Direct C3-Selective Arylation of N-Unsubstituted Indoles with Aryl Chlorides, Triflates, and Nonaflates Using a Palladium-Dihydroxyterphenylphosphine Catalyst

Article abstract of DOI:10.1021/acs.joc.0c01494

A palladium-dihydroxyterphenylphosphine (DHTP) catalyst was successfully applied to the direct C3-arylation of N-unsubstituted indoles with aryl chlorides, triflates, and nonaflates. This catalyst showed C3-selectivity, whereas catalysts with other structurally related ligands exhibited N1-selectivity. Complex formation between the lithium salts of the ligand and the indole is assumed to accelerate the arylation at the C3 position. Reactions using 3-alkylindoles afforded 3,3-disubstituted indolenines, which can be further converted to the corresponding indoline derivatives.

Full text of DOI:10.1021/acs.joc.0c01494

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Article
Direct C3-Selective Arylation of N-Unsubstituted Indoles
with Aryl Chlorides, Triflates, and Nonaflates Using
Palladium-Dihydroxyterphenylphosphine Catalyst
Miyuki Yamaguchi, Ryoya Hagiwara, Kanami Gayama, Kohei
Suzuki, Yusuke Sato, Hideyuki Konishi, and Kei Manabe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01494 • Publication Date (Web): 30 Jul 2020
Downloaded from pubs.acs.org on July 31, 2020
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Page 1 of 12
The Journal of Organic Chemistry
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Direct C3-Selective Arylation of N-Unsubstituted Indoles with Aryl
Chlorides, Triflates, and Nonaflates Using Palladium-
Dihydroxyterphenylphosphine Catalyst
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Miyuki Yamaguchi, Ryoya Hagiwara, Kanami Gayama, Kohei Suzuki, Yusuke Sato, Hideyuki
Konishi, and Kei Manabe*
School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
Ar
R2
R2
R1
R1
PCy2
N
H
N
H
OH
Ar-X
(X = Cl, OTf, ONf)
Pd(OAc)2 (cat.)
Cy-DHTP HO
Cy-DHTP
(cat.)
t-BuOLi
R3
R3
R3
N
Ar
Ar
NaBH3CN
R1
R1
R1
N
N
H
H
ABSTRACT: A palladium–dihydroxyterphenylphosphine (DHTP) catalyst was successfully applied to the direct C3-
arylation of N-unsubstituted indoles with aryl chlorides, triflates, and nonaflates. This catalyst showed C3-selectivity,
whereas catalysts with other structurally related ligands exhibited N1-selectivity. Complex formation between the lithium
salts of the ligand and the indole is assumed to accelerate the arylation at the C3-position. Reactions using 3-alkylindoles
afforded 3,3-disubstituted indolenines, which can be further converted to the corresponding indoline derivatives.
Scheme 1. Pd-Catalyzed Arylation of N-Unsubstituted
Indoles
INTRODUCTION
Indole and related skeletons are ubiquitous structural
Pd cat.
(ligand)
base
motifs often found in pharmaceuticals1-6 and natural
Ar
R
R
R
R
compounds,1,7 and their arylated species have attracted
attention because of their diverse biological activities.8-14
Among them, 3-arylindoles are known to show
antimicrobial,8-10 anti-inflammatory,11 anticancer,12 and
enzyme-inhibition13,14 activities. Therefore, much synthetic
effort has been made to obtain these classes of
compounds.15-20 Palladium-catalyzed direct arylation of N-
unsubstituted indole is a powerful tool for 3-arylated
indole synthesis (Scheme 1).17-25 However, achieving high
C3-selectivity over C2- and N-selectivity is still
challenging.16,17,24 A recent paper reported Pd-catalyzed C3-
selective arylation of N-unsubstituted indole with aryl
iodides/bromides using lithium hexamethyldisilazide
(LiHMDS) as the base and transient directing group.26 In
+
Ar
X
or
Ar or
N
H
N
N
H
N
H
X = I, Br, Cl, OTf
(mainly I and Br)
Ar
N-arylated
C3-arylated
C2-arylated
Our research group has been investigating ligand-
controlled site-selective cross coupling using palladium
catalysts. were
Hydroxyterphenylphosphines30-32
developed as ligands and found to be effective for
accelerating
Kumada–Tamao–Corriu
coupling,30,31,33
Sonogashira coupling,34 and Cacchi cyclization35 of bromo-
or chloro-groups at the ortho-position of phenols or
anilines.
Among
these
ligands,
dihydroxyterphenylphosphine (DHTP) 1a bearing two
hydroxy groups (Figure 1) showed the highest reactivity
and ortho-selectivity. We assume that the complex
formation between the substrate and the ligand 1a via their
metal phenoxide/anilide is a key to control the site
selectivity and reactivity. We further applied the Pd–based
1a as catalyst to the direct C3-arylation of N-unsubstituted
comparison, the C3-selective arylation with aryl chlorides
has been limited.27,
In addition, arylation of N-
28
unsubstituted indole with aryl triflates usually gives only
the N-arylated products.29
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indoles with aryl chlorides and triflates (Scheme 2a).36 In
nonaflates (Scheme 2c). This method was further applied
to the dearomative arylation of 3-alkylindoles to afford 3-
alkyl-3-arylindolines.
1
2
3
4
5
6
7
8
this reaction, we assume that the lithium salt of indole and
the ligand 1a form a heteroaggregate, in which the C3
position of indole is close to the Pd atom, and arylation
proceeds selectively at the C3 position (Scheme 2b).
However, several substrates including 2-substituted indole
showed low reactivity to give the C3-arylated products in
poor yield. In addition, arylation of 3-methylindole
afforded 3-aryl-3-methylindolenine in moderate yield. 3,3-
Disubstituted indolenine is also an important structural
motif, and it can be converted into various derivatives such
as 3,3-disubstituted indolines.37 Therefore, effective
methods for preparing indolenines have been developed.37-
48 Among them, dearomatization of 3-substituted indoles41-
RESULTS AND DISCUSSION
We began optimization of the reaction conditions using
indole 2 and 4-chlorotoluene 3a as model substrates (Table
1). The reactions were conducted under the same
conditions as in our previous study of site-selective cross-
couplings,34 using catalysts derived from palladium acetate
and a phosphine ligand, lithium tert-butoxide as a base,
and toluene as a solvent. The reaction hardly progressed
when there was no ligand (entry 1). The reaction using
tricyclohexylphosphine afforded the desired C3-arylated
indole 4 in low yield, with a small amount of N-arylated
indole 5 as byproduct (entry 2). When the reaction was
conducted with tri-tert-butylphosphine, N-arylated 5 was
obtained in moderate yield (entry 3). Use of
triphenylphosphine gave no arylated products (entry 4).
