A general synthesis of indole-3-carboxylic esters by palladium-catalyzed direct oxidative carbonylation of 2-alkynylaniline derivatives

Article abstract of DOI:10.1002/ejoc.201200120

A general synthesis of indole-3-carboxylic esters by direct Pd-catalyzed oxidative carbonylation of readily available 2-alkynylaniline derivatives is reported. In particular, 2-alkynylanilines bearing an internal triple bond and a secondary amino group (1) were directly converted into indole-3-carboxylic esters 2 in fair to good yields (50-84%) when let to react with CO, O ₂, and an alcohol in the presence of the PdI2/ KI catalytic system, under relatively mild conditions [100 °C and 20 atm (at 25 °C) of a 4:1 mixture CO/air]. On the other hand, under similar conditions, but in the presence of HC(OMe)₃, 2-alkynylanilines bearing an internal triple bond and a primary amino group (7) afforded 1-(dimethoxymethyl) indole-3-carboxylic esters 9 through the intermediate formation of N-(dimethoxymethyl)-2-alkynylaniline derivatives II. Compounds 9 could be conveniently converted into Nunsubstituted indole-3-carboxylic esters 10 by a simple acidic treatment carried out in MeOH/H₂O at 80 °C.

Full text of DOI:10.1002/ejoc.201200120

FULL PAPER
DOI: 10.1002/ejoc.201200120
A General Synthesis of Indole-3-carboxylic Esters by Palladium-Catalyzed
Direct Oxidative Carbonylation of 2-Alkynylaniline Derivatives
Bartolo Gabriele,*[a] Lucia Veltri,[b] Raffaella Mancuso,[b] Giuseppe Salerno,[b] and
Mirco Costa[c]
Keywords: Synthetic methods / Nitrogen heterocycles / Alkynes / Carbonylation / Cyclization / Palladium
A general synthesis of indole-3-carboxylic esters by direct
Pd-catalyzed oxidative carbonylation of readily available 2-
alkynylaniline derivatives is reported. In particular, 2-alk-
ynylanilines bearing an internal triple bond and a secondary
amino group (1) were directly converted into indole-3-carb-
oxylic esters 2 in fair to good yields (50–84%) when let to
react with CO, O2, and an alcohol in the presence of the PdI2/
KI catalytic system, under relatively mild conditions [100 °C
and 20 atm (at 25 °C) of a 4:1 mixture CO/air]. On the other
hand, under similar conditions, but in the presence of
HC(OMe)3, 2-alkynylanilines bearing an internal triple bond
and a primary amino group (7) afforded 1-(dimethoxymeth-
yl)indole-3-carboxylic esters 9 through the intermediate for-
mation of N-(dimethoxymethyl)-2-alkynylaniline derivatives
II. Compounds 9 could be conveniently converted into N-
unsubstituted indole-3-carboxylic esters 10 by a simple
acidic treatment carried out in MeOH/H2O at 80 °C.
suitably substituted arylhydroxylamines and methyl pro-
piolate,[14] the Pd0-catalyzed intramolecular α-arylation of
β-(2-iodoanilino) esters,[15] the CuI-catalyzed intramolecu-
lar amination of (2-bromophenyl)acetates,[16] and the Pd0-
catalyzed reductive cyclization of 2-(2-nitrophenyl)acryl-
ates,[17] among others.[18] Metallation of the indole ring at
C-3 followed by the reaction with an alkyl chloroformate
has also been reported.[19]
An attractive alternative method for the synthesis of in-
dole-3-carboxylic esters 2 would consist in the direct oxidat-
ive carbonylation of 2-alkynylanilines 1, according to Equa-
tion (1). The possibility to obtain some particular indole-3-
carboxylic esters by oxidative carbonylation of simple or N-
(methylsulfonyl)-substituted 2-alkynylanilines has been
briefly mentioned in the literature (30–76%, 4 examples).[20]
The general applicability of this method, however, was not
demonstrated; moreover, an excess of a metallic reoxidant
(CuCl2, 3 equiv. with respect to the substrate) and of two
different bases (2 equiv. of AcONa and 2 equiv. of K2CO3)
was needed for the reaction to occur, with a maximum turn-
over number of ca. 11 mol of product per mol of palladium.
Therefore, the development of a more efficient, selective
and general method for the direct synthesis of 2 by oxidat-
ive carbonylation of 1 is still highly desirable. In this work,
we report such a method, which is based on the use of the
Introduction
Indole-3-carboxylic esters are a very important class of
heterocyclic compounds. A variety of molecules incorporat-
ing this heterocyclic motif has in fact shown a wide range of
biological activities,[1–10] including anticancer,[1] antiviral,[2]
antibacterial,[3] antiinflammatory,[4] 5-HT4 antagonist,[5] in-
hibitor of 5-lipoxygenase,[6] serotonin receptor antagonist,[7]
modulator of nicotinic receptors,[8] and S1P receptor antag-
onist[9] activities, among others.[10] Moreover, these com-
pounds have proved to be valuable synthetic intermediates
for the preparation of different indole derivatives.[11] Indole-
3-carboxylic esters have been so far obtained by various
synthetic approaches. More specifically, compounds be-
longing to the sub-class of 5-oxyindole-3-carboxylic ester
have been prepared by a classical method, involving the re-
action between benzoquinone and β-aminocrotonic esters
(Nenitzescu reaction).[12] More recently, several novel ap-
proaches have been developed, mainly based on cyclization
reactions and transition-metal catalysis, which include the
intramolecular Pd-catalyzed condensation of halophenylen-
amino esters,[13] the DMAP-promoted reaction between
[a] Dipartimento di Scienze Farmaceutiche, Università della
Calabria,
87036 Arcavacata di Rende (CS), Italy
Fax: +39-0984-492044
E-mail: b.gabriele@unical.it
[b] Dipartimento di Chimica, Università della Calabria,
87036 Arcavacata di Rende (CS), Italy
[c] Dipartimento d Chimica Organica e Industriale, Università di
Parma,
43100 Parma, Italy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200120.
Eur. J. Org. Chem. 2012, 2549–2559
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FULL PAPER
PdI2/KI system as the catalyst,[21] in the presence of only (Scheme 1; anionic iodide ligands are omitted for clar-
oxygen as the oxidizing agent; see Equation (1), catalyst: ity).[22] Reactions were carried out at 80 °C in a 3:1
PdI2/KI, [OX] = (1/2)O2, [OXH2] = H2O.
HC(OMe)3/MeOH mixture as the solvent, in the presence
of 2 mol-% of PdI2 in conjunction with an excess of KI (KI/
PdI2 molar ratio 10:1), and under a total pressure of 40 atm
of a 4:1 mixture CO/air.
Results and Discussion
The reactivity showed by [(alkoxymethyl)(2-alkynylaryl)]-
amines I in this process was completely different from that
we previously observed in the case of 2-ethynylanilines
bearing a terminal triple bond and a primary or secondary
amino group (5) which, under analogous conditions, selec-
tively led to dihydroindol-2-one derivatives 6 through a cy-
clocarbonylation–alkoxycarbonylation process, (Scheme 2,
path a),[23] and from that observed in the case of 2-alk-
ynylanilines bearing an internal triple bond and a primary
amino group (7), which led to the formation of acyclic carb-
amates 8 through the intermediate formation of isocyanates
(Scheme 2, path b).[23,24]
We have recently reported an innovative approach to 1-
(alkoxyarylmethyl)indole-3-carboxylic esters 4, based on an
unprecedented multicomponent cascade reaction, involving
ROH addition to the imino group of 2-alkynylaniline
imines 3 to give [(alkoxymethyl)(2-alkynylaryl)]amines I as
intermediates, followed by the PdI2-catalyzed reaction of
the latter with CO, ROH, and O2 to give the final products
In fact, in the case of I (Scheme 1), formation of an iso-
cyanate cannot occur, since the amino group in I is second-
ary, while the cyclocarbonylation-alkoxycarbonylation
mechanism is hindered by the fact that an internal triple
bond does not insert into a palladium-carbamoyl bond for
steric reasons.[25] Therefore, an alternative mechanism takes
place, involving 5-endo-dig intramolecular nucleophilic at-
tack of nitrogen to the triple bond coordinated to PdII, fol-
lowed by alkoxycarbonylation, to give 2, HI and Pd0. The
latter is then reoxidated to PdI2 according to the mecha-
nism we demonstrated several years ago,[26] involving oxi-
dation of HI by O2 to give I2, followed by oxidative addition
of the latter to Pd0 to regenerate PdI2 (Scheme 1).
Scheme 1. Multicomponent cascade reaction leading to 1-(alkoxy-
arylmethyl)indole-3-carboxylic esters
imines 3 through the intermediate formation of [(alkoxymethyl)(2-
4 from 2-alkynylaniline
These results and considerations prompted us to study
in detail the reactivity of N-substituted 2-alkynylanilines 1,
alkynylaryl)]amines I.[22]
Scheme 2. Formation of dihydroindol-2-one derivatives 6 and (2-alkynylphenyl)carbamates 8 through PdI2/KI-catalyzed oxidative carb-
onylation of 2-alkynylaniline derivatives 5 and 7, respectively.[23,24]
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General Synthesis of Indole-3-carboxylic Esters
bearing a secondary amino group and an internal triple Table 1. Reactions of N-benzyl-2-(phenylethynyl)aniline (1a) with
CO, O2 and MeOH in the presence of PdI2/KI catalytic system.[a]
bond, under PdI2-catalyzed oxidative carbonylation condi-
tions, in order to develop a general and convenient synthe-
sis of indole-3-carboxylic esters 2, according to Scheme 3.
