A Method for Synthesis of 3-Hydroxy-1-indanones via Cu-Catalyzed Intramolecular Annulation Reactions

Article abstract of DOI:10.1021/acs.joc.8b02149

We report a facile and highly efficient method that copper-catalyzed intramolecular annulation to synthesize 3-hydroxy-1-indanones employing simple 2-ethynylbenzaldehyde as starting materials was achieved successfully. This protocol provided a simple synthetic approach to afford 3-hydroxy-1-indanones under mild conditions in good to excellent yields.

Full text of DOI:10.1021/acs.joc.8b02149

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Article
A method for synthesis of 3-hydroxy-1-indanones via
Cu–catalyzed intramolecular annulation reactions
Guoxue He, Chenglin Wu, Jianhui Zhou, Qiaolan Yang,
Chunmei Zhang, Yu Zhou, Huabei Zhang, and Hong Liu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02149 • Publication Date (Web): 08 Oct 2018
Downloaded from http://pubs.acs.org on October 8, 2018
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A method for synthesis of 3-hydroxy-1-indanones via Cu–catalyzed
intramolecular annulation reactions
a
b
b
b
b
b
Guoxue He, Chenglin Wu, Jianhui Zhou, Qiaolan Yang, Chunmei Zhang, Yu Zhou, Huabei
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a,
b,
Zhang, * and Hong Liu *
aKey Laboratory of Radiopharmaceuticals of Ministry of Education, College of Chemistry, Beijing Normal
University, No. 19 Xinjiekouwai Street, Haidian District, Beijing 100875, People's Republic of China
bState key Laboratory of Drug Research and Key Laboratory of Receptor Research, Shanghai Institute of
Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China.
ABSTRACT
We report a facile and highly efficient method that copper-catalyzed intramolecular
annulation
to
synthesize
3-hydroxy-1-indanones
employing
simple
2
-ethynylbenzaldehyde as starting materials was achieved successfully. This protocol
provided a simple synthetic approach to afford 3-hydroxy-1-indanones under mild
conditions in good to excellent yields.
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INTRODUCTION
Indanone skeleton is one of the most important privileged scaffolds and are widely
distributed in various natural products and pharmaceutical molecules (Figure 1) 1-12 that
exhibit a broad spectrum of biological activities.13-18 Donepezil from a synthetic
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-substituted-1-indanones was verified to be an AChE inhibitor and was approved for the
1
treatment of Alzheimer’s disease. Other natural-source indanone skeletons, such as
2
3-6
7
8,9
tripartin, pterosins, fused-indanone Ligustrone C, spiro-indanone coleophomone D
and sibiricine10,11 with a 3-hydroxy-1-indanone scaffold were found to have intriguing
anti-cancer activities, anti-spasmodic activities, anti-fungal and anti-viral activities,
respectively.
X
O
O
O
O
O
HO
R
Cl
HO
OH
OH
Cl
Tripartin
A Histone Demethylase Inhibitor
N
Pterosins
Donepezil
X= OH, Cl, OAc, OGlu
R= H, Me
Antispasmodic activity
O
N
O
O
O
OMe
O
O
O
O
HO
HO
HO O
O
OH
O
O
Coleophomone D
Antifungal activity,
Sibiricine
Antiviral and Antimicrobial
Ligustrone C
Cercospora beticola toxin
Inhibition of human heart chymase
Figure 1 Some natural product frameworks fused 1-indanone core
These significant biological potentials from 3-substituted-1-indanones aroused high
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desire to develop efficient and convenient methods to synthesize these intriguing
indanone scaffolds. Therefore, some synthetic strategies were frequently reported.19-28
Remarkably, Xiao’s group29 in 2011 reported
a
direct synthesis of
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3-hydroxy-1-indanones via a Pd-catalyzed olefination and ethylene glycol-promoted
aldol-type annulation casade with good yields (Scheme 1a). In 2013, our group reported
an intriguing strategy for the preparation of chiral 3-alkyl substituted indanones with
excellent ee values via an asymmetric Michael addition of N-tert-butanesulfinyl imidates
with α,β-unsaturated diesters only using LDA as a base in the absence of transition metals
3
0
31
and further annulation reaction (Scheme 1b). Meanwhile, Toste groups had fulfilled a
pioneering gold(I)-catalyzed enantioselective carboalkoxylation of alkynes to build a
series of chiral 3-methoxy-1-indanones and gave excellent enantioselectivities with
3
2
33
8
3-99% ee (Scheme 1c). Thereafter, You and Wong groups have also developed two
other gold-catalyzed tandem reactions from 2-ethynylbenzaldehyde to give a series of
racemic 3-alkoxy-1-indanones, respectively. Although these advances have been reported,
the majority of the protocols were restricted to intricate starting materials, expensive
transition-metal catalysts or multiple operations. Therefore, developing more efficient
synthetic methods toward 3-substituted-1-indanones are imperative. To extend our
studies to construct more diversified 3-substituted-1-indanones, especially for
3-hydroxy-1-indanones with potential biological effects, our new studies has displayed
that 2-ethynylbenzaldehyde could be effectively transformed into 3-hydroxy-1-indanones
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under the presence of simple CuI as a catalyst. This intramolecular annulation reaction is
a highly effective synthetic strategy with more mild reaction conditions and more simple
and cheap starting materials.