In the cases of 2-phosphinobiphenyl-type ligands (Cy-
JohnPhos,49 XPhos,50 or SPhos51), N-arylation instead of C3-
arylation proceeded smoothly, and N-arylated 5 was
obtained in good yield (entries 5–7). Bidentate ligands were
found to be ineffective (entries 8 and 9). On the other hand,
reaction with the HBF4 salt of DHTP 1a bearing
dicyclohexylphosphino group selectively afforded the C3-
arylated 4 in high yield (entry 10). DHTP 1b bearing
diphenylphosphino group also exhibited C3-selectivity,
though the yield of 4 was low (entry 11). When
hydroxyterphenyl phosphine 1c bearing only one hydroxy
group was used, the site selectivity of arylation decreased,
and N-arylated 5 was obtained as the major product (entry
12). This result is consistent with our previous studies of
Kumada–Tamao–Corriu coupling30,31,33 and Sonogashira
coupling,34 in which the ligand with two hydroxy groups
performed better than that with one hydroxy group.
Ligand 1d bearing two methoxy groups instead of hydroxy
groups did not give any arylated product (entry 13),
supporting our hypothesis that high reactivity and
excellent C3-selectivity require the formation of a complex
between the hydroxy groups of ligand 1a and the NH group
of indole 2 via their lithium salts.
9
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
48
is a useful tool for 3,3-disubstituted indolenines
including Pd-catalyzed intramolecular dearomative
arylation,48 but there has been no successful example of
intermolecular dearomative arylation with aryl chlorides
or sulfonates except our previous work (Scheme 2a).36
Cy2P
OH
OH
1a
Cy-DHTP:
Figure 1. Dihydroxyterphenylphosphine
Scheme 2. Pd–DHTP-Catalyzed C3-Selective Arylation
of N-Unsubstituted Indoles
(a) Previous work: C3-Arylation of indoles with aryl chlorides and triflates (Ref. 36)
R
Pd(OAc)2
Ar
Ar
1a
t-BuOLi
·HBF4
Me
Ar
R
N
H
R
+
Ar
toluene
N
N
N
H
H
X
C3-selective
30-95%
R = 2-phenyl, 2-methyl: R = 3-methyl:
(X = Cl, OTf)
35-36%
52%
1a
(b) Complex formation between indole and Pd– catalyst
Li
O
N
Li
N
Pd PCy2
Pd PCy2
OLi
OLi
Li
OLi
Next, the effect of solvents was studied using Pd–1a
catalyst. High yields of 4 were achieved when using xylene
or mesitylene as solvent instead of toluene (entries 14 and
15). In the case of 1,4-dioxane, 4 was obtained in moderate
yield (entry 16). The effect of bases was then examined
using toluene as solvent. Use of sodium or potassium tert-
butoxide did not give any arylated product (entries 17 and
18). To evaluate the effect of lithium salts, other lithium
bases were screened but found to be ineffective for this
reaction (entries 19–21).
(c) This work: C3-Arylation of indole with aryl chlorides, triflates, and nonaflates
Pd(OAc)2
Ar
R1
R1
1a
·HBF4
t-BuOLi
R2
R2
+
Ar X
N
N
H
H
(R2 = H, alkyl, aryl)
(X = Cl, OTf, ONf)
R2 = H: up to 91%
R2 = alkyl, aryl: up to 74%
Dearomative arylation of 3-alkylindole
Pd(OAc)2
R3
R3
R3
Ar
1a
Ar
·HBF4
t-BuOLi
+
Ar X
N
H
N
dearomative
C3-arylation
reduction
N
(X = Cl, OTf,
ONf)
H
Using the optimized reaction conditions, arylating
agents bearing other leaving groups were tested as
reactants instead of chloride 3a. We chose aryl sulfonates
since they can be easily prepared from the corresponding
phenols. When 4-methylphenyl triflate 3b was employed,
the desired 4 was obtained in 75% yield (entry 22). 4-
indolenine
indoline
up to 85%
Herein, we report details for the C3-arylation of N-
unsubstituted indoles with aryl chlorides, triflates, and
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The Journal of Organic Chemistry
Methylphenyl nonaflate 3c was more effective as it
triflates.52 In addition, the nonaflating reagent
1
2
3
4
afforded 4 in 88% yield (entry 23). Decreasing the amount
of nonaflate 3c to 1.2 equivalents further improved the yield
(entry 24). Nonaflates have been used as an effective
alternative to triflates in various cross-couplings, showing
higher stability and slightly higher reactivity than
perfluorobutanesulfonyl fluoride, which is used in
preparing nonaflates from phenols, is less expensive than
triflating reagents such as Tf2O. Therefore, we decided to
use aryl nonaflates for further study.
5
6
7
Table 1. Optimization of Reaction Conditions in the Pd-Catalyzed C3-Arylation of Indole
8
9
Pd(OAc)2 (2 mol %)
ligand (4 mol %)
base (3 equiv)
Ar
Ar
Me
+
+
+
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
N
Ar
N
Ar
N
N
X
solvent, 110 °C, 20 h
H
H
4
5
6
3
2
(2 equiv)
Ar = p-tolyl
yield (%)a
entry
ligand
X
solvent
base
4
5
6
1
no ligand
PCy3
Cl (3a)
Cl (3a)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuONa
t-BuOK
Li2CO3
1
nd
6
nd
trace
9
2
18
3
P(t-Bu)3·HBF4
PPh3
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
Cl (3a)
OTf (3b)
ONf (3c)
ONf (3c)
1
65
nd
86b
62b
76b
nd
nd
1
4
nd
nd
nd
nd
nd
nd
85 (81)b
19
nd
4
5
Cy-JohnPhos
XPhos
6
8
7
SPhos
2
8
Xantphos
DPPE
nd
nd
3
9
10
11
1a·HBF4
1b
1
trace
2
12
13
14
15
16
17
18
19
20
21
22
23
24c
1c·HBF4
1d
12
31
nd
81
nd
2
nd
6
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
1a·HBF4
mesitylene
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
85
62
nd
nd
1
1
1
3
5
nd
nd
nd
nd
nd
1
nd
nd
nd
nd
nd
13
LiOH
2
Li3PO4
nd
75b
88b
91b
t-BuOLi
t-BuOLi
t-BuOLi
2
6
<3
<7
aNMR yield. nd = not detected. bIsolated yield. c1.2 equiv of ArONf was used.
