Rhodium(III)-Catalyzed Oxidative Coupling of N-Phenylindole-3-carboxylic Acids with Alkenes and Alkynes via C4-H and C2-H/C2′-H Bond Cleavage

Article abstract of DOI:10.1021/acs.joc.8b00638

The rhodium(III)-catalyzed direct alkenylation of N-phenylindole-3-carboxylic acids with alkenes including acrylate ester, acrylamide, and acrylonitrile proceeds smoothly at the C4-position through regioselective C-H bond cleavage directed by the carboxyl group. In marked contrast, the indole substrates react with diarylacetylenes accompanied by cleavage of the C2-H and C2′-H bonds and decarboxylation to produce 5,6-diarylindolo[1,2-a]quinolone derivatives. DFT calculations have suggested that the smooth insertion of an alkene to a C4-rhodated six-membered metallacycle intermediate leads to the C4 alkenylated products, while the latter annulation at the C2- and C2′-positions is attributable to facile reductive elimination in the corresponding seven-membered metallacycles formed by the double C-H bond cleavage and alkyne insertion.

Full text of DOI:10.1021/acs.joc.8b00638

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Article
Rhodium(III)-Catalyzed Oxidative Coupling of N-Phenylindole-3-carboxylic
Acids with Alkenes and Alkynes via C4–H and C2–H/C2’–H Bond Cleavage
Takeshi Okada, Asumi Sakai, Tomoaki Hinoue, Tetsuya Satoh, Yoshihiro
Hayashi, Susumu Kawauchi, Kona Chandrababunaidu, and Masahiro Miura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00638 • Publication Date (Web): 30 Apr 2018
Downloaded from http://pubs.acs.org on April 30, 2018
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Rhodium(III)-Catalyzed Oxidative Coupling of N-
Phenylindole-3-carboxylic Acids with Alkenes and
Alkynes via C4–H and C2–H/C2’–H Bond Cleavage
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†
§
†
*,§
¶
Takeshi Okada, Asumi Sakai, Tomoaki Hinoue, Tetsuya Satoh, Yoshihiro Hayashi, Susumu
¶
Kawauchi, Kona Chandrababunaidu, and Masahiro Miura
†
*,†
†
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita,
Osaka 565-0871, Japan
§
Department of Chemistry, Graduate School of Science, Osaka City University, 3-3-138
Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan
¶
Department of Chemical Science and Engineering, School of Materials and Chemical
Technology, Tokyo Institute of Technology, Ookayama, Meguro-ku, Tokyo 152-8552, Japan
KEYWORDS: rhodium catalyst; oxidative coupling; C–H bond cleavage; indole; carboxylic
acid.
Ar
H
R
4
CO2H
R
Ar
3
Ar
Ar
CO2H
Rh-cat.
Rh-cat.
N
H
H
2
N
Ag salt
Ag salt
2'
N
C4–H
cleavage
C2–H/C2'–H
cleavage
Ph
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ABSTRACT: The rhodium(III)-catalyzed direct alkenylation of N-phenylindole-3-carboxylic
acids with alkenes including acrylate ester, acrylamide, and acrylonitrile proceeds smoothly at
the C4-position through regioselective C–H bond cleavage directed by the carboxyl group. In
marked contrast, the indole substrates react with diarylacetylenes accompanied by cleavage of
the C2–H and C2’–H bonds and decarboxylation to produce 5,6-diarylindolo[1,2-a]quinolone
derivatives. DFT calculations have suggested that the smooth insertion of an alkene to a C4-
rhodated six-membered metallacycle intermediate leads to the C4 alkenylated products, while the
latter annulation at the C2 and C2’ positions is attributable to facile reductive elimination in the
corresponding seven-membered metallacycles formed by the double C-H bond cleavage and
alkyne insertion.
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INTRODUCTION
Since variously substituted indoles can be seen in a broad range of biologically active natural and
unnatural compounds, the development of regioselective substitution methods on indole
skeletons has been of substantial importance in organic synthesis field. As one of the most
powerful, straightforward tools for the regioselective substitution on aromatic compounds, the
1
transition-metal-catalyzed C–H bond functionalization utilizing directing groups has been
extensively studied, and the direct methods have been employed for derivatizing indoles. Most of
such reactions on indoles with use of C-3 directing groups take place on the more electron-rich
2
pyrrole ring (C-2), although those at the phenyl ring (C-4) are observed in some cases. For the
former examples, we reported the palladium-, rhodium-, and ruthenium-catalyzed oxidative
coupling reactions of indole-3-carboxylic acids as well as those of indole-2-carboxylic acids with
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alkenes and alkynes through cleavage of the C2–H bond (or C3-H bond in the case of the 2-
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3
carboxylic acids). The carboxylic function is especially useful as it can be used in further
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derivatization reactions and also removable after the coupling event. To obtain mechanistic
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information about the rhodium-catalyzed reaction, we examined the H/D exchange reaction of N-
t
(4-BuC6H4)phenylindole-3-carboxylic acid as a representative substrate, which allows the
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assignment of each of the protons in its H NMR analysis, by using CD3CO2D as a D-source
(Scheme 1). Interestingly, we observed the deuterium incorporation at the C4- and C2’-positions
in addition to the expected C2-position. Thus, the C–H bond cleavage steps, i.e. paths (a), (b),
and (c) appear to be reversible. This observation encouraged us to develop new site-selective
functionalization methods for indole-3-carboxylic acid derivatives under rhodium catalysis.
t
Scheme 1. H/D Exchange of N-(4-BuC6H4)phenylindole-3-carboxylic acid
10% D H/D
4
CO2H
CO2Me
1) [Cp*RhCl2]2 2) MeI
16% D
H/D
2
N
N
AgOAc
K2CO3
DMF
H/D
H/D
2'
CD3CO2D
10% D
PhCl
120 oC, 6 h
rt, 12 h
But
But
H
O
Cp*
Cp*
(a)
O
O
Rh
CO2H
ORh
X
path(a)
–HX
H
N
N
Cp*RhX2
–HX
(b)
N
+HX
path(b)
–HX
But
But
But
CO2H
+HX
O
CO2H
Rh
O
Cp*
X
path(c)
–HX
Rh
N
N
N
+HX
–HX
Cp*
Rh Cp*
H
+HX
(c)
But
But
But
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In the above context of our studies, we have found that N-phenylindole-3-carboxylic acids
undergo oxidative alkenylation at the C4-position upon treatment with alkenes such as acrylates
in the presence of a Cp*Rh(III) catalyst and a silver salt oxidant (Scheme 2a). In marked contrast,
it has been observed that N-phenylindole-3-carboxylic acids couple with diarylacetylenes under
similar conditions through cleavage of the C2-H and C2’-H bonds accompanied by
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decarboxylation to produce 5,6-diarylindolo[1,2-a]quinolone derivatives. Although similar
tetracyclic compounds, which are fluorescent in the solid state, could also be obtained under
3e
palladium catalysis, the product yields were moderate to low and the substrate scope was rather
limited.
Recently, the ruthenium- and palladium-catalyzed C4-alkenylation of indole nuclei utilizing
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formyl- and sulfonylamino-directing groups, respectively, were reported. Afterward, Prabhu and
co-workers demonstrated that the C4-alkenylation of 3-(trifluoroacetyl)indoles can be achieved
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under rhodium catalysis (Scheme 2b). However, under their conditions, the reaction utilizing a
7a
carboxyl directing group gave a complex mixture. After the initiation of this work, Zhang and
co-workers disclosed that treatment of indole-3-carboxylic acids with alkenes by using a
rhodium catalyst and a copper oxidant leads to dialkenylation at the C2- and C4-positions and
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spontaneous decarboxylation to produce 2,4-dialkenylated indole derivatives (Scheme 2c). In the
present case, only the C-4 mono-alkenylation occurs and the carboxyl group remains in the
alkenylated products. As a preliminary attempt, we have combined the C4-alkenylion with the
subsequent coupling with an alkyne in a one-pot manner.
