Palladium-Catalyzed Cascade Arene/Alkyne Annulation: Synthesis of Fluorene-Benzoxazine Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b02224

A palladium-catalyzed cascade arene/alkyne annulation reaction for the synthesis of fluorene-benzoxazine derivatives is developed. This transformation involves a 6-exo-dig cyclization, a 1,3-oxazine vinylpalladium intermediate, and a C-H bond activation.

Full text of DOI:10.1021/acs.orglett.6b02224

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Cascade Arene/Alkyne Annulation: Synthesis of
Fluorene-Benzoxazine Derivatives
Zhong-Jian Cai, Fang-Hui Li, Shun-Yi Wang,* and Shun-Jun Ji*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science &
Collaborative Innovation Center of Suzhou Nano Science and Technology, Soochow University, Suzhou 215123, China
S
* Supporting Information
ABSTRACT: A palladium-catalyzed cascade arene/alkyne annulation reaction for the
synthesis of fluorene-benzoxazine derivatives is developed. This transformation
involves a 6-exo-dig cyclization, a 1,3-oxazine vinylpalladium intermediate, and a C−
H bond activation.
he design and characterization of polycyclic aromatic
hydrocarbons (PAHs) has been studied intensively in the
inhibitors, and C1r serine protease inhibitors (Figure 1).17
Several synthetic procedures to build benzoxazine derivatives,
which suffer from limitations, such as low yield, bad
regioselectivity, and/or harsh reaction conditions, were
T
fields of electrochemistry, photochemistry, and functional
materials science since the PAHs exhibit excellent stability,
enhanced ability to transport charge, and superior fluorescent
properties in the solid state.1 Fluorene is one of most important
PAHs since it could be extensively applied to the manufacture of
advanced materials2 and used as effective ligands3 and unique
protecting groups.4 Fluorene also could be employed in the
pharmaceutical industry.5−7 For example, it could be used as an
anti-inflammatory agent,5 a cyclophilin A inhibitor,6 and a
cholesterol acyltransferase (ACAT) inhibitor (Figure 1).7
reported.18 Recently, Saito, Novak
́
, Zeni, and Wang et al.
reported several efficient strategies to synthesize substituted
benzoxazines through palladium-, iron-, copper-, or iodine-
catalyzed/mediated regioselective 6-exo-dig cyclization of o-
ethynylanilides.19 Moreover, the tandem radical reaction strategy
was employed in the manufacturing of CF3-containing and SCN-
containing benzoxazines, respectively.20 To the best of our
knowledge, the direct and efficient methodology for the
construction of fluorene-benzoxazines has not been developed.
Devising novel transition-metal-catalyzed hydroarylation of
alkynes via direct C−H bond functionalization that achieves the
construction of multiple bonds in one step is a significant
challenge in modern organic synthesis.21 Such domino processes
avoid prefunctionalization, as well as protection−deprotection
steps, which represent a more environmentally friendly and
economic strategy for construction of polycyclic aromatic
hydrocarbons (PAHs).22 In 2000, a palladium-catalyzed intra-
molecular hydroarylation of alkynes through 6-endo-dig cycliza-
tion of electron-rich aromatic rings was first reported by
Fujiwara’s group.23 Afterward, it was found that some other
transition metals24 and Lewis acids25 can promote this
transformation successfully (Scheme 1, eq 1). A Friedel−
Crafts-type electrophilic aromatic substitution mechanism is
generally accepted for this transformation. In contrast,
Gevorgyan and co-workers report the first example of C−H
bond activation/annulations of electron-neutral and -deficient
ortho-alkynyl biaryls via a 5-exo-dig cyclization (Scheme 1, eq
2).26 Shortly afterward, the arene/alkyne annulation via C−H
bond activation has been exploited to construct various
privileged polycyclic aromatic hydrocarbons (PAHs) effec-
tively.27 Recently, Jin and co-workers reported a novel and
efficient palladium-catalyzed dual C−H bond activation/
Figure 1. Fluorene and benzoxazine derivatives.
