I2O5-Mediated 1,5-Cyclization of Aryldiynes with H2O: A Way to Access 3-Acyl-1-indenone Derivatives

Article abstract of DOI:10.1021/acs.joc.8b03151

A facile I₂O₅-mediated 1,5-cyclization of aryldiynes with H₂O has been successfully developed, leading to a broad range of substituted 3-acyl-1-indenones in moderate to excellent yields. The protocol has advantages of a me

Full text of DOI:10.1021/acs.joc.8b03151

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Article
I2O5-Mediated 1,5-Cyclization of Aryldiynes with
H2O: A Way to Access 3-Acyl 1-Indenone Derivatives
Bingwei Zhou, Huan Yang, Hongwei Jin, and Yunkui Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03151 • Publication Date (Web): 17 Jan 2019
Downloaded from http://pubs.acs.org on January 17, 2019
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I2O5-Mediated 1,5-Cyclization of Aryldiynes with H2O: A Way to Access 3-Acyl
1-Indenone Derivatives
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Bingwei Zhou, Huan Yang, Hongwei Jin* and Yunkui Liu*
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, College of Chemical
Engineering, Zhejiang University of Technology, Hangzhou 310014, People’s Republic of China
TOC graphic
O18
R2
R1
R1
R1
R1
I2O5
R2
R3
O18
MeCN : H2
= 4 : 1 (V/V)
50 oC, 24 h
R3
18O
24 examples, up to 92% yield
Metal-free process
Simple operation
Mild reaction conditions
Water as the oxygen source
ABSTRACT: A facile I2O5-mediated 1,5-cyclization of aryldiynes with H2O has been successfully
developed leading to a broad range of substituted 3-acyl 1-indenones in moderate to excellent yields.
The protocol has advantages of metal-free process, mild reaction conditions, simple operation, and
broad functional group tolerance. In the reaction, H2O is used as both a co-solvent and an oxygen
source.
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INTRODUCTION
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1-Indenones are known as an important class of carbocyclic compounds and their frameworks are
found to widely exist in natural products and synthetically bioactive molecules.1 The 1-indenone
derivatives can exhibit versatile utilities in organic synthesis, drug discovery, materials science,
and among others.2 Consequently, it is of great interest to develop efficient and reliable methods
for their synthesis. The intramolecular cyclization of aromatic carbonyl compounds under acidic
conditions represents the most common way to access 1-indenones.3 In recent years, most of
methods for the construction of 1-indenones mainly focus on metal-involved cyclization reactions.
For example, transition metal-catalyzed cross-coupling reactions4 and direct C-H annulations5 have
been extensively studied in the last decade. More recently, the metal-free approaches via radical6 or
ionic pathway7 for the synthesis of 1-indenone derivatives have received an increasing attention
due to concerns about issues of environmental pollution and pharmaceutical purification. Despite
some advances made over the past few years, it is still highly desirable to develop novel methods
for the construction of diverse substituted 1-indenones from easily available precursors, in simple
operation, and under metal-free reaction conditions.
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Aryldiynes represent a class of valuable building blocks in synthetic chemistry which can
undergo either a typical Bergman 1,6-cyclization8 or the regio-variant 1,5-cyclization.9-12 The latter
transformation of aryldiynes enabled the formation of fulvenes induced by electrophiles,9
radicals,10 transition metals,11 etc., and these types of reactions have been well studied.9-12 In
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contrast, the construction of 3-acyl 1-indenones from 1,5-cyclization reaction of aryldiynes has
been less explored.11b,13 Schumann and co-workers reported an annulation reaction of
1,2-bis(phenylethynyl)benzene with sulfur under air affording 3-benzoyl-2-phenyl-1H-inden-1-one
(2b) in 56% yield (Scheme 1a), but the reaction required high temperature (120 ºC) and only gave
one example.13a In 1996, Sankararaman et al described the synthesis of 3-acyl 1-indenones through
the cyclization of aryldiynes via chemical, photochemical or electrochemical oxidation, but with
narrow scope of substrates (Scheme 1b).13b Later, Wu et al synthesized 1-indenones as side
products (yields of 11-23%) during the study of Pd-catalyzed cyclization of aryldiynes (Scheme
1c).11b As such, the development of general and efficient methods for the construction of diverse
functionalized 1-indenones from aryldiynes is highly expected. Our current research interests focus
on the development of nucleophilic hydroxyl group-triggered cascade reactions to access complex
molecules using water as the hydroxyl source.14,15 Previously, we disclosed that the
Cu(0)/Selecfluor system may in situ generate an active XCuOH species (X = F or BF4) in the
presence of water which is readily to undergo the addition of hydroxyl group to carbon-carbon
multiple bonds and induce successive tandem reactions.14 Very recently, we found that an
I2O5/H2O system could undergo the generation of the hydroxyl radical species under metal-free
conditions and induce tandem cyclization of 1,6-enynes to access strained
1H-cyclopropa[b]naphthalene-2,7-diones.15 In this study, we describe an I2O5-mediated
1,5-cyclization of aryldiynes with H2O, which provides an efficient and convenient approach for
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the synthesis of 3-acyl 1-indenones in moderate to excellent yields under metal-free conditions
(Scheme 1d).
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Scheme 1. Synthesis of 3-Acyl 1-Indenones from Aryldiynes
Previous work:
O
Ph
Sulfur
Ph
a)
DCM, 120 oC, air
56%
O
Ph
R
Ph
2b
O
condition i or ii or iii
R
b)
I
: R = H;
2e
: R = 4-MeOPh
O
R
R
i: TPP+BF4-, MeCN, O2, hv.
I
2e
: 76%; : 78%
-
ii: 10 mol% TBPA+SbCl6 , DCM, -78 oC, O2.
2e
2e
: 60%
: 88%
O
iii: anodic oxidation, Pt, MeCN, O2, TEAP.
