Me2AlCl-mediated carboxylation, ethoxycarbonylation, and carbamoylation of indoles

Article abstract of DOI:10.1016/j.tet.2015.12.028

Various 1-methyl-, 1-triisopropylsilyl-, and 1-benzylindoles are carboxylated under CO₂ pressure (3.0 MPa) with the aid of 1.0 molar equiv of Me₂AlCl to give 1-substituted indole-3-carboxylic acids in good to excellent yields. Mechanistic studies suggest that the intermediate, an indol-3-ylaluminum ate complex, was reversibly formed by electrophilic addition of Me₂AlCl to the substrate followed by deprotonation of the resulting adduct. This method is successfully extended to alkoxycarbonylation with ethyl chloroformate and carbamoylation with naphthalen-1-yl isocyanate, which afford ethyl indole-3-carboxylates and N-naphthalen-1-ylindole-3-carboxamides, respectively.

Full text of DOI:10.1016/j.tet.2015.12.028

Tetrahedron xxx (2015) 1e12
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Me2AlCl-mediated carboxylation, ethoxycarbonylation, and
carbamoylation of indoles
*
Koji Nemoto, Shinya Tanaka , Megumi Konno, Satoru Onozawa, Masafumi Chiba,
*
Yuuki Tanaka, Yosuke Sasaki, Ryo Okubo, Tetsutaro Hattori
Department of Biomolecular Engineering, Graduate School of Engineering, Tohoku University, 6-6-11 Aramaki-Aoba, Aoba-ku, Sendai 980-8579, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Various 1-methyl-, 1-triisopropylsilyl-, and 1-benzylindoles are carboxylated under CO2 pressure
(3.0 MPa) with the aid of 1.0 molar equiv of Me2AlCl to give 1-substituted indole-3-carboxylic acids in
good to excellent yields. Mechanistic studies suggest that the intermediate, an indol-3-ylaluminum ate
complex, was reversibly formed by electrophilic addition of Me2AlCl to the substrate followed by de-
protonation of the resulting adduct. This method is successfully extended to alkoxycarbonylation with
ethyl chloroformate and carbamoylation with naphthalen-1-yl isocyanate, which afford ethyl indole-3-
carboxylates and N-naphthalen-1-ylindole-3-carboxamides, respectively.
Received 9 November 2015
Received in revised form 7 December 2015
Accepted 12 December 2015
Available online xxx
Keywords:
Indole
Alumination
Carboxylation
Alkoxycarbonylation
Carbamoylation
Ó 2015 Published by Elsevier Ltd.
1. Introduction
requires a two-step metalationecarbonation sequence.8 During the
course of our studies on the carboxylation of aromatic compounds
Indole-3-carboxylic acid is an important structural motif found
in various artificial drugs, such as Tropisetron and Dolasetron, se-
rotonin receptor antagonists used for the treatment of nausea and
vomiting,1 and Arbidol, a broad-spectrum antiviral drug.2 There-
fore, a number of synthetic approaches have been reported for the
construction of this motif via cyclization reactions such as Fischer3
and SaegusaeIto syntheses,4 FriedeleCrafts acylation,5 carbonation
of arylmetal species,6 and so on.7,8 Among these approaches, the
carbonation of arylmetal species is one of the most straightforward
methods. However, the deprotonative metalation of indoles with
strong bases generally proceeds at the most acidic 2-position, as
demonstrated in lithiation,6 magnesiation,9 zincation,9a,10 alumi-
nation,11 and cupration.12 In relation to this, Iwao and co-workers
reported that 1-(2,2-diethylbutanoyl)indole was lithiated at the 3-
with the aid of aluminum-based Lewis acids,14,15 we have recently
found that 1-methylindoles are carboxylated under CO2 pressure in
the presence of Me2AlCl.16 Herein, we wish to report in detail the
Me2AlCl-mediated carboxylation of indoles and the extension of
this methodology to alkoxycarbonylation and carbamoylation
reactions.
2. Results and discussion
2.1. Carboxylation of indoles with CO2
In our preliminary study,16 we reported that 1-methylindole-3-
carboxylic acid (2a) was obtained in 85% yield by treating 1-
methylindole (1a) with CO2 (3 MPa) in the presence of Me2AlCl
(1.0 molar equiv) in a tolueneehexane mixture at room tempera-
ture for 3 h; hexane was incidentally included in the solvent, as
a hexane solution of Me2AlCl was used. Further screening of the
reaction conditions revealed that the reaction proceeds even under
atmospheric pressure of CO2, although acid 2a was obtained in
a lower yield (36%). On the other hand, increasing the temperature
to 80 ꢀC improved the acid yield (96%) (Table 1, entry 1). Accord-
ingly, we adopted this temperature as standard and investigated
the applicability of the reaction to the preparation of 5-substituted
indole-3-carboxylic acids, which are versatile synthetic
position
with
bulky
sec-BuLieN,N,N0,N00,N00-pentam-
ethyldiethylenetriamide, whereas a sterically undemanding super
base, sec-BuLietert-BuOK, promoted lithiation at the 2-position.6
Electrophilic borylation with borenium ions also provides reliable
access to indol-3-ylmetal species, because the 3-position is most
susceptible to electrophilic substitution.13 However, these methods
* Corresponding authors. Tel.: þ81 22 795 7262; fax: þ81 22 795 7293; e-mail
addresses: tanaka@orgsynth.che.tohoku.ac.jp (S. Tanaka), hattori@orgsynth.che.
tohoku.ac.jp (T. Hattori).
http://dx.doi.org/10.1016/j.tet.2015.12.028
0040-4020/Ó 2015 Published by Elsevier Ltd.
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2
K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
Table 1
Table 2
a
a
Carboxylation of 1-methylindols with CO2
Carboxylation of 1-substituted and unsubstituted indoles with CO2
Entry
Substrate
R
Product
Yield (%)b
Entry
Substrate
X
R
T (ꢀC)
Product
Yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
d
2a
2b
2c
2d
2e
2f
96
63
64
79
81
94
95
98
1
3a
3a
3a
4a
4b
4b
4c
4d
4e
4f
H
H
H
d
rt
rt
80
rt
6a
6a
6a
7a
7b
7b
7c
7d
7e
7f
28
21
37
98
74
95
81
98
95
72
98
66
92
95
5-F
2c
3
d
5-Br
5-Me
5-Ph
5-MeO
2-Me
2-Ph
d
4
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
Bn
d
5
5-F
5-F
5-Br
5-Me
5-Ph
5-MeO
d
80
80
80
80
80
80
rt
80
80
80
6d
7
1g
1h
2g
2h
8
9
a
Reaction conditions: substrate (1.00 mmol), Lewis acid (1.0 molar equiv), tolu-
10e
11
12
13
14
ene (1.0e3.0 mL)ehexane (1 mL), CO2 (3.0 MPa), 80 ꢀC, 3 h.
b
Isolated yield.
5a
5b
5g
5h
8a
8b
8g
8h
Bn
Bn
Bn
5-F
2-Me
2-Ph
intermediates for pharmaceuticals.17 Compound 1b, bearing
a pharmacologically interesting fluorine atom,18 and compound 1c,
bearing a bromine atom useful for further functionalization by
transition metal-catalyzed coupling reactions,17a,19 gave the corre-
sponding acids in moderate yields (entries 2 and 3). Presumably,
the electron-withdrawing nature of these substituents reduced the
reactivity of the indole ring. Electron-rich indoles 1d and 1e,
bearing methyl and phenyl groups, respectively, afforded higher
yields than halogenated 1b and 1c; however, these yields are lower
than the yield of acid 2a with no substituent at the 5-position
(entries 4 and 5 compared with entries 1e3). This was attributed
to acid-mediated decomposition and oligomerization of the sub-
strates,20 which is facilitated by the electron-donating groups. In
the case of 5-phenylindole 1e, dephenylation contributes to the
reduced yield, as evidenced by the formation of indole 1a (4%) and
its carboxylation product 2a (6%), along with the desired product 2e
(12%) when the reaction was performed at room temperature. It is
noteworthy that the methoxy group (1f), having strong co-
ordination ability to aluminum-based Lewis acids, was well toler-
ated by this reaction (entry 6). The carboxylation of 2-methyl- and
2-phenylindoles (1g and 1h, respectively) proceeded almost
quantitatively (entries 7 and 8), suggesting that the steric bulk of
the substituents at the 2-position prevented the decomposition and
oligomerization expected in the reaction of 5-substituted indoles.
We next investigated the carboxylation of 1-silyl- and 1-
benzylindoles (4 and 5, respectively) as well as that of unsub-
stituted indole 3a, which provides an easy access to N-unsub-
stituted indole-3-carboxylic acids (Table 2). Okauchi et al. reported
that N-unsubstituted indoles were efficiently acylated at the 3-
position with various acyl chlorides at 0 ꢀC in the presence of
Me2AlCl or Et2AlCl.20 Kobayashi and co-workers demonstrated that
tert-BuOLi mediated the carboxylation of N-unsubstituted indoles
in DMF at 100 ꢀC under atmospheric pressure of CO2 to afford the
corresponding indole-3-carboxylic acids in good to excellent
yields.8 This transformation was presumably mediated by a 3-H-
indolyl anion formed by deprotonation of the NeH group in the
presence of the strong base. However, the carboxylation of N-
unsubstituted indole 3a was sluggish at room temperature,
affording acid 6a in 28% yield (entry 1). Under the reaction condi-
tions, compound 3a was completely metalated at the 1-position, as
evidenced by the fact that treatment of 3a with 1.0 molar equiv of
Me2AlCl in tolueneehexane at room temperature for 3 h gave 1-
deuterated indole 3a after quenching with D2O. Increasing the
amount of Me2AlCl to 2.0 molar equiv (entry 2) or increasing the
temperature to 80 ꢀC (entry 3) had little effect on the yield. On the
other hand, the reaction of 1-triisopropylsilyl (TIPS)-substituted
indole 4a proceeded smoothly at room temperature to give the
a
Reaction conditions: substrate (1.00 mmol), Me2AlCl (1.0 molar equiv), toluene
(1.0e3.0 mL)ehexane (1.0 mL), CO2 (3.0 MPa), rt or 80 ꢀC, 3 h.
b
Isolated yield.
Me2AlCl (2.0 molar equiv) was employed.
Reaction time was prolonged to 24 h.
Reaction time was prolonged to 8 h.
c
d
e
corresponding acid 7a in 98% yield (entry 4), which was higher than
the yield obtained from the carboxylation of 1-methylindole (1a)
under the same conditions (85%). This can be attributed to the
electron-donating nature of the TIPS moiety, which increased the
reactivity of the indole ring toward this electrophilic reaction, or to
the steric bulk of the TIPS moiety, which prevented the de-
composition and oligomerization of the substrate. The reaction of
1-TIPS-5-substituted indoles 4be4f also proceeded smoothly at
80 ꢀC to afford the corresponding acids in good to excellent yields
(entries 5e10). On the other hand, the use of the TIPS group for the
protection of 2-substituted indoles proved to be troublesome,
presumably because of the steric hindrance between the TIPS
moiety and the substituent at the 2-position. For example, the
carboxylation of 1-TIPS-2-methylindole resulted in deprotection of
the TIPS group to yield indole-3-carboxylic acid (6a) in 95%.
Moreover, the TIPS derivative of 2-phenylindole could not be pre-
pared by deprotonation of 2-phenylindole with butyllithium and
subsequent silylation of the resulting indol-1-yllithium with TIPSCl.
These problems could be overcome by using 1-benzyl derivatives.
The carboxylation of 1-benzyl-2-substituted indoles 5g and 5h gave
acids 8g and 8h, respectively, in excellent yields (entries 13 and 14).
On the other hand, 1-benzyl-substituted indole 5a and 5-
fluoroindole 5b gave the corresponding acids in yields equal to or
lower than those obtained from the reaction of 1-TIPS-substituted
indoles 4a and 4b (entries 11 and 12 compared with entries 4 and
5). The TIPS and benzyl moieties could be readily removed from
acids 7a and 8a by treatment with TBAF21 and AlCl3,22 respectively
(Scheme 1).
In our preliminary report,16,23 we suggested that the carboxyl-
ation reaction proceeds via metalation of the indole ring by
Me2AlCl, followed by carbonation of the resulting indol-3-
ylaluminum species. This assumption was based on the observa-
tion that treatment of 1-methylindole with Me2AlCl gave 3-
deuterio-1-methylindole after quenching with D2O. However,
some 2-substituted 1-methylindoles were not deuterated under
the same conditions. We then reinvestigated the quenching re-
action and found that 1-methylindole was not deuterated when the
metalated indole was quenched with D2O containing
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K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
3
Scheme 1. Deprotection of 1-substituted indoles. Reagents and conditions: (a) TBAF
(10 molar equiv), THF, rt; (b) AlCl3 (5.0 molar equiv), benzene, ꢁ10 ꢀC to rt.
5.0 molar equiv of triethylamine. On the other hand, deuteration
occurred when D2O and 1-methylindole were successively added to
a solution of Me2AlCl in tolueneehexane. These observations in-
dicate that the deuteration does not result from the trapping of an
indol-3-ylaluminum species by D2O but from the HeD exchange of
1-methylindole under acidic conditions via an electrophilic aro-
matic substitution (SEAr) mechanism. Thus, we propose a revised
reaction mechanism, illustrated in Scheme 2. First, electrophilic
addition of Me2AlCl to indole 1a affords zwitterionic species A.
