Acylative Coupling of Amine and Indole Using Chloroform as a Carbonyl Group

Article abstract of DOI:10.1002/ejoc.201800571

Chloroform-mediated acylative coupling of amines with indoles has been developed. When indoles and amines in chloroform were treated with dimethylzinc in the presence of air, the three-component aminocarbonylation reaction proceeded via in-situ generation of phosgene from chloroform and O₂ to provide indole-3-carboxamides in a single operation. Application to the synthesis of biologically active compounds and intramolecular acylation are also described.

Full text of DOI:10.1002/ejoc.201800571

DOI: 10.1002/ejoc.201800571
Full Paper
Aminocarbonylation
Acylative Coupling of Amine and Indole Using Chloroform as a
Carbonyl Group
Yuika Nishida,[a] Norihiko Takeda,[a] Kenji Matsuno,[b] Okiko Miyata*[a] and
Masafumi Ueda*[a]
Abstract: Chloroform-mediated acylative coupling of amines ceeded via in-situ generation of phosgene from chloroform and
with indoles has been developed. When indoles and amines in O2 to provide indole-3-carboxamides in a single operation. Ap-
chloroform were treated with dimethylzinc in the presence of plication to the synthesis of biologically active compounds and
air, the three-component aminocarbonylation reaction pro- intramolecular acylation are also described.
Introduction
indole skeleton [Scheme 1, Equation (1) and Equation (2)].[5]
Aminocarbonylation of indole with carbon monoxide and
amines via the generation of the 3-iodoindole intermediate in
the presence of a palladium catalyst and iodine have also been
reported [Equation (3)].[6]
Indole-3-carboxamides are widely found in natural products
such as scholarisine N,[1] leptoclinidamine C[2] and kingamide
A[3] (Figure 1). The structure also is found in pharmaceutically
relevant small molecules. For example, RO5028442 displays po-
tent and selective brain-penetrant hV1a antagonist activity.[4]
Therefore, much effort has focused on the synthesis of indole-
3-carboxamide.
Figure 1. Natural compounds and biologically active indole-3-carboxamides.
Traditional nucleophilic acyl substitution reactions are a well-
known synthetic strategy for these compounds, though these
methods need a pre-installed carbonyl moiety in the amine or
Scheme 1. Strategy for the synthesis of indole-3-carboxamides.
We propose using phosgene to achieve direct carbamoyl-
ation of indole with amines without pre-functionalization.[7]
Phosgene is a versatile reagent for the synthesis of some impor-
tant classes of organic compounds, including acyl chloride, iso-
cyanate, ureas, carbonates, acid anhydrides, and heterocycles
through chlorination, acylation, and dehydration reactions.[8]
However, phosgene is difficult to handle and is a highly toxic
gas. Therefore, less harmful phosgene equivalents such as di-
phosgene and triphosgene were developed; however, these
[a] Kobe Pharmaceutical University,
Motoyamakita, Higashinada, Kobe 658-8558, Japan
E-mail: masa-u@kobepharma-u.ac.jp
miyata@kobepharma-u.ac.jp
http://www.kobepharma-u.ac.jp/medchem/
[b] Department of Chemistry and Life Science, Kogakuin University,
Nakano, Hachi-oji, Tokyo 192-0015, Japan
E-mail: matz@cc.kogakuin.ac.jp
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800571.
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species were less reactive than phosgene.[9] Alternatively, in-situ
generation of phosgene[8a,8b] provides a safer method, because
highly reactive phosgene is consumed immediately by nucleo-
philes, ensuring low stationary concentrations.[10,11] We recently
reported a novel method for in-situ generation of phosgene
from chloroform in the presence of dimethylzinc and O2, and
its application to the chlorolactamization of homoallylic
amines.[12] As part of our program studying the utility of chloro-
form as a C1 unit,[12,13] we report a direct three-component
coupling of amine, indole, and phosgene generated in situ from
chloroform via Friedel–Crafts-type carbamoylation [Equation
(4)].
Scheme 2. Proposed reaction mechanism for acylative coupling.
With the optimized condition (Table 1, entry 5) in hand, vari-
ous amines were surveyed (Scheme 3). N-Methylaniline, an
acyclic aromatic amine, gave the desired amide 3bA. Aliphatic
amines were then examined. Cyclic amines such as tetrahydro-
isoquinoline and piperidine gave corresponding amides 3cA
Results and Discussion
We initially executed a screening experiment to determine the and 3dA in good yields. Several aliphatic cyclic amines of differ-
optimal conditions for acylative coupling of tetrahydroquinoline ent ring sizes also gave carbamoylated products 3eA and 3fA.
with 1-methylindole (Table 1). A chloroform solution of tetra- A lower yield was obtained with morpholine, probably due to
hydroquinoline 1a and indole 2A (1 equiv. each) was treated the instability of morpholine in the presence of radicals.[15]
with dimethylzinc (8 equiv.) in the presence of air.[12] The de-
sired indole-3-carboxamide 3aA was formed, albeit in low yield.
Nucleophilic attack of indole was considered rather ineffective
because the formation of complex side products, including urea
derivatives of 1a and N-acetyltetrahydroquinoline formed by
nucleophilic acyl substitution of carbamoyl chloride B with 1a
or dimethylzinc, was observed. To improve the yield of 3aA, the
amount of nucleophile 2A was increased and reaction time was
extended (entries 2–5). As expected, an excellent yield of 3aA
was obtained when the reaction was carried out with 4 equiv.
of 2A for 48 h (entry 5).[14] Decreasing the amount of dimethyl-
zinc from 8 to 6 equiv. led to a lower yield of the desired prod-
uct (entry 6).
Table 1. Optimization of the reaction conditions.[a]
Entry
1a [equiv.] 2A [equiv.] Me2Zn [equiv.] Time
Yield [%][b]
[h]
1
2
3
4
5
6
1
1
1
1
1
1
1
2
2
3
4
4
8
8
8
8
8
6
24
24
48
48
48
48
18
20
56
67
93
76
[a] Reactions were performed with 0.3 mmol of 1a at a 0.1
M
concentration.
[b] Isolated yield.
The possible reaction mechanism for this acylative coupling
is outlined in Scheme 2. Dimethylzinc and O2 initiated radical
decomposition of chloroform to form phosgene via the tri-
chloromethyl radical.[13] Phosgene is consumed immediately for
the acylation of zinc amide A, which leads to the formation of
Scheme 3. Reaction of various amines with Me2Zn and CHCl3. Conditions:
1b–m (0.3 mmol), 2A (1.2 mmol), Me2Zn (2.4 mmol), CHCl3 (3.0 mL). Yields
of isolated products are given in parentheses.
