N-Heterocyclic Carbene-Catalyzed Formal Conjugate Hydroacylation: An Atom-Economic Synthesis of 1 H-Indol-3-yl Esters

Article abstract of DOI:10.1021/acs.joc.8b01488

An atom-economic synthesis of useful 1H-indol-3-yl esters has been demonstrated by an N-heterocyclic carbene (NHC)-catalyzed formal conjugate hydroacylation of 2-phenyl-indol-3-ones with readily accessible aldehydes. This reaction involves a reductive hydride transfer process that was rarely investigated in the field of NHC catalysis. In this process, the hydrogen from the aldehydes was formally transferred to a heteroatom with NHC catalysis for the first time.

Full text of DOI:10.1021/acs.joc.8b01488

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Article
N-Heterocyclic Carbene-Catalyzed Formal Conjugate Hydroacylation:
An Atom Economic Synthesis of 1H-Indol-3-yl Esters
Jindong Zhu, Shuaishuai Fang, Kewen Sun, Chao Fang, Tao Lu, and Ding Du
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01488 • Publication Date (Web): 16 Aug 2018
Downloaded from http://pubs.acs.org on August 16, 2018
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electrophiles (Scheme 1).
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O
X
N
R'
OH
OH
E
R
N
O
N
O
or
O
R
Benzoin
R
9
NHC
N
X
R
H
acyl anions
a1-d1 umpolung
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R
EWG
Stetter reaction
Scheme 1. NHC-catalyzed hydroacylations via the a1-d1 umpolung process.
In 2006, Scheidt and coworkers24 reported an NHCꢀcatalyzed unique
hydroacylation reduction of activated ketones with aldehydes via a Cannizzaroꢀtype
hydride transfer process (Scheme 2a). In this process, the collapse of NHCꢀbound
intermediate I afforded an acylazolium intermediate accompanied with the generation
of a hydride adding to the carbon of ketones. However, after this finding, there are
very limited examples of NHCꢀcatalyzed hydroacylations that involve a hydride
transfer process.25ꢀ29 Chen’s group28 reported a carbeneꢀcatalyzed conjugate reduction
of alkenes through an intramolecular 1,5ꢀhydride transfer from the aldehyde group.
Recently, Wang’s group29 disclosed a novel intramolecular NHCꢀcatalyzed
dehydrogenative coupling reaction of enals via a hydride transfer process. Among
these NHCꢀcatalyzed hydroacylations, the hydride was either transferred to the carbon
of unsaturated double bonds or transferred to combine with the proton. To the best of
our knowledge, there is no documented literature related to NHCꢀcatalyzed
hydroacylation with the hydride transferred to a heteroatom. Herein, we report a novel
NHCꢀcatalyzed formal conjugate hydroacylation of 2ꢀarylꢀ3Hꢀindolꢀ3ꢀones 2 with
aldehydes 1. In this reaction, the hydride was formally transferred to the nitrogen of
substrates 2, affording a series of 2ꢀaryl 1Hꢀindolꢀ3ꢀyl esters. It is noteworthy that
indolꢀ3ꢀyl esters are important materials in organic synthesis as well as in bioorganic
chemistry, and also distribute in many bioactive compounds.30ꢀ35
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a) Hydride transferred to the carbon of carbonyls (Scheidt's work)
N
N
O
O
O
O
H
N
H
O
R
O
R1
OEt
N
OEt
R
O
R1
R
H
1,2-addition
hydroacylation
NHC
N
I
X
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b) Hydride transferred to the carbon of alkenes (Chen's work)
COOMe
CHO
NHC
CN
CN
Ph
MeOH
1,5-hydride transfer
Ph
H
CN
CN
c) Hydride transferred to combine with the proton (Wang's work)
O
R3
O
O
NH
R2
H
NHC
R1
+ H-H
N
R2
O
dehydrogenative
coupling
R3
R1
d) Hydride formally transferred to the nitrogen (this work)
R1
O
R2
O
R2
O
O
R3
NHC
+
R3
R1
H
N
H
formal conjugate
hydroacylation
N
1
2
3
Scheme 2. NHC-catalyzed hydroacylations via a hydride transfer process.
RESULTS AND DISCUSSION
We initiated our study by examining the reaction of benzaldehyde 1a with
2ꢀphenylꢀindolꢀ3ꢀone 2a in the presence of an NHC (Table 1). In a preliminary
investigation of the efficiency of carbene precursors A-E, the reaction catalyzed by
catalyst A, C or D afforded the desired product 3a in moderate yields (entries 1ꢀ5).
Further screening of the bases and solvents (entries 6ꢀ12) convinced us that Cs2CO3
and THF are the optimal base and solvent, respectively, affording product 3a in 64%
yield (entry 7). It was found that the reaction yield could be enhanced to 80% when
the catalystꢀloading was increased to 15 mol% (entry 13), and further increase of the
catalystꢀloading to 20 mol% did not lead to significant enhancement of the yield
(entry 14). Therefore, the optimal reaction conditions were established as shown in
entry 13.