Cy2P iPr
PCy2
MeO
MeO
PPh2
HO
PCy2
HO
Cy2P OMe
PCy2
iPr
iPr
HO
OMe
1d
1b
1c
Cy-JohnPhos
XPhos
SPhos
significantly improved the yield of the desired C3-arylated
indoles. Aryl nonaflates having substituents at the para-
position afforded the corresponding C3-arylated indoles 4,
in high yields. In the case of 3-
trifluoromethylphenyl nonaflate, the desired indole 9 was
The scope of arylating agents and indoles was
investigated using the optimized reaction conditions
(Scheme 3). In most cases, the use of aryl nonaflates
instead of the corresponding chlorides or triflates
7, and
8
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obtained in 66% yield. Benzo[d][1,3]dioxol-5-yl nonaflate 140 °C, the yield of 15 was moderate (entry 9). 4-
1
2
3
4
5
6
7
8
and 2,3-dihydro-1H-inden-5-yl nonaflate showed higher
reactivities than the corresponding triflates to give 10 and
11, respectively. The reaction of 5-fluoroindole with
nonaflate 3a afforded 12 in high yield. On the other hand,
7-(4-methoxyphenyl)indole was found to be less reactive
and resulted in a moderate yield of 13.
Bromotoluene also afforded 15 in moderate yield (entry 10).
From these results, we determined that the best reaction
occurs when using chloroarenes in xylene at 140 °C.
Table 2. Effect of Solvent and Temperature on the Pd-
Catalyzed C3-Arylation of 2-Phenylindole with 4-
Chlorotoluene
Scheme 3. Scope of the Pd-Catalyzed C3-Arylation of
N-Unsubstituted Indoles a
9
Ph
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
Pd(OAc)2 (2 mol %)
N
H
Ar
Ar
1a
·HBF4 (4 mol %)
Pd(OAc)2 (2 mol %)
t-BuOLi (3 equiv)
14
Ar
1a
·HBF4 (4 mol %)
Ph
Ph
R
+
+
Ph
+
R
t-BuOLi (3 equiv)
Me
N
N
N
solvent, temp, 48 h
H
+
Ar X
Ar
Ar
N
H
toluene, 110 °C, 20 h
N
15
Ar = p-tolyl
16
17
Cl
X = Cl: 2 equiv
H
R'
3a
(2 equiv)
R'
X = OTf: 2 equiv
X = ONf: 1.2 equiv
4, 7 13
–
CF3
temper
ature
(°C)
yield (%)a
Me
F
OMe
en
try
solvent
15
16
17
N
H
1b
2
toluene
toluene
xylene
110
35
52
39
62
trace
trace
trace
6
nd
nd
nd
nd
nd
nd
nd
41
N
N
H
N
H
9
H
49%c (X = Cl)
67% (X = ONf)
110
8
4
7
35% (X = Cl)
57% (X = OTf)
89% (X = ONf)
73% (X = Cl)
78% (X = OTf)
88% (X = ONf)
81% (X = Cl)
78% (X = OTf)
91% (90%)b
(X = ONf)
3
110
Me
4
5
xylene
130
140
150
140
160
140
140
O
O
Me
xylene
79 (58) c <3
6
7
xylene
66
9
N
H
F
mesitylene
mesitylene
xylene
64
6
13
N
H
N
H
N
H
8
9d
nd
<63e
44
<13
nd
trace
11
10
12
OMe
nd
62% (X = OTf)
89% (X = ONf)
51% (X = OTf)
75% (X = ONf)
53% (X = Cl)
90% (X = ONf)
50% (X = Cl)
53% (X = ONf)
10f xylene
trace
c
d
aNMR yield. nd = not detected. b20 h. Isolated yield. 4-
aIsolated yield. b1-mmol scale. c1.2 equiv of 3-
chlorobenzotrifluoride was used.
Methylphenyl nonaflate 3c was used instead of 3a. eContained
a small amount of impurities. 4-Bromotoluene was used
f
instead of 3a.
Next, we examined the arylation of 2-phenylindole 14
with 4-chlorotoluene 3a (Table 2). When the reaction was
conducted under the standard conditions used in the
arylation of unsubstituted indole 2, the yield of the desired
C3-arylated product 15 was only 35%, and a large amount
of 14 was recovered (entry 1). A longer reaction time (48 h)
effectively increased the yield of 15 (entry 2). We then
changed the solvent from toluene to xylene, of which
boiling point is higher, and investigated the effect of
reaction temperature (entries 3–6). When the reaction was
carried out at 110 °C, the yield of 15 was decreased (entry 3).
By increasing the reaction temperature to 130 °C, the yield
of the desired 15 was increased, and a small amount of N-
arylated indole 16 was obtained (entry 4). The reaction at
140 °C proceeded smoothly to afford 15 in 79% yield (entry
5). When the temperature was further elevated to 150 °C,
the yield of 15 was decreased (entry 6). Next, mesitylene
was tested as a solvent, and reaction in it at 140 °C gave 15
in good yield (entry 7). On the other hand, a higher
reaction temperature (160 °C) caused overarylation, and
the C3,N-diarylated indole 17 was obtained as a major
product (entry 8). When the reaction was conducted using
the corresponding nonaflate 3c with xylene as solvent at
To gain insight into the mechanism of overarylation, C3-
arylated indole 15 and N-arylated indole 16 were
individually arylated using xylene or mesitylene as solvent
(Scheme 4). When the reactions were conducted in xylene
at 140 °C, N-arylation of C3-arylated of 15 gave a small
amount of C3,N-diarylated indole 17, and the C3-arylation
of N-arylated 16 did not proceed. On the other hand, when
using mesitylene as solvent at 160 °C, arylation of 15 and 16
both gave the C3,N-diarylated 17 in moderate yield. In the
case of C3-arylated 15, N-arylation proceeded and 17 was
obtained in <42% yield. Surprisingly, N-arylated 16 also
afforded 17 in 54% yield. These results indicate that a
higher reaction temperature (160 °C) may enable other
catalytic pathways that do not require the complex
formation between indoles and the Pd–1a catalyst, and
therefore C3,N-diarylated 17 was formed from both C3-
arylated 15 and N-arylated 16.