Furthermore, we have performed DFT calculations to provide rational insight into the different
site-selectivity in the reactions with alkenes and alkynes: The dominant origins of such C2/C4
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selectivity have been little known. These results for the experimental and theoretical studies are
described herein.
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Scheme 2. Regioselective C–H Bond Functionalization of Indoles
R
a)
CO2H
R
H
4
CO2H
C4-H cleavage
3
N
Rh-cat.
Ag salt
H
Ph
2
N
H
2'
Ar
Ar
Ar
Ar
N
C2-H, C2'-H cleavage
R
b)
DG = COCF3
COCF3
R
Rh-cat.
Cu salt
DG
N
Me
N
DG = CO2H
Me
complex mixture
R
c)
R
Rh-cat.
Cu salt
CO2H
R
N
N
Me
Me
RESULTS AND DISCUSSION
Coupling with Alkenes
In an initial attempt, N-phenylindole-3-carboxylic acid (1a) (0.2 mmol) was treated with butyl
acrylate (2a) (0.4 mmol) in the presence of [Cp*RhCl2]2 (0.005 mmol, 2.5 mol %) and AgOAc
o
(0.4 mmol) in PhCl under N2 at 120 C for 12 h. As a result, the desired C4-alkenylated product
was selectively formed, and it was successively methyl-esterified for its quantification to afford
methyl (E)-4-(3-butoxy-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-carboxylate (3aa) in 57%
GC yield (Table 1, entry 1). The use of other solvents such as o-xylene, tert-amyl alcohol,
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dioxane, and DMF diminished the yield of 3aa (entries 2-5). In PhCl, Ag2CO3 was found to be as
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o
effective as AgOAc (entry 6). Interestingly, decreasing the reaction temperature to 80 C
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enhanced the yield to 77% (entry 8). However, a further decrease to 60 C reduced it to 61%
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(entry 9).
a
Table 1. Reaction of N-Phenylindole-3-carboxylic Acid (1a) with Butyl Acrylate (2a)
CO2Bun
H
CO2Me
CO2H
1) [Cp*RhCl2]2 2) MeI
+
CO2Bun
N
N
AgOAc
solvent
K2CO3
DMF
Ph
Ph
1a
2a
3aa
entry
solvent
PhCl
o-xylene
AmtOH
dioxane
DMF
PhCl
PhCl
PhCl
PhCl
temp (oC)
yield (%)b
1
2
3
4
5
6c
7
8
9
120
120
120
120
120
120
100
80
57
41
41
23
11
57
72
77 (75)
61
60
a
Reaction conditions: 1) 1a (0.2 mmol), 2a (0.4 mmol), [Cp*RhCl2]2 (0.005 mmol), AgOAc
(0.4 mmol) in solvent (2 mL) under N2 for 12 h, unless otherwise noted: 2) With the addition of
b
MeI (1.2 mmol), K2CO3 (0.6 mmol), and DMF (2 mL) at rt for 12 h. GC yield based on the
amount of 1a used. Value in parentheses indicates yield after purification. Ag2CO3 (0.2 mmol)
was employed in place of AgOAc.
c
Under the conditions in entry 8 of Table 1, the reactions of 1a with various alkenes 2b-h were
next examined (Table 2). A series of acrylate esters 2b-f reacted with 1a regioselectively to
produce the corresponding C4-alkenylindole derivatives 3ab-af, as in the coupling of 1a and 2a
(entries 1-5). Besides the esters, N,N-dimethylacrylamide (2g) and acrylonitrile (2h) could also
be employed for the present coupling to give the C4-alkenylated products 3ag and 3ah,
respectively (entries 6 and 7). In contrast to these electron-deficient alkenes, styrene was less
reactive to give only a trace amount of an alkenylated product. Under similar conditions, p-
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methyl-, tert-butyl-, and chloro-substituted phenylindole-3-carboxylic acids 1b-d reacted with 2a
to afford 3ba-da (entries 8-10). 7-Methyl, 6-chloro, and 5-methoxy indole substrates 1e-g also
underwent the coupling with 2a to form 3ea-ga (entries 11-13). A benzo-fused indole substrate,
1-phenyl-1H-benzo[g]indole-3-carboxylic acid (1h) was also alkenylated at the C4 position
under standard conditions to produce 3ha in 73% yield (entry 14).
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a
Table 2. Reaction of N-Arylindole-3-carboxylic Acids 1 with Alkenes 2
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R
4
5
6
7
H
CO2Me
CO2H
1) [Cp*RhCl2]2 2) MeI
+
N
N
R
AgOAc
solvent
K2CO3
DMF
Ar
Ar
8
1
2
3
9
yield (%)b
entry
1
2
product
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R
CO2H
CO2Me
R
N
Ph
N
Ph
2b: R = CO2Bui
2c: R = CO2But
2d: R = CO2Cy
2e: R = CO2Et
2f: R = CO2Me
2g: R = CONMe2
2h: R = CN
3ab: R = CO2Bui
3ac: R = CO2But
3ad: R = CO2Cy
3ae: R = CO2Et
3af: R = CO2Me
3ag: R = CONMe2
3ah: R = CN
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68
65
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68
71
54
1
2
3
4
5
6
7
1a
CO2Bun
CO2Me
CO2H
CO2Bun
N
N
Ar
Ar
8
9
10
1b: Ar = 4-MeC6H4
1c: Ar = 4-ButC6H4
1d: Ar = 4-ClC6H4
2a
77
77
50
3ba: Ar = 4-MeC6H4
3ca: Ar = 4-ButC6H4
3da: Ar = 4-ClC6H4
CO2Bun
R3
R2
R3
CO2Me
CO2H
R2
CO2Bun
N
N
R1
R1
Ph
Ph
1e: R1 = Me, R2 = R3 = H
1f: R2 = Cl, R1 = R3 = H
1g: R3 = OMe, R1 = R2 = H
2a
74
67
56
3ea: R1 = Me, R2 = R3 = H
3fa: R2 = Cl, R1 = R3 = H
3ga: R3 = OMe, R1 = R2 = H
11
12
13
CO2Bun
CO2Me
CO2H
CO2Bun
N
N
Ph
Ph
14
1h
2a
73
3ha
a
Reaction conditions: 1) 1 (0.2 mmol), 2 (0.4 mmol), [Cp*RhCl2]2 (0.005 mmol), AgOAc (0.4
o
mmol) in PhCl (2 mL) at 80 C under N2 for 12 h, unless otherwise noted: 2) With the addition of
b
MeI (1.2 mmol), K2CO3 (0.6 mmol), and DMF (2 mL) at rt for 12 h. Isolated yield.
9
In addition, the decarboxylation of a 4-alkenylated indole-3-carboxylic acid was examined. As
expected, treatment of (E)-4-(3-butoxy-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-carboxylic
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9a
acid (3aa’) under Goossen’s conditions gave (E)-4-(3-butoxy-3-oxoprop-1-en-1-yl)-1-phenyl-
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1H-indole (3aa’’) in 72% yield (Scheme 3).