Ar
PdX2, CuX2
(X = Cl, Br)
Ar
c)
MeCN, 60 oC, 2 h
O
11-23%
Ar
Ar
This work:
R2
O
R1
R1
R1
d)
I2O5 (4 equiv)
R2
R3
MeCN : H2O = 4 : 1 (V/V)
50 oC, 24 h
R1
R3
O
50-92%
RESULTS AND DISCUSSION
Initially, 1,2-bis(p-tolylethynyl)benzene 1a was chosen as the model substrate to optimize the
reaction conditions (Table 1). We first carried out the reaction of 1a with I2O5 and H2O in acetonitrile
o
at 50 C for 24 hours and the desired product 2a was obtained in 37% yield (entry 1, Table 1). It was
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found that the volume ratio of acetonitrile versus H2O has a significant effect on the yield of 2a and a
solvent mixture with a ratio of MeCN/H2O = 4:1 (V/V) gave the best yield of 2a (entries 2-5, Table 1).
Either elevating the temperature (entry 7, Table 1) or prolonging the reaction time (entry 8, Table 1)
could not further improve the yield. Solvent screening experiments indicated that a combined
MeCN/H2O = 4:1 (V/V) solvent system was the most suitable medium for the reaction (entries 9-13 vs
4, Table 1). In addition, several other oxidants (PhI(OAc)2 and K2S2O8) were investigated and all
showed inferior efficiency than that of I2O5 (entries 14, 15 vs 4, Table 1). A controlled experiment
revealed that no desired product was obtained in the absence of I2O5 (entry 16, Table 1). Finally, either
decreasing or increasing the amount of I2O5 resulted in a reduced yield of 2a (entries 17-18 vs 4, Table
1).
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Table 1. Optimization of Reaction Conditionsa
O
p-Tolyl
oxidant (4 equiv)
p-Tolyl
H2O
+
solvent, temp, 24 h
O
p-Tolyl
p-Tolyl
1a
2a
entry
catalyst
solventb
temp (ºC)
yield of 2a (%)c
1
2
3
4
I2O5
I2O5
I2O5
I2O5
MeCN:H2O (400:1, V/V)
MeCN:H2O (40:1, V/V)
MeCN:H2O (5:1, V/V)
MeCN:H2O (4:1, V/V)
50
50
50
50
37
53
79
87 (81d)
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5
I2O5
I2O5
MeCN:H2O (3:1, V/V)
50
35
70
50
50
50
50
50
50
50
50
50
50
50
75
10
6
MeCN:H2O (4:1, V/V)
MeCN:H2O (4:1, V/V)
MeCN:H2O (4:1, V/V)
THF:H2O (4:1, V/V)
DCM:H2O (4:1, V/V)
dioxane:H2O (4:1, V/V)
toluene:H2O (4:1, V/V)
DMF:H2O (4:1, V/V)
MeCN:H2O (4:1, V/V)
MeCN:H2O (4:1, V/V)
MeCN:H2O (4:1, V/V)
MeCN:H2O (4:1, V/V)
MeCN:H2O (4:1, V/V)
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7
I2O5
80
8
I2O5
22e, 85f
76
9
I2O5
10
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13
14
15
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17
18
I2O5
71
I2O5
73
I2O5
0
I2O5
58
PhI(OAc)2
K2S2O8
--g
14
0
0
h
I2O5
79
i
I2O5
81
aReaction conditions: 1a (0.1 mmol), oxidant (4 equiv), solvent (1.5 mL), given temperature for
b
24 h unless otherwise noted. Solvent mixtures were prepared in terms of volume ratios (V/V).
cLC yields were given. Isolated yield shown in parentheses. The reaction time is 12 h. The
d
e
f
g
h
reaction time is 28 h. No oxidant; only the starting materials were recovered. I2O5 (2 equiv).
iI2O5 (6 equiv).
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With the optimized reaction conditions in hand, we next examined the scope of aryldiynes 1 (Table
2). At first, a range of symmetric aryldiynes bearing para-substituted aryl rings at the alkyne moieties
of 1 were evaluated under the standard reaction conditions (2a-i, Table 2). Substrates containing either
electron-rich or electron-deficient aryl rings underwent the cyclization smoothly and gave the desired
products in moderate to excellent yields. It was found that symmetric aryldiynes possessing ortho- or
meta-substituted aryl rings at the alkyne moieties of 1 generally gave decreased yields of 2 compared to
those of para-substituted ones presumably due to the steric hindrance effect (2j-o vs 2a-i, Table 2).
Aryldiynes bearing heteroaromatic rings or aliphatic groups at the alkyne moieties of 1 were also
workable for the reaction and afforded the corresponding products in moderate yields (2q, 2r, Table 2).
In addition, asymmetric aryldiynes were also examined under the standard reaction conditions. For
example, when 1s was used, regioisomer 2s was predominantly produced along with a small amount of
2sʹ (total 83% yield of 2s and 2sʹ with a ratio of 2s : 2sʹ = 6 : 1 base on the 1H NMR analysis; the
structure of the major isomer is determined by the GC-MS analysis, see Supporting Information); when
substrate 1t was used, two regioisomers 2t and 2tʹ were obtained in a total yield of 78% with a ratio of
2t : 2tʹ = 1.2 : 1 base on the GC-MS analysis (see Supporting Information). According to our proposed
mechanism (Scheme 3, vide infra), we presumed that 1s may undergo 5-endo-dig cyclization more
favorably to mainly produce 2s while 1t may proceed via 5-exo-dig cylization more favorably to
mainly deliver 2t (Scheme 3, vide infra). Furthermore, the substituents on phenyl ring A were
investigated. Aryldiynes bearing either electron-donating or electron-withdrawing groups could
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undergo the annulation smoothly and afford the target indenones in moderate yields (52-70%, 2u-x,
Table 2). Finally, a gram-scale (5 mmol of 1a used) synthesis of 2a was also tried, and the target
indenone 2a was obtained in 75% yield (eq. 1).