Furthermore, aliphatic acyclic amines were examined. The re-
the carbamoyl chloride B. Subsequent Friedel–Crafts-type action with primary amines did not give the desired product
aminocarbonylation of indole 2A with carbamoyl chloride B due to the predominant formation of urea derivatives. Simple
provides carboxamide 3aA.
dialkylamines such as diethylamine, di-n-propylamine, and di-
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isopropylamine were tolerated and converted into the corre- to synthesize biologically active indole alkaloids with properties
sponding indole-3-carboxamides 3hA–3jA, along with minor such as cytotoxicity against the A375 human melanoma cell
amount of urea derivatives. Notably, the allylic moiety of diallyl- line (5aA),[16] inhibitor of p38α MAP kinase (5bB),[17] and
amine did not impede the reaction and 3kA formed in 63 % dopamine D4 receptor agonist (5cM)[18] (Scheme 5). Reaction
yield. In the case of N-benzylamines, it is noteworthy that the of the corresponding piperazines and indoles under optimized
formation of indolinone derivatives by intramolecular Friedel– conditions gave the desired biologically active compounds 5aA,
Crafts-type aminocarbonylation was not observed.[8c] Thus, the 5bB and 5cM in just one step.
desired intermolecular acylative coupling products 3lA and
3 mA were formed selectively.
Several indole derivatives were next tested under optimized
reaction conditions (Scheme 4). Indole (2B) reacted selectively
at the indole 3-position to give the corresponding 3-amino-
carbonylated product 3aB, in which acylation of the indole
nitrogen atom did not occur. The methyl group at the indole 2-
position did not prevent the reaction and the desired amide
3aC was obtained in 43 % yield. In addition, substituents such
as methyl, methoxy, halogen, ester group were investigated.
The methyl group on the benzene ring was tolerated, giving
the desired indole-3-carboxamides in moderate yields (3aD–
3aF). However, the methoxy, halogen, and ester substituted
substrate resulted in diminished yields (3aG–3aL).
Scheme 5. Reaction of piperazine derivatives for the preparation of biologi-
cally active compounds. Conditions for 5aA and 5bB: piperazines 4a–b
(0.3 mmol), indoles 2A–B (1.2 mmol), Me2Zn (2.4 mmol), CHCl3 (3.0 mL). Con-
ditions for 5cM: piperazine 4c (0.15 mmol), indole 2M (0.6 mmol), Me2Zn
(1.2 mmol), CHCl3 (1.5 mL). Yields of isolated products are given in parenthe-
ses.
The scope of the three-component coupling reaction was
expanded to the synthesis of pyrrolecarboxyamides, which are
found in many biologically active compounds, such as ator-
vastatin[19] (Scheme 6). The three-component coupling reaction
of N-methylpyrrole (6a) with tetrahydroquinoline 1a in chloro-
form proceeded efficiently to give a 1:1 mixture of pyrrole-3-
Scheme 4. Reaction of various indole derivatives with Me2Zn and CHCl3. Con-
ditions: 1a (0.3 mmol), 2B–L(1.2 mmol), Me2Zn (2.4 mmol), CHCl3 (3.0 mL).
Yields of isolated products are given in parentheses.
To determine the applicability of this aminocarbonylation re-
action, we next examined the reaction of indole with piperazine
Scheme 6. Intermolecular reaction with pyrroles and intramolecular reaction
of phenylethylamines.
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2:1) afforded 3aA–mA, 3aB–aI in the yields shown in Table 1 entry
5, Scheme 3 and Scheme 4, respectively.
carboxyamide 7a and pyrrole-2-carboxyamide 8a in good
yields. Finally, the possibility of an intramolecular acylative cou-
pling was investigated for the construction of dihydroisoquin-
olinone, which is an important core structure, especially in
alkaloids.[20] When N-phenyl- or N-methyl-phenylethylaniline 9a
and 9b was treated with Me2Zn in chloroform, the expected
acylative cyclization provided dihydroisoquinolinones 10a and
10b in good yields. It is noted that the reaction of N-benzyl-
phenylamine (9c) gave dihydroisoquinolinone 10c as a sole
product despite the possibility of forming indolinone 11c.
[3′,4′-Dihydro-1′(2′H)-quinolinyl](1-methyl-1H-indol-3-yl)meth-
anone (3aA): Colorless crystals; 80.8 mg, 93 %; M.p.: 153–154 °C
(hexane/CHCl ). IR (CHCl ): ν = 3009, 2948, 1615, 1602, 1579,
˜
3
3
1
1531 cm–1. H NMR (300 MHz, CDCl3): δ = 7.62 (d, J = 8.0 Hz, 1 H),
7.30–7.04 (m, 6 H), 6.98 (t, J = 7.0 Hz, 1 H), 6.86 (t, J = 7.0 Hz, 1 H),
3.97 (t, J = 6.5 Hz, 2 H), 3.72 (s, 3 H), 2.87 (t, J = 6.5 Hz, 2 H), 2.05
(quint, J = 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.2,
140.0, 136.4, 133.2, 131.3, 128.2, 126.5, 125.6, 124.9, 124.0, 122.2,
121.3, 121.0, 110.9, 109.3, 44.6, 33.2, 27.1, 24.4 ppm. HRMS (ESI) m/z:
calcd. for C19H19N2O [M + H]+ 291.1492, found 291.1483.
N,1-Dimethyl-N-phenyl-1H-indole-3-carboxamide (3bA):[24] Col-
Conclusions
orless crystals; 37.5 mg, 47 %; M.p.: 131–136 °C (hexane/CHCl3). IR
(CHCl3): ν = 3690, 1613, 1594, 1529 cm–1. 1H NMR (300 MHz, CDCl3):
˜
We have developed a novel Friedel–Crafts-type aminocarbonyl-
ation reaction using chloroform as a phosgene precursor. The
three-component coupling of amine, indole, and phosgene
generated in situ from chloroform provided biologically impor-
tant indolecarboxamides, while an intramolecular version of this
reaction produced dihydroisoquinolinone. Efforts to further
clarify the reaction mechanism, determine the scope of the pro-
posed methodology, and demonstrate the synthetic utility of
the products are currently underway in our laboratory.
δ = 8.30–8.24 (m, 1 H), 7.39–7.16 (m, 8 H), 6.12 (s, 1 H), 3.52 (s, 3
H), 3.49 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.9, 145.7,
136.0, 132.7, 129.4, 128.1, 127.7, 127.0, 122.43, 122.40, 121.2, 109.4,
109.0, 38.2, 33.0 ppm. HRMS (ESI) m/z: calcd. for C17H17N2O [M +
H]+ 265.1335, found 265.1332.