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Scheme 3. Decarboxylation of 3aa’
CO2Bun
CO2H
CO2Bun
H
CuO (0.05 mmol)
phen (0.05 mmol)
quinoline (0.05 mmol)
K2CO3 (0.05 mmol)
N
N
NMP, 160 oC, 6 h
3aa' (0.3 mmol)
3aa'', 72%
Coupling with Alkynes
As described above, the reaction of 1a with diphenylacetylene (4a) proceeded through
cleavage of the C2–H and C2’–H bonds and decarboxylation to give rise to an indolo[1,2-
10
a]quinolone framework. Thus, treatment of 1a (0.3 mmol) with 4a (0.2 mmol) in the presence
o
of [Cp*RhCl2]2 (0.005 mmol, 2.5 mol %) and Ag2CO3 (0.2 mmol) in o-xylene under N2 at 120 C
for 24 h afforded 5,6-diphenylindolo[1,2-a]quinolone (5aa) in 78% yield (Table 3). Variously
substituted diphenylacetylenes 4b-h also coupled with 1a to produce 5ab-ah in fair to good
yields. The reactions of di(2-naphthyl)- (4i) and di(2-thienyl)- (4j) acetylenes with 1a could be
conducted in similar manners to give 5ai and 5aj. The reaction of 4-octyne was sluggish to give
the corresponding annulated product in a poor yield (> 20%). In addition to 1a, N-(p-substituted
t
phenyl)-, N-(2-naphthyl)-, and N-(9-Bucarbazol-3-yl)indole-3-carboxylic acids 1b-d,i,j reacted
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with 4a or 4d to give the corresponding tetra-, penta-, and hexacyclic products 5ba-da, 5cd, 5ia,
and 5jd.
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a
Table 3. Reaction of N-Arylindole-3-carboxylic Acids 1 with Alkynes 4
CO2H
Ar
Ar
Ar
[Cp*RhCl2]2
N
N
+
Ag2CO3
Ar
o-xylene
R
R
1
4
5
% yieldb
product
R
OMe
OMe
OMe
N
N
R
OMe
5aa: R = H
5ab: R = Me
5ac: R = OMe 70
5ad: R = But
5ae: R = Cl
5af: R = Br
78
86
5ah
84
70
75
73
56
5ag: R = CF3
S
N
N
S
5ai
70
5aj
32
R
N
N
N
R
Me
But
Cl
5da
5ba
79
5ca: R = H
84
89
5cd: R = But 87
But
N
N
But
N
Bun
5jd
5ia
70
32
a
Reaction conditions: 1 (0.3 mmol), 4 (0.2 mmol), [Cp*RhCl2]2 (0.005 mmol), Ag2CO3 (0.2
o
mmol) in o-xylene (2 mL) at 120 C under N2 for 24 h, unless otherwise noted. Isolated yield
based on the amount of 4 used.
b
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We next examined the one-pot three-component coupling of 1c, 2e, and 4a through the C4-
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alkenylation and successive alkyne annulation at the C2- and C2’-positions. Thus, 1c (0.2 mmol)
was treated with 2e (0.4 mmol) in the presence of [Cp*RhCl2]2 (0.005 mmol) and AgOAc (0.4
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o
mmol) in PhCl under N2 at 80 C for 12 h. After evaporation of the solvent under vacuum, 4a (0.2
mmol), [Cp*RhCl2]2 (0.005 mmol), Ag2CO3 (0.2 mmol), and o-xylene were added and heated at
o
120 C under N2 for 24 h. From the resulting reaction mixture, the corresponding three-
component coupling product 6a was isolated in 36% yield (Scheme 4). Similarly, the three-
component coupling of 1a, 2e, and 4d furnished 6b, albeit with a low yield.
Scheme 4. Three-Component Coupling
CO2Et
H
Ar
Ar
CO2Et
(2e, 0.4 mmol)
[Cp*RhCl2]2
(0.005 mmol)
CO2H
(4, 0.2 mmol)
[Cp*RhCl2]2
(0.005 mmol)
Ar
Ar
H
H
N
R
N
R
AgOAc (0.4 mmol)
PhCl, 80 oC, 12 h
Ag2CO3 (0.2 mmol)
o-xylene, 120 oC, 24 h
1 (0.2 mmol)
6a:R = But, Ar = Ph, 36%
6b:R = H, Ar = 4-ButC6H4, 11%
DFT Calculation for Acrylonitrile Insertion
In order to clarify the cause of the different site-selectivity in the reactions with alkenes and
with alkynes on N-arylindole-3-carboxylic acids 1, DFT calculations were performed for the
insertion reaction of acrylonitrile (2h) as well as that of diphenylacetylene (4a) into three
rhodacycles A, B, and C (Figure 1). The rhodacycles A, B, and C are likely involved as the
intermediates in the present coupling reactions as implied by Scheme 1. Six possible insertion
positions are indicated by I - VI in Figure 1. In the acrylonitrile insertion reaction, there are four
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transition states (TS) per an insertion position due to the orientation of the cyano group.
Therefore, 24 insertion TSs and intermediates were calculated for the acrylonitrile insertion
reactions.
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Figure 1. Six possible alkene and alkyne insertion positions (I - VI) in rhodacycle intermediates
A, B, and C.
The 24 intermediates of the acrylonitrile insertion with the activation free energy (∆G‡) and the
reaction free energy (∆G) are shown in Figure S1 (see Supporting Information). The insertion
reaction, in which the acrylonitrile is inserted into Position I with the cyano group orienting to
the Rh side as shown in Figure 2, has the lowest activation free energy among the 24 insertion
reactions. The result shows that the acrylonitrile kinetically advantageously inserts into Position
I, which is consistent with the experimental observation that the alkenes are coupled at the C4-
position of the indole substrate.
Figure 2 shows the Gibbs free energy diagram for the entire reaction from the insertion
reaction to the β-hydrogen elimination. The Gibbs free energy is a relative value based on the
energy of the rhodacycle intermediate A and acrylonitrile. Acrylonitrile coordinates to Rh of A
to form π-complex intermediate D. Then, acrylonitrile inserts into the Rh-C bond of D leading to
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intermediate D-IM1 via transition state D-TS1. The activation free energy and reaction free
energy of the insertion reaction are 9.0 and –16.0 kcal mol–1, respectively, indicating that this
reaction proceeds rapidly.
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Figure 2. Gibbs free energy diagram in the insertion reaction of acrylonitrile to rhodacycle
–1
intermediate A. The relative Gibbs free energy are given in kcal mol .
A β-hydrogen approaching to Rh is necessary to undergo β-hydrogen elimination in the
intermediate D-IM1. However, as shown in Figure 3(a), Rh and β-hydrogen are spatially
separated (3.278 Å) in D-IM1. Therefore, we searched for another conformer in which the β-
hydrogen is placed proximally to Rh. As a result, a metastable conformer D-IM2 with the Rh
and β-hydrogen distance of 1.872 Å was found, as shown in Figure 3(b). D-IM2 was 7.8 kcal
mol–1 less stable than D-IM1. This indicates that the β-hydrogen transfer proceeds after changing
the conformation from D-IM1 to D-IM2.
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Figure 3. Structures of (a) conformer D-IM1 and (b) meta-stable conformer D-IM2.
The length of β C-H bond proximal to Rh of D-IM2 is extended to 1.166 Å, while that of D-
IM1 is 1.088 Å. This bond extension indicates the presence of an agostic interaction. The
activation free energy of the β-hydrogen transfer from D-IM2 through D-TS2 to D-IM3 was 6.5
kcal mol–1. The low activation free energy may be due to the agostic interaction. This indicates
that the conformational change to D-IM2 induces the β-hydrogen transfer promptly.
In summary, the activation free energy of the acrylonitrile insertion into Position I leading to
D-IM1 was the lowest activation free energy among the possible 24 insertion reactions. After
changing the conformation from D-IM1 to D-IM2, a β-hydrogen elimination easily proceeds to
form C4-coupled precursor D-IM3. Therefore, the regioselectivity of the coupling with alkenes
is ascribed to the activation free energy of the insertion reaction (D-TS1).
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DFT Calculation for Diphenylacetylene Insertion
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In the diphenylacetylene insertion reaction, there is one transition state (TS) per an insertion
position shown in Figure 1. Thus, DFT calculations were performed for the six types of insertion
reactions. The Gibbs free energy diagram is shown in Figure 4. The Gibbs free energy is a
relative value based on the energy of the rhodacycle intermediates A, B, or C and
diphenylacetylene. Coordination of a diphenylacetylene to Rh in A, B, and C, leads to π-complex
intermediates E, F, and G, respectively. The diphenylacetylene inserts into the Rh-C or Rh-O
bond of E, F, and G via the six types of TSs (E-TS1, E-TS2, F-TS1, F-TS2, G-TS1, and G-
TS2) forming the intermediates E-IM1, E-IM2, F-IM1, F-IM2, G-IM1, and G-IM2. The
reaction from G to G-IM2 has the lowest activation free energy of 11.3 kcal mol–1 with a
negative value of the reaction free energy in the six insertion reactions. However, the anticipated
product G-P by reductive elimination in G-IM2 was not detected at all in our experiments.