Scheme 4. Mechanistic Study of Overarylation
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Pd(OAc)2 (2 mol %)
1a
t-BuOLi (3 equiv)
Pd(OAc)2 (2 mol %)
1a
t-BuOLi (3 equiv)
Ar
Ar
·HBF4 (4 mol %)
Ar
·HBF4 (4 mol %)
R
Me
1
2
3
4
5
6
7
8
R
R'
Ph
R'
+
Ar X
Ph
+
N
N
N
Cl
xylene, 140 °C, 48 h
solvent, temp, 48 h
N
H
H
H
Ar
(2 equiv)
3a
17
15
15, 18 29
–
(2 equiv)
xylene, 140 °C: 3%
mesitylene, 160 °C: <42%
(contained a trace amount
of impurities)
Me
OMe
F
Me
Pd(OAc)2 (2 mol %)
1a
Me
Ar
·HBF4 (4 mol %)
Me
t-BuOLi (3 equiv)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
+
N
N
N
H
N
N
H
N
Ar
N
9
Cl
solvent, temp, 48 h
H
H
H
15
18
19
20
32% (X = Cl)
21
Ar
17
16
3a
10
11
12
13
14
15
16
58% (X = Cl)
29% (X = Cl)
41% (X = Cl)
24% (X = Cl)
(2 equiv)
xylene, 140 °C: nd
<63%b (X = ONf)
44%b (X = Br)
mesitylene, 160 °C: 54%
Ar = p-tolyl
Me
Me
Me
Me
Ph
With the optimized conditions at hand, we investigated
Me
C10H21
Me
Me
Ph
N
H
N
N
H
24
N
H
25
reactions using various arylating agents and 2-substituted
indoles (Scheme 5). Chloroarenes bearing methoxy or
fluoro group afforded the corresponding C3-arylated
indoles 18 and 19. In the cases of 3-chlorotoluene and 2-
chlorotoluene, the desired products 20 and 21 were
obtained in low yield. A series of 2-substituted indoles were
then tested. Reaction using 2-methylindole proceeded
smoothly to afford the desired 22 in good yield. When 2-
decylindole was used, the desired 23 was obtained in
H
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
22
23
71% (X = Cl)
53% (X = Cl)
38% (X = Cl)
63% (X = Cl)
Me
Me
Me
Me
F
F
OMe
Ph
N
H
26
N
N
N
H
H
H
27
28
29
53% (X = Cl)
57% (X = Cl)
74% (59%)c
36% (X = Cl)
64%d (X = Cl)
moderate
yield.
2-Phenethyllindole
gave
the
(X = Cl)
corresponding C3-arylated 24 in 38% yield. Reactions with
2-phenylindoles bearing various substituents on the 2-
phenyl moiety afforded 25–27 in moderate yields. When
the reaction was conducted for 48 h using 5-methyl-2-
phenylindole, the yield of the desired 28 was low, and a
large amount of C3,N-diarylated indole (19%) was obtained.
A shorter reaction time (24 h) was found to be effective for
improving the yield of 28 by suppressing the overarylation.
5-Fluoro-2-phenylindole gave C3-arylated 29 in moderate
yield.
aIsolated yield. bNMR yield. c1-mmol scale. d24 h.
Subsequent investigation was carried out for the
dearomative C3-arylation of 3-alkylindoles (Table 3). 3-
Methylindole 30 was selected as a model substrate, and its
reactions were conducted using 4 mol% Pd catalyst. Due
to
instability
of
the
obtained
3-methyl-3-(p-
tolyl)indolenine 31, reduction with NaBH3CN53 was carried
out after work-up to give the more stable 3-methyl-3-(p-
tolyl)indoline 33. First, effects of the solvent and the
temperature were examined using 2 equivalents of 4-
chlorotoluene 3a as arylating agent. When the reaction was
carried out in toluene at 110 °C, the desired 33 was obtained
in 52% yield with N-arylated indole 32 as a byproduct
(entry 1). The use of xylene did not increase the yield of 33
(entry 2), while a higher reaction temperature (140 °C)
resulted in decreased 33 and increased 32 yields (entry 3).
The use of mesitylene did not improve the yield of 33 either
(entries 4 and 5). Other arylating agents were then tested
using toluene as solvent. Reaction with the corresponding
triflate 3b gave the desired 33 in 56% yield (entry 6). To our
delight, when nonaflate 3c was used, the C3-arylation
proceeded smoothly and the yield of 33 increased (entry 7).
A shorter reaction time was found to further improve the
yield (entry 8). By decreasing the amount of nonaflate 3c
to 1.2 equivalents, the formation of N-arylated 32 was
suppressed, and indoline 33 was obtained in 85% yield
(entry 9). Among the tested arylating agents, nonaflate 3c
gave the best yield in a shorter reaction time.
Scheme 5. Scope of the C3-Arylation of 2-Substituted
Indolesa
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Table 3. Optimization of Reaction Conditions in the
Page 6 of 12
Pd(OAc)2 (4 mol %)
1a
t-BuOLi (3.5 equiv)
R
R
Ar
·HBF4 (8 mol %)
NaBH3CN
(10 equiv)
1
2
3
4
Pd-Catalyzed Dearomative C3-Arylation of 3-
Methylindole
+
Ar
X
N
N
CH2Cl2 / MeOH
rt, 1 h
toluene, 110 °C, 12 h
H
H
X = Cl: 2 equiv
X = OTf: 2 equiv
Me
33 40
–
X = ONf: 1.2 equiv
5
6
7
8
Pd(OAc)2 (4 mol %)
Me
N
Ar
1a
Me
Ar
·HBF4 (8 mol %)
NaBH3CN
(10 equiv)
H
Me
OMe
F
t-BuOLi (3.5 equiv)
30
+
Me
Me
Me
Me
N
Me
solvent, temp, 20 h
CH2Cl2
MeOH
rt, 1 h
/
N
31
H
Me
+
33
9
X
N
N
H
N
N
3
H
H
H
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
(y equiv)
33
34
35
36
N
Ar = p-tolyl
52% (X = Cl)b
56% (X = OTf)b
85% (69%)c
(X = ONf)
26% (X = Cl)b
34% (X = OTf)b
61% (X = ONf)
22% (X = Cl)b
23% (X = OTf)b
71% (X = ONf)
32% (X = Cl)b
Ar
32
57% (X = ONf)
yield (%)a
X
entr
y
temp
(°C)
Me
solvent
(y equiv)
Cl (2)
33
52
45
24
44
34
56
67
77
85
32
Me
Me
Me
Et
Me
1
toluene
xylene
xylene
110
110
140
<12
20
Me
N
H
N
H
N
H
N
H
2
Cl (2)
37
38
39
40
3
Cl (2)
27
34% (X = Cl)b
77% (X = ONf)
26% (X = Cl)b
34% (X = ONf)
46% (X = OTf)b
66% (X = ONf)
28% (X = Cl)b
4
5
Cl (2)
mesitylene 110
mesitylene 120
14
43% (X = ONf)
Cl (2)
26
aIsolated yield. bArylation time: 20 h. c1-mmol scale.
6
7
8b
9b
OTf (2)
ONf (2)
ONf (2)
ONf (1.2)
toluene
toluene
toluene
toluene
110
110
110
110
16
<10
<3
CONCLUSIONS
We developed C3-selective arylation of N-unsubstituted
indoles using catalyst derived from Pd and
trace
aIsolated yield. bArylation time: 12 h.
a
dihydroxyterphenylphosphine ligand 1a. The use of aryl
nonaflates effectively increased the yield of the desired C3-
arylated products. In the cases of 2-substituted indoles,
reactions at higher temperature using xylene as solvent
improved the product yield. Dearomative C3-arylation of
C3-alkylindoles also proceeded well when employing this
catalyst system and aryl nonaflates. This method enables
the facile synthesis of various indoles and their derivatives
from readily available compounds.
