Copper-Catalyzed Synthesis of Multisubstituted Indoles through Tandem Ullmann-Type C-N Formation and Cross-dehydrogenative Coupling Reactions

Article abstract of DOI:10.1021/acs.joc.8b00353

Multisubstituted indoles were synthesized via a one-pot tandem copper-catalyzed Ullmann-type C-N bond formation/intramolecular cross-dehydrogenative coupling process at 130 °C in DMSO. The methodology allows practical and modular assembly of indoles in go

Full text of DOI:10.1021/acs.joc.8b00353

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Copper-Catalyzed Synthesis of Multisubstituted Indoles Through Tandem
Ullmann-Type C-N Formation and Cross-dehydrogenative Coupling Reactions
Yue Li, Jinsong Peng, Xin Chen, Baichuan Mo, Xue Li, Peng Sun, and Chunxia Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00353 • Publication Date (Web): 17 Apr 2018
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Copper-Catalyzed Synthesis of Multisubstituted Indoles Through
Tandem Ullmann-Type C-N Formation and Cross-dehydrogenative
Coupling Reactions
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Yue Li, Jinsong Peng*, Xin Chen, Baichuan Mo, Xue Li, Peng Sun, and Chunxia Chen*
Department of Chemistry and Chemical Engineering, College of Science, Northeast
Forestry University, Harbin 150040, P. R. China
Abstract
O
OR2
OR2
CuI (10 mol%), L (35 mol%)
O
℃
KHCO3, DMSO, air, 130 , 48 h
Ar
R1
I
Ar
+
N
R1
PCy2
H2N
H
R1= Aryl, R2= Me, Et
26 examples
60-90% yield
L
tandem Ullmann-type C-N coupling and
cross-dehydrogenative-coupling
Multisubstituted indoles were synthesized via a one-pot tandem copper-catalyzed
Ullmann-type C-N bond formation/intramolecular cross-dehydrogenative coupling
process at 130 ℃ in DMSO. The methodology allows practical and modular
assembly of indoles in good to excellent yields from readily available aryl iodides and
enamines.
The indole subunit represents an important heterocyclic motif that widely exists in
natural products,1 pharmaceuticals and agrochemicals,2 and advanced organic
functional materials.3 In particular, indole scaffolds are generally utilized as
“privileged structures” for drug discovery and development, numerous substituted
indoles display a wide range of biological activities, for example, anticancer,
antibacterial, anti-inflammatory and so on.4
Since the first report of Fischer indole synthesis,5 a variety of powerful methods have
been well established for the construction of indole scaffold over the last hundred
years.6 Despite the availability of numerous procedure, the development of new,
more efficient and atom economical methods is still highly desirable. Over the past
decades, transition-metal-catalyzed inter- and intramolecular C−C and/or C−N bond
forming reaction has emerged as one of the most powerful routes for the synthesis
of indoles.7 Among the various transition metal catalysis, copper-mediated
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Ullmann-type C-heteroatom8 and C-C cross-coupling reactions9 have received
increased attention in the synthesis of heterocycles10 due to their economic
attractiveness, excellent functional group tolerance and potential in large-scale
applications. As an attractive alternative strategy for the construction of
heterocycles, copper-catalyzed C−H funcꢀonalizaꢀon11 has aroused great interest
due to its improved atom and step economy. These copper-catalyzed cross-coupling
reactions have been employed for the synthesis of indoles.12
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Various methodologies have been established to construct indole backbone through
transition metal-catalyzed C–H activation.7f, 13 Initiated by the first examples of
Pd-catalyzed intramolecular cross-dehydrogenative coupling (CDC) reaction to
synthesize carbazoles and dibenzofurans,14 specific CDC strategy has recently been
receiving considerable attention for the synthesis of indoles from enamines and
imines (Scheme 1). In 2008, Glorius reported an efficient synthesis of indoles via
Pd-catalyzed oxidative cyclization of N-aryl enaminones/esters with Cu(OAc)2 as the
oxidant.15 Subsequent to this original work, much effort has been focused on the
improvement of this transformation. Different transition metals, oxidants, and
reaction conditions have been widely explored to enlarge the substrate scope and
improve the efficiency (Scheme 1, path a).16-29 To render the process more efficient
and easier, domino reactions have evolved as highly economic alternative to CDC
approaches by using simple and easily available substrates. Due to the possible
tautomerization of imines to enamines, recently, Yoshikai group30 developed a new
route to indoles through Pd-catalyzed two fold C-H bond cleavage from N-aryl imines
directly derived from simple and obtainable anilines and ketones (Scheme 1, path b).
In addition, one-pot methods have also been established to provide indoles through
sequential addition/Rh or Pd-catalyzed CDC reaction of anilines and alkynes by
Fagnou,31 Jiao,32 and Zhang,33 respectively (Scheme 1, path c).
