Cleavage and Reassembly of the C═O Bond of 2-Alkynylbenzaldehydes: A Metal-Free Access to Inden-1-ones

Article abstract of DOI:10.1021/acs.joc.1c00780

A metal-free approach to inden-1-ones from 2-alkynylbenzaldehydes mediated by pyrrolidine has been developed. The reaction proceeds under mild conditions in a step- and atom-economy process by cleaving the C═O bond and constructing new C-C as well as C═O bonds. Oxygen-18 and deuterium labeling experiments revealed an aza-Petasis-Ferrier rearrangement of an intermediate 1-amino-3-methylene-dihydroisobenzofuran.

Full text of DOI:10.1021/acs.joc.1c00780

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Cleavage and Reassembly of the CO Bond of
2‑Alkynylbenzaldehydes: A Metal-Free Access to Inden-1-ones
Tao Liu,§ Tuanli Yao,* Feng Zhang,§ Ying Ju, and Jiajing Tan*
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ABSTRACT: A metal-free approach to inden-1-ones from 2-alkynylbenzaldehydes
mediated by pyrrolidine has been developed. The reaction proceeds under mild
conditions in a step- and atom-economy process by cleaving the CO bond and
constructing new C−C as well as CO bonds. Oxygen-18 and deuterium labeling
experiments revealed an aza-Petasis−Ferrier rearrangement of an intermediate 1-
amino-3-methylene-dihydroisobenzofuran.
Recently, we disclosed a base-catalyzed cyclization of N-
tert-butyl-2-(1-alkynyl)benzaldimines for the synthesis of 3-
amino-1-indenones, which was proposed to proceed through
a cascade of 5-exo-dig cyclization of N-tert-butyl-2-(1-
alkynyl)benzaldimines and thermal rearrangement of 3-
methylene-2λ2-isoindolin-1-ols.12a Inspired by our12 and
Wong’s previous work,10a we proposed that, if an electron-
deficient group was installed at the terminus of the alkyne, it
might not only promote 5-exo-dig cyclization of 2-alkynyl
aldehydes but also facilitate the elimination of the amino
group from the in situ generated 3-amino-indanones, which
should directly afford inden-1-ones as the final product.13
Thus, we herein report our recent efforts in developing a
metal-free synthesis of indenones from 2-alkynylbenzalde-
hydes by formal cleavage of a CO bond and reassembly of
new C−C and CO bonds.
INTRODUCTION
■
The indenone skeleton is ubiquitous in pharmaceutical and
natural products, which exhibit various biological activities
(Figure 1).1 Indenone derivatives are also versatile synthetic
precursors of many important aromatic and heterocyclic
compounds.2 A variety of methodologies for indenone
synthesis have been reported, including dehydrohalogenation
or dehydroxylation of the corresponding indanones,3
cyclization of 1,3-diarylpropynones,4 and aldol condensation
of substituted ortho-aroylpropiophenones.5 Although 2,3-
disubstituted indenones could be prepared by transition-
metal-catalyzed annulation of functionalized arenes with
alkynes,6 the intermolecular annulation often displayed a
low regioselectivity when using unsymmetrical internal
alkynes. Nevertheless, the Dong group recently developed
an elegant and straightforward method to construct
indenones from aryl iodides and unsaturated carboxylic
anhydrides via Pd/norbornene (NBE) catalysis, which proved
to be superior to previous methods in terms of
regioselectivity and was successfully applied to the synthesis
of pauciflorol F and acredinone A.7
During the past several years, 2-alkynyl aldehydes have
emerged as a valuable synthon for the preparation of carbo-
or heterocycles (Scheme 1).8 In most of the previously
reported reactions, a transition metal catalyst was indis-
pensable to activate the alkyne motif and/or the aldehyde
group. With regard to the synthesis of indenones from 2-
alkynyl aldehydes, there were only two examples of the
formation of indenone chelated iron complexes via a
photolytic reaction of 2-alkynylbenzaldehydes and Fe(CO)5.9a
Moreover, a gold-catalyzed cyclization of cyclic 2-alkynylalde-
hyde derived acetals for the synthesis of indenone derivatives
has been reported by Yamada and Sajiki.9b Despite the fact
that the metal-free synthesis of 3-amino-1-indanones and 3-
amino-1-indenones have been achieved by Wong10a and
Verma,10b respectively, the direct cyclization of ortho-alkynyl
aldehydes to generate indenones under metal-free conditions,
to the best of our knowledge, has not yet been realized.11
RESULTS AND DISCUSSION
■
We initiated our study by using ethyl 4-[(2-formylphenyl)-
ethynyl]benzoate (1a) as the model substrate. In the
presence of N,N-dimethylpyridin-4-amine (DMAP) or
diethylamine (Et2NH) in DCM at room temperature,
cyclization product 2a was not observed and 1a was
recovered in both cases (Table 1, entries 1 and 2). With
pyrrolidine, we were pleased to observe a 70% isolated yield
of 2a with full conversion of 1a (entry 3).14 On the other
hand, piperidine led to an incomplete reaction (entry 4).
Switching the solvent to chloroform, acetonitrile, DMF, or
THF led to lower yields of 2a, and most of the
transformations were incomplete even with prolonged
Received: April 2, 2021
Published: July 2, 2021
https://doi.org/10.1021/acs.joc.1c00780
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© 2021 American Chemical Society
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Figure 1. Natural products containing an indenone moiety.
deactivation in transition metal catalysis, was amenable to
give the expected inden-1-one 2j in a 55% yield.15
Disubstituted phenyl groups with at least one electron-
withdrawing group could also be used to afford 2k−n in
good yields. Notably, these electron-deficient functionalities
in the product could serve as a synthetic handle for further
derivatization of these bicyclic products. In accordance with
our working hypothesis, no desired product was formed when
a phenyl, alkyl, or ester group is on the remote end of alkyne
(not shown), demonstrating a certain limitation of our
protocol.
Scheme 1. Synthesis of Inden-1-ones from 2-Alkynyl
Aldehydes and Their Derivatives
We then turned our attention to varying the substitution
on the aromatic ring of the aldehyde (Table 3). Both halides
and electron-donating substituents were well tolerated on
both the meta and para positions in 2o−v. The single-crystal
X-ray structure of 2q provided the direct evidence of the
cleavage of the carbonyl group.16 The incorporation of the
electron-donating methoxy group at the para position of
aldehyde 1t decelerated the reaction remarkably, and the
cyclization occurred only at an elevated temperature.
Sterically hindered aldehyde 1w bearing both ortho and
meta substitutions was also viable to afford inden-1-one 2w in
75% yield. Besides, heterocyclic cyclopenta[b]quinolin-3-one
2x and cyclopenta[b]pyridin-7-one 2y were readily prepared
under standard conditions with high efficiency. Benzalde-
hydes 1z and 1z′, both of which have an electron-
withdrawing CF3 group on the aromatic ring of the aldehyde,
afforded a mixture of isomers 2z and 2z′ through different
mechanistic pathways (see Scheme 4). In each case, the
major inden-1-one product is the one involving a cleavage of
the carbonyl functionality.
Under standard reaction conditions, a gram-scale experi-
ment was performed on 1a, which proceeded with the same
efficiency as the milligram-scale reaction (Scheme 2a). The
synthetic utility of this method was further demonstrated by
product derivatization including selective reduction, Michael
addition, and hydrogenation (Scheme 2b). 1-Indanones 3 and
6, as well as inden-1-ol 4, were obtained from the
corresponding inden-1-one 2 in good to excellent yields,
respectively. Interestingly, when 2-(2-nitrophenyl)-1H-inden-
1-one (2f) was subjected to Pd/C-catalyzed hydrogenation
conditions, antioxidant 5,10-dihydroindeno[1,2-b]indole
(DHII, 5)17 could be easily prepared in 73% yield. This
one-pot transformation underwent a cascade of reduction of
both the CC bond and nitro group, intramolecular
condensation, and isomerization.
reaction time (entries 5−8). When using 4.0 mL of DCM or
employing 1.25 equiv of pyrrolidine, the reactions were
incomplete even after elongated reaction time and 2a was
obtained in lower yields (entries 9 and 10). All efforts to
develop a catalytic reaction by using a sub-stoichiometric
quantity of pyrrolidine with different additives did not work
(entries 11−15). Thus, the optimum reaction conditions
were assumed to be the one displayed in Table 1, entry 3.
We next investigated the scope of substituents at the
terminus of acetylenes (Table 2). When a phenyl group on
the remote end of alkyne was substituted with electron-
withdrawing substitutions such as ester, nitro, cyano, acyl, or
CF3 at the para position, the corresponding inden-1-one
products 2a−e were obtained in 50−87% yields. When the
electro-withdrawing group was at the meta or ortho position,
the reactions still proceeded smoothly to give inden-1-ones
2f−i in good to excellent yields. Moreover, the electron-
deficient pyridine ring, which often caused catalyst
To explore the mechanism of this reaction, we have
performed a series of control experiments (Scheme 3a). The
target product was not observed under standard reaction
conditions, when N-(p-tolylsulfonyl)imine or (R,E)-N-(tert-
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a
Table 1. Optimization of Reaction Conditions
b
entry
amine (equiv)
solvent
additive (equiv)
time (h)
conv. (%)
yield (%)
1
2
3
4
5
6
7
8
DMAP (2.0)
Et2NH (2.0)
DCM
DCM
DCM
DCM
CHCl3
MeCN
DMF
THF
DCM
DCM
DCM
DCM
DCM
DCM
DCM
24
24
24
32
31
9
24
48
36
32
32
32
32
32
32
0
0
0
0
pyrrolidine (2.0)
piperidine (2.0)
pyrrolidine (2.0)
pyrrolidine (2.0)
pyrrolidine (2.0)
pyrrolidine (2.0)
pyrrolidine (2.0)
pyrrolidine (1.5)
pyrrolidine (0.5)
pyrrolidine (0.5)
pyrrolidine (0.5)
pyrrolidine (0.5)
pyrrolidine (0.5)
100
51
96
100
89
86
96
90
0
70
39
62
56
29
48
55
42
0
0
6
10
0
c
9
10
11
12
13
Et3N (1.5)
Cs2CO3 (1.5)
DBU (1.5)
DBU (1.5)
AcOH (0.4)
0
16
35
0
d
14
15
a
b
c
d
Reaction conditions: 1a (0.25 mmol) and amine (2.0 equiv), solvent (2.0 mL). Isolated yield. DCM (4.0 mL) used. 40 °C.
a b
,
Table 2. Scope of the Substituents on the Acetylenes
alkynes, as no incorporation of 18O in indenone product 2c
was detected in LC-MS when running the reaction in the
presence of 15 equiv of H218O in acetonitrile. Moreover, this
labeling study could exclude the formation of an aminal
intermediate generated by aldehyde and pyrrolidine in the
reaction.10a With C1-deuterated aldehyde as the substrate
(1c-d), C3-deuterated indenone product (2c-d) was obtained
with a good level of deuterium retention either under
standard conditions or in the presence of 10 equiv of water,
further providing evidence to the proposed mechanistic
pathway.