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Table 2. Substrate scope for aryldiynes 1a
R2
O
R1
R1
R2
I2O5 (4 equiv)
A
A
R1
MeCN : H2O = 4 : 1 (V/V)
R1
50 oC, 24 h
O
R3
R3
1
2
2a
2b
2c
2d
2e
2i
2j
2k
2l
2m
2n
2o
2p
: R = 4-Me, 81%
: R = 4-CO2Me, 65%
: R = 3-Cl, 70%
: R = 3-Br, 59%
: R = 3-CN, 50%
: R = 2-Me, 71%
: R = 2-Cl, 58%
: R = 2-Br, 51%
O
: R = H, 75%
n
: R = 4- Propyl, 70%
: R = 4-Ph, 69%
R
: R = 4-OMe, 90%
: R = 4-OC5H11, 87%
O
2f
2g
: R = 4-F, 80%
: R = 4-Cl, 92%
: R = 3,4-di-Me, 84%
R
2h
O
O
O
O
Ph
R
S
O
O
+
O
O
S
2s 2t
,
R
2s' 2t'
,
b
b
2s
2s'
R = OMe:
= 71% ;
= 12%
c
2q
: 72%
2r
: 55%
R
c
2t
2t'
R = F: = 43% ;
= 35%
O
MeO
MeO
O
O
F
p-Tolyl
Ph
O
F
O
O
p-Tolyl
Ph
R
2u
2v
: R = H, 52%
: R = Me, 60%
2w
2x
: 65%
: 70%
aReaction conditions: 1 (0.3 mmol), I2O5 (4 equiv), MeCN/H2O (4/1 (V/V), 4.5 mL), 50 ºC for 24 h.
bThe structure of the major regioisomer 2s was determined by the GC-MS analysis and the yield of 2s
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was calculated based on the H NMR analysis. The structure and yield of regioisomers were
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O
p-Tolyl
I2O5 (4 equiv)
p-Tolyl
(eq. 1)
CH3CN : H2O = 4 : 1(V/V)
O
50 oC, 24 h,
p-Tolyl
p-Tolyl
1a
(1.53 g, 5 mmol)
2a
(1.27 g, 75%)
To gain insight into the reaction mechanism, we performed radical scavenging experiments by an
extra addition of TEMPO15,16 to the model reaction. As expected, the annulation reaction was almost
suppressed and the similar result was obtained by using BHT (Butylated hydroxytoluene) as a radical
scavenger (Scheme 2a). In these cases, the starting material 1a was almost recovered. However, when
N-tert-buthyl-α-phenylnitrone (PBN) was used as a radical scavenger, the reaction could still proceed
well (Scheme 2a). We think that TEMPO and BHT may react with I2O5 directly under the reaction
conditions, thus a cyclization may be inhibited.17 To probe the source of the oxygen atoms in 2, several
additional experiments were carried out (Scheme 2b-d). It was found that an attempt to run the
annulation of 1a in a degassed acetonitrile-water mixture (4:1, V/V) could still give 2a in 85% LC yield
(Scheme 2b). Note that only small amount of product (8% LC yield) was detected when we performed
the model reaction in a dehydrated acetonitrile (Scheme 2c). When substrate 1b was subjected to the
standard reaction conditions except using a MeCN/H2O18 = 4:1 (V/V) solvent system, the
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double-18O-incorporated product 2b-[O18]2 ([M+H]+: m/z = 315) was detected by the MS analysis
(Scheme 2d, also see Supporting Information). All these results disclosed that H2O should be the sole
oxygen source for the formation of the two carbonyl groups in 3-acyl 1-indenones 2.
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Scheme 2. Preliminary Mechanistic Studies
a) Radical scavenging experiments
O
p-Tolyl
std conditions
p-Tolyl
radical scavenger
O
p-Tolyl
p-Tolyl
1a
2a
2a
BHT
2a
PBN
2a
TEMPO
Yield of
Yield of
Yield of
4 equiv
8 equiv
39%
2%
4 equiv
8 equiv
23%
trace
4 equiv
8 equiv
74%
69%
1a
b) Reaction of
under standard reaction conditions except under a
degassed MeCN-H2O mixture
std conditions
1a
2a
: 85% LC yield
: 8% LC yield
+
H2O
except in degassed
MeCN/H2O = 4 : 1 (V/V)
c) Control experiment by removal of H2O
std conditions
1a
2a
except in dehydrated MeCN
d) 18O-labeling experiment
18O
Standard conditions
18O
Ph
1b
H2
O18
Ph
2b-[18O]
2: detected by MS
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On the basis of our mechanistic experiments and previous literature,15,18-22 a possible mechanism for
the I2O5-mediated annulation of 1a with H2O is proposed in Scheme 3. First, HIO3 was produced upon
the hydrolysis of I2O5 by water.18 Then the decomposition of HIO3 may generate HOI and O2.19 In
solution, HOI may release I+ and OH- species. Activation of the carbon-carbon triple bond of 1a by I+
may produce intermediate A.19 5-Exo-dig cyclization of A may generate intermediate B (Path I).15,19,20
The redox reaction between B and HIO3 yielded an vinyl-λ3-iodane intermediate C that underwent
substitution by H2O to generate intermediate D.15,21a,22 Alternatively, 5-Endo-dig cyclization of A
followed by the oxidation of the resulting intermediate F by HIO3 may deliver intermediate G.15,21a
Substitution of IIII moiety in G by H2O could also deliver intermediate D (Path II).15,21a,22 Finally, the
tautomerization of D to E followed by the oxidation of the resulting intermediate E gave the final
product 2a.
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Scheme 3. Proposed Mechanism for the Oxidative Annulation of 1a
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More Favorable
HO-
HO-
F
OH
G
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H2O
oxidation
2a
E
D
+
+
IIII
I
I
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HO-
OMe
HIO3
1s
For
:
1t
For
:
5-endo-dig
5-exo-dig
Path II
OH
5-endo-dig cyclization
2t
HIO3
HOI
2s
+
I
I O
2
H2O
+
5
A
I
F
O2
I+
HO-
+
HO-
1a
OH
5-exo-dig cyclization
Path I
+
I
I
std reaction conditions
A
B
HIO3
OH
O
OH
oxidation
H2O
2a
IIII
C
O
OH
E
D
CONCLUSION
In summary, we have successfully developed a facile 1,5-cyclization of aryldiynes with water by using
commercially available, inexpensive, and easily handled I2O5 as the oxidant. The present protocol
provides an efficient and convenient way to access a range of diverse functionalized 3-acyl indenones
by using water as the green oxygen source under metal-free reaction conditions. Further studies on
cyclization reactions involving the I2O5/H2O system are underway in our laboratory.
