Synthesis of cyclopentadienyl alkyl ethers via Pd-catalyzed cyclotrimerization of diarylacetylenes

Article abstract of DOI:10.1039/c3ra41326h

A novel efficient tandem cyclization-methoxylation reaction has been developed to synthesize cyclopentadienyl alkyl ethers via palladium-catalyzed trimerization of diarylethynes and elimination of one dimethoxymethyl benzene molecule. The reaction mechanism was investigated by the Q-Tof APCI-HRMS technique, and the fluorescent properties of the obtained compounds were studied in the solid state and in solution.

Full text of DOI:10.1039/c3ra41326h

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Synthesis of cyclopentadienyl alkyl ethers via Pd-
catalyzed cyclotrimerization of diarylacetylenes3
Cite this: DOI: 10.1039/c3ra41326h
Ranran Cai,a Mengmeng Huang,*a Xiuling Cui,a Jianye Zhang,a Chenxia Du,a
Yusheng Wub and Yangjie Wu*a
Received 19th March 2013,
Accepted 19th June 2013
DOI: 10.1039/c3ra41326h
www.rsc.org/advances
A novel efficient tandem cyclization–methoxylation reaction has
been developed to synthesize cyclopentadienyl alkyl ethers via
palladium-catalyzed trimerization of diarylethynes and elimina-
tion of one dimethoxymethyl benzene molecule. The reaction
mechanism was investigated by the Q-Tof APCI-HRMS technique,
and the fluorescent properties of the obtained compounds were
studied in the solid state and in solution.
Herein, we report an efficient tandem cyclization–methoxyla-
tion reaction to access cyclopentadienyl alkyl ethers via palladium-
catalyzed trimerization of diarylethynes. The reaction mechanism
is proposed based on Q-Tof APCI-HRMS results. To the best of our
knowledge, it is the first example of generating cyclopentadienyl
alkyl ethers through trimerization of diarylethynes via palladium-
catalyzed reaction under mild conditions.
Initially, the cyclization of diphenylethyne was chosen as a
model reaction to screen the reaction conditions (Table 1). This
reaction proceeded in the presence of 2 mol% Pd(OAc)2 to give
the product 3a in 77% yield and 4a in 11% yield without any
additives (Table 1, entry 1). The oxidant played an important role
in the formation of 3a (Table 1, entries 1–5). Benzoquinone and
Cu(OAc)2 led to a lower yield of the desired product 3a (Table 1,
entries 3–4). When Pd(OAc)2 was replaced with [2,6-
PyCH3(CH2CPh2O)]2Pd?2AcOH 513 or [PdCl{C5H5FeC5H3C(CH3)=
N(C6H4-4-CH3)}PPh3)] 6,14 the yield of 3a did not improve
(Table 1, entries 6–7). The presence of triphenylphosphine
(Table 1, entries 8–9) and increasing the catalyst loading of
Pd(OAc)2 from 2 mol% to 5 mol% could not improve the
formation of 3a. However, higher catalyst loading resulted in a
reduced reaction time from 24 h to 4 h (Table 1, entry 10). The
yield of 3a increased to 86% when the reaction was carried out in
the dark (Table 1, entry 11). In all cases, the tetra-substituted
furan 4a was obtained as the by-product.
Polycyclic aromatic compounds containing cyclopentadienyl rings
are widely present in natural products, functional materials and
biologically active compounds.1 These compounds are widely
useful as ligands or ligand precursors in transition metal
catalysis,2 and can be easily converted to fused aromatic
compounds.3 Conventionally, the synthesis of cyclopentadienyl
derivatives required active precursors, such as zirconacyclopenta-
dienes,4 Schrock type carbene complexes5 and lithiobutadienes6
which were prepared in multiple steps, and subjected to ring-
expanding rearrangement via transition-metal-catalyzed reac-
tions.7
Disubstituted alkynes as active starting materials have attracted
much attention in palladium-catalyzed cyclization reactions owing
to the palladium atom coordinating alkynes to generate a
metallacyclopentene, which is the key intermediate in some
carbocyclization reactions.8 Tetrasubstituted furans,9 benzene
derivatives,10 as well as highly substituted 8,8a-dihydrocyclopen-
ta[a]indenes11 were all synthesized by dimerization or trimeriza-
tion of diarylalkynes. The intermediate 2 was proposed to exist in
the catalytic cycle of the palladium-catalyzed cyclization reaction
(Scheme 1).11 Therefore, we conceived that intermediate 2 could
interact with alcohols to produce cyclopentadienyl alkyl ethers.12
aCollege of chemistry and molecular sciences, Henan Key Laboratory of Chemical
Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of Henan
Universities, Zhengzhou University, Zhengzhou, 450052, P.R. China.