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Scheme 1. Strategies for Synthesis of 3-substituted-1-indanones
Previous work:
HO
R
R
OR
Br/Cl
R
a)
R
R
OR
Pd
O
O
CONH2
b)
COOEt
COOEt
R
R
R
S
S
R
O
N
R
N
O
R'
COOEt
MeO
MeO
O
COOEt
(dr up to 99:1)
OMe
OMe
c)
[Au]
OMe
O
83-99% ee
This work:
O
HO
R2
Cu, Pyrrolidine
AcOH, THF, H O, r.t.
R2
R1
R1
2
O
RESULTS AND DISCUSSION
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To optimize the reaction conditions, we initially treated 1a with a series of Cu
catalysts in DCE at room temperature (Table 1, entries 1–7). Surprisingly, the desired
product 2a was observed in all conditions. However, the yields of 2a with Cu (I) as
catalyst are superior to that of Cu (II), CuI seems to be the best choice for this
transformation. Encouraged by these results, we have further screened various solvents,
such as CH OH, PhCH , Me CO, CH CN, DMF, 1,4-Dioxane and THF (Table 1, entries
1
1
1
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-14). The results demonstrated that the yield of product 2a could be increased to 60% in
THF (Table 1, entry 14). Further explorations about the reaction temperature did not
improve the yield of the product 2a (Table 1, entries 15-17). Besides, we attempted to
decrease the amount of additives (pyrrolidine and AcOH) to a half, and the yield of target
product 2a could surprisingly increased to 73% (Table 1, entry 18). However, the
reaction did not work under the absence of pyrrolidine (Table 1, entry 19), which
indicated the addition of pyrrolidine is important for this transformation. Surely, the
absence of CuI could also not produce the target indanone scaffold (Table 1, entry 20).
To further improve the yield of target products, 2 equiv of H O as an additive was
2
investigated (Table 1, entry 21), and surprisingly an excellent yield (87%) was detected.
Altogether, the optimum result could be obtained by the treatment of
2
-ethynylbenzaldehyde (1a) with 0.1 equiv of CuI, 1 equiv of pyrrolidine, 1 equiv of
AcOH, 2 equiv of H O in THF at room temperature for 12 h.
2
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Table 1. Optimization of metal-catalyzed reactions of 1a.a
O
OH
O
Catalyst, Pyrrolidine
H
AcOH, Solvent
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9
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1a
2a
entry catalyst (10 mol%)
solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
T (°C) time (h) yield(%)b
1
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
24
24
24
24
24
24
24
24
24
24
24
24
24
52
45
39
19
23
25
11
0
CuI
2
CuBr
3
CuCl
4
CuCl2
5
Cu(OTf)2
6
Cu(OAc)2
7
CuSO4
8
CuI
CH OH
3
9
40
13
34
31
11
CuI
PhCH3
1
0
CuI
CuI
CuI
CuI
Me CO
2
11
CH CN
3
1
1
2
3
DMF
1
,4-Dioxane
14
CuI
CuI
r.t.
40
24
24
60
50
THF
THF
1
5
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CuI
CuI
CuI
CuI
0
THF
THF
THF
THF
THF
THF
60
80
r.t.
r.t.
r.t.
r.t.
24
24
24
24
24
12
32
18
73
0
18c
1
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0
9d
1
2
0
0
2
1e
CuI
87
a
Reaction conditions: 1a (0.4 mmol), catalyst (10 mol %), pyrrolidine (2 equiv), AcOH
(
2 equiv), solvent (3 mL), for 12−24 h. b Isolated yields. c Catalyst (10 mol %),
pyrrolidine (1 equiv), AcOH (1 equiv). d Catalyst (10 mol %), AcOH (1 equiv), no
e
pyrrolidine. Catalyst (10 mol %), pyrrolidine (1 equiv), AcOH (1 equiv), additive H O
2
(2 equiv).
With the optimal conditions in hand, we explored the scope of substrate and the
results are summarized in Table 2. Most of the starting materials 1a–1t reacted smoothly
to produce corresponding desired products 2a–2t in moderate to good yields, respectively
(Table 2). Whether introducing electron-donating groups or electron-withdrawing groups
1
into R group, an excellent yields could be detected, such as alkyl (2b, 2g and 2j),
methoxy (2c and 2h), and halides (2d, 2i, 2k, 2e and 2l and 2f). Besides,
2
-ethynylbenzaldehyde involving ester groups or di-substituted groups also gave the
corresponding indanone scaffold (2m, 2n, 2o, 2p and 2q). Besides, fused
2
2
-ethynylbenzaldehyde,
such
1-ethynyl-2-naphthaldehyde
and
-ethynyl-1-naphthaldehyde (1r and 1s) are also tolerated for this transformation and
give the target products 2r and 2s with good yields. We also attempted to exploited
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2
-ethynylphenylethanone (1t) as the starting material for this transformation, and it is
intriguing that the desired produce were obtained with a moderate yield.