On the basis of these investigations, a plausible mechanism
is proposed (Scheme 4). Initially, the nucleophilic addition of
pyrrolidine to aldehyde 1 generates hemiaminal I. In pathway
A, 5-exo-dig cyclization of the hydroxy group generates
intermediate II.13b The cyclization is facilitated by electron-
deficient groups at the terminus of the triple bond. Next, the
corresponding 1-amino-3-methylene-dihydroisobenzofuran II
undergoes fragmentation, followed by cyclization of the
enolate onto the iminium ion, to form 3-amino-1-indanone
IV (aza-Petasis−Ferrier rearrangement). Subsequent elimi-
nation of pyrrolidine under basic conditions eventually affords
inden-1-one 2 (carbonyl-cleavage product). In pathway B, 5-
exo-dig cyclization of the amino group and fragmentation of
V generates intermediate VI. Intramolecular nucleophilic
addition of the enamine to the aldehyde, followed by a
hydride shift to the iminium ion, produces 3-amino-1-
indanone VIII,18 which is then converted to inden-1-one 2′
(non-carbonyl-cleavage product) via elimination of pyrroli-
dine. Normally, pathway A dominates the reaction and
affords inden-1-one 2 (carbonyl-cleavage product) exclusively.
When an electron-withdrawing CF3 group is on the aromatic
ring of the aldehyde (such as 1z and 1z′), the alkyne is
sufficiently polarized. As such, pathway B (5-exo-dig
cyclization of the amino group) can compete with pathway
A (5-exo-dig cyclization of the hydroxy group), which leads to
a
Reaction conditions: 1 (0.25 mmol), pyrrolidine (2.0 equiv), DCM
b
(2.0 mL). Isolated yield.
butylsulfinyl)imine were used as analogues of aldehyde 1b.
The labeling experimental results could exclude the potential
reaction pathway involving Michael addition of pyrrolidine to
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Table 3. Scope of the Substituents on the Aromatic Ring
of Aldehyde
Scheme 2. Scalability Study and Derivatization of the
Inden-1-one Products
a
Scheme 3. Mechanistic Studies
a
Reaction conditions: 1 (0.25 mmol), pyrrolidine (2.0 equiv), DCM
b
(2.0 mL), 24 h. Isolated yield. The yield in parentheses is based on
the recovery of 1. 48 h. 40 °C. 6 h.
c
d
e
the formation of inden-1-one 2′ (non-carbonyl-cleavage
product) as a minor product.
CONCLUSIONS
■
In summary, we have developed a metal-free, pyrrolidine-
mediated synthesis of inden-1-ones from 2-alkynylbenzalde-
hydes under mild reaction conditions in good to excellent
yields by cleaving the CO bond and constructing new C−
C and CO bonds. The synthetic utility of this “cut and
sew” protocol is further demonstrated by the gram-scale
synthesis and derivatization of the inden-1-one products. The
preliminary mechanistic study reveals an aza-Petasis−Ferrier
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equiv), 2-ethynylbenzaldehyde (1.3 mmol, 1.3 equiv), and Et3N (3.0
equiv). The resulting mixture was heated in an oil bath at 80 °C
under argon. The progress of the reaction was monitored by TLC
analysis to establish its completion. After cooling to room
temperature, the reaction was diluted with ethyl acetate (20 mL),
washed with water (20 mL) and brine (20 mL), dried (MgSO4),
and concentrated. The residue was purified by column chromatog-
raphy (Silica Gel, petroleum ether/ethyl acetate).
Scheme 4. Proposed Mechanism
2-((2-Methoxypyridin-3-yl)ethynyl)benzaldehyde (1j). This prod-
uct was obtained as an amorphous coloress solid (0.178 g, 75%) by
using 3-iodo-2-methoxypyridine (0.235 g, 1.0 mmol) and 2-
ethynylbenzaldehyde (0.170 g, 1.3 mmol). Rf = 0.36 (PE/EtOAc
1
= 10:1); mp 96−98 °C; H NMR (400 MHz, CDCl3) δ 10.66 (s,
1H), 8.14 (dd, J = 5.0, 1.7 Hz, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.74
(dd, J = 7.4, 1.7 Hz, 1H), 7.62 (d, J = 7.3 Hz, 1H), 7.55 (td, J =
7.6, 1.1 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 6.91−6.86 (m, 1H), 4.02
(s, 3H);13C{1H} NMR (101 MHz, CDCl3) δ 194.1, 165.7, 149.0,
143.3, 137.9, 135.7, 134.9, 130.7, 129.0, 128.5, 118.4, 108.5, 93.0,
92.1, 56.0; IR (neat) 1693, 1577, 1467, 1399 cm−1; HRMS (ESI)
m/z: [M + H]+ calculated for C15H12NO2 238.0863; found
238.0857.
Ethyl 2-Fluoro-6-((2-formylphenyl)ethynyl)benzoate (1k). This
product was obtained as a yellow oil (0.258 g, 87%) by using ethyl
2-fluoro-6-iodobenzoate (0.294 g, 1.0 mmol) and 2-ethynylbenzal-
dehyde (0.170 g, 1.3 mmol). Rf = 0.49 (PE/EtOAc = 5:1); 1H
NMR (400 MHz, CDCl3) δ 10.57 (s, 1H), 7.94 (d, J = 7.8 Hz,
1H), 7.63−7.56 (m, 2H), 7.47 (t, J = 7.5 Hz, 1H), 7.43−7.39 (m,
2H), 7.18−7.10 (m, 1H), 4.44 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 191.9, 164.5, 160.0
(C-F, 1 JC‑F = 254.5 Hz), 136.4, 134.0, 133.6, 131.9 (C-F, 3 JC‑F
=
9.1 Hz), 129.5, 128.9 (C-F, 4 JC‑F = 3.0 Hz), 127.5, 126.2, 124.0
(C-F, 2 JC‑F = 17.2 Hz), 123.1 (C-F, 3 JC‑F = 5.1 Hz), 117.2 (C-F, 2
JC‑F = 22.2 Hz), 92.7 (C-F, 4 JC‑F = 4.0 Hz), 89.7, 62.4, 14.4; 19F
NMR (376 MHz, CDCl3) δ −112.47 to −112.54 (m, 1F); IR
(neat) 1731, 1698, 1597, 1456, 1269 cm−1; HRMS (ESI) m/z: [M
+ H]+ calculated for C18H14FO3297.0921; found 297.0915.
Ethyl 2-((2-Formylphenyl)ethynyl)-5-methylbenzoate (1l). This
product was obtained as a colorless oil (0.267 g, 91%) by using
ethyl 2-iodo-5-methylbenzoate (0.290 g, 1.0 mmol) and 2-
ethynylbenzaldehyde (0.169 g, 1.3 mmol). Rf = 0.43 (PE/EtOAc
rearrangement of the corresponding 1-amino-3-methylenedi-
hydroisobenzofuran intermediate. Further investigations are
currently undergoing in our group.
1
= 10:1); H NMR (400 MHz, CDCl3) δ 10.70 (s, 1H), 7.89 (d, J =
7.8 Hz, 1H), 7.76 (s, 1H), 7.62 (d, J = 7.2 Hz, 1H), 7.53−7.50 (m,
2H), 7.38 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 7.9 Hz, 1H), 4.36 (q, J =
7.1 Hz, 2H), 2.35 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR
(101 MHz, CDCl3) δ 192.7, 166.0, 139.2, 136.2, 134.2, 133.8,
133.3, 132.7, 131.9, 131.2, 128.7, 127.3, 127.0, 119.9, 95.3, 89.0,
61.4, 21.4, 14.4; IR (neat) 1696, 1593, 1497, 1290 cm−1; HRMS
(ESI) m/z: [M + H]+ calculated for C19H17O3 293.1172; found
293.1164.
Methyl 4-((2-Formylphenyl)ethynyl)-3-methoxybenzoate (1m).
This product was obtained as an amorphous colorless solid (0.147 g,
50%) by using methyl 4-iodo-3-methoxybenzoate (0.292 g, 1.0
mmol) and 2-ethynylbenzaldehyde (0.169 g, 1.3 mmol). Rf = 0.28
(PE/EtOAc = 10:1); mp 122−124 °C; 1H NMR (400 MHz,
CDCl3) δ 10.67 (s, 1H), 7.91 (d, J = 7.8 Hz, 1H), 7.64−7.58 (m,
2H), 7.57−7.48 (m, 3H), 7.41 (t, J = 7.5 Hz, 1H), 3.94 (s, 3H),
3.89 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 192.3, 166.5,
160.3, 136.1, 133.9, 133.2, 133.1, 131.8, 129.0, 127.2, 126.8, 121.9,
116.4, 111.4, 92.2, 91.7, 56.2, 52.6; IR (neat) 2949, 1722, 1688,
1403, 1292 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for
C18H15O4 295.0965; found 295.0969.
EXPERIMENTAL SECTION
■
General Information. NMR spectra were recorded on a Bruker
AM 400 MHz spectrometer and calibrated using residual
undeuterated solvent as an internal reference (CDCl3 (1H): δ =
7.26 ppm; CDCl3 (13C): δ = 77.16 ppm). High-resolution mass
analysis was performed using a Bruker maXis impact q-TOF Mass
Spectrometer or a Thermo Scientific Q Exactive Hybrid Quadru-
pole-Orbitrap Mass Spectrometer. The crystal data for 2q were
collected at 169.97(10) K with a Rigaku XtaLAB Synergy four-circle
diffractometer under Cu Kα radiation (λ = 1.54184 Å). Melting
points were determined on a Stanford Research Systems OptiMelt
apparatus. The infrared (IR) spectra were acquired as thin films
using a universal ATR sampling accessory on a Bruker Vertex 80
FT-IR spectrometer, and the absorption frequencies are reported in
cm−1. Flash chromatography separations were carried out using silica
1
gel columns. The new compounds were characterized by H NMR,
13C{1H} NMR, HRMS, and IR. The structures of known
compounds were further confirmed by comparing their 1H NMR
data with those of the literature. All reagents and solvents were used
as received from commercial sources without further purification.
Compounds 1a,19 1b,20 1c,21 1d,22 1e,21 1f,23 1g,24 1h,25 1i,26 1o−
t,12a 1v,12a 1w,12a 1y,z′,12a and 729 were prepared by following the
literature procedure.
General Procedure for the Synthesis of 2-Alkynylbenzal-
dehydes. To a solution of aryl halide (1.0 mmol, 1.0 equiv) in
MeCN (6.7 mL) were added PdCl2(PPh3)2 (0.05 mmol, 0.05
2-((4-Methoxy-2-nitrophenyl)ethynyl)benzaldehyde (1n). This
product was obtained as an amorphous yellow solid (0.280 g,
99%) by using 1-iodo-4-methoxy-2-nitrobenzene (0.279 g, 1.0
mmol) and 2-ethynylbenzaldehyde (0.170 g, 1.3 mmol). Rf = 0.16
(PE/EtOAc = 10:1); mp 112−114 °C; 1H NMR (400 MHz,
CDCl3) δ 10.62 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.69−7.54 (m,
4H), 7.45 (t, J = 7.6 Hz, 1H), 7.15 (dd, J = 8.7, 2.6 Hz, 1H), 3.89
(s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 191.9, 160.3, 150.4,
136.4, 136.0, 134.0, 133.8, 129.4, 127.5, 126.4, 120.2, 110.1, 109.9,
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91.6, 90.9, 56.3; IR (neat) 1689, 1589, 1526, 1463, 1345 cm−1;
HRMS (ESI) m/z: [M + H]+ calculated for C16H12NO4 282.0761;
found 282.0754.
brine (20 mL), dried (MgSO4), and concentrated. The residue was
purified by column chromatography (Silica Gel, petroleum ether/
ethyl acetate) to afford 1c-d as an amorphous colorless solid (0.125
1
6-((4-Nitrophenyl)ethynyl)benzo[d][1,3]dioxole-5-carbaldehyde
(1u). This product was obtained as an amorphous yellow solid
(0.245 g, 83%) by using 1-iodo-4-nitrobenzene (0.249 g, 1.0 mmol)
and 6-ethynylbenzo[d][1,3]dioxole-5-carbaldehyde (0.169 g, 1.3
g, 90%): Rf = 0.23 (PE/EtOAc = 10:1); mp 106−107 °C; H NMR
(400 MHz, CDCl3) δ 10.56 (s, 0.03H), 7.95 (d, J = 7.7 Hz, 1H),
7.69−7.57 (m, 6H), 7.50 (t, J = 7.5 Hz, 1H); 13C{1H} NMR (101
MHz, CDCl3) δ190.8 (t, JC‑D = 27.9 Hz), 136.3, 134.1, 133.7, 132.4,
129.7, 128.1, 127.4, 125.6, 118.5, 112.6, 94.3, 89.4 (one carbon
missing due to overlap); IR (neat) 2229, 1685, 1559, 1541, 1457
cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C16H9DNO
233.0820; found 233.0819.