Finally, the scope of the dearomative C3-arylation was
tested (Scheme 6). In all cases, reactions using nonaflates
gave higher yield of the products (33–40) than those using
chlorides and triflates. Aryl nonaflates bearing methyl-,
methoxy-, and fluoro group at the para-position gave the
corresponding indolines 33–35 in good to high yield. When
phenyl nonaflate was used, indoline 36 was obtained in
moderate yield. Reaction with 3-methylpheyl nonaflate
also proceeded smoothly to afford 37 in good yield. On the
other hand, 2-methylphenyl nonaflate gave the product 38
in only 34% yield. It seems that the steric hindrance
between the 3-methyl group of 30 and the o-methyl group
of the nonaflate caused the low reactivity. In the case of
2,3-dihydro-1H-inden-5-yl nonaflate, the yield of the
desired 39 was 66%. Reaction using 3-ethylindole instead
of 30 also proceeded, and the desired 40 was obtained in
moderate yield.
EXPERIMENTAL SECTION
General Information. Unless otherwise noted, all
reactions were performed under argon atmosphere.
Reactions were monitored by TLC on Merck silica gel 60
F254 plates or Wako Pure Chemical Industry NH2 silica gel
60 F254 plates and visualized by UV lump at 254 nm.
Preparative TLC was performed on Merck silica gel 60 F254
0.5 mm plates or Wako Pure Chemical Industry NH2 silica
gel 60 F254 0.5 mm plates. NMR spectra were measured on
1
a JEOL AL-400 NMR spectrometer (400 MHz for H
spectra), a JEOL ECA500 NMR spectrometer (500 MHz for
1H spectra, 125 MHz for 13C spectra, and 470 MHz for 19F
spectra), a JEOL JNM-ECX500 NMR spectrometer (500
MHz for 1H spectra and 125 MHz for 13C spectra), and JEOL
Scheme 6. Scope of the Pd-Catalyzed Dearomative C3-
Arylation of 3-Substituted Indoles a
1
JNM-ECZ500R/S1 NMR spectrometer (500 MHz for H
spectra and 125 MHz for 13C spectra). For 1H NMR,
tetramethylsilane (TMS) (δ = 0) in CDCl3 served as an
internal standard. For 13C NMR, CDCl3 (δ = 77.0) served as
an internal standard. NMR data were processed by using
ACDLABS 12.0 1D processor or Delta NMR software v5.3.1.
Infrared spectra were measured on a SHIMADZU IR
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The Journal of Organic Chemistry
Prestige-21 spectrometer (ATR). High-resolution mass procedure. Purification by preparative TLC (SiO2,
1
2
3
4
5
6
7
8
spectra (HRMS) were measured on a Bruker MicrOTOF
time-of-flight mass spectrometer (ESI) and a JEOL JMS-
T100TD time-of-flight mass spectrometer (DART).
Preparative HPLC was performed on Japan Analytical
Industry LC-9201 using JALGEL-1H, 2H columns (solvent:
chloroform, flow rate: 3.5 mL/min, detection: 254 nm) or
Japan Analytical Industry LaboACE LC-5060 using a
JALGEL-2HR column (solvent: ethyl acetate, flow rate: 10
mL/min, detection: 254 nm).
hexane/ethyl acetate = 5/1) afforded 7 as a pale yellow solid
(94 mg, 89%).
3-(4-Methoxyphenyl)-1H-indole (8).79 Prepared from
2 and 4-methoxyphenyl nonaflate following the typical
procedure. Purification by preparative TLC (SiO2,
hexane/dichloromethane = 1/1) afforded 8 as a white solid
(99 mg, 88%).
3-((3-Trifluoromethyl)phenyl)-1H-indole
(9).80
9
Prepared from 2 and (3-fluoromethyl)phenyl nonaflate
following the typical procedure. Purification by
preparative TLC (SiO2, hexane/ethyl acetate = 5/1, then
hexane/ethyl acetate = 3/1) afforded 9 as a white solid
(88 mg, 67%).
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
Materials. Ligands 1a·HBF4, 1b, and 1d were prepared
according
to
the
reported
procedure.32
7-(4-
Methoxyphenyl)-1H-indole was prepared according to the
reported procedure.54 2-Decyl-1H-indole55 and 2-
phenethyl-1H-indole55
were
chloroacetanilide and corresponding alkynes.56 2-(4-
Methylphenyl)-1H-indole,57
2-(4-methoxylphenyl)-1H-
prepared
from
2-
3-(2,3-Dihydro-1H-inden-5-yl)-1H-indole
(10).36
Prepared from 2 and 2,3-dihydro-1H-inden-5-yl nonaflate
following the typical procedure. Purification by
preparative TLC (SiO2, hexane/ethyl acetate = 5/1, twice)
and preparative HPLC (ethyl acetate) afforded 10 as a white
solid (111 mg, 89%).
3-(Benzo[d][1,3]dioxol-5-yl)-1H-indole (11).81 Prepared
from 2 and benzo[d][1,3]dioxol-5-yl nonaflate following the
typical procedure. Purification by preparative TLC (SiO2,
hexane/ethyl acetate = 5/1, twice) afforded 11 as a white
solid (91 mg, 75%).
indole,58 5-methyl-2-phenyl-1H-indole,59 and 5-fluoro-2-
phenyl-1H-indole60 were prepared from corresponding N-
tosyl-2-chloroanilines and corresponding alkynes.34 3-
Ethyl-1H-indole was prepared according to the reported
procedure.61 4-Methylphenyl trifluoromethanesulfonate
(3b),62 4-methoxyphenyl trifluoromethanesulfonate,63,64 4-
fluorophenyl
benzo[d][1,3]dioxol-5-yl trifluoromethanesulfonate,66 and
2,3-dihydro-1H-inden-5-yl
trifluoromethanesulfonate67
trifluoromethanesulfonate,65
5-Fluoro-3-(p-tolyl)-1H-indole (12).36 Prepared from 5-
fluoroindole and 3c following the typical procedure.
Purification by preparative TLC (SiO2, hexane/ethyl
acetate = 5/1) and preparative HPLC (chloroform) afforded
12 as a pale-yellow solid (102 mg, 90%).
were prepared from corresponding phenols using
trifluoromethanesulfonic anhydride and pyridine in
dichloromethane.68 4-Methylphenyl nonaflate (3c),69 3-
trifluoromethylphenyl nonaflate,70 4-methoxyphenyl
nonaflate,71 4-fluorophenyl nonaflate,72 phenyl nonaflate,73
3-methylphenyl nonaflate,72 2-methylphenyl nonaflate,71
benzo[d][1,3]dioxol-5-yl nonaflate,74 and 2,3-dihydro-1H-
inden-5-yl nonaflate were prepared from corresponding
phenols using perfluorobutanesulfonyl fluoride and
triethylamine in dichloromethane or acetonitrile. Other
reagents and anhydrous solvents were purchased from
commercial suppliers and used without further
purification.