Entry
KI/PdI2
molar ratio
T [°C] Conc. t [h] Conv. of Yield of
of 1a[b]
1a [%][c] 2a [%][d]
1
10
10
5
50
10
10
10
10
10
80
80
80
80
80
80
80
100
100
0.2
0.2
0.2
0.2
0.5
0.1
0.05
0.2
0.2
3
3
3
3
3
3
3
1
1
90
79
93
38
95
87
83
100
100
64
56
61
16
15
72
75
72
66
2[e]
3
4
5
6
7
8
9[f]
[a] Unless otherwise noted, all reactions were carried out under
20 atm (at 25 °C) of a 4:1 mixture of CO/air in the presence of
2 mol-% of PdI2. [b] Mmol of starting 1a per mL of solvent. [c]
Determined by GLC. [d] GLC yield based on starting 1a. The for-
mation of unidentified heavy products (chromatographically immo-
bile materials) accounted for the difference between the substrate
conversion and the product yield. [e] The reaction was carried out
under 40 atm (at 25 °C) of a 4:1 mixture CO/air. [f] The reaction
was carried out with 1 mol-% of PdI2.
Scheme 3. Mechanistic hypothesis for the formation of indole-3-
carboxylic esters 2 by PdI2-catalyzed oxidative carbonylation of N-
substituted 2-alkynylanilines 1, bearing a secondary amino group
and an internal triple bond.
N-Benzyl-2-(phenylethynyl)aniline (1a) was used as a
model substrate for assessing the reactivity of secondary 2-
alkynylanilines 1 under PdI2-catalyzed oxidative carb-
onylation conditions. Carbonylation of 1a was initially car-
ried out in MeOH at 80 °C and under 20 atm (at 25 °C) of
This very promising initial result confirmed the validity
a 4:1 mixture of CO/air, in the presence of 2 mol-% of PdI2 of our work hypothesis (Scheme 3). We then carried out a
and 20 mol-% of KI, with a substrate concentration of systematic study on the influence of the reaction parameters
0.2 mmol per mL of solvent. After 3 h, conversion of 1a on product yield; the results obtained by varying pressure,
was ca. 90%, with formation of methyl 1-benzyl-2-phenyl- KI/PdI2 molar ratio, temperature, 1a concentration, and 1a/
1H-indole-3-carboxylate (2a) in 64% GLC (Table 1, entry Pd molar ratio are reported in Table 1, entries 2–9. As can
1).
be seen from Table 1, the optimal reaction conditions in
Table 2. Synthesis of N-substituted indole-3-carboxylic esters 2 by PdI2/KI-catalyzed oxidative carbonylation of N-substituted 2-alk-
ynylanilines 1.[a]
Entry
1
R
R1
R2
R3
R4
Time [h]
2
Yield of 2 [%][b]
1
2
3
4
1a
1b
1c
1d
1e
1f
1g
1h
1i
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bu
iBu
Bn
Bn
Ph
p-Br-C6H4
p-Me-C6H4
H
H
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
1.5
2
1
2
3
1
3
3
3
2a
2b
2c
2d
2e
2f
2g
2h
2i
72 (76)
74
81
74
69
77
73
78
72
Bu
Ph
Ph
Ph
Ph
Ph
Bu
H
5
Cl
Me
H
H
H
H
H
Me
6
H
7[c]
8
CF3
Me
H
H
H
9
10
11
12
1j
1c
1f
5
2
3
2j
2cЈ
2fЈ
50
84
73
p-Me-C6H4
Ph
H
Et
[a] Unless otherwise noted, all reactions were carried out in ROH (substrate concentration: 0.05 mmol of 1 per mL of ROH) at 100 °C
under 20 atm (at 25 °C) of a 4:1 mixture of CO/air in the presence of 2 mol-% of PdI2 and 20 mol-% of KI. [b] Isolated yield (GLC yield)
based on starting 1. [c] The reaction was carried out with a substrate concentration of 0.2 mmol of 1g per mL of MeOH.
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FULL PAPER
Scheme 4. Formation of 1-(dialkoxymethyl)indole-3-carboxylic esters 9 from primary 2-alkynylanilines 7 in the presence of HC(OR4)3,
and hydrolysis of 9 to give N-unsubstituted indole-3-carboxylic esters 10.
terms of product yield corresponded to a substrate concen- (Scheme 4). N-unsubstitued indole-3-carboxylic esters 10
tration of 0.05 mmol of 1a per mL of MeOH at 100 °C and would then be easily produced by removal of the acetal
under 20 atm total pressure, in the presence of 2 mol-% of group of 9 under acidic conditions (Scheme 4).
PdI2 in conjunction with 20 mol-% of KI. Under these con-
ditions, 2a was obtained, after 1.5 h reaction time, in 76% H) was allowed to react under the conditions already opti-
GLC yield (72% isolated, Table 2, entry 1). mized for N-substituted 2-alkynylanilines 1 [100 °C and
Thus, 2-(phenylethynyl)aniline 7a (R1 = Ph, R2 = R3 =
The reaction was then successfully extended to several 20 atm (at 25 °C) of a 4:1 mixture CO/air, in the presence
differently substituted 2-alkynylaniniles bearing a second- of 2 mol-% of PdI2 and 20 mol-% of KI, 7a concentration
ary amino group 1b–j, as shown by the results reported in = 0.05 mmol of 7a per mL of solvent], but in a 2:1
Table 2, entries 2–10. As can be seen, fair to high yields HC(OMe)3/MeOH mixture as the solvent (R4 = Me). After
(50–81%) of the corresponding N-substituted indole-3- 3 h, methyl 1-(dimethoxymethyl)-2-phenyl-1H-indole-3-
carboxylic esters 2b–j could be obtained by varying the sub- carboxylate (9a) and methyl 2-phenyl-1H-indole-3-carb-
stituent on the triple bond as well as on nitrogen and on the oxylate (10a) were indeed obtained in 46% and 2% isolated
aromatic ring. In particular, electron-withdrawing as well yields, respectively (Table 3, entry 1). According to the syn-
as electron-releasing groups on the aromatic ring could be thetic hypothesis shown in Scheme 4, selective formation of
tolerated, and both benzyl and simple alkyl groups (includ- the N-unsubstituted indole 10a (48% isolated yield) was at-
ing bulky substituents, such as isobutyl, entry 10) could be tained after treatment of the carbonylation crude with
present on nitrogen. In the case of particularly deactivated aqueous HCl (Table 3, entry 1). A higher overall isolated
substrates, such as 1g (R3 = CF3), better results were ob- yield of 10a (55%) could be obtained by carrying out the
served working with a higher substrate concentration carbonylation step in the presence of a larger amount of
(Table 2, entry 7). The reaction could also be carried out catalyst (5 mol-%, Table 3, entry 2). The validity of this 2-
using a higher alcohol, such as EtOH, as the reactant and step protocol was then assessed with other substrates 7b–d,
solvent, as shown in Table 2, entries 11 and 12.
bearing different aryl or alkyl substituents on the triple
As we have seen above, N-unsubstituted indole-3-carbox- bond (R1 = 3-thienyl, p-Br-C6H4, butyl), which were suc-
ylic esters could not be obtained by direct PdI2/KI-cata- cessfully converted into the corresponding indole-3-carbox-
lyzed oxidative carbonylation of primary 2-alkynylanilines ylic esters 10b–d in moderate to fair overall yields (45–63%,
7, since acyclic carbamates
8 were formed instead Table 3, entries 3–5).
(Scheme 2, path b). We have, however, explored the possibil-
ity to obtain N-unsubstituted indole-3-carboxylic esters in
an indirect way, by transforming in situ the primary amino
group of 7 into a secondary group using an easily remov-
able substituent. We accordingly tested the reactivity of 7
Conclusions
In conclusion, we have found that a variety of 2-alk-
under oxidative carbonylation conditions and in the pres- ynylanilines bearing an internal triple bond and a second-
ence of HC(OR)3, in order to obtain the selective formation ary amino group (1) can be conveniently converted into N-
of 1-(dialkoxymethyl)indole-3-carboxylic esters 9 through substituted indole-3-carboxylic esters 2 in fair to high yields
the intermediate formation of acetal derivatives II (50–84%) in one step by PdI2/KI-catalyzed oxidative 5-
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General Synthesis of Indole-3-carboxylic Esters
Table 3. Synthesis of N-unsubstituted indole-3-carboxylic esters 10
by PdI2/KI-catalyzed oxidative carbonylation of primary 2-alk-
ynylanilines 7 followed by acidic treatment.[a,b]
Experimental Section
General: Melting points were taken on a Reichert Thermovar appa-
1
ratus. H NMR and 13C NMR spectra were recorded at 25 °C in
CDCl3 solutions with a Bruker DPX Avance 300 or 500 spectrome-
ter operating at 300 MHz and 75 MHz, or 500 MHz and 126 MHz,
respectively, with Me4Si as internal standard. 19F NMR spectra
were recorded at 25 °C in CDCl3 solutions with a Bruker DPX
Avance 500 spectrometer at 471 MHz with CF2Br2 as internal stan-
dard. Chemical shifts (δ) and coupling constants (J) are given in
ppm and in Hz, respectively. IR spectra were taken with a JASCO
FT-IR 4200 spectrometer. Mass spectra were obtained using a Shi-
madzu QP-2010 GC–MS apparatus at 70 eV ionization voltage or
an ABSciex API 2000 mass spectrometer equipped with a turbo
ion spray ionization source in the positive mode [ion spray voltage
(IS) 4500 V; curtain gas 10 psi; temperature 25 °C; ion source gas
(1) 20 psi; declustering and focusing potentials 50 and 400 V,
respectively]. Microanalyses were carried out with a Carlo Erba
Elemental Analyzer Mod. 1106. All reactions were analyzed by
TLC on silica gel 60 F254 (Merck) or on neutral alumina (Merck)
and by GLC using a Shimadzu GC-2010 gas chromatograph and
capillary columns with polymethylsilicone + 5% phenylsilicone as
the stationary phase (HP-5). Column chromatography was per-
formed on silica gel 60 (Merck, 70–230 mesh) or neutral alumina
90 (Merck, 70–230 mesh). Evaporation refers to the removal of sol-
vent under reduced pressure.
Entry
7
R1
Yield of
Yield of
Overall yield
9 [%][c]
10 [%][c]
of 10 [%][d]
1[e]
2
3
4
5
7a Ph
7a Ph
7b 3-thienyl
7c p-Br-C6H4
7d Bu
46
52
59
58
30
2
4
5
0
16
48
55
63
56
45
Preparation of Substrates: N-Substituted 2-alkynylanilines 1a–j
were prepared by reductive amination of the corresponding pri-
mary 2-alkynylanilines [prepared in their turn by Sonogashira cou-
pling between the appropriate 2-haloaniline and 1-alkynes, as we
previously described[22] and as described below for 4-methyl-2-
(phenylethynyl)aniline]. All other materials were commercially
available and were used without further purification.