1
mmol). Rf = 0.26 (PE/EtOAc = 1:1); mp 219−221 °C; H NMR
(400 MHz, CDCl3) δ 10.44 (s, 1H), 8.26−8.22 (m, 2H), 7.69−7.64
(m, 2H), 7.38 (s, 1H), 7.04 (s, 1H), 6.11 (s, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 189.5, 152.7, 149.7, 147.6, 132.8, 132.5,
129.4, 124.0, 122.2, 112.4, 106.7, 102.9, 93.1, 90.1; IR (neat) 1676,
1596, 1516, 1474, 1344 cm−1; HRMS (ESI) m/z: [M + H]+
calculated for C16H10NO5 296.0553; found 296.0551.
General Procedure for Pyrrolidine-Mediated Synthesis of
Inden-1-ones. To a solution of 2-alkynylbenzaldehyde (0.25 mmol,
1.0 equiv) in DCM (2.0 mL) was added pyrrolidine (0.5 mmol, 2.0
equiv), and the resulting mixture was stirred at room temperature.
The progress of the reaction was monitored by TLC analysis to
establish its completion. The reaction was concentrated, and the
residue was purified by column chromatography (Silica Gel,
petroleum ether/ethyl acetate).
Ethyl 4-((3-Formylquinolin-2-yl)ethynyl)benzoate (1x). This
product was obtained as an amorphous colorless solid (0.285g,
87%) by using ethyl 4-iodobenzoate (0.276 g, 1.0 mmol) and 2-
ethynylquinoline-3-carbaldehyde (0.236 g, 1.3 mmol). Rf = 0.34
(PE/EtOAc = 10:1); mp 156−158 °C; 1H NMR (400 MHz,
CDCl3) δ 10.77 (s, 1H), 8.79 (s, 1H), 8.25 (d, J = 8.5 Hz, 1H),
8.08 (d, J = 8.5 Hz, 2H), 7.99 (d, J = 8.0 Hz, 1H), 7.90 (t, J = 7.1
Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.67 (t, J = 7.1 Hz, 1H), 4.39 (q,
J = 7.1 Hz, 2H), 1.40 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 190.6, 166.0, 150.3, 143.5, 137.6, 133.4, 132.4,
131.5, 129.9, 129.8, 129.6, 129.1, 128.7, 126.7, 125.9, 94.3, 88.0,
61.6, 14.5; IR (neat) 1716, 1595, 1550, 1399, 1281 cm−1; HRMS
(ESI) m/z: [M + H]+ calculated for C21H16NO3 330.1125; found
330.1122.
Procedure for the Synthesis of Ethyl (S,E)-4-((2-(((tert-
Butylsulfinyl)imino)methyl)phenyl)ethynyl)benzoate (8). To a
solution of (S,E)-2-methyl-N-(2-((trimethylsilyl)ethynyl)-
benzylidene)propane-2-sulfinamide (0.61 g, 2.0 mmol, 1.0 equiv)
in MeOH (4.0 mL) and DCM (4.0 mL) was added K2CO3 (1.1 g,
8.0 mmol, 4.0 equiv). The resulting mixture was heated in an oil
bath at 80 °C under argon. The progress of the reaction was
monitored by TLC analysis to establish its completion. The
completed reaction was quenched with water (20 mL), extracted
with ethyl acetate (20 mL), washed with brine (20 mL), dried
(MgSO4), and concentrated. The crude product is used as is in the
next step.
Ethyl 4-(1-Oxo-1H-inden-2-yl)benzoate (2a). This product was
obtained as an amorphous orange solid (0.048 g, 70%) by using
ethyl 4-((2-formylphenyl)ethynyl)benzoate (0.069 g, 0.25 mmol)
and pyrrolidine (0.036 g, 0.5 mmol). Rf = 0.55 (PE/EtOAc = 5:1);
1
mp 112−114 °C; H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.4
Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.75 (s, 1H), 7.47 (d, J = 7.1
Hz, 1H), 7.36 (t, J = 7.4 Hz, 1H), 7.23 (t, J = 7.1 Hz, 1H), 7.10 (d,
J = 7.1 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 196.7, 166.5, 144.6, 143.6,
135.8, 135.4, 134.5, 131.3, 130.2, 130.0, 129.5, 127.2, 123.5, 122.7,
61.3, 14.5; IR (neat) 1709, 1603, 1456, 1274 cm−1; HRMS (ESI)
m/z: [M + H]+ calculated for C18H15O3 279.1016; found 279.1008.
2-(4-Nitrophenyl)-1H-inden-1-one (2b). This product was
obtained as an amorphous yellow solid (0.055 g, 87%) by using
2-((4-nitrophenyl)ethynyl)benzaldehyde (0.063 g, 0.25 mmol) and
pyrrolidine (0.036 g, 0.5 mmol), and the spectral data were
consistent with the literature.27 1H NMR (400 MHz, CDCl3) δ 8.24
(d, J = 9.0 Hz, 2H), 7.98 (d, J = 9.0 Hz, 2H), 7.85 (s, 1H), 7.51 (d,
J = 7.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 7.28 (t, J = 7.4 Hz, 1H),
7.16 (d, J = 7.2 Hz, 1H).
4-(1-Oxo-1H-inden-2-yl)benzonitrile (2c). This product was
obtained as an amorphous red solid (0.044 g, 76%) by using 4-
((2-formylphenyl)ethynyl)benzonitrile (0.059 g, 0.25 mmol) and
pyrrolidine (0.036 g, 0.5 mmol). Rf = 0.36 (PE/EtOAc = 5:1); mp
To a solution of 1-iodo-4-nitrobenzene (0.249 g, 1.0 mmol, 1.0
equiv) in MeCN (4.6 mL) were added PdCl2(PPh3)2 (0.035 g, 0.05
mmol, 0.05 equiv), (S,E)-N-(2-ethynylbenzylidene)2-methylpropane-
2-sulfinamide (0.350 g, 1.5 mmol, 1.5 equiv), and Et3N (3.0 equiv).
The resulting mixture was heated in an oil bath at 80 °C under
argon. The progress of the reaction was monitored by TLC analysis
to establish its completion. After cooling to room temperature, the
reaction was diluted with ethyl acetate (20 mL), washed with water
(20 mL) and brine (20 mL), dried (MgSO4), and concentrated. The
residue was purified by column chromatography (Silica Gel,
petroleum ether/ethyl acetate). This product was obtained as an
amorphous brown solid (0.337 g, 95%). Rf = 0.26 (PE/EtOAc =
1
144−145 °C; H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.4 Hz,
2H), 7.78 (s, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 7.1 Hz,
1H), 7.38 (t, J = 7.4 Hz, 1H), 7.27 (t, J = 7.6 Hz, 1H), 7.13 (d, J =
7.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ 196.2, 145.5,
143.2, 136.0, 134.7, 134.4, 132.5, 131.1, 130.0, 127.8, 123.6, 123.0,
119.0, 111.8; IR (neat) 2226, 1701, 1601, 1452 cm−1; HRMS (ESI)
m/z: [M + H]+ calculated for C16H10NO 232.0757; found 232.0752.
(4-Acetylphenyl)-1H-inden-1-one (2d). This product was ob-
tained as an amorphous orange solid (0.031 g, 50%) by using 2-((4-
acetylphenyl)ethynyl)benzaldehyde (0.062 g, 0.25 mmol) and
pyrrolidine (0.036 g, 0.5 mmol). Rf = 0.33 (PE/EtOAc = 5:1);
1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8.4 Hz, 2H), 7.88 (d, J
= 8.4 Hz, 2H), 7.76 (s, 1H), 7.47 (d, J = 7.1 Hz, 1H), 7.36 (t, J =
7.4 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.11 (d, J = 7.1 Hz, 1H),
2.60 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 197.9, 196.6,
144.8, 143.6, 136.6, 136.1, 135.2, 134.5, 131.3, 129.6, 128.8, 127.5,
123.5, 122.7, 26.9; IR (neat) 1711, 1675, 1600, 1454, 1357 cm−1;
HRMS (ESI) m/z: [M + H]+ calculated for C17H13O2 249.0910;
found 249.0906.
1
10:1); mp 117−118 °C; H NMR (400 MHz, CDCl3) δ 9.21 (s,
1H), 8.22 (d, J = 8.5 Hz, 2H), 8.12−8.08 (m, 1H), 7.73 (d, J = 8.5
Hz, 2H), 7.64 (dd, J = 7.1, 1.1 Hz, 1H), 7.56−7.44 (m, 2H), 1.28
(s, 9H); 13C{1H} NMR (101 MHz, CDCl3) δ 161.4, 147.5, 135.1,
133.2, 132.7, 132.2, 129.8, 129.6, 127.8, 124.5, 123.9, 94.3, 90.9,
58.2, 22.9; IR (neat) 1593, 1519, 1343, 1268, 1082 cm−1;HRMS
(ESI) m/z: [M + H]+ calculated for C19H19N2O3S 355.1111; found
355.1103.
Procedure for the Synthesis of 4-((2-(Formyl-d)phenyl)-
ethynyl)benzonitrile (1c-d). To a solution of 2-iodobenzaldehyde-
α-d30 (0.139 g, 0.6 mmol, 1.0 equiv) in MeCN (1.0 mL) were
added PdCl2(PPh3)2 (0.0085 g, 0.012 mmol, 0.02 equiv), 4-
ethynylbenzonitrile (0.092 g, 0.72 mmol, 1.2 equiv), Et3N (3.0 mL),
and CuI (0.0012 g, 0.006 mmol, 0.01 equiv). The resulting mixture
was heated in an oil bath at 55 °C under argon for 2 h. The
progress of the reaction was monitored by TLC analysis to establish
its completion. After cooling to room temperature, the reaction was
diluted with ethyl acetate (40 mL), washed with water (20 mL) and
2-(4-(Trifluoromethyl)phenyl)-1H-inden-1-one (2e). This product
was obtained as an amorphous orange solid (0.044 g, 65%) by using
2-((4-(trifluoromethyl)phenyl)ethynyl)benzaldehyde (0.068 g, 0.25
mmol) and pyrrolidine (0.036 g, 0.5 mmol). Rf = 0.49 (PE/EtOAc
1
= 10:1); mp 125−127 °C; H NMR (400 MHz, CDCl3) δ 7.90 (d,
J = 8.3 Hz, 2H), 7.74 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 7.48 (d, J =
7.1 Hz, 1H), 7.37 (t, J = 7.4 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 7.12
(d, J = 7.2 Hz, 1H); 13C{1H} (101 MHz, CDCl3) δ 196.5, 144.6,
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1
143.6,135.1, 135.0, 134.6, 131.2, 130.3 (C-F, 2 JC‑F = 32.3 Hz),
= 10:1); H NMR (400 MHz, CDCl3) δ 7.51 (s, 1H), 7.46 (d, J =
7.0 Hz, 1H), 7.44−7.39 (m, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.23 (d,
J = 7.9 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.15−7.07 (m, 2H), 4.28
(q, J = 7.1 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 195.4, 165.4, 160.6 (C-F, 1 JC‑F = 254.5 Hz), 144.9,
144.0, 137.5 (C-F, 4 JC‑F = 3.0 Hz), 134.5, 132.9 (d, 3 JC‑F = 3.0
Hz), 132.0 (C-F,3 JC‑F = 10.1 Hz), 130.7, 129.3, 125.5 (C-F, 4 JC‑F
= 3.0 Hz), 123.7, 122.7, 121.3 (C-F, 2 JC‑F = 15.2 Hz), 116.5 (C-F,
2 JC‑F = 22.2 Hz), 62.0, 14.3; 19F NMR (376 MHz, CDCl3) δ
−112.76 to −112.84 (m, 1F); IR (neat) 1717, 1598, 1457, 1262
cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C18H14FO3
297.0921; found 297.0913.