[3′,4′-Dihydro-2′(1′H)-isoquinolinyl](1-methyl-1H-indol-3-yl)-
methanone (3cA): A colorless oil; 58.9 mg, 68 %. IR (neat): ν = 3000,
˜
1
2931, 1611, 1533 cm–1. H NMR (300 MHz, CDCl3): δ = 7.58 (d, J =
8.0 Hz, 1 H), 7.26 (s, 1 H), 7.22–6.96 (m, 6 H), 6.91 (m, 1 H), 4.73 (s,
2 H), 3.78 (t, J = 5.5 Hz, 2 H), 3.66 (s, 3 H), 2.82 (t, J = 5.5 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.6, 136.4, 134.5, 133.5, 131.0,
128.6, 126.4, 126.23, 126.16, 122.3, 120.75, 120.73, 110.6, 109.6,
109.3, 47.5, 43.2, 33.1, 29.3 ppm. HRMS (ESI) m/z: calcd. for
Experimental Section
General Information: Melting points (uncorrected) were deter-
mined on BÜCHI M-565 or Yanaco NP-S3. IR spectra were obtained
on a Parkin Elmer SpectrumOne A spectrometer. NMR spectra were
recorded at 300 MHz/75 MHz (1H NMR/13C NMR), 500 MHz/125 MHz
(1H NMR/13C NMR) or 600 MHz/150 MHz (1H NMR/13C NMR) using
Varian Gemini-300 (300 MHz), Varian MERCURY plus 300 (300 MHz),
Varian NMR system AS 500 (500 MHz), or Bruker Avance III HD
(600 MHz) spectrometers. Chemical shifts (δ) are reported in ppm
with solvent resonance or tetramethylsilane as the internal stan-
dard. High-resolution mass spectra were obtained by ESI method
on a Thermo Fisher Scientific Exactive. Flash column chromatogra-
phy was performed using E. Merck Kieselgel 60 (230–240 mesh).
Medium-pressure column chromatography was performed using
Lobar größe B (E. Merck 310–25, Lichroprep Si60). Preparative TLC
separation was carried out on precoated silica gel plates (E. Merck
60F254). CHCl3 (stabilized by amylene for HPLC, Cat. No. 07278–1B)
C
19H19N2O [M + H]+ 291.1492, found 291.1488.
(1-Methyl-1H-indol-3-yl)(piperidin-1′-yl)methanone (3dA):[25]
A
yellow solid; 56.7 mg, 78 %; M.p.: 99–101 °C (hexane/CHCl3). IR
(CHCl3): ν = 3000, 2940, 1600, 1538 cm–1. 1H NMR (300 MHz, CDCl3):
˜
δ = 7.67 (d, J = 7.5 Hz, 1 H), 7.34 (s, 1 H), 7.32–7.12 (m, 3 H), 3.75
(s, 3 H), 3.66–3.60 (m, 4 H), 1.73–1.54 (m, 6 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.1, 136.1, 130.8, 126.0, 122.0, 120.4 (2 C),
110.8, 109.4, 46.1 (br), 32.9, 26.3, 24.7 ppm. HRMS (ESI) m/z: calcd.
for C15H19N2O [M + H]+ 243.1492, found 243.1488.
(1-Methyl-1H-indol-3-yl)(pyrrolidin-1′-yl)methanone (3eA):[25]
A
white solid; 41.7 mg, 61 %; M.p.: 105–108 °C (hexane/CHCl3). IR
(CHCl3): ν = 3694, 2991, 1598, 1536 cm–1. 1H NMR (300 MHz, CDCl3):
˜
δ = 8.13 (d, J = 7.5 Hz, 1 H), 7.32 (s, 1 H), 7.30–7.16 (m, 3 H), 3.75
(s, 3 H), 3.65 (m, 4 H), 1.92 (m, 4 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 165.1, 136.2, 130.4, 127.3, 122.3, 122.0, 120.7, 111.1, 109.1, 47.5
(br), 33.1, 25.5 (br) ppm. HRMS (ESI) m/z: calcd. for C14H17N2O [M +
H]+ 229.1335, found 229.1332.
and Me2Zn (1.0
M n-hexane solution, Cat. No. 11384–25) were pur-
chased from Kanto Chemical Co., Inc. Unless otherwise stated, all
the reagents and solvents were used as received from the manufac-
turer. Starting materials 2D,[21a] 2E,[21b] 2F,[21c,21d] 2G,[21e,21f]
2H,[21c,21d] 2I,[21a] 2J,[21g] 2K,[21h] 2L,[21b] 2M,[21i] 4b,[22a] 9a[23a] and
9b[23b] were prepared according to the literature procedures. The
physical and spectroscopic data of 2D,[21a] 2E,[21b] 2F,[21j] 2G,[21j]
2H,[21d] 2I,[21a] 2J,[21g] 2K,[21k] 2L,[21b] 2M,[21d] 4b,[22b] 9a[23c,23d] and
9b[23b] were consistent with those reported in the literature.
(Azepan-1′-yl)(1-methyl-1H-indol-3-yl)methanone (3fA):[25]
A
white solid; 42.0 mg, 55 %; M.p.: 113–114 °C (hexane/CHCl3). IR
1
(CHCl3): ν = 2935, 1600, 1538 cm–1. H NMR (300 MHz, CDCl3): δ =
˜
7.79 (d, J = 8.0 Hz, 1 H), 7.32–7.13 (m, 4 H), 3.77 (s, 3 H), 3.68 (t, J =
6.0 Hz, 4 H), 1.76 (m, 4 H), 1.60 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.0, 136.3, 129.5, 126.7, 122.2, 121.1, 120.4, 112.2,
109.3, 48.1 (br), 33.0, 28.7 (br), 27.5 (br) ppm. HRMS (ESI) m/z: calcd.
for C16H21N2O [M + H]+ 257.1648, found 257.1664.
General Procedure for Friedel–Crafts-Type Carbamoylation:
[Table 1 entry 5, Scheme 3 and Scheme 4]. 1a–m (0.3 mmol) and
(1-Methyl-1H-indol-3-yl)-4-morpholinylmethanone (3gA):[26]
A
2A–F (1.2 mmol) were dissolved in CHCl3 (3.0 mL) under air atmos- colorless oil; 17.3 mg, 24 %. IR (neat): ν = 3478, 2966, 2914, 2853,
˜
1
phere. Me2Zn (1.0
M
in hexane, 2.4 mL, 2.4 mmol) was added to
1611, 1536 cm–1. H NMR (300 MHz, CDCl3): δ = 7.70–7.65 (m, 1 H),
the mixture under nitrogen atmosphere at room temperature. After 7.44 (s, 1 H), 7.35 (dd, J = 8.5, 0.5 Hz, 1 H), 7.32–7.19 (m, 2 H), 3.82
being stirred at the same temperature for 48 h, the reaction mixture
was diluted with sat. NH4Cl and extracted with CHCl3. The organic
phase was dried with MgSO4 and concentrated under reduced pres-
sure. Purification of the residue by preparative TLC (hexane/AcOEt =
(s, 3 H), 3.74 (s, 8 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.6,
136.4, 131.6, 125.8, 122.4, 120.9, 120.4, 110.1, 109.7, 67.1, 45.8, 33.1
ppm. HRMS (ESI) m/z: calcd. for C14H17N2O2 [M + H]+ 245.1285,
found 245.1283.