E-mail: wyj@zzu.edu.cn; hmm@zzu.edu.cn
bTetranov Biopharm LLC., 75 Daxue Road, Zhengzhou, Henan 450052, P.R. China
Electronic supplementary information (ESI) available. CCDC 880444, 881630 and
3
880445. For ESI and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ra41326h
Scheme 1 Metal-catalyzed cyclotrimerizations of alkyne 1a.
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Table 1 Palladium-catalyzed cyclization of diphenylethyne 1aa
Table 2 Preparation of cyclopentadienyl alkyl ethers 3 from symmetrical alkynes
1a
Entry
1
Ar
R
3b
4b
6
Entry
Oxidant
Catalyst
Additive
3ae
4ae
Me
81
1
2
3
4
5
6
7
K2S2O8
K2S2O8
Benzoq-uinone
Cu(OAc)2
—
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
5
—
77
68
13
NRf
NRf
73
43
48
41
76
86
11
14
19
NRf
NRf
11
30
30
13
12
11
TsOH?H2O
TsOH?H2O
TsOH?H2O
—
TsOH?H2O
TsOH?H2O
TsOH?H2O
—
2
3
Me
Me
68
73
13
6
5
8b
9b
10c
11d
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
—
—
trace
a
Reaction conditions: 1a (0.5 mmol), catalyst (2 mol%), oxidant (0.3
mmol), additive (0.1 mmol), MeOH (3 mL), 60 uC, 24 h, under
b
c
d
anaerobic atmosphere. 4 mol% PPh3. 5 mol% Pd(OAc)2, 4 h.
mol% Pd(OAc)2, in the dark, 24 h. GC yields based on 1a. No
5
e
f
4
5
Me
Me
62
70
5
6
reaction.
Under the optimal reaction conditions (Table 1, entry 11), the
scope and limitation of the substrates were explored. As shown in
Table 2, symmetrical diarylethynes with electron-donating groups
could be transformed into the desired products in moderate to
good yields (Table 2, entries 1–6). Diarylethynes with electron-
withdrawing groups gave lower yields. Compound 3g was obtained
in 42% yield (Table 2, entry 7), and 1h only gave a trace amount of
the desired product 3h (Table 2, entry 8). Unexpectedly, 3g was
obtained in relatively high yield (53%) under natural light (Table 2,
entry 7). The reaction of diphenylethyne 1a could also proceed in
ethanol to give the corresponding product 3i in 63% yield (Table 2,
entry 9), which suggested that one of the possible intermediates of
this reaction is a cyclopentadienyl cation. The structures of 3a
(Fig. 1), 3f and 4a were determined by single X-ray diffraction
6
7
Me
Me
72
5
4
42, 53c
8
Me
Et
trace
63
7
5
(ESI ).
3
In addition, an unexpected result was obtained (Scheme 2):
when 1,2-diarylethyne 1j was reacted under the same conditions as
above, the cyclopentadiene 5j was isolated in 19% yield from the
mixture of products.