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Table 1. Optimization of the reaction conditions a
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entry
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cat
A
B
C
D
E
A
A
A
A
A
A
A
A
A
base
DBU
DBU
DBU
DBU
DBU
DIPEA
Cs2CO3
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
solvent
THF
THF
THF
THF
THF
THF
THF
THF
yield (%)b
50
trace
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40
trace
trace
64
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trace
40
9
1,2ꢀDCE
Toluene
1,4ꢀdioxane
CH3CN
THF
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13c
14d
80
83
THF
a
Unless otherwise stated, all reactions were performed with 0.26 mmol of 1a, 0.2 mmol of 2a,
0.02 mmol of a catalyst, 0.06 mmol of a base, and 100 mg of 4Å MS in a dry solvent at 60 oC for
2.5 h under N2. b Isolated yields based on 2a. c 15 mol% of A was used. d 20 mol% of A was used.
After optimizing the reaction conditions, we examined the scope and limitations of
this reaction. Initially, a variety of aldehydes 1 were used to react with
2ꢀphenylꢀ3Hꢀindolꢀ3ꢀone 2a in the presence of catalyst A (Table 2). Substituted
benzaldehydes 1b-m with diverse substituents at different positions were well
tolerated to this protocol, furnishing the desired products 3b-m in moderate to high
yields (entries 1ꢀ12). Notably, the reaction time of 2ꢀmethylbenzaldehyde 1m was
shorter than other substrates since prolonged reaction time led to a lower yield due to
the decomposition of product 3m under this condition. Gratifyingly, 1ꢀ and
2ꢀnaphthaldehyde as well as 2ꢀfuraldehyde and 2ꢀthenaldehyde were also suitable to
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this reaction, affording products 3n-q in high yields (entries 13ꢀ16). The reaction of
cinnamaldehyde 1r equally worked smoothly to give product 3r in 75% yield (entry
17). Unfortunately, 3ꢀphenylpropiolaldehyde 1s, ethyl 2ꢀoxoacetate 1t and aliphatic
aldehyde 1u were not tolerated to this protocol (entry 18ꢀ20).
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Table 2. Scope of the reaction between aldehydes 1 and 2-phenyl-3H-indol-3-one
2a a
entry
1
R1, 1
3, yield (%) b
3b, 87
3c, 85
3d, 87
3e, 98
3f, 98
3g, 88
3h, 83
3i, 92
3j, 97
3k, 97
3l, 62
3m, 97
3n, 96
3o, 96
3p, 93
3q, 96
3r, 75
0
4ꢀFC6H4, b
4ꢀClC6H4, c
4ꢀBrC6H4, d
4ꢀMeC6H4, e
4ꢀOMeC6H4, f
3ꢀFC6H4, g
3ꢀClC6H4, h
3ꢀOMeC6H4, i
3ꢀMeC6H4, j
2ꢀClC6H4, k
2ꢀOMeC6H4, l
2ꢀMeC6H4, m
1ꢀnaphthyl, n
2ꢀnaphthyl, o
2ꢀthienyl, p
2ꢀfuryl, q
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12c
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, r
, s
CO2Et, t
nꢀBu, u
0
0
a Unless otherwise stated, all reactions were performed with 0.26 mmol of 1, 0.2 mmol of 2a, 0.03
o
mmol of catalyst A, 0.06 mmol of Cs2CO3, and 100 mg of 4Å MS in dry THF at 60 C for 2.5 h
under N2. b Isolated yields based on 2a. c The reaction time was 1 h.
We then moved to investigate the scope of the reaction between benzaldehyde 1a
and diverse 2ꢀarylꢀ3Hꢀindolꢀ3ꢀones 2 (Table 3). It was found that the reaction of
2ꢀsubstitutedꢀphenylꢀ3Hꢀindolꢀ3ꢀones 2b-f worked equally well to afford products
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3s-w in good to high yields (entries 1ꢀ5). However, due to the instability of the
products under the reaction conditions, the reaction of substrates 2b, 2e and 2f should
be monitored carefully and quenched timely as long as substrates 2 were completely
consumed (entries 1, 3 and 5). We were happy to find that the reaction of substrate 2g
with a steric hindered 1ꢀnaphthyl group also gave rise to product 3x in 91% yield
(entry 6). Finally, two typical 5ꢀsubstituted 2ꢀ phenylꢀ3Hꢀindolꢀ3ꢀones 2h and 2i were
tested (entries 7 and 8). The reaction of substrate 2h with 5ꢀOMe group afforded
product 3y in a good yield, while the reaction of substrate 2i with 5ꢀCl group gave
product 3z in a lower yield. However, the reaction of 6ꢀOMeꢀsubstituted 2ꢀphenyl
indolꢀ3ꢀone 2j resulted in low conversion of the substrates without any desired
product (entry 9).
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Table 3. Scope of the reaction between 1a and 2-aryl-3H-indol-3-ones 2 a
entry
R2, R3, 2
time (h)
0.8
2.5
2.5
1
3, yield (%) b
3s, 87
3t, 96
1
2
H, 4ꢀClC6H4, b
H, 4ꢀMeC6H4, c
H, 4ꢀOMeC6H4, d
H, 3ꢀClC6H4, e
H, 3ꢀMeC6H4, f
H, 1ꢀnaphthyl, g
5ꢀOMe, C6H5, h
5ꢀCl, C6H5, i
3
3u, 96
3v, 89
3w, 85
3x, 91
3y, 87
3z, 53
0
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5
1.2
2.5
2.5
2.5
5
6
7
8
9c
6ꢀOMe, C6H5, j
a Unless otherwise stated, all reactions were performed with 0.26 mmol of 1a, 0.2 mmol of 2, 0.03
mmol of catalyst A, 0.06 mmol of Cs2CO3, and 100 mg of 4Å MS in dry THF at 60 oC under N2. b
Isolated yields based on 2. c Low conversion of both 1a and 2j was observed via TLC.