7-(4-Methoxyphenyl)-3-(p-tolyl)-1H-indole
(13).36
Prepared from 7-(4-methoxyphenyl)indole and 3c
following the typical procedure. Purification by
preparative TLC (SiO2, hexane/ethyl acetate = 5/1) and
preparative HPLC (chloroform) afforded 13 as a white solid
(83 mg, 53%).
Typical experimental procedure for C3-selective
arylation of 2-substituted indoles. 2-Phenyl-3-(p-
tolyl)-1H-indole (15).82 Xylene (0.5 mL) was added to
Pd(OAc)2 (2.2 mg, 0.01 mmol), 1a·HBF4 (10.9 mg, 0.02
mmol), t-BuOLi (120 mg, 1.5 mmol), and 2-phenylindole 14
(96.6 mg, 0.50 mmol) in a sealed tube under argon. To this
solution was added 4-chlorotoluene 3a (118 µL, 1.0 mmol).
The reaction mixture was stirred at rt for 1 h, and then at
140 °C using an oil bath for 48 h. The resulting suspension
was quenched with brine (5 mL) at rt and extracted with
diethyl ether (20 mL × 3). The combined organic layers
were dried over anhydrous Na2SO4 and concentrated, and
then the residue was purified by preparative TLC (SiO2,
Typical experimental procedure for C3-selective
arylation of N-unsubstituted indoles. 3-(p-Tolyl)-1H-
indole (4, Table 1, Entry 24).75,76 Toluene (0.5 mL) was
added to Pd(OAc)2 (2.2 mg, 0.01 mmol), 1a·HBF4 (10.9 mg,
0.02 mmol), t-BuOLi (120 mg, 1.5 mmol), and indole 2 (58.6
mg, 0.50 mmol) in a sealed tube under argon. To this
solution was added 4-methylphenyl nonaflate 3c (234 mg,
0.60 mmol). The reaction mixture was stirred at rt for 1 h,
and then at 110 °C using an oil bath for 20 h. The resulting
suspension was quenched with brine (5 mL) at rt and
extracted with diethyl ether (20 mL × 3). The combined
organic layers were dried over anhydrous Na2SO4 and
concentrated, and then the residue was purified by
preparative TLC (SiO2, hexane/ethyl acetate = 5/1) to give
3-(p-tolyl)-1H-indole 4 (94 mg, 91% yield) as a pale-yellow
solid. One-mmol scale reaction afforded 186 mg of 4 (90%).
hexane/ethyl acetate
= 5/1) and preparative HPLC
(chloroform) to give 2-phenyl-3-(p-tolyl)-1H-indole 15 (82
mg, 58% yield) as a yellow solid.
2-Phenyl-1,3-di-p-tolyl-1H-indole (17, Table 2, Entry
8). Purification by preparative TLC (SiO2, hexane/ ethyl
acetate = 5/1, then hexane/ ethyl acetate = 100/1) afforded
17 as a yellow solid (77 mg, 41%). 1H NMR (500 MHz, CDCl3)
δ = 7.78 (dd, J = 2.3, 6.3 Hz, 1 H), 7.33 - 7.28 (m, 1 H), 7.28 -
1-(p-Tolyl)-1H-indole (5).77 a pale yellow oil.
3-(4-Fluorophenyl)-1H-indole (7).78 Prepared from 2
and 4-fluorophenyl nonaflate following the typical
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7.23 (m, 2 H), 7.23 - 7.18 (m, 2 H), 7.18 - 7.07 (m, 11 H), 2.36
Page 8 of 12
110.4, 36.0, 28.2, 21.2. IR (ATR) 3396, 1456, 816, 741, 696 cm-
1
(s, 3 H), 2.35 (s, 3 H) 13C{1H} NMR (125 MHz, CDCl3) δ =
138.0, 136.9, 136.8, 135.5, 135.3, 131.9, 131.8, 131.2, 130.0,
129.6, 129.0, 128.0, 127.8, 127.5, 127.2, 122.5, 120.6, 119.6,
116.3, 110.7, 21.2, 21.1. IR (ATR) 3030, 2918, 2859, 1512, 1454,
1368, 1236, 1107, 810, 731 cm-1. HRMS (ESI) m/z: [M+H]+
Calcd. for C28H24N 374.1903; Found: 374.1908.
HRMS (DART) m/z: [M+H]+ Calcd. for C23H22N 312.1747;
1
2
3
4
5
6
7
8
Found: 312.1755.
2,3-Di-p-tolyl-1H-indole (25).86 Prepared from 2-(p-
tolyl)-1H-indole and 3a following the typical procedure.
Purification
by
preparative
TLC
(SiO2,
hexane/dichloromethane = 1/1) and preparative HPLC
(ethyl acetate) afforded 25 as a yellow oil (94 mg, 63%).
3-(4-Methoxyphenyl)-2-phenyl-1H-indole
(18).83
Prepared from 14 and 4-chloroanisole following the typical
procedure. Purification by preparative TLC (SiO2,
hexane/dichloromethane = 1/1) and preparative HPLC
(chloroform) afforded 18 as a gray solid (44 mg, 29%).
2-(4-Methoxyphenyl)-3-(p-tolyl)-1H-indole
(26).83
9
Prepared from 2-(4-methoxyphenyl)-1H-indole and 3a
following the typical procedure. Purification by
preparative TLC (SiO2, hexane/dichloromethane = 1/1) and
preparative HPLC (ethyl acetate) afforded 26 as a yellow oil
(90 mg, 57%).
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
3-(4-Fluorophenyl)-2-phenyl-1H-indole
(19).84
Prepared from 14 and 1-chloro-4-fluorobenzene following
the typical procedure. Purification by preparative TLC
(SiO2, hexane/dichloromethane = 2/3) and preparative
HPLC (ethyl acetate) afforded 19 as a yellow solid (60 mg,
41%).
2-(4-Fluorophenyl)-3-(p-tolyl)-1H-indole
(27).86
Prepared from 2-(4-fluorophenyl)-1H-indole and 3a
following the typical procedure. Purification by
preparative TLC (SiO2, hexane/dichloromethane = 2/1,
then NH2 silica, hexane/chloroform = 1/1 (twice)) afforded
27 as a pale pink solid (111 mg, 74%). One-mmol scale
reaction afforded 89 mg of 27 (59%).
2-Phenyl-3-(m-tolyl)-1H-indole (20).82 Prepared from
14 and 3-chlorotoluene following the typical procedure.
Purification
by
preparative
TLC
(SiO2,
hexane/dichloromethane = 1/1) and preparative HPLC
(ethyl acetate) afforded 20 as a yellow oil (45 mg, 32%).