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General Information. Unless otherwise stated, commercially available reagents were purchased
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from chemical suppliers and used without purifications. The H and C NMR spectra were recorded
on a spectrometer at 25 C in CDCl3 or DMSO-d6 at 500 MHz and 125 MHz, respectively. Proton
chemical shifts (δ) are relative to tetramethylsilane (TMS, δ = 0.00) as internal standard and expressed
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in ppm. Chemical shifts of C NMR were reported relative to the solvent signal (CDCl3: δ = 77.16
ppm; DMSO-d6: δ = 39.51 ppm). GC-MS experiments were performed with EI source; high resolution
mass spectra (HRMS) were obtained on a TOF MS instrument with EI or ESI source. Acetonitrile is
dehydrated by CaH2 before preparation of the combined MeCN/H2O solvent system. Flash column
chromatography was performed on silica gel (100-200 mesh) with the indicated solvent mixtures.
Preparation of the starting material aryldiynes 1.23 Pd(PPh3)2Cl2 (28.1 mg, 0.04 mmol, 2 mol %)
and CuI (3.8 mg, 0.02 mmol, 1 mol %) were placed to a septum-capped one neck flask which was then
charged with Et3N (15 mL) and the resulting mixture was degassed by freeze-pump-thaw technique. An
aryl halide (2 mmol) and an appropriate acetylene (1.2 equiv based on aryl halide) were successively
added via syringe to the stirred reaction mixture. After that the reaction mixture was stirred at room
temperature until all the aryl halide has been consumed (monitored by TLC or GC). The Et3N was
removed under reduced pressure and the residue was dissolved in toluene (10 mL) and filtered through
a small pad of silica gel, which then was rinsed with toluene (10 mL  2). The combined organic layer
was concentrated under reduced pressure and the residue was purified by flash chromatography using
hexane or hexane/EtOAc mixture as an eluent. Enediynes 1a-x were synthesized according to this
general procedure from the corresponding o-diiodobenzenes with appropriate terminal alkynes. Their
1H and 13C NMR spectra were in line with the previous literature.9f,10b,11c,20
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Typical procedure for the I2O5-mediated 5-exo-dig cyclization of aryldiynes with H2O. To a 25
mL Schlenk tube were added 1,2-bis(p-tolylethynyl)benzene 1a (91.8 mg, 0.3 mmol), I2O5 (400.8 mg,
4 equiv, 1.2 mmol) and mixed solvent (MeCN:H2O = 4:1 (V/V), 4.5 mL). The mixture was stirred at 50
ºC for 24 h. H2O (4 mL) and saturated Na2S2O3 (4 mL) were added at room temperature. Then, the
reaction mixture was extracted with CH2Cl2 and purified by flash column chromatography (petroleum
ether/EtOAc, = 10 : 1 (V/V)). The product was isolated as a yellow solid (82.0 mg, 81%).
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3-(4-methylbenzoyl)-2-(p-tolyl)-1H-inden-1-one (2a). Yellow solid (82.0 mg, 81%); m.p. 152-155
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oC; H NMR (500 MHz, CDCl3): δ 7.86 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 7.0 Hz, 1H), 7.38-7.34 (m,
3H), 7.29-7.26 (m, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 6.99 (d, J = 7.2 Hz, 1H),
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2.37 (s, 3H), 2.28 (s, 3H); C{1H} NMR (125 MHz, CDCl3): δ 196.3, 194.4, 150.1, 145.6, 144.4,
139.0, 134.3, 134.0, 132.8, 129.6, 129.5, 129.2, 129.11, 129.09, 126.9, 123.7, 121.5, 21.8, 21.3; HRMS
(ESI) for C24H19O2 [M+H]+: calcd 339.1380, found 339.1385.
o
1
3-benzoyl-2-phenyl-1H-inden-1-one (2b).13b Yellow solid (70.1 mg, 75%); m.p. 113-115 C; H
NMR (500 MHz, CDCl3): δ 7.95-7.93 (m, 2H), 7.63 (d, J = 7.0 Hz, 1H), 7.54-7.50 (m, 1H), 7.45-7.43
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(m, 2H), 7.40-7.35 (m, 3H), 7.32-7.29 (m, 1H), 7.25-7.22 (m, 3H), 7.06 (d, J = 7.3 Hz, 1H); C{1H}
NMR (125 MHz, CDCl3): δ 196.0, 194.6, 150.4, 144.1, 135.2, 134.6, 134.39, 134.36, 129.7, 129.6,
129.4, 129.3, 129.0, 128.8, 128.3, 123.9, 121.8.
3-(4-propylbenzoyl)-2-(4-propylphenyl)-1H-inden-1-one (2c). Yellow solid (83.2 mg, 70%); m.p.
o
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159-161 C; H NMR (500 MHz, CDCl3): δ 7.86 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 7.1 Hz, 1H),
7.39-7.34 (m, 3H), 7.27 (t, J = 7.4 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 7.06-7.02 (m, 3H), 2.60-2.57 (m,
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2H), 2.51-2.48 (m, 2H), 1.64-1.52 (m, 4H), 0.91-0.85 (m, 6H); C{1H} NMR (125 MHz, CDCl3): δ
196.4, 194.3, 150.0, 149.9, 144.4, 143.7, 134.4, 134.3, 133.1, 129.6, 129.5, 129.2, 129.0, 128.9, 128.4,
127.1, 123.7, 121.6, 38.0, 37.7, 24.1, 23.9, 13.6; HRMS (ESI) for C28H27O2 [M+H]+: calcd 395.2006,
found 395.2003.
