Syntheses of N-Alkyl 2-Arylindoles from Saturated Ketones and 2-Arylethynylanilines via Cu-Catalyzed Sequential Dehydrogenation/Aza-Michael Addition/Annulation Cascade

Article abstract of DOI:10.1021/acs.joc.9b03091

We describe here a Cu-catalyzed and 4-OH-TEMPO-mediated sequential dehydrogenation/aza-Michael addition/annulation cascade reaction for the construction of N-alkyl 2-arylindoles from facilely available saturated ketones and 2-arylethynylanilines. This rea

Full text of DOI:10.1021/acs.joc.9b03091

pubs.acs.org/joc
Article
Syntheses of N‑Alkyl 2‑Arylindoles from Saturated Ketones and
2‑Arylethynylanilines via Cu-Catalyzed Sequential
Dehydrogenation/Aza-Michael Addition/Annulation Cascade
Fei Ling, Dingguo Song, Linlin Chen, Tao Liu, Mengyao Yu, Yan Ma, Lian Xiao, Min Xu,
and Weihui Zhong*
Cite This: J. Org. Chem. 2020, 85, 3224−3233
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ABSTRACT: We describe here a Cu-catalyzed and 4-OH-TEMPO-mediated sequential dehydrogenation/aza-Michael addition/
annulation cascade reaction for the construction of N-alkyl 2-arylindoles from facilely available saturated ketones and 2-
arylethynylanilines. This reaction shows high regioselectivity and tolerates a variety of functional groups. Moreover, 3-alkyl-
substituted indoles can also be achieved when using 2-alkylethynylanilines as starting materials.
tion reaction under iron−palladium cooperative catalysis
(Scheme 1, path a).11 Subsequently, You’s group achieved an
elegant work of regio- and enantioselective synthesis of N-allyl
2-arylindoles via one-pot iridium-catalyzed allylic amination/
transition-metal-catalyzed cyclization reactions (Scheme 1,
path b).12 Very recently, Tokuyama and co-workers reported
the silver-mediated amination of bromopyrroloindolines with
2-ethynylanilines with subsequent 5-endo-dig cyclization for
constructing an N-linked indole segment at the 3-position of
pyrroloindoline, in which AgNTf2 plays a dual role in the
activation of both a bromo group and an alkyne moiety
(Scheme 1, path c).13 Notably, the group of Wang and Lv first
realized a cheap copper-catalyzed coupling/cyclization reaction
of 2-alkynylanilines and boronic acids for the one-pot access to
N-alkyl 2-arylindoles, albeit with a low efficiency and limited
structural scope (Scheme 1, path d).14 Despite the remarkable
advances, the development of a novel, practical, and efficient
INTRODUCTION
■
Indoles are an important class of N-heterocycles widely utilized
in organic chemistry and material science.1 In particular, 2-
arylindoles have received remarkable attention due to their
preponderance as core structures in numerous biologically
active molecules, pharmaceuticals, and natural products
(Figure 1).2 For example, pipendoxifene,3 bazedoxifene,2a
and zindoxifene4 are selective estrogen receptor modulators
exhibiting preeminent activities in the treatment of osteopo-
rosis. Compound A is a potent inhibitor of protein kinase C,5
while compound B shows high antimicrobial activity.6
Moreover, other functionalized 2-arylindoles (C and D) are
also regarded as generic GABAA agonists,7 CDK inhibitors,
and cytotoxic agents.8
Due to their widespread occurrence in nature as well as their
remarkable biological activities, various synthetic methods have
been developed to access N-alkyl 2-arylindoles.9 In this
context, the metal-catalyzed coupling reactions of 2-arylethy-
nylanilines with various partners represent one of the most
efficient and straightforward approaches for generating these
scaffolds (Scheme 1).10 In 2007, Prim and Campagne
described the assembly of trisubstituted indole from 2-
(arylalkynyl)anilines and methyl vinyl ketone through
sequential Michael addition and intramolecular hydroamina-
Received: November 15, 2019
Published: February 4, 2020
https://dx.doi.org/10.1021/acs.joc.9b03091
© 2020 American Chemical Society
J. Org. Chem. 2020, 85, 3224−3233
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Figure 1. Potential drugs containing N-alkyl 2-arylindole scaffolds.
Scheme 1. Syntheses of N-Alkyl 2-arylindoles from 2-Arylethynylanilines
method from readily available starting materials for the direct
synthesis of N-alkyl 2-arylindoles remains highly desirable.
Recently, copper-catalyzed direct β-C(sp3)-H functionaliza-
tion of saturated ketones has emerged as an appealing and
powerful methodology for the construction of C−X bonds,
because of the low cost and abundance of such ketones.15 In
2016, Su’s group reported the first example of a Cu-catalyzed
dehydrogenation−conjugate addition tandem reaction for the
direct β-functionalization of inactivated ketones with various
nucleophiles.16 Inspired by this fantastic work, the research
community has devoted much attention to the Cu-catalyzed
one-pot cascade reactions for synthesizing versatile N-hetero-
cycles, including pyrimidines,17 pyrazoles,18 quinolines,19
pyridines,20 and isoindolin-1-ones.21 However, the construc-
tion of indole rings through β-C(sp3)-H functionalization of
saturated ketones remains an unexploited field. Herein, we
would like to report an example of Cu-catalyzed sequential
dehydrogenation/aza-Michael addition/annulation reactions of
saturated ketones and 2-arylethynylanilines via C(sp3)−H
bond amination and hydroamination of alkyne to produce
versatile N-alkyl 2-arylindoles (Scheme 1, path e). This
protocol features a moderate scope of possible substrates,
tolerates various functional groups, and could be easily
conducted as a gram-scale operation. Moreover, the
regioselectivity of this reaction was changed when employing
2-alkylalkynylanilines, delivering 3-alkyl-substituted indoles.
RESULTS AND DISCUSSION
■
The initial assay was carried out by subjecting 2-
(phenylethynyl)aniline (1a) to propiophenone (2a) with
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Cu(OAc)2, 2,2′-bipyridine (bpy), and 4-hydroxy-2,2,6,6-
tetramethylpiperidi- ne-1-oxyl (4-OH-TEMPO) in toluene at
120 °C for 24 h (Table 1, entry 1). Pleasantly, the desired 1-
17). Furthermore, a reduced yield was observed under
changing temperatures (Table 1, entries 18 and 19). Notably,
this protocol could be handily conducted as a multigram-scale
procedure, forming 3aa in 1.25 g and 77% yield (Table 1, entry
20).
a
Table 1. Optimization of the Reaction Conditions
With the optimal conditions in hand, we set out to probe its
versatility in the sequential dehydrogenation/aza-Michael
addition/annulation cascade reactions. The scope of this
reaction was first explored with a range of 2-(arylalkynyl)-
anilines 1 with propiophenone (2a) and the results are
depicted in Scheme 2. The substitution patterns of aryl
moieties had a slight effect on this reaction: ortho- and meta-
substituted substrates gave slightly lower yields than those
bearing para-substituents (3ba vs 3ha; 3ca vs 3ea). Substrates
with electron-donating groups on aryl groups generated higher
yields than those bearing electron-withdrawing groups. In
addition, variations of R1 led to the formation of 3ia−ma in
moderate yields. The naphthyl group was also tolerated in this
transformation, producing 3na in 58% yield. Delightfully,
functionalized pyrrolo[2,3-b]pyridine 3oa cloud be obtained in
75% yield via the current strategy. It was noteworthy that the
regioselectivity of this reaction was changed on turning aryl
moieties to alkyl groups, delivering 3-alkyl substituted indoles
4pa, 4qa, 4rg, and 4sg containing free N−H bonds in 60−80%
yields.