Ethyl 5-Methyl-2-(1-oxo-1H-inden-2-yl)benzoate (2l). This
product was obtained as a yellow oil (0.035 g, 48%) by using
ethyl 2-((2-formylphenyl)ethynyl)-5-methylbenzoate (0.073 g, 0.25
mmol) and pyrrolidine (0.036 g, 0.5 mmol), and 1l (0.010 g) was
recovered. Rf = 0.44 (PE/EtOAc = 10:1); 1H NMR (400 MHz,
CDCl3) δ 7.77 (s, 1H), 7.45 (d, J = 7.1 Hz, 1H), 7.37 (s, 1H),
7.36−7.29 (m, 2H), 7.23 (d, J = 7.6 Hz, 1H), 7.18 (t, J = 7.4 Hz,
1H), 7.07 (d, J = 7.2 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 2.39 (s,
3H), 1.20 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
203.5, 175.4, 152.2, 149.4, 148.1, 146.4, 141.8, 140.4, 138.7, 138.6,
137.7, 137.1, 136.3, 131.1, 129.8, 68.9, 28.9, 21.9 (one carbon
missing due to overlap); IR (neat) 1717, 1599, 1449, 1281 cm−1;
HRMS (ESI) m/z: [M + H]+ calculated for C19H17O3 293.1172;
found 293.1162.
129.6, 127.7, 125.7 (C-F, 3 JC‑F = 4.0 Hz), 124.3 (C-F, 1 JC‑F
=
273.7 Hz), 123.6, 122.7; 19F NMR (376 MHz, CDCl3) δ −62.70 (s,
3F); IR (neat) 1713, 1601, 1460, 1112 cm−1; HRMS (ESI) m/z:
[M + H]+ calculated for C16H10F3O 275.0678; found 275.0676.
2-(2-Nitrophenyl)-1H-inden-1-one (2f). This product was ob-
tained as an amorphous orange solid (0.038 g, 60%) by using 2-((2-
nitrophenyl)ethynyl)benzaldehyde (0.063 g, 0.25 mmol) and
pyrrolidine (0.036 g, 0.5 mmol). Rf = 0.32 (PE/EtOAc = 5:1);
1
mp 109−111 °C; H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.1
Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.57−7.42 (m, 4H), 7.38 (t, J =
7.5 Hz, 1H), 7.23 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H);
13C{1H} NMR (101 MHz, CDCl3) δ 194.1, 148.8, 144.0, 143.6,
136.9, 134.4, 133.2, 131.2, 130.6, 129.5, 129.3, 126.9, 124.8, 123.9,
122.8; IR (neat) 1710, 1601, 1518, 1457, 1350 cm−1; HRMS (ESI)
m/z: [M + H]+ calculated for C15H10NO3 252.0655; found
252.0647.
2-(1-Oxo-1H-inden-2-yl)benzonitrile (2g). This product was
obtained as an amorphous orange solid (0.030g, 53%) by using 2-
((2-formylphenyl)ethynyl)benzonitrile (0.057 g, 0.25 mmol) and
pyrrolidine (0.035 g, 0.5 mmol). Rf = 0.48 (PE/EtOAc = 5:1); mp
1
191−193 °C; H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.76 (d,
J = 8.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.64 (t, J = 7.8 Hz, 1H),
7.51 (d, J = 7.1 Hz, 1H), 7.44−7.38 (m, 2H), 7.28 (t, J = 7.3 Hz,
1H), 7.18 (d, J = 7.2 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3)
δ 195.8, 147.8, 143.5, 134.7, 134.5, 134.2, 133.4, 132.9, 130.5, 130.3,
130.0, 128.5, 123.7, 123.4, 118.8, 111.0; IR (neat) 2221, 1711, 1598,
1454 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C16H10NO
232.0757; found 232.0752.
Methyl 3-Methoxy-4-(1-oxo-1H-inden-2-yl)benzoate (2m). This
product was obtained as an amorphous orange solid (0.056 g, 75%)
by using methyl 4-((2-formylphenyl)ethynyl)-3-methoxybenzoate
(0.076 g, 0.25 mmol) and pyrrolidine (0.035 g, 0.5 mmol). Rf =
Methyl 2-(1-Oxo-1H-inden-2-yl)benzoate (2h). This product was
obtained as an orange oil (0.038 g, 57%) by using methyl 2-((2-
formylphenyl)ethynyl)benzoate (0.066 g, 0.25 mmol) and pyrroli-
1
0.52 (PE/EtOAc = 5:1); mp 149−151 °C; H NMR (400 MHz,
CDCl3) δ 8.08 (s, 1H), 8.01 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 8.1,
1.4 Hz, 1H), 7.58 (d, J = 1.3 Hz, 1H), 7.44 (d, J = 7.1 Hz, 1H),
7.34 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.1
Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 197.3, 167.0, 158.2, 148.1, 144.5, 134.3, 131.5, 130.6,
130.38, 130.36, 129.3, 125.0, 123.2, 122.6, 122.0, 111.6, 55.9, 52.5;
IR (neat) 1711, 1598, 1451, 1291, 1269 cm−1; HRMS (ESI) m/z:
[M + H]+ calculated for C18H15O4 295.0965; found 295.0959.
2-(4-Methoxy-2-nitrophenyl)-1H-inden-1-one (2n). This product
was obtained as an amorphous orange solid (0.037 g, 51%) by using
2-((4-methoxy-2-nitrophenyl)ethynyl)benzaldehyde (0.070 g, 0.25
mmol) and pyrrolidine (0.035 g, 0.5 mmol). Rf = 0.32 (PE/EtOAc
1
dine (0.036 g, 0.5 mmol). Rf = 0.32 (PE/EtOAc = 10:1); H NMR
(400 MHz, CDCl3) δ 7.95 (d, J = 7.8 Hz, 1H), 7.52 (t, J = 7.5 Hz,
1H), 7.46 (d, J = 7.1 Hz, 1H), 7.44−7.39 (m, 2H), 7.37−7.33 (m,
2H), 7.19 (t, J = 7.4 Hz, 1H), 7.09 (d, J = 7.1 Hz, 1H), 3.77 (s,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 195.6, 168.0, 144.5,
142.4, 140.4, 134.3, 132.5, 132.2, 131.0, 130.4, 130.2, 128.8, 128.7,
123.6, 122.4, 52.4 (one carbon missing due to overlap); IR (neat)
1716, 1599, 1444, 1271 cm−1; HRMS (ESI) m/z: [M + H]+
calculated for C17H13O3 265.0859; found 265.0854.
(3-Nitrophenyl)-1H-inden-1-one (2i). This product was obtained
as an amorphous orange solid (0.056 g, 90%) by using 2-((3-
nitrophenyl)ethynyl)benzaldehyde (0.062 g, 0.25 mmol) and
pyrrolidine (0.035 g, 0.5 mmol). Rf = 0.46 (PE/EtOAc = 5:1);
mp 149−151 °C; 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H),
8.22−8.13 (m, 2H), 7.82 (s, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.50 (d,
J = 7.1 Hz, 1H), 7.39 (t, J = 7.4 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H),
7.15 (d, J = 7.1 Hz, 1H); 13C{1H} NMR (101 MHz, CDCl3) δ
196.1, 148.7, 144.9, 143.3, 134.7, 134.1, 133.3, 133.2, 131.1, 129.9,
129.8, 123.7, 123.1, 123.0, 122.1; IR (neat) 1709, 1596, 1526, 1447,
1348 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C15H10NO3
252.0655; found 252.0649.
(2-Methoxypyridin-3-yl)-1H-inden-1-one (2j). This product was
obtained as an orange oil (0.033 g, 55%) by using 2-((2-
methoxypyridin-3-yl)ethynyl)benzaldehyde (0.059 g, 0.25 mmol)
and pyrrolidine (0.035 g, 0.5 mmol), and 1j (0.014 g) was
recovered. Rf = 0.51 (PE/EtOAc = 10:1); 1H NMR (400 MHz,
CDCl3) δ 8.42 (dd, J = 7.6, 1.8 Hz, 1H), 8.10 (s, 1H), 8.07 (dd, J =
4.9, 1.7 Hz, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7.33 (t, J = 7.4 Hz, 1H),
7.18 (t, J = 7.4 Hz, 1H), 7.08 (d, J = 7.2 Hz, 1H), 6.94 (dd, J = 7.5,
4.9 Hz, 1H), 4.03 (s, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
197.8, 161.9, 147.0, 145.7, 144.7, 138.3, 134.4, 130.8, 130.1, 129.1,
123.2, 122.6, 117.1, 115.2, 53.8; IR (neat) 1710, 1585, 1443, 1370
cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C15H12NO2
238.0863; found 238.0856.
1
= 5:1); mp 161−163 °C; H NMR (400 MHz, CDCl3) δ 7.54 (d, J
= 2.6 Hz, 1H), 7.45 (s, 1H), 7.44 (d, J = 7.2 Hz, 1H), 7.39−7.33
(m, 2H), 7.24−7.18 (m, 1H), 7.15 (dd, J = 8.5, 2.6 Hz, 1H), 7.11
(d, J = 7.3 Hz, 1H), 3.88 (s, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 194.6, 160.3, 149.6, 144.3, 142.9, 136.8, 134.5, 132.2,
130.7, 129.2, 123.9, 122.7, 119.8, 119.1, 109.8, 56.2; IR (neat) 1601,
1530, 1448, 1353, 1269 cm−1; HRMS (ESI) m/z: [M + H]+
calculated for C16H12NO4 282.0761; found 282.0754.
Ethyl 4-(5-Fluoro-1-oxo-1H-inden-2-yl)benzoate (2o). This
product was obtained as an amorphous orange solid (0.032 g,
43%) by using ethyl 4-((4-fluoro-2-formylphenyl)ethynyl)benzoate
(0.074 g, 0.25 mmol) and pyrrolidine (0.035 g, 0.5 mmol), and 1o
(0.005 g) was recovered. Rf = 0.42 (PE/EtOAc = 10:1); mp 168−
1
170 °C; H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 8.7 Hz, 2H),
7.85 (d, J = 8.6 Hz, 2H), 7.66 (s, 1H), 7.46 (dd, J = 7.9, 5.1 Hz,
1H), 6.91−6.80 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 194.8, 167.0 (C-F, 1
JC‑F = 255.5 Hz), 166.4, 146.7 (C-F, 3JC‑F = 10.1 Hz), 142.1 (C-F, 4
JC‑F = 3.0 Hz), 136.9, 135.4, 130.6, 130.0, 127.4, 127.1 (C-F, 4 JC‑F
= 3.0 Hz), 125.4 (C-F, 3JC‑F = 10.1 Hz), 115.0 (C-F, 2 JC‑F = 23.2
Hz), 111.3 (C-F, 2 JC‑F = 25.3 Hz), 61.3, 14.5; 19F NMR (376
MHz, CDCl3) δ −103.47 to −103.56 (m, 1F); IR (neat) 1709,
1603, 1467, 1278 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for
C18H14FO3 297.0921; found 297.0914.