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N,N-Diethyl-1-methyl-1H-indole-3-carboxamide (3hA):[27] A col-
175 °C (hexane/CHCl3). IR (CHCl3): ν = 3694, 2996, 2931, 2250, 1600,
˜
1
orless oil; 43.3 mg, 63 %. IR (neat): ν = 2970, 2935, 1721, 1609,
1538 cm–1. H NMR (300 MHz, CDCl3): δ = 7.45 (d, J = 8.0 Hz, 1 H),
˜
1
1536 cm–1. H NMR (300 MHz, CDCl3): δ = 7.76 (dd, J = 8.0, 1.0 Hz,
7.23 (d, J = 6.5 Hz, 1 H), 7.18–6.98 (m, 4 H), 6.91 (td, J = 7.0, 1.0 Hz,
1 H), 6.86–6.79 (m, 1 H), 4.08–3.96 (m, 1 H), 3.90–3.75 (m, 1 H), 3.63
(s, 3 H), 2.91–2.82 (m, 2 H), 2.32 (s, 3 H), 2.02 (quint, J = 6.5 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 167.4, 139.6, 139.5, 136.3, 130.4,
128.3, 125.9, 125.6, 123.8, 123.6, 121.3, 120.5, 119.7, 109.2, 108.8,
45.1, 29.6, 27.3, 24.3, 11.4 ppm. HRMS (ESI) m/z: calcd. for C20H21N2O
[M + H]+ 305.1648, found 305.1642.
1 H), 7.34–7.15 (m, 4 H), 3.80 (s, 3 H), 3.57 (q, J = 7.0 Hz, 4 H), 1.22
(t, J = 7.0 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.7, 136.3,
129.3, 126.6, 122.3, 120.8, 120.5, 111.1, 109.4, 41.2 (br), 33.0, 13.8
ppm. HRMS (ESI) m/z: calcd. for C14H19N2O [M + H]+ 231.1492, found
231.1489.
1-Methyl-N,N-dipropyl-1H-indole-3-carboxamide (3iA): A color-
less oil; 52.4 mg, 68 %. IR (neat): ν = 2961, 2931, 2875, 1611,
˜
[3′,4′-Dihydro-1′(2′H)-quinolinyl](1,7-dimethyl-1H-indol-3-yl)-
methanone (3aD): Colorless crystals; 47.5 mg, 52 %; M.p.:
1
1536 cm–1. H NMR (300 MHz, CDCl3): δ = 7.73 (d, J = 8.0 Hz, 1 H),
7.33–7.14 (m, 4 H), 3.76 (s, 3 H), 3.48 (t, J = 7.5 Hz, 4 H), 1.72–1.55
(m, 4 H), 0.88 (br. t, J = 7.0 Hz, 6 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 167.2, 136.2, 129.6, 126.4, 122.1, 120.6, 120.4, 111.2, 109.4, 48.2
(br), 32.9, 21.3, 11.1 ppm. HRMS (ESI) m/z: calcd. for C16H23N2O [M
+ H]+ 259.1805, found 259.1803.
190–191 °C (hexane/AcOEt). IR (CHCl3): ν = 3007, 1618, 1578,
˜
1
1492 cm–1. H NMR (300 MHz, CDCl3): δ = 7.51 (dd, J = 7.5, 1.0 Hz,
1 H), 7.14 (br. d, J = 7.2 Hz, 1 H), 7.06 (dd, J = 7.0, 1.5 Hz, 1 H), 6.98–
6.84 (m, 5 H), 3.95 (s, 3 H), 3.94 (t, J = 6.5 Hz, 2 H), 2.85 (t, J = 6.5 Hz,
2 H), 2.72 (s, 3 H), 2.02 (quint, J = 6.5 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 166.1, 139.9, 135.1, 134.4, 131.1, 128.2, 127.5,
125.5, 124.9, 124.8, 123.8, 121.1, 119.3, 110.5, 44.7, 37.4, 27.2, 24.5,
19.8 ppm. HRMS (ESI) m/z: calcd. for C20H21N2O [M + H]+ 305.1648,
found 305.1649.
1-Methyl-N,N-bis(1′-methylethyl)-1H-indole-3-carboxamide
(3jA): Colorless crystals; 40.9 mg, 53 %; M.p.: 162–165 °C (hexane/
CHCl3). IR (CHCl3): ν = 3694, 1604, 1538 cm–1 1H NMR (300 MHz,
.
˜
CDCl3): δ = 7.72 (d, J = 7.5 Hz, 1 H), 7.29–7.18 (m, 2 H), 7.16–7.10
(m, 2 H), 3.95 (m, 2 H), 3.74 (s, 3 H), 1.38 (d, J = 6.5 Hz, 12 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 166.3, 136.2, 127.8, 126.7, 122.1, 120.4,
120.1, 113.0, 109.2, 48.1, 32.9, 21.3 ppm. HRMS (ESI) m/z: calcd. for
[3′,4′-Dihydro-1′(2′H)-quinolinyl](1,6-dimethyl-1H-indol-3-yl)-
methanone (3aE): Colorless crystals; 60.3 mg, 66 %; M.p.: 187–
188 °C (hexane/AcOEt). IR (CHCl3): ν = 3007, 1617, 1602, 1543,
˜
C
16H23N2O [M + H]+ 259.1805, found 259.1802.
1
1492 cm–1. H NMR (300 MHz, CDCl3): δ = 7.45 (d, J = 8.0 Hz, 1 H),
7.14 (d, J = 7.0 Hz, 1 H), 7.09–7.04 (m, 1 H), 7.07 (s, 1 H), 7.05 (s, 1
H), 6.95 (td, J = 7.0, 1.0 Hz, 1 H), 6.91 (d, J = 8.0, 1.0 Hz, 1 H), 3.95
(t, J = 6.5 Hz, 2 H), 3.67 (s, 3 H), 2.85 (t, J = 6.5 Hz, 2 H), 2.45 (s, 3
H), 2.03 (quint, J = 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.5, 140.1, 136.8, 133.0, 132.1, 131.3, 128.3, 125.7, 124.9, 124.2,
124.0, 122.8, 120.9, 110.7, 109.4, 44.5, 33.0, 27.0, 24.3, 21.7 ppm.