Next, the scope of this reaction was examined with a range
of ketones 2 and 1a (Scheme 3). Ortho- or meta-substituted
aryl ketones gave slightly higher yields than those with para-
substituents. Both electron-donating and electron-withdrawing
groups reacted with 1a smoothly to give the desired products
in 74−84% yields, in which the electronic effect was not
observed. Notably, hetero-aryl ketones like 1-(pyridin-3-
yl)propan-1-one (2h) and 1-(thiophen-2-yl)propan-1-one
(2i) were well tolerated in this reaction, delivering the
corresponding products 3ah and 3ei in 64 and 73% yields,
respectively. Delightfully, this transformation was also
compatible with dialkyl ketones, giving 3aj in moderate yield.
Unfortunately, the reaction failed to give any desired product
when employing highly hindered ketones.
yield
b
entry
1
Cu salts
ligand
bpy
solvent
oxidant
(%)
Cu(OAc)2
toluene 4-OH-
74
TEMPO
toluene 4-OH-
TEMPO
toluene 4-OH-
TEMPO
toluene 4-OH-
TEMPO
toluene 4-OH-
TEMPO
toluene 4-OH-
TEMPO
toluene 4-OH-
TEMPO
toluene 4-OH-
TEMPO
1,10-phen toluene 4-OH-
TEMPO
toluene 4-OH-
TEMPO
4-OH-
TEMPO
2
3
4
5
6
7
8
9
Cu(acac)2
bpy
63
47
42
48
50
51
65
59
66
67
65
CuNO2·2H2O bpy
Cu(OTf)2
Cu(TFA)2
CuCl2·2H2O
CuBr
bpy
bpy
bpy
bpy
bpy
CuTc
Cu(OAc)2
10 Cu(OAc)2
11 Cu(OAc)2
12 Cu(OAc)2
DMAP
bpy
PhCl
PhCF3
DCB
DMSO 4-OH-
TEMPO
DMF
bpy
4-OH-
TEMPO
4-OH-TEMPO
13 Cu(OAc)2
14 Cu(OAc)2
bpy
bpy
82
52
15 Cu(OAc)2
16 Cu(OAc)2
bpy
4-OH-
58
76
TEMPO
TEMPO
O2
bpy
bpy
bpy
DCB
DCB
DCB
17 Cu(OAc)2
c
To get an insight into the reaction mechanism for access to
N-alkyl 2-arylindoles, several control experiments were
conducted. We initially synthesized 2-phenyl-1H-indole (5a)
to test whether 5a is an intermediate or not. Thus, a mixture of
5a and 2i was subjected to the standard reaction conditions for
24 h; however, the reaction did not give the desired product
3ai, but afforded the 3-alkyl-substituted indole 4ai instead in a
yield of 67% (eq 1). Moreover, decreasing the reaction time
18
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
4-OH-
TEMPO
4-OH-
TEMPO
4-OH-
TEMPO
79
64
77
d
19
bpy
bpy
DCB
DCB
e
20
a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), Cu salts (0.05
mmol), ligand (0.1 mmol), 4-OH-TEMPO (0.5 mmol), solvent (3
mL), air, 24 h. Isolated yield. Conducted at 130 °C. Conducted at
b
c
d
e
110 °C. Reaction was conducted on a 5.0 mmol scale of 1a.
phenyl-3-(2-phenyl-1H-indol-1-yl)propan-1-one 3aa was iso-
lated in 74% yield. To improve the reaction yield, a set of
copper salts such as Cu(acac)2, CuNO2·2H2O, Cu(OTf)2, etc.
were first examined, but none of them showed better results
than Cu(OAc)2 (Table 1, entries 1−8). Moreover, switching
bpy with other N-containing ligands like 1,10-phen (1,10-
phenanthroline) and 4-dimethylaminopyridine (DMAP) could
not increase the catalytic efficiency (Table 1, entries 9 and 10).
Next, screening of reaction solvents showed that o-dichlor-
obenzene (o-DCB) was the best solvent to afford 3aa in 82%
yield (Table 1, entries 11−15). It was worth noting that
changing the oxidant from 4-OH-TEMPO to TEMPO led to a
slight decrease in the yield, while the reaction did not proceed
when using O2 as the only oxidant (Table 1, entries 16 and
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a
Scheme 2. Substrate Scope of 1 with 2a
a
Reaction conditions: 1 (0.5 mmol), 2a (0.6 mmol), Cu(OAc)2 (0.05 mmol), bpy (0.1 mmol), 4-OH-TEMPO (0.5 mmol), DCB (3 mL), 120 °C,
air, 24 h.
a
Scheme 3. Substrate Scope of 1a with 2
a
Reaction conditions: 1a (0.5 mmol), 2 (0.6 mmol), Cu(OAc)2 (0.05 mmol), bpy (0.1 mmol), 4-OH-TEMPO (0.5 mmol), DCB (3 mL), 120 °C,
air, 24 h. N. R. = no reaction.
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Scheme 4. Mechanistic Hypothesis
from 24 to 6 h resulted in the generation of intermediate 6a in
23% yield, accompanied by a 37% yield of 3aa (eq 2). Finally,
the aza-Michael addition product 6a underwent intramolecular
cyclization smoothly to provide the targeted product 3aa in
85% yield under the current conditions (eq 3). These control
experiments indicated that the aza-Michael addition step
occurred prior to the annulation step when synthesizing N-
alkyl 2-arylindoles.