Ethyl 2-Fluoro-6-(1-oxo-1H-inden-2-yl)benzoate (2k). This
product was obtained as a yellow oil (0.041 g, 55%) by using
ethyl 2-fluoro-6-((2-formylphenyl)ethynyl)benzoate (0.074 g, 0.25
mmol) and pyrrolidine (0.035 g, 0.5 mmol). Rf = 0.28 (PE/EtOAc
Ethyl 4-(5-Chloro-1-oxo-1H-inden-2-yl)benzoate (2p). This
product was obtained as an amorphous orange solid (0.055 g,
70%) by using ethyl 4-((4-chloro-2-formylphenyl)ethynyl)benzoate
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Article
(0.078 g, 0.25 mmol) and pyrrolidine (0.035 g, 0.5 mmol). Rf =
0.45 (PE/EtOAc = 5:1); mp 166−168 °C; H NMR (400 MHz,
(s, 1H), 7.00 (s, 1H), 6.66 (s, 1H), 6.04 (s, 2H); 13C{1H} NMR
(101 MHz, CDCl3) δ 194.6, 152.6, 148.8, 147.3, 144.6, 139.7,
138.0, 133.3, 127.6, 125.3, 124.1, 106.1, 105.3, 102.6; IR (neat)
1655, 1587, 1513, 1470, 1396, 1334 cm−1; HRMS (ESI) m/z: [M +
H]+ calculated for C16H10NO5 296.0553; found 296.0552.
1
CDCl3) δ 8.04 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.3 Hz, 2H), 7.68
(s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.7 Hz, 1H), 7.08 (s,
1H), 4.36 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); 13C{1H}
NMR (101 MHz, CDCl3) δ 194.9, 166.2, 145.3, 142.7, 140.4, 136.5,
135.1, 130.4, 129.8, 129.2, 128.8, 127.2, 124.2, 123.1, 61.1, 14.4; IR
(neat) 1709, 1600, 1450, 1279 cm−1; HRMS (ESI) m/z: [M + H]+
calculated for C18H14ClO3 313.0626; found 313.0622.
Ethyl 4-(5-Oxo-5H-indeno[5,6-d][1,3]dioxol-6-yl)benzoate (2v).
This product was obtained as an amorphous purple solid (0.045 g,
55%) by using ethyl 4-((6-formylbenzo[d][1,3]dioxol-5-yl)ethynyl)-
benzoate (0.080 g, 0.25 mmol) and pyrrolidine (0.035 g, 0.5 mmol).
1
Ethyl 4-(5-Methoxy-1-oxo-1H-inden-2-yl)benzoate (2q). This
product was obtained as a crystalline red solid (0.049 g, 64%) by
using ethyl 4-((2-formyl-4-methoxyphenyl)ethynyl)benzoate (0.077
g, 0.25 mmol) and pyrrolidine (0.035 g, 0.5 mmol), and 1q (0.004
g) was recovered. Rf = 0.41 (PE/EtOAc = 5:1); mp 138−140 °C;
1H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.5 Hz, 2H), 7.86 (d, J
= 8.4 Hz, 2H), 7.62 (s, 1H), 7.44 (d, J = 8.0 Hz, 1H), 6.67 (d, J =
2.1 Hz, 1H), 6.62 (dd, J = 8.0, 2.1 Hz, 1H), 4.37 (q, J = 7.1 Hz,
2H), 3.85 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 195.2, 166.5, 165.1, 146.2, 142.4, 136.8, 136.0,
130.2, 129.9, 127.3, 125.4, 124.0, 111.4, 111.0, 61.2, 55.9, 14.5; IR
(neat) 1709, 1595, 1479, 1279 cm−1; HRMS (ESI) m/z: [M + H]+
calculated for C19H17O4 309.1121; found 309.1112.
Rf = 0.43 (DCM); mp 187−189 °C; H NMR (400 MHz, CDCl3)
δ 8.02 (d, J = 8.5 Hz, 2H), 7.81 (d, J = 8.5 Hz, 2H), 7.54 (s, 1H),
6.97 (s, 1H), 6.61 (s, 1H), 6.01 (s, 2H), 4.36 (q, J = 7.1 Hz, 2H),
1.38 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
195.3, 166.6, 152.4, 148.2, 143.0, 140.1, 135.9, 134.6, 129.94,
129.87, 126.9, 125.3, 105.9, 105.0, 102.4, 61.2, 14.6; IR (neat) 2921,
1709, 1603, 1470 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for
C19H15O5 323.0914; found 323.0906.
Ethyl 4-(6-Oxo-6H-indeno[4,5-d][1,3]dioxol-7-yl)benzoate (2w).
This product was obtained as an amorphous orange solid (0.061 g,
75%) by using ethyl 4-((4-formylbenzo[d][1,3]dioxol-5-yl)ethynyl)-
benzoate (0.081 g, 0.25 mmol) and pyrrolidine (0.036 g, 0.5 mmol).
Rf = 0.37 (PE/EtOAc = 5:1); mp 174−176 °C; 1H NMR (400
MHz, CDCl3) δ 7.83 (d, J = 8.6 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H),
7.56 (s, 1H), 6.92 (dd, J = 7.5, 0.6 Hz, 1H), 6.35 (d, J = 7.5 Hz,
1H), 5.84 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.18 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 194.1, 166.5, 154.2,
141.6, 138.1, 136.6, 136.0, 130.2, 129.9, 127.2, 126.4, 122.0, 119.9,
106.6, 102.5, 61.3, 14.6; IR (neat) 1711, 1601, 1460, 1279 cm−1;
HRMS (ESI) m/z: [M + H]+ calculated for C19H15O5 323.0914;
found 323.0905.
Ethyl 4-(6-Fluoro-1-oxo-1H-inden-2-yl)benzoate (2r). This prod-
uct was obtained as an amorphous orange solid (0.041 g, 55%) by
using ethyl 4-((5-fluoro-2-formylphenyl)ethynyl)benzoate (0.074 g,
0.25 mmol) and pyrrolidine (0.035 g, 0.5 mmol). Rf = 0.50 (PE/
1
EtOAc = 5:1); mp 159−160 °C; H NMR (400 MHz, CDCl3) δ
8.03 (d, J = 8.4 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.72 (s, 1H),
7.17 (dd, J = 7.0, 2.1 Hz, 1H), 7.08−6.97 (m, 2H), 4.36 (q, J = 7.1
Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz,
CDCl3) δ 195.1 (C-F, 4 JC‑F = 1.3 Hz), 166.4, 163.9 (C-F, 1 JC‑F
=
Ethyl 4-(3-Oxo-3H-cyclopenta[b]quinolin-2-yl)benzoate (2x).
This product was obtained as an amorphous red solid (0.053 g,
64%) by using ethyl 4-((3-formylquinolin-2-yl)ethynyl)benzoate
(0.082 g, 0.25 mmol) and pyrrolidine (0.036 g, 0.5 mmol). Rf =
0.29 (DCM); mp 239−241 °C; 1H NMR (400 MHz, CDCl3) δ
8.22 (d, J = 8.3 Hz, 1H), 8.11−8.08 (m, 3H), 7.98 (d, J = 8.6 Hz,
2H), 7.77 (d, J = 7.1 Hz, 1H), 7.74 (s, 1H), 7.67 (td, J = 7.6, 1.5
Hz, 1H), 7.58 (td, J = 7.5, 1.2 Hz, 1H), 4.38 (q, J = 7.1 Hz, 2H),
1.40 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
194.1, 166.4, 153.4, 148.4, 144.4, 138.4, 135.1, 133.3, 132.1, 131.0,
130.4, 130.1, 129.6, 129.5, 129.0, 127.8, 127.3, 61.4, 14.6; IR (neat)
1711, 1591, 1445, 1274 cm−1; HRMS (ESI) m/z: [M + H]+
calculated for C21H16NO3 330.1125; found 330.1117.
Ethyl 4-(7-Oxo-7H-cyclopenta[b]pyridin-6-yl)benzoate (2y).
This product was obtained as an amorphous orange solid (0.052
g, 75%) by using ethyl 4-((3-formylpyridin-2-yl)ethynyl)benzoate
(0.070 g, 0.25 mmol) and pyrrolidine (0.036 g, 0.5 mmol). Rf =
0.28 (DCM/MeOH = 100:1); mp 140−142 °C; 1H NMR (400
MHz, CDCl3) δ 8.47 (d, J = 5.1 Hz, 1H), 8.05 (d, J = 8.5 Hz, 2H),
7.89 (d, J = 8.5 Hz, 2H), 7.82 (s, 1H), 7.45 (d, J = 7.4 Hz, 1H),
7.23−7.19 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz,
3H); 13C{1H} NMR (101 MHz, CDCl3) δ 195.3, 166.4, 151.3,
149.8, 142.2, 139.2, 134.9, 134.8, 130.8, 130.1, 129.1, 127.3, 126.9,
61.4, 14.5; IR (neat) 1720, 1603, 1443, 1280 cm−1; HRMS (ESI)
m/z: [M + H]+ calculated for C17H14NO3 280.0968; found
280.0961.
252.5 Hz), 144.3 (C-F, 5 JC‑F = 3.0 Hz), 139.1 (C-F, 5 JC‑F = 4.0
Hz), 135.9 (C-F, 4 JC‑F = 5.1 Hz), 135.5, 133.6 (C-F, 3 JC‑F = 7.1
Hz), 130.3, 130.0, 127.1, 123.7 (C-F, 3JC‑F = 8.1 Hz), 119.8 (C-F, 2
JC‑F = 23.2 Hz), 112.2 (C-F, 2 JC‑F = 25.3 Hz), 61.3, 14.5; IR (neat)
1709, 1603, 1477, 1277 cm−1; 19F NMR (376 MHz, CDCl3) δ
−110.22 to −110.39 (m, 1F); HRMS (ESI) m/z: [M + H]+
calculated for C18H14FO3 297.0921; found 297.0916.
Ethyl 4-(6-Methyl-1-oxo-1H-inden-2-yl)benzoate (2s). This
product was obtained as an amorphous red solid (0.044 g, 60%)
by using ethyl 4-((2-formyl-5-methylphenyl)ethynyl)benzoate (0.073
g, 0.25 mmol) and pyrrolidine (0.035 g, 0.5 mmol), and 1s (0.009
g) was recovered. Rf = 0.63 (PE/EtOAc = 5:1); mp 143−145 °C;
1H NMR (400 MHz, CDCl3) δ 8.03 (d, J = 8.7 Hz, 2H), 7.85 (d, J
= 8.6 Hz, 2H), 7.72 (s, 1H), 7.28 (s, 1H), 7.14 (d, J = 7.3 Hz, 1H),
6.98 (d, J = 7.3 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 2.33 (s, 3H),
1.38 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
197.0, 166.6, 144.9, 140.8, 140.0, 136.1, 134.7, 134.4, 131.7, 130.0,
129.9, 127.1, 124.6, 122.5, 61.2, 21.7, 14.6; IR (neat) 1711, 1593,
1447, 1367, 1275 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for
C19H17O3 293.1172; found 293.1166.