3-([1,1'-biphenyl]-4-carbonyl)-2-([1,1'-biphenyl]-4-yl)-1H-inden-1-one (2d). Yellow solid (96.3 mg,
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69%); m.p. 209-211 C; H NMR (500 MHz, CDCl3): δ 8.08-8.05 (m, 2H), 7.67 (d, J = 6.8 Hz, 1H),
7.64-7.60 (m, 3H), 7.59-7.58 (m, 1H), 7.58-7.55 (m, 2H), 7.54-7.51 (m, 4H), 7.46-7.39 (m, 6H),
7.35-7.31 (m, 2H), 7.09 (d, J = 7.2 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 196.1, 194.2, 150.5,
147.2, 144.3, 141.6, 140.2, 139.5, 134.5, 134.0, 133.9, 130.0, 129.8, 129.7, 129.4, 129.0, 128.8, 128.7,
128.5, 127.6, 127.55, 127.3, 127.1, 127.0, 123.9, 121.8; HRMS (ESI) for C34H23O2 [M+H]+: calcd
463.1693, found 463.1688.
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3-(4-methoxybenzoyl)-2-(4-methoxyphenyl)-1H-inden-1-one (2e).11b Red solid (99.9 mg, 90%); m.p.
120-122 oC (lit.11b 116-117 oC); 1H NMR (500 MHz, CDCl3): δ 7.95 -7.92 (m, 2H), 7.57 (d, J = 7.1 Hz,
1H), 7.46-7.43 (m, 2H), 7.34 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.4 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H),
6.86-6.83 (m, 4H), 6.79-6.77 (m, 2.4 Hz, 2H), 3.81 (s, 3H), 3.74 (s, 3H); C{1H} NMR (125 MHz,
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CDCl3): δ 196.6, 193.2, 164.6, 160.1, 149.1, 144.5, 134.3, 133.3, 131.8, 130.8, 129.6, 128.9, 128.3,
123.6, 122.4, 121.3, 114.1, 113.9, 55.5, 55.1.
3-(4-(pentyloxy)benzoyl)-2-(4-(pentyloxy)phenyl)-1H-inden-1-one (2f). Red solid (126.1 mg, 87%);
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m.p. 191-193 C; H NMR (500 MHz, CDCl3): δ 7.94-7.91(m, J = 5.8 Hz, 2H), 7.58 (d, J = 7.0 Hz,
1H), 7.45-7.43 (m, 2H), 7.36-7.33 (m, 1H), 7.25 (t, J = 7.3 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.85-6.83
(m, 2H), 6.79-6.78 (m, 2H), 3.98 (t, J = 6.6 Hz, 2H), 3.90 (t, J = 6.6 Hz, 2H), 1.81-1.72 (m, 4H),
1.44-1.33 (m, 8H), 0.95-0.91 (m, 6H); 13C{1H} NMR (125 MHz, CDCl3): δ 196.8, 193.3, 164.3, 159.7,
149.1, 144.7, 134.3, 133.4, 131.9, 130.8, 129.7, 128.8, 128.1, 123.6, 122.2, 121.4, 114.60, 114.5, 68.4,
68.0, 28.9, 28.7, 28.2, 28.1, 22.42, 22.38, 13.98, 13.96; HRMS (ESI) for C32H35O4 [M+H]+: calcd
483.2530, found 483.2535.
3-(4-fluorobenzoyl)-2-(4-fluorophenyl)-1H-inden-1-one (2g). Yellow solid (83.1 mg, 80%); m.p.
106-109 oC; 1H NMR (500 MHz, CDCl3): δ 7.97-7.93 (m, 2H), 7.63 (d, J = 7.1 Hz, 1H), 7.44-7.39 (m,
3H), 7.33 (t, J = 7.2 Hz, 1H), 7.07-7.03 (m, 3H), 6.98-6.93 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3):
δ 195.9, 192.9, 166.6 (d, J = 257.8 Hz) , 163.2 (d, J = 250.7 Hz), 149.8, 143.9, 134.6, 133.7, 132.2 (d, J
= 9.7 Hz), 131.6 (d, J = 2.9 Hz), 131.4 (d, J = 8.3 Hz), 129.6, 129.4, 125.8 (d, J = 3.3 Hz), 124.1, 121.9,
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116.3 (d, J = 22.2 Hz), 115.7 (d, J = 21.8 Hz); HRMS (ESI) for C22H13F2O2 [M+H]+: calcd 347.0878,
found 347.0884.
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3-(4-chlorobenzoyl)-2-(4-chlorophenyl)-1H-inden-1-one (2h). Yellow solid (104.9 mg, 92%); m.p.
140-143 oC; 1H NMR (500 MHz, CDCl3): δ 7.88-7.85 (m, 2H), 7.63 (d, J = 7.0 Hz, 1H), 7.41-7.31 (m,
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6H), 7.25-7.22 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H); C{1H} NMR (125 MHz, CDCl3): δ 195.5, 193.1,
150.1, 143.6, 141.3, 135.4, 134.6, 133.4, 133.3, 130.7, 130.6, 129.7, 129.4, 129.4, 128.8, 128.0, 124.2,
121.9; HRMS (ESI) for C22H13Cl2O2 [M+H]+: calcd 379.0287, found 379.0281.
methyl 4-(3-(4-(methoxycarbonyl)benzoyl)-1-oxo-1H-inden-2-yl)benzoate (2i). Yellow solid (83.2
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mg, 65%); m.p. 120-122 C; H NMR (500 MHz, CDCl3): δ 8.01-7.99 (m, 2H), 7.97-7.94 (m, 2H),
7.90-7.88 (m, 2H), 7.67 (d, J = 6.8 Hz, 1H), 7.48-7.46 (m, 2H), 7.45-7.42 (m, 1H), 7.38-7.35 (m, 1H),
7.11 (d, J = 7.2 Hz, 1H), 3.92 (s, 3H), 3.88 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 195.2, 193.7,
166.4, 165.8, 151.0, 143.4, 138.1, 135.1, 134.7, 134.1, 133.9, 130.4, 130.1, 130.0, 129.6, 129.5, 129.3,
129.2, 124.3, 122.2, 52.6, 52.2; HRMS (ESI) for C26H19O6 [M+H]+: calcd 427.1176, found 427.1172.
3-(3-chlorobenzoyl)-2-(3-chlorophenyl)-1H-inden-1-one (2j). Yellow solid (79.5 mg, 70%); m.p.