As described above, copper catalysis can be used in the formation of C-heteroatom
and C-C bonds through either classical Ullmann-type reactions or oxidative C-H
functionalization. Merging fundamentally different copper catalysis into one
operation is no doubt very challenging, however, such sequential one-pot process
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would provide a straightforward method for the synthesis of heterocycles. In a
continuation of our efforts to develop metal-catalyzed new synthetic protocols
involving C-H activation for the construction of heterocyclic frameworks,34 herein we
report a one-pot synthesis of multisubstituted indoles through a sequential
Cu-catalyzed Ullmann-type C-N formation and cross-dehydrogenative coupling
(Scheme 1, path d).35
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Scheme 1. Pathways for the Synthesis of Indoles Based on CDC Strategy
Iodobenzene 1a and enamine 2a were selected as the coupling partners for a
copper-catalyzed synthesis of indole 3aa. Reaction optimization results were
summarized in Table 1. Initially, a survey of reaction media was conducted in the
presence of CuI/1,10-phenanthroline L1 (phen) widely used for Ullmann-type C-N
bond formation.8 With K2CO3 as the base, reactions carried out in polar solvents such
as DMF, DMA and DMSO at 120 ℃ gave a similar yield, whereas the use of
1,4-dioxane and toluene led to lower yields (entries 1-5). As the best result was
obtained when DMSO was used (3aa was isolated in 35% yield, entry 3), the effect of
various bases (NEt3, KOH, Na2CO3, Li2CO3, K3PO4, NaHCO3, KHCO3, and NaOt-Bu) on
the reaction was then investigated in DMSO (entries 6−13). KHCO3 was found to be
the best base to achieve 3aa in 48% yield (entry 12). After an extensive screen of
copper catalysts [CuCl, CuBr, Cu(OAc)2, Cu(OTf)2, CuCl2, CuBr2, Cu2O, CuSO4, and CuI],
we found the nature of copper sources greatly influences the efficiency of twofold
arylation process (entries 14-21), the use of CuI gave the best result in 48% yield by
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Table 1. Optimization of Reaction Conditions for Cu-Catalyzed Synthesis of Indole 3aa
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O
OEt
OEt
Ph
copper catalyst (10 mol%)
ligand (35 mol%)
O
I
+
base, solvent, air, 120 ℃, 24 h
N
H
3aa
H2N
2a
Ph
1a
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entry
catalyst/
ligandb
CuI/L1
CuI/L1
CuI/L1
CuI/L1
base/solvent
yield %c entry
catalyst/ligandb
base/solvent
yield %c
1
2
3
4
K2CO3, DMF
K2CO3, DMA
28
30
35
8
19
20
21
22
CuBr2/L1
Cu2O/L1
KHCO3, DMSO
KHCO3, DMSO
25
25
45
38
K2CO3, DMSO
K2CO3,
1,4-dioxane
CuSO4·5H2O/L1 KHCO3, DMSO
CuI/L2
KHCO3, DMSO
5
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuI/L1
CuCl/L1
CuBr/L1
K2CO3, toluene
NEt3, DMSO
15
5
23
24
25
26
27
28
29
30
31
32d
33f
34f
35f
36f
CuI/L3
CuI/L4
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
35
40
6
7
KOH, DMSO
17
25
20
30
42
48
36
45
47
15
18
30
CuI/L5
45
8
Na2CO3, DMSO
Li2CO3, DMSO
K3PO4, DMSO
NaHCO3, DMSO
KHCO3, DMSO
NaOt-Bu, DMSO
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
CuI/PCy3
CuI/PtBu3·HBF4 KHCO3, DMSO
43
9
32
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12
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18
CuI/L6
CuI/L7
CuI/L8
CuI/L9
CuI/L6
CuI/L6
CuCl/L6
CuBr/L6
CuI/L6
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
69
40
41
33
80 (15)e
KHCO3, DMSO 88/82g/50h
Cu(OAc)2/L1
Cu(OTf)2/L1
CuCl2/L1
KHCO3, DMSO
KHCO3, DMSO
KHCO3, DMSO
75
78
65i/76j
aReaction conditions: 2a (0.2 mmol), 1a (0.24 mmol), base (0.4 mmol), catalyst (0.02 mmol), ligand (0.07 mmol) ,
solvent (1.0 mL). bL1
N1,N2-diphenylethane-1,2-diamine,
=
1,10-phenanthroline, L2
=
(1E,2E)-N1,N2-dimesitylethane-1,2-diimine, L3
L5
=
=
L4
=
N1,N2-bis(2,6-diisopropylphenyl)ethane-1,2-diamine,
1,3-bis(2,6-diisopropylphenyl)imidazolinium tetrafluoroborate, L6 = Johnphos, L7 = Mephos, L8 = Davephos, L9 =
x-phos. cIsolated yield. d130 ℃. eO2. f130 ℃ for 48 h. gN2. hWithout Johnphos (L6). i10 mol% L6. j20 mol% L6.
using KHCO3 and excess phen in DMSO after 24 h (entry 12). In order to increase the
yield of 3aa, we then investigated the effect of ligands (nitrogen-based bidentate
ligands L1-L4, N-heterocyclic carbene ligand L5, and phosphorus ligands L6-L9) on
the reaction (entries 22-31). Sterically hindered biaryl phosphine Johnphos (L6)36
performed best, and the yield was improved to 69% (entry 28). We carried out a set
of experiments to reveal the crucial role of the reaction temperature and time
(entries 32 and 33). With the reaction temperature and time increasing, higher yields
were obtained (69% vs 80% vs 88%, entries 28, 32 and 33). In addition, 3aa was
isolated in only 15% yield when the reaction was carried out under O2 (entry 32) and
was formed in good yield under an air atmosphere. A higher ratio of ligand to Cu is
preferable to afford a better result [65% (1:1), 76% (2:1), and 88% (3:1); entries 33
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and 36]. Finally, it is worth to note that the microwave-promoted tandem cyclization
can provide 3aa in 78% yield within 12 hours at 130 ℃. In general, excess Johnphos
(L6) for CuI was found to be the best catalyst system with KHCO3 as the base in
DMSO at 130 ℃ for 48 h.
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Encouraged by the above results, we then explored the scope and generality of the
present process. First, the limitations were assessed with different aryl iodides 1
using enamine 2a as the substrate (Table 2). As shown in Table 2, all
monosubstituted (including ortho-, meta-, and para-substituted substrates, entries
2-11 and 14-16), disubstituted (entry 13), or fused aryl iodides (entry 12) underwent
the reaction smoothly and afforded the corresponding indoles in good yields
(60-90%). In addition, both aryl bromide and chloride smoothly underwent the
cyclization to afford the desired product in 70% and 50% yield, respectively. The
yield for the aryl halide substrates follows the order aryl iodide > aryl bromide > aryl
chloride (entry 1, Table 2). For the para- and ortho-substituted aryl iodides, both
electron-donating and -withdrawing groups, such as −Me, −OMe, −F, −Cl, −CF3,
−CO2Et, and −CO2Me, were tolerant under the reaction conditions (Table 2, 3ba-3ka).
The incorporation of the group in the ortho and meta positions of aryl iodide seemed
not to hamper the reaction, and the corresponding indoles can be obtained in high
yields (Table 2, entries 9, 13, 14 and 15). When meta-substituted aryl iodides (1n, 1o
and 1p) were used, regioselectivity issues surfaced in the cross-dehydrogenative
coupling process, and a mixture of two regioisomers was obtained (Table 2, entries
14-16). Intramolecular aromatic C−H vinylaꢀon occurred at two different sites to give
products 3na, 3pa and 3oa, respectively (Table 2, entries 14-16). The ring-fused
1-iodonaphthalene also participated in this reaction and afforded product 3la in 81%
yield (Table 2, entry 12). When extending the substrate scope from aryl iodide to
vinyl iodide, for example, (E)-(2-iodovinyl)benzene 1q, the reaction cannot proceed
to give the corresponding pyrrole product. In addition, the use of heteroaromatic
2-iodopyridine 1r led to the formation of 2-phenyl-4H-pyrido[1,2-a]pyrimidin-4-one
3ra through Ullmann-type C-N cross coupling and intramolecular amidation in 60%
yield.
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Table 2. Variation of the Aryl Iodide Substratesa
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entry
S-1
P-3
yieldb
entry
S-1
P-3
yieldb
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aReaction conditions: 2a (0.2 mmol), aryl iodides 1 (0.24 mmol),
2.0 equiv of KHCO3, 10 mol% of CuI, 35 mol% of Johnphos,
c
DMSO (1.0 mL), 130 ℃, 48 h, air. bIsolated yield. The ratio of
the regioisomers was determined by NMR analysis.
Next, enamine substrates were examined in this process. As shown in Scheme 2, a
great variety of enamines 2a-2j can be smoothly converted into the corresponding
indoles in good yields (65-81%). Several functional groups (such as Me, OMe, F, and
Cl) are tolerated in the aryl fragment of enamine, and the electronic nature of the
aromatic motifs does not seem to affect the efficiency of this transformation.
However, when the scope of substrates is extended to aliphatic and carbocyclic
enamines,
for
example,
ethyl
(Z)-3-aminobut-2-enoate
2k
and
3-aminocyclohex-2-en-1-one 2l, the reaction did not give the corresponding products.
Enamine substrates with an aromatic ketone or nitro group were also examined
under the standard conditions, however, no product can be obtained.
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Scheme 2. Variation of the enamine unita,b
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aReaction conditions: 2 (0.2 mmol), aryl iodides 1a or 1b (0.24
mmol), 2.0 equiv of KHCO3, 10 mol% of CuI, 35 mol% of
Johnphos, DMSO (1.0 mL), 130 ℃, 48 h, air. b Isolated yield.
To gain insight into the mechanism of the reaction, some designed control
experiments were conducted. First, the cyclization of the N-methyl derivative of 2a
with iodobenzene 1a was attempted, only N-arylated intermediate was obtained in
92% yield and no indole product was observed. Second, N-phenyl derivative of 2a
(Ullmann coupling intermediate) was carried out under the optimized reaction
conditions, the desired 3aa was obtained in 70% yield. On the basis of the results
described above and the previous mechanistic studies,16, 37 a plausible catalytic cycle
for the synthesis of indoles was outlined in Scheme 3. The initial step involved the
coordination of enamine 2 to the Cu(I) center to form 4, which was followed by an
intermolecular oxidative addition of aryl iodide 1, affording an intermediate complex
5. The resulting complex 5 reacted with base to form Cu-N bond and afforded an
intermediate complex 6, which preceded the formation of N-aryl enamine 7 and
regeneration of catalytic Cu(I) species (Ullmann-type C-N coupling process).8d The
coordination of N-arylation intermediate 7 to CuI led to the formation of complex 8,
which was then transformed into a new C-Cu(I) intermediate 10 through the
sequential deprotonation of N-H and complexation of the resulting carbanion by Cu+
under basic conditions. The further deprotonation of the ester α-carbon of 10
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yielded the carbanion which attacked the C2-position of N-aryl moiety, and this C–C
bond formation proceeded rapidly when preceded by re-protonation of the N-atom
of intermediate 10 from B+-H. Hydride transfer to the Cu(I) center then finished the
formation of indole product 3 and gave Cu-H 13. However, an alternative pathway
via reductive elimination of six-membered copper-cycle intermediate 12 to give 3
could not be completely ruled out.16 Finally, Cu-H species reacted with the conjugate
acid of base, affording hydrogen and regenerating the active copper catalyst for the
next Ullmann-type C-N reaction (CDC process).37
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Scheme 3. Proposed mechanism for sequential Cu-catalyzed annulation of 1 and 2.
In summary, we have developed a Cu(I)-catalyzed 2-fold arylation process through a
tandem Ullmann-type C-N and cross-dehydrogenative coupling sequence. This
method allows the synthesis of multisubstituted indoles from enamines and aryl
iodides in high yields. Considering the valuable structure of the products and good
functionality tolerance, this tandem reaction could be of synthetic utility for the
discovery of drugs.
EXPERIMENTAL SECTION
General Experimental Methods. Chemicals were all purchased from commercial
supplies and used without further purification unless otherwise stated. Solvents
were dried and purified according to the standard procedures before use. Reactions
were monitored by analytical thin-layer chromatography (TLC). All reactions were
conducted in dried glassware. Purification of reaction products was done by flash
chromatography with 230−400 mesh silica gel. Enamine substrates were prepared
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according to the literature methods.38 Melting points were determined on a melting
point apparatus in open capillaries and are uncorrected. Infrared spectra of samples
were recorded from 4,000 to 500 cm−1 in ATR (attenuated total reflectance) mode
using an FT-IR instrument. 1H NMR spectra were recorded on a 400 MHz
spectrometer, and 13C NMR spectra were recorded at 100, 125 or 150 MHz. Unless
otherwise stated, deuterochloroform (CDCl3) was used as a solvent. Chemical shifts
(δ) are given in parts per million downfield relative to tetramethylsilane (TMS).
Chemical shifts for carbon resonances are reported in parts per million and are
referenced to the carbon resonance of the solvent CHCl3 (δ = 77.16 ppm). The
splitting patterns are reported as s (singlet), d (doublet), dd (double doublet), td
(triplet of doublet), t (triplet), q (quartet), br (broad), and m (multiplet). Coupling
constants are given in hertz. High-resolution mass spectra were recorded on a BIO
TOF Q mass spectrometer equipped with an electrospray ion source (ESI), operated
in the positive mode.
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General Procedures for Synthesis of Indole Derivatives. A 10 mL Schlenk tube or
standard vial equipped with a magnetic stirring bar was charged with enamines (0.2
mmol, 1.0 equiv), aryl iodides (0.24 mmol, 1.2 equiv) and KHCO3 (40 mg, 0.4 mmol,
2.0 equiv), and then CuI (0.02 mmol, 3.8 mg) and Johnphos (0.07 mmol, 24.5 mg)
were added. Finally, dimethyl sulfoxide (1.0 mL) was added to the mixture via
syringe at room temperature under air. The tube was sealed and put into a
preheated oil bath at 130 ℃ for 48 h. The mixture was cooled to room temperature,
quenched with water (3 mL), and diluted with ethyl acetate (5 mL). The layers were
separated, and the aqueous layer was extracted with 2 × 5 mL of ethyl acetate. The
combined organic extracts were dried over anhydrous sodium sulfate, filtered, and
concentrated in vacuo. The crude product was then purified by flash
chromatography on silica gel (H), eluting with 10−15% ethyl acetate/petroleum
ether.
Ethyl 2-phenyl-1H-indole-3-carboxylate (3aa). Yield, 88% (46.6 mg); white solid, mp
147-149 ℃ (lit.25a mp 150−152 °C); 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.23 –
8.21 (m, 1H), 7.63 – 7.61 (m, 2H), 7.42 – 7.39 (m, 3H), 7.35 – 7.33 (m, 1H), 7.29 – 7.23
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(m, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
165.6, 144.7, 135.3, 132.2, 129.7, 129.3, 128.2, 127.7, 123.3, 122.3, 122.2, 111.2,
104.8, 59.8, 14.4.
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Ethyl 5-methyl-2-phenyl-1H-indole-3-carboxylate (3ba). Yield, 82% (45.8 mg); white
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solid, mp 152-154 ℃ (lit.25a mp 155−157 °C); H NMR (400 MHz, CDCl3) δ 8.58 (s,
1H), 8.02 (s, 1H), 7.61 – 7.59 (m, 2H), 7.40 – 7.38 (m, 3H), 7.23 (d, J = 8.4 Hz, 1H),
7.07 (dd, J = 8.3, 1.3 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 1.27 (t, J = 7.1 Hz,
3H). 13C NMR (100 MHz, CDCl3) δ 165.6, 144.5, 133.6, 132.3, 131.6, 129.7, 129.1,
128.1, 128.0, 124.8, 121.8, 110.8, 104.3, 59.7, 21.8, 14.4.
Ethyl 5-methoxy-2-phenyl-1H-indole-3-carboxylate (3ca).25a Yield, 79% (46.6 mg);
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yellow oil; H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.66 –
7.58 (m, 2H), 7.49 – 7.37 (m, 3H), 7.25 (d, J = 7.2 Hz, 1H), 6.91 (dd, J = 8.7, 2.4 Hz, 1H),
4.28 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13C NMR (150 MHz, CDCl3)
δ 164.6, 154.6, 143.9, 131.1, 129.1, 128.5, 127.9, 127.5, 126.9, 112.3, 110.0, 103.1,
102.5, 58.6, 54.6, 13.2.
Ethyl 5-fluoro-2-phenyl-1H-indole-3-carboxylate (3da). Yield, 75% (42.5 mg); white
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solid, mp 149-151 ℃ (lit.25a mp 152−154 °C); H NMR (400 MHz, CDCl3) δ 8.69 (s,
1H), 7.87 (dd, J = 10.1, 2.5 Hz, 1H), 7.67 – 7.59 (m, 2H), 7.45 – 7.38 (m, 3H), 7.27 (dd,
J = 8.7, 4.5 Hz, 1H), 7.00 (td, J = 9.0, 2.6 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1
Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 165.1, 159.2 (d, 1JC-F = 235 Hz), 146.0, 131.66 (d,
3JC-F = 9 Hz), 129.5, 129.4, 128.4 (d, 3JC-F = 11 Hz), 128.2, 111.9, 111.8, 111.6 (d, 2JC-F
26 Hz), 107.5 (d, 2JC-F = 25 Hz), 104.9 (d, 4JC-F = 4 Hz), 59.9, 14.3.
=
Ethyl 5-chloro-2-phenyl-1H-indole-3-carboxylate (3ea). Yield, 60% (35.9 mg); white
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solid, mp 148-150 ℃ (lit.25a mp 151−153 °C); H NMR (400 MHz, CDCl3) δ 8.65 (s,
1H), 8.20 (d, J = 1.9 Hz, 1H), 7.66 – 7.60 (m, 2H), 7.46 – 7.40 (m, 3H), 7.28 (d, J = 9.2
Hz, 1H), 7.22 (dd, J = 8.6, 2.0 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.32 (t, J = 7.1 Hz, 3H).
13C NMR (150 MHz, CDCl3) δ 164.9, 145.6, 133.5, 131.6, 129.6, 129.5, 128.8, 128.2,
127.9, 123.6, 121.8, 112.0, 104.5, 59.9, 14.3.
Ethyl 2-phenyl-5-(trifluoromethyl)-1H-indole-3-carboxylate (3fa).25a Yield, 80% (53.3
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mg); white solid, mp 180-184 ℃; H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.54 (s,
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1H), 7.65 (dd, J = 6.3, 2.9 Hz, 2H), 7.53 – 7.41 (m, 5H), 4.32 (q, J = 7.1 Hz, 2H), 1.32 (t,
J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 164.8, 146.0, 136.5, 131.3, 129.7, 129.6,
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128.3, 127.1, 125.1 (q, JC-F = 270 Hz), 124.5 (q, JC-F = 32 Hz), 120.1 (q, JC-F = 4 Hz),
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111.4, 105.5, 60.1, 14.3.
3-Ethyl 5-methyl 2-phenyl-1H-indole-3,5-dicarboxylate (3ga).25b Yield, 70% (45.2 mg);
white solid, mp 156-160 ℃; 1H NMR (400 MHz, CDCl3) δ 8.96 (d, J = 1.1 Hz, 1H), 8.74
(s, 1H), 7.97 (dd, J = 8.5, 1.5 Hz, 1H), 7.66 (dd, J = 6.6, 2.9 Hz, 2H), 7.48 – 7.42 (m, 3H),
7.40 (d, J = 8.5 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H). 13C
NMR (150 MHz, CDCl3) δ 168.0, 164.9, 145.7, 137.7, 131.5, 129.6, 128.3, 127.3, 125.1,
124.7, 124.1, 113.8, 110.8, 105.8, 60.0, 52.1, 14.3.
Diethyl 2-phenyl-1H-indole-3,5-dicarboxylate (3ha). Yield, 65% (43.8 mg); white solid,
mp 190-192 ℃; IR (KBr, cm-1): 3276, 1704, 1677, 1471, 1446, 1430, 1316, 1285,
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1274, 1241, 1128, 1115, 1100; H NMR (400 MHz, CDCl3) δ 8.98 (s, 1H), 8.88 (s, 1H),
7.98 (d, J = 8.5 Hz, 1H), 7.67 (d, J = 3.9 Hz, 2H), 7.45 (m, 3H), 7.40 (d, J = 8.5 Hz, 1H),
4.40 (q, J = 7.1 Hz, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H), 1.34 (t, J = 7.1
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 166.5, 163.9, 144.7, 136.7, 130.4, 128.6, 128.5,
127.2, 126.2, 123.9, 123.6, 123.3, 109.8, 104.7, 59.8, 58.9, 13.4, 13.2. HRMS-ESI:
[M+H]+ calcd for C20H20NO4 m/z 338.1392, found m/z 338.1394.
Ethyl 7-methyl-2-phenyl-1H-indole-3-carboxylate (3ia).25a Yield, 85% (47.4 mg); white
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solid, mp 150-152 ℃; H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 8.07 (d, J = 8.1 Hz,
1H), 7.69 – 7.60 (m, 2H), 7.47 – 7.37 (m, 3H), 7.19 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 7.2
Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 2.50 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (150
MHz, CDCl3) δ 165.4, 144.2, 134.7, 132.3, 129.7, 129.1, 128.1, 127.3, 123.8, 122.3,
120.2, 119.9, 105.3, 59.7, 16.5, 14.3.
Ethyl 7-fluoro-2-phenyl-1H-indole-3-carboxylate (3ja). Yield, 80% (45.3 mg); white
solid, mp 143-145 ℃ (lit.29 mp 140−142 °C); 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H),
7.98 (d, J = 8.1 Hz, 1H), 7.66 (dd, J = 6.4, 2.6 Hz, 2H), 7.52 – 7.35 (m, 3H), 7.18 (td, J =
8.0, 5.0 Hz, 1H), 6.98 (dd, J = 10.7, 8.0 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 165.0, 149.1 (d, JC-F = 243 Hz), 145.0, 131.5,
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130.98 (d, 3JC-F = 4 Hz), 129.7, 129.5, 128.2, 123.6 (d, JC-F = 14 Hz), 122.3 (d, JC-F = 6
Hz), 117.95 (d, 4JC-F = 3 Hz), 108.1 (d, 2JC-F = 15 Hz), 105.6 (d, 4JC-F = 2 Hz), 59.9, 14.3.
Ethyl 7-chloro-2-phenyl-1H-indole-3-carboxylate (3ka). Yield, 78% (46.7 mg); white
solid, mp 145-147 ℃ (lit.29 mp 145−147 °C); 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H),
8.13 (d, J = 7.9 Hz, 1H), 7.76 – 7.60 (m, 2H), 7.54 – 7.42 (m, 3H), 7.27 (dd, J = 7.7, 1.0
Hz, 1H), 7.21 (t, J = 7.8 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13C
NMR (150 MHz, CDCl3) δ 159.6, 139.7, 127.2, 126.3, 124.5, 124.3, 123.8, 123.0, 117.6,
117.3, 115.6, 111.2, 100.7, 54.7, 9.1.
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Ethyl 2-phenyl-1H-benzo[g]indole-3-carboxylate (3la). Yield, 81% (51.1 mg); white
solid, mp 205-207 ℃ (lit.25a mp 204−206 °C); H NMR (400 MHz, CDCl3) δ 9.20 (s,
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1H), 8.32 (d, J = 8.8 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.71 –
7.66 (m, 3H), 7.54 (t, J = 7.0 Hz, 1H), 7.50 – 7.37 (m, 4H), 4.33 (q, J = 7.1 Hz, 2H), 1.33
(t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 164.5, 141.2, 131.2, 129.7, 129.0,
128.7, 127.9, 127.9, 127.1, 124.9, 123.6, 123.1, 121.8, 120.3, 120.0, 118.4, 105.4,
58.8, 13.3.
Ethyl 4,6-dimethyl-2-phenyl-1H-indole-3-carboxylate (3ma).25b Yield, 90% (52.7 mg);
white solid, mp 120-122 ℃; 1H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.54 – 7.52 (m,
2H), 7.46 – 7.36 (m, 3H), 6.99 (s, 1H), 6.84 (s, 1H), 4.22 (q, J = 7.1 Hz, 2H), 2.63 (s, 3H),
2.41 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 165.8, 139.3, 135.0,
132.2, 131.5, 130.0, 127.7, 127.6, 127.3, 124.3, 122.6, 107.6, 106.1, 59.4, 20.4, 20.1,
12.9.
Mixture of ethyl 6-methyl-2-phenyl-1H-indole-3-carboxylate (3na) and ethyl
4-methyl-2-phenyl-1H-indole-3-carboxylate (3n'a).25a Yield, 89% (49.7 mg); yellow oil,
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the ratio (3na:3n'a = 1.7:1) is determined by H NMR; H NMR (400 MHz, CDCl3) δ
9.30 – 9.25 (s, 2.6Hoverlap), 8.18 (d, J = 8.2 Hz, 1.7H3na), 7.83 (d, J = 7.7 Hz, 1H3n′a), 7.68
– 7.57 (m, 3.5H3na), 7.53 – 7.51 (m, 2.7Hoverlap), 7.40 – 7.36 (m, 8.4Hoverlap), 7.18 – 7.15
(m, 3.5H3na), 7.08 (m, 2.6Hoverlap), 4.31 – 4.23 (m, 5.2Hoverlap), 2.75 (s, 3H3n′a), 2.48 (s,
5H3na), 1.33 (t, J = 7.1 Hz, 5H3na), 1.21 (t, J = 7.1 Hz, 3H3n′a).
Mixture of ethyl 6-methoxy-2-phenyl-1H-indole-3-carboxylate (3oa) and ethyl
4-methoxy-2-phenyl-1H-indole-3-carboxylate (3o'a).25a Yield, 80% (47.2 mg); yellow
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oil; the ratio (3oa:3o'a = 1:1) is determined by H NMR; H NMR (400 MHz, CDCl3) δ
9.21 – 8.97 (br, 2Hoverlap), 8.05 (d, J = 8.8 Hz, 1H3oa), 7.54 (d, J = 3.7 Hz, 2H3oa), 7.46 (d,
J = 2.3 Hz, 2H3o′a), 7.27 (m, 6Hoverlap), 7.07 (t, J = 8.0 Hz, 1H3o′a), 6.95 – 6.81 (m,
2Hoverlap), 6.72 (s, 1H3oa), 6.53 (d, J = 7.9 Hz, 1H3o′a), 4.24 (q, J = 7.1 Hz, 4Hoverlap), 3.81
(s, 3H3o′a), 3.67 (s, 3H3oa), 1.26 (t, J = 7.1 Hz, 3H3oa), 1.18 (t, J = 7.1 Hz, 3H3o′a).
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Ethyl 6-chloro-2-phenyl-1H-indole-3-carboxylate (3pa).25a Yield, 45% (26.9 mg); white
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solid, mp 145-148 ℃; H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.10 (d, J = 8.6 Hz,
1H), 7.61 – 7.58 (m, 2H), 7.42 – 7.37 (m, 3H), 7.31 (d, J = 1.4 Hz, 1H), 7.22 (dd, J = 8.6,
1.7 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3)
δ 164.3, 144.3, 134.6, 130.6, 128.6, 128.5, 127.9, 127.2, 126.1, 125.3, 122.1, 121.8,
110.2, 59.0, 13.4.
Ethyl 4-chloro-2-phenyl-1H-indole-3-carboxylate (3p'a).25a Yield, 39% (23.3 mg); white
solid, mp 143-145 ℃; 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.53 (br, 2H), 7.37 (br,
3H), 7.22 – 7.20 (m, 2H), 7.14 – 7.10 (m, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1
Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 166.9, 139.8, 136.6, 131.0, 129.0, 128.7, 128.1,
125.8, 124.4, 123.6, 122.4, 109.9, 106.7, 61.3, 14.0.
Methyl 2-phenyl-1H-indole-3-carboxylate (3ab).15b Yield, 80% (40.2 mg); white solid,
mp 135-137 ℃; 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.24 (d, J = 6.9 Hz, 1H), 7.67
– 7.65 (m, 2H), 7.47 – 7.42 (m, 3H), 7.38 (dd, J = 6.1, 2.2 Hz, 1H), 7.34 – 7.28 (m, 2H),
3.85 (s, 3H). 13C NMR (125 MHz, CDCl3) δ 164.9, 143.7, 134.2, 131.1, 128.7, 128.4,
127.4, 126.7, 122.5, 121.4, 121.3, 110.1, 103.7, 50.1.
Ethyl 2-(p-tolyl)-1H-indole-3-carboxylate (3ac). Yield, 81% (45.2 mg); white solid, mp
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148-150 ℃ (lit.24 mp 144−146 °C); H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 8.31 –
8.18 (m, 1H), 7.56 (d, J = 8.0 Hz, 2H), 7.40 – 7.34 (m, 1H), 7.29 (dd, J = 6.2, 3.3 Hz, 2H),
7.25 (d, J = 7.9 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 2.41 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13
C
NMR (150 MHz, CDCl3) δ 165.5, 144.9, 139.3, 135.1, 129.5, 129.0, 128.8, 127.7, 123.1,
122.1, 122.0, 111.0, 104.4, 59.7, 21.4, 14.4.
Ethyl 2-(4-methoxyphenyl)-1H-indole-3-carboxylate (3ad). Yield, 79% (46.6 mg); white
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solid, mp 162-165 ℃ (lit.25a mp 165−167 °C); H NMR (400 MHz, CDCl3) δ 8.61 (s,
1H), 8.25 – 8.22 (m, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.38 – 7.36 (m, 1H), 7.30 – 7.27 (m,
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2H), 7.01 – 6.92 (m, 2H), 4.34 (q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).
13C NMR (151 MHz, CDCl3) δ 165.6, 160.3, 144.8, 135.1, 130.9, 127.7, 124.2, 122.9,
122.1, 121.9, 113.6, 110.9, 104.1, 59.7, 55.4, 14.4.