Ethyl 4-(6-Methoxy-1-oxo-1H-inden-2-yl)benzoate (2t). This
product was obtained as an amorphous purple solid (0.038 g,
49%) by using ethyl 4-((2-formyl-5-methoxyphenyl)ethynyl)-
benzoate (0.077 g, 0.25 mmol) and pyrrolidine (0.035 g, 0.5
mmol), and 1t (0.010 g) was recovered. Rf = 0.39 (PE/EtOAc =
1
Ethyl 4-(1-Oxo-5-(trifluoromethyl)-1H-inden-2-yl)benzoate (2z).
This product was obtained as an amorphous orange solid (0.041 g,
47%) by using ethyl 4-((2-formyl-4-(trifluoromethyl)phenyl)-
ethynyl)benzoate (0.087 g, 0.25 mmol) and pyrrolidine (0.036 g,
0.5 mmol). Rf = 0.61 (PE/EtOAc = 5:1); mp 156−158 °C; 1H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.5 Hz, 2H), 7.86 (d, J =
8.5 Hz, 2H), 7.80 (s, 1H), 7.57−7.52 (m, 2H), 7.33 (s, 1H), 4.37
(q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101
MHz, CDCl3) δ 195.2, 166.4, 144.4, 143.4, 136.8, 136.0 (C-F, 2 JC‑F
5:1); mp 115−117 °C; H NMR (400 MHz, CDCl3) δ 8.01 (d, J =
8.3 Hz, 2H), 7.81 (d, J = 8.3 Hz, 2H), 7.70 (s, 1H), 7.04 (s, 1H),
6.97 (d, J = 7.9 Hz, 1H), 6.75 (dd, J = 7.9, 2.1 Hz, 1H), 4.35 (q, J
= 7.1 Hz, 2H), 3.80 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 196.4, 166.6, 161.5, 145.6, 136.1, 135.3,
134.2, 133.5, 129.9, 129.7, 126.8, 123.6, 117.0, 111.4, 61.2, 56.0,
14.5; IR (neat) 1711, 1594, 1484, 1280 cm−1; HRMS (ESI) m/z:
[M + H]+ calculated for C19H17O4 309.1121; found 309.1114.
6-(4-Nitrophenyl)-5H-indeno[5,6-d][1,3]dioxol-5-one (2u). This
product was obtained as an amorphous purple solid (0.043 g, 58%)
by using 6-((4-nitrophenyl)ethynyl)benzo[d][1,3]dioxole-5-carbalde-
hyde (0.074 g, 0.25 mmol) and pyrrolidine (0.035 g, 0.5 mmol). Rf
= 32.3 Hz), 135.0, 133.8, 130.8, 130.1, 127.5, 127.0 (C-F, 3 JC‑F
4.0 Hz), 123.6 (C-F, 1 JC‑F = 274.7 Hz), 123.3, 119.2 (C-F, 3 JC‑F
=
=
4.0 Hz), 61.4, 14.5; 19F NMR (376 MHz, CDCl3) δ −63.36 (s, 3F);
IR (neat) 1711, 1602, 1431, 1280 cm−1; HRMS (ESI) m/z: [M +
H]+ calculated for C19H14F3O3 347.0890; found 347.0886.
1
= 0.31 (PE/DCM = 1:1); mp 199−201 °C; H NMR (400 MHz,
CDCl3) δ 8.21 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.7 Hz, 2H), 7.65
9462
https://doi.org/10.1021/acs.joc.1c00780
J. Org. Chem. 2021, 86, 9455−9465

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Ethyl 4-(1-Oxo-6-(trifluoromethyl)-1H-inden-2-yl)benzoate (2z′).
This product was obtained as an amorphous orange solid (0.044 g,
51%) by using ethyl 4-((2-formyl-5-(trifluoromethyl)phenyl)-
ethynyl)benzoate (0.086 g, 0.25 mmol) and pyrrolidine (0.035 g,
0.5 mmol). Rf = 0.49 (PE/EtOAc = 5:1); mp 166−168 °C; 1H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.3 Hz, 2H), 7.87 (d, J =
8.3 Hz, 2H), 7.79 (s, 1H), 7.69 (s, 1H), 7.66 (d, J = 7.7 Hz, 1H),
7.23 (d, J = 8.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1
Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 194.8, 166.4, 146.9,
143.1, 137.4, 135.0, 131.8 (q, 3 JC‑F = 4.0 Hz), 131.63, 131.59 (C-F,
2 JC‑F = 32.3 Hz), 130.9, 130.1, 127.5, 123.8 (C-F, 1 JC‑F = 270.7
Hz), 122.5, 120.2 (C-F, 3JC‑F = 3.0 Hz), 61.4, 14.5; 19F NMR (376
MHz, CDCl3) δ −62.90 (s, 3F); IR (neat) 1711, 1608, 1445, 1281
cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C19H14F3O3
347.0890; found 347.0886.
mL) and filtered through a short pad of Celite. The filtrate was
concentrated, and the residue was purified by column chromatog-
raphy (Silica Gel, petroleum ether/ethyl acetate). This product was
obtained as a colorless oil (0.035 g, 62%). Rf = 0.23 (PE/EtOAc =
1
5:1); H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.2 Hz, 2H), 7.79
(d, J = 7.7 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.52 (d, J = 7.7 Hz,
1H), 7.41 (t, J = 7.6 Hz, 1H), 7.24 (d, J = 8.2 Hz, 2H), 4.33 (q, J =
7.0 Hz, 2H), 3.94 (dd, J = 8.4, 4.1 Hz, 1H), 3.69 (dd, J = 17.5, 8.4
Hz, 1H), 3.25 (dd, J = 17.5, 4.0 Hz, 1H), 1.35 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 205.4, 166.6, 153.7, 144.9,
136.2, 135.5, 130.3, 129.4, 128.12, 128.09, 126.7, 124.8, 61.1, 53.5,
35.7, 14.5; IR (neat) 1713, 1602, 1462, 1274 cm−1; HRMS (ESI)
m/z: [M + H]+ calculated for C18H17O3 281.1172; found 281.1170.
Labeling Experiments. To a solution of 2-alkynylbenzaldehyde
1c (0.0289 g, 0.125 mmol, 1.0 equiv) in dried MeCN (1.5 mL)
were added H218O (0.0338 g, 1.88 mmol, 15 equiv) and pyrrolidine
(0.0178 g, 0.25 mmol, 2.0 equiv). The resulting mixture was stirred
at room temperature for 4 h. The reaction was concentrated and the
residue was purified by column chromatography (Silica Gel,
petroleum ether/ethyl acetate) to afford 2c (0.0185 g, 64%). No
incorporation of 18O in indenone 2c was observed in LC-MS.
To a solution of deuterated 2-alkynylbenzaldehyde 1c-d (0.023 g,
0.10 mmol, 1.0 equiv) in MeCN (0.8 mL) were added H2O (0.018
g, 1.88 mmol, 10 equiv) and pyrrolidine (0.014 g, 0.20 mmol, 2.0
equiv). The resulting mixture was stirred at room temperature for 5
h. The reaction was concentrated and the residue was purified by
column chromatography (Silica Gel, petroleum ether/ethyl acetate)
to afford 2c-d (0.0093 g, 40%). 1H NMR showed 88% of
deuteration in 2c-d.
trans-Ethyl 4-(1-(Nitromethyl)-3-oxo-2,3-dihydro-1H-inden-2-
yl)benzoate (3). To a solution of 2a (0.0557 g, 0.2 mmol, 1.0
equiv) in MeNO2 (2.0 mL) was added DBU (0.003 g, 0.02 mmol,
0.1 equiv). The resulting mixture was stirred at room temperature
for 2 h. The completed reaction was concentrated, and the residue
was purified by column chromatography (Silica Gel, petroleum
ether/ethyl acetate). This product was obtained as a yellow oil
1
(0.059 g, 87%). Rf = 0.22 (PE/EtOAc = 5:1); H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 7.9 Hz, 1H), 7.75−
7.69 (m, 1H), 7.56−7.52 (m, 2H), 7.18 (d, J = 8.3 Hz, 2H), 4.85
(dd, J = 12.9, 5.7 Hz, 1H), 4.71 (dd, J = 12.9, 7.9 Hz, 1H), 4.33 (q,
J = 7.1 Hz, 2H), 4.23−4.17 (m, 1H), 3.82 (d, J = 4.2 Hz, 1H), 1.35
(t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ 202.1,
166.3, 150.7, 142.6, 136.2, 136.1, 130.5, 130.1, 129.9, 128.3, 125.4,
125.3, 78.1, 61.2, 58.1, 46.0, 14.5; IR (neat) 1715, 1602, 1551, 1463,
1370, 1278 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for
C19H18NO5 340.1179; found 340.1179.
To a solution of deuterated 2-alkynylbenzaldehyde 1c-d (0.023 g,
0.10 mmol, 1.0 equiv) in DCM (0.8 mL) was added pyrrolidine
(0.014 g, 0.20 mmol, 2.0 equiv). The resulting mixture was stirred at
room temperature for 5 h. The reaction was concentrated and the
residue was purified by column chromatography (Silica Gel,
petroleum ether/ethyl acetate) to afford 2c-d (0.012 g, 52%) as
Ethyl 4-(1-Hydroxy-1H-inden-2-yl)benzoate (4). To a solution of
2a (0.0557g, 0.2 mmol, 1.0 equiv) in MeOH (4.6 mL) was added
CeCl3·7H2O (0.082 g, 0.22 mmol, 1.1 equiv). After stirring at 0 °C
for 10 min, NaBH4 (0.0083 g, 0.22 mmol, 1.1 equiv) was added and
the mixture was stirred at the same temperature for 3 min. After
warming-up to room temperature, the reaction was further stirred
for 10 min. The reaction was quenched with satd. NaCl (5 mL) and
extracted with EtOAc (2 × 10 mL). The combined organic layers
were dried (MgSO4) and concentrated. The residue was purified by
column chromatography (Silica Gel, petroleum ether/ethyl acetate).
This product was obtained as an amorphous colorless solid (0.053 g,
1
an amorphous red solid. H NMR showed 84% of deuteration in 2c-
1
d. Rf = 0.31 (PE/EtOAc = 5:1); mp 146−147 °C; H NMR (400
MHz, CDCl3) δ 7.90 (d, J = 8.1 Hz, 2H), 7.76 (s, 0.16H), 7.64 (d,
J = 8.0 Hz, 2H), 7.47 (d, J = 7.1 Hz, 1H), 7.38 (t, J = 7.4 Hz, 1H),
7.25 (t, J = 7.3 Hz, 1H), 7.12 (d, J = 7.1 Hz, 1H); 13C{1H} NMR
(101 MHz, CDCl3) δ 196.1, 145.4, 145.1 (t, JC‑D = 25.8 Hz), 143.3,
143.2, 136.0, 134.6, 134.5, 134.4, 132.5, 131.2, 130.0, 127.8, 123.6,
123.0, 119.0, 111.9; IR (neat) 2361, 1699, 1559, 1398 cm−1; HRMS
(ESI) m/z: [M + H]+ calculated for C16H9DNO 233.0820; found
233.0819.