In order to further explore the utility of this protocol, a scaleꢀup synthesis and
derivatization of product 3a were carried out as shown in Scheme 3. With a 1.5 mmol
scale under the standard conditions, the reaction yield of 3a was maintained. The
acylation of NꢀH free product 3a with acetyl chloride afforded compound 4a in 82%
yield.
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Scheme 3. A scale-up synthesis and acylation of 3a.
A plausible mechanism for this transformation is proposed as shown in Scheme 4
using 1a and 2a as the model substrates. Deprotonation of carbene precursor A with a
base gives rise to carbene A that attacks the carbonyl group of benzaldehyde 1a to
form the tetrahedral intermediate. A rapid hydride transfer from II to the carbonyl of
2a via a 1,2ꢀaddition (similar to the Cannizzaroꢀtype reaction) affords acylazolium III
and intermediate IV, which undergoes 1,3ꢀH shift to give intermediate V (path a).
There is another possible pathway for the generation of V; hydride transfer from II to
2a via a direct conjugate addition could also furnish intermediate V and acylazolium
III (path b). Since the hydride includes a proton and two electrons, the hydride
transfer process may be also considered as that the proton transfers to the nitrogen of
2a coupled with the transfer of two electrons.36 Finally, Oꢀacylation of V with III
affords product 3a accompanied with the release of NHC A’ for the next catalytic
cycle. In terms of the structure of the products, hydrogen and acyl group of the
aldehydes were transferred to the nitrogen and oxygen of 2ꢀarylꢀ3Hꢀindolꢀ3ꢀones,
respectively, in an atomꢀeconomic manner.
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Scheme 4. Proposed mechanism for this hydroacylation reaction.
CONCLUSION
In conclusion, we have explored a transitionꢀmetalꢀfree NHCꢀcatalyzed formal
conjugate hydroacylation of 2ꢀarylꢀ3Hꢀindolꢀ3ꢀones with diverse aldehydes. This is
the first example related to NHCꢀcatalyzed hydroacylation with hydride formally
transferred to a heteroatom. This protocol also offers a rapid and efficient pathway for
the atomꢀeconomic synthesis of useful 2ꢀaryl 1Hꢀindolꢀ3ꢀyl esters starting from
simple materials.
EXPERIMENTAL SECTION
General Information. All reactions were carried out in dry glassware, and were
monitored by analytical thinꢀlayer chromatography (TLC), which was visualized by
ultraviolet light (254 nm). All solvents were obtained from commercial sources and
were purified according to standard procedures. All aldehydes 1 are commercially
available and 2ꢀarylꢀ3Hꢀindolꢀ3ꢀones 2 are prepared according to known procedures.37
Purification of the products was accomplished by flash chromatography using silica
gel (200ꢀ300 mesh). All NMR spectra were recorded on Bruker spectrometers,
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running at 300 MHz or 500 MHz for 1H and 75 MHz or 125 MHz for 13C respectively.
Chemical shifts (δ) and coupling constants (J) are reported in ppm and Hz
respectively. The solvent signals were used as references (residual CHCl3 in CDCl3:
δH = 7.26 ppm, δc = 77.0 ppm). The following abbreviations are used to indicate the
multiplicity in NMR spectra: s (singlet); d (doublet); t (triplet); q (quartet); m
(multiplet). High resolution mass spectrometry (HRMS) was recorded on TOF
perimer for ESI+.
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General procedure for the synthesis of 1H-indol-3-yl esters 3. To an ovenꢀdried 10
mL flask was charged with an aldehyde 1 (0.26 mmol), an 2ꢀarylꢀ3Hꢀindolꢀ3ꢀone 2
(0.2 mmol), 19.5 mg of Cs2CO3 (0.06 mmol), 10 mg of catalyst A (0.03 mmol), and
100 mg of 4 Å molecular sieves. Then, 2 mL of dry THF was added and the resulting
o
mixture was stirred at 60 C under N2. Upon completion of the reaction as monitored
by TLC, the mixture was cooled to room temperature and filtered. The filtrate was
concentrated under reduced pressure and the residue was purified by flash
chromatography on silica gel using hexane/ethyl acetate (15:1) as the eluent to afford
products 3.
Procedure for the scale-up synthesis of product 3a. To an ovenꢀdried 25 mL flask
was charged with benzaldehyde 1a (207 mg, 1.95 mmol), 2ꢀphenylꢀ3Hꢀindolꢀ3ꢀone
2a (311 mg, 1.5 mmol), Cs2CO3 (159 mg, 0.45 mmol), catalyst A (77 mg, 0.225
mmol), and 200 mg of 4 Å molecular sieves. Then, 10 mL of dry THF was added and
o
the resulting mixture was stirred at 60 C under N2. Upon completion of the reaction
as monitored by TLC, the mixture was cooled to room temperature and filtered. The
filtrate was concentrated under reduced pressure and the residue was purified by flash
chromatography on silica gel using hexane/ethyl acetate (15:1) as the eluent to afford
394 mg (84%) of products 3a as a yellowish solid.
Procedure for the acylation of compound 3a. To an ovenꢀdried 25 mL flask was
charged with compound 3a (63 mg, 0.2 mmol) and 2 mL of dry DMF followed by
addition of NaH (80 mg, 2 mmol, 60%) at 0 oC. Then, DMF (1 mL) solution of acetyl
o
chloride (78 mg, 1 mmol) was added dropwise at 0 C. The resulting mixture was
o
stirred at 0 C until the completion of the reaction as monitored by TLC. Then, the
reaction mixture was quenched with 10 mL of water and was further extracted with
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EtOAc (10 mL×3
)
. The combined organic phase was washed with brine (20 mL) and
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was dried over anhydrous Na2SO4. The mixture was then filtered and the resulting
filtrate was concentrated under reduced pressure. The obtained residue was purified
by flash chromatography on silica gel using hexane/ethyl acetate (20:1) as the eluent
to afford 58 mg (82%) of product 4.
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2-Phenyl-1H-indol-3-yl benzoate (3a). 50 mg (80%), yellowish solid, mp: 142ꢀ144oC.
1H NMR (300 MHz, CDCl3) δ 8.39ꢀ8.25 (m, 2H), 8.11 (brs, 1H), 7.69ꢀ7.66 (m, 3H),
7.56 (t, J = 7.5 Hz, 2H), 7.48ꢀ7.34 (m, 4H), 7.31 (d, J = 7.4 Hz, 1H), 7.25ꢀ7.18 (m,
1H), 7.13 (t, J = 7.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 165.0, 133.7, 133.6,
130.6, 130.4, 129.3, 129.0, 128.7, 127.7, 127.0, 126.2, 126.1, 123.1, 122.3, 120.4,
117.9, 111.5. HRMS (ESI) calcd for C21H16NO2 (M+H)+: 314.1181, found 313.1171.
2-Phenyl-1H-indol-3-yl 4-fluorobenzoate (3b). 58 mg (87%), yellowish solid, mp:
153ꢀ155oC. 1H NMR (300 MHz, CDCl3) δ 8.36ꢀ8.30 (m, 2H), 8.20 (brs, 1H), 7.62 (d,
J = 7.3 Hz, 2H), 7.44 (d, J = 7.8 Hz, 1H), 7.37 (t, J = 7.4 Hz, 2H), 7.32ꢀ7.10 (m, 6H).
13C NMR (75 MHz, CDCl3) δ 166.3 (d, J = 253.5 Hz), 164.0, 133.6, 133.0 (d, J = 9.4
Hz), 130.5, 129.0, 127.8, 126.9, 126.2, 126.1, 125.4 (d, J = 2.9 Hz), 123.1, 122.2,
120.5, 117.8, 115.9 (d, J = 21.9 Hz), 111.5. HRMS (ESI) calcd for C21H15FNO2
(M+H)+: 332.1087, found 332.1086.
2-Phenyl-1H-indol-3-yl 4-chlorobenzoate (3c). 59 mg (85%), yellowish solid, mp:
1
165ꢀ167oC. H NMR (300 MHz, CDCl3) δ 8.24 (d, J = 8.5 Hz, 2H), 8.16 (brs, 1H),
7.62 (d, J = 7.4 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.46ꢀ7.34 (m, 3H), 7.31 (d, J = 8.1
Hz, 2H), 7.21 (t, J = 7.2 Hz, 1H), 7.14 (t, J = 7.3 Hz, 1H). 13C NMR (75 MHz, CDCl3)
δ 164.1, 140.3, 133.6, 131.7, 130.5, 129.1, 129.0, 127.8, 127.7, 126.8, 126.2, 126.1,
123.2, 122.1, 120.5, 117.8, 111.5. HRMS (ESI) calcd for C21H15ClNO2 (M+H)+:
348.0791, found 348.0790.
2-Phenyl-1H-indol-3-yl 4-bromobenzoate (3d). 68 mg (87%), yellowish solid, mp:
160ꢀ162oC. 1H NMR (300 MHz, CDCl3) δ 8.20ꢀ8.17 (m, 3H), 7.72 (d, J = 7.5 Hz, 2H),
7.65 (d, J = 7.0 Hz, 2H), 7.47ꢀ7.14 (m, 7H). 13C NMR (75 MHz, CDCl3) δ 164.3,
133.7, 132.1, 131.9, 130.5, 129.1, 128.2, 127.9, 127.3, 126.9, 126.3, 126.2, 123.2,
122.2, 120.6, 117.9, 111.5. HRMS (ESI) calcd for C21H15BrNO2 (M+H)+: 392.0286,
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2-Phenyl-1H-indol-3-yl 4-methylbenzoate (3e). 64 mg (98%), yellowish solid, mp:
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92ꢀ94oC. H NMR (300 MHz, CDCl3) δ 8.20ꢀ8.18 (m, 3H), 7.60 (d, J = 6.8 Hz, 2H),
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7.42 (d, J = 7.3 Hz, 1H), 7.34ꢀ7.28 (m, 4H), 7.26ꢀ7.20 (m, 2H), 7.18ꢀ7.07 (m, 2H),
2.46 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 165.1, 144.6, 133.6, 130.6, 130.4, 129.4,
128.9, 127.6, 127.0, 126.5, 126.1, 126.0, 123.0, 122.3, 120.3, 117.9, 111.5. HRMS
(ESI) calcd for C22H18NO2 (M+H)+: 328.1338, found 328.1332.
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2-Phenyl-1H-indol-3-yl 4-methoxybenzoate (3f). 67 mg (98%), yellowish solid, mp:
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198ꢀ200oC. H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 7.3 Hz, 2H), 8.11 (brs, 1H),
7.68 (t, J = 6.9 Hz, 1H), 7.59ꢀ7.52 (m, 4H), 7.43 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 7.0
Hz, 1H), 7.21ꢀ7.06 (m, 2H), 6.87 (d, J = 7.6 Hz, 2H), 3.79 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 165.0, 159.3, 133.6, 133.5, 130.4, 129.4, 128.7, 127.5, 126.4, 126.2, 123.3,
122.7, 122.5, 120.3, 117.6, 114.5, 111.3, 55.3. HRMS (ESI) calcd for C22H18NO3
(M+H)+: 344.1287, found 344.1286.
2-Phenyl-1H-indol-3-yl 3-fluorobenzoate (3g). 58 mg (88%), yellowish solid, mp:
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130ꢀ132oC. H NMR (300 MHz, CDCl3) δ 8.20 (brs, 1H), 8.13 (d, J = 7.5 Hz, 1H),
8.02 (d, J = 9.1 Hz, 1H), 7.65 (d, J = 7.0 Hz, 2H), 7.61 ꢀ7.51 (m, 1H), 7.51ꢀ7.36 (m,
4H), 7.36ꢀ7.28 (m, 2H), 7.26ꢀ7.14 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 162.7 (J =
246 Hz), 163.8 (J = 3.0 Hz), 133.6, 131.4 (J = 7.5 Hz), 130.5, 130.4 (J = 8.0 Hz),
129.0, 127.8, 126.8, 126.3, 126.2, 126.1, 123.2, 122.1, 120.8 (J = 21.2 Hz), 120.5,
117.8, 117.2 (J = 22.8 Hz), 111.5. HRMS (ESI) calcd for C21H15FNO2 (M+H)+:
332.1087, found 332.1089.
2-Phenyl-1H-indol-3-yl 3-chlorobenzoate (3h). 58 mg (83%), yellowish solid, mp:
139ꢀ141oC. 1H NMR (300 MHz, CDCl3) δ 8.30 (t, J = 1.8 Hz, 1H), 8.23ꢀ8.12 (m, 2H),
7.69ꢀ7.59 (m, 3H), 7.50 (t, J = 7.9 Hz, 1H), 7.45ꢀ7.36 (m 3H), 7.34 – 7.27 (m, 2H),
7.25ꢀ7.18 (m, 1H), 7.17ꢀ7.11 (m, 1H). 13C NMR (75 MHz, CDCl3) δ 163.8, 134.9,
133.7, 133.6, 130.9, 130.4, 130.3, 130.0, 129.0, 128.5, 127.8, 126.7, 126.3, 126.1,
123.2, 122.0, 120.5, 117.8, 111.5. HRMS (ESI) calcd for C21H15ClNO2 (M+H)+:
348.0791, found 348.0785.
2-Phenyl-1H-indol-3-yl 3-methoxybenzoate (3i). 63 mg (92%), yellowish solid, mp:
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154ꢀ156oC. H NMR (300 MHz, CDCl3) δ 8.17 (brs, 1H), 7.96 (d, J = 7.2 Hz, 1H),
7.85 (s, 1H), 7.68 (d, J = 7.0 Hz, 2H), 7.54ꢀ7.10 (m, 9H), 3.92 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 164.8, 159.9, 133.8, 130.7, 129.7, 129.0, 127.7, 127.2, 126.3, 126.2,
123.1, 122.8, 122.4, 120.5, 120.3, 118.0, 114.8, 111.4, 55.5. HRMS (ESI) calcd for
C22H18NO3 (M+H)+: 344.1287, found 344.1290.
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2-Phenyl-1H-indol-3-yl 3-methylbenzoate (3j). 63 mg (97%), yellowish solid, mp:
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144ꢀ146oC. H NMR (300 MHz, CDCl3) δ 8.20 (brs, 1H), 8.11 (s, 2H), 7.59 (d, J =
7.1 Hz, 2H), 7.48ꢀ7.41 (m, 3H), 7.31 (t, J = 7.0 Hz, 2H), 7.27ꢀ7.18 (m, 2H), 7.15ꢀ7.07
(m, 2H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 165.2, 138.6, 134.5, 133.6, 130.9,
130.6, 129.1, 128.9, 128.6, 127.6, 127.5, 127.0, 126.2, 126.1, 123.0, 122.2, 120.3,
117.8, 111.5. HRMS (ESI) calcd for C22H18NO2 (M+H)+: 328.1338, found 328.1335.
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2-Phenyl-1H-indol-3-yl 2-chlorobenzoate (3k). 67 mg (97%), yellow oil. H NMR
(300 MHz, CDCl3) δ 8.15ꢀ8.08 (m, 2H), 7.66 (d, J = 7.2 Hz, 2H), 7.60ꢀ7.48 (m, 3H),
7.45ꢀ7.36 (m, 3H), 7.32 (d, J = 7.5 Hz, 2H), 7.25ꢀ7.14 (m, 2H). 13C NMR (75 MHz,
CDCl3) δ 163.9, 134.4, 133.7, 133.1, 131.8, 131.3, 130.6, 129.6, 128.9, 127.9, 126.9,
126.8, 126.5, 126.4, 123.2, 122.2, 120.6, 118.0, 111.5. HRMS (ESI) calcd for
C21H15ClNO2 (M+H)+: 348.0791, found 348.0790.
2-Phenyl-1H-indol-3-yl 2-methoxybenzoate (3l). 43 mg (62%), yellowish solid, mp:
157ꢀ159oC. 1H NMR (300 MHz, CDCl3) δ 8.24 (brs, 1H), 8.13 (d, J = 7.3 Hz, 1H),
7.73 (d, J = 6.9 Hz, 2H), 7.64ꢀ7.56 (m, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.38 (t, J = 6.9
Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 7.22ꢀ7.07 (m, 4H), 3.95 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 164.5, 159.8, 134.3, 133.7, 132.3, 130.8, 128.8, 127.6, 127.2, 126.2, 123.0,
122.5, 120.34, 120.30, 119.3, 118.2, 112.3, 111.4, 56.0. HRMS (ESI) calcd for
C22H18NO3 (M+H)+: 344.1287, found 344.1280.
2-Phenyl-1H-indol-3-yl 2-methylbenzoate (3m). 63 mg (97%), yellowish solid, mp:
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108ꢀ110oC. H NMR (300 MHz, CDCl3) δ 8.32 (d, J = 7.9 Hz, 1H), 8.18 (brs, 1H),
7.70ꢀ7.60 (m, 2H), 7.53 (td, J = 7.5, 1.3 Hz, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.43ꢀ7.33
(m, 4H), 7.33ꢀ7.26 (m, 2H), 7.24ꢀ7.11 (m, 2H), 2.71 (s, 3H). 13C NMR (75 MHz,
CDCl3) δ 165.5, 141.5, 133.7, 132.8, 132.0, 131.3, 130.6, 128.9, 128.4, 127.7, 127.0,
126.3, 126.1, 126.0, 123.0, 122.3, 120.4, 117.8, 111.5. HRMS (ESI) calcd for
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C22H18NO2 (M+H)+: 328.1338, found 328.1333.
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2-Phenyl-1H-indol-3-yl 1-naphthoate (3n). 70 mg (96%), yellowish solid, mp:
82ꢀ84oC. 1H NMR (300 MHz, CDCl3) δ 9.08 (d, J = 8.2 Hz, 1H), 8.61 (d, J = 6.5 Hz,
1H), 8.23ꢀ8.07 (m, 2H), 7.93 (d, J = 7.6 Hz, 1H), 7.72ꢀ7.47 (m, 6H), 7.39ꢀ7.10 (m,
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6H). C NMR (75 MHz, CDCl3) δ 165.5, 134.4, 134.0, 133.8, 131.8, 131.4, 130.7,
129.0, 128.7, 128.3, 127.8, 127.1, 126.5, 126.2, 125.9, 125.7, 124.6, 123.1, 122.4,
120.5, 117.9, 111.5. HRMS (ESI) calcd for C25H18NO2 (M+H)+: 364.1338, found
364.1331.
2-Phenyl-1H-indol-3-yl 2-naphthoate (3o). 70 mg (96%), yellowish solid, mp:
170ꢀ171oC. 1H NMR (300 MHz, CDCl3) δ 8.88 (s, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.13
(brs, 1H), 8.05ꢀ7.85 (m, 3H), 7.73ꢀ7.52 (m, 4H), 7.47 (d, J = 7.1 Hz, 1H), 7.42ꢀ7.04
(m, 6H). 13C NMR (75 MHz, CDCl3) δ 165.2, 136.0, 133.8, 132.7, 132.2, 130.7,
129.6, 129.0, 128.7, 128.5, 127.9, 127.7, 127.3, 126.9, 126.6, 126.3, 126.2, 125.7,
123.2, 122.5, 120.5, 118.0, 111.5. HRMS (ESI) calcd for C25H18NO2 (M+H)+:
364.1338, found 364.1337.
2-Phenyl-1H-indol-3-yl thiophene-2-carboxylate (3p). 59 mg (93%), yellowish solid,
mp: 159ꢀ161oC. 1H NMR (300 MHz, CDCl3) δ 8.16ꢀ8.09 (m, 2H), 7.75ꢀ7.67 (m, 3H),
7.52 (d, J = 7.5 Hz, 1H), 7.41 (t, J = 7.2 Hz, 2H), 7.35ꢀ7.11 (m, 5H). 13C NMR (75
MHz, CDCl3) δ 160.4, 134.9, 133.7, 133.6, 132.6, 130.6, 129.0, 128.1, 127.7, 127.0,
126.3, 126.2, 123.1, 122.4, 120.5, 118.1, 111.4. HRMS (ESI) calcd for C19H14NO2S
(M+H)+: 320.0745, found 320.0746.
2-Phenyl-1H-indol-3-yl furan-2-carboxylate (3q). 58 mg (96%), yellowish solid, mp:
135ꢀ137oC. H NMR (300 MHz, CDCl3) δ 8.12 (brs, 1H), 7.71ꢀ7.56 (m, 3H),
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2H), 6.59 (s, 1H). C NMR (75 MHz, CDCl3) δ 156.8, 147.3, 144.0, 133.7, 130.5,
128.9, 127.8, 126.5, 126.4, 126.2, 123.2, 122.3, 120.5, 119.6, 118.0, 112.2, 111.4.
HRMS (ESI) calcd for C19H14NO3 (M+H)+: 304.0974, found 304.0972.
2-Phenyl-1H-indol-3-yl cinnamate (3r). 51 mg (75%), yellowish solid, mp:
175ꢀ177oC. H NMR (300 MHz, CDCl3) δ 8.16 (brs, 1H), 7.98 (d, J = 16.0 Hz, 1H),
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7.69ꢀ7.58 (m, 4H), 7.50ꢀ7.36 (m, 6H), 7.35ꢀ7.27 (m, 2H), 7.24ꢀ7.11 (m, 2H), 6.79 (d,
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J = 16.0 Hz, 1H). C NMR (75 MHz, CDCl3) δ 165.3, 147.0, 134.1, 133.6, 130.8,
130.6, 129.00, 128.97, 128.4, 127.7, 127.0, 126.12, 126.09, 123.1, 122.3, 120.4, 117.9,
116.7, 111.5. HRMS (ESI) calcd for C23H18NO2 (M+H)+: 340.1338, found 340.1341.
2-(4-Chlorophenyl)-1H-indol-3-yl benzoate (3s). 60 mg (87%), yellowish solid, mp:
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147ꢀ149oC. H NMR (300 MHz, CDCl3) δ 8.36ꢀ8.26 (m, 2H), 8.18 (brs, 1H), 7.69 (t,
J = 7.4 Hz, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 7.5 Hz,
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1H), 7.28ꢀ7.23 (m, 2H), 7.22ꢀ7.14 (m, 2H), 7.14ꢀ7.07 (m, 1H). C NMR (75 MHz,
CDCl3) δ 165.0, 133.9, 133.7, 133.5, 130.4, 129.2, 129.0, 128.9, 128.8, 127.2, 127.1,
125.1, 123.4, 122.1, 120.6, 117.8, 111.5. HRMS (ESI) calcd for C21H15ClNO2 (M+H)+:
348.0791, found 348.0788.
2-(4-Methylphenyl)-1H-indol-3-yl benzoate (3t). 63 mg (96%), yellowish solid, mp:
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152ꢀ154oC. H NMR (300 MHz, CDCl3) δ 8.33ꢀ8.30 (m, 2H), 8.11 (brs, 1H),
7.72ꢀ7.64 (m, 1H), 7.61ꢀ7.52 (m, 4H), 7.45 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 8.0 Hz,
1H), 7.23ꢀ7.08 (m, 4H), 2.35 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 164.9, 137.7,
133.6, 130.4, 129.7, 129.5, 128.7, 128.5, 127.8, 126.8, 126.5, 126.1, 122.9, 122.5,
120.4, 117.9, 111.4, 21.2. HRMS (ESI) calcd for C22H18NO2 (M+H)+: 328.1338,
found 328.1331.
2-(4-Methoxyphenyl)-1H-indol-3-yl benzoate (3u). 66 mg (96%), yellowish solid,
mp: 141ꢀ143oC. H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 8.8 Hz, 2H), 8.18 (brs,
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1H), 7.64 (d, J = 7.4 Hz, 2H), 7.45 (d, J = 7.7 Hz, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.26
(t, J = 7.3 Hz, 2H), 7.18 (t, J = 7.2 Hz, 1H), 7.12 (t, J = 7.4 Hz, 1H), 7.03 (d, J = 8.8
Hz, 2H), 3.91 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 164.7, 164.0, 133.7, 132.5, 130.6,
128.9, 127.6, 127.2, 126.14, 126.06, 123.0, 122.4, 121.6, 120.4, 118.0, 114.0, 111.4,
55.5. HRMS (ESI) calcd for C22H18NO3 (M+H)+: 344.1287, found 344.1280.
2-(3-Chlorophenyl)-1H-indol-3-yl benzoate (3v). 62 mg (89%), yellowish solid, mp:
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112ꢀ114oC. H NMR (300 MHz, CDCl3) δ 8.41ꢀ8.30 (m, 2H), 8.20 (brs, 1H),
7.75ꢀ7.69 (m, 1H), 7.68ꢀ7.56 (m, 3H), 7.53ꢀ7.46 (m, 2H), 7.33ꢀ7.18 (m, 4H),
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7.17ꢀ7.10 (m, 1H). C NMR (75 MHz, CDCl3) δ 164.9, 134.9, 133.9, 133.8, 132.3,
130.4, 130.2, 129.1, 128.8, 127.8, 127.6, 126.0, 124.7, 124.1, 123.6, 122.2, 120.6,
118.1, 111.6. HRMS (ESI) calcd for C21H15ClNO2 (M+H)+: 348.0791, found
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2-(3-Methylphenyl)-1H-indol-3-yl benzoate (3w). 56 mg (85%), yellow oil. 1H NMR
(300 MHz, CDCl3) δ 8.37ꢀ8.24 (m, 2H), 8.11 (brs, 1H), 7.73ꢀ7.63 (m, 1H), 7.56 (t, J =
7.5 Hz, 2H), 7.51ꢀ7.43 (m, 3H), 7.37 (d, J = 8.1 Hz, 1H), 7.30 (d, J = 7.7 Hz, 1H),
7.25ꢀ7.18 (m, 1H), 7.16ꢀ7.10 (m, 2H), 2.34 (s, 3H). 13C NMR (75 MHz, CDCl3) δ
164.9, 138.6, 133.62, 133.57, 130.5, 130.4, 129.6, 129.3, 128.9, 128.7, 128.6, 126.8,
126.3, 123.4, 123.1, 122.3, 120.4, 118.0, 111.4, 21.5. HRMS (ESI) calcd for
C22H18NO2 (M+H)+: 328.1338, found 328.1333.
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2-(Naphthalen-1-yl)-1H-indol-3-yl benzoate (3x). 66 mg (91%), yellowish solid, mp:
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61ꢀ63oC. H NMR (300 MHz, CDCl3) δ 8.26ꢀ8.03 (m, 4H), 7.91 (d, J = 6.8 Hz, 2H),
7.70 (d, J = 6.6 Hz, 1H), 7.62ꢀ7.48 (m, 5H), 7.46ꢀ7.37 (m, 3H), 7.35ꢀ7.28 (m, 1H),
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7.23 (t, J = 7.1 Hz, 1H). C NMR (75 MHz, CDCl3) δ 164.9, 133.8, 133.3, 131.7,
130.2, 129.3, 129.1, 128.4, 128.2, 128.0, 126.7, 126.2, 125.96, 125.93, 125.3, 123.0,
121.8, 120.5, 118.2, 111.4. HRMS (ESI) calcd for C25H18NO2 (M+H)+: 364.1338,
found 364.1336.
5-Methoxy-2-phenyl-1H-indol-3-yl benzoate (3y). 60 mg (87%), yellowish solid, mp:
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139ꢀ141oC. H NMR (300 MHz, CDCl3) δ 8.39ꢀ8.28 (m, 2H), 8.14 (brs, 1H), 7.70 (t,
J = 7.4 Hz, 1H), 7.65ꢀ7.52 (m, 4H), 7.35 (t, J = 7.4 Hz, 2H), 7.30ꢀ7.22 (m, 1H),
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7.21ꢀ7.13 (m, 1H), 6.85 (dd, J = 7.4, 2.2 Hz, 2H), 3.81 (s, 3H). C NMR (75 MHz,
CDCl3) δ 164.9, 154.5, 133.7, 130.6, 130.4, 129.2, 128.9, 128.8, 128.7, 127.6, 126.9,
126.8, 125.9, 122.5, 113.8, 112.5, 98.9, 55.7. HRMS (ESI) calcd for C22H18NO3
(M+H)+: 344.1287, found 344.1285.
5-Chloro-2-phenyl-1H-indol-3-yl benzoate (3z). 37 mg (53%), yellowish solid, mp:
140ꢀ142oC. 1H NMR (300 MHz, CDCl3) δ 8.38ꢀ8.24 (m, 3H), 7.70 (t, J = 7.4 Hz, 1H),
7.63ꢀ7.51 (m, 4H), 7.41ꢀ7.25 (m, 4H), 7.12ꢀ7.05 (m, 2H). 13C NMR (75 MHz, CDCl3)
δ 165.1, 133.9, 131.9, 130.4, 130.0, 129.0, 128.9, 128.8, 128.0, 127.7, 126.2, 126.1,
126.0, 123.4, 123.1, 117.2, 112.6. HRMS (ESI) calcd for C21H15ClNO2 (M+H)+:
348.0791, found 348.0793.
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1-Acetyl-2-phenyl-1H-indol-3-yl benzoate (4). yellowish solid, mp: 111ꢀ113oC. H
NMR (300 MHz, CDCl3) δ 8.50 (d, J = 8.0 Hz, 1H), 8.19ꢀ8.09 (m, 2H), 7.65 (t, J =
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7.4 Hz, 1H), 7.56ꢀ7.40 (m, 9H), 7.34 (d, J = 7.8 Hz, 1H), 2.08 (s, 3H). 13C NMR (75
MHz, CDCl3) δ 171.0, 164.8, 135.1, 133.8, 133.7, 130.5, 130.3, 129.7, 129.0, 128.8,
128.6, 128.5, 128.4, 126.2, 123.9, 123.1, 117.6, 116.5, 27.7. HRMS (ESI) calcd for
C23H18NO3 (M+H)+: 356.1287, found 356.1290.
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ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra of the compounds.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: ddmn9999@cpu.edu.cn
ORCID
Ding Du: 0000ꢀ0002ꢀ4615ꢀ5433
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work is funded by the National Natural Science Foundation of China (No.
21572270), the Qing Lan Project of Jiangsu Province, and the Priority Academic
Program Development of Jiangsu Higher Education Institutions.
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