Based on the control experiments and previous work on Cu-
catalyzed activation of saturated ketones,15−21 the proposed
mechanism is depicted in Scheme 4 applying 2-
(phenylethynyl)aniline (1a) and propiophenone (2a) as
template substrates. Initially, 2a was transformed into enone
A through a Cu-catalyzed oxidative dehydrogenation reaction,
followed by the copper-promoted nucleophilic attack of 1a to
form the key intermediate C. Next, copper-assisted 5-endo
cyclization of C would provide species E.22 Finally,
protonation of species E led to the formation of the desired
product 3aa along with the release of Cu(II). On the other
hand, when utilizing 2-(hex-1-yn-1-yl)aniline (1o) as a
substrate, the copper-assisted annulation reaction occurred
first, leading to the indole intermediate H. Subsequently,
indole I was generated via the protonation of the copper
complex H. Finally, the nucleophilic attack of I on the α,β-
unsaturated ketone 2a occurred to afford 2,3-dialkylindole 4oa
through a copper-assisted 1,4-Michael addition.23
EXPERIMENTAL SECTION
■
General Information. All commercial materials were used as
received unless otherwise noted. Commercially available chemicals
were obtained from Energy Chemical, TCI, Alfa Aesar, J&K. 1H NMR
spectra were recorded at 400 MHz and 13C{1H} NMR spectra were
recorded at 100 MHz, using TMS as the internal standard. The
multiplicities are reported as follows: singlet (s), doublet (d), doublet
of doublets (dd), multiplet (m), triplet (t), and broad resonances
(br). IR spectra were recorded on a Varian 2000 Infrared
spectrophotometer and are reported as cm−1. Mass spectroscopy
data of the products were collected on an HRMS-TOF instrument.
General Procedure. General Procedure for the Synthesis of 2-
(Arylethynyl)aniline.24 2-Iodoaniline (5 mmol), aryl acetylene (5.5
mmol), CuI (0.15 mmol), and Pd(PPh3)2Cl2 (0.05 mmol) were
added into triethylamine (15 mL), and the mixture was stirred at
room temperature in N2 until the 2-iodoaniline disappeared. The
solution was diluted with EtOAc and then washed with brine. The
organic layer was dried over anhydrous Na2SO4, concentrated, and
then purified by flash column chromatography on silica gel to afford
the desired substrate.
General Procedure for the Synthesis of 2-Alkynylaniline.25 2-
Iodoaniline (5 mmol), alkyl acetylene (5.5 mmol), CuI (0.15 mmol),
and Pd(PPh3)2Cl2 (0.05 mmol) were added into triethylamine (15
mL), and the mixture was stirred at 40 °C in N2 until the 2-
iodoaniline disappeared. Then, the solution was diluted with EtOAc
and washed with brine. The organic layer was dried over anhydrous
Na2SO4, concentrated, and then purified by flash column chromatog-
raphy on silica gel to afford the desired substrate.
General Procedure for the Synthesis of 3 and 4. A mixture of 2-
alkynylanilines (1, 0.5 mmol), saturated ketones (2, 0.6 mmol),
Cu(OAc)2 (9.1 mg, 0.05 mmol), 2,2′-bipyridine (15.6 mg, 0.1 mmol),
and 4-OH-TEMPO (86.1 mg, 0.5 mmol) in 3 mL of DCB was heated
at 120 °C in an oil bath for 24 h. Then, the reaction was cooled to
room temperature, and the solvent was removed under vacuum. The
crude product was purified by column chromatography on silica gel
(n-hexane/EtOAc = 60:1) to yield indoles 3. Products 4 were
synthesized in a similar way.
CONCLUSIONS
■
In summary, we have established a novel and expedient
strategy for the synthesis of versatile 2-substituted indoles,
especially N-alkyl 2-arylindoles, via Cu-catalyzed and 4-OH-
TEMPO-mediated cascade reactions from saturated ketones
and 2-alkynylanilines. With the advantages of simple and
economic starting materials and a cheap, highly regioselective,
and high-efficiency catalytic system, this protocol provides an
alternative synthetic pathway to access multisubstituted indoles
in both academic and industrial fields.
Analytical Data of the Products 3 and 4. 1-Phenyl-3-(2-
phenyl-1H-indol-1-yl)propan-1-one (3aa). White solid (133.4 mg,
82%), mp 134−137 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 7.76 (d,
J = 7.2 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.60−7.38 (m, 9H), 7.25
(d, J = 7.2 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.61 (s, 1H), 4.69 (t, J =
8.0 Hz, 2H), 3.29 (t, J = 7.8 Hz, 2H). 13C{1H} NMR (100 MHz,
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CDCl3, ppm) δ 197.8, 141.1, 137.2, 136.2, 133.4, 132.7, 129.4, 128.7,
128.6, 128.5, 128.2, 128.0, 121.9, 120.7, 120.2, 109.8, 102.9, 39.3,
38.5. IR (thin film) ν 1674, 1184, 1140, 1116, 758, 728 cm−1. HRMS
(ESI-TOF) calcd for C23H19NNaO [M + Na]+: 348.1359; found,
348.1352.
130.8, 128.7, 128.4, 128.0, 122.5, 122.3, 120.9, 120.4, 109.9, 103.3,
39.3, 38.4. IR (thin film) ν 1681, 1457, 1281, 1184, 1140, 1116, 758,
728 cm−1. HRMS (ESI-TOF) calcd for C23H18BrNNaO [M + Na]+:
426.0464; found: 426.0471.
3-(2-(4-Fluorophenyl)-1H-indol-1-yl)-1-phenylpropan-1-one
(3ha). Red oil (106.5 mg, 62%). 1H NMR (400 MHz, CDCl3, ppm) δ
8.09 (dd, J = 5.0, 1.9 Hz, 1H), 8.02−7.92 (m, 2H), 7.59−7.52 (m,
4H), 7.47−7.43 (m, 2H), 7.40−7.35 (m, 3H), 6.54 (dd, J = 7.4, 5.1
Hz, 1H), 5.95 (t, J = 6.4 Hz, 1H), 3.99 (q, J = 6.0 Hz, 2H), 3.37 (t, J =
6.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 199.7, 157.9,
149.2, 147.6, 139.3, 136.9 (JC−F = 9 Hz), 133.2, 131.6, 128.5, 128.3
(JC−F = 34 Hz) 128.1, 122.8, 122.4 (JC−F = 262 Hz), 111.9, 103.6,
84.4, 77.2, 38.5, 36.3. 19F NMR (377 MHz, CDCl3) δ −113.06. IR
(thin film) ν 1674, 1460, 1382, 1226, 797, 755 cm−1. HRMS (ESI-
TOF) calcd for C23H18FNNaO [M + Na]+: 366.1264; found:
366.1250.
3-(5-Fluoro-2-phenyl-1H-indol-1-yl)-1-phenylpropan-1-one
(3ia). White solid (133.9 mg, 78%), mp 122−123 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.79−7.71 (m, 2H), 7.57−7.41 (m, 6H), 7.39
(t, J = 8.0 Hz, 2H), 7.35−7.25 (m, 2H), 6.98 (td, J = 9.2, 2.4 Hz, 1H),
6.52 (s, 1H), 4.63 (t, J = 7.8 Hz, 2H), 3.22 (t, J = 7.8 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.6, 158.2 (JC−F = 234
Hz), 142.7, 136.1, 133.8, 133.5, 132.4, 129.3, 128.8, 128.7 (JC−F = 10
Hz), 128.7, 128.5, 127.9, 110.4 (JC−F = 10 Hz), 110.2(JC−F = 26 Hz),
105.0 (JC−F = 23 Hz), 102.8 (JC−F = 5 Hz), 39.5, 38.4. 19F NMR (377
MHz, CDCl3) δ −113.24. IR (thin film) ν 1687, 1494, 1375, 1222,
790, 752 cm−1. HRMS (ESI-TOF) calcd for C23H18FNNaO [M +
Na]+: 366.1264; found: 366.1255.
3-(5-Chloro-2-phenyl-1H-indol-1-yl)-1-phenylpropan-1-one
(3ja). White solid (127.7 mg, 71%), mp 132−135 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.75 (d, J = 7.2 Hz, 2H), 7.60 (d, J = 2.0 Hz,
1H), 7.53 (t, J = 7.6 Hz, 1H), 7.50−7.42 (m, 5H), 7.38 (t, J = 7.6 Hz,
2H), 7.33 (s, 1H), 7.18 (dd, J = 8.8, 2.0 Hz, 1H), 6.49 (s, 1H), 4.63
(t, J = 7.6 Hz, 2H), 3.21 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 197.5, 142.4, 136.1,135.6, 133.5, 132.3, 129.4,
129.3, 128.8, 128.7, 128.5, 127.9, 125.8, 122.1, 120.1, 110.8, 102.5,
39.4, 38.4. IR (thin film) ν 1674, 1472, 1362, 1284, 754, 719 cm−1.
HRMS (ESI-TOF) calcd for C23H18ClNNaO [M + Na]+: 382.0969;
found: 382.0956.
3-(5-Methoxy-2-phenyl-1H-indol-1-yl)-1-phenylpropan-1-one
(3ka). White solid (119.1 mg, 67%), mp 155−158 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.75 (d, J = 7.2 Hz, 2H), 7.55−7.34 (m, 8H),
7.30 (d, J = 8.8 Hz, 1H), 7.11 (d, J = 2.0 Hz, 1H), 6.90 (dd, J = 8.8,
2.4 Hz, 1H), 6.49 (s, 1H), 4.63 (t, J = 8.0 Hz, 2H), 3.87 (s, 3H), 3.23
(t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.8,
154.5, 141.7, 136.2, 133.4, 132.8, 132.5, 129.3, 128.9, 128.7, 128.6,
128.2, 128.0, 112.1, 110.6, 102.7, 102.5, 55.9, 39.5, 38.5. IR (thin
film) ν 1671, 1456, 1374, 1245, 745, 674 cm−1. HRMS (ESI-TOF)
calcd for C24H21NNaO2 [M + Na]+: 378.1464; found: 378.1460.
Methyl 1-(3-oxo-3-phenylpropyl)-2-phenyl-1H-indole-5-carbox-
ylate (3la). White solid (86.2 mg, 45%), mp 167−169 °C. 1H
NMR (400 MHz, CDCl3, ppm) δ 8.43 (d, J = 1.6 Hz, 1H), 7.98 (dd, J
= 8.7, 1.7 Hz, 1H), 7.79 (d, J = 7.1 Hz, 2H), 7.58−7.40 (m, 9H), 6.67
(s, 1H), 4.70 (t, J = 8.0 Hz, 2H), 3.97 (s, 3H), 3.28 (t, J = 8.0 Hz,
2H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.5, 168.1, 142.5,
139.7, 136.1, 133.6, 132.1, 129.4, 128.9, 128.7, 128.6, 128.0, 127.9,
123.7, 123.3, 122.2, 109.5, 104.2, 51.9, 39.5, 38.4. IR (thin film) ν
1676, 1457, 1340, 1246, 756, 723 cm−1. HRMS (ESI-TOF) calcd for
C25H21NNaO3 [M + Na]+: 406.1413; found: 406.1402.
3-(2-(2-Fluorophenyl)-1H-indol-1-yl)-1-phenylpropan-1-one
1
(3ba). White solid (103.0 mg, 60%), mp 92−95 °C. H NMR (400
MHz, CDCl3, ppm) δ 7.82 (d, J = 7.6 Hz, 2H), 7.71 (d, J = 7.6 Hz,
1H), 7.57 (t, J = 7.2 Hz, 1H), 7.52−7.39 (m, 5H), 7.34−7.27 (m,
2H), 7.26−7.16 (m, 2H), 6.63 (s, 1H), 4.57 (t, J = 7.6 Hz, 2H), 3.39
(t, J = 7.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.9,
160.2 (JC−F = 246 Hz), 136.9, 136.3, 134.7, 133.5, 132.6 (JC−F = 3
Hz), 130.7 (JC−F = 8 Hz), 128.7, 128.4, 128.0, 124.5 (JC−F = 4 Hz),
122.2, 120.9, 120.6 (JC−F = 15 Hz), 120.1, 116.0 (JC−F = 22 Hz),
109.8, 103.9, 39.6 (JC−F = 2 Hz), 38.3 (JC−F = 2 Hz). 19F NMR (377
MHz, CDCl3) δ −124.37. IR (thin film) ν 1677, 1471, 1382, 1190,
741, 711 cm−1. HRMS (ESI-TOF) calcd for C23H18FNNaO [M +
Na]+: 366.1264; found: 366.1261.
3-(2-(3-Methoxyphenyl)-1H-indol-1-yl)-1-phenylpropan-1-one
(3ca). White solid (131.5 mg, 74%), mp 122−123 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.74 (d, J = 7.6 Hz, 2H), 7.63 (d, J = 8.0 Hz,
1H), 7.50 (t, J = 7.6 Hz, 1H), 7.42−7.32 (m, 4H), 7.23 (t, J = 7.6 Hz,
1H), 7.14 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.03 (s, 1H),
6.94 (dd, J = 8.4, 2.4 Hz, 1H), 6.57 (s, 1H), 4.66 (t, J = 8.0 Hz, 2H),
3.81 (s, 3H), 3.24 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 197.8, 159.8, 141.0, 137.3.136.2, 134.1, 133.5, 129.8,
128.7, 128.5, 128.0, 122.0, 121.7, 120.8, 120.2, 115.1, 113.8, 109.9,
103.0, 55.1, 39.4, 38.6. IR (thin film) ν 1671, 1184, 1140, 1116, 758,
728 cm−1. HRMS (ESI-TOF) calcd for C24H21NNaO2 [M + Na]+:
378.1464; found: 378.1456.
1-Phenyl-3-(2-(p-tolyl)-1H-indol-1-yl)propan-1-one (3da). White
solid (117.1 mg, 69%), mp 149−150 °C. 1H NMR (400 MHz,
CDCl3, ppm) δ 7.76 (d, J = 7.2 Hz, 2H), 7.64 (d, J = 8.0 Hz, 1H),
7.52 (t, J = 7.2 Hz, 1H), 7.43−7.34 (m, 5H), 7.28−7.20 (m, 3H),
7.15 (t, J = 7.2 Hz, 1H), 6.54 (s, 1H), 4.64 (t, J = 8.0 Hz, 2H), 3.25 (t,
J = 8.0 Hz, 2H), 2.41 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3,
ppm) δ 197.8, 141.2, 138.1, 137.1, 136.2, 133.4, 129.8, 129.5, 129.2,
128.6, 128.5, 128.0, 121.8, 120.7, 120.1, 109.8, 102.6, 39.3, 38.5, 21.3.
IR (thin film) ν 1675, 1462, 1354, 1207, 783, 740 cm−1. HRMS (ESI-
TOF) calcd for C24H21NNaO [M + Na]+: 362.1515; found:
362.1518.
3-(2-(4-Methoxyphenyl)-1H-indol-1-yl)-1-phenylpropan-1-one
(3ea). White solid (142.1 mg, 80%), mp 134−135 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.78−7.72 (m, 2H), 7.63 (d, J = 7.6 Hz, 1H),
7.56−7.48 (m, 1H), 7.44−7.35 (m, 5H), 7.26−7.19 (m, 1H), 7.14
(td, J = 7.6, 0.8 Hz, 1H), 6.98 (td, J = 8.8, 2.4 Hz, 2H), 6.51 (s, 1H),
4.63 (t, J = 7.8 Hz, 2H), 3.85 (s, 3H), 3.24 (t, J = 7.8 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 197.9, 159.6, 140.9, 137.0,
136.2, 133.4, 130.6, 128.6, 128.5, 128.0, 125.1, 121.7, 120.6, 120.1,
114.2, 109.7, 102.4, 55.4, 39.2, 38.5. IR (thin film) ν 1674, 1459,
1382, 1225, 755, 556 cm−1. HRMS (ESI-TOF) calcd for
C24H21NNaO2 [M + Na]+: 378.1464; found: 378.1457.
3-(2-(4-Chlorophenyl)-1H-indol-1-yl)-1-phenylpropan-1-one
(3fa). White solid (151.1 mg, 84%), mp 139−140 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.76 (d, J = 7.6 Hz, 2H), 7.64 (d, J = 7.6 Hz,
1H), 7.53 (t, J = 7.6 Hz, 1H), 7.48−7.33 (d, J = 15.0 Hz, 7H), 7.25 (t,
J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.56 (s, 1H), 4.63 (t, J = 7.6
Hz, 2H), 3.23 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3,
ppm) δ 197.6, 139.7, 137.3, 136.1, 134.3, 133.5, 131.2, 130.5, 129.0,
128.7, 128.4, 128.0, 122.2, 120.9, 120.3, 109.9, 103.3, 39.3, 38.4. IR
(thin film) ν 1672, 1461, 1381, 1213, 759, 749 cm−1. HRMS (ESI-
TOF) calcd for C23H18ClNNaO [M + Na]+: 382.0969; found:
382.0962.
3-(2-(4-Bromophenyl)-1H-indol-1-yl)-1-phenylpropan-1-one
(3ga). White solid (153.6 mg, 76%), mp 142−144 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.76 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 8.0 Hz,
1H), 7.59 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.44−7.32 (m,
5H), 7.26 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.56 (s, 1H),
4.64 (t, J = 8.0 Hz, 2H), 3.24 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 197.6, 139.7, 137.3, 136.1, 133.5, 132.0, 131.6,
3-(5,7-Dichloro-2-phenyl-1H-indol-1-yl)-1-phenylpropan-1-one
1
(3ma). White solid (124.2 mg, 63%), mp 188−190 °C. H NMR
(400 MHz, CDCl3, ppm) δ 7.80−7.72 (m, 2H), 7.55−7.43 (m, 7H),
7.38 (t, J = 8.8 Hz, 2H), 7.19 (d, J = 2.0 Hz, 1H), 6.48 (s, 1H), 4.92
(t, J = 8.0 Hz, 2H), 3.25 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 197.2, 144.8, 136.2, 133.4, 132.3, 131.7, 131.2,
129.7, 128.9, 128.8, 128.6, 127.9, 125.7, 123.5, 118.9, 117.2, 103.6,
41.1, 40.2. IR (thin film) ν 1676, 1476, 1384, 1271, 748, 716 cm−1.
HRMS (ESI-TOF) calcd for C23H17Cl2NNaO [M + Na]+: 416.0579;
found: 416.0584.
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1-Phenyl-3-(2-phenyl-1H-benzo[g]indol-1-yl)propan-1-one
(3na). White solid (108.9 mg, 58%), mp 167−170 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 8.46 (dd, J = 8.1, 1.6 Hz, 1H), 8.36 (dd, J = 8.2,
1.4 Hz, 1H), 8.08 (s, 1H), 7.74 (dd, J = 8.4, 1.4 Hz, 2H), 7.65−7.44
(m, 9H), 7.36 (t, J = 7.8 Hz, 2H), 6.65 (s, 1H), 5.06 (t, J = 8.0 Hz,
2H), 3.35 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3,
ppm) δ 197.7, 140.0, 137.2, 136.2, 133.5, 131.2, 131.1, 128.9, 128.7,
128.5, 128.0, 122.1, 120.9, 120.3, 116.0, 115.8, 109.9, 103.1, 39.3,
38.4. IR (thin film) ν 1674, 1478, 1363, 1245, 749, 717 cm−1. HRMS
(ESI-TOF) calcd for C27H21NNaO [M + Na]+: 398.1515; found:
398.1508
1-Phenyl-3-(2-phenyl-1H-pyrrolo[2,3-b]pyridin-1-yl)propan-1-
one (3oa). Yellow solid (122.4 mg, 75%), mp 132−135 °C. 1H NMR
(400 MHz, CDCl3, ppm) δ 7.83 (dd, J = 8.0, 0.8 Hz, 2H), 7.72 (d, J =
8.0 Hz, 1H), 7.63−7.56 (m, 1H), 7.56−7.49 (m, 2H), 7.46−7.43 (m,
3H), 7.36−7.29 (m, 1H), 7.27−7.17 (m, 3H), 6.70−6.54 (m, 1H),
4.69 (t, J = 8.0 Hz, 2H), 3.30 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 197.7, 140.0, 137.2, 136.2, 133.6, 131.2, 131.1,
128.7, 128.5, 128.0, 122.1, 120.9, 120.3, 116.0, 115.8, 109.9, 103.1,
39.3, 38.4. IR (thin film) ν 1676, 1493, 1394, 1281, 752, 746 cm−1.
HRMS (ESI-TOF) calcd for C22H18N2NaO [M + Na]+: 349.1311;
found: 349.1306.
1H), 7.59 (d, J = 7.6 Hz, 2H), 7.54 (t, J = 7.6 Hz, 1H), 7.44−7.32 (m,
5H), 7.26 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 6.56 (s, 1H),
4.64 (t, J = 8.0 Hz, 2H), 3.24 (t, J = 8.0 Hz, 2H). 13C{1H} NMR (100
MHz, CDCl3, ppm) δ 197.6, 139.7, 137.3, 136.1, 133.5, 132.0, 131.6,
130.8, 128.7, 128.4, 128.0, 122.5, 122.3, 120.9, 120.4, 109.9, 103.3,
39.3, 38.4. IR (thin film) ν 1674, 1479, 1388, 1253, 756, 741 cm−1.
HRMS (ESI-TOF) calcd for C23H18BrNNaO [M + Na]+: 426.0464;
found: 426.0469.
1-(4-Methoxyphenyl)-3-(2-phenyl-1H-indol-1-yl)propan-1-one
(3ag). White solid (125.7 mg, 75%), mp 121−122 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.73 (d, J = 8.8 Hz, 2H), 7.65 (d, J = 8.0 Hz,
1H), 7.54−7.36 (m, 6H), 7.27−7.20 (m, 1H), 7.15 (t, J = 7.4 Hz,
1H), 6.84 (d, J = 8.8 Hz, 2H), 6.56 (s, 1H), 4.64 (t, J = 7.6 Hz, 2H),
3.83 (s, 3H), 3.20 (t, J = 7.6 Hz, 2H). 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 196.3, 163.7, 141.1, 137.2, 132.8, 130.3, 129.4, 128.7,
128.5, 128.2, 121.9, 120.7, 120.1, 113.8, 109.9, 102.9, 55.5, 39.5, 38.1.
IR (thin film) ν 1675, 1495, 1354, 1284, 1175, 842, 750 cm−1. HRMS
(ESI-TOF) calcd for C24H21NNaO2 [M + Na]+: 378.1464; found:
378.1468.
3-(2-Phenyl-1H-indol-1-yl)-1-(pyridin-3-yl)propan-1-one (3ah).
White solid (104.4 mg, 64%), mp 167−169 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 8.94 (s, 1H), 8.73 (d, J = 3.5 Hz, 1H), 8.00 (dt,
J = 8.0, 2.0 Hz, 1H), 7.65 (d, J = 7.8 Hz, 1H), 7.52−7.40 (m, 6H),
7.33 (dd, J = 8.0, 4.8 Hz, 1H), 7.28−7.23 (m, 1H), 7.17 (t, J = 7.0 Hz,
1H), 6.57 (s, 1H), 4.69 (t, J = 7.8 Hz, 2H), 3.3 (t, J = 8.0 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 196.8, 153.8, 149.5, 141.0,
137.2, 135.3, 132.7, 131.5, 129.3, 128.8, 128.5, 128.3, 123.6, 122.1,
120.9, 120.3, 109.8, 103.2, 39.0, 38.6. IR (thin film) ν 1677, 1459,
1376, 1351, 1210, 748, 739 cm−1. HRMS (ESI-TOF) calcd for
C22H18N2NaO [M + Na]+: 349.1311; found: 349.1302.
1-(2-Fluorophenyl)-3-(2-phenyl-1H-indol-1-yl)propan-1-one
1
(3ab). White solid (137.7 mg, 80%), mp 82−83 °C. H NMR (400
MHz, CDCl3, ppm) δ 7.80 (td, J = 7.8, 0.8 Hz, 1H), 7.66 (d, J = 7.8
Hz, 1H), 7.50−7.45 (m, 5H), 7.43−7.41 (m, 2H), 7.24−7.14 (m,
3H), 7.10−7.05 (m, 1H), 6.57 (s, 1H), 4.65 (t, J = 7.8 Hz, 2H), 3.32
(t, J = 8.6 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 195.9
(JC−F = 4 Hz), 162.1 (JC−F = 254 Hz), 141.2, 137.2, 135.0 (JC−F = 9
Hz), 132.8, 129.4, 128.7, 128.4, 128.2, 124.5 (JC−F = 4 Hz), 121.9,
120.7, 120.1, 116.7 (JC−F = 24 Hz), 109.8, 102.8, 43.3 (JC−F = 8 Hz),
38.9 (JC−F = 2 Hz). 19F NMR (377 MHz, CDCl3) δ −109.04. IR (thin
film) ν 1676, 1472, 1464, 1350, 815, 777 cm−1. HRMS (ESI-TOF)
calcd for C23H18FNNaO [M + Na]+: 366.1264; found: 366.1260.
1-(3-Chlorophenyl)-3-(2-phenyl-1H-indol-1-yl)propan-1-one
(3ac). White solid (151.1 mg, 84%), mp 137−139 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.73 (t, J = 2.0 Hz, 1H), 7.65 (d, J = 8.0 Hz,
1H), 7.58 (td, J = 8.0, 1.2 Hz, 1H), 7.52−7.44 (m, 5H), 7.43−7.37
(m, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.27−7.21 (m, 1H), 7.19−7.12 (m,
1H), 6.56 (s, 1H), 4.67 (t, J = 8.0 Hz, 2H), 3.21 (t, J = 8.0 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 196.6, 141.0, 137.7, 137.2,
3-(2-Phenyl-1H-indol-1-yl)-1-(thiophen-2-yl)propan-1-one (3ei).
White solid (131.9 mg, 73%), mp 140−143 °C. 1H NMR (400 MHz,
CDCl3, ppm) δ 7.61 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 4.0 Hz, 1H),
7.39 (d, J = 8.0 Hz, 3H), 7.35 (d, J = 4.0 Hz, 1H) 7.22 (t, J = 6.0 Hz,
1H), 7.13 (t, J = 8.0 Hz, 1H), 7.00−6.97 (m, 3H), 6.49 (s, 1H), 4.60
(t, J = 8.0 Hz, 2H), 3.84 (s, 3H), 3.15 (t, J = 8.0 Hz, 2H). 13C{1H}
NMR (100 MHz, CDCl3, ppm) δ 190.6, 159.7, 143.7, 140.9, 137.0,
134.2, 132.3, 130.6, 128.5, 128.2, 125.0, 121.8, 120.6, 120.2, 114.3,
109.8, 102.5, 55.4, 39.3, 39.1. IR (thin film) ν 1675, 1473, 1362, 1254,
1146, 828, 746 cm−1. HRMS (ESI-TOF) calcd for C22H19NNaO2S
[M + Na]+: 384.1024; found: 384.1029.
135.0, 133.3, 132.7, 123.0, 129.3, 128.8, 128.5, 128.3, 128.1, 126.0,
122.0, 120.8, 120.2, 109.8, 103.1, 39.1, 38.5. IR (thin film) ν 1674,
1475, 1349, 1336, 804, 775 cm−1. HRMS (ESI-TOF) calcd for
C23H18ClNNaO [M + Na]+: 382.0969; found: 382.0973.
4-(2-Phenyl-1H-indol-1-yl)butan-2-one (3aj). Colorless liquid
(85.6 mg, 65%). H NMR (400 MHz, CDCl3, ppm) δ 7.66 (d, J =
1
7.8 Hz, 1H), 7.49 (d, J = 4.0 Hz, 4H), 7.50 (dd, J = 8.0, 3.6 Hz, 1H),
7.38 (d, J = 8.2 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 7.17 (t, J = 8.4 Hz,
1H), 6.58 (s,, 1H), 4.51 (t, J = 7.6 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H),
2.05 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 206.3, 141.0,
137.1, 132.7, 129.3, 128.7, 128.4, 128.2, 121.9, 120.7, 120.1, 109.8,
102.9, 43.1, 38.5, 30.1, 29.7. IR (thin film) ν 1673, 1485, 1340, 1215,
858, 752, cm−1. HRMS (ESI-TOF) calcd for C18H17NNaO [M +
Na]+: 286.1202; found: 286.1198.
3-(2-Butyl-1H-indol-3-yl)-1-phenylpropan-1-one (4pa). White
solid (122.2 mg, 80%), mp 55−56 °C. 1H NMR (400 MHz,
CDCl3, ppm) δ 7.93−7.85 (m, 2H), 7.60−7.52 (m, 2H), 7.44 (t, J =
8.0 Hz, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.08
(d, J = 7.2 Hz, 1H), 6.27 (s, 1H), 4.56 (t, J = 7.6 Hz, 2H), 3.40 (t, J =
7.6 Hz, 2H), 2.75 (t, J = 7.6 Hz, 2H), 1.79−1.68 (m, 2H), 1.53−1.41
(m, 2H), 0.97 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3,
ppm) δ 198.0, 140.9, 136.4, 136.3, 133.6, 128.7, 128.4, 128.0, 120.7,
112.0, 119.5, 108.8, 99.3, 38.5, 38.1, 30.8, 26.4, 22.6, 14.0. IR (thin
film) ν 1676, 1583, 1396, 1375, 1209, 1067, 778, 747 cm−1. HRMS
(ESI-TOF) calcd for C21H23NNaO [M + Na]+: 328.1672; found:
328.1673.
1-(4-Fluorophenyl)-3-(2-phenyl-1H-indol-1-yl)propan-1-one
(3ad). White solid (127.0 mg, 74%), mp 120−121 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.75 (t, J = 6.8 Hz, 2H), 7.65 (d, J = 8.0 Hz,
1H), 7.58−7.34 (m, 6H), 7.25 (t, J = 7.0 Hz, 1H), 7.16 (t, J = 7.5 Hz,
1H), 7.03 (t, J = 8.4 Hz, 2H), 6.57 (s, 1H), 4.65 (t, J = 7.6 Hz, 2H),
3.20 (t, J = 7.8 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ
196.2, 165.9 (JC−F = 254 Hz), 141.0, 137.2, 132.7, 132.6 (JC−F = 3
Hz), 130.7 (JC−F = 9 Hz), 129.4, 128.8, 128.5, 128.3, 122.0, 120.8,
120.2, 115.8 (JC−F = 22 Hz), 109.8, 103.1, 39.3, 38.4. 19F NMR (377
MHz, CDCl3) δ −104.42. IR (thin film) ν 1676, 1472, 1351, 1209,
1157, 981, 793, 777 cm−1. HRMS (ESI-TOF) calcd for
C23H18FNNaO [M + Na]+: 366.1264; found: 366.1258
1-(4-Chlorophenyl)-3-(2-phenyl-1H-indol-1-yl)propan-1-one
(3ae). White solid (143.9 mg, 80%), mp 141−143 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.66 (d, J = 8.4 Hz, 3H), 7.55−7.37 (m, 6H),
7.34 (d, J = 8.0 Hz, 2H), 7.25 (t, J = 7.6 Hz, 1H), 7.16 (t, J = 7.5 Hz,
1H), 6.57 (s, 1H), 4.65 (t, J = 7.6 Hz, 2H), 3.19 (t, J = 7.6 Hz, 2H).
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 196.6, 141.0, 139.9, 137.2,
3-(2-(tert-Butyl)-1H-indol-3-yl)-1-phenylpropan-1-one (4qa).
White solid (91.6 mg, 60%), mp 51−52 °C. H NMR (400 MHz,
CDCl3, ppm) δ 8.02−7.95 (m, 2H), 7.63−7.56 (m, 1H), 7.49 (t, J =
7.6 Hz, 2H), 7.25 (dd, J = 7.5, 1.6 Hz, 1H), 7.21−7.13 (m, 1H), 6.69
(d, J = 8.4 Hz, 1H), 6.64 (t, J = 7.6 Hz, 1H), 3.71 (t, J = 6.4 Hz, 2H),
3.33 (t, J = 6.4 Hz, 2H), 1.36 (s, 9H). 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 198.8, 148.1, 136.8, 133.3, 131.9, 129.0, 128.7, 128.0,
134.5, 132.7, 129.4, 129.3, 129.0, 128.7, 128.5, 128.3, 122.0, 120.8,
120.2, 109.8, 103.1, 39.2, 38.4. IR (thin film) ν 1672, 1496, 1346,
1221, 1154, 785, 754 cm−1. HRMS (ESI-TOF) calcd for
C23H18ClNNaO [M + Na]+: 382.0969; found: 382.0975.
1-(4-Bromophenyl)-3-(2-phenyl-1H-indol-1-yl)propan-1-one
(3af). White solid (153.6 mg, 76%), mp 167−170 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.76 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 8.0 Hz,
1
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116.5, 109.3, 109.0, 104.7, 38.4, 37.9, 31.2, 28.3. IR (thin film) ν
1675, 1587, 1440, 1237, 773, 742 cm−1. HRMS (ESI-TOF) calcd for
C21H23NNaO [M + Na]+: 328.1672; found: 328.1678.