1
95%). Rf = 0.34 (PE/EtOAc = 5:1); mp 99−101 °C; H NMR (400
MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H),
7.53 (d, J = 7.1 Hz, 1H), 7.32−7.26 (m, 2H), 7.26−7.20 (m, 1H),
7.13 (s, 1H), 5.48 (s, 1H), 4.31 (q, J = 7.1 Hz, 2H), 2.06 (s, 1H),
1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
166.7, 147.7, 145.7, 141.7, 138.3, 130.1, 129.4, 129.1, 126.9, 126.5,
123.9, 121.9, 76.5, 61.2, 14.5; IR (neat) 3211, 1714, 1595, 1461,
1280 cm−1; HRMS (ESI) m/z: [M + H]+ calculated for C18H17O3
281.1172; found 281.1165.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00780.
1
Copies of H, 19F, and 13C{1H} NMR data and X-ray
5,10-Dihydroindeno[1,2-b]indole (5). To a solution of 2f (0.0503
g, 0.2 mmol, 1.0 equiv) in EtOAc (2.0 mL) was added Pd/C (10 wt
%, 0.0213 mg, 0.02 mmol, 0.1 equiv). The reaction mixture was
stirred under H2 (1 atm, balloon) at room temperature for 18 h.
The suspension was diluted with EtOAc (6 mL) and filtered
through a short pad of Celite. The filtrate was concentrated, and the
residue was purified by column chromatography (Silica Gel,
petroleum ether/ethyl acetate = 5:1). This product was obtained
as an amorphous colorless solid (0.030 g, 73%), and the spectral
data were consistent with the literature.28 1H NMR (400 MHz,
CDCl3) δ 8.33 (s, 1H), 7.66−7.60 (m, 1H), 7.53 (d, J = 7.4 Hz,
1H), 7.50−7.40 (m, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.23−7.12 (m,
3H), 3.72 (s, 2H).
crystal data for 2q (PDF)
Accession Codes
CCDC 1983775 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Ethyl 4-(1-Oxo-2,3-dihydro-1H-inden-2-yl)benzoate (6). To a
solution of 2a (0.0557 g, 0.2 mmol, 1.0 equiv) in EtOAc (2.0 mL)
was added Pd/C (10 wt %, 21.3 mg, 0.02 mmol, 0.1 equiv). The
reaction mixture was stirred under H2 (1 atm, balloon) at room
temperature for 0.5 h. The suspension was diluted with EtOAc (10
Corresponding Authors
Tuanli Yao − Key Laboratory of Chemical Additives for
China National Light Industry, College of Chemistry and
Chemical Engineering, Shaanxi University of Science and
9463
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(3) (a) Marvel, C. S.; Hinman, C. W. The Synthesis of Indone and
some Related Compounds. J. Am. Chem. Soc. 1954, 76, 5435−5437.
(b) Chanda, T.; Chowdhury, S.; Koley, S.; Anand, N.; Singh, M. S.
Thionyl chloride mediated dehydroxylation of 3-hydroxyindanones
to indenones. Tetrahedron Lett. 2015, 56, 4603−4606. (c) Petrignet,
J.; Roisnel, T.; Gree, R. Application of the intramolecular
isomerization-aldolisation from allylic alcohols and allylic silyl ethers
to the synthesis of indanones and indenones. Chem. - Eur. J. 2007,
13, 7374−7384.
(4) Vasilyev, A. V.; Walspurger, S.; Pale, P.; Sommer, J. A new, fast
and efficient synthesis of 3-arylindenones: intramolecular cyclization
of 1,3-diarylpropynones in super acids. Tetrahedron Lett. 2004, 45,
3379−3381.
(5) Harrowven, D. C.; Newman, N. A.; Knight, C. A. On the
identity of a neo-lignan from the fruits of Virola sebifera.
Tetrahedron Lett. 1998, 39, 6757−6760.
(6) For selected recent examples, see: (a) Chen, S.; Yu, J.; Jiang,
Y.; Chen, F.; Cheng, J. Rhodium-Catalyzed Direct Annulation of
Aldehydes with Alkynes Leading to Indenones: Proceeding through
in Situ Directing Group Formation and Removal. Org. Lett. 2013,
15, 4754−4757. (b) Banerji, B.; Majumder, L.; Adhikary, S. A
Metal-Free Oxidative Carboannulation Approach towards Synthesis
of 2,3-Diarylindenones and their Regioisomers. ChemistrySelect 2018,
3, 1381−1384. (c) Harada, Y.; Nakanishi, J.; Fujihara, H.; Tobisu,
M.; Fukumoto, Y.; Chatani, N. Rh(I)-Catalyzed Carbonylative
Cyclization Reactions of Alkynes with 2-Bromophenylboronic Acids
Leading to Indenones. J. Am. Chem. Soc. 2007, 129, 5766−5771.
(d) Morimoto, T.; Yamasaki, K.; Hirano, A.; Tsutsumi, K.; Kagawa,
N.; Kakiuchi, K.; Harada, Y.; Fukumoto, Y.; Chatani, N.; Nishioka,
T. Rh(I)-Catalyzed CO Gas-Free Carbonylative Cyclization
Reactions of Alkynes with 2-Bromophenylboronic Acids Using
Formaldehyde. Org. Lett. 2009, 11, 1777−1780. (e) Yan, X.; Zou,
S.; Zhao, P.; Xi, C. MeOTf-induced carboannulation of arylnitriles
and aromatic alkynes: a new metal-free strategy to construct
indenones. Chem. Commun. 2014, 50, 2775−2777. (f) Li, B. J.;
Wang, H. Y.; Zhu, Q. L.; Shi, Z. J. Rhodium/Copper-Catalyzed
Annulation of Benzimides with Internal Alkynes: Indenone Synthesis
through Sequential C-H and C-N Cleavage. Angew. Chem., Int. Ed.
2012, 51, 3948−3952. (g) Qi, Z.; Wang, M.; Li, X. Access to
Indenones by Rhodium(III)-Catalyzed C-H Annulation of Arylni-
trones with Internal Alkynes. Org. Lett. 2013, 15, 5440−5443.
(h) Feng, Y.; Zhang, H.; Yu, Y.; Yang, L.; Cui, X. Ferrocene-
Initiated Oxidative Cyclization of Benzaldehyde with Alkyne: New
Strategy to Substituted Indenones. Eur. J. Org. Chem. 2019, 2019,
2740−2744.
Technology, Xi’an 710021, China; orcid.org/0000-
0003-2905-6596; Email: yaotuanli@sust.edu.cn
Jiajing Tan − Department of Organic Chemistry, College of
Chemistry, Beijing Advanced Innovation Center for Soft
Matter Science and Engineering, Beijing University of
Chemical Technology, Beijing 100029, People’s Republic of
China; Email: tanjj@mail.buct.eud.cn
Authors
Tao Liu − Key Laboratory of Chemical Additives for China
National Light Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
Feng Zhang − Key Laboratory of Chemical Additives for
China National Light Industry, College of Chemistry and
Chemical Engineering, Shaanxi University of Science and
Technology, Xi’an 710021, China
Ying Ju − Key Laboratory of Chemical Additives for China
National Light Industry, College of Chemistry and Chemical
Engineering, Shaanxi University of Science and Technology,
Xi’an 710021, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00780
Author Contributions
§T.L. and F.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
T.Y. thanks Shaanxi University of Science and Technology for
financial support of this research (BJ15-33). J.T. is grateful
for the support of the National Natural Science Foundation
of China (21702013), and the Fundamental Research Funds
for the Central Universities (XK1802-6) at the BUCT.
REFERENCES
■
(1) (a) Zhang, W.; Liu, Z.; Li, S.; Lu, Y.; Chen, Y.; Zhang, H.;
Zhang, G.; Zhu, Y.; Zhang, G.; Zhang, W.; Liu, J.; Zhang, C.
Fluostatins I- K from the South China Sea- Derived Micro-
monospora Rosaria SCSIO N160. J. Nat. Prod. 2012, 75, 1937−
1943. (b) Anstead, G. M.; Wilson, S. R.; Katzenellenbogen, J. A. 2-
Arylindenes and 2-Arylindenones: Molecular Structures and
Considerations in the Binding Orientation of Unsymmetrical
Nonsteroidal Ligands to the Estrogen Receptor. J. Med. Chem.
1989, 32, 2163−2171. (c) Morrell, A.; Placzek, M.; Parmley, S.;
Grella, B.; Antony, S.; Pommier, Y.; Cushman, M. Optimization of
the Indenone Ring of Indenoisoquinoline Topoisomerase I
Inhibitors. J. Med. Chem. 2007, 50, 4388−4404. (d) Ahn, J. H.;
Shin, M. S.; Jung, S. H.; Kang, S. K.; Kim, K. R.; Rhee, S. D.; Jung,
W. H.; Yang, S. D.; Kim, S. J.; Woo, J. R.; Lee, J. H.; Cheon, H. G.;
Kim, S. S. Indenone Derivatives: a Novel Template for Peroxisome
Proliferator- Activated Receptor γ (PPARγ) Agonists. J. Med. Chem.
2006, 49, 4781−4784. (e) Ouyang, D. W.; Ni, X.; Xu, H. Y.; Chen,
J.; Yang, P. M.; Kong, D. Y. Pterosins from Pteris multifida. Planta
Med. 2010, 76, 1896−1900.
(7) Liu, F.; Dong, Z.; Wang, J.; Dong, G. Palladium/Norbornene-
Catalyzed Indenone Synthesis from Simple Aryl Iodides: Concise
Syntheses of Pauciflorol F and Acredinone A. Angew. Chem., Int. Ed.
2019, 58, 2144−2148.
(8) For reviews, see: (a) Chen, L.; Chen, K.; Zhu, S. Transition-
Metal-Catalyzed Intramolecular Nucleophilic Addition of Carbonyl
Groups to Alkynes. Chem. 2018, 4, 1208−1262. (b) Wang, H.;
Kuang, Y.; Wu, J. 2- Alkynylbenzaldehyde: A Versatile Building
Block for the Generation of Cyclic Compounds. Asian J. Org. Chem.
2012, 1, 302−312 and references therein. For selected recent
references, see: (c) Yao, T.; Liu, T.; Zhang, C. Palladium- catalyzed
domino Heck /intermolecular cross- coupling: efficient synthesis of
4- alkylated isoquinoline derivatives. Chem. Commun. 2017, 53,
2386−2389. (d) Yang, J.; Wei, X.; Yu, Y.; Zhu, Y.; Zhao, Y. H.; Xie,
W.; Zhao, L. Catalyst and additive free 6-endo-dig cyclization of
ortho-Alkynylarylaldimines in Water: An Environmentally Friendly
Access to Isoquinolines. Tetrahedron Lett. 2020, 61, 151454−
151458. (e) Qiu, S.; Chen, L.; Jiang, H.; Zhu, S. CuCl/Et3N-
Catalyzed Synthesis of Indanone-Fused 2-Methylene Pyrrolidines
from Enynals and Propargylamines. Org. Lett. 2017, 19, 4540−4543.
(f) Qiu, S.; Liang, R.; Wang, Y.; Zhu, S. Domino Reaction between
Nitrosoarenes and Ynenones for Catalyst-Free Preparation of
Indanone-Fused Tetrahydroisoxazoles. Org. Lett. 2019, 21, 2126−
2129. (g) Zhang, R.; Zhu, H.; Meng, X.; Cao, Z.; Chen, G.; Tian,
(2) (a) Zhang, S.; Zhao, Y.; Liu, Y.; Chen, D.; Lan, W.; Zhao, Q.;
Dong, C.; Xia, L.; Gong, P. Synthesis and Antitumor Activities of
Novel 1, 4- Disubstituted Phthalazine Derivatives. Eur. J. Med. Chem.
2010, 45, 3504−3510. (b) Deliomeroglu, M. K.; Ozcan, S.; Balci,
M. A Short and Efficient Construction of the Dibenzo[c, h]
chromen- 6- one Skeleton. ARKIVOC 2010, 2010, 148−160.
(c) Jeffrey, J. L.; Sarpong, R. Concise Synthesis of Pauciflorol F
using a Larock Annulation. Org. Lett. 2009, 11, 5450−5453.
9464
https://doi.org/10.1021/acs.joc.1c00780
J. Org. Chem. 2021, 86, 9455−9465

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
L.; Sun, X.; You, J. Base-Mediated Domino Reaction of ortho-
Carbonylated Alkynyl-Substituted Arenealdehydes with Indoles:
Access to Indole-Functionalized Isobenzofurans. Eur. J. Org. Chem.
2017, 2017 (18), 2615−2620. (h) He, Y.; Zheng, Z.; Liu, Q.;
Zhang, X.; Fan, X. Solvent-Regulated Coupling of 2-Alkynylbenzal-
dehydes with Cyclic Amines: Selective Synthesis of Fused N-
Heterocycles and Functionalized Naphthalene Derivatives. Org. Lett.
2020, 22, 9053−9058. (i) Zou, L.; Huang, J.; Liao, N.; Liu, Y.; Guo,
Q.; Peng, Y. Catalytic Asymmetric Three-Component Reaction of 2-
Alkynylbenzaldehydes, Amines and Dimethylphosphonate. Org. Lett.
2020, 22, 6932−6937.
(9) (a) Mathur, P.; Jha, B.; Raghuvanshi, A.; Joshi, R. K.; Mobin,
S. M. Photolytic Reaction of Substituted (Ethynyl)benzaldehyde and
Fe(CO)5: Formation of Indenone and Chelated Iron Complexes. J.
Organomet. Chem. 2012, 712, 7−14. (b) Yamada, T.; Park, K.;
Tachikawa, T.; Fujii, A.; Rudolph, M.; Hashmi, A. S. K.; Sajiki, H.
Gold-Catalyzed Cyclization of 2-Alkynylaldehyde Cyclic Acetals via
Hydride Shift for the Synthesis of Indenone Derivatives. Org. Lett.
2020, 22, 1883−1888.
(10) (a) Cui, J. F.; Tang, R.; Yang, B.; Lai, N. C.-H.; Jiang, J. J.;
Deng, J. R.; Wong, M. K. Metal-Free Cyclocarboamination of ortho-
Formyl Phenylacetylenes with Secondary Amines: Access to 1, 3-
Diamino-1H-Indenes and 3-Amino-1-Indanones. Adv. Synth. Catal.
2019, 361, 569−577. (b) Saini, K. M.; Saunthwal, R. K.; Sushmita;
Verma, A. K. Transition-Metal-Free Reverse Reactivity of (2-
Alkynyl)-Arylaldimines: Assembly of Functionalized Amino-Inden-
ones. Chem. - Eur. J. 2020, 26, 1017−1021.
(11) For iodide-mediated cyclization of ortho-alkynylaryl ketones,
see: Chuangsoongnern, P.; Surinrach, C.; Tummatorn, J.;
Thongsornkleeb, C.; Ruchirawat, S. Iodine-Mediated Cyclization of
ortho-Alkynylaryl Ketones for the Synthesis of Indenone Derivatives.
Eur. J. Org. Chem. 2017, 2017 (34), 5102−5109.
(12) (a) Guo, Z.; Liu, T.; Liang, X.; Wu, Y.; Yao, T. Cs2CO3
Catalyzed Intramolecular Aminocarbonylation of Alkynes: Synthesis
of 3-Amino-1H-inden-1-ones from N-tert-Butyl-2-(1-alkynyl) ben-
zaldimines. Adv. Synth. Catal. 2020, 362, 1053−1057. (b) Yao, T.;
Liang, X.; Guo, Z.; Yang, D. Highly stereoselective synthesis of (Z)
−3-methoxy-1-methyleneisoindoles via DMAP catalyzed cyclization
of methyl 2-alkynylbenzimidates. Tetrahedron 2019, 75, 3088−3100.
(13) For related Petasis−Ferrier rearrangement cascade of
aminaloalkynes, see: (a) Gade, A. B.; Patil, N. T. Gold(I)-Catalyzed
Hydroaminaloxylation and Petasis−Ferrier Rearrangement Cascade
of Aminaloalkynes. Org. Lett. 2016, 18, 1844−1847. (b) Lee, A.;
Zhu, J. L.; Feoktistova, T.; Brueckner, C. A.; Cheong, P. H.-Y.;
Scheidt, K. A. Carbene-Catalyzed Enantioselective Decarboxylative
Annulations to Access Dihydrobenzoxazinones and quinolones.
Angew. Chem., Int. Ed. 2019, 58, 5941−5945. (c) Cao, Z.; Zhang,
H.; Zhang, X.; Zhang, L.; Meng, X.; Chen, G.; Zhao, X.-E.; Sun, X.;
You, J. Gold-catalyzed tandem cycloisomerization/Petasis-Ferrier
rearrangement: a direct route to 3-alkoxyindanones from enynals
and alcohols. RSC Adv. 2015, 5, 103155−103158.
(14) For related reactions using pyrrolidine as catalyst, see:
(a) Xiong, W.; Wang, X.; Shen, X.; Hu, C.; Wang, X.; Wang, F.;
Zhang, G.; Wang, C. Synthesis of Flavonols via Pyrrolidine
Catalysis: Origins of the Selectivity for Flavonol versus Aurone. J.
Org. Chem. 2020, 85, 13160−13176. (b) Shibuya, R.; Lin, L.;
Nakahara, Y.; Mashima, K.; Ohshima, T. Dual platinum and
pyrrolidine catalysis in the direct alkylation of allylic alcohols:
Selective synthesis of monoallylation products. Angew. Chem., Int.
Ed. 2014, 53, 4377−4381. (c) Song, A.; Chen, X.; Song, X.; Zhang,
X.; Zhang, S.; Wang, W. Synthesis of Benzoxazoles via an Amine-
Catalyzed [4 + 1] Annulation. Org. Lett. 2013, 15, 2510−2513.
(15) (a) Kotschy, A.; Timári, G. Heterocycles from Transition Metal
arylation of α-(2-pyridinyl) acetates with heteroaryl halides. Chin.
Chem. Lett. 2020, 31, 91−94. (d) Tan, J. J.; Chen, Y.; Li, H.;
Yasuda, N. Suzuki-Miyaura Cross-Coupling Reactions of Unpro-
tected Haloimidazoles. J. Org. Chem. 2014, 79, 8871−8876 and
references therein.
(16) CCDC 1983775 contains the supplementary crystallographic
data for 2q. The data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via http://www.ccdc.cam.
ac.uk/data_request/cif.
(17) Brown, D. W.; Graupner, P. R.; Sainsbury, M.; Shertzer, H. G.
New antioxidants incorporating indole and indoline chromophores.
Tetrahedron 1991, 47, 4383−4408.
(18) (a) Eberle, M. K.; Kahle, G. G. A 1,3-Hydride Shift in the
Rearrangement of (l-Phenylallyl)oxyacetic Acid to 2-Ethyl-2-phenyl-
1,3-dioxolan-4-one. J. Am. Chem. Soc. 1977, 99, 6038−6042.
(b) Chebolu, R.; Kommi, D. N.; Kumar, D.; Bollineni, N.;
Chakraborti, A. K. Hydrogen-Bond-Driven Electrophilic Activation
for Selectivity Control: Scope and Limitations of Fluorous Alcohol-
Promoted Selective Formation of 1,2-Disubstituted Benzimidazoles
and Mechanistic Insight for Rationale of Selectivity. J. Org. Chem.
2012, 77, 10158−10167.
(19) Allen, C. P.; Benkovics, T.; Turek, A. K.; Yoon, T. P.
Oxaziridine-mediated intramolecular amination of sp3-hybridized C-
H bonds. J. Am. Chem. Soc. 2009, 131, 12560−12561.
(20) Korich, A. L.; Hughes, T. S. Arylene Imine Macrocycles of
C3h and C3 Symmetry from Reductive Imination of Nitro-
formylarenes. Org. Lett. 2008, 10, 5405−5408.
(21) Kaiser, R. P.; Mosinger, J.; Cisarova, I.; Kotora, M. Synthesis
of selectively 4-substituted 9, 9′-spirobifluorenes and modulation of
their photophysical properties. Org. Biomol. Chem. 2017, 15, 6913−
6920.
(22) Alfonsi, M.; Dell’Acqua, M.; Facoetti, D.; Arcadi, A.; Abbiati,
G.; Rossi, E. Microwave-Promoted Synthesis of N-Heterocycles by
Tandem Imination/Annulation of γ- and δ-Ketoalkynes in the
Presence of Ammonia. Eur. J. Org. Chem. 2009, 2009, 2852−2862.
(23) Saifuddin, M.; Samala, S.; Krishna, D. G. V.; Kundu, B. A
sequential one-pot protocol for the synthesis of dihydrobenzo[6, 7]
indolo[3′, 4′:3, 4, 5] azepino[2, 1- a] isoquinolines using a gold-
silver combined catalyst. Synthesis 2013, 45, 1553−1563.
(24) Mukherjee, A.; Liu, R. S. Chemoselectivities in the Platinum-
Catalyzed Hydrative Carbocyclizations of Oxo-Alkyne-Nitrile
Functionalities. Org. Lett. 2011, 13, 660−663.
(25) Mehta, S.; Waldo, J. P.; Larock, R. C. Competition Studies in
Alkyne Electrophilic Cyclization Reactions. J. Org. Chem. 2009, 74,
1141−1147.
(26) Bucher, J.; Stoesser, T.; Rudolph, M.; Rominger, F.; Hashmi,
A. S. K. CO-Extrusion in Homogeneous Gold Catalysis: Reactivity
of Gold Acyl Species Generated through Water Addition to Gold
Vinylidenes. Angew. Chem., Int. Ed. 2015, 54, 1666−1670.
(27) Zhang, J. B.; Han, X. L. An unexpected addition of acetic acid
to ortho-electron-deficient alkynyl-substituted aryl aldehydes cata-
lyzed by palladium(II) acetate. Adv. Synth. Catal. 2014, 356, 2465−
2470.
(28) Gore, S.; Baskaran, S.; Koenig, B. Fischer Indole Synthesis in
Low Melting Mixtures. Org. Lett. 2012, 14, 4568−4571.
(29) Gao, Y. N.; Shi, F. C.; Xu, Q.; Shi, M. Enantioselective
Synthesis of Isoquinolines: Merging Chiral-Phosphine and Gold
Catalysis. Chem. - Eur. J. 2016, 22, 6803−6807.
(30) Li, X. M.; Wu, S. C.; Chen, S. Q.; Lai, Z. W.; Luo, H. B.;
Sheng, C. Q. One-Pot Synthesis of Deuterated Aldehydes from
Arylmethyl Halides. Org. Lett. 2018, 20, 1712−1715.
Catalysis; Springer: Dordrecht, 2005. (b) Dufert, M. A.; Billingsley,
̈
K. L.; Buchwald, S. L. Suzuki-Miyaura Cross-Coupling of
Unprotected, Nitrogen-Rich Heterocycles: Substrate Scope and
Mechanistic Investigation. J. Am. Chem. Soc. 2013, 135, 12877−
12885. (c) Jin, C. C.; Xu, K.; Fan, X.; Liu, C. Y.; Tan, J. J. Direct
benzylic functionalization of pyridines: Palladium-catalyzed mono-α-
9465
https://doi.org/10.1021/acs.joc.1c00780
J. Org. Chem. 2021, 86, 9455−9465