135-137 oC; 1H NMR (500 MHz, CDCl3): δ 7.88 (t, J = 1.8 Hz, 1H), 7.75-7.73 (m, 1H), 7.66-7.64 (m,
1H), 7.51-7.49 (m, 1H), 7.44-7.37 (m, 2H), 7.37-7.29 (m, 2H), 7.25-7.21 (m, 2H), 7.19-7.16 (m, 1H),
7.10 (d, J = 7.3 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 195.1, 192.9, 150.3, 143.4, 136.6, 135.3,
134.6, 134.4, 134.4, 133.9, 131.2, 130.2, 129.9, 129.7, 129.3, 129.26, 129.0, 127.5, 127.5, 124.3, 122.1;
HRMS (ESI) for C22H13Cl2O2 [M+H]+: calcd 379.0287, found 379.0297.
3-(3-bromobenzoyl)-2-(3-bromophenyl)-1H-inden-1-one (2k). Red-brown solid (82.1 mg, 59%); m.p.
127-129 oC; 1H NMR (500 MHz, CDCl3): δ 8.02 (t, J = 1.7 Hz, 1H), 7.78-7.76 (m, 1H), 7.64-7.62 (m,
2H), 7.56 (t, J = 1.7 Hz, 1H), 7.43-7.40 (m, 1H), 7.37-7.32 (m, 2H), 7.28-7.26 (m, 1H), 7.23 (t, J = 7.9
Hz, 1H), 7.10 (t, J = 7.9 Hz, 2H); C{1H} NMR (125 MHz, CDCl3): δ 195.1, 192.7, 150.1, 143.3,
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137.2, 136.8, 134.6, 133.9, 132.2, 132.1, 131.9, 131.4, 130.4, 129.8, 129.3, 127.9, 127.8, 124.2, 123.2,
122.4, 122.1; HRMS (ESI) for C22H13Br2O2 [M+H]+: calcd 466.9277, found 466.9283.
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3-(3-(3-cyanobenzoyl)-1-oxo-1H-inden-2-yl)benzonitrile (2l). Black solid (54.2 mg, 50%); m.p.
181-183 oC; 1H NMR (500 MHz, CDCl3): δ 8.16 (t, J = 1.4 Hz, 1H), 8.11-8.09 (m, 1H), 7.83-7.81 (m,
1H), 7.71-7.68 (m, 2H), 7.61-7.59 (m, 1H), 7.57-7.53 (m, 2H), 7.48-7.44 (m, 1H), 7.42-7.38 (m, 2H),
7.10 (d, J = 7.2 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 194.4, 191.8, 150.4, 142.8, 137.3, 135.7,
134.9, 133.5, 133.4, 133.0, 132.8, 132.7, 132.6, 130.6, 130.4, 130.14, 129.4, 129.0, 124.7, 122.4, 117.9,
117.2, 113.7, 113.0; HRMS (ESI) for C24H13N2O2 [M+H]+: calcd 361.0972, found 361.0967.
3-(2-methylbenzoyl)-2-(o-tolyl)-1H-inden-1-one (2m). Yellow solid (72.0 mg, 71%); m.p. 120-122
oC; 1H NMR (500 MHz, DMSO-d6): δ 7.63 (d, J = 7.1 Hz, 1H), 7.56-7.54 (m, 1H), 7.45-7.42 (m, 1H),
7.35-7.29 (m, 2H), 7.26-7.23 (m, 1H), 7.12-7.03 (m, 4H), 7.01-7.00 (m, 2H), 2.52 (s, 3H), 2.23 (s, 3H);
13C{1H} NMR (125 MHz, DMSO-d6): δ 195.9, 195.8, 152.4, 143.9, 138.9, 138.7, 136.5, 136.1, 134.2,
132.2, 131.6, 130.2, 123.0, 129.7, 129.7, 129.6, 129.2, 128.8, 125.2, 125.1, 123.9, 122.3, 20.7, 20.5;
HRMS (ESI) for C24H19O2 [M+H]+: calcd 339.1380, found 339.1387.
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153-155 C; H NMR (500 MHz, CDCl3): δ 7.66 (d, J = 7.1 Hz, 1H), 7.61 (d, J = 7.4 Hz, 1H),
7.53-7.48 (m, 2H), 7.39-7.36 (m, 1H), 7.19-7.16 (m, 1H), 7.15-7.12 (m, 2H), 7.11-7.06 (m, 4H);
13C{1H} NMR (125 MHz, CDCl3): δ 195.4, 193.1, 150.3, 143.0, 137.2, 137.1, 134.5, 133.7, 132.5,
132.0, 130.9, 130.2, 130.0, 129.9, 129.6, 129.5, 129.2, 129.1, 126.5, 126.1, 124.2, 123.3; HRMS (ESI)
for C22H13Cl2O2 [M+H]+: calcd 379.0287, found 379.0282.
3-(2-bromobenzoyl)-2-(2-bromophenyl)-1H-inden-1-one (2o). Red-brown solid (72.3 mg, 51%); m.p.
115-118 oC; 1H NMR (500 MHz, CDCl3): δ 7.67-7.65 (m, 2H), 7.54-7.51 (m, 1H), 7.45-7.43 (m, 1H),
7.40-7.37 (m, 1H), 7.35-7.33 (m, 2H), 7.14-7.06 (m, 4H), 7.01-6.98 (m, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 195.1, 193.8, 149.6, 143.1, 139.3, 139.0, 134.5, 133.0, 132.32, 132.31, 131.2, 130.8, 130.1,
123.0, 129.5, 127.0, 126.7, 124.2, 123.4, 123.4, 120.1; HRMS (ESI) for C22H13Br2O2 [M+H]+: calcd
466.9277, found 466.9284.