AUTHOR INFORMATION
Corresponding Author
■
Weihui Zhong − Key Laboratory for Green Pharmaceutical
Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences and Institute of
Pharmaceutical Science and Technology, Zhejiang University of
Technology, Hangzhou 310014, China; orcid.org/0000-
0003-0349-2226; Email: weihuizhong@zjut.edu.cn
Methyl 1-(3-oxo-3-phenylpropyl)-2-phenyl-1H-indole-5-carbox-
ylate (4rg). White solid (129.2 mg, 74%), mp 145−147 °C. 1H
NMR (400 MHz, CDCl3, ppm) δ 7.90 (d, J = 8.9 Hz, 2H), 7.58 (d, J
= 7.6 Hz, 1H), 7.33 (d, J = 8.1 Hz, 1H), 7.20−7.09 (m, 2H), 6.93 (d,
J = 9.0 Hz, 2H), 6.30 (s, 1H), 4.60−4.54 (m, 2H), 3.89 (s, 3H),
3.41−3.34 (m, 2H), 2.80−2.73 (m, 2H), 1.82−1.74 (m, 2H), 1.48−
1.36 (m, 4H), 0.94 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz,
CDCl3, ppm) δ 196.6, 163.8, 141.1, 136.3, 130.3, 129.5, 128.4, 120.7,
120.0, 120.5, 113.9, 108.9, 99.2, 55.5, 38.3, 38.1, 31.7, 28.3, 26.7, 22.6,
14.1. IR (thin film) ν 1674, 1478, 1363, 1279, 745, 726 cm−1. HRMS
(ESI-TOF) calcd for C23H27NNaO2 [M + Na]+: 372.1934; found:
406.1921
1-(4-Methoxyphenyl)-3-(2-propyl-1H-indol-3-yl)propan-1-one
(4sg). White solid (115.7 mg, 72%), mp 154−156 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 7.91 (d, J = 8.9 Hz, 2H), 7.59 (d, J = 7.8 Hz,
1H), 7.37−7.30 (m, 1H), 7.22−7.09 (m, 2H), 6.97−6.90 (m, 2H),
6.31 (s, 1H), 4.64−4.55 (m, 2H), 3.89 (s, 3H), 3.41−3.33 (m, 2H),
2.80−2.72 (m, 2H), 1.87−1.78 (m, 2H), 1.10 (t, J = 7.3 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3, ppm) δ 196.6, 163.8, 140.8, 136.3,
Authors
Fei Ling − Key Laboratory for Green Pharmaceutical
Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences and Institute of
Pharmaceutical Science and Technology, Zhejiang University of
Technology, Hangzhou 310014, China; orcid.org/0000-
0002-4274-912X
Dingguo Song − Key Laboratory for Green Pharmaceutical
Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, China
Linlin Chen − Key Laboratory for Green Pharmaceutical
Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, China
Tao Liu − Key Laboratory for Green Pharmaceutical
Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, China
Mengyao Yu − Key Laboratory for Green Pharmaceutical
Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, China
Yan Ma − Institute of Pharmaceutical Science and Technology,
Zhejiang University of Technology, Hangzhou 310014, China
Lian Xiao − Key Laboratory for Green Pharmaceutical
Technologies and Related Equipment of Ministry of Education,
College of Pharmaceutical Sciences, Zhejiang University of
Technology, Hangzhou 310014, China
130.3, 129.6, 128.4, 120.7, 120.0, 119.5, 113.9, 108.9, 99.3, 55.6, 38.3,
38.1, 28.8, 21.9, 14.1. IR (thin film) ν 1672, 1484, 1372, 1265, 748,
716 cm−1. HRMS (ESI-TOF) calcd for C21H23NNaO2 [M + Na]+:
372.1934; found: 406.1921.
General Procedure for the Synthesis of 4ai.23a A mixture of 2-
phenyl-1H-indole (5a, 96.6 mg, 0.5 mmol), butan-2-one (2i, 43.3 mg,
0.6 mmol), Cu(OAc)2 (9.1 mg, 0.05 mmol), 2,2′-bipyridine (15.6 mg,
0.1 mmol), and 4-OH-TEMPO (86.1 mg, 0.5 mmol) in 3 mL of DCB
was heated at 120 °C for 24 h. Then, the reaction was cooled to room
temperature, and the solvent was removed under vacuum. The crude
product was purified by column chromatography on silica gel (n-
hexane/EtOAc = 50:1) to yield 4ai (88.2 mg, 67%) as a white solid.
Analytical Data of 4ai. 4-(2-Phenyl-1H-indol-3-yl)butan-2-one
1
(4ai). Colorless liquid (88.2 mg, 67%). H NMR (400 MHz, CDCl3,
ppm) δ 7.57−7.53 (m, 2H), 7.35 (m, 4H), 7.21 (m, 1H), 6.72−6.61
(m, 2H), 3.53 (t, J = 6.3 Hz, 2H), 2.79 (t, J = 6.3 Hz, 2H), 2.19 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 207.6, 148.4, 132.3,
131.5, 123.0, 128.4, 128.2, 123.3, 116.6, 109.5, 108.0, 95.3, 85.8, 42.8,
38.0, 30.4. HRMS (ESI-TOF) calcd for C18H17NNaO [M + Na]+:
286.1202; found: 286.1186.
General Procedure for the Synthesis of 6a. A mixture of 2-
alkynylanilines (1, 0.5 mmol), saturated ketones (2, 0.6 mmol),
Cu(OAc)2 (9.1 mg, 0.05 mmol), 2,2′-bipyridine (15.6 mg, 0.1 mmol),
and 4-OH-TEMPO (86.1 mg, 0.5 mmol) in 3 mL of DCB was heated
at 120 °C in an oil bath for 6 h. Then, the reaction was cooled to
room temperature, and the solvent was removed under vacuum. The
crude product was purified by column chromatography on silica gel
(n-hexane/EtOAc = 60:1) to yield 6a in 23% yield.
Min Xu − Collaborative Innovation Center of Yangtze River
Delta Region Green Pharmaceuticals, Zhejiang University of
Technology, Hangzhou 310014, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.9b03091
Notes
The authors declare no competing financial interest.
Analytical Data of 6a. 1-Phenyl-3-((2-(phenylethynyl)phenyl)-
1
amino)propan-1-one (6a). Yellow liquid (37.4 mg, 78%). H NMR
ACKNOWLEDGMENTS
(400 MHz, CDCl3, ppm) δ 8.00 (dd, J = 8.4, 1.4 Hz, 2H), 7.62−7.54
(m, 3H), 7.48 (t, J = 7.7 Hz, 2H), 7.42−7.32 (m, 4H), 7.27−7.23 (m,
1H), 6.79−6.66 (m, 2H), 5.28 (s, 1H), 3.76 (t, J = 6.3 Hz, 2H), 3.37
(t, J = 6.4 Hz, 2H). 13C{1H} NMR (100 MHz, CDCl3, ppm) δ 196.6,
163.8, 140.8, 136.3, 130.3, 1296, 128.4, 120.7, 120., 119.5, 113.9,
108.9, 99.3, 55.6, 38.3, 38.1, 28.8, 21.9, 14.1. IR (thin film) ν 1675,
1548, 1437, 1255, 848, 756, 723 cm−1. HRMS (ESI-TOF) calcd for
C23H19NNaO [M + Na]+: 348.1359; found: 348.1340
■
We thank the National Natural Science Foundation of China
(Nos. 21706234, 21676253, and 21978271) and the Natural
Science Foundation of Zhejiang Province of China (Nos.
LY19B060011 and LY15B060007) for financial support.
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ASSOCIATED CONTENT
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.9b03091.
Copies of NMR spectra of products (PDF)
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