Therefore, the activation free energy of the insertion reaction does not simply determine the
regioselectivity of the coupling with alkynes.
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Figure 4. Gibbs free energy diagram in the 4 types of insertion reactions of diphenylacetylene to
the rhodacycle intermediates (a) A, (b) B, and (c) C. The relative Gibbs free energies are given in
–1
kcal mol .
The insertion intermediates lead to the coupling products E-P, F-P, and G-P by the reductive
elimination of Rh. Although we carefully explored TS of the reductive elimination of E-IM2, it
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was not found. The reductive elimination of E-IM1 has an activation free energy of 38.2 kcal
mol–1, which is higher than that of the reverse reaction of the diphenylacetylene insertion (30.5
kcal mol–1), indicating that the reductive elimination of E-IM1 is slower than the
diphenylacetylene desorption. This is consistent with the experimental observation that the
alkyne did not couple at the C4-position at all.
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The activation free energies of the reductive elimination of F-IM1 and F-IM2 are 18.7 and
11.4 kcal mol–1, respectively, which are significantly lower than that of the reductive elimination
of E-IM1 (38.2 kcal mol–1) and the diphenylacetylene desorption of F-IM1 and F-IM2 (29.3 and
42.2 kcal mol–1). This result shows that the reductive eliminations of F-IM1 and F-IM2 proceed
to form the coupling product F-P, which corresponds to the C2/C2'-coupled product observed in
our experiments. Therefore, the experimental observation that diphenylacetylene reacted at the
C2- and C2'-positions can be explained by the low activation free energy of reductive
eliminations in F-IM1 and F-IM2.
The activation free energy of the reductive elimination of G-IM1 and G-IM2 (20.4 and 23.2
kcal mol–1) are higher than that of the reductive eliminations of F-IM1 and F-IM2 (18.7 and
11.4 kcal mol–1), indicating that the reductive elimination of G-IM1 and G-IM2 is slower than
that of F-IM1 and F-IM2. This is consistent with the fact that the coupling reaction of the N-
phenylindole with alkynes predominantly gave the products coupled at the C2- and C2'-positions.
CONCLUSIONS
We have demonstrated that N-phenylindole-3-carboxylic acids undergo alkenylation at the C-4
position on treatment with alkenes such as acrylate ester, acrylamide, and acrylonitrile in the
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presence of a rhodium(III) catalyst and a silver salt oxidant via regioselective C–H bond
cleavage. On the other hand, we have observed that the indoles react with diarylacetylenes
through cleavage of the C2–H and C2’–H bonds and decarboxylation to selectively furnish the
corresponding annulated products in good yields even under similar conditions. A one-pot three-
component coupling of the mother substrate N-phenylindole-3-carboxylic acid with an alkene
and an alkyne has also been shown.
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Since the site-selective introduction of functional substituents onto arenes and heteroarenes
2
involving indoles is currently of substantial importance, we have also performed DFT
calculations to provide rational insight into the observed different site-selectivity with alkenes
and alkynes in the present catalytic system. As a result, it has been suggested that the smooth
insertion of an alkene to a C4-rhodated metallacycle intermediate is the key for the selective
alkenylation. As for the annulation with alkynes at the C2 and C2’ positions, the facile reductive
elimination in the corresponding alkyne-inserted seven-membered metallacycles seems to be the
key factor. The information obtained in this work would be helpful in designing new catalytic
substitution reactions on benzo-fused heteroarenes of importance medicinal and materials
chemistry.
EXPERIMENTAL SECTION
1
13
General. H and C NMR spectra were recorded at 400 and 100 MHz for CDCl3 solutions.
HRMS data were obtained by APCI using a TOF mass spectrometer. GC analysis was carried
out using a silicon OV-17 column (i. d. 2.6 mm x 1.5 m). GC-MS analysis was carried out using
a CBP-1 capillary column (i. d. 0.25 mm x 25 m). The structures of all products listed below
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were unambiguously determined by H and C NMR with the aid of NOE, COSY, HMQC, and
5
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HMBC experiments.
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N-Arylindole-3-carboxylic acid 1a-j8,12 and alkynes 4b-h,j13 and 4i14 were prepared according
to published procedures.
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The following experimental procedures may be regarded as typical in methodology and scale.
Rh-Catalyzed Reaction of N-Arylindole-3-carboxylic acids 1 with Alkenes 2. To a 20 mL
two-necked flask with a reflux condenser, a balloon, and a rubber cup were added N-arylindole-
3-carboxylic acid 1 (0.2 mmol), alkene 2 (0.4 mmol), [Cp*RhCl2]2 (0.005 mmol, 3 mg), AgOAc
(0.4 mmol, 67 mg), dibenzyl (ca. 30 mg) as internal standard, and chlorobenzene (2 mL). Then
the resulting mixture was stirred under nitrogen at 80 °C (bath temperature). After cooling, CH3I
(1.2 mmol), K2CO3 (0.6 mmol, 83 mg), and DMF (2 mL) were added and the resulting mixture
was stirred under air at room temperature for 12 h. Then the reaction mixture was diluted by
ethyl acetate (100 mL). The organic layer was washed by water (100 mL, three times) and dried
over Na2SO4. After evaporation of the solvents under vacuum, product 3 was isolated by column
chromatography on silica gel using hexane−ethyl acetate as eluent. Further purification by GPC
(gel permeation chromatography) was performed, if needed.
Calculation Method
The DFT calculations were employed by the long-range and dispersion corrected ωB97X-D
15 16
functional. The 6-311G(d,p) basis set was used for H, C, N, and O atoms. The Stuttgart-
17
Dresden SDD effective core potential basis set was used for Rh atom with an additional f
18
polarization function (ζf(Rh)=1.350). The solvent effect of o-xylene was taken account by the
19
Polarizable Continuum Model using the integral equation formalism (IEFPCM) for DFT
calculations. Acrylonitrile and diphenylacetylene were selected as the alkene and alkyne
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molecules, respectively. The optimized molecular structures were verified by vibrational
analysis; equilibrium structures did not have imaginary frequencies and transition state structures
had only one imaginary frequency corresponding to the reaction coordinate. Additionally, the
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intrinsic reaction coordinate (IRC) calculations were carried out to check whether the transition
state leading to the reactant and the product. Gibbs free energies were calculated by using the
unscaled vibrational frequencies. All calculations were carried out using the Gaussian 16
21
program.
Characterization Data of Products
Methyl (E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-carboxylate (3aa):
purified by column chromatography on silica gel (hexane/EtOAc = 10:1); orange oil; 57 mg
1
(75%); H NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.4 Hz, 3H), 1.50 (sext, J = 7.4 Hz, 2H), 1.74
(quint, J = 6.9 Hz, 2H), 3.93 (s, 3H), 4.26 (t, J = 6.6 Hz, 2H), 6.42 (d, J = 15.8 Hz, 1H), 7.29 (d,
J = 7.9 Hz, 1H), 7.46-7.49 (m, 4H), 7.55-7.59 (m, 3H), 8.12 (s, 1H), 9.30 (d, J = 16.7 Hz, 1H);
13
C NMR (100 MHz, CDCl3) δ 14.0, 19.4, 31.0, 51.7, 64.4, 110.0, 112.7, 118.5, 121.5, 123.7,
125.1, 125.5, 128.4, 129.6, 130.0, 137.0, 138.1, 138.2, 146.0, 165.0, 167.6; HRMS m/z calcd for
+
C23H24NO4 ([M+H] ) 378.1700, found 378.1699.