3-(3,4-dimethylbenzoyl)-2-(3,4-dimethylphenyl)-1H-inden-1-one (2p). Yellow solid (92.3 mg, 84%);
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m.p. 154-156 oC; 1H NMR (500 MHz, CDCl3): δ 7.75 (s, 1H), 7.68-7.67 (m, 1H), 7.60 (d, J = 7.0 Hz,
1H), 7.36-7.33 (m, 1H), 7.29-7.25 (m, 2H), 7.19-7.17 (m, 1H), 7.13 (d, J = 7.9 Hz, 1H), 7.01-6.96 (m,
2H), 2.27 (s, 3H), 2.24 (s, 3H), 2.18 (s, 3H), 2.17 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 196.5,
194.7, 150.3, 144.5, 144.3, 137.7, 137.3, 136.5, 134.3, 134.1, 133.3, 130.4, 130.2, 130.1, 129.7, 129.6,
129.0, 127.4, 126.8, 123.6, 121.5, 20.2, 19.7, 19.6, 19.6; HRMS (ESI) for C26H23O2 [M+H]+: calcd
367.1693, found 367.1698.
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3-(3,4-dimethylbenzoyl)-2-(3,4-dimethylphenyl)-1H-inden-1-one (2q). Yellow solid (69.6 mg, 72%);
m.p. 130-132 oC; 1H NMR (500 MHz, CDCl3): δ 8.09-8.08 (m, 1H), 7.94-7.93 (m, 1H), 7.63 – 7.62 (m,
1H), 7.58 (d, J = 7.0 Hz, 1H), 7.38-7.33 (m, 2H), 7.29–7.26 (m, 1H), 7.21-7.19 (m, 1H), 7.15-7.14 (m,
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1H), 7.02 (d, J = 7.3 Hz, 1H); C{1H} NMR (125 MHz, CDCl3): δ 196.3, 188.1, 148.3, 144.4, 140.6,
136.0, 134.5, 130.1, 129.5, 129.2, 128.5, 127.7, 127.5, 127.3, 126.9, 125.6, 123.9, 121.7; HRMS (ESI)
for C18H11O2S2 [M+H]+: calcd 323.0195, found 323.0189.
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2-butyl-3-pentanoyl-1H-inden-1-one (2r). Yellow solid (44.6 mg, 55%); m.p. 87-89 C; H NMR
(500 MHz, CDCl3): δ 8.29-8.27 (m, 1H), 8.13-8.11 (m, 1H), 7.88-7.82 (m, 2H), 2.42-2.39 (m, 2H),
2.12-2.08 (m, 2H), 1.61-1.55 (m, 2H), 1.37-1.30 (m, 6H), 0.92-0.84 (m, 6H); 13C{1H} NMR (125 MHz,
CDCl3): δ 188.5, 172.6, 160.4, 135.2, 134.6, 131.1, 130.5, 128.0, 126.1, 102.3, 37.7, 33.1, 26.4, 24.0,
22.5, 22.0, 13.7, 13.6; HRMS (ESI) for C18H23O2 [M+H]+: calcd 271.1693, found 271.1698.
3-benzoyl-2-(4-methoxyphenyl)-1H-inden-1-one
(2s)
and
3-(4-methoxybenzoyl)-2-phenyl
-1H-inden-1-one (2sʹ). Inseparable regioisomers: 2s:2sʹ = 6:1; Red solid (85.0 mg, 83% total yield);
m.p. 123-126 oC; 1H NMR (500 MHz, CDCl3) (peaks for major product 2s): δ 7.95-7.93 (m, 2H), 7.61
(d, J = 7.0 Hz, 2H), 7.55-7.52 (m, 1H), 7.42-7.35 (m, 5H), 7.29-7.26 (m, 1H), 7.03 (d, J = 7.4 Hz, 1H),
13
6.79-6.76 (m, 2H), 3.75 (s, 3H); C{1H} NMR (125 MHz, CDCl3) (peaks for major product 2s): δ
196.6, 195.0, 160.3, 148.5, 144.5, 135.3, 134.5, 134.4, 131.0, 129.6, 129.5, 129.0, 128.9, 123.9, 122.3,
121.5, 114.1, 114.0, 55.3; HRMS (ESI) for C23H17O3 [M+H]+: calcd 341.1172, found 341.1177.
3-benzoyl-2-(4-fluorophenyl)-1H-inden-1-one (2t) and 3-(4-fluorobenzoyl)-2-phenyl-1H-inden
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-1-one (2tʹ). Inseparable regioisomers: 2t:2tʹ = 1.2:1; Yellow solid (77.2 mg, 78% total yield); m.p.
101-103 oC; 1H NMR (500 MHz, CDCl3): δ 7.97-7.96 (m, 2H), 7.64-7.62 (m, 1H), 7.45-7.38 (m, 4H),
7.37-7.23 (m, 3H), 7.09-7.00 (m, 2H), 6.95-6.92 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3): we failed
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to assign those peaks for each isomer due to the substantial overlaps appearing in C NMR spectra;
HRMS (ESI) for C22H14FO2 [M+H]+: calcd 329.0972, found 329.0976.
3-benzoyl-5,6-dimethoxy-2-phenyl-1H-inden-1-one (2u). Purple solid (58.2 mg, 52%); m.p. 145-147
oC; 1H NMR (500 MHz, CDCl3): δ 7.91-7.89 (m, 2H), 7.50-7.47 (m, 1H), 7.37-7.35 (m, 2H), 7.32 (t, J
= 7.8 Hz, 2H), 7.23 (s, 1H), 7.21-7.18 (m, 3H), 6.70 (s, 1H), 3.94 (s, 3H), 3.88 (s, 3H); 13C{1H} NMR
(125 MHz, CDCl3): δ 195.5, 194.7, 153.7, 149.4, 148.3, 138.8, 135.3, 134.5, 134.2, 129.9, 129.4, 129.3,
128.7, 128.7, 128.2, 121.8, 108.2, 106.1, 56.4, 56.4; HRMS (ESI) for C24H19O4 [M+H]+: calcd
371.1278, found 371.1270.
5,6-dimethoxy-3-(4-methylbenzoyl)-2-(p-tolyl)-1H-inden-1-one (2v). Purple solid (71.8 mg, 60%);
o
1
m.p. 152-154 C; H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H),
7.21 (s, 1H), 7.15 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H),
2.35 (s, 3H), 2.25 (s, 3H); C{1H} NMR (125 MHz, CDCl3): δ 195.9, 194.6, 153.6, 149.3, 148.1,
13
145.5, 139.1, 138.79, 133.78, 132.9, 129.61, 129.55, 129.2, 129.1, 127.2, 121.8, 108.1, 105.9, 56.5,
56.4, 21.8, 21.3; HRMS (ESI) for C26H23O4 [M+H]+: calcd 399.1591, found 399.1597.