5-Methyl-2-phenyl-3-(p-tolyl)-1H-indole
(28).
Prepared from 5-methyl-2-phenylindole and 3a following
the typical procedure. Purification by preparative TLC
(SiO2, hexane/dichloromethane = 1/1 , then NH2 silica,
hexane dichloromethane = 1/1 (twice)) afforded 28 as a
yellow solid (95 mg, 64%). 1H NMR (500 MHz, CDCl3) δ =
8.02 (br. s., 1 H), 7.43 (s, 1 H), 7.38 (d, J = 6.9 Hz, 2 H), 7.34
- 7.21 (m, 6 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.04 (d, J = 8.0 Hz,
1 H), 2.41 (s, 3 H), 2.38 (s, 3 H). 13C{1H} NMR (125 MHz,
CDCl3) δ = 135.7, 134.2, 133.9, 132.9, 132.1, 130.0, 129.6, 129.2,
129.1, 128.6, 128.0, 127.4, 124.2, 119.3, 114.5, 110.5, 21.5, 21.2. IR
(ATR) 1661, 1591, 1514, 1447, 1296, 819, 794, 763, 694 cm-1.
HRMS (ESI) m/z: [M−H]− Calcd. for C22H18N 296.1445;
Found: 296.1437.
2-Phenyl-3-(o-tolyl)-1H-indole (21).82 Prepared from
14 and 2-chlorotoluene following the typical procedure.
Purification
by
preparative
TLC
(SiO2,
hexane/dichloromethane = 1/1) and preparative HPLC
(ethyl acetate) afforded 21 as a white solid (34 mg, 24%).
2-Methyl-3-(p-tolyl)-1H-indole (22).85 Prepared from
2-methylindole and 3a following the typical procedure.
Purification by preparative TLC (SiO2, hexane/ethyl
acetate = 5/1 then NH2 silica, hexane/ethyl acetate = 5/1
(three times)) afforded 22 as a dark-yellow oil (78 mg, 71%).
2-Decyl-3-(p-tolyl)-1H-indole (23). Prepared from 2-
decylindole and 3a following the typical procedure.
5-Fluoro-2-phenyl-3-(p-tolyl)-1H-indole
(29).83
Purification
by
preparative
TLC
(SiO2,
Prepared from 5-fluoro-2-phenylindole and 3a following
the typical procedure. Purification by preparative TLC
(SiO2, hexane/dichloromethane = 2/1, then NH2 silica,
hexane/chloroform = 1/2 (twice)) afforded 29 as a yellow
solid (79 mg, 53%).
hexane/dichloromethane = 4/1) afforded 23 as a brown oil
(92 mg, 53%). 1H NMR (500 MHz, CDCl3) δ = 7.84 (s, 1 H),
7.62 (d, J = 7.8 Hz, 1 H), 7.38 (d, J = 7.8 Hz, 2 H), 7.33 - 7.17
(m, 3 H), 7.15 (t, J = 7.8 Hz, 1 H), 7.09 (t, J = 7.8 Hz, 1 H),
2.78 (t, J = 7.8 Hz, 2 H), 2.40 (s, 3 H), 1.63 (quin, J = 7.3 Hz,
2 H), 1.37 - 1.08 (m, 14 H), 0.88 (t, J = 6.8 Hz, 3 H). 13C{1H}
NMR (125 MHz, CDCl3) δ = 135.9, 135.3, 135.1, 132.4, 129.5,
129.2, 128.0, 121.4, 119.7, 118.9, 114.2, 110.3, 31.9, 29.9, 29.6,
29.5, 29.4, 29.34, 29.29, 26.3, 22.7, 21.2, 14.1. IR (ATR) 3406,
2920, 2850, 2360, 1508, 1458, 1438, 1327, 817, 740 cm-1. HRMS
(DART) m/z: [M+H]+ Calcd. for C25H34N 348.2686; Found:
348.2695.
Typical experimental procedure for C3-selective
dearomative arylation of 3-substituted indoles. 3-
methyl-3-(p-tolyl)-indoline (33).53 Toluene (0.5 mL) was
added to Pd(OAc)2 (4.5 mg, 0.02 mmol), 1a·HBF4 (21.8 mg,
0.04 mmol), t-BuOLi (140 mg, 1.75 mmol), and 3-
methylindole 30 (65.8 mg, 0.50 mmol) in a sealed tube
under argon. To this solution was added 4-methylphenyl
nonaflate 3c (234 mg, 0.60 mmol). The reaction mixture
was stirred at rt for 30 min, and then at 110 °C using an oil
bath for 12 h. The resulting suspension was quenched with
brine (5 mL) at rt and extracted with diethyl ether (20 mL
× 3). The combined organic layers were dried over
anhydrous Na2SO4 and concentrated to give crude mixture.
The crude mixture was dissolved in dichloromethane (13
mL) and methanol solution (3 mL) of NaBH3CN (314 mg,
5.0 mmol) was added. After 30 min of stirring at rt, silica
gel (3.29 g) was added and stirred for 30 min. The resulting
2-Phenethyl-3-(p-tolyl)-1H-indole (24). Prepared
from 2-phenethylindole and 3a following the typical
procedure. Purification by preparative TLC (SiO2,
hexane/dichloromethane = 1/1) and preparative HPLC
1
(chloroform) afforded 24 as a yellow oil (59 mg, 38%). H
NMR (500 MHz, CDCl3) δ = 7.75 - 7.45 (m, 2 H), 7.36 - 7.29
(m, 2 H), 7.29 - 7.17 (m, 6 H), 7.17 - 7.03 (m, 4 H), 3.09 (t, J
= 7.8 Hz, 2 H), 2.92 (t, J = 7.8 Hz, 2 H), 2.39 (s, 3 H). 13C{1H}
NMR (125 MHz, CDCl3) δ = 141.0, 135.5, 135.1, 134.7, 132.1,
129.4, 129.2, 128.5, 128.4, 127.8, 126.3, 121.5, 119.8, 119.0, 114.6,
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The Journal of Organic Chemistry
suspension was filtered, and solvent was removed in (m, 2 H), 6.97 (d, J = 7.4 Hz, 1 H), 6.75 (t, J = 7.4 Hz, 1 H),
1
2
3
4
5
6
7
8
vaduo. To the residue was added water (5 mL) and
extracted with dichloromethane (20 mL × 3). The
combined organic layers were dried over anhydrous
Na2SO4 and concentrated. The residue was purified by
preparative TLC (SiO2, hexane/ethyl acetate =20/1, twice)
to give 95 mg (85% yield) of 3-methyl-3-(p-tolyl)-indoline
(33) as a pale-yellow oil. One-mmol scale reaction afforded
154 mg of 33 (69%).