0
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8
9
0
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Table 2. The scope for the synthesis of 3-hydroxyindanones 2a-2t.a, b
O
HO
R2
CuI (10 mol %), Pyrrolidine (1 equiv)
R2
R1
R1
AcOH (1 equiv), H O (2 equiv), THF, r.t, 12 h
2
O
1a-1t
2a-2t
OH
O
OH
O
OH
O
OH
O
OH
OH
O
O
F
Cl
Br
O
2a, 87%
2b, 84%
2c, 85%
2d, 71%
2e, 91%
2f, 87%
OH
OH
OH
OH
OH
OH
O
F
O
O
O
O
O
O
F
Cl
2l, 86%
2
g, 83%
2h, 80%
2i, 84%
2j, 89%
2k, 84%
OH
OH
OH
OH
OH
OH
O
O
F
F
F
O
O
O
O
O
O
O
O
O
O
2m, 71%
2n, 82%
HO
2o, 82%
2p, 83%
2q, 74%
2r, 75%
OH
O
O
2s, 71%
2t, 46%
a
Reaction conditions: 1a (0.4 mmol), catalyst (10 mol %), pyrrolidine (1 equiv), AcOH
b
(1 equiv), H O (2 equiv), THF (3 mL), for 12 h. Isolated yields.
2
To further evaluate the efficiency and potential applications of this reaction, we
performed a gram-scale preparation of the product 2a, and we can isolated this product
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with up to 81% yield (Scheme 2). Besides, the transformation of the product 2a to other
derivatives were also studied and the results displayed that compound 2a can be easily
converted
to
1H-indene-1,3(2H)-dione
(3)
through
Jones
reagent,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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1
2
,3-dihydro-1H-indene-1,3-diol (4) via NaBH , 3-methoxy-2,2-dimethyl-2,3-dihydro-
4
H-inden-1-one (5) in the presence of NaH/CH I, and can also form the
3
-benzylidene-1H-indene-1,3(2H)-dione (6) by a two-step operations involving an
-
oxidation and a condensation reaction, indene-1,3-diones showed some important
antibacterial, antifungal and anti-inflammatory activity.34
Scheme 2. Gram-scale experiment and further transformations of the 2a
O
OH
CuI (10 mol %), Pyrrolidine (1 equiv)
H
AcOH (1 equiv), THF, H O, r.t., 12 h
2
O
2a
1a
1g
922 mg, 81%
O
O
OH
OH
CrO
3, conc.
4
H
2SO4
O
NaBH
3OH
CH
3
, 95%
4, 98%
1
)
Jones
O
I
O
CH3
reage
OH
2)
Benzal
nt
2a
C
NaH,
2H5
dehyde,
reflux
OH,
O
O
6
, 91%
5
, 65%
Antibacterial, Antifungal,
Anti-inflammatory activity
A plausible mechanism is proposed for the formation of cyclization product via
CuI-catalyzed cascade annulation (Scheme 3). We presume that compound 1a firstly
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formed the intermediate A through an initial activation of the alkyne functionality via CuI
catalyst, then hydration of alkyne to afford intermediate B, closely followed
acid-catalyzed elimination of catalyst to obtain intermediate C according to the reported
0
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2
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study by Hassam. The intermediate C was finally converted into the target product 2a
via a subsequent Aldol reaction which was illustrated by a control experiment. In control
experiment, we could obtain the target product 2a in 91% yield by the treatment of
commercial available 2-acetylbenzaldehyde (the intermediate C) under the presence of
pyrrolidine. Conversely, the target product 2a could not be detected under the absence of
pyrrolidine.
Scheme 3. Proposed Mechanism for CuI-catalyzed Formation of 2a
O
O
1a
H
O
H
Cu
OH
C
H
N
H
O
O
H O
2
H
H
O
OH
OH
A
H
H2O
2a
Cu
Cu
N
B
N
H
H2O
D
E
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CONCLUSION
In conclusion, we have developed a facile method for the construction of diverse
3-hydroxy-1-indanones via inexpensive copper iodide catalyzed intramolecular
annulation. This paper presents a highly efficient, operationally simple and convenient
manner under mild conditions to prepare 3-hydroxy-1-indanones in moderate to good
yields. This method would be useful in organic synthesis in virtue of the easy availability
of the starting materials.
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EXPERIMENTAL SECTION
2-Ethynylbenzaldehyde (1a) derivatives are commercially available, with a purity of
more than 97% and used as received without further purification, some among them were
3
6
obtained by references. CuI–catalyzed reactions at room temperature and in the air.
TLC was performed on silica gel GF254 plates (Qingdao Marine Chemical Co., Ltd.,
China) and was visualized with UV lamp (254 nm). Flash column chromatography was
1
performed on silica gel (200−400 mesh). H NMR spectra were recorded on 400 MHz
NMR spectrometer (Bruker). 13C NMR spectra were recorded on 100 MHz NMR
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13
spectrometer. The H and C chemical shifts are referenced to signals at δ 0.00 (TMS).
1H NMR coupling constants (J) are reported in Hertz (Hz) and multiplicities are indicated
as follows: s (singlet), d (doublet), t (triplet) and m (multiplet). HRMS were performed
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using TOF and DFS analyzer. All new products were identified through H NMR, C
NMR and HRMS.
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General Procedure for the Synthesis of 3-hydroxy-2,3-dihydro-1H-inden-1-one (2a)
Derivatives. A solution of 2-ethynylbenzaldehyde (52 mg, 0.4 mmol) in THF (3 mL) was
stirred, pyrrolidine (0.35 mL, 0.4 mmol), AcOH (0.25 mL, 0.4 mmol), H O (0.14 mL, 0.8
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mmol) and CuI (10 mol%) was added and stirred at room temperature for about 12 h in
the air (monitored by TLC). Removal of the solvent under vacuum, and the residue was
purified on a silica gel column chromatography (eluent: EtOAc/PE=1:6) to provide the
corresponding product 2a as brown solid (59 mg, 87%).
1
3
-Hydroxy-2,3-dihydro-1H-inden-1-one (2a). Brown solid, 59 mg, 87%; mp 51-53 °C. H
NMR (400 MHz, CDCl ) δ 7.76~7.63 (m, 3H), 7.47 (dd, J = 11.0, 4.3 Hz, 1H), 5.40 (dd,
3
J = 6.7, 2.8 Hz, 1H), 3.29 (s, 1H), 3.08 (dd, J = 18.9, 6.8 Hz, 1H), 2.59 (dd, J = 18.9, 2.9
1
3
1
Hz, 1H). C { H} NMR (100 MHz, CDCl ) δ 203.8, 155.3, 136.3, 135.4, 129.5, 126.0,
3
+
123.2, 68.4, 47.1; HRMS (ESI-TOF) m/z calcd for C H O [M+H] 149.0597, found
9
9
2
1
3
1
49.0598.
-Hydroxy-5-methyl-2,3-dihydro-1H-inden-1-one (2b). Brown solid, 54 mg, 84%; mp
1
15-117 °C. H NMR (400 MHz, CDCl ) δ 7.63 (d, J = 7.9 Hz, 1H), 7.50 (s, 1H), 7.29 (d,
3
J = 7.8 Hz, 1H), 5.38 (dd, J = 6.8, 2.8 Hz, 1H), 3.10 (dd, J = 18.8, 6.8 Hz, 1H), 2.60 (dd,
1
3
1
J = 18.8, 2.9 Hz, 1H), 2.47 (s, 3H), 2.17 (s, 1H). C { H} NMR (100 MHz, CDCl ) δ
3
2
02.8, 155.6, 146.7, 134.2, 130.8, 126.1, 123.1, 68.5, 47.4, 22.2; HRMS (ESI-TOF) m/z
+
calcd for C H O [M+H] 163.0754, found 163.0754.
1
0
11
2
3
-Hydroxy-5-methoxy-2,3-dihydro-1H-inden-1-one (2c). Brown solid, 60 mg, 85%; mp
1
1
28-129 °C. H NMR (400 MHz, CDCl ) δ 7.61 (d, J = 8.5 Hz, 1H), 7.11 (d, J = 2.2 Hz,
3
1H), 6.95 (dd, J = 8.5, 2.2 Hz, 1H), 5.31 (dd, J = 6.8, 2.9 Hz, 1H), 3.88 (s, 3H), 3.04 (dd,
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J = 18.7, 6.8 Hz, 1H), 2.85 (d, J = 6.7 Hz, 1H), 2.56 (dd, J = 18.7, 3.0 Hz, 1H). C { H}
NMR (100 MHz, CDCl ) δ 201.9, 165.8, 158.4, 129.5, 125.0, 117.6, 108.8, 68.3, 55.8,
3
+
47.4. HRMS (EI-DFS) m/z calcd for C H O [M] 178.0630, found 178.0624.
1
0
10
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
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2
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=
-Fluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2d). Brown solid, 46 mg, 71%; mp
1
39-140 °C. H NMR (400 MHz, CD OD) δ 7.75 (dd, J = 8.5, 5.2 Hz, 1H), 7.43 (dd, J =
3
.5, 2.3 Hz, 1H), 7.26 (td, J = 8.8, 2.3 Hz, 1H), 5.34 (dd, J = 6.8, 3.0 Hz, 1H), 3.11 (dd, J
1
3
1
18.8, 6.9 Hz, 1H), 2.54 (dd, J = 18.8, 3.0 Hz, 1H). C { H} NMR (100 MHz, CD OD)
3
δ 202.6, 168.8 (d, J = 253.7 Hz), 159.6 (d, J = 9.4 Hz), 132.6 (d, J = 1.9 Hz), 125.1 (d, J
=
10.4 Hz), 117.1 (d, J = 24.2 Hz), 112.5 (d, J = 22.6 Hz),, 67.1 (d, J = 1.9 Hz), 46.6.
+
HRMS (EI-DFS) m/z calcd for C H FO [M] 166.0430, found 166.0425.
9
7
2
5
-Chloro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2e). Brown solid, 66 mg, 91%; mp
1
1
37-138 °C. H NMR (400 MHz, CDCl ) δ 7.7, 7.7 (d, J = 8.2 Hz, 1H), 7.5 (dd, J = 8.2,
3
1.5 Hz, 1H), 5.4 (dd, J = 6.7, 2.8 Hz, 1H), 3.1 (dd, J = 18.9, 6.9 Hz, 1H), 2.7, 2.6 (dd, J =
13
1
1
1
1
5
1
2
8.9, 3.1 Hz, 1H). C { H} NMR (100 MHz, CDCl ) δ 201.8, 156.6, 141.9, 134.8, 130.3,
3
26.3, 124.5, 68.1, 47.3. HRMS (EI-DFS) m/z calcd for C H ClO [M] 182.0135, found
9
7
2
82.0129.
-Bromo-3-hydroxy-2,3-dihydro-1H-inden-1-one (2f). Brown solid, 79 mg, 87%; mp
1
29-130 °C. H NMR (400 MHz, CDCl ) δ 7.90~7.85 (m, 1H), 7.60 (dt, J = 15.1, 4.7 Hz,
3
H), 5.40 (dd, J = 6.8, 3.0 Hz, 1H), 3.10 (dd, J = 18.9, 6.9 Hz, 1H), 2.61 (dd, J = 18.9,
1
3
1
3.1 Hz, 1H). C { H} NMR (100 MHz, CDCl ) δ 202.1, 156.7, 135.1, 133.1, 130.7,
3
+
1
29.4, 124.6, 68.1, 47.2. HRMS (EI-DFS) m/z calcd for C H BrO [M] 225.9629, found
9
7
2
2
25.9624.
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3
-Hydroxy-6-methyl-2,3-dihydro-1H-inden-1-one (2g). Brown solid, 54 mg, 83%; mp
1
1
27-128 °C. H NMR (400 MHz, CDCl ) δ 7.60 (d, J = 7.7 Hz, 1H), 7.57~7.44 (m, 2H),
3
5.41 (d, J = 4.3 Hz, 1H), 3.12 (dd, J = 18.8, 6.7 Hz, 1H), 2.62 (dd, J = 18.8, 2.6 Hz, 1H),
0
1
2
3
4
5
6
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8
9
0
1
2
3
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8
9
0
1
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9
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0
1
2
3
4
5
6
7
8
9
0
13
1
2
1
.43 (s, 3H), 1.68 (s, 1H). C { H} NMR (100 MHz, CDCl ) δ 203.4, 152.6, 139.8,
3
36.7, 136.5, 125.6, 123.2, 68.4, 47.6, 21.3. HRMS (ESI-TOF) m/z calcd for C H O
2
1
0
11
+
[M+H] 163.0754, found 163.0754.
3
6
-Hydroxy-6-methoxy-2,3-dihydro-1H-inden-1-one (2h). Brown solid, 57 mg, 80%; mp
1
7-69 °C. H NMR (400 MHz, CDCl ) δ 7.59 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 8.4, 2.5
3
Hz, 1H), 7.14 (d, J = 2.5 Hz, 1H), 5.38 (dd, J = 6.5, 2.4 Hz, 1H), 3.85 (s, 3H), 3.12 (dd, J
1
3
1
= 18.9, 6.6 Hz, 1H), 2.62 (dd, J = 18.9, 2.6 Hz, 1H). C { H} NMR (100 MHz, CDCl ) δ
3
2
03.6, 160.9, 148.2, 137.8, 126.9, 124.4, 104.4, 69.0, 55.7, 47.8. HRMS (EI-DFS) m/z
+
calcd for C H O [M] 178.0630, found 178.0624.
1
0
10
3
6-Fluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2i). Brown solid, 56 mg, 84%; mp
1
5
1-52 °C. H NMR (400 MHz, CDCl ) δ 7.63 (dd, J = 8.3, 4.5 Hz, 1H), 7.32 (ddd, J = 9.4,
3
7
.5, 2.3 Hz, 2H), 5.36 (dd, J = 6.5, 2.3 Hz, 1H), 3.10 (dd, J = 19.0, 6.7 Hz, 1H), 2.60 (dd,
1
3
1
J = 19.0, 2.8 Hz, 1H), 2.13 (s, 1H). C { H} NMR (100 MHz, CDCl ) δ 202.00 (d, J =
3
2
.8 Hz), 164.9 (d, J = 249.3 Hz), 150.7 (d, J = 2.2 Hz), 138.4 (d, J = 7.5 Hz), 127.7 (d, J
=
8.4 Hz), 123.1 (d, J = 23.8 Hz), 109.3 (d, J = 21.9 Hz), 68.0, 47.8. HRMS (EI-DFS) m/z
+
calcd for C H FO [M] 166.0430, found 166.0425.
9
7
2
3-Hydroxy-7-methyl-2,3-dihydro-1H-inden-1-one (2j). Brown solid, 58 mg, 89%; mp
1
4
9-50 °C. H NMR (400 MHz, CDCl ) δ 7.53~7.49 (m, 2H), 7.20 (dd, J = 5.5, 2.4 Hz,
3
1
H), 5.33 (dd, J = 6.9, 3.0 Hz, 1H), 3.04 (dd, J = 18.7, 6.9 Hz, 1H), 2.60 (s, 3H), 2.59 (s,
1
3
1
1H), 2.54 (d, J = 3.0 Hz, 1H). C { H} NMR (100 MHz, CDCl ) δ 204.4, 156.0, 138.5,
3
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34.7, 133.8, 131.3, 123.2, 68.0, 47.6, 18.4. HRMS (ESI-TOF) m/z calcd for C H O
2
1
0
11
+
[M+H] 163.0754, found 163.0750.
7-Fluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2k). Brown solid, 56 mg, 84%; mp
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
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4
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4
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5
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5
5
5
5
5
6
0
1
2
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6
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9
0
1
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7
8
9
0
1
2
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7
8
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1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
5
8-59 °C. H NMR (400 MHz, CDCl ) δ 7.64 (td, J = 7.9, 4.9 Hz, 1H), 7.48 (d, J = 7.6
3
Hz, 1H), 7.07 (t, J = 8.7 Hz, 1H), 5.39 (dd, J = 6.9, 3.1 Hz, 1H), 3.22 (s, 1H), 3.09 (dd, J
1
3
1
=
18.9, 6.9 Hz, 1H), 2.63 (dd, J = 18.9, 3.1 Hz, 1H). C { H} NMR (100 MHz, CDCl ) δ
3
1
1
4
99.8 (d, J = 1.2 Hz), 159.4 (d, J = 263.1 Hz), 157.4 (d, J = 1.5 Hz), 137.4 (d, J = 8.2 Hz),
24.0 (d, J = 12.9 Hz), 121.9 (d, J = 4.2 Hz), 116.3 (d, J = 19.2 Hz), 68.1 (d, J = 1.7 Hz),
+
7.6. HRMS (ESI-TOF) m/z calcd for C H FO [M+H] 167.0503, found 167.0499.
9
8
2
7-Chloro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2l). Brown solid, 63 mg, 86%; mp
1
6
2-64 °C. H NMR (400 MHz, CDCl ) δ 7.59 (dt, J = 15.1, 7.5 Hz, 2H), 7.40 (d, J = 7.2
3
Hz, 1H), 5.36 (dd, J = 6.9, 3.1 Hz, 1H), 3.13 (dd, J = 18.8, 6.9 Hz, 1H), 2.66 (dd, J = 18.8,
1
3
1
3.2 Hz, 1H). C { H} NMR (100 MHz, CDCl ) δ 200.1, 157.4, 135.7, 132.3, 131.3,
3
+
1
31.0, 124.4, 67.4, 47.7. HRMS (ESI-TOF) m/z calcd for C H ClO [M+H] 183.0207,
9
8
2
found 183.0212.
Methyl 1-hydroxy-3-oxo-2,3-dihydro-1H-indene-5-carboxylate (2m). Brown solid, 59 mg,
1
7
1%; mp 99-100 °C. H NMR (400 MHz, CD OD) δ 8.35 (dd, J = 8.0, 1.6 Hz, 1H), 8.28
3
(s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 5.41 (dd, J = 6.9, 3.1 Hz, 1H), 3.95 (s, 3H), 3.16 (dd, J
1
3
1
=
18.9, 6.9 Hz, 1H), 2.57 (dd, J = 18.9, 3.1 Hz, 1H). C { H} NMR (100 MHz, CD OD)
3
δ 203.4, 166.1, 160.4, 136.4, 135.4, 131.2, 126.4, 123.6, 67.4, 51.6, 46.6. HRMS (EI-DFS)
+
m/z calcd for C H O [M] 206.0579, found 206.0574.
1
1
10
4
3
-Hydroxy-5,6-dimethoxy-2,3-dihydro-1H-inden-1-one (2n). Brown solid, 68 mg, 82%;
1
mp 111-113 °C. H NMR (400 MHz, CDCl ) δ 7.12 (d, J = 7.9 Hz, 2H), 5.34 (dd, J = 6.5,
3
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.5 Hz, 1H), 3.98 (s, 3H), 3.91 (s, 3H), 3.09 (dd, J = 18.7, 6.6 Hz, 1H), 2.58 (dd, J = 18.7,
1
3
1
2
.6 Hz, 1H), 2.25 (s, 1H). C { H} NMR (100 MHz, CDCl ) δ 201.8, 155.9, 151.0, 150.3,
3
129.5, 106.6, 103.5, 68.4, 56.4, 56.2, 47.4. HRMS (ESI-TOF) m/z calcd for C H O
4
1
1
13
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
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7
8
9
0
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4
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6
7
8
9
0
1
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5
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+
[M+H] 209.0808 found 209.0807.
5
8
7
1
,6-Difluoro-3-hydroxy-2,3-dihydro-1H-inden-1-one (2o). Brown solid, 60 mg, 82%; mp
1
6-88 °C. H NMR (400 MHz, CD OD) δ 7.62 (dd, J = 9.6, 6.9 Hz, 1H), 7.55 (dd, J = 8.9,
3
.5 Hz, 1H), 5.33 (dd, J = 6.7, 2.1 Hz, 1H), 3.12 (dd, J = 18.9, 6.8 Hz, 1H), 2.53 (dd, J =
1
3
1
8.9, 2.9 Hz, 1H). C { H} NMR (100 MHz, CD OD) δ 201.90 (d, J = 2.4 Hz), 156.5
3
(dd, J = 256.3, 14.5 Hz), 153.6 (dd, J = 7.4, 2.7 Hz), 152.9 (dd, J = 250.2, 14.6 Hz),
132.8 (dd, J = 5.5, 2.5 Hz), 114.5 (d, J = 18.6 Hz), 110.5 (dd, J = 18.0, 1.9 Hz), 66.9 (d, J
+
=
1.4 Hz), 46.5. HRMS (EI-DFS) m/z calcd for C H F O [M] 184.0336, found
9
6
2
2
1
84.0330.
5-Fluoro-3-hydroxy-6-methyl-2,3-dihydro-1H-inden-1-one (2p). Brown solid, 60 mg,
1
8
9
2
3%; mp 124-126 °C. H NMR (400 MHz, CDCl ) δ 7.54 (d, J = 7.1 Hz, 1H), 7.29 (d, J =
3
.0 Hz, 1H), 5.35 (dd, J = 6.7, 2.5 Hz, 1H), 3.16 (s, 1H), 3.08 (dd, J = 18.9, 6.8 Hz, 1H),
1
3
1
.59 (dd, J = 18.9, 2.9 Hz, 1H), 2.32 (d, J = 1.8 Hz, 3H). C { H} NMR (100 MHz,
CDCl ) δ 202.2, 167.4 (d, J = 255.4 Hz), 155.8 (d, J = 9.4 Hz), 132.3 (d, J = 2.3 Hz),
3
1
27.8 (d, J = 19.6 Hz), 126.2 (d, J = 7.2 Hz), 112.3 (d, J = 23.5 Hz), 67.9 (d, J = 1.8 Hz),
+
4
7.3, 14.8 (d, J = 4.1 Hz). HRMS (EI-DFS) m/z calcd for C H FO [M] 180.0587,
10
9
2
found 180.0581.
7
-Hydroxy-6,7-dihydro-5H-indeno[5,6-d][1,3]dioxol-5-one (2q). Brown solid, 57 mg,
1
7
4%; mp 132-133 °C. H NMR (400 MHz, CD OD) δ 7.08 (s, 1H), 7.00 (s, 1H), 6.12 (dd,
3
J = 2.5, 0.7 Hz, 2H), 5.22 (dd, J = 6.6, 2.5 Hz, 1H), 3.05 (dd, J = 18.7, 6.6 Hz, 1H), 2.48
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(
dd, J = 18.7, 2.6 Hz, 1H). C { H} NMR (100 MHz, CD OD) δ 202.6, 155.0, 154.2,
3
1
49.8, 130.7, 104.8, 102.8, 100.5, 67.2, 46.7. HRMS (EI-DFS) m/z calcd for C H O
10 8 4
+
[M] 192.0423, found 192.0417.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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3
7
8
7
-Hydroxy-2,3-dihydro-1H-cyclopenta[a]naphthalen-1-one (2r). Brown solid, 59 mg,
1
5%; mp 109-110 °C. H NMR (400 MHz, CDCl ) δ 9.03 (d, J = 8.3 Hz, 1H), 8.06 (d, J =
3
.4 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.67~7.62 (m, 1H),
.60~7.54 (m, 1H), 5.42 (dd, J = 6.6, 2.6 Hz, 1H), 3.17 (dd, J = 18.6, 6.6 Hz, 1H), 2.70
1
3
1
(
dd, J = 18.6, 2.7 Hz, 1H). C { H} NMR (100 MHz, CDCl ) δ 203.8, 157.4, 136.5,
3
1
33.5, 130.6, 129.2, 128.5, 128.2, 127.3, 124.6, 122.4, 68.2, 47.7. HRMS (ESI-TOF) m/z
+
calcd for C H O [M+H] 199.0754, found 199.0755.
1
3
11
2
1
-Hydroxy-1,2-dihydro-3H-cyclopenta[a]naphthalen-3-one (2s). Brown solid, 56 mg,
1
7
1%; mp 124-126 °C. H NMR (400 MHz, CD OD) δ 9.02 (d, J = 8.3 Hz, 1H), 8.20 (d, J
3
= 8.4 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.67 (ddd, J = 8.3, 7.0,
.3 Hz, 1H), 7.60 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 5.40 (dd, J = 6.6, 2.6 Hz, 1H), 3.17 (dd,
1
1
3
1
J = 18.5, 6.6 Hz, 1H), 2.63 (dd, J = 18.8, 3.0 Hz, 1H). C { H} NMR (100 MHz, CD OD)
3
δ 204.8, 158.8, 136.3, 133.6, 129.9, 128.7, 128.5, 128.1, 126.9, 123.9, 122.6, 67.2, 46.9.
+
HRMS (ESI-TOF) m/z calcd for C H O [M+H] 199.0754, found 199.0756.
1
3
11
2
3
-Hydroxy-3-methyl-2,3-dihydro-1H-inden-1-one (2t). Brown solid, 30 mg, 46%; mp
1
7
1-73 °C. H NMR (400 MHz, CDCl ) δ 7.67 (d, J = 5.3 Hz, 3H), 7.48~7.43 (m, 1H),
3
1
3
1
2.86 (s, 2H), 2.59 (dd, J = 22.4, 15.4 Hz, 1H), 1.69 (s, 3H). C { H} NMR (100 MHz,
CDCl ) δ 203.5, 158.7, 135.6, 135.3, 129.3, 123.6, 123.1, 74.5, 53.8, 29.2. HRMS
3
+
(
ESI-TOF) m/z calcd for C H O [M+H] 163.0754, found 163.0749.
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General Procedure for the Synthesis of 1H-indene-1,3(2H)-dione (3).
3
-Hydroxy-2,3-dihydro-1H-inden-1-one (148 mg, 1 mmol) in Me CO (10 mL) was
2
stirred, Jones reagent (CrO 26 mg, conc H SO 2 mL, H O 1 mL) was added and stirred
3
2
4
2
0
1
2
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9
0
at room temperature for about 2 h in the air (monitored by TLC). Removal of the solvent
under vacuum, and the residue was purified on a silica gel column chromatography
(
eluent: EtOAc/PE=1:8) to provide the corresponding product 3 as yellow powder (139
mg, 95%).