5,6-dimethyl-3-(4-methylbenzoyl)-2-(p-tolyl)-1H-inden-1-one (2w). Black solid (77.0 mg, 70%); m.p.
138-140 oC; 1H NMR (500 MHz, CDCl3): δ 7.84 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.21 (s,
1H), 7.15 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 6.63 (s, 1H), 3.93 (s, 3H), 3.86 (s, 3H), 2.35 (s,
3H), 2.25 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3): δ 195.9, 194.6, 153.6, 149.3, 148.1, 145.5, 139.1,
138.8, 133.8, 132.9, 129.6, 129.6, 129.2, 129.1, 127.2, 121.8, 108.1, 105.9, 56.5, 56.4, 21.8, 21.3;
HRMS (ESI) for C26H23O2 [M+H]+: calcd 367.1693, found 367.1697.
3-benzoyl-5,6-difluoro-2-phenyl-1H-inden-1-one (2x). Yellow solid (67.5 mg, 65%); m.p. 124-127
oC; 1H NMR (500 MHz, CDCl3): δ 7.77-7.75 (m, 2H), 7.56-7.53 (m, 1H), 7.48-7.45 (m, 1H), 7.38-7.35
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(m, 2H), 7.34-7.31 (m, 2H), 7.20-7.16 (m, 3H), 7.07-7.04 (m, 1H); 13C{1H} NMR (125 MHz, CDCl3):
δ 192.3, 190.0, 158.8 (dd, J1 = 248.8 Hz, J2 = 71.3 Hz), 158.3 (dd, J1 = 253.8 Hz, J2 = 17.5 Hz), 135.0,
132.0, 131.8 (d, J = 1.3 Hz), 129.9, 129.7, 129.1, 128.6, 122.7 (dd, J1 = 15.0 Hz, J2 = 6.3 Hz), 121.6,
120.8 (d, J = 26.3 Hz), 120.6 (dd, J1 = 18.8 Hz, J2 = 11.3 Hz), 116.4 (dd, J1 = 25.0 Hz, J2 = 3.8 Hz),
100.2 (d, J = 2.5 Hz), 81.2 (d, J = 2.5 Hz); HRMS (ESI) for C22H13F2O2 [M+H]+: calcd 347.0878,
found 347.0871.
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Gram-scale synthesis of 2a. To
a
50 mL round-bottomed flask were added
1,2-bis(p-tolylethynyl)benzene 1a (1.5 g, 5 mmol), I2O5 (6.7 g, 4 equiv, 20 mmol), MeCN/H2O (4/1
o
(V/V), 25 mL). The reaction was stirred at 50 C for 24 h. After completion of the reaction, H2O (10
mL) and saturated Na2S2O3 (15 mL) was added at room temperature. Then, the reaction mixture was
extracted with DCM and purified by flash chromatography on silica gel (petroleum ether/EtOAc, V/V
=10 : 1). The product was isolated as a yellow solid (1.27 g, 75%).
Radical inhibition reactions. To a 25 mL Schlenk tube were added 1,2-bis(p-tolylethynyl)benzene
1a (91.8 mg, 0.3 mmol), I2O5 (400.8 mg, 4 equiv, 1.2 mmol), TEMPO, butylated hydroxytoluene
(BHT), or N-tert-buthyl-α-phenylnitrone (PBN), MeCN/H2O (4/1 (V/V), 4.5 mL). The reaction was
stirred at 50 oC for 24 h. After completion, samples were taken for LC analysis.
Controlled experiment by removal of O2. 1,2-Bis(p-tolylethynyl)benzene 1a (91.8 mg, 0.3 mmol),
I2O5 (400.8 mg, 4 equiv, 1.2 mmol), MeCN/H2O (4/1 (V/V, 4.5 mL) were added to a 10-mL flask
equipped with a high-vacuum PTFE valve-to-glass seal. Then the resultant mixture in the sealed tube
was frozen by immersion of the flask in liquid N2. When solvent was completely frozen, the flask was
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opened to the vacuum (high vacuum) and pumped for 2-3 minutes, with the flask still immersed in
liquid N2. The flask was then closed and warmed until solvent completely melted. This process was
repeated three times and after the last cycle the flask was backfilled with an inert Ar gas. The reaction
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o
was stirred at 50 C for 24 h under Ar atmosphere. After completion, samples were taken for LC
analysis.
Controlled experiment by removal of H2O. To a 25 mL Schlenk tube were added
1,2-bis(p-tolylethynyl)benzene 1a (91.8 mg, 0.3 mmol), I2O5 (400.8 mg, 4 equiv, 1.2 mmol) and
o
anhydrous acetonitrile (4 mL). The reaction was stirred at 50 C for 24 h. After completion, samples
were taken for LC analysis.
18O-Labeling experiment. To a 25 mL Schlenk tube were added 1,2-bis(phenylethynyl)benzene 1b
(83.5 mg, 0.3 mmol), I2O5 (400.8 mg, 4 equiv, 1.2 mmol) and MeCN/H2O18 (4/1 (V/V), 4.5 mL). The
o
reaction was stirred at 50 C for 24 h. H2O (4 mL) and saturated Na2S2O3 (4 mL) was added at room
temperature. Then, the reaction mixture was extracted with DCM and purified by flash chromatography
on silica gel (petroleum ether/EtOAc = 10 : 1 (V/V)) as a yellow solid (68.0 mg, 73%). The
double-18O-incorporated product 2b-[O18]2 (m/z = 315 [M+H]+) was detected by the MS analysis (see
Figure S1 in Supporting Information).
ASSOCIATED CONTENT
Supporting Information
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13
Charts for mechanistic studies as well as copies of H and C NMR spectra of the products. This
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material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
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Corresponding Author
*E-mail: ykuiliu@zjut.edu.cn; jhwei828@zjut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Natural Science Foundation of China (No. 21772176 and 21372201) for
financial support.
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