Hence, efficient synthetic methods leading to functionalized
fluorenes are expected to assist the rapid developments of
fluorene-based functional molecules.8 Generally, the fluorene
derivatives could be obtained via Brønsted or Lewis acid
promoted Friedel−Crafts-type reactions.9 Recently, transition-
metal-catalyzed direct C−H bond activation,10 diazo insertion,11
cation rearrangement reaction,12 and radical reaction13 have
emerged as efficient tools for the construction of fluorene
derivatives. Benzoxazine derivatives are an important branch of
N-heterocycles and play increasingly crucial roles in the area of
medicinal science over the past decades because of their distinct
biological and pharmaceutical activities such as fungicidal, anti-
inflammatory, and anticonvulsant activities.14 They are also
confirmed as the progesterone receptor modulators,15 DNA-
binding antitumor agents,16 human leukocyte elastase (HLE)
Received: July 27, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02224
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Organic Letters
Letter
a
Scheme 1. Hydroarylation of Alkynes
Table 1. Optimization of the Reaction Conditions
b
entry
cat. (equiv)
oxidant
yield
44
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
Pd(OAc)2 (0.1)
BQ (0.5 equiv) + O2
O2
23
28
36
BQ (0.5 equiv) + Ar
BQ (0.5 equiv) + air
Ar
NR
46
BQ (1.0 equiv) + O2
BQ (2.0 equiv) + O2
BQ (3.0 equiv) + O2
BQ (2.0 equiv) + O2
67
63
c
90 (86)
a
Reaction conditions: 1a (0.5 mmol), cat. (0.05 mmol), and oxidant as
b
indicated; solvent (2.0 mL) was stirred at 40 °C for 12 h. The yields
were determined by LC analysis using biphenyl as the internal
c
standard. The reaction was stirred at 60 °C with Pd(OAc)2 (0.025
mmol) for 6 h, followed by addition of Pd(OAc)2 (0.025 mmol) and
stirring at 60 °C for another 6 h.
annulation of bisbiaryl alkynes for construction of important and
useful 9,9′-bifluorenylidene (9, 9′BF) and its derivatives
(Scheme 1, eq 3). The unexpected mechanistic evidence
indicates an unusual mechanism that the reaction proceeds
through dual C−H bond activation followed by an annulation
with a C−C triple bond; it is distinct from the previously
reported hydroarylation.28 As a continuation of our ongoing
effort toward development of fluorene derivatives and
benzoxazine derivatives, as well as direct C−H functionaliza-
tion,29 we report herein a novel palladium-catalyzed hydro-
arylation of alkynes via direct C−H bond functionalization for
the first synthesis of fluorene-benzoxazine derivatives (Scheme 1,
eq 4).
Table 2. Substrate Scope for Palladium-Catalyzed Cascade
a
Arene/Alkyne Annulation
At the outset of this study, the cascade coupling reaction of
ortho-alkynyl biaryl 1a was carried out in DMSO (2 mL), at 40
°C, using a catalytic amount of Pd(OAc)2 as the promoter and
0.5 equiv of BQ (benzoquinone) with oxygen as a combined
oxidant system. To our delight, the desired fluorene-benzoxazine
2a was formed in 44% LC-yield. To improve the yield, various Pd
catalysts, solvents, and oxidants were screened (for details, see
Supporting Information). The desired fluorene-benzoxazine 2a
was formed in a lower yield when the reaction was carried out in
the presence of O2 without BQ (Table 1, entry 2). Similar low
yields were obtained when the reaction was operated under an Ar
or air atmosphere (Table 1, entries 3−4). Not surprisingly, no
desired fluorene-benzoxazine 2a was detected when the reaction
was carried out without BQ and O2 (Table 1, entry 5). An
improvement in reaction yield was obtained when the amount of
BQ was increased to 1.0, 2.0, and 3.0 equiv, thus giving the
desired fluorene-benzoxazine 2a in 46%, 67%, and 63% yield,
respectively (Table 1, entries 6−8). Gratifyingly, the desired
fluorene-benzoxazine 2a was obtained in 90% LC-yield (86%
isolated yield) when the reaction temprature was increased to 60
°C and the 10 mol % Pd(OAc)2 was added twice (Table 1, entry
9).
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (0.05 mmol), BQ (1.0
mmol), and DMSO (2 mL), O2 (1 atm). The reaction was stirred at
60 °C with Pd(OAc)2 (0.025 mmol) for 6 h, followed by addition of
Pd(OAc)2 (0.025 mmol) and stirring at 60 °C for another 6 h.
biaryl led to an efficient reaction which generated 2e in 73%
isolated yield. Moreover, methyl substituents at the para, meta,
and ortho position of the biphenyl ring afford the desired
fluorene-benzoxazines 2f−h in good yields.