[a] Unless otherwise noted, all carbonylation reactions were carried
out at 100 °C for 3 h under 20 atm (at 25 °C) of a 4:1 mixture of
CO/air, in a 2:1 (v/v) HC(OMe)3/MeOH mixture as the solvent
(0.05 mmol of starting 7 per mL of solvent, 1–2 mmol scale based
on 7), in the presence of 5 mol-% of PdI2 and with a KI/PdI2 molar
ratio of 10:1. [b] The acidic treatment was carried out on the crude
products deriving from the carbonylation reaction, by dilution with
MeOH, water and concd. HCl followed by heating of the resulting
mixture at 80 °C for 15 h (see the Exp. Section for details). [c] Iso-
lated yield based on starting 7, referred to the oxidative carb-
onylation step. [d] Overall isolated yield based on starting 7, re-
ferred to the oxidative carbonylation step followed by the acidic
treatment. [e] The carbonylation reaction was carried out in the
presence of 2 mol-% of PdI2 and 20 mol-% of KI.
Preparation of 4-Methyl-2-(phenylethynyl)aniline: To a stirred solu-
tion of 2-iodo-4-methylaniline[27] (1.6 g, 6.9 mmol) in DMF (1 mL)
and Et2NH (1 mL) were added under nitrogen phenylacetylene
(0.91 g, 8.9 mmol), Pd(PPh3)4 (40 mg, 0.034 mmol) and CuI
(13 mg, 0.068 mmol). The reaction mixture was stirred overnight
under nitrogen at room temperature, and then 0.1 n HCl (30 mL)
and Et2O (30 mL) were added. The organic layer was separated,
the aqueous layer was extracted with diethyl ether (2ϫ 30 mL),
and the combined organic phases were dried with Na2SO4. After
filtration and evaporation of the solvent, the product was purified
by column chromatography on silica gel using 9:1 hexane/AcOEt
as eluent, to give 4-methyl-2-(phenylethynyl)aniline as a yellow so-
lid (m.p. 129–131 °C, ref.[28] 129–130 °C), whose spectroscopic data
agreed with those reported in the literature[28,29] (yield: 1.01 g, 71%
based on starting 2-iodo-4-methylaniline).
endo-dig heterocyclization-alkoxycarbonylation, carried out
using only oxygen as the oxidant. This reactivity is comple-
mentary to that we previously observed in the case of 2-
ethynylanilines bearing a terminal triple bond and a pri-
mary or secondary amino group (5) which, under analo-
gous conditions, selectively led to dihydroindol-2-one deriv-
atives 6,[23] and to that observed in the case of 2-alkynylanil-
ines bearing an internal triple bond and a primary amino
General Procedure for the Preparation of N-Substituted 2-Alk-
ynylaniline 1a–j: To a stirred solution of the 2-alkynylaniline deriva-
tive (9.61 mmol) [2-(phenylethynyl)aniline: 1.86 g; 2-(4-bromophen-
group (7), which led to the formation of acyclic carbamates ylethynyl)aniline: 2.62 g; 2-(p-tolylethynyl)aniline: 1.99 g; 2-(hex-1-
8.[23,24]
ynyl)aniline: 1.66 g; 4-chloro-2-(phenylethynyl)aniline: 2.19 g; 4-
methyl-2-(phenylethynyl)aniline: 1.99 g; 5-(trifluoromethyl)-2-
(phenylethynyl)aniline: 2.51 g; 5-methyl-2-(phenylethynyl)aniline:
We have also found that an indirect way to obtain N-
unsubstituted indol-3-carboxylic esters 10 from 7 may con-
1.99 g] in anhydrous MeOH (37 mL) were added under nitrogen the
sist in a simple 2-step procedure, involving oxidative carb-
aldehyde (11.5 mmol) (benzaldehyde: 1.22 g; butyraldehyde: 0.83 g;
onylation of 7 carried out in the presence of trimethyl or-
isobutyraldehyde: 0.83 g), anhydrous ZnCl2 (1.57 g, 11.5 mmol)
thoformate [which in situ converts the primary amino group
of 7 into a secondary N-(dimethoxymethyl)amino group],
and NaBH3CN (0.72 g, 11.5 mmol). The reaction mixture was re-
fluxed under nitrogen for 2 h. After cooling, the reaction mixture
to give 1-(dialkoxymethyl)indole-3-carboxylic esters 9, fol-
lowed by acidic treatment of the reaction crude to achieve
nitrogen deprotection.
was diluted with 1 m aqueous NaOH (12 mL), concentrated by ro-
tary evaporation and then extracted with Et2O (3ϫ 20 mL). The
combined organic phases were dried with Na2SO4. After filtration
Eur. J. Org. Chem. 2012, 2549–2559
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B. Gabriele, L. Veltri, R. Mancuso, G. Salerno, M. Costa
FULL PAPER
and evaporation of the solvent, the products were purified by col-
umn chromatography on silica gel using 9:1 hexane/AcOEt as the
eluent.
65 (21). C19H21N (263.38): C 86.65, H 8.04, N 5.32; found C 86.64,
H 8.06, N 5.30.
N-Benzyl-4-chloro-2-(phenylethynyl)aniline (1e): Yield: 2.07 g, start-
N-Benzyl-2-(phenylethynyl)aniline (1a): Yield: 1.99 g, starting from
ing from 2.19 g of 4-chloro-2-(phenylethynyl)aniline (68%). Yellow
1.86 g of 2-(phenylethynyl)aniline (73%). Colorless solid, m.p. 56–
solid, m.p. 83–86 °C. IR (KBr): ν = 3398 (m), 2205 (vw), 1591 (w),
˜
57 °C. IR (KBr): ν = 3410 (m), 2208 (w), 1581 (m), 1575 (m), 1510 1566 (w), 1488 (s), 1468 (m), 1412 (m), 1384 (m), 1321 (m), 1262
˜
(s), 1430 (m), 1384 (m), 1326 (m), 1265 (m), 1162 (w), 1024 (w),
749 (s), 692 (m) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.53–7.44
(m, 2 H, aromatic), 7.43–7.24 (m, 9 H, 8 H aromatic + 3-H), 7.19–
7.10 (m, 1 H, 5-H), 6.66 (td, J = 7.5, 1.0 Hz, 1 H, 4-H), 6.57 (dis-
torted d, br., J = 8.5, 0.8 Hz, 1 H, 6-H), 5.13 (br. s, 1 H, NH), 4.42
(m), 1150 (w), 1121 (w), 1067 (w), 879 (m), 803 (m), 754 (s), 689
(s) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.50–7.44 (m, 2 H,
aromatic), 7.37–7.25 (m, 9 H, 8 H aromatic + 3-H), 7.08 (dd, J =
8.9, 2.4 Hz, 1 H, 5-H), 6.47 (d, J = 8.9 Hz, 1 H, 6-H), 5.12 (t, br.,
J = 5.7 Hz, 1 H, NH), 4.43 (d, J = 5.7 Hz, 2 H, CH2Ph) ppm. 13C
(d, J = 4.9 Hz, 2 H, CH2Ph) ppm. 13C NMR (75 MHz, CDCl3): δ NMR (75 MHz, CDCl3): δ = 147.3, 138.7, 131.5, 131.4, 129.8,
= 148.7, 139.2, 132.2, 131.4, 130.0, 128.7, 128.37, 128.18, 127.2,
127.1, 123.3, 116.7, 110.0, 107.6, 95.3, 86.1, 47.7 ppm. GC–MS:
128.8, 128.5, 128.4, 127.4, 127.0, 122.8, 121.0, 111.1, 109.0, 96.2,
84.7, 47.8 ppm. GC–MS: m/z (%) = 319 (9) [M + 2]+, 317 (26)
m/z (%) = 283 (20) [M+], 207 (17), 206 (100), 204 (11), 178 (7), 165 [M+], 316 (11), 242 (32), 240 (100), 204 (10), 191 (10), 190 (8), 176
(12), 128 (4), 91 (22), 65 (9). C21H17N (283.37): C 89.01, H 6.05,
N 4.94; found C 89.01, H 6.07, N 4.92.
(5), 164 (9), 163 (9), 91 (34), 65 (11). C21H16ClN (317.81): C 79.36,
H 5.07, Cl 11.16, N 4.41; found C 79.40, H 5.06, Cl 11.14, N 4.40.
N-Benzyl-2-(4-bromophenylethynyl)aniline (1b): Yield: 2.60 g, start-
N-Benzyl-4-methyl-2-(phenylethynyl)aniline (1f): Yield: 2.21 g, start-
ing from 2.62 g of 2-(4-bromophenylethynyl)aniline (75%). Yellow
ing from 1.99 g of 4-methyl-2-(phenylethynyl)aniline (77%). Yellow
solid, m.p. 67–68 °C. IR (KBr): ν = 3409 (m), 2210 (w), 1600 (m), solid, m.p. 36–37 °C. IR (KBr): ν = 3483 (m), 2196 (w), 1614 (w),
˜
˜
1571 (m), 1511 (s), 1384 (m), 1327 (m), 1266 (m), 1163 (w), 1067 1511 (s), 1489 (w), 1451 (w), 1401 (m), 1384 (m), 1317 (m), 1273
(w), 1008 (m), 827 (m), 750 (s) cm–1. 1H NMR (300 MHz, CDCl3): (w), 1157 (w), 1068 (w), 1024 (w), 792 (m), 731 (m), 685 (m) cm–1.
δ = 7.49–7.43 (m, 2 H, aromatic), 7.42–7.27 (m, 8 H, 7 H aromatic
+ 3-H), 7.21–7.13 (m, 1 H, 5-H), 6.67 (td, J = 7.7, 0.8 Hz, 1 H, 4-
1H NMR (300 MHz, CDCl3): δ = 7.50–7.44 (m, 2 H, aromatic),
7.40–7.19 (m, 9 H, 8 H aromatic + 3-H), 6.96 (dd, J = 8.5, 1.8 Hz,
H), 6.58 (br. d, J = 8.5 Hz, 1 H, 6-H), 5.08 (br. s, 1 H, NH), 4.46 1 H, 5-H), 6.48 (d, J = 8.5 Hz, 1 H, 6-H), 4.99 (t, br., J = 5.7 Hz,
(d, J = 5.3 Hz, 2 H, CH2Ph) ppm. 13C NMR (75 MHz, CDCl3): δ 1 H, NH), 4.42 (d, J = 5.7 Hz, 2 H, CH2Ph), 2.21 (s, 3 H, Me)
= 148.8, 139.0, 132.8, 132.2, 131.6, 130.3, 128.7, 127.3, 127.0, 122.4,
ppm. 13C NMR (75 MHz, CDCl3): δ = 146.6, 139.4, 132.4, 131.4,
122.2, 116.7, 110.0, 107.2, 94.2, 87.2, 47.7 ppm. GC–MS: m/z (%) 130.7, 128.6, 128.4, 128.1, 127.1, 127.0, 125.7, 123.3, 110.1, 107.5,
= 363 (27) [M + 2]+, 361 (27) [M+], 286 (95), 284 (100), 206 (55), 95.0, 86.2, 47.9, 20.2 ppm. GC–MS: m/z (%) = 297 (28) [M+], 296
204 (30), 191 (18), 190 (17), 176 (9), 164 (20), 163 (18), 91 (57), 65
(17). C21H16BrN (362.26): C 69.62, H 4.45, Br 22.06, N 3.87; found
C 69.54, H 4.46, Br 22.12, N 3.88.
(12), 221 (19), 220 (100), 204 (11), 191 (10), 178 (15), 152 (5), 91
(34), 65 (11). C22H19N (297.39): C 88.85, H 6.44, N 4.71; found C
88.82, H 6.46, N 4.72.
N-Benzyl-2-(p-tolylethynyl)aniline (1c): Yield: 2.07 g, starting from
1.99 g of 2-(2-p-tolylethynyl)aniline (72%). Colorless solid, m.p.
N-Benzyl-2-(phenylethynyl)-5-(trifluoromethyl)aniline (1g): Yield:
2.75 g, starting from 2.51 g of 5-(trifluoromethyl)-2-(phenylethyn-
73–75 °C. IR (KBr): ν = 3410 (m), 2207 (vw), 1600 (m), 1572 (m), yl)aniline (82%). Colorless solid, m.p. 54–56 °C. IR (KBr): ν =
˜
˜
1512 (s), 1448 (m), 1384 (w), 1362 (m), 1326 (m), 1266 (m), 1180 3436 (m), 2204 (vw), 1612 (m), 1577 (m), 1521 (w), 1434 (m), 1335
(w), 1163 (w), 1061 (w), 1017 (w), 989 (w), 930 (w), 818 (s), 749 (s), (s), 1274 (m), 1163 (s), 1120 (s), 1081 (w), 1021 (w), 913 (w), 850
728 (s), 695 (m) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.20
(m, 8 H, 7 H aromatic + 3-H), 7.15–7.06 (m, 3 H, 2 H aromatic +
5-H), 6.63 (td, J = 7.7, 0.8 Hz, 1 H, 4-H), 6.54 (d, J = 8.1 Hz, 1
H, 6-H), 5.13 (t, br., J = 4.8 Hz, 1 H, NH), 4.39 (d, J = 4.8 Hz, 2
(w), 814 (m), 755 (m), 689 (m) cm–1. 1H NMR (300 MHz, CDCl3):
δ = 7.49–7.42 (m, 2 H, aromatic), 7.40–7.25 (m, 9 H, 8 H aromatic
+ 3-H), 6.90 (br. d, J = 8.1 Hz, 1 H, 4-H), 6.80 (br. s, 1 H, 6-H),
5.24 (t, br., J = 5.7 Hz, 1 H, NH), 4.45 (d, J = 5.7 Hz, 2 H, CH2Ph)
H, CH2Ph), 2.31 (s, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): ppm. 13C NMR (75 MHz, CDCl3): δ = 148.7, 138.3, 132.3, 131.60
δ = 148.6, 139.1, 138.3, 132.0, 131.3, 129.8, 129.1, 128.6, 127.1,
127.0, 120.2, 116.6, 109.9, 107.8, 95.4, 85.3, 47.6, 21.4 ppm. GC–
(q, J = 32.0 Hz), 131.56, 128.9, 128.7, 128.5, 127.6, 127.2, 124.2 (q,
J = 272.6 Hz), 122.6, 113.1 (q, J = 4.0 Hz), 111.0, 106.2 (q, J =
MS: m/z (%) = 297 (29) [M+], 296 (18), 221 (19), 220 (100), 206 4.0 Hz), 97.1, 84.7, 47.7 ppm. 19F NMR (471 MHz, CDCl3): δ =
(24), 204 (13), 191 (6), 179 (8), 178 (12), 165 (2), 152 (3), 128 (4), –63.0 (s, 3 F, CF3) ppm. GC–MS: m/z (%) = 351 (19) [M+], 275
115 (2), 91 (13). C22H19N (297.39): C 88.85, H 6.44, N 4.71; found (19), 274 (100), 233 (8), 204 (7), 190 (7), 163 (4), 91 (76), 65 (24).
C 88.84, H 6.46, N 4.70.
C22H16F3N (351.36): C 75.20, H 4.59, F 16.22, N 3.99; found C
75.16, H 4.57, F 16.27, N 4.00.
N-Benzyl-2-(hex-1-ynyl)aniline (1d): Yield: 1.74 g, starting from
1.66 g of 2-(hex-1-ynyl)aniline (69%). Yellow oil. IR (film): ν =
N-Benzyl-5-methyl-2-(phenylethynyl)aniline (1h): Yield: 1.75 g,
˜
3400 (m, br.), 2930 (m), 2860 (m), 2221 (vw), 1600 (m), 1577 (m),
1508 (s), 1458 (m), 1323 (m), 1282 (s), 1161 (w), 1028 (w), 745 (s),
starting from 1.99 g of 5-methyl-2-(phenylethynyl)aniline (61%).
Yellow solid, m.p. 101–102 °C. IR (KBr): ν = 3308 (m, br.), 2230
˜
698 (m) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.36–7.18 (m, 6 (w), 1664 (m), 1537 (m), 1490 (w), 1385 (w), 1315 (m), 1280 (m),
H, 5 H aromatic + 3-H), 7.09–7.02 (m, 1 H, 5-H), 6.58 (td, J =
7.5, 1.2 Hz, 1 H, 4-H), 6.50 (br. d, J = 8.1 Hz, 1 H, 6-H), 4.99 (br.
1258 (m), 1158 (m), 1112 (m), 1009 (m), 856 (w), 756 (m), 692 (m)
cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.48–7.42 (m, 2 H, aro-
s, 1 H, NH), 4.33 (br. s, 2 H, CH2Ph), 2.41 (t, J = 6.9 Hz, 2 H, matic), 7.41–7.23 (m, 9 H, 8 H aromatic + 3-H), 6.49 (dd, J = 7.7,
CH2CH2CH2CH3), 1.59–1.33 (m, 4 H, CH2CH2CH3), 0.86 (t, J = 0.8 Hz, 1 H, 4-H), 6.41 (br. s, 1 H, 6-H), 5.05 (br. s, 1 H, NH), 4.42
7.3 Hz, 3 H, Me) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.6, (br. s, 2 H, CH2Ph), 2.40 (s, 3 H, Me) ppm. 13C NMR (75 MHz,
139.2, 131.9, 129.0, 128.6, 127.2, 127.1, 116.4, 109.6, 108.6, 96.2,
77.1, 47.8, 30.9, 22.0, 19.3, 13.6 ppm. GC–MS: m/z (%) = 263 (100)
[M+], 234 (7), 220 (21), 218 (18), 206 (87), 186 (88), 172 (4), 156
CDCl3): δ = 148.7, 140.3, 139.2, 131.9, 131.3, 128.7, 128.3, 127.9,
127.2, 127.1, 123.5, 117.7, 110.6, 104.8, 94.7, 86.2, 47.7, 22.1 ppm.
GC–MS: m/z (%) = 297 (100) [M+], 220 (6), 206 (28), 191 (5), 179
(6), 144 (12), 143 (15), 130 (21), 115 (19), 103 (7), 91 (81), 77 (12), (19), 178 (12), 152 (2), 128 (2), 115 (1), 102 (2), 91 (70), 77 (9),
2554
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2549–2559

General Synthesis of Indole-3-carboxylic Esters
65(9). C22H19N (297.39): C 88.85, H 6.44, N 4.71; found C 88.80,
H 6.47, N 4.73.
282 (6), 280 (5), 235 (5), 219 (3), 204 (7), 190 (8), 179 (7), 165 (3),
131 (2), 91 (100), 65 (14). C23H19NO2 (341.40): C 80.92, H 5.61, N
4.10; found C 80.83, H 5.62, N 4.09.
N-Butyl-2-(phenylethynyl)aniline (1i): Yield: 1.20 g, starting from
1.86 g of 2-(phenylethynyl)aniline (50%). Yellow oil. IR (film): ν =
˜
Methyl 1-Benzyl-2-(4-bromophenyl)-1H-indole-3-carboxylate (2b):
Yield: 258 mg, starting from 300 mg of 1b (74%) (Table 2, entry 2).
3410 (m), 2206 (vw), 1596 (m), 1575 (m), 1511 (m), 1456 (m), 1324
(w), 1283 (w), 1216 (m), 1162 (w), 756 (s) cm–1. 1H NMR
(500 MHz, CDCl3): δ = 7.47–7.40 (m, 2 H, aromatic), 7.33–7.21
(m, 4 H, 3 H aromatic + 3-H), 7.15–7.09 (m, 1 H, 4-H), 6.58–6.50
(m, 2 H, 5-H + 6-H), 4.56 (br. s, 1 H, NH), 3.15–3.07 (m, 2 H,
CH2CH2CH2CH3), 1.62–1.54 (m, 2 H, CH2CH2CH3), 1.44–1.34
(m, 2 H, CH2CH3), 0.89 (t, J = 7.4 Hz, 3 H, Me) ppm. 13C NMR
(126 MHz, CDCl3): δ = 148.0, 131.1, 130.4, 129.0, 127.4, 127.1,
122.4, 115.0, 108.5, 106.2, 94.0, 85.1, 42.2, 30.5, 19.2, 12.9 ppm.
GC–MS: m/z (%) = 249 (34) [M+], 220 (6), 207 (17), 206 (100), 204
(19), 179 (16), 178 (21), 165 (6), 152 (4), 128 (8), 102 (4), 77 (5).
C18H19N (249.35): C 86.70, H 7.68, N 5.62; found C 86.68, H 7.70,
N 5.62.
Colorless solid, m.p. 125–127 °C. IR (KBr): ν = 1709 (s), 1633 (m),
˜
1481 (w), 1454 (w), 1384 (m), 1229 (m), 1148 (s), 1120 (w), 1072
(w), 1011 (w), 741 (m), 698 (m) cm–1. 1H NMR (300 MHz, CDCl3):
δ = 8.28–8.23 (m, 1 H, 4-H), 7.56–7.50 (m, 2 H, aromatic), 7.35–
7.17 (m, 8 H, aromatic), 6.92–6.86 (m, 2 H, aromatic), 5.18 (s, 2 H,
CH2Ph), 3.79 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ
= 165.4, 145.6, 136.7, 136.5, 131.8, 131.4, 130.1, 128.8, 127.6, 126.6,
125.9, 123.7, 123.4, 122.4, 122.1, 110.7, 105.9, 50.9, 47.6 ppm. GC–
MS: m/z (%) = 421 (40) [M + 2]+, 419 (38) [M+], 390 (5), 388 (5),
340 (3), 280 (4), 249 (8), 190 (10), 178 (7), 163 (4), 91 (100), 65
(12). C23H18BrNO2 (420.30): C 65.73, H 4.32, Br 19.01, N 3.33;
found C 65.75, H 4.32, Br 19.05, N 3.34.
2-(Hex-1-ynyl)-N-isobutylaniline (1j): Yield: 1.32 g, starting from
Methyl 1-Benzyl-2-p-tolyl-1H-indole-3-carboxylate (2c): Yield:
240 mg, starting from 246 mg of 1c (81%) (Table 2, entry 3). Color-
1.66 g of 2-(hex-1-ynyl)aniline (60%). Yellow oil. IR (film): ν =
˜
3418 (m), 2212 (vw), 1642 (m), 1602 (m), 1509 (m), 1458 (m), 1323
(m), 1162 (w), 742 (s) cm–1. 1H NMR (500 MHz, CDCl3): δ = 7.22
(dd, J = 7.2, 1.6 Hz, 1 H, 3-H), 7.16–7.07 (m, 1 H, 4-H), 6.63–6.45
(m, 2 H, 5-H + 6-H), 4.66 (br. s, 1 H, NH), 2.96 (br. d, J = 6.5 Hz,
2 H, CH2CHMe2), 2.46 (t, J = 6.9 Hz, 2 H, CH2CH2CH2CH3),
1.91 (nonuplet, J = 6.5 Hz, 1 H, CH2CHMe2), 1.66–1.40 (m, 4 H,
CH2CH2CH3), 0.99 (d, J = 6.5 Hz, 6 H, CH3CHCH3), 0.94 (t, J =
7.0 Hz, 3 H, CH2CH3) ppm. 13C NMR (126 MHz, CDCl3): δ =
149.0, 131.8, 129.0, 115.8, 109.3, 108.3, 95.9, 77.2, 51.3, 31.1, 28.1,
22.0, 20.4, 19.3, 13.6 ppm. GC–MS: m/z (%) = 229 (66) [M+], 200
(3), 187 (26), 186 (45), 172 (35), 156 (12), 144 (100), 131 (69), 130
(22), 115 (21), 103 (11), 89 (7), 77 (11). C16H23N (229.36): C 83.79,
H 10.11, N 6.11; found C 83.78, H 10.10, N 6.12.
less solid, m.p. 90–92 °C. IR (KBr): ν = 1706 (s), 1496 (m), 1461
˜
(m), 1429 (m), 1384 (m), 1350 (m), 1283 (m), 1230 (m), 1185 (w),
1147 (s), 1118 (m), 1017 (w), 829 (m), 754 (m) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.28–8.22 (m, 1 H, 4-H), 7.32–7.15 (m, 10
H, aromatic), 6.93–6.87 (m, 2 H, aromatic), 5.17 (s, 2 H, CH2Ph),
3.77 (s, 3 H, CO2Me), 2.38 (s, 3 H, CH3C6H4) ppm. 13C NMR
(75 MHz, CDCl3): δ = 165.6, 147.4, 138.9, 136.9, 136.2, 130.0,
128.8, 128.7, 128.1, 127.4, 126.7, 125.9, 122.9, 122.2, 122.0, 110.8,
105.4, 50.7, 47.5, 21.4 ppm. GC–MS: m/z (%) = 355 (100) [M+],
324 (29), 297 (6), 294 (3), 264 (6), 249 (13), 218 (6), 204 (11), 193
(9), 177 (4), 165 (3), 139 (3), 91 (75), 65 (9). C24H21NO2 (355.43):
C 81.10, H 5.96, N 3.94; found C 81.15, H 5.94, N 3.95.
Ethyl 1-Benzyl-2-p-tolyl-1H-indole-3-carboxylate (2cЈ): Yield:
257 mg, starting from 246 mg of 1c (84%) (Table 2, entry 11). Col-
Synthesis of N-Substituted Indole-3-carboxylic Esters 2a–f, 2cЈ, 2fЈ,
2h–j (Table 2, entries 1–6, 8–12): A 250 mL stainless steel autoclave
was charged in the presence of air with PdI2 (6.0 mg, 1.67ϫ
10–2 mmol), KI (27.7 mg, 0.17 mmol), anhydrous ROH (R = Me
or Et, 16.7 mL) and 0.83 mmol of N-substituted-2-alkynylaniline
[N-benzyl-2-(phenylethynyl)aniline (1a): 235 mg; N-benzyl-2-(4-
bromophenylethynyl)aniline (1b): 300 mg; N-benzyl-2-(p-tolylethy-
nyl)aniline (1c): 246 mg; N-benzyl-2-(hex-1-ynyl)aniline (1d):
218 mg; N-benzyl-4-chloro-2-(phenylethynyl)aniline (1e): 264 mg;
N-benzyl-4-methyl-2-(phenylethynyl)aniline (1f): 246 mg; N-benzyl-
5-methyl-2-(phenylethynyl)aniline (1h): 246 mg; N-butyl-2-(phenyl-
ethynyl)aniline (1i): 207 mg; N-isobutyl-2-(hex-1-ynyl)aniline (1j):
190 mg]. The autoclave was sealed and, while the mixture was
stirred, the autoclave was pressurized with CO (16 atm) and air (up
to 20 atm). After being stirred at 100 °C for the time required (see
Table 3), the autoclave was cooled, degassed and opened. The sol-
vent was evaporated, and the products were purified by column
chromatography on silica gel using 95:5 to 9:1 hexane/AcOEt as
eluent.
orless solid, m.p. 92–93 °C. IR (KBr): ν = 1695 (s), 1535 (m), 1496
˜
(w), 1465 (m), 1417 (m), 1353 (m), 1291 (m), 1236 (m), 1157 (m),
1116 (m), 1030 (w), 789 (w), 752 (s), 696 (w) cm–1. 1H NMR
(300 MHz, CDCl3): δ = 8.32–8.25 (m, 1 H, 4-H), 7.31–7.13 (m, 10
H, aromatic), 6.93–6.86 (m, 2 H, aromatic), 5.16 (s, 2 H, CH2Ph),
4.24 (q, J = 7.3 Hz, 2 H, CO2CH2CH3), 2.37 (s, 3 H, CH3C6H4),
1.22 (t, J = 7.3 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.1, 147.2, 138.9, 137.0, 136.3, 130.1, 128.72, 128.65,
128.3, 127.4, 126.9, 126.0, 122.9, 122.1, 122.0, 110.7, 105.7, 59.4,
47.5, 21.4, 14.3 ppm. GC–MS: m/z (%) = 369 (70) [M+], 324 (18),
297 (29), 278 (2), 262 (2), 250 (5), 233 (3), 218 (5), 204 (9), 190 (4),
179 (9), 165 (2), 115 (2), 91 (100), 65 (10). C25H23NO2 (369.46): C
81.27, H 6.27, N 3.79; found C 81.20, H 6.25, N 3.80.
Methyl 1-Benzyl-2-butyl-1H-indole-3-carboxylate (2d): Yield:
197 mg, starting from 218 mg of 1d (74%) (Table 2, entry 4). Yellow
solid, m.p. 72–74 °C. IR (KBr): ν = 1691 (s), 1469 (m), 1416 (s),
˜
1358 (m), 1298 (w), 1235 (m), 1174 (s), 1116 (m), 1078 (m), 1039
Methyl 1-Benzyl-2-phenyl-1H-indole-3-carboxylate (2a): Yield: (m), 824 (m), 789 (m), 730 (m), 658 (w) cm–1. 1H NMR (300 MHz,
205 mg, starting from 235 mg of 1a (72%) (Table 2, entry 1). Color-
CDCl3): δ = 8.18 (br. d, J = 8.1 Hz, 1 H, 4-H), 7.27–7.08 (m, 6 H,
aromatic), 6.97–6.89 (m, 2 H, aromatic), 5.31 (s, 2 H, CH2Ph), 3.92
(s, 3 H, CO2Me), 3.18–3.07 (m, 2 H, CH2CH2CH2CH3), 1.59–1.32
(m, 4 H, CH2CH2CH3), 0.88 (t, J = 7.1 Hz, 3 H, CH2CH3) ppm.
less solid, m.p. 126–127 °C. IR (KBr): ν = 1697 (s), 1539 (m), 1497
˜
(m), 1437 (m), 1410 (m), 1351 (w), 1284 (m), 1238 (m), 1188 (m),
1151 (s), 1119 (w), 1086 (m), 1029 (w), 927 (w), 822 (m), 727 (m)
1
cm–1. H NMR (300 MHz, CDCl3): δ = 8.27 (dt, J = 7.8, 1.1 Hz, 13C NMR (75 MHz, CDCl3): δ = 166.2, 149.9, 136.6, 136.3, 128.8,
1 H, 4-H), 7.45–7.18 (m, 11 H, aromatic), 6.93–6.87 (m, 2 H, aro-
127.6, 126.7, 125.8, 122.3, 121.9, 121.6, 109.9, 103.9, 50.7, 46.5,
matic), 5.18 (s, 2 H, CH2Ph), 3.76 (s, 3 H, CO2Me) ppm. 13C NMR 31.6, 25.5, 22.8, 13.8 ppm. GC–MS: m/z (%) = 321 (51) [M+], 280
(75 MHz, CDCl3): δ = 165.6, 147.1, 136.9, 136.3, 131.2, 130.2, (12), 279 (58), 246 (15), 221 (9), 220 (45), 218 (19), 188 (4), 170 (4),
129.1, 128.7, 128.1, 127.4, 126.7, 126.0, 123.1, 122.2, 122.0, 110.8,
156 (4), 129 (5), 115 (4), 91 (100). C21H23NO2 (321.41): C 78.47, H
7.21, N 4.36; found C 78.42, H 7.20, N 4.37.
105.6, 50.8, 47.6 ppm. GC–MS: m/z (%) = 341 (90) [M+], 310 (24),
Eur. J. Org. Chem. 2012, 2549–2559
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2555

B. Gabriele, L. Veltri, R. Mancuso, G. Salerno, M. Costa
FULL PAPER
Methyl 1-Benzyl-5-chloro-2-phenyl-1H-indole-3-carboxylate (2e): Methyl 1-Butyl-2-phenyl-1H-indole-3-carboxylate (2i): Yield:
Yield: 216 mg, starting from 264 mg of 1e (69%) (Table 2, entry 5). 183 mg, starting from 207 mg of 1i (72%) (Table 2, entry 9). Yellow
Colorless solid, m.p. 170–171 °C. IR (KBr): ν = 1689 (s), 1538 (w),
solid, m.p. 69–71 °C IR (KBr): ν = 1705 (s), 1652 (m), 1543 (w),
˜
˜
1482 (m), 1457 (m), 1384 (m), 1224 (m), 1158 (m), 1128 (w), 1065
1409 (m), 1384 (m), 1264 (w), 1222 (w), 1161 (m), 1108 (m), 1021
(m), 1027 (w), 888 (m), 803 (w), 736 (m) cm–1. 1H NMR (300 MHz, (w), 768 (m), 704 (m) cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.28–
CDCl3): δ = 8.24 (br. d, J = 2.0 Hz, 1 H, 4-H), 7.47–7.38 (m, 3 H, 8.20 (m, 1 H, 4-H), 7.53–7.45 (m, 3 H, aromatic), 7.44–7.35 (m, 3
aromatic), 7.37–7.31 (m, 2 H, aromatic), 7.27–7.20 (m, 3 H, aro- H, aromatic), 7.35–7.26 (m, 2 H, aromatic), 4.00–3.91 (m, 2 H,
matic), 7.17 (distorted dd, J = 8.5, 2.0 Hz, 1 H, 6-H), 7.11 (dis-
CH2CH2CH2CH3), 3.74 (s, 3 H, CO2Me), 1.70–1.55 (m, 2 H,
torted d, J = 8.5 Hz, 1 H, 7-H), 6.91–6.85 (m, 2 H, aromatic), 5.17 CH2CH2CH3), 1.24–1.10 (m, 2 H, CH2CH3), 0.77 (t, J = 7.3 Hz,
(s, 2 H, CH2Ph), 3.77 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.1, 148.2, 136.5, 134.8, 130.8, 130.1, 129.3, 128.8,
128.2, 127.8, 127.7, 126.0, 123.5, 121.7, 111.9, 105.4, 50.9, 47.8
ppm. GC–MS: m/z (%) = 377 (21) [M + 2]+, 375 (59) [M+], 344
3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.6, 146.8,
135.9, 131.7, 130.1, 128.9, 128.1, 126.7, 122.7, 122.0, 121.9, 110.2,
50.7, 43.7, 31.8, 19.9, 13.5 ppm. GC–MS: m/z (%) = 307 (5) [M+],
281 (16), 258 (16), 251 (64), 236 (15), 220 (79), 207 (43), 193 (42),
(10), 284 (2), 269 (4), 253 (2), 213 (3), 190 (8), 178 (3), 91 (100), 65 191 (37), 176 (16), 165 (38), 135 (27), 117 (28), 115(30), 105 (24),
(11). C23H18ClNO2 (375.85): C 73.50, H 4.83, N 3.73; found C
73.59, H 4.84, N 3.72.
91 (43), 83 (19), 77 (38), 73 (54), 69 (41). C20H21NO2 (307.39): C
78.15, H 6.89, N 4.56; found C 78.20, H 6.88, N 4.57.
Methyl 1-Benzyl-5-methyl-2-phenyl-1H-indole-3-carboxylate (2f):
Yield: 228 mg, starting from 246 mg of 1f (77%) (Table 2, entry 6).
Methyl 2-Butyl-1-isobutyl-1H-indole-3-carboxylate (2j): Yield:
119 mg, starting from 190 mg of 1j (50%) (Table 2, entry 10). Yel-
Colorless solid, m.p. 132–134 °C. IR (KBr): ν = 2923 (m), 1685 (s),
˜
low oil. IR (film): ν = 2960 (m), 1688 (s), 1533 (m), 1463 (m), 1440
˜
1462 (m), 1405 (s), 1384 (w), 1243 (w), 1149 (m), 788 (m), 722 (m)
cm–1. 1H NMR (300 MHz, CDCl3): δ = 8.07 (br. s, 1 H, 4-H),
7.46–7.30 (m, 5 H, aromatic), 7.25–7.16 (m, 3 H, aromatic), 7.09
(distorted d, J = 8.1 Hz, 1 H, 7-H), 7.03 (distorted dd, J = 8.1,
1.0 Hz, 1 H, 6-H), 6.93–6.84 (m, 2 H, aromatic), 5.13 (s, 2 H,
CH2Ph), 3.75 (s, 3 H, CO2Me), 2.49 (s, 3 H, Me at C-5) ppm. 13C
NMR (75 MHz, CDCl3): δ = 165.6, 147.0, 137.0, 134.7, 131.7,
131.4, 130.1, 129.0, 128.7, 128.0, 127.4, 127.0, 126.0, 124.6, 121.7,
110.4, 105.1, 50.7, 47.5, 21.6 ppm. GC–MS: m/z (%) = 355 (76)
[M+], 324 (19), 296 (6), 264 (5), 249 (9), 232 (7), 218 (4), 204 (6),
193 (8), 176 (3), 91 (100), 65 (13). C24H21NO2 (355.43): C 81.10, H
5.96, N 3.94; found C 81.17, H 5.94, N 3.94.
(m), 1420 (w), 1216 (m), 1158 (w), 1114 (m), 1024 (w), 757 (s) cm–1.
1H NMR (300 MHz, CDCl3): δ = 8.17–8.09 (m, 1 H, 4-H), 7.32–
7.12 (m, 3 H, aromatic), 3.91 (s, 3 H, CO2Me), 3.90 (d, J = 6.9 Hz,
2 H, CH2CHMe2), 3.25–3.09 (m, 2 H, CH2CH2CH2CH3), 2.21
(nonuplet, 1 H, CH2CHMe2), 1.68–1.35 (m, 4 H, CH2CH2CH3),
0.97 (t, J = 7.3 Hz, 3 H, CH2CH3), 0.91 (d, J = 6.9 Hz, 6 H,
CH3CHCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.3, 150.0,
136.2, 126.8, 121.8, 121.6, 110.1, 103.3, 50.6, 50.5, 31.9, 29.3, 25.6,
22.9, 20.3, 13.8 ppm. GC–MS: m/z (%) = 287 (100) [M+], 156 (29),
245 (79), 244 (43), 230 (45), 212 (35), 202 (62), 190 (18), 189 (91),
184 (26), 172 (15), 170 (24), 158 (18), 144 (13), 130 (24), 115 (16).
C18H25NO2 (287.40): C 75.22, H 8.77, N 4.87; found C 75.18, H
8.75, N 4.86.
Ethyl 1-Benzyl-5-methyl-2-phenyl-1H-indole-3-carboxylate (2fЈ):
Yield: 225 mg, starting from 246 mg of 1f (73%) (Table 2, entry
Synthesis of Methyl 1-Benzyl-2-phenyl-6-(trifluoromethyl)-1H-ind-
ole-3-carboxylate (2g) (Table 2, entry 7): A 35 mL stainless steel
autoclave was charged in the presence of air with PdI2 (6.0 mg,
1.67ϫ10–2 mmol), KI (27.7 mg, 0.17 mmol), anhydrous MeOH
(4.2 mL) and N-benzyl-5-(trifluoromethyl)-2-(phenylethynyl)aniline
1g (292 mg; 0.83 mmol). The autoclave was sealed and, while the
mixture was stirred, the autoclave was pressurized with CO
(16 atm) and air (up to 20 atm). After being stirred at 100 °C for
3 h, the autoclave was cooled, degassed and opened. The solvent
was evaporated, and the product 2g was purified by column
chromatography on silica gel using 95:5 hexane/AcOEt. Yield:
247 mg, starting from 292 mg of 1g (73%) (Table 3, entry 7). Color-
12). Colorless solid, m.p. 109–111 °C. IR (KBr): ν = 1694 (s), 1536
˜
(w), 1483 (m), 1456 (m), 1402 (m), 1347 (w), 1313 (w), 1166 (m),
1081 (m), 998 (m), 934 (w), 783 (m), 745 (m), 706 (m) cm–1. 1H
NMR (300 MHz, CDCl3): δ = 8.11–8.08 (m, 1 H, 4-H), 7.44–7.30
(m, 5 H, aromatic), 7.25–7.18 (m, 3 H, aromatic), 7.10 (distorted
d, J = 8.4 Hz, 1 H, 7-H), 7.04 (distorted dd, J = 8.4, 1.5 Hz, 1 H,
6-H), 6.93–6.87 (m, 2 H, aromatic), 5.16 (s, 2 H, CH2Ph), 4.20 (q,
J = 7.2 Hz, 2 H, CO2CH2CH3), 2.50 (s, 3 H, Me at C-5), 1.16 (t,
J = 7.2 Hz, 3 H, CO2CH2CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 165.2, 146.8, 137.1, 134.8, 131.7, 130.3, 128.8, 128.7, 127.9,
127.4, 127.3, 126.0, 124.6, 121.7, 110.4, 105.5, 59.3, 47.6, 21.6, 14.1
ppm. GC–MS: m/z (%) = 369 (100) [M+], 341 (4), 324 (23), 297
(23), 250 (3), 232 (4), 204 (4), 179 (4), 91 (56). C25H23NO2 (369.46):
C 81.27, H 6.27, N 3.79; found C 81.42, H 6.25, N 3.78.
less solid, m.p. 121–122 °C. IR (KBr): ν = 1701 (s), 1533 (w), 1480
˜
(w), 1436 (m), 1410 (m), 1339 (m), 1308 (m), 1278 (w), 1223 (m),
1
1151 (s), 1116 (m), 1061 (m), 871 (m), 832 (m), 702 (m) cm–1. H
Methyl 1-Benzyl-6-methyl-2-phenyl-1H-indole-3-carboxylate (2h):
Yield: 231 mg, starting from 246 mg of 1h (78%) (Table 2, entry 8).
NMR (300 MHz, CDCl3): δ = 8.36 (br. d, J = 8.1 Hz, 1 H, 4-H),
7.57–7.49 (m, 2 H, aromatic), 7.48–7.38 (m, 3 H, aromatic), 7.37–
7.29 (m, 2 H, aromatic), 7.27–7.19 (m, 3 H, aromatic), 6.92–6.83
(m, 2 H, aromatic), 5.23 (s, 2 H, CH2Ph), 3.76 (s, 3 H, CO2Me)
ppm. 13C NMR (75 MHz, CDCl3): δ = 165.0, 149.3, 130.6, 130.0,
129.5, 129.2, 128.9, 128.7, 128.5, 128.2, 127.8, 125.9, 125 6 (q, J =
32.1 Hz), 124.8 (q, J = 271.7 Hz), 122.7, 118.9 (q, J = 3.3 Hz),
108.2 (q, J = 4.5 Hz), 106.1, 51.0, 47.8 ppm. 19F NMR (471 MHz,
CDCl3): δ = –60.8 (s, 3 F, CF3) ppm. GC–MS: m/z (%) = 409 [M+]
(40), 378 (6), 348 (2), 318 (2), 303 (5), 272 (2), 190 (3), 91 (100), 65
(12). C24H18F3NO2 (409.40): C 70.41, H 4.43, N 3.42; found C
70.48, H 4.41, N 3.43.
Yellow solid, m.p. 99–101 °C. IR (KBr): ν = 1702 (s), 1535 (w),
˜
1495 (w), 1437 (m), 1401 (m), 1275 (w), 1239 (w), 1188 (m), 1129
(s), 1082 (m), 810 (m), 775 (w), 701 (m) cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.13 (br. d, J = 8.5 Hz, 1 H, 4-H), 7.43–7.29 (m, 5 H,
aromatic), 7.26–7.18 (m, 3 H, aromatic), 7.13 (dd, J = 8.5, 0.8 Hz,
1 H, 5-H), 7.02 (d, J = 0.8 Hz, 1 H, 7-H), 6.93–6.86 (m, 2 H,
aromatic), 5.15 (s, 2 H, CH2Ph), 3.75 (s, 3 H, CO2Me), 2.42 (s, 3
H, Me at C-6) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.6, 146.6,
137.1, 136.8, 133.0, 131.4, 130.2, 128.9, 128.7, 128.0, 127.4, 124.6,
124.0, 121.7, 110.6, 105.5, 50.7, 47.4, 21.8 ppm. GC–MS: m/z (%)
= 355 (95) [M+], 324 (20), 296 (7), 264 (5), 249 (9), 232 (6), 218 (5),
204 (6), 193 (8), 178 (4), 165 (2), 138 (1), 118 (2), 91 (100), 65 (10). Synthesis of 1-(Dimethoxymethyl)indole-3-carboxylic Esters 9a–d
C24H21NO2 (355.43): C 81.10, H 5.96, N 3.94; found C 81.14, H
5.97, N 3.93.
(Table 3, entries 2–5): A 250 mL stainless steel autoclave was
charged in the presence of air with PdI2 (24.9 mg, 6.91ϫ
2556
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2549–2559

General Synthesis of Indole-3-carboxylic Esters
10–2 mmol), KI (114.8 mg, 0.69 mmol), HC(OMe)3 (18.4 mL), an-
hydrous MeOH (9.2 mL), and the 2-alkynylaniline (1.38 mmol) {2-
(phenylethynyl)aniline (7a): 267 mg; 2-(thiophen-3-ylethynyl)an-
iline (7b): 275 mg; 2-[2-(4-bromophenyl)ethynyl]aniline (7c):
375 mg; 2-(hex-1-ynyl)aniline (7d): 239 mg}. The autoclave was se-
aled and, while the mixture was stirred, the autoclave was pressur-
ized with CO (16 atm) and air (up to 20 atm). After being stirred
at 100 °C for 3 h, the autoclave was cooled, degassed and opened.
The solvent was evaporated, and products were purified by column
chromatography on neutral alumina using 98:2 hexane/acetone (for
9a, 9b, 9d) or pure hexane (for 9c) as eluent.
3 H, CH2CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 166.2, 148.8,
134.4, 126.8, 122.6, 122.2, 121.4, 112.7, 105.4, 104.7, 54.5, 50.8,
32.1, 25.4, 22.9, 13.9 ppm. MS (ESI+, direct infusion): m/z (%) =
328 [M + Na]+. C17H23NO4 (305.37): C 66.86, H 7.59, N 4.59;
found C 66.91, H 7.57, N 4.60.
Synthesis of Indole-3-carboxylic Esters 10a–d (Table 3, entries 2–5):
A 250 mL stainless steel autoclave was charged in the presence of
air with PdI2 (24.9 mg, 6.91ϫ 10–2 mmol), KI (114.8 mg,
0.69 mmol), HC(OMe)3 (18.4 mL), anhydrous MeOH (9.2 mL),
and the 2-alkynylaniline (1.38 mmol) {2-(phenylethynyl)aniline
(7a): 267 mg; 2-(thiophen-3-ylethynyl)aniline (7b): 275 mg; 2-[2-(4-
bromophenyl)ethynyl]aniline (7c): 375 mg; 2-(hex-1-ynyl)aniline
(7d): 239 mg}. The autoclave was sealed and, while the mixture was
stirred, the autoclave was pressurized with CO (16 atm) and air (up
Methyl
(9a): Yield: 235 mg, starting from 267 mg of 7a (52%) (Table 3,
entry 2). Yellow solid, m.p. 48–50 °C. IR (KBr): ν = 2986 (m), 1674
1-(Dimethoxymethyl)-2-phenyl-1H-indole-3-carboxylate
˜
(s), 1490 (m), 1447 (m), 1394 (s), 1265 (m), 1164 (m), 1080 (m), to 20 atm). After being stirred at 100 °C for 3 h, the autoclave was
1
1052 (m), 763 (m), 692 (m) cm–1. H NMR (300 MHz, CDCl3): δ
= 8.24–8.18 (m, 1 H, 4-H), 7.94–7.87 (m, 1 H, 7-H), 7.54–7.40 (m, crude products were diluted with MeOH (2.4 mL), water (2.0 mL)
5 H, aromatic), 7.34–7.24 (m, 2 H, aromatic), 5.58 [s, 1 H, and concd HCl (37% w/w, 0.2 mL) in this order. The mixture was
CH(OMe)2], 3.73 (s, 3 H, CO2Me), 3.25 (s, 6 H, CH3OCHOCH3) heated at 80 °C with stirring for 15 h in a Schlenk flask. After cool-
cooled, degassed and opened. The solvent was evaporated, and the
ppm. 13C NMR (75 MHz, CDCl3): δ = 165.4, 145.5, 133.8, 131.1,
130.3, 129.3, 128.2, 126.8, 123.4, 122.7, 121.7, 113.9, 106.5, 105.5,
54.4, 50.9 ppm. GC–MS (direct injection): m/z = 325 (19) [M+],
294 (6), 265 (16), 251 (7), 234 (6), 220 (12), 190 (5), 165 (6), 121
(2), 89 (2), 75 (100). C19H19NO4 (325.36): C 70.14, H 5.89, N 4.31;
found C 70.20, H 5.91, N 4.30.
ing, Et2O (5 mL) was added to the mixture and phases were sepa-
rated. The aqueous layer was extracted with Et2O (3ϫ 5 mL), and
the combined organic phases were dried with Na2SO4. After fil-
tration and evaporation of the solvent, the products were purified
by column chromatography on silica gel using hexane/AcOEt 9:1
as eluent.
Methyl 1-(Dimethoxymethyl)-2-(thiophen-3-yl)-1H-indole-3-carb-
oxylate (9b): Yield: 270 mg, starting from 275 mg of 7b (59%)
Methyl 2-Phenyl-1H-indole-3-carboxylate (10a):[30] Yield: 190 mg,
starting from 267 mg of 7a (55%) (Table 3, entry 2). Colorless solid,
(Table 3, entry 3). Yellow solid, m.p. 86–89 °C. IR (KBr): ν = 1710
m.p. 153–154 °C, ref.[20] 150–151 °C. IR (KBr): ν = 3302 (m, br.),
˜
˜
(s), 1463 (m), 1401 (m), 1311 (w), 1265 (m), 1214 (m), 1146 (m),
1692 (s), 1496 (w), 1468 (m), 1416 (m), 1235 (m), 1174 (m), 1039
1
1107 (m), 1071 (m), 993 (m) cm–1. H NMR (300 MHz, CDCl3): δ
(m), 752 (m), 730 (m), 698 (m) cm–1. 1H NMR (300 MHz, CDCl3):
= 8.22–8.14 (m, 1 H, 4-H), 7.94–7.86 (m, 1 H, 7-H), 7.50–7.44 (m, δ = 8.56 (br. s, 1 H, NH), 8.25–8.17 (m, 1 H, 4-H), 7.69–7.60 (m,
2 H, aromatic), 7.33–7.24 (m, 2 H, aromatic), 7.21 (dd, J = 4.4,
2 H, aromatic), 7.48–7.34 (m, 4 H, aromatic), 7.32–7.21 (m, 2 H,
1.6 Hz, 1 H, 4-H on thienyl ring), 5.67 [s, 1 H, CH(OMe)2], 3.78 aromatic), 3.83 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz, CDCl3):
(s, 3 H, CO2Me), 3.28 (s, 6 H, CH3OCHOCH3) ppm. 13C NMR δ = 165.8, 144.6, 135.1, 132.0, 129.5, 129.3, 128.2, 127.5, 123.3,
(75 MHz, CDCl3): δ = 165.3, 140.2, 134.3, 130.7, 129.6, 127.0, 122.2, 122.1, 111.0, 104.5, 50.9 ppm. GC–MS: m/z (%) = 251 (92)
125.4, 123.5, 122.7, 121.8, 114.0, 107.4, 105.9, 54.3, 50.8 ppm. MS
(ESI+, direct infusion): m/z (%) = 354 [M + Na]+, 332 [M + H]+.
C17H17NO4S (331.39): C 61.61, H 5.17, N 4.23, S 9.68; found C
61.69, H 5.18, N 4.21, S 9.71.
[M+], 221 (19), 220 (100), 193 (15), 191 (17), 190 (13), 165 (38), 139
(5), 126 (5), 96 (15), 82 (5). C16H13NO2 (251.28): C 76.48, H 5.21,
N 5.57; found C 76.40, H 5.21, N 5.58.
Methyl 2-(Thiophen-3-yl)-1H-indole-3-carboxylate (10b): Yield:
224 mg, starting from 275 mg of 7b (63%) (Table 3, entry 3). Color-
Methyl 2-(4-Bromophenyl)-1-(dimethoxymethyl)-1H-indole-3-carb-
oxylate (9c): Yield: 325 mg, starting from 375 mg of 7c (58%)
less solid, m.p. 91–92 °C. IR (KBr): ν = 3446 (m br.), 1709 (s), 1569
˜
(Table 3, entry 4). Colorless solid, m.p. 94–96 °C. IR (KBr): ν =
1694 (s), 1456 (m), 1402 (m), 1347 (w), 1313 (w), 1218 (m), 1190
(w), 1437 (m), 1384 (w), 1366 (w), 1267 (m), 1213 (m), 1189 (m),
˜
1145 (m), 1108 (s), 1070 (s), 993 (m), 785 (m), 756 (m) cm–1. 1H
(m), 1166 (m), 1127 (m), 1081 (m), 998 (m), 871 (m), 783 (m), 743 NMR (300 MHz, CDCl3): δ = 8.93 (br. s, 1 H, NH), 8.21–8.13 (m,
1
(m) cm–1. H NMR (300 MHz, CDCl3): δ = 8.23–8.15 (m, 1 H, 4- 1 H, 4-H), 7.78 (dd, J = 2.8, 1.2 Hz, 1 H, 2-H on thienyl ring), 7.45
H), 7.94–7.86 (m, 1 H, 7-H), 7.69–7.61 (m, 2 H, aromatic), 7.38–
7.27 (m, 4 H, aromatic), 5.57 [s, 1 H, CH(OMe)2], 3.77 (s, 3 H,
CO2Me), 3.27 (s, 6 H, CH3OCHOCH3) ppm. 13C NMR (75 MHz,
CDCl3): δ = 165.3, 143.9, 134.2, 132.9, 132.0, 131.5, 126.7, 123.8,
123.7, 122.8, 121.8, 114.0, 107.0, 105.6, 54.4, 50.9 ppm. MS (ESI+,
direct infusion): m/z (%) = 428 [M + 2 + Na]+, 426 [M + Na]+.
(distorted dd, J = 5.2, 1.2 Hz, 1 H, 5-H), 7.33–7.18 (m, 4 H, aro-
matic), 3.87 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz, CDCl3): δ
= 166.1, 139.5, 135.1, 132.2, 128.5, 127.6, 126.3, 125.4, 123.3, 122.2,
122.1, 111.0, 104.3, 51.0 ppm. GC–MS: m/z (%) = 257 (53) [M+],
227 (13), 226 (67), 207 (14), 199 (10), 193 (9), 171 (9), 154 (9), 135
(12), 118 (7), 105 (6), 91 (13), 73 (19), 69 (10). C14H11NO2S
C19H18BrNO4 (404.25): C 56.45, H 4.49, Br 19.77, N 3.46; found (257.31): C 65.35, H 4.31, N 5.44, S 12.44; found C 65.32, H 4.31,
C 56.51, H 4.47, Br 19.83, N 3.45.
N 5.42, S 12.48.
Methyl 2-Butyl-1-(dimethoxymethyl)-1H-indole-3-carboxylate (9d):
Yield: 125 mg, starting from 239 mg of 7d (30%) (Table 3, entry 5).
Methyl 2-(4-Bromophenyl)-1H-indole-3-carboxylate (10c): Yield:
256 mg, starting from 375 mg of 7c (56%) (Table 3, entry 4). Color-
Yellow oil. IR (film): ν = 2956 (m), 2932 (m), 1680 (s), 1472 (s),
less solid, m.p. 169–172 °C. IR (KBr): ν = 3299 (m br.), 1683 (s),
˜
˜
1333 (w), 1208 (m), 1117 (m), 1099 (m), 1075 (m), 750 (s) cm–1. 1H 1492 (m), 1426 (m), 1389 (w), 1336 (w), 1279 (m), 1213 (m), 1127
NMR (300 MHz, CDCl3): δ = 8.07–7.99 (m, 1 H, 4-H), 7.73–7.65
(m), 1067 (m), 1043 (m), 1011 (m), 829 (m), 786 (m), 753 (m) cm–1.
(m, 1 H, 7-H), 7.20–7.10 (m, 2 H, 5-H + 6-H), 6.02 [s, 1 H, 1H NMR (300 MHz, CDCl3): δ = 8.89 (br. s, 1 H, NH), 8.22–8.12
CH(OMe)2], 3.86 (s, 3 H, CO2Me), 3.34 (s, 6 H, CH3OCHOCH3),
3.25–3.17 (m, H, CH2CH2CH2CH3), 1.65–1.50 (m, H,
(m, 1 H, 4-H), 7.49–7.40 (m, 4 H, aromatic), 7.35–7.23 (m, 3 H,
2
2
aromatic), 3.81 (s, 3 H, CO2Me) ppm. 13C NMR (75 MHz, CDCl3):
CH2CH2CH3), 1.50–1.36 (m, 2 H, CH2CH3), 0.91 (t, J = 7.3 Hz, δ = 165.9, 143.2, 135.3, 131.3, 131.0, 130.8, 127.4, 123.6, 123.5,
Eur. J. Org. Chem. 2012, 2549–2559
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2557

B. Gabriele, L. Veltri, R. Mancuso, G. Salerno, M. Costa
FULL PAPER
[6]
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122.3, 122.2, 111.2, 104.8, 51.0 ppm. GC–MS: m/z (%) = 331 (98)
[M + 2]+, 329 (100) [M+], 300 (74), 298 (76), 271 (9), 235 (12),
219 (44), 191 (19), 190 (31), 164 (13), 163 (13), 125 (14), 96 (17).
C16H12BrNO2 (330.18): C 58.20, H 3.66, Br 24.20, N 4.24; found
C 58.28, H 3.65, Br 24.27, N 4.23.
[7]
[8]
Methyl 2-Butyl-1H-indole-3-carboxylate (10d): Yield: 145 mg, start-
ing from 239 mg of 7d (45%) (Table 3, entry 5). Colorless solid,
m.p. 67–69 °C, ref.[20] 67–68 °C. IR (KBr): ν = 3287 (m br.), 1664
˜
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(s), 1581 (w), 1457 (m), 1384 (w), 1327 (w), 1209 (m), 1118 (m),
1
1074 (m), 787 (m), 743 (m) cm–1. H NMR (300 MHz, CDCl3): δ
= 8.92 (br. s, 1 H, NH), 8.18–8.08 (m, 1 H, 4-H), 7.34–7.14 (m, 3
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H, aromatic), 3.93 (s,
3 H, CO2Me), 3.17–3.09 (m, 2 H,
CH2CH2CH2CH3), 1.74–1.62 (m, 2 H, CH2CH2CH3), 1.44–1.29
(m, 2 H, CH2CH3), 0.89 (t, J = 7.3 Hz, 3 H, CH2CH3) ppm. 13C
NMR (75 MHz, CDCl3): δ = 166.7, 149.0, 134.6, 127.2, 122.3,
121.7, 121.3, 110.8, 103.9, 50.8, 31.4, 27.7, 22.6, 13.8 ppm. GC–
MS: m/z (%) = 231 (77) [M+], 200 (26), 189 (100), 188 (52), 170
(46), 158 (27), 157 (18), 156 (58), 143 (15), 130 (89), 129 (36), 128
(46), 115 (17), 102 (19), 89 (10), 77 (11). C14H17NO2 (231.29): C
72.70, H 7.41, N 6.06; found C 72.76, H 7.39, N 6.05.
Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of the H and 13C NMR spectra for all products.
Acknowledgments
Financial support from the Ministero dell’Istruzione, dell’Univer-
sità e della Ricerca (MIUR) and from the University of Calabria
(Rende, Italy) is gratefully acknowledged [Progetto di Ricerca d’In-
teresse Nazionale (PRIN), 2008A7P7YJ].
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Received: February 1, 2012
Published Online: March 14, 2012
Eur. J. Org. Chem. 2012, 2549–2559
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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