9d
Based on the literature and our experimental results, a
plausible reaction mechanism is proposed (Scheme 3). Initially,
the reaction of Pd(OAc)2 and diarylethyne at a certain temperature
produces two intermediates: 1-palladacyclopentadiene II15 and
1-palladacycloheptatriene IV, which provide two possible paths in
the catalytic cycle. Route A: the 1-palladacyclopentadiene II is
transformed into 1,4-dione III by an oxidant,16 which smoothly
forms the product 4.17 Route B: 1-palladacycloheptatriene IV is
transformed into a Schrock-type carbene complex V,18,19 which
possibly reacts with methanol in a nucleophilic addition to the
carbene metal atom to give intermediate VI. Then, the following
reductive elimination and electron transfer at VI generates by-
product VII and cation VIII. Cyclopentadienyl cation VIII could be
a
Reaction conditions: 1,2-diarylethyne (0.5 mmol), Pd(OAc)2 (5
mol%), K2S2O8 (0.3 mmol), MeOH (3 mL), 60 uC, 24 h, in the dark.
b
c
d
Isolated yield. Not in the dark. In EtOH.
quenched with methanol to form 3 (Route C).20 On the other
hand, protonation of anion IX leads to the formation of
compound 5j (Route D). To determine the existence of anion IX,
deuterated methanol (99.8% D, 1.8 mL) was used as the solvent,
however, 5j–D was obtained only in 5% yield with 56% isotopic
purity. It was proved that the H+ (D+), which came from methanol,
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Fig. 1 The molecular structure of 3a.
reacted with anion IX to form 5j (5j–D). The Pd0 species can be
oxidized by K2S2O8 to generate the active PdII complex, which
completes the catalytic cycle. The by-product VII was isolated from
the reaction mixture and determined by gas chromatography-mass
+
spectrometry (principal ion of m/z 152.1; calcd for C9H12O2 : m/z
152.2). Cation VIII and anion IX were detected by high resolution
accurate mass measurements (APCI-MS, principal cation of m/z
445.1947; calcd for C35H25+: m/z 445.1951; principal anion of m/z
Scheme 3 Proposed reaction mechanism for the formation of cyclopentadienyl
alkyl ether 3, tetrasubstituted furan 4 and cyclopentadiene 5j.
615.0010; calcd for C35H20Cl52: m/z 615.0008; see ESI ).
3
Finally, we explored the photophysical properties of the
products 3a–3i. These compounds have fluorescent properties in
the solid state and in solution. In the solid state, these compounds
show fluorescence absorption within a range of 447 to 485 nm,
while their fluorescence absorption in solution (ethyl acetate)
ranged from 426 to 467 nm (Fig. 2). It was found that the
electronic effect of functional groups at the benzene ring had no
In summary, we have developed an efficient tandem cycliza-
tion–methoxylation reaction to synthesize highly substituted
cyclopentadienyl alkyl ethers via palladium-catalyzed trimerization
of diarylethynes. This catalytic system was applied to various
symmetrical diarylethynes which provided the desired products in
moderate to good yields. The reaction mechanism was proposed
based on results from Q-Tof APCI-HMRS. The structures of 3a, 3f
and 4a were determined by single X-ray diffraction. The
significant influence on the maximum emission wavelength (lem
)
in solution. However, the maximum emission wavelength was
related to their substituent groups in the solid state: strong
electron-donating groups produced a larger red-shift. Compared
with 3a, compound 3i produced a strong blue-shift in solution, but
a slight red-shift in the solid state. In addition, the fluorescence
quantum yields for compounds 3d, 3g and 3i were 0.23, 0.22, and
0.6 respectively, which were analyzed in solution (5 6 1025 mol
L21 in ethyl acetate) using quinine sulfate in 0.1 M aqueous
sulfuric acid as the standard.
Fig. 2 Fluorescence spectra of products 3. [A] Measured at a concentration of 5 6
1025 mol L21 in ethyl acetate. [B] In the solid state.
Scheme 2 The unexpected formation of 5j and 5j–D.
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Rhodiumcatalyzed Organic Reactions, ed. P. A. Evans, Wiley-
fluorescent properties of the obtained products were studied in
the solid state and in solution. Further investigations of the scope
of the reaction and employing the products as functional materials
are in progress.
This work was supported by the National Nature Science
Foundation of China (No. 21172200).
¨
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