HRMS (ESI) m/z: calcd. for C20H21N2O [M + H]+ 305.1648, found
305.1647.
1-Methyl-N,N-di-(2′-propen-1′-yl)-1H-indole-3-carboxamide
(3kA): A colorless oil; 47.9 mg, 63 %. IR (neat): ν = 2918, 1615,
˜
1
1531 cm–1. H NMR (300 MHz, CDCl3): δ = 7.93 (dt, J = 8.0, 1.0 Hz,
1 H), 7.37 (s, 1 H), 7.35–7.18 (m, 3 H), 5.96–5.82 (m, 2 H), 5.27 (s, 2
H), 5.22 (dd, J = 6.5, 1.5 Hz, 2 H), 4.15 (d, J = 5.5 Hz, 4 H), 3.79 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.0, 136.4, 133.7, 129.6,
127.1, 122.4, 121.2, 120.8, 117.0, 109.8, 109.3, 49.1 (br), 33.1 ppm.
HRMS (ESI) m/z: calcd. for C16H19N2O [M + H]+ 255.1492, found
255.1490.
[3′,4′-Dihydro-1′(2′H)-quinolinyl](1,5-dimethyl-1H-indol-3-yl)-
N,1-Dimethyl-N-(phenylmethyl)-1H-indole-3-carboxamide
methanone (3aF): A colorless oil; 44.4 mg, 49 %. IR (neat): ν = 2944,
˜
(3lA):[26] A colorless oil; 44.3 mg, 53 %. IR (neat): ν = 2914, 1611,
1
1624, 1579, 1529 cm–1. H NMR (300 MHz, CDCl3): δ = 7.48 (d, J =
˜
1
1533 cm–1. H NMR (300 MHz, CDCl3): δ = 7.85 (dd, J = 7.0, 1.0 Hz,
0.5 Hz, 1 H), 7.19–6.94 (m, 6 H), 6.87 (td, J = 7.5, 1.0 Hz, 1 H), 3.96
(t, J = 6.5 Hz, 2 H), 3.66 (s, 3 H), 2.86 (t, J = 6.5 Hz, 2 H), 2.37 (s, 3
H), 2.03 (quint, J = 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
166.4, 140.1, 134.9, 133.1, 131.4, 130.4, 128.1, 126.9, 125.5, 125.0,
123.9, 123.8, 121.1, 110.2, 109.0, 44.6, 33.1, 27.1, 24.5, 21.5 ppm.
HRMS (ESI) m/z: calcd. for C20H21N2O [M + H]+ 305.1648, found
305.1645.
1 H), 7.38–7.15 (m, 9 H), 4.78 (s, 2 H), 3.72 (s, 3 H), 3.05 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 167.4, 137.5, 136.4, 130.4, 128.5, 127.3,
127.2, 126.9, 122.3, 121.1, 120.8, 110.2, 109.4, 53.1 (br), 35.3, 33.0
ppm. HRMS (ESI) m/z: calcd. for C18H19N2O [M + H]+ 279.1492, found
279.1487.
1-Methyl-N,N-bis(phenylmethyl)-1H-indole-3-carboxamide
(3mA): A colorless foam; 74.5 mg, 70 %. IR (neat): ν = 3026, 2914,
˜
[3′,4′-Dihydro-1′(2′H)-quinolinyl](5-methoxy-1-methyl-1H-indol-
3-yl)methanone (3aG): Colorless crystals; 41.4 mg, 43 %; M.p.: 128–
1710, 1615, 1531 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.96–7.92 (m,
1 H), 7.39–7.18 (m, 14 H), 4.72 (s, 4 H), 3.70 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 167.6, 137.3, 136.5, 129.9, 128.6, 127.5, 127.2,
127.1, 122.5, 121.1, 120.9, 109.8, 109.4, 49.6 (br), 33.1 ppm. HRMS
(ESI) m/z: calcd. for C24H23N2O [M + H]+ 355.1805, found 335.1802.
130 °C (hexane/CHCl ). IR (CHCl ): ν = 1622, 1604, 1576, 1529 cm–1
.
˜
3
3
1H NMR (300 MHz, CDCl3): δ = 7.20–7.04 (m, 5 H), 6.98 (td, J = 7.5,
1.5 Hz, 1 H), 6.88 (dd, J = 7.5, 1.5 Hz, 1 H), 6.84 (dd, J = 9.0, 3.5 Hz,
1 H), 3.98 (t, J = 6.5 Hz, 2 H), 3.73 (s, 3 H), 3.68 (s, 3 H), 2.86 (t, J =
6.5 Hz, 2 H), 2.06 (quint, J = 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 166.3, 155.1, 140.2, 133.5, 131.6, 131.5, 128.1, 127.1,
125.7, 124.9, 124.0, 113.1, 110.3, 110.1, 102.6, 55.6, 44.4, 33.3, 27.2,
24.5 ppm. HRMS (ESI) m/z: calcd. for C20H21N2O2 [M + H]+ 321.1598,
found 321.1592.
[3′,4′-Dihydro-1′(2′H)-quinolinyl](1H-indol-3-yl)methanone
(3aB): A white powder; 43.6 mg, 53 %; M.p.: 187–192 °C (hexane/
CHCl3). IR (CHCl3): ν = 3690, 3026, 1600 cm–1 1H NMR (300 MHz,
.
˜
CDCl3): δ = 9.23 (br. s, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.26–7.01 (m,
6 H), 6.95 (td, J = 7.5, 1.5 Hz, 1 H), 6.84 (td, J = 7.5, 1.5 Hz, 1 H), 3.95
(t, J = 6.5 Hz, 2 H), 2.84 (t, J = 6.5 Hz, 2 H), 2.02 (quint, J = 6.5 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.2, 139.7, 135.7, 131.5,
129.4, 128.4, 125.7, 125.6, 125.0, 124.3, 122.5, 121.1, 120.7, 111.6,
44.8, 26.9, 24.3 ppm. HRMS (ESI) m/z: calcd. for C18H17N2O [M + H]+
277.1335, found 277.1332.
[3′,4′-Dihydro-1′(2′H)-quinolinyl](5-bromo-1-methyl-1H-indol-3-
yl)methanone (3aH): A colorless oil; 40.7 mg, 37 %. IR (neat): ν =
˜
2944, 1622, 1579, 1527 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.74
(d, J = 2.0 Hz, 1 H), 7.28–6.95 (m, 6 H), 6.88–6.82 (m, 1 H), 3.94 (t,
J = 6.5 Hz, 2 H), 3.66 (s, 3 H), 2.85 (t, J = 6.5 Hz, 2 H), 2.04 (quint,
J = 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.5, 139.8,
135.1, 133.9, 131.8, 128.3, 128.1, 125.6, 125.2, 124.8, 124.4, 124.0,
[3′,4′-Dihydro-1′(2′H)-quinolinyl](1,2-dimethyl-1H-indol-3-yl)-
methanone (3aC): Yellowish crystals; 39.4 mg, 43 %; M.p.: 172–
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114.7, 110.8, 110.5, 44.4, 33.3, 27.1, 24.4 ppm. HRMS (ESI) m/z: calcd.