Methyl (E)-4-(3-Isobutoxy-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-carboxylate (3ab):
purified by column chromatography on silica gel (hexane/EtOAc = 10:1); orange oil; 48 mg
1
(64%); H NMR (400 MHz, CDCl3) δ 1.04 (d, J = 6.7 Hz, 6H). 2.08 (sep, J = 6.7 Hz, 1H), 3.92 (s,
3H), 4.04 (d, J = 6.6 Hz, 2H), 6.43 (d, J = 15.3 Hz, 1H), 7.24-7.35 (m, 1H), 7.46-7.50 (m, 4H),
13
7.54-7.60 (m, 3H), 8.12 (s, 1H), 9.32 (d, J = 15.8 Hz, 1H); C NMR (100 MHz, CDCl3) δ 19.4,
28.1, 51.7, 70.7, 110.0, 112.7, 118.5, 121.5, 123.7, 125.2, 125.5, 128.4, 129.58, 130.0, 136.9,
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138.1, 138.2, 145.9, 165.0, 167.6; HRMS m/z calcd for C23H24NO4 ([M+H] ) 378.1700, found
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378.1698.
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Methyl
(E)-4-(3-(tert-Butoxy)-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-carboxylate
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(3ac): purified by column chromatography on silica gel (hexane/EtOAc = 10:1); orange oil; 51
1
mg (68%); H NMR (400 MHz, CDCl3) δ 1.58 (s, 9H), 3.92 (s, 3H), 6.37 (d, J = 15.8 Hz, 1H),
7.23-7.36 (m, 1H), 7.45-7.49 (m, 4H), 7.55-7.59 (m, 3H), 8.12 (s, 1H), 9.23 (d, J = 15.8 Hz, 1H);
13
C NMR (100 MHz, CDCl3) δ 28.4, 51.7, 80.2, 110.0, 112.5, 120.4, 121.4, 123.6, 125.1, 125.5,
128.4, 129.7, 130.0, 136.9, 138.1, 138.2, 144.8, 165.0, 166.9; HRMS m/z calcd for C23H24NO4
+
([M+H] ) 378.1700, found 378.1680.
Methyl (E)-4-(3-(Cyclohexyloxy)-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-carboxylate
(3ad): purified by column chromatography on silica gel (hexane/EtOAc = 10:1); orange solid; 49
1
mg (65%); mp 142-144 °C; H NMR (400 MHz, CDCl3) δ 1.29-1.61 (m, 7H), 1.81-1.97 (m, 4H),
3.93 (s, 3H), 6.42 (d, J = 15.8 Hz, 1H), 7.25-7.30 (m, 1H), 7.45-7.49 (m, 4H), 7.54-7.59 (m, 3H),
13
8.12 (s, 1H), 9.27 (d, J = 15.8 Hz, 1H); C NMR (100 MHz, CDCl3) δ 23.9, 25.7, 31.9, 51.7, 72.5,
110.0, 112.6, 119.1, 121.5, 123.6, 125.1, 125.4, 128.4, 129.6, 130.0, 136.9, 138.1, 138.2, 145.6,
+
165.0, 166.9; HRMS m/z calcd for C25H26NO4 ([M+H] ) 404.1856, found 404.1865.
Methyl (E)-4-(3-Ethoxy-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-carboxylate (3ae):
purified by column chromatography on silica gel (hexane/EtOAc = 10:1); orange oil; 46 mg
1
(66%); H NMR (400 MHz, CDCl3) δ 1.38 (t, J = 7.1 Hz, 3H), 3.94 (s, 3H), 4.32 (q, J = 7.1 Hz,
2H), 6.42 (d, J = 15.8 Hz, 1H), 7.28 (t, J = 8.0 Hz, 1H), 7.45-7.49 (m, 4H), 7.55-7.59 (m, 3H),
13
8.13 (s, 1H), 9.29 (d, J = 15.8 Hz, 1H); C NMR (100 MHz, CDCl3) δ 14.6, 51.7, 60.5, 110.0,
112.8, 118.5, 121.6, 123.7, 125.1, 125.5, 128.4, 129.6, 130.0, 137.0, 138.1, 138.2, 146.0, 165.0,
+
167.5; HRMS m/z calcd for C21H20NO4 ([M+H] ) 350.1387, found 350.1372.
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Methyl (E)-4-(3-Methoxy-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-carboxylate (3af):
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purified by column chromatography on silica gel (hexane/EtOAc = 10:1); orange solid; 46 mg
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1
(68%); mp 107-110 °C; H NMR (400 MHz, CDCl3) δ 3.86 (s, 3H), 3.94 (s, 3H), 6.42 (d, J =
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15.8 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.46-7.50 (m, 4H), 7.55-7.59 (m, 3H), 8.13 (s, 1H), 9.31
13
(d, J = 15.8 Hz, 1H); C NMR (100 MHz, CDCl3) δ 51.76, 51.83, 109.9, 112.8, 118.1, 121.6,
123.7, 125.1, 125.5, 128.5, 129.5, 130.1, 137.1, 138.1, 138.2, 146.3, 165.0, 167.9; HRMS m/z
+
calcd for C20H18NO4 ([M+H] ) 336.1230, found 336.1221.
Methyl
(E)-4-(3-(Dimethylamino)-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole-3-
carboxylate (3ag): purified by column chromatography on silica gel (hexane/EtOAc = 3:1);
1
orange solid; 49 mg (71%); mp 153-155 °C; H NMR (400 MHz, CDCl3) δ 3.10 (s, 3H), 3.22 (s,
3H), 3.94 (s, 3H), 6.82 (d, J = 15.3 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.44-7.50 (m, 4H), 7.52-
13
7.59 (m, 3H), 8.10 (s, 1H), 9.05 (d, J = 15.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ 36.0, 37.7,
51.8, 110.2, 112.0, 118.3, 121.3, 123.6, 124.9, 125.5, 128.3, 130.0, 130.8, 136.6, 138.0, 138.3,
+
143.4, 165.0, 167.3; HRMS m/z calcd for C21H21N2O3 ([M+H] ) 349.1547, found 349.1546.
Methyl (E)-4-(2-Cyanovinyl)-1-phenyl-1H-indole-3-carboxylate (3ah): purified by column
chromatography on silica gel (hexane/EtOAc = 3:1); orange solid; 33 mg (54%); mp 128-
1
129 °C; H NMR (400 MHz, CDCl3) δ 3.92 (s, 3H), 5.85 (d, J = 16.5 Hz, 1H), 7.29 (t, J = 7.9 Hz,
13
1H), 7.46-7.53 (m, 5H), 7.55-7.60 (m, 2H), 8.14 (s, 1H), 9.21 (d, J = 16.6 Hz, 1H); C NMR
(100 MHz, CDCl3) δ 51.8, 96.1, 109.6, 113.7, 119.0, 120.9, 123.7, 124.8, 125.5, 128.6
+
(overlapped), 130.1, 137.3, 137.9, 138.2, 152.0, 164.8; HRMS m/z calcd for C19H15N2O2 ([M+H] )
303.1128, found 303.1114.
Methyl (E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-1-(p-tolyl)-1H-indole-3-carboxylate (3ba):
purified by column chromatography on silica gel (hexane/EtOAc = 10:1); orange solid; 60 mg
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(77%); mp 99-102 °C; H NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.4 Hz, 3H), 1.50 (sext, J = 7.4
Hz, 2H), 1.74 (quint, J = 6.9 Hz, 2H), 2.46 (s, 3H), 3.92 (s, 3H), 4.26 (t, J = 6.6 Hz, 2H), 6.42 (d,
J = 15.8 Hz, 1H), 7.26 (t, J = 7.8 Hz, 1H), 7.32-7.41 (m, 4H), 7.44 (d, J = 8.2 Hz, 1H), 7.57 (d, J
9
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60
13
= 7.5 Hz, 1H), 8.09 (s, 1H), 9.31 (d, J = 15.9 Hz, 1H); C NMR (100 MHz, CDCl3) δ 14.0, 19.4,
21.3, 31.0, 51.7, 64.4, 109.6, 112.8, 118.4, 121.4, 123.5, 125.1, 125.3, 129.5, 130.6, 135.6, 137.1,
+
138.3, 138.5, 146.0, 165.0, 167.6; HRMS m/z calcd for C24H26NO4 ([M+H] ) 392.1856, found
392.1866.