Next, we set out to explore the scope of this tandem reaction
by employing differently substituted ortho-ethynylanilides as
shown in Table 3. It is found that the desired fluorene-
benzoxazines could be obtained in good yields when the methyl,
ethyl, methoxy, and chlorine substituted benzamides were
applied to this reaction (2i−n, 71−88%). Meanwhile, the N,
Having established the optimized reaction conditions, the
scope of this domino reaction was explored by varying the
substituents (R1) on the biphenyl ring (Table 2). Replacing the
substituent of the biphenyl ring with halogen groups, such as
fluorine and chlorine, resulted in a good yield of 2b, 2c, and 2d,
respectively. Luckily, a single crystal of 2b was cultivated, and the
structure of 2b was further confirmed by single-crystal X-ray
analysis. As expected, the presence of an electron-rich substituent
B
DOI: 10.1021/acs.orglett.6b02224
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the basis of these observations, a plausible mechanism for
the palladium-catalyzed cascade arene/alkyne annulation is
illustrated in Scheme 3. The Pd(OAc)2 activated alkyne π-
Table 3. Substrate Scope for Palladium-Catalyzed Cascade
Arene/Alkyne Annulation
a
Scheme 3. A Plausible Mechanism
a
Reaction conditions: 1 (0.5 mmol), Pd(OAc)2 (0.05 mmol), BQ (1.0
mmol), DMSO (2 mL), O2 (1 atm). The reaction was stirred at 60 °C
with Pd(OAc)2 (0.025 mmol) for 6 h, followed by addition of
Pd(OAc)2 (0.025 mmol) and stirring at 60 °C for another 6 h.
bond is attacked by the carbonyl oxygen to afford 1,3-oxazine
vinylpalladium species A via a 6-exo-dig cyclization. The C−H
bond activation occurred to provide a six-membered palladacycle
B. The desired fluorene-benzoxazine 2a was formed through a
reductive elimination of B. Meanwhile, the Pd(II) species are
regenerated from oxidation of the Pd(0) species by BQ and O2 to
start a new catalytic cycle.
In summary, we have developed a novel and straightforward
method for the first synthesis of fluorene-benzoxazine derivatives
through the palladium-catalyzed cascade arene/alkyne annula-
tion. Kinetic isotope effect studies and control experiments seem
to converge on a description that this transformation involves a 6-
exo-dig cyclization, a 1,3-oxazine vinylpalladium intermediate,
and a C−H bond activation. The domino reaction is operation-
ally simple, is compatible with a broad substrate scopes, and
represents an efficient, step- and atom-economic way for the
construction of scarcely known fluorene-benzoxazine derivatives.
N-dimethylamino and trifluoromethyl-substituted ortho-ethyny-
lanilide could proceed smoothly and generate the desired
products 2o and 2p in 35% and 32% yield, respectively. Notably,
the reaction could smoothly convert into the fluorene-
benzoxazine derivatives in moderate yields when 2-naphthamide,
cinnamamide, and thiophene-2-carboxamide were used (2q−s,
34−61%). Furthermore, an acceptable yield (70%) was obtained
when pivaloyl-substituted ortho-ethynylanilide was subjected to
the reaction (2t).
Interestingly, an unexpected product spiro[fluorene-quino-
lin]-4′-one 2a′ was obtained when fluorene-benzoxazine 2a was
treated with EtOH under reflux conditions, and the structure of
2a′ was unambiguously confirmed based on single-crystal X-ray
analysis (Scheme 2). The fluorene-benzoxazine 2a may undergo
Scheme 2. Construction of Spiro[fluorene-quinolin]-4′-one
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02224.
Crystal structure data for 2b (CIF)
Crystal structure data for 2a′ (CIF)
Detailed experimental procedures and characterization
data (PDF)
an addition of imine with EtOH, a ring-opening-closing reaction.
Further investigations to understand the mechanism of this
reaction are ongoing in our laboratory.
To gather further insight into the palladium-catalyzed arene/
alkyne annulation, kinetic isotope effect studies were performed
under the standard conditions (for more details, see the
Supporting Information). An intramolecular isotope effect of
KH/KD = 1.94 was obtained for the hydroarylation of alkyne.
This, together with the significant intermolecular KIE (KH/KD =
2.57), implies the C−H bond cleavage occurs during the rate-
determining step.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: shunyi@suda.edu.cn.
*E-mail: shunjun@suda.edu.cn.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b02224
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Organic Letters
Letter
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ACKNOWLEDGMENTS
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We gratefully acknowledge the Natural Science Foundation of
China (21372174, 21542015), PAPD, the Major Basic Research
Project of the Natural Science Foundation of the Jiangsu Higher
Education Institutions (No. 16KJA150002), and Soochow
University for financial support, and State and Local Joint
Engineering Laboratory for Novel Functional Polymeric
Materials.
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