2H-pyranonaphthoquinones
has emerged as a powerful tool for chemical synthesis.5 This
synthetic strategy is attractive from the viewpoint of synthetic
simplicity and step economy. Much progress has been achieved
in terms of synthesis efficiency and atom economy in the highly
selective functionalization of C−H bonds involving directing
substituents.6,7 In addition, Pd-catalyzed Tsuji−Trost allylic
substitution reactions are widely employed for constructing C−
O, C−C, C−N, and C−S bonds.8 Recently, the notion of
combining several metal-mediated processes in relay-type
domino sequences has drawn particular attention.9 Therefore,
in this context, we were attracted to developing a tandem
palladium-catalyzed synthesis of 2H-pyranonaphthoquinones
through a C−H/C−H coupling and sequential intramolecular
C−O bond formation with an exceptionally mild protocol.
We initially investigated the reaction conditions for 2-
hydroxy-1,4-naphthoquinone (5a) and tert-butyl-(2-methylbut-
3-en-2-yl) carbonate (6a) as model substrates. When 5a was
treated with 6a in the presence of Pd(OAc)2, the oxidant
Cu(OAc)2, and the base NaOAc in DMF at room temperature
for 3 h, the desired natural product 1a was gratifyingly obtained
in 43% yield (Table 1, entry 1). The effect of temperature was
first optimized, and the yield was substantially increased by
raising the temperature to 45 °C (entries 2−3). We then turned
toward examining the effect of solvent, and THF was found to
be the best one for this reaction among the tested solvents
(entries 4−8). When the model reaction was performed in the
presence of Pd(OAc)2 (10.0 mol %), THF as solvent at 45 °C
Figure 1. Examples of natural 2H-pyranonaphthoquinones.
are obtained in small quantities from plant extracts.3 Therefore,
much effort has been devoted to their synthesis, and
considerable advances have been developed over the past
several decades.4 However, the present methods for the
synthesis of these compounds are very limited, and in view of
minimizing the waste/side product formation in 2H-pyrano-
naphthoquinone synthesis, the search for an additional efficient
synthesis protocol is necessary.
During the past several decades, palladium-catalyzed
functionalization of C−H activation/C−C bond formation
Received: May 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01304
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Organic Letters
Letter
a
ab
,
Table 1. Reaction Optimization
Scheme 1. Substrate Scope of Naphthoquinones
temp
b
entry
cat.
Pd(OAc)2
oxidant
solvent
(°C)
yield
1
2
3
4
5
Cu(OAc)2 DMF
Cu(OAc)2 DMF
Cu(OAc)2 DMF
Cu(OAc)2 dioxane
25
35
45
45
45
43
48
55
44
35
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2 dioxane/
H2O
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Cu(OAc)2 toluene
Cu(OAc)2 THF
Cu(OAc)2 AcOH
45
45
45
45
45
45
45
45
45
45
45
45
trace
82
7
8
60
9
Na2S2O8
AgOAc
BQ
THF
THF
THF
THF
32
10
11
12
13
14
15
16
17
trace
NR
20
AgNO3
c
Cu(OAc)2 THF
Cu(OAc)2 THF
Cu(OAc)2 THF
Cu(OAc)2 THF
Cu(OAc)2 THF
45
trace
trace
trace
Pd(TFA)2
Pd(dba)2
d
Pd(OAc)2
(5.0 mol %)
70
a
Reaction conditions: 5 (0.50 mmol), 6a (2.5 mmol, 5.0 equiv),
a
Reaction conditions: 5a (0.50 mmol), 6a (2.5 mmol, 5.0 equiv), Pd
catalyst (10.0 mol %), oxidant (2.0 equiv), and base (2.0 equiv) in
Pd(OAc)2 (10.0 mol %), Cu(OAc)2 (2.0 equiv), and NaOAc (2.0
equiv) in THF (15 mL) for 3 h under air. Isolated yield. The
reaction was carried out at 60 °C.
b
c
b
c
solvent (15 mL) for 3 h under air. Isolated yield. Under nitrogen.
d
10 h. NR = No reaction.
(DNQ),10,11 which were supposed to be effective anticancer
drugs (Figure S2).
To further expand the substrate scope, we next turned our
attention toward testing the feasibility of the replacement of 6a
(Scheme 2). Different olefinic alcohol derivatives reacted well
for 3 h, Cu(OAc)2 is the most effective common oxidant
among Na2S2O8, AgOAc, BQ (1,4-benzoquinone), and AgNO3
(entries 9−12). Conducting the reaction under a nitrogen
atmosphere (balloon) decreased the isolated yield sharply to
45% (entry 13). In addition, when Pd(OAc)2 was replaced by
PdCl2, Pd(TFA)2, and Pd(dba)2, poor results were observed
(entries 14−16). Lowering the catalyst loading from 10.0 to 5.0
mol % was unfavorable, and no reaction was observed in the
absence of the catalyst (entry 17). Therefore, we concluded
that the optimized reaction conditions consist of Pd(OAc)2
(10.0 mol %), Cu(OAc)2 (2 equiv), NaOAc (2 equiv), and
THF (solvent) at 45 °C for 3 h under air.