Methyl
(E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-1-(4-(tert-butyl)phenyl)-1H-indole-3-
carboxylate (3ca): purified by column chromatography on silica gel (hexane/EtOAc = 10:1);
1
orange solid; 67 mg (77%); mp 105-107 °C; H NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.4 Hz,
3H), 1.40 (s, 9H), 1.51 (quint, J = 7.5 Hz, 2H), 1.93 (sext, J = 6.9 Hz, 2H), 3.92 (s, 3H), 4.26 (t, J
= 6.6 Hz, 2H), 6.42 (d, J = 15.8 Hz, 1H), 7.26 (t, J = 7.9 Hz, 1H), 7.38-7.41 (m, 2H), 7.49 (dd, J
13
= 0.72, 8.2 Hz, 1H), 7.55-7.58 (m, 3H), 8.11 (s, 1H), 9.31 (d, J = 15.9 Hz, 1H); C NMR (100
MHz, CDCl3) δ 14.0, 19.4, 31.0, 31.5, 34.9, 51.7, 64.4, 109.6, 112.9, 118.4, 121.4, 123.5, 125.0,
125.1, 126.9, 129.5, 135.5, 137.1, 138.2, 146.0, 151.6, 165.0, 167.6; HRMS m/z calcd for
+
C27H32NO4 ([M+H] ) 434.2326, found 434.2338.
Methyl
(E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-1-(4-chlorophenyl)-1H-indole-3-
carboxylate (3da): purified by column chromatography on silica gel (hexane/EtOAc = 10:1);
1
orange solid; 41 mg (50%); mp 134-136 °C; H NMR (400 MHz, CDCl3) δ 0.99 (t, J = 7.4 Hz,
3H), 1.50 (sext, J = 7.5 Hz, 2H), 1.74 (quint, J = 6.8 Hz, 2H), 3.93 (s, 3H), 4.26 (t, J = 6.6 Hz,
2H), 6.42 (d, J = 15.8 Hz, 1H), 7.29 (t, J = 7.8 Hz, 1H), 7.40-7.50 (m, 3H), 7.53-7.59 (m, 3H),
13
8.08 (s, 1H), 9.27 (d, J = 15.8 Hz, 1H); C NMR (100 MHz, CDCl3) δ 14.0, 19.4, 31.0, 51.8, 64.5,
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110.4, 112.4, 118.7, 121.7, 123.9, 125.1, 126.7, 129.7, 130.3, 134.3, 136.6, 136.7, 138.0, 145.7,
5
6
+
164.8, 167.6; HRMS m/z calcd for C23H23ClNO4 ([M+H] ) 412.1310, found 412.1326.
7
8
9
Methyl (E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-7-methyl-1-phenyl-1H-indole-3-carboxylate
(3ea): purified by column chromatography on silica gel (hexane/EtOAc = 19:1); white solid; 59
10
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60
1
mg (74%); mp 244.9 °C; H NMR (400 MHz, CDCl3) δ 0.98 (t, J = 7.4 Hz, 3H), 1.45-1.54 (m,
2H), 1.69-1.76 (m, 2H), 1.95 (s, 3H), 3.89 (s, 3H), 4.25 (t, J = 6.6 Hz, 2H), 6.39 (d, J = 15.8 Hz,
1H), 6.99 (d, J = 7.7 Hz, 1H), 7.37-7.39 (m, 2H), 7.46-7.51 (m, 4H), 7.93 (s, 1H), 9.26 (d, J =
13
15.9 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.8, 19.2, 19.6, 30.8, 51.5, 64.1, 108.9, 117.2,
121.2, 124.2, 125.3, 126.4, 127.2, 127.8, 128.9, 129.0, 137.0, 139.0, 140.1, 145.9, 164.9, 167.6;
+
HRMS m/z calcd for C24H26NO4 ([M+H] ) 392.1856, found 392.1831.
Methyl (E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-6-chloro-1-phenyl-1H-indole-3-carboxylate
(3fa): purified by column chromatography on silica gel (hexane/EtOAc = 19:1); white solid; 55
1
mg (67%); mp 198 °C; H NMR (400 MHz, CDCl3) δ 0.98 (t, J = 7.4 Hz, 3H), 1.45-1.54 (m, 2H),
1.69-1.76 (m, 2H), 3.91 (s, 3H), 4.25 (t, J = 6.6 Hz, 2H), 6.40 (d, J = 15.9 Hz, 1H), 7.42-7.48 (m,
13
3H), 7.49-7.52 (m, 2H), 7.55-7.60 (m, 2H), 8.09 (s, 1H), 9.22 (d, J = 15.9 Hz, 1H); C NMR
(100 MHz, CDCl3) δ 13.8, 19.2, 30.8, 51.6, 64.4, 109.9, 112.2, 119.6, 121.5, 123.5, 125.3, 128.6,
129.6, 130.0, 130.5, 137.3, 137.5, 138.4, 144.4, 164.4, 167.1; HRMS m/z calcd for C23H23ClNO4
+
([M+H] ) 412.1310, found 412.1343.
Methyl
(E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-5-methoxy-1-phenyl-1H-indole-3-
carboxylate (3ga): purified by column chromatography on silica gel (hexane/EtOAc = 19:1);
1
colorless gum; 47 mg (56%); H NMR (400 MHz, CDCl3) δ 0.97 (t, J = 7.4 Hz, 3H), 1.44-1.54
(m, 2H), 1.69-1.77 (m, 2H), 3.90 (s, 3H), 3.93 (s, 3H), 4.25 (t, J = 6.7 Hz, 2H), 6.84 (d, J = 16.0
Hz, 1H), 6.98 (d, J = 9.1 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.45-7.47 (m, 3H), 7.53-7.57 (m, 2H),
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8.07 (s, 1H), 9.04 (d, J = 16.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.8, 19.2, 30.9, 51.6, 56.6,
5
6
64.1, 109.4, 109.9, 112.7, 116.3, 121.3, 125.1, 127.0, 128.1, 129.9, 132.8, 137.3, 138.1, 141.0,
7
8
+
155.9, 165.1, 168.7; HRMS m/z calcd for C24H26NO5 ([M+H] ) 408.1805, found 408.1820.
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Methyl (E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-1-phenyl-1H-benzo[g]indole-3-carboxylate
(3ha): purified by column chromatography on silica gel (hexane/EtOAc = 19:1); white solid; 65
1
mg (73%); mp 228.9 °C; H NMR (400 MHz, CDCl3) δ 1.0 (t, J = 7.4 Hz, 3H), 1.47-1.56 (m, 2H),
1.72-1.79 (m, 2H), 3.93 (s, 3H), 4.28 (t, J = 6.6 Hz, 2H), 6.53 (d, J = 15.7 Hz, 1H), 7.16-7.22 (m,
2H), 7.37-7.40 (1m, 1H), 7.47-7.51 (m, 2H), 7.57-7.63 (m, 3H), 7.92 (d, J = 8.8 Hz, 2H), 7.95 (s,
13
1H), 9.17 (dd, J = 0.6, 15.7 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.8, 19.2, 30.9, 51.6, 64.3,
110.2, 118.5, 120.8, 121.8, 122.5, 123.0, 124.8, 126.2, 127.3, 128.5, 129.4, 129.4, 129.9, 131.2,
+
132.0, 136.7, 140.7, 146.3, 165.1, 167.4; HRMS m/z calcd for C27H26NO4 ([M+H] ) 428.1856,
found 428.1864.