6.70 (d, J = 8.0 Hz, 1 H), 3.68 (d, J = 9.2 Hz, 1 H), 3.52 (d, J =
8.6 Hz, 1 H), 2.85 (t, J = 7.2 Hz, 4 H), 2.03 (quin, J = 7.4 Hz,
2 H), 1.69 (s, 3 H). 13C{1H} NMR (125 MHz, CDCl3) δ = 150.6,
145.6, 144.2, 142.0, 137.3, 127.5, 124.4, 124.1, 123.9, 122.5,
118.9, 109.9, 63.9, 49.5, 32.9, 32.3, 26.4, 25.5. IR (ATR) 1605,
1485, 1460, 1310, 1246, 1024, 818, 741 cm-1. HRMS (ESI) m/z:
[M+H]+ Calcd. for C18H20N 250.1590; Found: 250.1580.
3-Ethyl-3-(p-tolyl)indoline (40). Prepared from 3-
ethylindole and 3c following the typical procedure.
Purification by preparative TLC (SiO2, hexane/ethyl
acetate =20/1, twice) afforded 40 as a pale yellow oil (51 mg,
3-Methyl-1-(p-tolyl)-1H-indole (32).87 Colorless oil.
9
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
3-(4-Methoxyphenyl)-3-methylindoline
(34).53
Prepared from 30 and 4-methoxyphenyl nonaflate
following the typical procedure. Purification by
preparative TLC (SiO2, hexane/diethyl ether = 4/1) afforded
34 as a pale-orange solid (73 mg, 61%).
3-(4-Fluorophenyl)-3-methylindoline (35).53 Prepared
from 30 and 4-fluorophenyl nonaflate following the typical
procedure. Purification by preparative TLC (SiO2,
hexane/ethyl acetate =10/1) afforded 35 as a pale-yellow oil
(80 mg, 71%).
3-Methyl-3-phenylindoline (36).53 Prepared from 30
and phenyl nonaflate following the typical procedure.
Purification by preparative TLC (SiO2, hexane/ethyl
acetate =20/1, twice) afforded 36 as a colorless oil (60 mg,
57%).
1
43%). H NMR (500 MHz, CDCl3) δ =7.24 (d, J = 7.8 Hz, 2
H), 7.09 (d, J = 8.0 Hz, 2 H), 7.05 (t, J = 7.8 Hz, 2 H), 6.75 (t,
J = 7.2 Hz, 1 H), 6.68 (d, J = 7.4 Hz, 1 H), 3.66 (d, J = 9.2 Hz,
1 H), 3.57 (d, J = 9.2 Hz, 1 H), 2.30 (s, 3 H), 2.15 (td, J = 7.2,
14.3 Hz, 1 H), 2.11 - 1.98 (m, 6 H), 0.84 (t, J = 7.2 Hz, 3 H).
13C{1H} NMR (125 MHz, CDCl3) δ = 151.2, 143.3, 135.5, 134.7,
128.9, 127.5, 126.7, 125.1, 118.5, 109.9, 61.1, 53.7, 31.2, 20.8, 9.4.
IR (ATR) 1603, 1512, 1185, 1460, 1377, 1308, 1244, 812, 740 cm-1.
HRMS (ESI) m/z: [M+H]+ Calcd. for C17H20N 238.1590;
Found: 238.1581.
ASSOCIATED CONTENT
Supporting Information. The Supporting Information is
available free of charge on the ACS Publications website.
3-Methyl-3-(m-tolyl)indoline (37). Prepared from 30
and 3-methylphenyl nonaflate following the typical
procedure. Purification by preparative TLC (SiO2,
hexane/ethyl acetate =20/1, twice) afforded 37 as a pale
yellow oil (86 mg, 77%). 1H NMR (500 MHz, CDCl3) δ = 7.17
(t, J = 7.4 Hz, 1 H), 7.14 - 7.04 (m, 3 H), 7.00 (d, J = 7.4 Hz, 1
H), 6.96 (d, J = 7.4 Hz, 1 H), 6.75 (t, J = 7.2 Hz, 1 H), 6.70 (d,
J = 7.4 Hz, 1 H), 3.69 (d, J = 8.6 Hz, 1 H), 3.52 (d, J = 9.2 Hz,
1 H), 2.30 (s, 3 H), 1.69 (s, 3 H). 13C{1H} NMR (125 MHz,
CDCl3) δ = 150.6, 147.6, 137.6, 137.0, 128.0, 127.6, 127.2, 126.9,
124.1, 123.6, 118.9, 109.9, 63.7, 49.5, 26.2, 21.6. IR (ATR) 3375,
2963, 1604, 1485, 1460, 1310, 1244, 1028, 785, 742 cm-1. HRMS
(ESI) m/z: [M+H]+ Calcd. for C16H18N 224.1434; Found:
224.1438.
Experimental procedures, spectroscopic data, and NMR
spectra of all products (PDF)
AUTHOR INFORMATION
Corresponding Author
*Email: manabe@u-shizuoka-ken.ac.jp
ACKNOWLEDGMENT
This work was partially supported by JSPS KAKENHI (Grant
Numbers 15H04634 and 17K08214), Hamamatsu Foundation
for Science and Technology Promotion, the Research
Foundation for Pharmaceutical Sciences, University of
Shizuoka, and the Platform Project for Supporting Drug
Discovery and Life Science Research (Basis for Supporting
Innovative Drug Discovery and Life Science Research
(BINDS)) from Japan Agency for Medical Research and
Development (AMED).
3-Methyl-3-(o-tolyl)indoline (38). Prepared from 30
and 2-methylphenyl nonaflate following the typical
procedure. Purification by preparative TLC (SiO2,
hexane/ethyl acetate =20/1, twice) afforded 38 as a pale
yellow oil (39 mg, 34%). 1H NMR (500 MHz, CDCl3) δ = 7.48
- 7.37 (m, 1 H), 7.21 - 7.10 (m, 3 H), 7.05 (t, J = 7.8 Hz, 1 H),
6.79 (d, J = 7.4 Hz, 1 H), 6.71 - 6.61 (m, 2 H), 3.90 (d, J = 9.7
Hz, 1 H), 3.48 (d, J = 9.7 Hz, 1 H), 2.04 (s, 3 H), 1.73 (s, 3 H).
13C{1H} NMR (125 MHz, CDCl3) δ = 150.0, 144.0, 137.6, 137.2,
132.6, 127.4, 127.0, 126.7, 125.4, 123.5, 118.6, 109.4, 61.0, 49.9,
28.7, 21.7. IR (ATR) 3385, 2963, 1605, 1485, 1460, 1312, 1258,
1233, 1024, 753 cm-1. HRMS (ESI) m/z: [M+H]+ Calcd. for
C16H18N 224.1434; Found: 224.1432.
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