Scheme 2. Substrate Scope of Olefinic Alcohol
a b
,
Derivatives
With the optimized reaction conditions in hand, other
naphthoquinones were systematically screened. As shown in
Scheme 1, a relatively broad range of naphthoquinone
derivatives with substituents at the C5, C6, or C7 position of
the naphthoquinone ring were successfully transformed to
desired products in moderate to good yields. The electronic
nature has a slight influence on the reaction outcome. For
example, the electron-rich groups such as −CH3 and −OCH3
substituted naphthoquinones were tolerated in this trans-
formation, providing the desired products 1b−1f in 40−84%
yields. Of particular note, 5-methoxy naphthoquinone showed
inferior reactivity compared to the corresponding 6- or 7-
methoxy naphthoquinone, and a higher temperature (60 °C)
was required. In addition, the electron-withdrawing substituted
naphthoquinones also showed good reactivity and gave good
yields. To our interest, the nitrogen-containing heteroaromatic
substrate also gave the cyclization product 1k in 45% yield. This
compound could be regarded as the merged molecule for two
natural products α-xiloidone and deoxynyboquinone
a
Reaction conditions: 5 (0.50 mmol), 6 (2.5 mmol, 5.0 equiv),
Pd(OAc)2 (10.0 mol %), Cu(OAc)2 (2.0 equiv), and NaOAc (2.0
equiv) in THF (15 mL) for 3 h under air. Isolated yield.
b
with naphthoquinones and generated the corresponding
products in 58−82% yields (1a, 1l−q). As shown in Scheme
2, the Pd(OAc)2 catalyst allowed the coupling of 6c with
naphthoquinones bearing electron-donating, electron-neutral,
and electron-withdrawing groups at the naphthoquinone ring to
produce 1n−q in 58−71% yields. To demonstrate the
practicability of the method, the model procedure was
successfully scaled up with comparable yield. The natural
B
DOI: 10.1021/acs.orglett.5b01304
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
product 1a (1.78 g, 74%) was prepared when the reaction was
run in 10 mmol scale (Scheme 3).
the alkoxide and the palladium acetate gives the complex B,
which then formed the anionic species C. Next, Pd(II)
catalyzed the C−H bond activation at the 3-position carbon
atom of C assisted by the hydroxyl group to afford a C3-
palladated species D, which was further followed by the
migratory alkene insertion to form species E. Subsequently, the
obtained E underwent β-H elimination to afford the product F
and Pd(0) species. The Pd(0) can catalyze the formation of the
π-allylpalladium complex as a cationic species with inversion of
configuration, leading to the formation of the alkoxide.12
Meanwhile, the removal of the Boc protecting group would be
conducted simultaneously in the presence of Pd(0), forming
the intermediate H. Then, the nucleophile alkoxide attacked the
backside of the coordinated π-allyl giving the target compound
1a and Pd(0) catalyst, which is reoxidized by 2 equiv of
Cu(OAc)2 to regenerate the Pd(II) catalyst to complete the
catalytic cycle. The mechanism provided a rational explanation
for the generation of compounds 8 and 9 in the control
experiment (Scheme 4a).
Scheme 3. Scale-up Experiment
To gain insight into the reaction mechanism, we conducted
some additional control experiments (Scheme 4). When
Scheme 4. Control Experiments
In conclusion, we have developed a simple, mild, and scalable
strategy for the preparation of 2H-pyranonaphthoquinones
through a one-pot Pd-catalyzed reaction. This transformation
includes C−H insertion, C−C bond formation, and an
intramolecular Tsuji−Trost reaction successively in one pot.
Scalable production of the product can make this reaction a
method of choice for the synthesis of 2H-pyranonaphtho-
quinones. Further investigations into the mechanism and
applications of this reaction are currently underway in our
laboratory.
substrate 5a and 5 equiv of 3-methyl-1-butene (7) were
subjected to the standard conditions, the reaction was found to
be stagnated at the stage of C−H/C−H coupling to produce
the products 8 and 9 (Scheme 4a). In addition, when the
hydroxyl group in the model substrate (5a) was protected with
methyl group, the reaction would fail to conduct a C−H/C−H
coupling reaction (Scheme 4b). From all these control
experiments it is speculated that the reaction proceeds through
a C−H bond activation/C−C bond formation/intramolecular
Tsuji−Trost reaction cascade in the presence of the hydroxyl
group.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01304.
AUTHOR INFORMATION
Corresponding Authors
■
A possible catalytic cycle for these reactions, employing
model substrates 5a and 6a for illustrative purposes, is shown in
Scheme 5 based on these experiments. The first step is the
formation of the complex A as a sodium salt. Exchange between
*E-mail: zxj@cpu.edu.cn.
*E-mail: youqd@163.com.
Notes
Scheme 5. Possible Mechanism for Reactions
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are thankful for the financial support of the National
Natural Science Foundation of China (No. 81302636), the
Natural Science Foundation of Jiangsu Province of China (No.
BK20130656), the Program of State Key Laboratory of Natural
Medicines, China Pharmaceutical University (No.
SKLNMZZ201202), and the Priority Academic Program
Development of Jiangsu Higher Education Institutions
(PAPD).
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DOI: 10.1021/acs.orglett.5b01304
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