(E)-4-(3-Butoxy-3-oxoprop-1-en-1-yl)-1-phenyl-1H-indole (3aa’’): purified by column
chromatography on silica gel (hexane/EtOAc = 19:1); yellow solid; 69 mg (72%); mp 65-67 ꢀ;
1
H NMR (300 MHz, CDCl3) δ 0.99 (t, J = 7.2 Hz, 3H), 1.47 (sext, J = 7.2Hz, 2H), 1.72 (quin, J =
6.6 Hz, 2H), 4.25 (t, J = 15.9 Hz, 2H), 6.65 (d, J = 15.9Hz, 1H), 6.97 (dd, J = 0.6, 3.3 Hz, 1H),
13
7.23 (t, J = 7.8 Hz, 1H), 7.39-7.58 (m, 8H), 8.13 (d, J = 16.2 Hz, 1H); C NMR (75 MHz,
CDCl3) δ 13.8, 19.0, 30.9, 64.4, 102.0, 112.6, 118.5, 120.6, 122.4, 124.7, 126.98, 127.01, 128.4,
+
129.3, 129.7, 136.5, 139.4, 143.1, 167.6; HRMS m/z calcd for C21H22NO2 [M+H] 320.16505,
found 320.16447.
3e
5,6-Diphenylindolo[1,2-a]quinoline (5aa): purified by column chromatography on silica gel
1
(hexane/EtOAc = 20:1); yellow solid; 58 mg (78%); mp 196-199 °C; H NMR (400 MHz,
CDCl3) δ 6.38 (s, 1H), 7.10-7.28 (m, 10H), 7.35 (t, J = 8.2 Hz, 2H), 7.40-7.44 (m, 2H), 7.61 (t, J
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= 7.2 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 8.52 (d, J = 8.5 Hz, 1H), 8.67 (d, J = 8.4 Hz, 1H); C
NMR (100 MHz, CDCl3) δ 98.8, 114.5, 115.4, 121.4, 122.0, 122.1, 122.7, 125.5, 127.1, 127.3,
128.01, 128.04, 128.46, 128.47, 130.35, 130.39, 131.2, 131.3, 132.9, 133.4, 136.4, 137.5, 137.6,
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+
137.7; HRMS m/z calcd for C28H20N ([M+H] ) 370.1590, found 370.1599.
3e
5,6-Di(p-tolyl)indolo[1,2-a]quinoline (5ab): purified by column chromatography on silica
1
gel (hexane/EtOAc = 20:1); green solid; 68 mg (86%); mp 219-220 °C; H NMR (400 MHz,
CDCl3) δ 2.33 (s, 3H), 2.34 (s, 3H), 6.45 (s, 1H), 7.06-7.11 (m, 6H), 7.12-7.17 (m, 2H), 7.20
(ddd, J = 0.8, 7.2, 7.2 Hz, 1H), 7.35 (ddd, J = 0.8, 8.4, 8.4 Hz, 1H), 7.40-7.44 (m, 2H), 7.60 (ddd,
J = 1.6, 7.2, 7.2 Hz, 1H), 7.75 (dd, J = 0.8, 8.0 Hz, 1H), 8.52 (dd, J = 0.8, 8.4 Hz, 1H), 8.66 (dd,
13
J = 0.8, 8.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ 21.4, 21.5, 98.7, 114.5, 115.4, 121.3, 121.9,
122.0, 122.6, 125.8, 125.9, 128.3, 128.5, 128.8, 130.2, 130.4, 131.0, 131.2, 132.8, 133.4, 134.5,
+
134.8, 136.4, 136.6, 136.8, 138.0; HRMS m/z calcd for C30H24N ([M+H] ) 398.1903, found
398.1904.
3e
5,6-Bis(4-methoxyphenyl)indolo[1,2-a]quinoline (5ac): purified by column chromatography
1
on silica gel (hexane/EtOAc = 20:1); green solid; 60 mg (70%); mp 264-267 °C; H NMR (400
MHz, CDCl3) δ 3.809 (s, 3H), 3.811 (s, 3H), 6.47 (s, 1H), 6.80-6.84 (m, 4H), 7.10 (d, J = 6.8 Hz,
2H), 7.19 (d, J = 8.8 Hz, 2H), 7.22 (d, J = 7.2 Hz, 1H), 7.35 (dd, J = 7.1, 7.1 Hz, 1H), 7.42 (dd, J
= 1.6, 8.4 Hz, 1H), 7.46 (dd, J = 1.6, 8.0 Hz, 1H), 7.61 (dd, J = 1.6, 7.6, 7.5 Hz, 1H), 7.76 (d, J =
13
7.2 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.66 (d, J = 8.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ
55.30, 55.31, 98.6, 113.5 (overlapped), 114.5, 115.4, 121.3, 121.9, 122.0, 122.7, 125.9, 128.3,
128.4, 129.8, 130.4, 131.0, 131.5, 132.3, 132.7, 133.4, 136.3, 138.1, 158.5, 158.6; HRMS m/z
+
calcd for C30H24NO2 ([M+H] ) 430.1802, found 430.1801.
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3e
5,6-Bis(4-tert-butylphenyl)indolo[1,2-a]quinoline
(5ad):
purified
by
column
5
6
chromatography on silica gel (hexane/EtOAc = 20:1); green solid; 67 mg (70%); mp 278-
7
8
1
280 °C; H NMR (400 MHz, CDCl3) δ 1.28 (s, 18H), 6.55 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 7.14
9
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(d, J = 8.4 Hz, 2H), 7.22-7.25 (m, 5H), 7.35 (ddd, J = 0.8, 7.2, 7.2 Hz, 1H), 7.42 (ddd, J = 1.6,
7.2, 7.2 Hz, 1H), 7.53 (dd, J = 1.6, 8.0 Hz, 1H), 7.61 (ddd, J = 1.6, 7.2, 7.2 Hz, 1H), 7.77 (d, J =
13
7.6 Hz, 1H), 8.53 (d, J = 8.4 Hz, 1H), 8.67 (d, J = 8.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ
31.4 (overlapped), 34.6 (overlapped), 98.6, 114.5, 115.4, 121.3, 121.8, 121.9, 122.6, 124.6
(overlapped), 125.6, 128.2, 128.5, 130.0, 130.5, 130.9, 131.4, 133.1, 133.4, 134.5, 134.7, 136.4,
+
137.9, 149.8, 149.9; HRMS m/z calcd for C36H36N ([M+H] ) 482.2842, found 482.2847.
3e
5,6-Bis(4-chlorophenyl)indolo[1,2-a]quinoline (5ae): purified by column chromatography
1
on silica gel (hexane/EtOAc = 10:1); yellow solid; 66 mg (75%); mp 253-256 °C; H NMR (400
MHz, CDCl3) δ 6.44 (s, 1H), 7.12 (ddd, J = 2.0, 2.0, 8.5 Hz, 2H), 7.17-7.25 (m, 3H), 7.27-7.31
(m, 4H), 7.34-7.40 (m, 2H), 7.45 (ddd, J = 1.4, 8.4, 8..4 Hz, 1H), 7.64 (ddd, J = 1.6, 8.6, 8.6 Hz,
13
1H), 7.78 (d, J = 7.2 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.68 (d, J = 8.4 Hz, 1H); C NMR (100
MHz, CDCl3) δ 99.0, 114.5, 115.6, 121.5, 122.3, 122.4, 122.9, 124.9, 128.2, 128.58 (overlapped),
128.63, 128.9, 130.3, 130.4, 131.67, 131.70, 132.4, 133.4, 133.5, 135.7, 135.8, 136.4, 137.1;
+
HRMS m/z calcd for C28H18Cl2N ([M+H] ) 438.0811, found 438.0811.