Subsequent deprotonation of adduct A affords ate complex B. Al-
ternatively, HCl may be eliminated from adduct A to form indoly-
laluminum species C; hereafter, we assume the formation of
complex B in order to simplify the explanation. The ate complex is
in equilibrium with substrate 1a through adduct A. The position of
the equilibrium lies significantly to the left, as suggested by the fact
that quenching the reaction between 1a and Me2AlCl with alkaline
D2O did not afford 1-deuterioindole. The protonolysis of complex B
may be an alternative and direct pathway to substrate 1a. Under
CO2 pressure, the carbonation of complex B shifts the equilibrium
to the right to form aluminum carboxylate D. Ingleson and co-
workers reported that upon treatment with 1-methylindole in
toluene at 80 ꢀC, AlCl3 added to the aromatic ring to give a zwit-
terionic species similar to adduct A, as evidenced by X-ray ana-
lysis.13a We tried to detect adduct A by 1H NMR spectroscopy
(Fig. 1). However, the spectrum of 1-methylindole (Fig. 1a) was not
affected by the addition of 1.0 molar equiv of Me2AlCl, except that
the doublet signal at 6.51 ppm, which was assigned to the aromatic
proton at the 2-position, slightly shifted to lower field (6.53 ppm)
(Fig. 1b). Moreover, heating the mixture at 80 ꢀC for 3 h did not
change the spectrum (Fig. 1c). These observations indicate that the
reaction of 1-methylindole with Me2AlCl does not afford adduct A
(and therefore complex B) in an amount detectable by 1H NMR
analysis. Nevertheless, the presence of these species was strongly
suggested by the following experiments. The treatment of 1-
Fig. 1. 1H NMR spectra of 1-methylindole (1a) (a), after adding 1.0 molar equiv of
Me2AlCl (b), and after heating the mixture at 80 ꢀC for 3 h (c). Measurement condi-
tions: toluene-d8ehexane (3:2), 293 K.
methylindole with 1.0 molar equiv of Me2AlCl in tolueneehexane
at ꢁ30 ꢀC for 18 h gave indole dimer 9 in quantitative yield (Scheme
2). The formation of dimer 9 can be rationalized by the SEAr re-
action of adduct A with indole 1a, followed by protodemetalation.
The yield of dimer 9 decreased with increasing temperature; the
reaction carried out at ꢁ30 ꢀC, room temperature, and 80 ꢀC for 3 h
gave dimer 9 in 28%, 7%, and 2% yield with recovery of indole 1a in
37%, 82%, and 85% yield, respectively. Presumably, higher temper-
atures facilitate the deprotonation of adduct A to form complex B
(Scheme 2), thus decreasing the concentration of A, species re-
quired for dimer formation. On the other hand, intermolecular HeD
exchange was observed when an equimolar mixture of 3-deuterio-
1-methylindole and 1-benzylindole was treated with Me2AlCl at
room temperature (Scheme 3); after alkaline workup, 1-
methylindole and 1-benzylindole with deuteration levels of 49%
and 52%, respectively, were recovered. This finding indicates that
adduct A loses a proton to afford complex B. Therefore, it may be
concluded that the carboxylation proceeds via adduct A and ate
complex B, as shown in Scheme 2.
Scheme 2. Feasible mechanism for the carboxylation of indoles.
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4
K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
bearing substituents at the 5- or 2-position gave the correspond-
ing esters in good to excellent yields (entries 2e8). Replacement of
the 1-methyl moiety by a TIPS group did not improve the yield,
except for the case of 5-phenyl derivative 4e (entries 9e14 com-
pared with entries 1e6). Similar to the carboxylation, 1-benzyl
derivatives were found to be useful for the reaction of 2-
substituted indoles (entries 15 and 16).
Scheme 3. HeD exchange between 1-substituted indoles. Reagents and conditions:
Me2AlCl (1.0 molar equiv), hexane, rt, 3 h then Et3N (5.0 molar equiv) in H2O.
2.3. Carbamoylation of indoles with isocyanates
2.2. Ethoxycarbonylation of indoles with ethyl chloroformate
Finally, the carbamoylation of indoles was investigated (Table 4).
The treatment of 1-methylindole (1a) with isopropyl cyanate in the
presence of Me2AlCl under the conditions optimized for the
ethoxycarbonylation gave acetamide 14a in 68% yield, accompa-
nied by a trace amount of indole-3-carboxamide 13a (entry 1).
Interestingly, the ratio of indole-3-carboxamide 13 to acetamide 14
increased when aryl isocyanates were employed, and nearly com-
plete selectivity for compound 13 was achieved with naphthalen-1-
yl isocyanate (entries 2e4). Among solvents tested, dichloro-
methane and 1,2-dichloroethane were more effective than toluene
(entries 5e8). Next, we examined the carbamoylation of various
indoles with naphthalen-1-yl isocyanate in dichloromethane (Table
5). The reaction of 1-methylindoles bearing substituents at the 5- or
2-position gave the corresponding indole-3-carboxamides in good
yields, regardless of the electronic properties of the substituents
(entries 1e7). The reaction of 1-TIPS derivatives of 5-substituted
and unsubstituted indoles and of 1-benzyl derivatives of 2-
substituted indoles also proceeded in good yields, except for 5-
methoxyindole 4f (entries 8e15). The carbamoylation probably
proceeds through the formation of ate complex B (Scheme 2), fol-
lowed by nucleophilic addition of the complex to the isocyanate.
However, we cannot rule out the possibility of an SEAr reaction of 1-
methylindole with phenyl isocyanate activated by Me2AlCl, mech-
anism that has been proposed for the carbamoylation of benzene
derivatives.25 On the other hand, the formation of N-phenyl-
acetamide is explained by the direct methylation of phenyl iso-
cyanate with Me2AlCl. Indeed, using 1.0 molar equiv of Me2AlCl in
tolueneehexane, even at ꢁ30 ꢀC, phenyl isocyanate was methyl-
ated to give N-phenylacetamine in 90% yield.
Next, we investigated the ethoxycarbonylation of indoles with
ethyl chloroformate in the presence of Me2AlCl. As mentioned
earlier, indoles are acylated with acyl chlorides in the presence of
Me2AlCl,20 indicating that Me2AlCl metalates indoles more easily
than it alkylates acyl chlorides. This relative reactivity between
indoles and acyl chlorides toward Me2AlCl should apply to that
between indoles and ethyl chloroformate, because of the lower
reactivity of ethyl chloroformate toward nucleophiles as compared
with that of acyl chlorides. On the other hand, alkoxycarbonylium
species ROeC^Oþ, generated from alkyl chloroformates with the
aid of a Lewis acid, are known to be easily decarbonated to form
alkyl cations.24 Therefore, in order to achieve the ethox-
ycarbonylation of indoles, Me2AlCl has to metalate indoles more
rapidly than it cleaves the CeCl bond of ethyl chloroformate.
Pleasingly, when 1-methylindole (1a) was treated with a slight
excess of ethyl chloroformate in the presence of Me2AlCl in tolue-
neehexane at room temperature, the corresponding methyl ester
10a was obtained in a good yield (Table 3, entry 1). The reaction
gave no ethylated product, which was expected to be formed by
FriedeleCrafts alkylation of the substrate with the ethyl cation
generated from ethyl chloroformate.24 Instead, when the reaction
temperature was increased to 80 ꢀC, a small amount (9%) of acid 2a
was obtained along with ester 10a (76%), This indicates that, at this
temperature, Me2AlCl cleaved the CeCl bond of ethyl chlor-
oformate, releasing CO2, which carbonated ate complex B (Scheme
2). The substrate scope of the ethoxycarbonylation was investigated
at room temperature (Table 3). The reaction of 1-methylindoles
In conclusion, we have described the substitution reactions of 1-
substituted indoles at the 3-position, using CO2, ethyl chlor-
oformate, and naphthalen-1-yl isocyanate, with the aid of Me2AlCl.
Mechanistic studies suggested the intermediacy of an indol-3-
Table 3
Ethoxycarbonylation of indols with ethyl chloroformatea
Table 4
Carbamoylation of 1-methylindole (1a) with various isocyanatesa
Entry
Substrate
X
R
Product
Yield (%)b
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Me
Me
Me
Me
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
Bn
d
10a
10b
10c
10d
10e
10f
10g
10h
11a
11b
11c
11d
11e
11f
86
73
72
100
75
81
78
88
82
74
51
82
85
52
55
64
5-F
5-Br
5-Me
5-Ph
5-MeO
2-Me
2-Ph
d
Entry
R
Solvent
13
Yield (%)b 14
Yield (%)b
1
2
3
4
5
6
7
8
i-Pr
Ph
PhMeehexane
PhMeehexane
13a Trace
13b 30
13c 29
13d 62
13d 62
13d 81
14a 68d
14b 79
14c 57
14d Trace
14d de
14d de
14d ee
14d de
9
4-ClC6H4 PhMeehexane
10
11
12
13
14c
15
16
5-F
Npc
Npc
Npc
Npc
Npc
PhMeehexane
PhClehexane
CH2Cl2ehexane
CH2ClCH2Clehexane 13d 84
Et2Oehexane 13d Trace
5-Br
5-Me
5-Ph
5-MeO
2-Me
2-Ph
5g
5h
12g
12h
a
Reaction conditions: 1a (1.00 mmol), RNCO (1.2 molar equiv), Me2AlCl
Bn
(1.0 molar equiv), solvent (4.0 mL) including hexane (1.0 mL), rt, 3 h.
a
b
Reaction conditions: substrate (1.00 mmol), ClCO2Et (1.2 molar equiv), Me2AlCl
Isolated yield unless otherwise noted.
c
(1.0 molar equiv), toluene (1.0e3.0 mL)ehexane (1.0 mL), rt, 3 h.
Np¼naphthalen-1-yl.
b
d
Isolated yield.
Reaction time was prolonged to 8 h.
Determined by 1H NMR analysis.
c
e
Not determined.
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K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
5
Table 5
J¼1.3, 7.4 Hz), 7.41e7.47 (4H, m), 7.62e7.66 (2H, m), 7.93 (1H, s), 8.10
(1H, br); 13C NMR (100 MHz, CDCl3)
103.0,111.2,119.2,121.9,124.8,
Carbamoylation of indoles with naphthalen-1-yl isocyanatea
d
126.3, 127.4, 128.4, 128.6, 133.4, 135.3, 142.5.
3.3. General procedure for the preparation of 1-
methylindoles
Indoles were methylated by a similar procedure to that reported
in the literature.26 To a stirred suspension of NaH (60% dispersion in
mineral oil; 480 mg, 12.0 mmol) in DMF (10 mL) was added drop-
wise a solution of an indole (10.0 mmol) in DMF (10 mL) at 0 ꢀC, and
the mixture was stirred at room temperature for 30 min. To the
Entry
Substrate
X
R
Product
Yield (%)b
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
4a
4b
4c
4d
4e
4f
Me
Me
Me
Me
Me
Me
Me
TIPS
TIPS
TIPS
TIPS
TIPS
TIPS
Bn
5-F
15b
15c
15d
15e
15f
15g
15h
16a
16b
16c
16d
16e
16f
73
67
70
72
66
78
86
84
72
52
76
70
32
77
70
5-Br
5-Me
5-Ph
5-MeO
2-Me
2-Ph
d
mixture was added dropwise iodomethane (d 2.28; 934
mL,
15.0 mmol) at 0 ꢀC, and the resulting mixture was stirred at room
temperature overnight. The reaction was quenched with water and
the aqueous layer was extracted with ethyl acetate. The combined
organic layer was dried over MgSO4 and evaporated to leave a res-
idue, which was purified by column chromatography using the
indicated eluent.
9
5-F
10
11
12
13
14
15
5-Br
5-Me
5-Ph
5-MeO
2-Me
2-Ph
5g
5h
17g
17h
3.3.1. 5-Fuluoro-1-methyl-1H-indole (1b).26 Hexaneeethyl acetate
Bn
(2:1) as the eluent; crystals (91%); 1H NMR (400 MHz, CDCl3)
d 3.74
a
Reaction conditions: substrate (1.00 mmol), Np-NCO (1.2 molar equiv), Me2AlCl
(3H, s), 6.42 (1H, d, J¼2.8 Hz), 6.96 (1H, td, J¼2.8, 9.1), 7.06 (1H, d,
(1.0 molar equiv), CH2Cl2 (2.0e3.0 mL)ehexane (1.0 mL), rt, 3 h.
J¼2.8 Hz), 7.18e7.27 (2H, m); 13C NMR (100 MHz, CDCl3)
d 33.1,
b
Isolated yield.
100.8 (d, J¼4.8 Hz), 105.5 (d, J¼23.3 Hz), 109.7 (d, J¼9.8 Hz), 109.8
(d, J¼26.4 Hz), 128.6 (d, J¼10.2 Hz), 130.3, 133.4, 157.8 (d, J¼233 Hz).
ylaluminum ate complex. Further investigations are underway to
extend the substrate scope of these reactions to alkenes.
3.3.2. 5-Bromo-1-methyl-1H-indole (1c).27e29 Hexaneeethyl ace-
tate (4:1) as the eluent; crystals (96%); 1H NMR (400 MHz, CDCl3)
d
3.75 (3H, s), 6.42 (1H, d, J¼2.8 Hz), 7.04 (1H, d, J¼2.8 Hz), 7.18 (1H,
3. Experimental
3.1. General
d, J¼8.7 Hz), 7.29 (1H, td, J¼2.1, 8.7 Hz), 7.74 (1H, t, J¼2.1 Hz); 13C
NMR (100 MHz, CDCl3)
130.1, 135.3.
d 33.0, 100.5, 110.6, 112.6, 123.3, 124.3, 129.9,
Melting points were taken with a Stuart SMP3 micro melting
point apparatus and are uncorrected. IR spectra were recorded on
a Shimadzu FT-IR-8300 or Thermo Fisher Scientific Nicolet 6700 FT-
IR spectrometer. 1H and 13C NMR spectra were recorded on a Bruker
AVANCE III 400 or DPX-400 spectrometer, using tetramethylsilane
as an internal standard. HRMS spectra were measured using a JEOL
JMS-700 at the Technical Division, School of Engineering, Tohoku
3.3.3. 1,5-Dimethyl-1H-indole (1d).29 Hexaneechloroform (1:1) as
the eluent; an oil (91%); 1H NMR (400 MHz, CDCl3)
2.44 (3H, s),
d
3.70 (3H, s), 6.37 (1H, dd, J¼1.0, 3.0 Hz), 6.96 (1H, d, J¼3.0 Hz), 7.03
(1H, dd, J¼1.0, 8.4 Hz), 7.18 (1H, d, J¼8.4 Hz), 7.40 (1H, t, J¼1.0 Hz);
13C NMR (100 MHz, CDCl3)
128.3, 128.7, 128.8, 135.1.
d 21.4, 32.7, 100.2, 108.8, 120.4, 123.1,
University. Kanto Chemical silica gel 60N (63e210
mm) and
3.3.4. 1-Methyl-5-phenyl-1H-indole
(1:1) as the eluent; crystals (44%); 1H NMR (400 MHz, CDCl3)
(1e).30 Hexaneechloroform
3.82
(40e50 m) were used for column chromatography and flash
m
d
chromatography, respectively. Merck silica gel 60GF254 was used for
analytical and preparative TLC. Water- and air-sensitive reactions
were routinely carried out under nitrogen. Toluene and ethanol
were distilled from sodium diphenyl ketyl and Mg turnings, re-
spectively. DMF, dichloromethane, and 1,2-dichloroethane were
distilled from CaH2. Dry THF and diethyl ether were of commercial
grade. Indoles 1a, 1g, 1h, and 3a were purchased from commercial
suppliers.
(3H, s), 6.55 (1H, t, J¼3.2 Hz), 7.09 (1H, t, J¼3.2 Hz), 7.33 (1H, td,
J¼1.0, 7.3 Hz), 7.38e7.52 (3H, m), 7.67 (2H, m), 7.86 (1H, d,
J¼8.6 Hz); 13C NMR (100 MHz, CDCl3)
d 32.9, 101.3, 109.4, 119.4,
121.4, 126.2, 127.4, 128.6, 128.9, 129.5, 132.8, 136.2, 142.6.
3.3.5. 5-Methoxy-1-methyl-1H-indole (1f).29 Hexaneechloroform
(1:1) as the eluent; crystals (88%); 1H NMR (400 MHz, CDCl3)
d 3.75
(3H, s), 3.86 (3H, s), 6.39e6.42 (1H, m), 6.87e6.92 (1H, m),
7.00e7.03 (1H, m), 7.09e7.12 (1H, m), 7.19e7.24 (1H, m); 13C NMR
3.2. 5-Phenyl-1H-indole26
(100 MHz, CDCl3)
132.1, 154.0.
d 33.0, 55.9, 100.4, 102.5, 110.0, 111.9, 128.8, 129.3,
A mixture of 5-bromoindole (1.96 g, 10.0 mmol), and tetrakis(-
triphenylphosphine)palladium(0) (578 mg, 0.500 mmol), and tol-
uene (15 mL) was stirred at room temperature for 30 min. To the
mixture were added phenylboronic acid (1.83 g, 15.0 mmol), 2 M
NaHCO3 (15 mL), and ethanol (10 mL), and the resulting mixture
was refluxed for 4 h. After cooling to room temperature, the re-
action was quenched with water and the aqueous layer was
extracted with chloroform. The combined organic layer was dried
over MgSO4, and evaporated. The residue was purified by column
chromatography with hexaneechloroform (1:1) as an eluent to
give the title compound as crystals (1.05 g, 54%), 1H NMR (400 MHz,
3.4. General procedure for the preparation of 1-(triisopro-
pylsilyl)indoles
Indoles were silylated by a similar procedure to that reported in
the literature.21a To a stirred solution of an indole (5.00 mmol) in
THF (18 mL) was added dropwise butyllithium (2.6 M in hexane;
2.3 mL, 6.0 mmol) at ꢁ20 ꢀC, and the mixture was stirred at this
temperature for 1 h. To the mixture was added dropwise a solution
of TIPSCl (d 0.91; 1.27 mL, 6.0 mmol) in THF (4 mL), and the
resulting mixture was stirred for a further 2 h. The reaction was
quenched with water and the aqueous layer was extracted with
CDCl3)
d
6.60 (1H, t, J¼2.5 Hz), 7.20 (1H, t, J¼2.5 Hz), 7.31 (1H, tt,
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6
K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
ethyl acetate. The combined organic layer was dried over MgSO4
and evaporated to leave a residue, which was purified by flash
chromatography using the indicated eluent.
3.5.1. 1-Benzyl-1H-indole (5a).28,31 Hexaneeethyl acetate (30:1) as
the eluent; an oil (quantitative yield); 1H NMR (400 MHz, CDCl3)
d
5.27 (2H, s), 6.54(1H, dd, J¼0.6, 3.2 Hz), 7.07e7.17 (5H, m), 7.22e7.28
(4H, m), 7.64(1H, d, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 50.2,101.8,
3.4.1. 1-Triisopropylsilyl-1H-indole (4a).28,21b Hexane as the eluent;
109.8, 119.6, 121.1, 121.8, 126.9, 127.7, 128.4, 128.8, 128.9, 136.4, 137.7.
an oil (91%); 1H NMR (400 MHz, CDCl3)
d
1.14 (18H, d, J¼7.5 Hz), 1.71
(3H, sept, J¼7.5 Hz), 6.62 (1H, dd, J¼0.8, 3.2 Hz), 7.08e7.16 (2H, m),
7.25e7.26 (1H, m), 7.51 (1H, dd, J¼1.1, 7.9 Hz), 7.63 (1H, dd, J¼1.1,
3.5.2. 1-Benzyl-5-fluoro-1H-indole (5b).32 Hexaneeethyl acetate
(10:1) as the eluent; crystals (quantitative yield); 1H NMR
7.9 Hz); 13C NMR (100 MHz, CDCl3)
120.5, 121.3, 131.1, 131.4, 140.8.
d
12.8, 18.1, 104.7, 113.9, 119.7,
(400 MHz, CDCl3)
J¼2.4, 9.1 Hz), 7.09 (2H, d, J¼6.6 Hz), 7.14e7.17 (2H, m), 7.25e7.32
(4H, m); 13C NMR (100 MHz, CDCl3)
d
5.30 (2H, s), 6.50 (1H, d, J¼3.1 Hz), 6.90 (1H, td,
d
50.4, 101.6 (d, J¼4.6 Hz), 105.6
3.4.2. 5-Fluoro-1-triisopropylsilyl-1H-indole (4b).21c Hexane as the
eluent; an oil (85%); 1H NMR (400 MHz, CDCl3)
1.13 (18H, d,
(d, J¼23.1 Hz), 110.0 (d, J¼26.2 Hz), 110.3 (d, J¼9.8 Hz), 126.7, 127.7,
d
128.8, 128.9 (d, J¼10.1 Hz), 129.9, 132.9, 137.2, 157.9 (d, J¼233 Hz).
J¼7.6 Hz), 1.67 (3H, sept, J¼7.6 Hz), 6.57 (1H, d, J¼3.3 Hz), 6.88 (1H,
td, J¼3.3, 9.0 Hz), 7.24e7.28 (2H, m), 7.40 (1H, dd, J¼3.3, 9.0 Hz); 13
C
3.5.3. 1-Benzyl-2-methyl-1H-indole (5g).32 Hexaneeethyl acetate
NMR (100 MHz, CDCl3)
d
12.9, 18.2, 104.8 (d, J¼4.4 Hz), 105.2 (d,
(10:1) as the eluent; an oil (quantitative yield); 1H NMR (400 MHz,
J¼26.7 Hz), 109.5 (d, J¼26.7 Hz), 114.3 (d, J¼9.9 Hz), 131.9 (d,
J¼9.8 Hz), 132.9, 137.2, 157.9 (d, J¼233 Hz).
CDCl3)
(2H, m), 7.05e7.10 (2H, m), 7.18e7.26 (4H, m), 7.54e7.56 (1H, m);
13C NMR (100 MHz, CDCl3)
12.7, 46.4, 100.4, 109.2, 119.5, 119.7,
d
2.35 (3H, s), 5.28 (2H, s), 6.32 (1H, t, J¼0.8 Hz), 6.94e6.96
d
3.4.3. 5-Bromo-1-triisopropylsilyl-1H-indole (4c).21d Hexane as the
120.7, 125.9, 127.2, 128.1, 128.7, 136.7, 137.1, 137.9.
eluent; an oil (74%); 1H NMR (400 MHz, CDCl3)
d 1.14 (18H, d,
J¼7.5 Hz), 1.67 (3H, sept, J¼7.5 Hz), 6.56 (1H, t, J¼3.4 Hz), 7.20e7.26
3.5.4. 1-Benzyl-2-phenyl-1H-indole (5h).33 Hexaneeethyl acetate
(2H, m), 7.37 (1H, dd, J¼5.8, 8.7 Hz), 7.74 (1H, dd, J¼1.8, 5.8 Hz); 13
C
(10:1) as the eluent; crystals (34%); 1H NMR (400 MHz, CDCl3)
NMR (100 MHz, CDCl3)
132.4, 133.3, 139.5.
d
12.8, 18.1, 104.3, 113.1, 115.2, 123.0, 124.1,
d
5.37 (2H, s), 6.65 (1H, d, J¼4.5 Hz), 7.03e7.05 (2H, m), 7.13e7.19
(3H, m), 7.23e7.29 (3H, m), 7.36e7.40 (3H, m), 7.42e7.46 (2H, m),
7.66e7.69 (1H, m); 13C NMR (100 MHz, CDCl3)
47.7, 102.3, 110.5,
d
3.4.4. 5-Methyl-1-triisopropylsilyl-1H-indole (4d).21a Hexane as the
eluent; an oil (98%); 1H NMR (400 MHz, CDCl3)
1.13 (18H, d,
120.1, 120.5, 121.9, 125.9, 127.1, 128.0, 128.3, 128.5, 128.7, 129.2,
132.7, 138.0, 138.2, 141.8.
d
J¼7.6 Hz), 1.68 (3H, sept, J¼7.6 Hz), 2.43 (3H, s), 6.53 (1H, dd, J¼1.1,
3.2 Hz), 6.96 (1H, dd, J¼1.1, 8.5 Hz), 7.20 (1H, d, J¼3.2 Hz), 7.39 (1H,
3.6. Typical procedure for the carboxylation of indoles (entry
1 in Table 1)
d, J¼8.5 Hz), 7.41 (1H, t, J¼1.1 Hz); 13C NMR (100 MHz, CDCl3)
d 12.9,
18.3, 21.4, 104.4, 113.6, 120.5, 123.0, 129.0, 131.3, 131.9, 139.2.
In a 50 mL autoclave equipped with a glass inner tube and
3.4.5. 5-Phenyl-1-triisopropylsilyl-1H-indole (4e). Hexaneechloroform
a magnetic stirring bar were charged indole 1a (d 1.05; 125 mL,
(10:1) as the eluent; an oil (94%); IR (KBr) 3059, 3023, 2947, 2868, 1462,
1.00 mmol), Me2AlCl (1.0 M solution in hexane; 1.0 mL, 1.0 mmol),
toluene (1.0 mL) under nitrogen atmosphere, and the apparatus
was purged with CO2 by repeated pressurization and subsequent
expansion, the final pressure being adjusted to 3.0 MPa. After the
mixture was stirred at 80 ꢀC for 3 h, the reactor was allowed to cool
to room temperature and depressurized. The reaction mixture was
quenched with 2 M HCl and the aqueous layer was extracted with
ethyl acetate. The combined organic layer was extracted with 0.5 M
Na2CO3 and the extract was acidified by the addition of concen-
trated HCl to liberate the free carboxylic acid, which was extracted
with ethyl acetate. The extract was dried over MgSO4 and evapo-
rated to leave a residue, which was purified by column chroma-
tography with chloroformeethyl acetate (1:1) as an eluent to give
acid 2a as crystals (168 mg, 96%).
1296, 1138, 1017, 883, 754, 691, 656, 579 cmꢁ1 1H NMR (400 MHz,
;
CDCl3)
d
1.14 (18H, d, J¼7.6 Hz), 1.69 (3H, sept, J¼7.6 Hz), 6.66 (1H, d,
J¼2.9 Hz), 7.25e7.28 (2H, m), 7.38e7.42 (3H, m), 7.55 (1H, d, J¼8.6 Hz),
7.65 (2H, d, J¼8.3 Hz), 7.85 (1H, d, J¼1.6 Hz); 13C NMR (100 MHz, CDCl3)
d
12.9, 18.2, 105.3, 114.1, 119.1, 121.3, 126.3, 127.4, 128.7, 131.9, 132.1, 133.3,
140.5, 142.5; HRMS (EI) calcd for C23H31NSi Mþ 349.2226, found
349.2224.
3.4.6. 5-Methoxy-1-triisopropylsilyl-1H-indole
chloroform (10:1) as the eluent; an oil (60%), 1H NMR (400 MHz,
CDCl3)
(4f).21a Hexanee
d
1.13 (18H, d, J¼7.6 Hz),1.67 (3H, sept, J¼7.6 Hz), 3.83 (3H, s),
6.55 (1H, dd, J¼0.6, 3.1 Hz), 6.80 (1H, dd, J¼2.6, 9.0 Hz), 7.09 (1H, d,
J¼2.6 Hz), 7.22 (1H, d, J¼3.1 Hz), 7.39 (1H, dd, J¼9.0 Hz); 13C NMR
(100 MHz, CDCl3)
132.0, 135.8, 154.1.
d
12.9, 18.2, 55.7, 102.2, 104.6, 111.4, 114.6, 132.0,
The carboxylation of other indoles was conducted by a similar
procedure. The crude product was routinely purified by column
chromatography using chloroformeethyl acetate (1:1) or chlor-
oformeethyl acetate (1:1) containing 1% (v/v) of acetic acid as an el-
uent. SeeTables 1 and 2 forthereactionconditionsandproductyields.
3.5. General procedure for the preparation of 1-benzylindoles
Indoles were benzylated by a similar procedure to that reported
in the literature.26 To a stirred suspension of NaH (60% dispersion in
mineral oil; 480 mg, 12.0 mmol) in DMF (10 mL) was added drop-
wise a solution of an indole (10.0 mmol) in DMF (10 mL) at 0 ꢀC, and
the mixture was stirred at room temperature for 30 min. To the
mixture was added dropwise (bromomethyl)benzene (d 1.43;
1.79 mL,15.0 mmol) at 0 ꢀC, and the resulting mixture was stirred at
room temperature overnight. The reaction was quenched with
water and the aqueous layer was extracted with ethyl acetate. The
combined organic layer was dried over MgSO4 and evaporated to
leave a residue, which was purified by column chromatography
using the indicated eluent.
3.6.1. 1-Methyl-1H-indole-3-carboxylic acid (2a).34 Crystals; 1H
NMR (400 MHz, DMSO-d6)
d
3.85 (3H, s), 7.20 (1H, td, J¼1.0, 7.9 Hz),
7.25 (1H, td, J¼1.0, 7.9 Hz), 7.52 (1H, dt, J¼1.0, 7.9 Hz), 8.00 (1H, dt,
J¼0.99, 7.9 Hz), 8.03 (1H, s), 11.9 (1H, s); 13C NMR (100 MHz, DMSO-
d6)
d 33.0, 106.1, 110.6, 120.7, 121.3, 122.2, 126.4, 136.1, 137.0, 165.6.
3.6.2. 5-Fluoro-1-methyl-1H-indole-3-carboxylic acid (2b). Crystals;
mp 217.6e222.4 ꢀC; IR (KBr) 3044, 2932,1668,1539,1483,1271,1229,
1107, 898, 802 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
3.86 (3H, s), 7.11
(1H, td, J¼2.6, 9.4 Hz), 7.56 (1H, dd, J¼4.5, 9.4 Hz), 7.65 (1H, dd, J¼2.6,
9.4 Hz), 8.11 (1H, s),12.1 (1H, s); 13C NMR (100 MHz, DMSO-d6)
33.3,
105.4 (d, J¼25.6 Hz),106.2 (d, J¼4.6 Hz),110.4 (d, J¼26.0 Hz),112.2 (d,
d
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K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
7
J¼10.0Hz),127.0(d, J¼10.9 Hz),133.7,137.6,158.4(d, J¼233Hz),165.4;
1478, 1451, 1352, 1337, 1258, 1194, 118, 876 cmꢁ1
(400 MHz, DMSO-d6)
;
1H NMR
HRMS (EI) calcd for C10H8FNO2 Mþ 193.0539, found 193.0537.
d
1.09 (18H, d, J¼7.5 Hz), 1.79 (3H, sept,
J¼7.5 Hz), 7.08 (1H, td, J¼2.7, 9.3 Hz), 7.63 (1H, dd, J¼4.3, 9.3 Hz),
3.6.3. 5-Bromo-1-methyl-1H-indole-3-carboxylic acid (2c).35 Crys-
7.71 (1H, dd, J¼2.7, 9.3 Hz), 7.97 (1H, s), 12.3 (1H, s); 13C NMR
tals; 1H NMR (400 MHz, DMSO-d6)
d
3.85 (3H, s), 7.39 (1H, dd, J¼1.9,
(100 MHz, DMSO-d6)
d
11.6, 17.6, 105.6 (d, J¼24.0 Hz), 110.7 (d,
8.7 Hz), 7.53 (1H, d, J¼8.7 Hz), 8.09 (1H, s), 8.14 (1H, d, J¼1.9 Hz); 13
C
J¼25.3 Hz), 110.8 (d, J¼3.6 Hz), 115.6 (d, J¼9.8 Hz), 129.4 (d,
J¼10.9 Hz), 137.3, 139.7, 158.2 (d, J¼235 Hz), 165.2; HRMS (EI) calcd
for C18H26FNO2Si Mþ 335.1717, found 335.1713.
NMR (100 MHz, DMSO-d6)
d 33.2, 105.8, 112.9, 114.3, 122.8, 124.7,
128.1, 135.8, 137.3, 165.2.
3.6.4. 1,5-Dimethyl-1H-indole-3-carboxylic acid (2d). Crystals; mp
246.5e253.8 ꢀC; IR (KBr) 2916, 1651, 1531, 1483, 1464, 1283, 1236,
3.6.12. 5-Bromo-1-triisopropylsilyl-1H-indole-3-carboxylic
acid
(7c). Crystals; mp 208.1e210.8 ꢀC; IR (KBr) 2951, 2870, 1667, 1533,
1111, 777 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
2.41 (3H, s), 3.81
170, 1443, 1350,1321,100, 1163, 1069, 797 cmꢁ1; 1H NMR (400 MHz,
(3H, s), 7.07 (1H, dd, J¼1.2, 8.4 Hz), 7.40 (1H, d, J¼8.4 Hz), 7.81 (1H, t,
DMSO-d6)
d
1.12 (18H, d, J¼7.5 Hz), 1.37 (3H, sept, J¼7.5 Hz), 7.35
J¼1.2 Hz), 7.97 (1H, s), 11.9 (1H, s); 13C NMR (100 MHz, DMSO-d6)
(1H, dd, J¼1.9, 8.6 Hz), 7.48 (1H, d, J¼8.6 Hz), 8.10 (1H, s), 8.15 (1H, d,
d
20.9, 32.7,105.3,110.0,120.1,123.4,126.4,129.8,135.2,135.7,165.4;
J¼1.9 Hz), 12.1 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d 12.1, 18.2,
HRMS (EI) calcd for C11H11NO2 Mþ 189.0790, found 189.0787.
107.7, 114.6, 115.0, 123.0, 125.4, 128.2, 135.0, 135.8, 164.0; HRMS (EI)
calcd for C18H26BrNO2Si Mþ 395.0916, found 395.0918.
3.6.5. 1-Methyl-5-phenyl-1H-indole-3-carboxylic acid (2e). Crysta-
ls; mp 123.5e129.9 ꢀC; IR (KBr) 3046, 2916, 2641, 1659, 1533, 1474,
3.6.13. 5-Methyl-1-triisopropylsilyl-1H-indole-3-carboxylic
acid
1366, 1296, 1234, 1115, 762 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
(7d). Crystals; mp 208.6e209.9 ꢀC; IR (KBr) 3024, 2947, 2868, 2660,
d
3.88 (3H, s), 7.35 (1H, tt, J¼1.2, 7.4 Hz), 7.48 (2H, t, J¼7.4 Hz), 7.56
2573, 1660, 1533, 1454, 1265, 1206, 1177, 1055, 883, 862, 800, 697,
(1H, dd, J¼1.5, 8.5 Hz), 7.62 (1H, d, J¼8.5 Hz), 7.67 (2H, dd, J¼1.2,
660, 571, 525 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 1.09 (18H, d,
7.4 Hz), 8.00 (1H, s), 8.27 (1H, d, J¼1.5 Hz), 12.1 (1H, s); 13C NMR
J¼7.5 Hz), 1.76 (3H, q, J¼7.5 Hz), 2.40 (3H, s), 7.04 (1H, dd, J¼1.3,
(100 MHz, DMSO-d6)
d 33.6, 107.0, 111.6, 119.2, 122.1, 127.2, 127.4,
8.5 Hz), 7.48 (1H, d, J¼8.5 Hz), 7.86 (2H, s), 12.1 (1H, s); 13C NMR
127.5, 129.4, 134.4, 137.1, 137.3, 141.9, 166.1; HRMS (EI) calcd for
C
(100 MHz, DMSO-d6) d 11.7,17.7, 21.0,110.1,113.8,120.5,124.0,128.8,
16H13NO2 Mþ 251.0946, found 251.0940.
130.3, 138.0, 139.0, 165.4; HRMS (EI) calcd for C19H29NO2Si Mþ
331.1968, found 331.1960.
3.6.6. 5-Methoxy-1-methyl-1H-indole-3-carboxylic acid (2f). Crysta
ls; mp 217.5e222.7 ꢀC; IR (KBr) 2940, 2855, 1651, 1532, 1487, 1276,
3.6.14. 5-Phenyl-1-triisopropylsilyl-1H-indole-3-carboxylic
(7e). Crystals, mp 172.5e175.6 ꢀC; IR (KBr) 2949, 2870, 1664, 1530,
1189, 1168, 1052, 957, 883, 761, 699 cmꢁ1 1H NMR (400 MHz,
CDCl3)
acid
1221, 1111, 802 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 3.78 (3H, s),
3.81 (3H, s), 6.87 (1H, dd, J¼2.5, 8.9 Hz), 7.42 (1H, d, J¼8.9 Hz), 7.48
;
(1H, d, J¼2.5 Hz), 7.96 (1H, s), 11.9 (1H, s); 13C NMR (100 MHz,
d
1.09 (18H, d, J¼7.5 Hz), 1.77 (3H, q, J¼7.5 Hz), 7.34 (1H, tt,
DMSO-d6)
d
33.6, 55.7, 102.7, 106.1, 112.0, 112.6, 127.7, 132.6, 136.6,
J¼1.4, 7.3 Hz), 7.44e7.50 (3H, m), 7.58 (1H, d, J¼8.7 Hz), 7.72 (2H, dt,
155.6, 166.2; HRMS (EI) calcd for C11H11NO3 Mþ 205.0739, found
205.0743.
J¼1.4, 7.3 Hz), 8.10 (1H, s), 8.49 (1H, d, J¼1.4 Hz); 13C NMR
(100 MHz, CDCl3)
d 12.7, 18.0, 110.2, 114.4, 120.1, 122.4, 126.7, 127.5,
128.6, 129.6, 135.5, 140.5, 140.9, 141.9, 170.5; HRMS (EI) calcd for
C
3.6.7. 1,2-Dimethyl-1H-indole-3-carboxylic acid (2g).36 Crystals; 1H
24H31NO2Si Mþ 393.2124, found 393.2122.
NMR (400 MHz, DMSO-d6)
m), 7.49 (1H, dt, J¼1.0, 7.7 Hz), 7.98 (1H, dt, J¼1.0, 7.7 Hz), 12.0 (1H,
s); 13C NMR (100 MHz, DMSO-d6)
11.3, 29.2, 102.8, 109.5, 120.4,
120.7, 121.2, 126.1, 135.9, 145.0, 166.3.
d 2.72 (3H, s), 3.72 (3H, s), 7.11e7.19 (2H,
3.6.15. 5-Methoxy-1-triisopropylsilyl-1H-indole-3-carboxylic
(7f). Crystals; mp 186.6e189.0 ꢀC; IR (KBr) 2938, 2872, 1663, 1528,
1454, 1275, 1198, 1034, 745 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
1.09 (18H, d, J¼7.5 Hz),1.76 (3H, q, J¼7.5 Hz), 3.80 (3H, s), 6.86 (1H,
dd, J¼2.6, 9.0 Hz), 7.50 (1H, d, J¼9.0 Hz), 7.55 (1H, d, J¼2.6 Hz), 7.98
(1H, s), 12.2 (1H, s); 13C NMR (100 MHz, DMSO-d6)
12.2, 18.2, 55.7,
acid
d
;
d
3.6.8. 1-Methyl-2-phenyl-1H-indole-3-carboxylic acid (2h).37 Crys-
tals; 1H NMR (400 MHz, DMSO-d6)
d
3.53 (3H, s), 7.24 (1H, td, J¼1.1,
d
7.9 Hz), 7.25 (1H, td, J¼1.1, 7.9 Hz), 7.45e7.53 (5H, m), 7.57 (1H, dt,
103.0, 110.9, 112.7, 115.5, 130.1, 136.0, 138.9, 155.4, 166.1; HRMS (EI)
J¼1.0, 7.9 Hz), 8.13 (1H, dt, J¼1.0, 7.9 Hz), 11.7 (1H, s); 13C NMR
calcd for C19H29NO3Si Mþ 347.1917, found 347.1922.
(100 MHz, DMSO-d6)
d 30.5, 104.2, 110.3, 120.9, 121.2, 122.1, 126.2,
127.6, 128.4, 130.2, 131.0, 136.2, 145.7, 165.3.
3.6.16. 1-Benzyl-1H-indole-3-carboxylic acid (8a).39 Crystals; 1H
NMR (400 MHz, DMSO-d6)
7.24e7.35 (5H, m), 7.52e7.54 (1H, m), 8.01e8.03 (1H, m), 8.23 (1H,
s), 12.1 (1H, s); 13C NMR (100 MHz, DMSO-d6)
49.2, 106.5, 110.8,
d 5.50 (2H, s), 7.16e7.21 (2H, m),
3.6.9. 1H-Indole-3-carboxylic acid (6a).38 Crystals; 1H NMR
(400 MHz, DMSO-d6)
8.00e8.02 (2H, m), 11.8 (1H, s), 11.9 (1H, br); 13C NMR (100 MHz,
DMSO-d6) 107.4,112.2,120.6,121.0,122.1,126.0,132.3,136.4,165.9.
d
7.13e7.21 (2H, m), 7.47 (1H, dd, J¼1.5, 7.0 Hz),
d
120.6,121.1,122.0,126.3,127.0,127.3,128.4,135.2,136.0,136.9,165.3.
d
3.6.17. 1-Benzyl-5-fluoro-1H-indole-3-carboxylic acid (8b). Crystals;
mp 185.9e191.1 ꢀC; IR (KBr) 3033, 2584,1661,1530,1407,1398,1265,
3.6.10. 1-Triisopropylsilyl-1H-indole-3-carboxylic acid (7a). Cryst-
als; mp 190.0e193.4 ꢀC; IR (KBr) 3059, 2959, 2868, 1657, 1537, 1485,
1188, 1091, 902 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
; d 5.51 (2H, s),
1393, 1370, 126, 1198, 1051 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
7.07 (1H, td, J¼2.6, 9.0 Hz), 7.26e7.36 (5H, m), 7.57 (1H, dd, J¼4.2,
d
1.12 (18H, d, J¼7.5 Hz), 1.38 (3H, sept, J¼7.5 Hz), 7.16e7.23 (2H, m),
7.50 (1H, dd, J¼1.8, 6.7 Hz), 8.01 (1H, dd, J¼1.8, 6.7 Hz), 8.04 (1H, s),
11.9 (1H, br); 13C NMR (100 MHz, DMSO-d6)
12.2, 18.3, 108.1, 112.9,
120.8, 121.7, 122.8, 126.4, 133.7, 137.0, 164.3; HRMS (EI) calcd for
18H27NO2Si Mþ 317.1811, found 317.1808.
9.0 Hz), 7.69 (1H, dd, J¼2.6, 9.8 Hz), 8.31 (1H, s),12.2 (1H, s); 13C NMR
(100 MHz, DMSO-d6)
d
49.7, 105.6 (d, J¼24.5 Hz), 107.0 (d, J¼4.4 Hz),
d
110.6 (d, J¼26.0 Hz), 112.6 (d, J¼9.9 Hz), 127.3 (d, J¼10.8 Hz), 127.3,
127.7, 128.7, 132.9, 137.0, 158.4 (d, J¼233 Hz), 165.3; HRMS (EI) calcd
for C16H12FNO2 Mþ 269.0852, found 269.0855.
C
3.6.11. 5-Fluoro-1-triisopropylsilyl-1H-indole-3-carboxylic
acid
3.6.18. 1-Benzyl-2-methyl-1H-indole-3-carboxylic acid (8g). Crystals;
mp 200.5e201.6 ꢀC; IR (KBr) 3029,1625,1537,1455,1436,1402,1360,
(7b). Crystals; mp 193.4e194.9 ꢀC; IR (KBr) 2955, 2868, 1674, 1537,
Please cite this article in press as: Nemoto, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.028

8
K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
1291, 1245, 1213, 1160, 1142, 1120 cmꢁ1; 1H NMR (400 MHz, DMSO-
d6)
3.10. Typical procedure for the ethoxycarbonylation of in-
doles (entry 1 in Table 3)
d
2.69 (3H, s), 5.52 (2H, s), 7.01 (2H, d, J¼7.3 Hz), 7.12e7.17 (2H, m),
7.24 (1H, t, J¼7.3 Hz), 7.31 (2H, t, J¼7.3 Hz), 7.48 (1H, dd, J¼3.4,
5.7 Hz), 8.02 (1H, dd, 1H, J¼3.4, 5.7 Hz), 12.1 (1H, s); 13C NMR
A mixture of indole 1a (d 1.05; 125
(1.0 M in hexane; 1.0 mL, 1.0 mmol), ethyl chloroformate (d 1.14;
114 L, 1.20 mmol), and toluene (1.0 mL) was stirred at room
mL, 1.00 mmol), Me2AlCl
(100 MHz, DMSO-d6) d 11.6, 45.7,103.9,110.1,120.8,121.2,121.7,126.1,
126.5, 127.2, 128.6, 136.0, 137.2, 144.8, 166.5; HRMS (EI) calcd for
m
C
17H15NO2 Mþ 265.1103, found 265.1102.
temperature for 3 h. The reaction was quenched by the addition of
saturated aqueous NH4Cl and the aqueous layer was extracted with
chloroform. The combined organic layer was dried over MgSO4 and
evaporated to leave a residue, which was purified by column
chromatography with hexaneeethyl acetate (2:1) as an eluent to
give ester 10a as crystals (174 mg, 86%).
The ethoxycarbonylation of other indoles was conducted by
a similar procedure. The crude product was purified by column
chromatography by using the indicated eluent, unless otherwise
noted. See Table 3 for the reaction conditions and product
yields.
3.6.19. 1-Benzyl-2-phenyl-1H-indole-3-carboxylic acid (8h). Crystals;
mp 204.2e205.8 ꢀC; IR (KBr) 3332, 2932, 2868, 1647, 1535, 1489,
1
1460, 1443, 1242, 1171, 1078, 756 cmꢁ1; H NMR (400 MHz, DMSO-
d6)
d
5.25 (2H, s), 6.86 (2H, d, J¼7.1 Hz), 7.18e7.23 (5H, m), 7.39e7.45
(6H, m), 8.17 (1H, d, J¼7.1 Hz), 11.8 (1H, s); 13C NMR (100 MHz,
DMSO-d6)
d 46.7, 105.5, 111.2, 121.5, 121.7, 122.7, 126.0, 126.8, 127.2,
127.9, 128.5, 128.8, 130.3, 131.2, 135.9, 137.1, 146.2, 165.6; HRMS (EI)
calcd for C22H17NO2 Mþ 327.1259, found 327.1254.
3.10.1. Ethyl 1-methyl-1H-indole-3-carboxylate (10a).41 Crystals; 1H
3.7. Deprotection of 1-triisopropylsilylindole 7a
NMR (400 MHz, CDCl3)
d
1.42 (3H, t, J¼7.1 Hz), 3.84 (3H, s), 4.34 (2H,
q, J¼7.1 Hz), 7.28e7.37 (3H, m), 7.80 (1H, s), 8.16e8.20 (1H, m); 13
C
To
a solution of 1-triisopropylsilylindole 7a (31.7 mg,
0.100 mmol) in THF (1.0 mL) was added TBAF (1.0 M solution in
THF; 1.0 mL, 1.0 mmol), and the mixture was stirred at room tem-
perature for 18 h. The reaction was quenched by the addition of
water and the aqueous layer was extracted with chloroform. The
combined organic layer was dried over MgSO4 and evaporated to
leave a residue, which was purified by TLC with chloroformeethyl
acetate (1:1) as a developer to give deprotected indole 6a (15.3 mg,
95%).
NMR (100 MHz, CDCl3)
122.8, 126.8, 135.2, 137.3, 165.2.
d 14.7, 33.4, 59.7, 107.4, 109.8, 121.8, 121.9,
3.10.2. Ethyl 5-fluoro-1-methyl-1H-indole-3-carboxylate
(10b). Hexaneeethyl acetate (2:1) as the eluent; crystals; mp
80.5e82.0 ꢀC; IR (KBr) 3123, 2961, 2903, 1686, 1535, 1481, 1373,
1267, 1224, 1150, 1105, 1030, 872, 802, 773 cmꢁ1
;
1H NMR
(400 MHz, CDCl3)
d
1.42 (3H, t, J¼7.1 Hz), 3.81 (3H, s), 4.37 (2H, q,
J¼7.1 Hz), 7.02 (1H, td, J¼2.6, 9.0 Hz), 7.23e7.26 (1H, m), 7.79 (1H, s),
7.81 (1H, dd, J¼2.6, 9.7 Hz); 13C NMR (100 MHz, CDCl3)
d 14.6, 33.7,
3.8. Deprotection of 1-benzylindole 8a
59.8, 106.9 (d, J¼24.8 Hz), 107.2 (d, J¼4.3 Hz), 110.5 (d, J¼9.7 Hz),
111.1 (d, J¼26.4 Hz), 127.2 (d, J¼11.0 Hz), 133.7, 136.3, 159.2 (d,
J¼236 Hz), 164.8; HRMS (EI) calcd for C12H12FNO2 Mþ 221.0852,
found 221.0856.
To a solution of 1-benzylindole 8a (25.1 mg, 0.100 mmol) in
benzene (1.0 mL) was added AlCl3 (66.7 mg, 0.500 mmol) at
ꢁ10 ꢀC, and the mixture was allowed to warm to room temper-
ature. After stirring at room temperature for 18 h, the mixture
was quenched with water and the aqueous layer was extracted
with chloroform. The combined organic layer was extracted with
0.5 M Na2CO3 and the extract was acidified by the addition of
concentrated HCl to liberate the free acid, which was extracted
with chloroform. The extract was dried over MgSO4 and evapo-
rated to leave a residue, which was purified by TLC with chlor-
oformeethyl acetate (1:1) as a developer to give 6a (15.8 mg,
98%).
3.10.3. Ethyl 5-bromo-1-methyl-1H-indole-3-carboxylate
(10c). Hexaneeethyl acetate (2:1) as the eluent; crystals; mp
71.7e73.6 ꢀC; IR (KBr) 2976, 292, 2901, 1686, 1533, 1468, 1377, 1223,
116, 1107, 1040, 842, 770 cmꢁ1 1H NMR (400 MHz, CDCl3)
; d 1.42
(3H, d, J¼7.1 Hz), 3.80 (3H, s), 4.38 (2H, q, J¼7.1 Hz), 7.19 (1H, t,
J¼7.8 Hz), 7.35e7.38 (1H, m), 7.74 (1H, dd, J¼6.4 Hz), 8.30 (1H, t,
J¼1.9 Hz); 13C NMR (100 MHz, CDCl3)
d 14.6, 33.6, 59.8, 106.9, 111.2,
115.6, 124.3, 125.7, 128.1, 135.8, 135.9, 164.6; HRMS (EI) calcd for
C
12H12BrNO2 Mþ 281.0051, found 281.0046.
3.10.4. Ethyl 1,5-dimethyl-1H-indole-3-carboxylate (10d). Hexanee
3.9. Formation of dimer 9 by the treatment of indole 1a with
Me2AlCl
ethyl acetate (2:1) as the eluent; an oil; IR (KBr) 2978, 2922, 1697,
1535, 1371, 1271, 1229, 1150, 1107, 1032, 795, 775 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
1.41 (3H, t, J¼7.1 Hz), 2.49 (3H, s), 3.79 (3H, s),
To a solution of indole 1a (d 1.05; 125 mL, 1.00 mmol) in tol-
4.38 (2H, q, J¼7.1 Hz), 7.11 (1H, dd, J¼1.2, 8.4 Hz), 7.22 (1H, d,
uene (1.0 mL) was added Me2AlCl (1.0 M solution in hexane;
1.0 mL, 1.0 mmol) at ꢁ30 ꢀC, and the mixture was stirred at this
temperature for 18 h. The reaction was quenched by the addition
of D2O and the aqueous layer was extracted with diethyl ether.
The combined organic layer was dried over MgSO4 and evapo-
rated. 1H NMR analysis of the residue using acetophenone as an
internal standard revealed that 1,10-dimethyl-20,30-dihydro-
1H,10H-2,30-biindole (9)40 was formed quantitatively, 1H NMR
J¼8.4 Hz), 7.73 (1H, s), 7.97 (1H, t, J¼1.2 Hz); 13C NMR (100 MHz,
CDCl3)
d 14.6, 21.6, 33.4, 59.5, 106.5, 109.4, 121.3, 124.3, 126.9, 131.3,
135.1,135.6,165.2; HRMS (EI) calcd for C13H15NO2 Mþ 217.1103, found
217.1102.
3.10.5. Ethyl 1-methyl-5-phenyl-1H-indole-3-carboxylate
(10e). Purified by crystallization from dichloromethaneehexane;
crystals; mp 123.5e129.9 ꢀC; IR (KBr) 3119, 3057, 2980, 2936, 1686,
1537, 1474, 1370, 1285, 1236, 1165, 1111, 1030, 891, 777, 762,
(400 MHz, CDCl3)
d
2.69 (3H, s), 3.24 (1H, dd, J¼11.2, 15.6 Hz),
3.34 (1H, dd, J¼8.8, 15.6 Hz), 3.80 (3H, s), 4.65 (1H, dd, J¼8.8,
11.2 Hz), 6.57 (1H, d, J¼7.6 Hz), 6.76 (1H, t, J¼7.2 Hz), 7.09e7.22
(4H, m), 7.25e7.31 (1H, m), 7.36 (1H, d, J¼8.4 Hz), 7.74 (1H, d,
700 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.42 (3H, t, J¼7.1 Hz), 3.79
(3H, s), 4.39 (2H, q, J¼7.1 Hz), 7.33 (1H, t, J¼7.5 Hz), 7.39 (1H, d,
J¼8.5 Hz), 7.46 (2H, t, J¼7.5 Hz), 7.55 (1H, dd, J¼1.3, 8.5 Hz), 7.69
(2H, d, J¼7.5 Hz), 7.80 (1H, s), 8.42 (1H, t, J¼1.3 Hz); 13C NMR
J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
d 32.7, 34.0, 37.8, 64.7, 107.1,
109.3, 115.1, 117.7, 118.9, 120.1, 121.7, 124.0, 126.8, 127.3, 127.5,
129.2, 137.5, 153.3.
(100 MHz, CDCl3)
d 14.6, 33.5, 59.7, 107.5, 110.0, 120.2, 122.5, 126.6,
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K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
9
127.1, 127.5, 128.7, 135.3, 135.6, 136.7, 142.1, 165.0; HRMS (EI) calcd
(100 MHz, CDCl3)
d
12.6, 14.6, 17.9, 59.9, 110.6, 115.5, 115.5, 124.3,
for C18H17NO2 Mþ 279.1259, found 279.1261.
125.4, 130.6, 139.3, 139.9, 164.8; HRMS (EI) calcd for C20H30BrNO2Si
Mþ 423.1229, found 423.1232.
3.10.6. Ethyl 5-methoxy-1-methyl-1H-indole-3-carboxylate
(10f). Hexaneeethyl acetate (2:1) as the eluent; crystals; mp
71.7e73.7 ꢀC; IR (KBr) 2984, 2936, 2901, 2832,1694,1532,1489,160,
1377, 1263, 1233,1206, 1150, 1103, 1059, 903, 847, 795, 768 cmꢁ1; 1H
3.10.12. Ethyl 5-methyl-1-triisopropylsilyl-1H-indole-3-carboxylate
(11d). Hexaneeethyl acetate (10:1) as the eluent; crystals; mp
74.1e76.1 ꢀC; IR (KBr) 2949, 2870,1705,1533,1454,1373,1314,1252,
NMR (400 MHz, CDCl3)
d
1.41 (3H, t, J¼7.1 Hz), 3.80 (3H, s), 3.90 (3H,
1161, 1126, 1059, 885, 793, 773, 696, 670, 575 cmꢁ1 1H NMR
;
s), 4.37 (2H, q, J¼7.1 Hz), 6.93 (1H, dd, J¼2.5, 8.9 Hz), 7.23 (1H, d,
(400 MHz, CDCl3)
d
1.15 (18H, d, J¼7.6 Hz), 1.43 (3H, t, J¼7.1 Hz), 1.71
J¼8.9 Hz), 7.67 (1H, d, J¼2.5 Hz), 7.72 (1H, s); 13C NMR (100 MHz,
(3H, sept, J¼7.6 Hz), 2.48 (3H, s), 4.40 (2H, q, J¼7.1 Hz), 7.03 (1H, dd,
CDCl3) d 14.6, 33.6, 55.7, 59.5, 102.9, 106.5, 110.6, 113.2, 127.5, 132.3,
J¼1.2, 8.5 Hz), 7.39 (1H, d, J¼8.5 Hz), 7.92 (1H, s), 7.98 (1H, t,
135.1, 155.8, 165.2; HRMS (EI) calcd for C13H15NO3 Mþ 233.1052,
found 233.1052.
J¼1.2 Hz); 13C NMR (100 MHz, CDCl3)
d 12.7, 14.6, 18.0, 21.5, 59.6,
110.4, 113.8, 121.3, 124.0, 129.1, 131.3, 138.5, 139.5, 165.4; HRMS (EI)
calcd for C21H33NO2Si Mþ 359.2281, found 359.2281.
3.10.7. Ethyl 1,2-dimethyl-1H-indole-3-carboxylate (10g).42 Hexanee
ethyl acetate (2:1) as the eluent; crystals; 1H NMR (400 MHz, CDCl3)
3.10.13. Ethyl 5-phenyl-1-triisopropylsilyl-1H-indole-3-carboxylate
(11e). Hexaneeethyl acetate (10:1) as the eluent; an oil; IR (KBr)
3061, 3024, 2949, 2868, 1703, 1535, 1456, 1371, 1317, 1267, 1169,
d
1.45 (3H, t, J¼7.1 Hz), 2.77 (3H, s), 3.69 (3H, s), 4.40 (2H, q, J¼7.1 Hz),
7.22e7.31 (3H, m), 8.10e8.15 (1H, m); 13C NMR (100 MHz, CDCl3)
12.0, 14.8, 29.7, 59.5, 104.2, 109.2, 121.7, 121.8, 122.2, 126.8, 136.7,
d
1059, 883, 760, 69, 662, 573 cmꢁ1; 1H NMR (400 MHz, CDCl3)
d 1.17
145.4, 166.4.
(18H, d, J¼7.6 Hz), 1.44 (3H, t, J¼7.1 Hz), 1.75 (3H, sept, J¼7.6 Hz),
4.42 (2H, q, J¼7.1 Hz), 7.32 (1H, tt, J¼1.2, 7.4 Hz), 7.42e7.47 (3H, m),
7.56 (1H, d, J¼8.4 Hz), 7.69 (2H, dt, J¼1.5, 8.4 Hz), 7.99 (1H, s), 8.43
3.10.8. Ethyl 1-methyl-2-phenyl-1H-indole-3-carboxylate
(10h). Hexaneeethyl acetate (2:1) as the eluent; crystals; mp
95.5e97.3 ꢀC; IR (KBr) 3057, 2980, 2936, 2903, 1686, 1539, 1470,
(1H, d, J¼1.5 Hz); 13C NMR (100 MHz, CDCl3)
d 12.7, 14.7, 18.0, 59.8,
111.2, 114.4, 120.0, 121.2, 126.6, 127.4, 128.6, 129.4, 135.2, 139.0,
140.8, 142.0, 165.3; HRMS (EI) calcd for C26H35NO2Si Mþ 421.2437,
found 421.2440.
1234, 1198, 1105, 1036, 739 cmꢁ1 1H NMR (400 MHz, CDCl3)
;
d
1.19 (3H, t, J¼7.1 Hz), 3.57 (3H, s), 4.21 (2H, q, J¼7.1 Hz),
7.29e7.36 (2H, m), 7.37e7.43 (3H, m), 7.48e7.51 (3H, m),
8.24e8.28 (1H, m); 13C NMR (100 MHz, CDCl3)
14.3, 31.0, 59.4,
d
3.10.14. Ethyl 5-methoxy-1-triisopropylsilyl-1H-indole-3-carboxylate
(11f). Hexaneeethyl acetate (5:1) as the eluent; crystals; mp
92.5e93.9 ꢀC; IR (KBr) 2949, 2870, 1703, 1530, 1485, 1452, 1373,
1316,1265,1211,1169,1059, 885, 696, 577 cmꢁ1; 1H NMR (400 MHz,
105.4, 109.8, 122.1, 122.2, 122.9, 126.8, 128.1, 129.0, 130.4, 131.8,
136.9, 146.9, 165.2; HRMS (EI) calcd for C18H17NO2 Mþ 279.1259,
found 279.1256.
CDCl3)
d
1.15 (18H, d, J¼7.4 Hz), 1.43 (3H, t, J¼6.8 Hz), 1.71 (3H, sept,
3.10.9. Ethyl 1-triisopropylsilyl-1H-indole-3-carboxylate
(11a). Hexaneeethyl acetate (10:1) as the eluent; crystals; mp
57.0e59.2 ꢀC; IR (KBr) 3053, 2949, 2870, 1707, 1537, 1483, 1451,
1398, 1379, 1341, 1316, 1244, 1188, 1146, 1117, 1055, 955, 883, 752,
J¼7.4 Hz), 3.89 (3H, s), 4.39 (2H, q, J¼6.8 Hz), 6.85 (1H, dd, J¼2.0,
9.0 Hz), 7.39 (1H, d, J¼9.0 Hz), 7.69 (1H, d, J¼2.0 Hz), 7.40 (1H, s); 13
C
NMR (100 MHz, CDCl3)
d 12.6, 14.6, 18.0, 55.6, 59.6, 102.9, 110.6,
112.6, 114.9, 129.8, 135.9, 138.7, 155.5; HRMS (EI) calcd for
C
698, 680, 652 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.16 (18H, d,
21H33NO3Si Mþ 375.2230, found 375.2229.
J¼7.5 Hz), 1.44 (3H, t, J¼7.1 Hz), 1.73 (3H, sept, J¼7.5 Hz), 4.41 (2H,
q, J¼7.1 Hz), 7.19e7.28 (2H, m), 7.51 (1H, d, J¼8.2 Hz), 7.97 (1H, s),
3.10.15. Ethyl 1-benzyl-2-methyl-1H-indole-3-carboxylate
(12g).41 Hexaneeethyl acetate (3:1) as the eluent; crystals; mp
100.5e102.1 ꢀC; IR (KBr) 3050, 2990, 2951, 2899, 1682, 1541, 1420,
8.19 (1H, d, J¼8.2 Hz); 13C NMR (100 MHz, CDCl3)
d 12.7, 14.6,
18.0, 59.7, 110.9, 114.2, 121.5, 121.8, 122.5, 128.8, 138.5, 141.3,
165.4; HRMS (EI) calcd for C20H31N O2Si Mþ 345.2124, found
345.2128.
1391, 1379, 1354, 1279, 1233, 1142, 1117, 1055, 785, 740, 696 cmꢁ1
;
1H NMR (400 MHz, CDCl3)
d
1.45 (3H, t, J¼7.1 Hz), 2.71 (3H, s), 4.40
(2H, q, J¼7.1 Hz), 5.31 (2H, s), 6.94 (2H, d, J¼6.2 Hz), 7.15e7.25 (6H,
3.10.10. Ethyl 5-fluoro-1-triisopropylsilyl-1H-indole-3-carboxylate
(11b). Hexaneeethyl acetate (10:1) as the eluent; crystals; mp
76.9e79.0 ꢀC; IR (KBr) 2953, 2870,1697,1532,1481,1449,1371,1317,
m), 8.18 (1H, d, J¼7.8 Hz); 13C NMR (100 MHz, CDCl3)
d 11.8, 14.6,
46.4, 59.4, 104.6, 109.5, 121.5, 121.7, 122.2, 125.9, 126.7, 127.6, 128.9,
136.3, 145.1, 166.1.
1252, 1190, 169, 1117, 1051, 885, 866, 772, 694 cmꢁ1 1H NMR
;
(400 MHz, CDCl3)
d
1.16 (18H, d, J¼7.6 Hz), 1.44 (3H, t, J¼7.1 Hz), 1.71
3.10.16. Ethyl 1-benzyl-2-phenyl-1H-indole-3-carboxylate
(12h).43 Hexaneeethyl acetate (3:1) as the eluent; crystals; mp
112.0e113.5 ꢀC; IR (KBr) 3055, 3023, 2980, 2903, 1694, 1535, 1485,
(3H, sept, J¼7.6 Hz), 4.40 (2H, q, J¼7.1 Hz), 6.95 (1H, dd, J¼2.7,
9.2 Hz), 7.42 (1H, dd, J¼4.3, 9.2 Hz), 7.83 (1H, dd, J¼2.7, 9.2 Hz),7.98
(1H, s); 13C NMR (100 MHz, CDCl3)
d
12.6, 14.6, 18.0, 59.9, 106.8 (d,
1460, 1404, 1348, 1283, 1236, 1161, 1121, 1032, 756, 721, 702 cmꢁ1
;
J¼25.3 Hz), 110.8 (d, J¼26.0 Hz), 111.1 (d, J¼4.4 Hz), 114.8 (d,
J¼9.5 Hz), 129.7 (d, J¼10.9 Hz), 137.6, 139.8, 159.0 (d, J¼236 Hz),
165.0; HRMS (EI) calcd for C20H30FNO2Si Mþ 363.2030, found
363.2034.
1H NMR (400 MHz, CDCl3)
d
1.18 (3H, t, J¼7.1 Hz), 4.21 (2H, q,
J¼7.1 Hz), 5.19 (2H, s), 6.90 (2H, m), 7.20e7.24 (5H, m), 7.25e7.45
(6H, m), 8.29 (1H, d, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d 14.1,
47.5, 59.3, 105.8, 110.6, 122.0, 122.1, 123.0, 125.9, 126.8, 127.4, 127.9,
128.6, 128.9, 130.1, 131.4, 136.3, 136.9, 146.8, 165.0.
3.10.11. Ethyl 5-bromo-1-triisopropylsilyl-1H-indole-3-carboxylate
(11c). Hexaneeethyl acetate (10:1) as the eluent; crystals; mp
106.4e108.9 ꢀC; IR (KBr) 2949, 2870, 1705, 1532, 1445, 1371, 1344,
1316, 1180, 1126, 1072, 885, 772, 696, 523 cmꢁ1; 1H NMR (400 MHz,
3.11. Typical procedure for the carbamoylation of indoles
(entry 6 in Table 4)
CDCl3)
d
1.14 (18H, d, J¼7.5 Hz), 1.44 (3H, t, J¼7.1 Hz), 1.70 (3H, sept,
To a stirred mixture of indole 1a (d 1.05; 125 mL, 1.00 mmol),
Me2AlCl (1.0 M in hexane; 1.0 mL, 1.0 mmol), and dichloromethane
(1.0 mL) was added dropwise a solution of naphthalen-1-yl
J¼7.5 Hz), 4.40 (2H, q, J¼7.1 Hz), 7.30 (1H, dd, J¼2.0, 8.8 Hz), 7.37
(1H, d, J¼8.8 Hz), 7.94 (1H, s), 8.32 (1H, d, J¼2.0 Hz); 13C NMR
Please cite this article in press as: Nemoto, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.028

10
K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
isocyanate (d 1.18; 172
m
L, 1.20 mmol) in dichloromethane (2.0 mL)
J¼7.8 Hz), 7.2 (2H, t, J¼7.8 Hz), 7.57 (2H, d, J¼7.8 Hz), 9.92 (1H, s); 13
C
at 0 ꢀC, and the mixture was stirred at room temperature for 3 h.
The reaction was quenched by the addition of saturated aqueous
NH4Cl and the aqueous layer was extracted with chloroform. The
combined organic layer was dried over MgSO4 and evaporated to
NMR (100 MHz, DMSO-d6) d 24.0, 118.9, 122.9, 128.6, 139.3, 168.2.
3.11.7. N-(4-Chlorophenyl)acetamide (14c).46 Purified by column
chromatography with chloroformeethyl acetate (6:1) as an eluent;
leave
a
residue, which was purified by crystallization from
crystals; 1H NMR (400 MHz, DMSO-d6)
d 2.04 (3H, s), 7.34 (2H, d,
dichloromethaneehexane to give amide 13d as crystals (243 mg,
81%).
J¼8.9 Hz), 7.60 (2H, d, J¼8.9 Hz), 10.1 (1H, s); 13C NMR (100 MHz,
DMSO-d6)
d 24.0, 120.4, 126.5, 128.6, 138.3, 168.4.
The carbamoylation of the other indoles, as well as that with the
other isocyanates, were conducted by a similar procedure. The
crude product was purified by the indicated method. See Tables 4
and 5 for the reaction conditions and product yields.
3.11.8. N-(Naphthalen-1-yl)acetamide (14d).47 Purified by column
chromatography with chloroformeethyl acetate (6:1) as an eluent;
crystals; 1H NMR (400 MHz, DMSO-d6)
d
2.19 (3H, s), 7.57e7.46 (3H,
m), 7.75 (2H, d, J¼8.2 Hz), 7.94e7.92 (1H, m), 8.09e8.07 (1H, m),
9.93 (1H, s); 13C NMR (100 MHz, DMSO-d6)
23.5, 121.5, 122.7,
3.11.1. N-Isopropyl-1-methyl-1H-indole-3-carboxamide (13a). Purified
by column chromatography with chloroformeethyl acetate (6:1) as an
eluent; crystals; mp 163.6e164.8 ꢀC; IR (KBr) 3327, 3109, 2967, 1614,
1541, 147, 1379, 1273, 1244, 743 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
125.0, 125.6, 125.7, 126.0, 127.7, 128.1, 133.7, 168.9.
3.11.9. 5-Fluoro-1-methyl-N-(naphthalen-1-yl)-1H-indole-3-
carboxamide (15b). Purified by column chromatography with
chloroformeethyl acetate (4:1) as an eluent; crystals; mp
188.5e191.1 ꢀC; IR (KBr) 3266, 3235, 1624, 1533, 1479, 1460, 1371,
d
1.17 (6H, d, J¼6.6 Hz), 3.04 (3H, s), 4.07e4.16 (1H, m), 7.13 (1H, ddd,
J¼1.0, 7.0, 7.8 Hz), 7.20 (1H, ddd, J¼1.3, 7.0, 8.1 Hz), 7.46 (1H, d,
J¼8.1 Hz), 7.63 (1H, d, J¼7.8 Hz), 8.01 (1H, s), 8.15 (1H, d, J¼7.8 Hz); 13
C
NMR (100 MHz, DMSO-d6)
d
22.7, 32.9, 40.0, 109.9, 110.1, 120.4, 121.2,
1271, 1148, 1109, 793, 762 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
121.8, 126.6, 131.5, 136.6, 163.5; HRMS (EI) calcd for C13H16N2O Mþ
216.1263, found 216.1261.
d
3.92 (3H, s), 7.13 (1H, td, J¼2.6, 9.7 Hz), 7.53e7.61 (4H, m), 7.68
(1H, d, J¼6.9 Hz), 7.82 (1H, d, J¼8.2 Hz), 7.88 (1H, dd, J¼2.6, 9.7 Hz),
7.95e7.99 (1H, m), 8.06e8.09 (1H, m), 8.48 (1H, s), 9.94 (1H, s); 13
NMR (100 MHz, DMSO-d6)
C
3.11.2. 1-Methyl-N-phenyl-1H-indole-3-carboxamide (13b).44 Purified
by column chromatography with chloroformeethyl acetate (6:1) as an
d
33.5, 105.9 (d, J¼24.6 Hz), 109.2 (d,
J¼26.1 Hz), 110.4 (d, J¼26.1 Hz), 111.8 (d, J¼9.9 Hz), 123.2, 123.3,
125.5, 125.6, 125.8, 125.9, 127.4 (d, J¼11.0 Hz), 128.0, 129.0, 133.6,
133.8, 134.0, 134.3, 158.2 (d, J¼232 Hz), 163.3; HRMS (EI) calcd for
eluent; crystals; 1H NMR (400 MHz, DMSO-d6)
d 3.89 (3H, s), 7.04 (1H,
tt, J¼1.1, 7.4 Hz), 7.19 (1H, ddd, J¼1.1, 7.0, 7.8 Hz), 7.26 (1H, ddd, J¼1.1,
7.0, 8.2 Hz), 7.33 (2H, dd, J¼7.4, 8.5 Hz), 7.54 (1H, d, J¼8.2 Hz), 7.77 (2H,
C
20H15FN2O Mþ 318.1168, found 318.1169.
dd, J¼1.1, 8.5 Hz), 8.20 (1H, d, J¼7.8 Hz), 8.27 (1H, s), 9.74 (1H, s); 13
C
NMR (100 MHz, DMSO-d6)
d
33.0, 109.4, 110.3, 119.5, 120.8, 121.1, 122.1,
3.11.10. 5-Bromo-1-methyl-N-(naphthalen-1-yl)-1H-indole-3-
carboxamide (15c). Purified by crystallization from dichlor-
omethaneehexane; crystals; mp 227.1e228.5 ꢀC; IR (KBr) 3210,
122.5, 126.7, 128.5, 132.4, 136.7, 139.7, 162.8.
3.11.3. N-(4-Chlorophenyl)-1-methyl-1H-indole-3-carboxamide
(13c). Purified by column chromatography with chloroformeethyl
acetate (6:1) as an eluent; crystals; mp 174.9e176.4 ꢀC; IR (KBr)
1634, 1499, 1470, 1458, 1375, 1256, 1115, 793, 773 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6)
d
3.92 (3H, s), 7.40 (1H, dd, J¼1.9, 8.5 Hz),
7.53e7.58 (4H, m), 7.67 (1H, d, J¼7.0 Hz), 7.83 (1H, d, J¼8.5 Hz),
7.96e7.98 (1H, m), 8.06e8.08 (1H, m), 8.35 (1H, d, J¼1.9 Hz), 8.46
3312, 1640, 1597, 1535, 1470, 1400, 1308, 1248, 826, 746 cmꢁ1 1H
;
NMR (400 MHz, DMSO-d6)
d
3.89 (3H, s), 7.20 (1H, ddd, J¼1.0, 7.1,
(1H, s), 9.99 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d 33.3, 108.7,
7.8 Hz), 7.27 (1H, ddd, J¼1.3, 7.1, 8.2 Hz), 7.36e7.40 (2H, m), 7.54 (1H,
112.5, 113.8, 123.1, 123.3, 124.6, 125.4, 125.5, 125.6, 125.9, 128.0,
128.5, 128.9, 133.7, 133.8, 133.9, 135.5, 163.1; HRMS (EI) calcd for
d, J¼8.2 Hz), 7.79e7.83 (2H, m), 8.19 (1H, d, J¼7.8 Hz), 8.26 (1H, s),
9.88 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d
33.1, 109.2, 110.4, 121.1,
C
20H15BrN2O Mþ 378.0368, found 378.0363.
121.2, 122.3, 126.1, 126.7, 128.4, 132.6, 136.8, 138.8, 162.9; HRMS (EI)
calcd for C16H13ClN2O Mþ 284.0716, found 284.0718.
3.11.11. 1,5-Dimethyl-N-(naphthalen-1-yl)-1H-indole-3-carboxamide
(15d). Purified by crystallization from dichloromethaneehexane;
crystals; mp 215.1e217.1 ꢀC; IR (KBr) 3198, 3048, 3009, 1636, 1535,
3.11.4. 1-Methyl-N-(naphthalen-1-yl)-1H-indole-3-carboxamide
(13d). Purified by crystallization from dichloromethaneehexane;
crystals; mp 210.9e212.7 ꢀC; IR (KBr) 3298, 3011, 3048, 2938, 1638,
1526, 1499, 1470, 1377, 1265, 1229, 1111, 795, 771, 746, 681 cmꢁ1; 1H
1485, 1458, 1370, 1275, 1231, 1115, 793, 770 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6)
d
2.41 (3H, s), 3.88 (3H, s), 7.09 (1H, dd, J¼1.5,
4.2 Hz), 7.44 (1H, d, J¼8.3 Hz), 7.52e7.56 (3H, m), 7.68 (1H, d,
J¼7.0 Hz), 7.81 (1H, d, J¼8.3 Hz), 7.95e7.97 (1H, m), 8.00 (1H, s),
8.08 (1H, m), 8.34 (1H, s), 9.85 (1H, s); 13C NMR (100 MHz, DMSO-
NMR (400 MHz, DMSO-d6)
d
3.92 (3H, s), 7.19 (1H, ddd, J¼1.1, 7.0,
8.0 Hz), 7.27 (1H, ddd, J¼1.1, 7.0, 8.0 Hz), 7.52e7.58 (4H, m), 7.68
(1H, d, J¼7.0 Hz), 7.82 (1H, d, J¼8.0 Hz), 7.95e7.99 (1H, m),
8.07e8.09 (1H, m), 8.19 (1H, d, J¼8.0 Hz), 8.41 (1H, s), 9.90 (1H, s);
d6)
d 21.3, 33.1, 108.8, 110.1, 120.9, 123.0, 123.5, 123.7, 125.3, 125.59,
125.62, 125.9, 127.1, 128.0, 129.0, 129.6, 132.8, 133.8, 134.3, 135.3,
13C NMR (100 MHz, DMSO-d6)
d
33.1,109.3,110.4,120.9,121.2,122.2,
163.6; HRMS (EI) calcd for
314.1407.
C
21H18N2O Mþ 314.1419, found
123.1, 123.4, 125.3, 125.6, 125.7, 125.9, 126.9, 128.0, 129.0, 132.8,
133.8, 134.2, 136.9, 163.6; HRMS (EI) calcd for C20H16N2O Mþ
300.1263, found 300.1263.
3.11.12. 1-Methyl-N-(naphthalen-1-yl)-5-phenyl-1H-indole-3-
carboxamide (15e). Purified by crystallization from dichlor-
omethaneehexane; crystals; mp 178.0e189.1 ꢀC; IR (KBr) 3233,
3119, 3053, 1636, 1352, 1497, 1474, 1458, 1371, 152, 1115, 793, 758,
3.11.5. N-Isopropylacetamide (14a).45 Purified by column chroma-
tography with chloroformeethyl acetate (6:1) as an eluent; an oil;
1H NMR (400 MHz, CDCl3)
d
1.15 (6H, d, J¼6.6 Hz), 1.95 (3H, s),
700 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 3.95 (3H, s), 7.34 (1H, t,
4.01e4.13 (1H, m), 5.30 (1H, br); 13C NMR (100 MHz, CDCl3)
d
22.6,
J¼7.5 Hz), 7.46 (1H, t, J¼7.5 Hz), 7.53e7.60 (4H, m), 7.65e7.71 (4H,
m), 7.82 (1H, d, J¼8.2 Hz), 7.96e7.99 (1H, m), 8.09e8.11 (1H, m),
8.44 (1H, s), 8.61 (1H, d, J¼1.3 Hz), 9.96 (1H, s); 13C NMR (100 MHz,
23.3, 41.3, 169.4.
3.11.6. N-Phenylacetamide (14b).46 Purified by column chroma-
tography with chloroformeethyl acetate (6:1) as an eluent; crys-
DMSO-d6) d 33.3, 109.6, 111.1, 119.3, 121.5, 123.2, 123.4, 125.4, 125.6,
125.7, 125.9, 126.6, 126.8, 127.3, 128.1, 128.9, 129.0, 133.5, 133.6,
tals; 1H NMR (400 MHz, DMSO-d6)
d
2.04 (3H, s), 7.02 (1H, t,
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K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
11
133.8, 134.1, 136.5, 141.5, 163.6; HRMS (EI) calcd for C26H20N2O Mþ
376.1576, found 376.1575.
127.4 (d, J¼11.0 Hz), 128.0, 129.0, 133.6, 133.8, 134.0, 134.3, 158.2 (d,
J¼232 Hz), 163.3; HRMS (EI) calcd for C28H33FN2OSi Mþ 460.2346,
found 460.2350.
3.11.13. 5-Methoxy-1-methyl-N-(naphthalen-1-yl)-1H-indole-3-
carboxamide (15f). Purified by column chromatography with
chloroformeethyl acetate (4:1) as an eluent; crystals; mp
205.2e206.7 ꢀC; IR (KBr) 3223, 1636, 1533, 1487, 1458, 1375, 1271,
3.11.18. 5-Bromo-N-(naphthalen-1-yl)-1-triisopropylsilyl-1H-indole-
3-carboxamide (16c). Purified by column chromatography with
chloroformeethyl acetate (40:1) as an eluent; crystals; mp
153.9e156.0 ꢀC; IR (KBr) 3279, 3051, 2949, 2870, 163, 1533, 1497,
1443, 1395, 1350, 1271, 1186, 1017, 883, 785, 770, 692, 521 cmꢁ1; 1H
1215, 1153, 1113, 797, 772 cmꢁ1 1H NMR (400 MHz, DMSO-d6)
;
d
3.77 (3H, s), 3.87 (3H, s), 6.90 (1H, dd, J¼7.0, 9.2 Hz), 7.46 (1H, d,
J¼9.2 Hz), 7.54 (3H, m), 7.68 (1H, d, J¼7.0 Hz), 7.72 (1H, d, J¼2.5 Hz),
7.81 (1H, d, J¼8.2 Hz), 7.95e7.97 (1H, m), 8.07e8.10 (1H, m), 8.36
NMR (400 MHz, DMSO-d6)
d
1.15 (18H, d, J¼7.4 Hz), 1.85 (3H, sept,
J¼7.4 Hz), 7.36 (1H, dd, J¼1.9, 8.4 Hz), 7.56e7.64 (5H, m), 7.87 (1H, d,
J¼8.4 Hz), 7.99e8.04 (2H, m), 8.42 (1H, d, J¼1.9 Hz), 8.57 (1H, s),
(1H, s), 9.86 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d 33.3, 55.2,
102.7,108.7,111.2,112.3,123.1, 123.4,125.3,125.6,125.6,125.9,127.6,
128.0, 129.1, 132.0, 132.9, 133.8, 134.2, 154.8, 163.7; HRMS (EI) calcd
for C21H18N2O2 Mþ 330.1368, found 330.1362.
10.2 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d 11.7, 17.7, 112.5, 114.0,
116.0, 123.3, 123.5, 123.8, 124.9, 125.5, 125.8, 125.9, 128.0, 129.2,
131.3, 133.6, 133.7, 136.2, 139.4, 163.1; HRMS (EI) calcd for
C
28H33BrN2OSi Mþ 520.1546, found 520.1545.
3.11.14. 1,2-Dimethyl-N-(naphthalen-1-yl)-1H-indole-3-carboxamide
(15g). Purified by crystallization from dichloromethaneehexane;
crystals; mp 199.3e201.1 ꢀC; IR (KBr) 3439, 3051, 1655, 128, 1495,
3.11.19. 5-Methyl-N-(naphthalen-1-yl)-1-triisopropylsilyl-1H-indole-
3-carboxamide (16d). Purified by column chromatography with
chloroformeethyl acetate (40:1) as an eluent; crystals; mp
127.3e130.7 ꢀC; IR (KBr) 3285, 3050, 2947, 2868, 1636, 1533, 1495,
1
1466, 1393, 1375, 1265, 1190, 1109, 800, 777, 748, 702, 569 cmꢁ1; H
NMR (400 MHz, DMSO-d6)
d 2.72 (3H, s), 3.77 (3H, s), 7.15e7.23 (2H,
m), 7.51e7.55 (4H, m), 7.71 (1H, d, J¼7.0 Hz), 7.81 (1H, d, J¼8.2 Hz),
1456, 1398, 1356, 1271, 1182, 1017, 883, 791, 770 cmꢁ1 1H NMR
;
7.92e7.99 (1H, m), 8.05e8.08 (1H, m), 9.71 (1H, s); 13C NMR
(400 MHz, DMSO-d6)
d
1.16 (18H, d, J¼7.5 Hz), 1.84 (3H, sept,
(100 MHz, DMSO-d6)
d
11.6, 29.4, 108.3, 109.7, 119.5, 120.3, 121.2, 122.3,
J¼7.5 Hz), 2.41 (3H, s), 7.05 (1H, dd, J¼1.6, 8.5 Hz), 7.51 (1H, d,
J¼8.5 Hz), 7.55e7.59 (3H, m), 7.63 (1H, d, J¼6.6 Hz), 7.86 (1H, d,
J¼8.0 Hz), 7.98e8.05 (2H, m), 8.07 (1H, s), 8.45 (1H, s), 10.1 (1H, s);
123.3, 125.3, 125.4, 125.5, 125.6, 125.7, 128.0, 128.7, 133.7, 134.8, 136.0,
140.9, 164.9; HRMS (EI) calcd for C21H18N2O Mþ 314.1419, found
314.1415.
13C NMR (100 MHz, DMSO-d6)
d 11.8, 17.7, 21.0, 112.6, 113.6, 121.1,
123.4, 123.7, 123.8, 125.5, 125.5, 125.7, 125.8, 128.0, 129.3, 129.6,
129.8, 133.7, 134.0, 135.0, 138.9, 163.5; HRMS (EI) calcd for
C
3.11.15. 1-Methyl-N-(naphthalen-1-yl)-2-phenyl-1H-indole-3-
carboxamide (15h). Purified by column chromatography with
chloroform as an eluent; crystals; mp 199.5e200.6 ꢀC; IR (KBr)
3439, 3053, 1655, 1530, 1497, 1466, 1393, 1375, 1265, 1190, 1109,
29H36N2OSi Mþ 456.2597, found 456.2593.
3.11.20. N-(Naphthalen-1-yl)-5-phenyl-1-triisopropylsilyl-1H-in-
dole-3-carboxamide (16e). Purified by column chromatography
with chloroformeethyl acetate (40:1) as an eluent; crystals; mp
148.5e150.9 ꢀC; IR (KBr) 3277, 2949, 2868, 1636, 1532, 1491, 1462,
1395, 1362, 1271, 1182, 1017, 883, 787, 770, 758, 696 cmꢁ1; 1H NMR
800, 775, 748, 702, 569 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d 3.63
(3H, s), 6.78 (1H, d, J¼8.3 Hz), 7.24e7.36 (3H, m), 7.49e7.43 (2H, m),
7.72e7.76 (7H, m), 7.86 (1H, d, J¼8.3 Hz), 8.06 (1H, d, J¼7.4 Hz), 8.15
(1H, d, J¼7.4 Hz), 8.78 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d 30.8,
109.9, 110.6, 119.3, 120.7, 121.2, 121.3, 122.6, 124.2, 125.5, 125.6,
125.8, 126.4, 126.5, 128.1, 129.1, 129.6, 130.6, 131.0, 133.5, 133.7,
136.5, 141.3, 163.5; HRMS (EI) calcd for C26H20N2O Mþ 376.1576,
found 376.1575.
(400 MHz, DMSO-d6)
d
1.17 (18H, d, J¼7.5 Hz), 1.86 (3H, sept,
J¼7.5 Hz), 7.32 (1H, t, J¼7.5 Hz), 7.45 (2H, t, J¼7.5 Hz), 7.51e7.59 (4H,
m), 7.65e7.68 (3H, m), 7.71 (1H, d, J¼8.4 Hz), 7.85 (1H, d, J¼8.4 Hz),
7.97e8.00 (1H, m), 8.04e8.07 (1H, m), 8.55e8.55 (2H, m), 10.2 (1H,
s); 13C NMR (100 MHz, DMSOd6)
d 11.9, 17.9, 113.5, 114.5, 120.0,
3.11.16. N-(Naphthalen-1-yl)-1-triisopropylsilyl-1H-indole-3-
carboxamide (16a). Purified by column chromatography with
chloroformeethyl acetate (40:1) as an eluent; crystals; mp
135.0e138.6 ꢀC; IR (KBr) 3269, 3050, 2949, 2868, 1636, 1533, 1495,
1466, 1451, 1395, 1371, 1346, 123, 1190, 1015, 957, 883, 793, 770, 748,
121.7, 123.5, 123.9, 125.6, 125.7, 125.8, 126.0, 126.7, 126.8, 128.1,
128.9, 129.4, 130.2, 133.6, 133.9, 134.0, 135.8, 140.3, 141.3, 163.6;
HRMS (EI) calcd for C34H38N2OSi Mþ 518.2753, found 518.2756.
3.11.21. 5-Methoxy-N-(naphthalen-1-yl)-1-triisopropylsilyl-1H-in-
dole-3-carboxamide (16f). Purified by column chromatography
with chloroformeethyl acetate (30:1) as an eluent; crystals; mp
186.1e186.6 ꢀC; IR (KBr) 3279, 2949, 2868, 1636, 1528, 1478, 1451,
681 cmꢁ1
;
1H NMR (400 MHz, DMSO-d6)
d
1.15 (18H, d, J¼7.5 Hz),
1.85 (3H, sept, J¼7.5 Hz), 7.16e7.24 (2H, m), 7.54e7.58 (3H, m), 7.62
(2H, d, J¼7.4 Hz), 7.85 (1H, d, J¼8.0 Hz), 7.97e8.04 (2H, m), 8.25 (1H,
dd, J¼1.1, 7.4 Hz), 8.50 (1H, s), 10.1 (1H, s); 13C NMR (100 MHz,
1395, 1364, 1269, 1182, 1034, 83, 791, 798, 696 cmꢁ1 1H NMR
;
DMSO-d6)
d
12.4, 18.3, 113.6, 114.5, 121.7, 121.9, 122.9, 123.9, 124.4,
(400 MHz, DMSO-d6)
d
1.14 (18H, d, J¼7.5 Hz), 1.82 (3H, sept,
126.1, 126.2, 126.3, 126.5, 128.6, 129.9, 130.0, 134.3, 134.5, 135.5,
141.2, 164.1; HRMS (EI) calcd for C28H34N2OSi Mþ 442.2440, found
442.2445.
J¼7.5 Hz), 3.75 (3H, s), 6.84 (1H, dd, J¼2.7, 9.0 Hz), 7.50 (1H, d,
J¼9.0 Hz), 7.54e7.58 (3H, m), 7.62 (1H, d, J¼7.2 Hz), 7.77 (1H, d,
J¼2.7 Hz), 7.84 (1H, d, J¼7.2 Hz), 7.97e8.04 (2H, m), 8.47 (1H, s), 10.1
(1H, s); 13C NMR (100 MHz, DMSO-d6)
d 11.9, 17.8, 55.1, 103.0, 112.2,
3.11.17. 5-Fluoro-N-(naphthalen-1-yl)-1-triisopropylsilyl-1H-indole-
3-carboxamide (16b). Purified by column chromatography with
chloroformeethyl acetate (40:1) as an eluent; crystals; mp
145.9e148.3 ꢀC; IR (KBr) 3275, 3051, 2949, 2868, 1636, 1532, 1474,
1449, 1395, 1358, 1254, 1192, 1018, 883, 791, 768, 696, 527 cmꢁ1; 1H
112.8, 114.7, 123.5, 123.9, 125.6, 125.7, 125.8, 126.0, 128.1, 129.4,
130.4, 133.8, 134.0, 135.4, 135.5, 154.6, 163.7; HRMS (EI) calcd for
C
29H36N2O2Si Mþ 472.2546, found 472.2547.
3.11.22. 1-Benzyl-2-methyl-N-(naphthalen-1-yl)-1H-indole-3-
carboxamide (17g). Purified by column chromatography with
chloroformeethyl acetate (30:1) as an eluent; crystals; mp
185.3e186.1 ꢀC; IR (KBr) 3227, 3050, 2920, 1628, 1545, 1489, 1468,
NMR (400 MHz, DMSO-d6)
d
1.16 (18H, d, J¼7.5 Hz), 1.85 (3H, sept,
J¼7.5 Hz), 7.08 (1H, td, J¼2.8, 9.5 Hz), 7.56e7.66 (5H, m), 7.87 (1H, d,
J¼8.0 Hz), 7.96 (1H, dd, J¼2.8, 9.5 Hz), 7.99e8.05 (2H, m), 8.60 (1H,
s), 10.2 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d
11.8, 17.8, 105.9 (d,
1398, 1337, 1242, 1146, 1028, 793, 773, 737, 696 cmꢁ1
(400 MHz, DMSO-d6) d
;
1H NMR
2.69 (3H, s), 5.56 (2H, s), 7.10 (2H, d,
J¼7.0 Hz), 7.15e7.20 (2H, m), 7.24e7.29 (1H, m), 7.31e7.36 (2H, m),
J¼24.6 Hz), 109.2 (d, J¼4.6 Hz), 110.5 (d, J¼26.1 Hz), 110.4 (d,
J¼26.1 Hz),111.8 (d, J¼9.9 Hz),123.2,123.4,125.5,125.6,125.7,125.9,
Please cite this article in press as: Nemoto, K.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.12.028

12
K. Nemoto et al. / Tetrahedron xxx (2015) 1e12
Yoshida, H.; Egusa, N.; Morohashi, N.; Hattori, T. J. Org. Chem. 2010, 75, 7855; (d)
Nemoto, K.; Onozawa, S.; Konno, M.; Morohashi, N.; Hattori, T. Bull. Chem. Soc.
Jpn. 2012, 85, 369; (e) Konno, M.; Chiba, M.; Nemoto, K.; Hattori, T. Chem. Lett.
2012, 41, 913.
7.50e7.56 (4H, m), 7.71 (1H, d, J¼7.0 Hz), 7.82 (1H, d, J¼8.2 Hz),
7.92e8.00 (2H, m), 8.05e8.10 (1H, m), 9.83 (1H, s); 13C NMR
(100 MHz, DMSO-d6)
d 11.8, 45.8, 109.2, 110.2, 119.8, 120.6, 121.6,
15. See also: Tanaka, S.; Tanaka, Y.; Chiba, M.; Hattori, T. Tetrahedron Lett. 2015, 56,
122.5, 123.5, 125.5, 125.6, 125.7, 125.8, 125.9, 126.4, 127.3, 128.1,
128.7, 128.8, 133.8, 134.8, 135.9, 137.6, 140.5, 164.9; HRMS (EI) calcd
for C27H22N2O Mþ 390.1732, found 390.1735.
3830.
16. Preliminary communication: Nemoto, K.; Onozawa, S.; Egusa, N.; Morohashi,
N.; Hattori, T. Tetrahedron Lett. 2009, 50, 4512.
17. (a) Boldron, C.; Besse, A.; Bordes, M.-F.; Tissandie, S.; Yvon, X.; Gau, B.; Badorc,
A.; Rousseaux, T.; Barre, G.; Meneyrol, J.; Zech, G.; Nazare, M.; Fossey, V.; Pfieger,
A.-M.; Bonnet-Lignon, S.; Millet, L.; Briot, C.; Dol, F.; Herault, J.-P.; Savi, P.;
Lassalle, G.; Delesque, N.; Herbert, J.-M.; Bono, F. J. Med. Chem. 2014, 57, 7293;
(b) Ivachtchenko, A. V.; Yamanushkin, P. M.; Mitkin, O. D.; Kisil, V. M.; Korzinov,
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Ivashchenko, A. A.; Ivanenkov, Y. A. Pharm. Chem. J. 2015, 49, 151.
18. For example, selective (GR 125487) or potent fluorinated serotonin receptor
antagonists (SDZ 206-830) have been reported: (a) Candura, S. M.; Messori, E.;
Franceschetti, G. P.; D’Agostino, G.; Vicini, D.; Tagliani, M.; Tonini, M. Br. J.
Pharmacol. 1996, 118, 1965; (b) Hoyer, D.; Neijt, H. C. Mol. Pharmacol. 1988, 33,
303.
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3.11.23. 1-Benzyl-N-(naphthalen-1-yl)-2-phenyl-1H-indole-3-car-
boxamide (17h). Purified by column chromatography with chlor-
oformeethyl acetate (40:1) as an eluent; crystals; mp
189.0e190.6 ꢀC; IR (KBr) 3410, 3051, 1655, 152, 1497, 1460, 1397,
1337, 1256, 1159, 1119, 79, 773, 754, 737, 702, 597 cmꢁ1 1H NMR
;
(400 MHz, DMSO-d6)
d
5.36 (2H, s), 6.81 (1H, d, J¼8.5 Hz), 6.95 (2H,
d, J¼6.8 Hz), 7.42e7.50 (3H, m), 7.16e7.28 (6H, m), 7.52e7.60 (3H,
m), 7.62e7.70 (3H, m), 7.86 (1H, d, J¼8.1 Hz), 8.04 (1H, d, J¼7.4 Hz),
8.12e8.17 (1H, m), 8.91 (1H, s); 13C NMR (100 MHz, DMSO-d6)
d
46.7, 110.8, 111.2, 119.5, 120.8, 121.3, 121.5, 122.8, 124.3, 125.5,
125.6, 125.8, 126.2, 126.6, 126.8, 127.3, 128.1, 128.5, 129.0, 129.7,
130.4, 130.9, 133.5, 133.6, 136.0, 137.4, 141.3, 163.5; HRMS (EI) calcd
for C32H24N2O Mþ 452.1889, found 452.1898.
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Acknowledgements
This study was supported in part by a Grant-in-Aid for Scientific
Research on a Priority Area ‘Advanced Molecular Transformations
of Carbon Resources’ from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. T.H. thanks Kazuo Tanaka,
the Koheleth private foundation for financial support.
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4854.
Supplementary data
Supplementary data (1H and 13C NMR spectral charts for novel
compounds) associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2015.12.028.
27. Diana, P.; Carbone, A.; Barraja, P.; Kelter, G.; Fiebig, H.-H.; Cirrincione, G. Bioorg.
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