6 H), 3.05 (t, J = 5.0 Hz, 4 H) ppm. 13C NMR (125 MHz, CD3OD): δ =
168.8, 154.0, 142.1, 138.2, 133.1, 127.7, 124.9, 123.6, 122.2, 122.0,
121.3, 119.8, 112.9, 111.09, 111.05, 56.0, 52.4, 46.6 (br), 33.3 ppm.
HRMS (ESI) m/z: calcd. for C21H24N3O2 [M + H]+ 350.1863, found
350.1857.
for C19H18N2O79Br [M + H]+ 369.0597, found 369.0597.
[3′,4′-Dihydro-1′(2′H)-quinolinyl](5-fluoro-1-methyl-1H-indol-3-
yl)methanone (3aI): A colorless oil; 41.7 mg, 45 %. IR (neat): ν =
˜
3009, 1624, 1578, 1485 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.23
(1H-Indol-3-yl)[4′-(phenylmethyl)piperazin-1′-yl]methanone
(5bB):[17] Compound 4b (52.8 mg, 0.3 mmol) and 2B (140.6 mg,
1.2 mmol) were dissolved in CHCl3 (3.0 mL) under air atmosphere.
(dd, J = 10.0, 2.5 Hz, 1 H), 7.19–7.14 (m, 2 H), 7.11 (s, 1 H), 7.02–6.90
(m, 3 H), 6.85 (td, J = 8.0, 1.0 Hz, 1 H), 3.95 (t, J = 6.5 Hz, 2 H), 3.70
(s, 3 H), 2.86 (t, J = 6.5 Hz, 2 H), 2.05 (quint, J = 6.5 Hz, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 166.0, 159.7, 157.8, 140.0, 134.7, 133.1,
131.8, 128.4, 127.3, 127.2, 125.8, 124.9, 124.4, 110.9, 110.7, 110.2,
110.1, 106.7, 106.5, 44.4, 33.4, 27.1, 24.4 ppm. HRMS (ESI) m/z: calcd.
for C19H18N2OF [M + H]+ 309.1398, found 309.1396.
Me2Zn (1.0
M in hexane, 0.6 mL, 0.6 mmol) was added 4 times at
2 h intervals to the mixture under a nitrogen atmosphere at room
temperature. After being stirred at the same temperature for 48 h,
the reaction mixture was diluted with sat. NH4Cl and extracted with
CHCl3. The organic phase was dried with MgSO4 and concentrated
under reduced pressure. Purification of the residue by preparative
TLC (hexane/AcOEt = 1:1) afforded 5bB (47.5 mg, 50 %) as colorless
[3′,4′-Dihydro-1′(2′H)-quinolinyl](6-fluoro-1-methyl-1H-indol-3-
yl)methanone (3aJ): A colorless oil; 26.6 mg, 29 %. IR (neat): ν =
˜
2918, 1621, 1531, 1490 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.51
crystals; M.p.: 184–187 °C (hexane/CHCl3). IR ([D6]DMSO): ν = 3694,
˜
(dd, J = 9.0, 5.5 Hz, 1 H), 7.18 (d, J = 7.0 Hz, 1 H), 7.09 (s, 1 H), 7.03–
6.96 (m, 2 H), 6.97–6.92 (m, 1 H), 6.89–6.82 (m, 2 H), 3.96 (t, J =
6.5 Hz, 2 H), 3.67 (s, 3 H), 2.86 (t, J = 6.5 Hz, 2 H), 2.05 (quint, J =
6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.0, 161.5, 158.3,
139.9, 136.6, 136.5, 133.6, 131.7, 128.3, 125.7, 124.9, 124.3, 122.9,
122.4, 122.3, 111.1, 110.0, 109.6, 96.1, 95.7, 44.4, 33.3, 27.1, 24.4
ppm. HRMS (ESI) m/z: calcd. for C19H18N2OF [M + H]+ 309.1398,
found 309.1399.
1
3470, 3004, 2815, 1604, 1540 cm–1. H NMR (500 MHz, [D6]DMSO):
δ = 11.56 (br. s, 1 H), 7.67–7.64 (m, 2 H), 7.42 (dt, J = 8.0, 1.0 Hz, 1
H), 7.33–7.30 (m, 4 H), 7.28–7.22 (m, 1 H), 7.13 (ddd, J = 8.0, 7.0,
1.5 Hz, 1 H), 7.08 (ddd, J = 8.0, 7.0, 1.5 Hz, 1 H), 3.61 (br. t, J = 4.0 Hz,
4 H), 3.51 (s, 2 H), 2.41 (br. t, J = 4.0 Hz, 4 H) ppm. 13C NMR (125 MHz,
[D6]DMSO): δ = 165.4, 137.8, 135.6, 128.9, 128.2, 127.9, 127.0, 125.9,
121.8, 120.09, 120.07, 111.9, 109.7, 61.9, 52.8, 44.4 (br) ppm. HRMS
(ESI) m/z: calcd. for C20H22N3O [M + H]+ 320.1757, found 320.1750.
Methyl 1-Methyl-3-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-
[1-(Phenylmethyl)-1H-indol-3-yl](4′-phenylpiperazin-1′-yl)meth-
anone (5cM):[18] Compound 4c (24.3 mg, 0.15 mmol) and 2
M
1H-indole-5-carboxylate (3aK): A colorless oil; 35.2 mg, 34 %. IR
(neat): ν = 2948, 1712, 1617 cm–1 1H NMR (300 MHz, CDCl3): δ =
.
˜
(124.4 mg, 0.6 mmol) were dissolved in CHCl3 (1.5 mL) under air
8.30 (br. s, 1 H), 7.91 (dd, J = 8.5, 1.5 Hz, 1 H), 7.28 (br. d, J = 8.5 Hz,
1 H), 7.22 (s, 1 H), 7.21–7.18 (br. d, J = 7.5 Hz, 1 H), 7.03–6.95 (m, 2
H), 6.89–6.82 (m, 1 H), 3.98 (t, J = 6.5 Hz, 2 H), 3.89 (s, 3 H), 3.75 (s,
3 H), 2.90 (t, J = 6.5 Hz, 2 H), 2.07 (quint, J = 6.5 Hz, 2 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 167.4, 165.3, 139.5, 138.6, 134.2, 132.0,
128.1, 125.6, 125.5, 124.7, 124.4, 123.9, 123.5, 122.9, 112.3, 109.1,
51.9, 44.6, 33.5, 27.1, 24.5 ppm. HRMS (ESI) m/z: calcd. for
atmosphere. Me2Zn (1.0 in hexane, 1.2 mL, 1.2 mmol) was added
M
to the mixture under a nitrogen atmosphere at room temperature.