5,6-Bis(4-bromophenyl)indolo[1,2-a]quinoline (5af): purified by column chromatography on
1
silica gel (hexane/EtOAc = 10:1); yellow solid; 77 mg (73%); mp 242-344 °C; H NMR (400
MHz, CDCl3) δ 6.44 (s, 1H), 7.05 (dd, J = 1.2, 8.4 Hz, 2H), 7.13 (dd, J = 1.2, 8.4 Hz, 2H), 7.23
(dd, J = 8.0, 8.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.42-7.47 (m, 5H),
7.64 (ddd, J = 1.6, 8.4 Hz, 1H), 7.78 (d, J = 7.6 Hz, 1H), 8.52 (d, J = 8.8 Hz, 1H), 8.67 (d, J =
13
8.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 99.1, 114.5, 115.6, 121.5, 121.6, 121.7, 122.2, 122.4,
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122.9, 124.9, 128.2, 128.9, 130.3 (overlapped), 131.5, 131.6, 131.8, 132.0, 132.8, 133.5, 136.2,
5
6
+
136.3, 136.4, 137.0; HRMS m/z calcd for C28H18Br2N ([M+H] ) 527.9787, found 527.9782.
7
8
3e
5,6-Bis(4-(trifluoromethyl)phenyl)indolo[1,2-a]quinoline (5ag): purified by column
9
10
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chromatography on silica gel (hexane/EtOAc = 10:1); yellow solid; 57 mg (56%); mp 240-
1
243 °C; H NMR (400 MHz, CDCl3) δ 6.42 (s, 1H), 7.25-7.33 (m, 4H), 7.38-7.41 (m, 3H), 7.48
(ddd, J = 2.0, 7.2, 7.2 Hz, 1H), 7.55-7.58 (m, 4H), 7.65-7.70 (m, 1H), 7.79 (d, J = 7.6 Hz, 1H),
13
8.54 (d, J = 8.4 Hz, 1H), 8.70 (d, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 99.3, 114.5,
115.7, 121.6, 122.4, 122.7, 122.8, 124.1 (q, J = 272.0 Hz, overlapped), 124.6, 125.3 (q, J = 3.8
Hz), 125.4 (q, J = 3.8 Hz), 128.1, 129.2, 129.5 (q, J = 32.5 Hz), 129.7 (q, J = 32.5 Hz) 130.1,
130.2, 130.3, 130.4, 130.7, 131.5, 131.8, 133.5, 136.5, 136.6; HRMS m/z calcd for C30H18F6N
+
([M+H] ) 506.1338, found 506.1337.
5,6-Bis(3,4-dimethoxyphenyl)indolo[1,2-a]quinoline
(5ah):
purified
by
column
chromatography on silica gel (hexane/EtOAc = 10:1); green solid; 82 mg (84%); mp 204-
1
207 °C; H NMR (400 MHz, CDCl3) δ 3.69 (s, 6H), 3.89 (s, 6H), 6.57 (s, 1H), 6.66-6.92 (m, 5H),
7.24 (dd, J = 8.0, 8.0 Hz, 2H), 7.37 (ddd, J = 0.8, 8.0, 8.0 Hz, 1H), 7.43 (ddd, J = 1.2, 8.4, 8.4 Hz,
1H), 7.54 (d, J = 7.6 Hz, 1H), 7.62 (ddd, J = 1.6, 7.2 7.2 Hz, 1H), 7.78 (dd, J = 0.8, 8.0 Hz, 1H),
13
8.53 (dd, J = 0.8, 8.8 Hz, 1H), 8.67 (d, J = 8.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ 55.89
(overlapped), 55.91 (overlapped), 98.7, 110.58, 100.64, 110.7, 114.5, 115.4, 121.3, 122.0, 122.1,
122.8, 123.5, 125.6, 125.9, 128.39, 128.42, 129.7, 130.1, 130.3, 130.4, 131.0, 132.6, 133.4, 136.3,
+
137.8, 148.0, 148.1, 148.5, 148.6; HRMS m/z calcd for C32H28NO4 ([M+H] ) 490.2013, found
490.2014.
5,6-Di(naphthalen-2-yl)indolo[1,2-a]quinolone (5ai): purified by column chromatography on
1
silica gel (hexane/EtOAc = 20:1); yellow solid; 66 mg (70%); mp 205-208 °C; H NMR (400
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The Journal of Organic Chemistry
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2
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MHz, CDCl3) δ 6.47 (s, 1H), 7.18 (ddd, J = 0.8, 8.0, 8.0 Hz, 1H), 7.34-7.48 (m, 9H), 7.63-7.75
5
6
13
(m, 9H), 7.87 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H), 8.72 (d, J = 7.6 Hz, 1H); C NMR (100 MHz,
7
8
9
CDCl3) δ 99.0, 99.1, 114.5, 115.5, 121.4, 122.1 (overlapped), 122.8, 125.7, 126.0, 126.09, 126.11
(overlapped), 126.2, 127.73, 127.77 (overlapped), 127.81, 128.2, 128.6 (overlapped), 129.1,
130.4, 131.4, 132.4, 132.6, 133.0, 133.11, 133.13, 133.2, 132.49, 133.5, 135.0, 135.1, 136.5,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
137.9; HRMS m/z calcd for C36H24N ([M+H] ) 470.1903, found 470.1903.
5,6-Di(thiophen-2-yl)indolo[1,2-a]quinoline (5aj): purified by column chromatography on
1
silica gel (hexane/EtOAc = 20:1); yellow solid; 24 mg (32%); mp 181-183 °C; H NMR (400
MHz, CDCl3) δ 6.82 (s, 1H), 7.01-7.05 (m, 2H), 7.06 (dd, J = 3.2, 4.8 Hz, 1H), 7.15 (dd, J = 1.2,
3.6 Hz, 1H), 7.25-7.29 (m, 1H), 7.34 (dd, J = 1.2, 5.2 Hz, 1H), 7.37-7.40 (m, 2H), 7.46 (ddd, J =
1.2, 8.4, 8.4 Hz, 1H), 7.62-7.66 (m, 2H), 7.82 (d, J = 7.2 Hz, 1H), 8.51 (d, J = 8.4 Hz, 1H), 8.65
13
(d, J = 8.0 Hz, 1H); C NMR (100 MHz, CDCl3) δ 99.9, 114.5, 115.4, 121.7, 122.2, 122.5, 123.0,
125.3, 125.9, 126.5, 126.6, 126.8, 126.9, 127.2, 128.6, 128.9, 129.1, 129.7, 129.96, 129.97, 130.3,
+
136.3, 137.85, 137.92; HRMS m/z calcd for C24H16NS2 ([M+H] ) 382.0719, found 382.0718.
10
3-Methyl-5,6-diphenylindolo[1,2-a]quinoline (5ba): purified by column chromatography on
1
silica gel (hexane/EtOAc = 40:1); green solid; 61 mg (79%); mp 194-196 °C; H NMR (400
MHz, CDCl3) δ 2.35 (s, 3H), 6.43 (s, 1H), 7.16-7.33 (m, 11H), 7.34 (ddd, J = 0.8, 7.2, 7.2 Hz,
1H), 7.40-7.44 (m, 2H), 7.76 (d, J = 8.0 Hz, 1H), 8.51 (d, J = 8.8 Hz, 1H), 8.57 (d, J = 8.4 Hz,
13
1H); C NMR (100 MHz, CDCl3) δ 21.2, 98.5, 114.4, 115.3, 121.3, 121.8, 121.9, 125.4, 127.1,
127.2, 128.00, 128.02, 128.5, 129.4, 130.3, 130.4, 131.2, 131.3, 132.2, 132.9, 133.3, 134.4,
+
137.61, 137.63, 137.8; HRMS m/z calcd for C29H22N ([M+H] ) 384.1747, found 384.1748.
3-tert-Butyl-5,6-diphenylindolo[1,2-a]quinoline (5ca): purified by column chromatography
1
on silica gel (hexane/EtOAc = 20:1); green solid; 71 mg (84%); mp 210-211 °C; H NMR (400
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