H-indene-1,3(2H)-dione (3). Yellow powder, 139 mg, 95%; mp 115-117 °C. H NMR
1
1
1
3
1
(
400 MHz, CDCl ) δ 8.06~7.95 (m, 2H), 7.91~7.81 (m, 2H), 3.25 (s, 2H). C NMR { H}
3
(100 MHz, CDCl ) δ 197.5, 143.4, 135.6, 123.2, 45.0. HRMS (EI-DFS) m/z calcd for
3
+
C H O [M] 146.0368, found 146.0362.
9
6
2
General Procedure for the Synthesis of 2,3-dihydro-1H-indene-1,3-diol (4).
3-Hydroxy-2,3-dihydro-1H-inden-1-one (148 mg, 1 mmol) in CH OH (10 mL) was
3
stirred, NaBH (190 mg, 5 mmol) was added and stirred at room temperature for about 1
4
h (monitored by TLC). Removal of the solvent under vacuum, and the residue was
purified on a silica gel column chromatography (eluent: EtOAc/PE=1:4) to provide the
corresponding product 4 as yellow liquid (147 mg, 98%).
1
2
,3-Dihydro-1H-indene-1,3-diol (4). Yellow liquid, 147 mg, 98%; H NMR (400 MHz,
CDCl ) δ 7.43 (dd, J = 5.4, 3.3 Hz, 2H), 7.36 (dd, J = 5.7, 3.1 Hz, 2H), 5.42 (t, J = 5.3 Hz,
3
1
3
1
2H), 2.35 (t, J = 5.3 Hz, 2H), 1.88 (s, 2H). C { H} NMR (100 MHz, CDCl ) δ 144.6,
3
+
1
1
29.1, 124.6, 74.3, 46.6. HRMS (EI-DFS) m/z calcd for C H O [M] 150.0681, found
9
10
2
50.0675.
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General
Procedure
for
the
Synthesis
of
3
-methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one
(5).
3-Hydroxy-2,3-dihydro-1H-inden-1-one (148 mg, 1 mmol) in THF (10 mL) was stirred,
1
1
1
1
1
1
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NaH (120 mg, 5 mmol) was added and stirred at room temperature for about 1 h
(monitored by TLC). Removal of the solvent under vacuum, and the residue was purified
on a silica gel column chromatography (eluent: EtOAc/PE=1:8) to provide the
corresponding product 5 as yellow solid (124 mg, 65%).
3
-Methoxy-2,2-dimethyl-2,3-dihydro-1H-inden-1-one (5). Yellow solid, 124 mg, 65%;
1
mp 65-67 °C. H NMR (400 MHz, CDCl ) δ 7.75 (d, J = 7.6 Hz, 1H), 7.66 (dd, J = 4.7,
3
0.9 Hz, 2H), 7.47 (ddd, J = 7.8, 4.5, 3.4 Hz, 1H), 4.52 (s, 1H), 3.66 (s, 3H), 1.36 (s, 3H),
13
1
1
1
.16 (s, 3H). C { H} NMR (100 MHz, CDCl ) δ 208.2, 151.4, 134.9, 134.3, 129.3,
3
26.2, 123.8, 87.0, 59.6, 51.1, 24.2, 19.8. HRMS (ESI-TOF) m/z calcd for C H O
2
1
2
15
+
[M+H] 191.1067, found 191.1064.
General Procedure for the Synthesis of 2-benzylidene-1H-indene-1,3(2H)-dione (6).
H-indene-1,3(2H)-dione (146 mg, 1 mmol) in C H OH (10 mL) was stirred,
1
2
5
benzaldehyde (127 mg, 1.2 mmol) was added and stirred at reflux for about 3 h
monitored by TLC). Removal of the solvent under vacuum, and the residue was purified
(
on a silica gel column chromatography (eluent: EtOAc/PE=1:6) to provide the
corresponding product 6 as yellow solid (213 mg, 91%).
2-Benzylidene-1H-indene-1,3(2H)-dione (6). Yellow solid, 213 mg, 91%; mp 144-146 °C.
1
H NMR (400 MHz, CDCl ) δ 8.48 (d, J = 7.1 Hz, 2H), 8.03 (d, J = 5.0 Hz, 2H), 7.92 (s,
3
1
3
1
1
H), 7.83 (dd, J = 5.1, 3.1 Hz, 2H), 7.55 (dd, J = 15.9, 8.3 Hz, 3H). C { H} NMR (100
MHz, CDCl ) δ 190.3, 189.0, 147.0, 142.6, 140.1, 135.4, 135.2, 134.2, 133.2, 133.1,
3
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+
1
29.2, 128.8, 123.4, 123.4. HRMS (ESI-TOF) m/z calcd for C H O [M+H] 235.0754,
16 11 2
found 235.0751.
0
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ASSOCIATED CONTENT
Supporting Information
The H and 13C NMR spectra of all synthesized compounds.
1
AUTHOR INFORMATION
Corresponding Author
*
E-mail: hliu@simm.ac.cn.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We are grateful to the National Natural Science Foundation of China (No. 21672232, 21632008, 81620108027) and the
Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020324) for financial support.
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995, 38, 4897-4905.
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(
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arylalkynes leading to 2,3-disubstituted indanones. Org. Chem. Front. 2016, 3, 1116-1119.
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Table of Content Graphic
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O
HO
R2
Cu, Pyrrolidine
R2
R1
R1
AcOH, THF, H O, r.t
2
O
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4
a~2t
6~91%
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Low cost
Mild conditions
Various useful transformations
General substrate scope

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