After being stirred at the same temperature for 72 h, the reaction
mixture was diluted with sat. NH4Cl and extracted with CHCl3. The
organic phase was dried with MgSO4 and concentrated under re-
duced pressure. Purification of the residue by preparative TLC (hex-
ane/AcOEt = 1:1) afforded 5cM (26.9 mg, 45 %) as colorless crystals;
C
21H21O3N2 [M + H]+ 349.1547, found 349.1548.
M.p.: 135–138 °C (hexane/CHCl3). IR (CHCl3): ν = 3621, 3017, 2974,
˜
1
1611, 1598, 1538 cm–1. H NMR (500 MHz, [D6]DMSO): δ = 7.97 (s,
Methyl 1-Methyl-3-(1,2,3,4-tetrahydroquinoline-1-carbonyl)-
1 H), 7.73 (d, J = 7.5 Hz, 1 H), 7.50 (d, J = 8.0 Hz, 1 H), 7.34–7.29 (m,
2 H), 7.28–7.20 (m, 5 H), 7.18–7.10 (m, 2 H), 6.97 (d, J = 8.0 Hz, 2 H),
6.80 (t, J = 7.0 Hz, 1 H), 5.47 (s, 2 H), 3.78 (t, J = 5.0 Hz, 4 H), 3.20
(t, J = 5.0 Hz, 4 H) ppm. 13C NMR (125 MHz, [D6]DMSO): δ = 165.1,
150.9, 137.5, 135.5, 131.5, 129.0, 128.6, 127.5, 127.2, 126.6, 122.1,
120.6, 120.5, 119.2, 115.8, 110.8, 109.2, 49.3, 48.7, 48.2, 46.2, 44.5
(br) ppm. HRMS (ESI) m/z: calcd. for C26H26N3O [M + H]+ 396.2070,
found 396.2066.
1H-indole-6-carboxylate (3aL): A colorless oil; 32.5 mg, 31 %. IR
(neat): ν = 2948, 1714, 1619 cm–1 1H NMR (300 MHz, CDCl3): δ =
.
˜
8.03 (br. s, 1 H), 7.75 (dd, J = 8.5, 1.5 Hz, 1 H), 7.55 (d, J = 8.5 Hz, 1
H), 7.28 (d, J = 5.0 Hz, 1 H), 7.18 (br. d, J = 7.5 Hz, 1 H), 7.01–6.96
(m, 2 H), 6.87–6.81 (m, 1 H), 3.97 (t, J = 6.5 Hz, 2 H), 3.92 (s, 3 H),
3.78 (s, 3 H), 2.87 (t, J = 6.5 Hz, 2 H), 2.07 (quint, J = 6.5 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 167.4, 165.4, 139.5, 135.9, 135.7,
131.6, 129.7, 128.1, 125.6, 124.6, 124.2, 123.8, 121.8, 120.7, 111.8,
111.2, 52.1, 44.4, 33.5, 27.2, 24.5 ppm. HRMS (ESI) m/z: calcd. for
C21H21O3N2 [M + H]+ 349.1547, found 349.1549.
Procedure for Friedel–Crafts-Type Carbamoylation of Pyrroles:
[Scheme 6]. 1a (40.0 mg, 0.3 mmol) and 6a (1.2 mmol) were dis-
solved in CHCl3 (3.0 mL) under air atmosphere. Me2Zn (1.0
M in
[4′-(2′-Methoxyphenyl)-piperazin-1′-yl](1-methyl-1H-indol-3-yl)-
methanone (5aA):[16] Compound 4a (57.7 mg, 0.3 mmol) and 2A
(157.4 mg, 1.2 mmol) were dissolved in CHCl3 (3.0 mL) under air
hexane, 2.4 mL, 2.4 mmol) was added to the mixture under a nitro-
gen atmosphere at room temperature. After being stirred at the
same temperature for 48 h, the reaction mixture was diluted with
sat. NH4Cl and extracted with CHCl3. The organic phase was dried
with MgSO4 and concentrated under reduced pressure. Purification
of the residue by preparative TLC (hexane/AcOEt = 1:1) afforded 7a
and 8a.
atmosphere. Me2Zn (1.0
M in hexane, 2.4 mL, 2.4 mmol) was added
to the mixture under a nitrogen atmosphere at room temperature.
After being stirred at the same temperature for 72 h, the reaction
mixture was diluted with sat. NH4Cl and extracted with CHCl3. The
organic phase was dried with MgSO4 and concentrated under re-
duced pressure. Purification of the residue by preparative TLC (hex- [3′,4′-Dihydro-1′(2′H)-quinolinyl](1-methyl-1H-pyrrol-3-yl)meth-
ane/AcOEt = 1:1) afforded 5aA (23.0 mg, 22 %) as colorless crystals; anone (7a): Colorless crystals; 24.4 mg, 34 %; M.p.: 93–96 °C (hex-
M.p.: 90–92 °C (hexane/CHCl3). IR (CHCl3): ν = 3690, 3000, 2940, ane/CHCl3). IR (CHCl3): ν = 3690, 1602 cm–1 1H NMR (300 MHz,
2819, 1602, 1536 cm–1. 1H NMR (500 MHz, CD3OD): δ = 7.71 (dt, J = CDCl3): δ = 7.14–7.04 (m, 2 H), 7.04–6.92 (m, 2 H), 6.87 (s, 1 H), 6.34
.
˜
˜
7.5, 1.0 Hz, 1 H), 7.60 (s, 1 H), 7.44 (dt, J = 8.5, 1.0 Hz, 1 H), 7.26
(ddd, J = 8.0, 7.0, 1.0 Hz, 1 H), 7.19 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H),
7.01 (ddd, J = 8.0, 7.0, 2.0 Hz, 1 H), 6.95 (td, J = 8.0, 1.5 Hz, 2 H),
6.89 (ddd, J = 8.0, 7.0, 1.5 Hz, 1 H), 3.90 (t, J = 5.0 Hz, 4 H), 3.85 (s,
(t, J = 2.0 Hz, 1 H), 5.86 (t, J = 2.0 Hz, 1 H), 3.88 (t, J = 6.5 Hz, 2 H),
3.56 (s, 3 H), 2.76 (t, J = 6.5 Hz, 2 H), 1.99 (quint, J = 6.5 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 166.0, 140.1, 131.9, 127.9, 126.3,
125.6, 125.3, 124.1, 121.2, 119.5, 110.3, 44.1, 36.3, 26.9, 24.4 ppm.