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Methyl 2-(4-methoxyphenyl)-1H-indole-3-carboxylate (3ae).15b Yield, 75% (42.2 mg);
white solid, mp 142-144 ℃; 1H NMR (400 MHz, CDCl3) δ 8.64 (s, 1H), 8.25 – 8.14 (m,
1H), 7.60 (d, J = 8.7 Hz, 2H), 7.37 (dd, J = 6.4, 2.1 Hz, 1H), 7.31 – 7.25 (m, 2H), 6.95 (d,
J = 8.7 Hz, 2H), 3.87 (s, 3H), 3.84 (s, 3H). 13C NMR (150 MHz, CDCl3) δ 166.1, 160.4,
144.9, 135.1, 130.9, 127.6, 124.1, 123.0, 122.1, 122.0, 113.6, 111.0, 103.8, 55.3, 50.9.
Ethyl 2-(4-fluorophenyl)-5-methyl-1H-indole-3-carboxylate (3bf). Yield, 78% (46.3 mg);
white solid, mp 160-162 ℃; IR (KBr, cm-1): 3306, 1659, 1495, 1475, 1449, 1274,
1222, 1163, 841, 802; 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 8.04 (s, 1H), 7.65 (dd,
J = 8.6, 5.4 Hz, 2H), 7.30 (d, J = 8.7 Hz, 1H), 7.18 – 7.12 (m, 3H), 4.33 (q, J = 7.1 Hz, 2H),
2.53 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 165.4, 163.2 (d, 1JC-F
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= 248 Hz), 143.3, 133.4, 131.7, 131.5 (d, JC-F = 8 Hz), 128.3 (d, JC-F = 3 Hz), 127.8,
124.9, 121.9, 115.2 (d, 2JC-F = 22 Hz), 110.6, 104.5, 59.7, 21.8, 14.4. HRMS-ESI: [M+H]+
calcd for C18H17FNO2 m/z 298.1243, found m/z 298.1241.
Methyl 2-(4-chlorophenyl)-1H-indole-3-carboxylate (3ag).25a Yield, 75% (42.8 mg);
white solid, mp 151-153 ℃; 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 8.28 – 8.14 (m,
1H), 7.58 (d, J = 8.5 Hz, 2H), 7.42 – 7.37 (m, 3H), 7.32 – 7.27 (m, 2H), 3.86 (s, 3H). 13C
NMR (150 MHz, CDCl3) δ 164.8, 142.3, 134.2, 129.8, 129.2, 128.0, 127.3, 126.3, 122.4,
121.2, 121.1, 110.1, 103.6, 49.9.
Ethyl 2-(m-tolyl)-1H-indole-3-carboxylate (3ah). Yield, 74% (41.3 mg); white solid, mp
143-145 ℃ (lit.29 mp 144−146 °C); 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.26 (d,
J = 7.5 Hz, 1H), 7.48 – 7.46 (m, 2H), 7.37 (t, J = 6.3 Hz, 1H), 7.34 – 7.27 (m, 3H), 7.24
(d, J = 7.7 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 2.40 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C
NMR (151 MHz, CDCl3) δ 164.5, 143.7, 136.6, 134.1, 130.9, 129.1, 128.8, 126.9, 126.6,
125.8, 122.0, 121.0, 120.9, 110.0, 103.4, 58.6, 20.3, 13.3.
Ethyl 2-(3-methoxyphenyl)-1H-indole-3-carboxylate (3ai). Yield, 65% (38.4 mg); white
solid, mp 136-138 ℃; IR (KBr, cm-1): 3261, 1651, 1603, 1475, 1461, 1438, 1379, 1280,
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1234, 1206, 1145, 1054, 785, 752; H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 8.32 –
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8.17 (m, 1H), 7.39 – 7.26 (m, 4H), 7.24 – 7.19 (m, 2H), 6.95 (d, J = 8.2 Hz, 1H), 4.32 (q,
J = 7.1 Hz, 2H), 3.81 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 165.6,
159.1, 144.4, 135.2, 133.3, 129.1, 127.6, 123.2, 122.1, 122.03, 122.02, 115.4, 114.5,
111.2, 104.6, 59.8, 55.3, 14.4. HRMS-ESI: [M+H]+ calcd for C18H18NO3 m/z 296.1287,
found m/z 296.1286.
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Ethyl 2-(3-fluorophenyl)-1H-indole-3-carboxylate (3aj). Yield, 69% (39.1 mg); white
solid, mp 160-162 ℃ (lit.29 mp 162−164 °C); 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H),
8.25 (d, J = 5.4 Hz, 1H), 7.47 – 7.36 (m, 4H), 7.32 – 7.28 (m, 2H), 7.14 (t, J = 7.4 Hz,
1H), 4.34 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 3H). 13C NMR (150 MHz, CDCl3) δ 164.2,
1
3
3
161.2 (d, JC-F = 245 Hz), 141.7, 134.2, 132.9 (d, JC-F = 8 Hz), 128.6 (d, JC-F = 8 Hz),
128.1, 126.4, 124.2 (d, 4JC-F = 3 Hz), 122.5, 121.2, 115.8 (d, 2JC-F = 23 Hz), 115.0 (d, 2JC-F
= 21 Hz), 110.1, 104.1, 58.9, 13.2
ASSOCIATED CONTENT
.
Supporting Information
1H and 13C NMR spectra of the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
*E-mail: jspeng1998@163.com, ccx1759@163.com
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful for financial support from the Fundamental Research Funds for the
Central Universities (2572015EB02), and Natural Science Foundation of Heilongjiang
Province (B2017002).
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