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HRMS (ESI) m/z: calcd. for C15H17N2O [M + H]+ 241.1335, found
241.1333.
Acknowledgments
This work was supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology of Japan
(MEXT) and the Uehara Memorial Foundation.
[3′,4′-Dihydro-1′(2′H)-quinolinyl](1-methyl-1H-pyrrol-2-yl)meth-
anone (8a): Colorless crystals; 26.2 mg, 36 %; M.p.: 108–111 °C (hex-
ane/CHCl3). IR (CHCl3): ν = 3690, 3017, 1602 cm–1 1H NMR
.
˜
(300 MHz, CDCl3): δ = 7.16–7.10 (m, 1 H), 7.04–6.94 (m, 3 H), 6.50
(t, J = 2.0 Hz, 1 H), 6.03 (dd, J = 4.0, 1.5 Hz, 1 H), 5.94 (dd, J = 4.0,
2.5 Hz, 1 H), 3.92 (t, J = 6.5 Hz, 2 H), 3.80 (s, 3 H), 2.81 (t, J = 6.5 Hz,
2 H), 2.01 (quint, J = 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 163.2, 139.8, 130.9, 128.7, 128.3, 126.5, 126.3, 126.2, 125.5, 124.7,
124.2, 122.7, 121.0, 115.2, 107.1, 45.8, 44.8, 35.9, 27.0, 26.9, 24.3,
23.5 ppm. HRMS (ESI) m/z: calcd. for C15H17N2O [M + H]+ 241.1335,
found 241.1333. 13C NMR signals were observed as a mixture of
rotamers.
Keywords: Acylation · Nitrogen heterocycles · Radical
reactions · Indole · Chloroform
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M in hexane, 2.4 mL, 2.4 mmol) was added
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to the solution of 9a in CHCl3 under a nitrogen atmosphere at room
temperature. After being stirred at the same temperature for 24 h,
the reaction mixture was diluted with sat. NH4Cl and extracted with
CHCl3. The organic phase was dried with MgSO4 and concentrated
under reduced pressure. Purification of the residue by preparative
TLC (hexane/AcOEt = 5:1) afforded 10a (47.9 mg, 72 %) as a white
solid; M.p.: 99–102 °C (hexane/CHCl3). IR (CHCl3): ν = 3009, 1652,
˜
1
1495 cm–1. H NMR (300 MHz, CDCl3): δ = 8.15 (d, J = 7.5 Hz, 1 H),
7.48–7.32 (m, 6 H), 7.28–7.16 (m, 2 H), 3.95 (t, J = 6.5 Hz, 2 H), 3.10
(t, J = 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 164.0, 143.0,
138.2, 131.9, 130.0, 128.7, 128.5, 127.0, 126.8, 126.1, 125.2, 49.2, 28.4
ppm. HRMS (ESI) m/z: Calcd for C15H14NO [M + H]+ 224.1070, found
224.1069.
2-Methyl-3,4-dihydroisoquinolin-1(2H)-one (10b):[29] Compound
9b (40.6 mg, 0.3 mmol) was dissolved in CHCl3 (30.0 mL) under air
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atmosphere. Me2Zn (1.0
M in hexane, 2.4 mL, 2.4 mmol) was added
to the solution of 9b in CHCl3 under a nitrogen atmosphere at room
temperature. After being stirred at the same temperature for 24 h,
the reaction mixture was diluted with sat. NH4Cl and extracted with
CHCl3. The organic phase was dried with MgSO4 and concentrated
under reduced pressure. Purification of the residue by preparative
TLC (hexane/AcOEt = 5:1) afforded 10b (29.8 mg, 62 %) as a color-
1
less oil. IR (neat): ν = 3491, 2944, 2858, 1645, 1604, 1576 cm–1. H
˜
NMR (300 MHz, CDCl3): δ = 8.08 (ddd, J = 7.5, 1.0, 0.5 Hz, 1 H), 7.40
(td, J = 7.0, 1.5 Hz, 1 H), 7.36–7.28 (m, 1 H), 7.17 (dt, J = 7.5, 0.5 Hz,
1 H), 3.56 (t, J = 6.5 Hz, 2 H), 3.15 (s, 3 H), 3.00 (t, J = 6.5 Hz, 2 H)
ppm. 13C NMR (75 MHz, CDCl3): δ = 164.7, 137.8, 131.4, 129.2, 127.9,
126.9, 126.8, 48.0, 35.1, 27.7 ppm. HRMS (ESI) m/z: Calcd for
C10H12NO [M + H]+ 162.0913, found 162.0912.
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2-Phenylmethyl-3,4-dihydroisoquinolin-1(2H)-one (10c):[30]
Compound 9c (31.7 mg, 0.15 mmol) was dissolved in CHCl3
(15.0 mL) under air atmosphere. Me2Zn (1.0
M in hexane, 1.2 mL,
1.2 mmol) was added to the solution of 9c in CHCl3 under a nitro-
gen atmosphere at room temperature. After being stirred at the
same temperature for 24 h, the reaction mixture was diluted with
sat. NH4Cl and extracted with CHCl3. The organic phase was dried
with MgSO4 and concentrated under reduced pressure. Purification
of the residue by preparative TLC (hexane/AcOEt = 5:1) afforded
10c (28.1 mg, 79 %) as a colorless oil. IR (neat): ν = 3026, 2901,
˜
1650, 1602 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.15 (dd, J = 7.5,
1.5 Hz, 1 H), 7.45–7.24 (m, 7 H), 7.16 (br. d, 1 H), 4.80 (s, 2 H), 3.49
(t, J = 6.5 Hz, 2 H), 2.93 (t, J = 6.5 Hz, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 164.4, 137.9, 137.3, 131.6, 129.3, 128.5, 128.4, 127.9,
127.3, 126.9, 126.8, 50.5, 45.5, 28.2 ppm. HRMS (ESI) m/z: Calcd for
C16H16NO [M + H]+ 238.1227, found 238.1224.
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Received: April 11, 2018
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Aminocarbonylation
Y. Nishida, N. Takeda, K. Matsuno,
O. Miyata,* M. Ueda* ........................ 1–9
Acylative Coupling of Amine and
Indole Using Chloroform as a Carb-
onyl Group
Chloroform-mediated acylative cou- in a three-component acylative cou-
pling of amines and indoles has been pling reaction in which in-situ genera-
developed. Indoles and amines in tion of phosgene produces indole-3-
chloroform were treated with dimeth- carboxamides.
ylzinc in the presence of air, resulting
DOI: 10.1002/ejoc.201800571
Eur. J. Org. Chem. 0000, 0–0
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9
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim