Functionalization of indole at C-5 or C-7 via palladium-catalysed double carbonylation. A facile synthesis of indole ketocarboxamides and carboxamide dimers

Article abstract of DOI:10.1016/j.tet.2015.11.007

Palladium-catalysed aminocarbonylation of 7-iodoindole derivatives (the parent compound and 5-bromo-7-iodoindole), as well as 5-iodoindole with various primary and secondary amines, including amino acid esters and chiral diamines, was carried out. In this

Full text of DOI:10.1016/j.tet.2015.11.007

Accepted Manuscript
Functionalization of Indole at C-5 or C-7 via Palladium-Catalysed Double
Carbonylation. A Facile Synthesis of Indole Ketocarboxamides and Carboxamide
Dimers
Attila Takács, Diána Marosvölgyi-Haskó, Zsuzsanna Kabak-Solt, Liliana Damas,
Fábio M.S. Rodrigues, Rui M.B. Carrilho, Marta Pineiro, Mariette M. Pereira, László
Kollár
PII:
S0040-4020(15)30191-5
10.1016/j.tet.2015.11.007
TET 27263
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 16 July 2015
Revised Date: 17 October 2015
Accepted Date: 6 November 2015
Please cite this article as: Takács A, Marosvölgyi-Haskó D, Kabak-Solt Z, Damas L, Rodrigues FMS,
Carrilho RMB, Pineiro M, Pereira MM, Kollár L, Functionalization of Indole at C-5 or C-7 via Palladium-
Catalysed Double Carbonylation. A Facile Synthesis of Indole Ketocarboxamides and Carboxamide
Dimers, Tetrahedron (2015), doi: 10.1016/j.tet.2015.11.007.
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ACCEPTED MANUSCRIPT
Functionalization of Indole at C-5 or C-7 via Palladium-Catalysed Double Carbonylation. A Facile
Synthesis of Indole Ketocarboxamides and Carboxamide Dimers.
A. Takács, D. Marosvölgyi-Haskó, Z. Kabak-Solt, L. Damas, F. M. S. Rodrigues, R. M. B. Carrilho, M.
Pineiro, M. M. Pereira* and L. Kollár*
Graphical abstract
O
CO, HNR'R"
I
R'R"N
N
Pd(OAc)2 / PPh3
N
O
H
H
1

ACCEPTED MANUSCRIPT
Functionalization of Indole at C-5 or C-7 via Palladium-Catalysed Double
Carbonylation. A Facile Synthesis of Indole Ketocarboxamides and
Carboxamide Dimers.
Attila Takács, a,b Diána Marosvölgyi-Haskó,a Zsuzsanna Kabak-Solt, a Liliana Damasc, Fábio M. S.
Rodriguesc, Rui M. B. Carrilhoc, Marta Pineiroc, Mariette M. Pereirac* and László Kollár a,b*
a) Department of Inorganic Chemistry, University of Pécs and Szentágothai Research Centre, H-7624
Pécs, P.O. Box 266, Hungary; e-mail: kollar@ttk.pte.hu
b) MTA-PTE Research Group for Selective Chemical Syntheses, H-7624 Pécs, Ifjúság u. 6., Hungary
c) Departamento de Quimica, Universidade de Coimbra, Rua Larga, 3004-535 Coimbra, Portugal
Abstract: Palladium-catalysed aminocarbonylation of 7-iodoindole derivatives (the
parent compound and 5-bromo-7-iodoindole), as well as 5-iodoindole with various
primary and secondary amines, including amino acid esters and chiral diamines, was
carried out. In this way, a highly selective double carbonylation reaction at the C-7
was performed resulting in the formation of the corresponding indol-7-
ylglyoxylamides when monoamines were used. The bromoarene moiety remained
intact, so bromo-substituted glyoxylamides of practical importance have been
synthesised in moderate to high yields. The use of chiral alkyl and aryl diamines as
nucheophiles allowed the synthesis of a new family of dimeric 7-indole derivatives
under moderate reaction conditions (10 bar, 100 ºC). The aminocarbonylation at the C-
5 position led to much lower chemoselectivities toward indol-5-ylglyoxylamides under
similar conditions (40 bar CO, 50oC).
The aminocarbonylation of iodoindoles shows a strikingly different chemoselectivity
depending on the basicity of the amine while primary and secondary amines of high
basicity gave 2-ketocarboxamides in up to 98% chemoselectivity, aniline resulted in
almost exclusive formation of the corresponding carboxamide product.
Key-words: carbonylation, 2-ketocarboxamide, palladium, carbon monoxide, iodoindole.
2

ACCEPTED MANUSCRIPT
1. Introduction
Carbonylation reactions are among the most widely used homogeneous catalytic reactions with several
practical applications reported.1-3 In addition to the parent hydroformylation used for the functionalization of
alkenes, 4-6 aminocarbonylation 7-9 has also gained several synthetic applications.
In this reaction, alkenyl and aryl triflates or their corresponding synthetic surrogates (iodoalkenes and
iodoaromatics, respectively) served as substrates. The seminal work of Heck et al. showed that this
methodology provides an excellent route to carboxamides of varying structure using carbon monoxide and
primary/secondary amines as N-nucleophiles.10 Moreover, Yamamoto et al. published a double carbonylation
process, where aromatic triflates and iodides insert two molecules of carbon monoxide resulting in the
formation of 2-ketocarboxamides.11
Among the number of substrates tested in aminocarbonylation,7-9 the functionalization of the indole
nucleus has been the topic of interest for many years.12,13 Special efforts have been devoted to the introduction
of functionalities at C-2. The palladium-catalysed alkoxycarbonylation and carbonylation (in the presence of
tributylstannane) of 2-iodoindole resulted in the formation of the corresponding 2-ester and 2-formyl
compounds, respectively.14 N-Protected and unprotected 2-iodoindole derivatives underwent
aminocarbonylation with various N-nucleophiles. This way, the efficiency of palladium-catalysed
aminocarbonylation for the introduction of amide side-chain was demonstrated.15 A carbonylative
alkoxycarbonylation-cyclocondensation reaction sequence based on 3-iodoindoles was developed leading to
compounds with protein kinase inhibitor activity.16 As direct preliminary work to our present research, the
aminocarbonylation of 7-iodoindole with piperidine in the presence of palladium(I)-dimers,17 as well as the
high-yielding palladium-catalysed aminocarbonylation of unprotected bromoindoles18 should be mentioned. In
the latter work, carboxamide functionalities were introduced at all positions within the benzene fragment of
the indoles, i.e., 4-, 5-, 6- and 7-carboxamides (among them amphetamine derivatives) were synthesised.
Furthermore, the synthesis of indole dimers is of great importance, since bis-indole derivatives are
relevant compounds that can be found in many natural products and pharmaceuticals.19 In particular, the
synthesis of bis-indole carboxamides remains a challenge for which the use of diamines as nucleophiles in
aminocarbonylation reactions was recently described as a promising synthetic approach.20
Although the double carbonyl insertion providing 2-ketocarboxamides is general in palladium-
catalysed aminocarbonylation of iodoaromatics,21 only the selective formation of carboxamides was observed
using iodo-N-heteroaromatics with an iodo substituent adjacent to the ring-nitrogen.22 2-
Carboxamidopyridines and carboxamidopyrazines were formed, while the corresponding 2-ketocarboxamides
were not observed. The aim of the selective synthesis of indoleketocarboxamides, i.e., a prevailing double
carbonylation in C-7 position being far from the ‘indole nitrogen’, seemed to be quite plausible, which is the
primary aim of this work.
3

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Prompted by the previous investigations of our group in the aminocarbonylation of iodoarenes,23-27
a
systematic study was carried out imploying unprotected iodoindoles. The most important achievement of this
work was the direct one-step synthesis of functionalised indoles bearing 2-ketocarboxamide functionalities and
the synthesis of chiral dimeric indole carboxamides.
2. Results and discussion
2.1. Aminocarbonylation of 7-iodoindole in the presence of various N-nucleophiles
Palladium(0) catalytic systems, formed in situ in the reaction of Pd(OAc)2 and two molar equivalents
of triphenylphosphine, have been used for the aminocarbonylation of 7-iodoindole (1) (Scheme 1). Primary (a,
b, e-h) and secondary amines (c, d) including functionalised amines (amino acid methylesters) have been used
as N-nucleophiles.
According to the generally accepted mechanism,7-10 palladium(0) catalysts are necessary to oxidatively
add the starting iodoalkene substrate. As in several cases before, instead of the coordinatively saturated ‘pre-
formed’ Pd(0) catalyst, Pd(PPh3)4, a highly active ‘phosphine-deficient’ Pd(OAc)2/2 PR3–type in situ catalyst
has been used. In fact, the catalytically active palladium intermediates contain one PR3 ligand only, since one
of the two equivalents of phosphine ligands is oxidized to the corresponding phosphine oxide.28-30
The aminocarbonylation of 7-iodoindole (1) (Scheme1), carried out at atmospheric carbon monoxide
pressure, resulted in the formation of indol-7-ylglyoxylamides (3) and the corresponding carboxamides (2), in
case of all the amines (Table 1, entries 1, 2 ,7, 9, 10, 14, 15), except for aniline (b). As observed previously,
the less basic aniline (b) and the sterically crowded methyl prolinate (h) exhibited lower reactivity, so no
reasonable conversion was obtained (entry 4 and entry 20, respectively). Surprisingly, the 2-ketocarboxamide-
type products (3), formed by double CO insertion, prevail in all cases. The chemoselectivity toward 3 was
found to be in the range of 60-90%, depending on the N-nucleophile. In spite of the formation of carboxamides
as minor products, we have been able to isolate 2a, 2c, 2d, 2g and characterise them as analytically pure
compounds.
The aminocarbonylations carried out at high (40 bar) carbon monoxide pressure showed high
chemoselectivity towards ketocarboxamides (3), i.e., the ketocarboxamide/carboxamide (3/2) ratios observed
at atmospheric pressure (vide supra) were substantially improved. These chemoselectivity values fall typically
in the range of 70-90%, in some cases up to 97% selectivities towards ketocarboxamides (entries 3, 8, 11, 13,
17, 21). A strikingly different behavior was observed for b. In spite of the high CO pressure, the high-yielding
formation of carboxamide 2b was observed, i.e., the ketocarboxamide-type product formed via double CO
insertion was detected in trace amounts by GC-MS (entries 5 and 6).
4

ACCEPTED MANUSCRIPT
HNR'R"
CO (1-40 bar), 50 oC
+
Pd(OAc)2 / PPh3
N
N
N
H
H
H
I
O
R'R''N
O
O
NR'R''
1
2
3
R'
H
H
R''
tBu
Ph
a
b
c
-(CH2)5-
-(CH2)2O(CH2)2-
d
e
f
H
H
H
H
CH2COOCH3
CH(CH3)COOCH3
g
h
CH(CH(CH3)2)COOCH3
-CH(COOCH3)(CH2)3-
Scheme 1. Aminocarbonylation of 7-iodoindole
5

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Table 1. Aminocarbonylation of 7-iodoindole (1) in the presence of Pd(OAc)2 + 2 PPh3 'in situ' catalyst a)
Entry
Amine
Reaction p(CO)
Conv. b)
[%]
Ratio of the carbonylated products b);
(isolated yield c)) [%]
time
[h]
[bar]
Carboxamide
Ketocarboxamide
(2)
(3)
1
2
t-BuNH2 (a)
t-BuNH2 (a)
t-BuNH2 (a)
aniline (b)
24
48
24
48
24
94
24
24
24
48
24
24
46
24
94
24
94
24
94
48
24
1
1
70
>98
>98
<2
17 (2a)
33 (2a); (25)
5 (2a)
83 (3a)
67 (3a); (36)
95 (3a); (58)
n.d.
3
40
1
4
n.d.
5
aniline (b)
40
40
1
95
>99 (2b)
>99 (2b); (51)
40 (2c); (33)
6 (2c)
<1 (3b)
6
aniline (b)
>98
>98
>98
71
<1 (3b)
7
piperidine (c)
piperidine (c)
morpholine (d)
morpholine (d)
morpholine (d)
GlyOMe (e)
GlyOMe (e)
AlaOMe (f)
AlaOMe (f)
AlaOMe (f)
AlaOMe (f)
ValOMe (g)
ValOMe (g)
ProOMe (h)
ProOMe (h)
60 (3c); (40)
94 (3c); (66)
93 (3d); (65)
78 (3d); (51)
97 (3d); (52)
94 (3e)
8
40
1
9
7 (2d)
10
11
12
13
14
15
16
17
18
19
20
21
1
82
22 (2d); (12)
3 (2d)
40
40
40
1
94
81
6 (2e)
>98
2
6 (2e)
94 (3e); (68)
65 (3f)
35 (2f)
1
61
33 (2f)
67 (3f)
40
40
40
40
1
82
20 (2f)
80 (3f)
>98
89
21 (2f)
79 (3f)
42 (2g)
58 (3g)
>98%
<2
45 (2g); (39)
n.d.
55 (3g); (45)
n.d.
40
95
3 (2h)
97 (3h); (57)
a) Reaction conditions (unless otherwise stated): 1 mmol substrate (1), amine nucleophile: 3 mmol of a (or 2
mmol of b / 1.5 mmol of c, d / 1.1 mmol of e, f, g, h), 0.025 mmol of Pd(OAc)2 (2.5 mol%), 0.05 mmol of
PPh3 (5 mol%), 0.5 mL of Et3N, 10 mL of DMF, 50 oC
b) determined by GC-MS
c) yields of the isolated target compound (based on the substrate (1))
6

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2.2. Aminocarbonylation of 5-iodoindole (4) in the presence of various N-nucleophiles
Surprisingly, the aminocarbonylation of 5-iodoindole (4) carried out using atmospheric carbon
monoxide pressure gave the corresponding carboxamide and 2-ketocarboxamide in only trace amounts (<1%).
The aminocarbonylations carried out at high (40 bar) carbon monoxide pressure showed moderate to
high chemoselectivities toward 2-ketocarboxamides (6) falling typically in the range of 79-94% (Table 2).
There are two exceptions: i) the use of the arylamine b with lower basicity resulted in a formation of the
corresponding carboxamide 5b (entry 3), i.e. no carbon monoxide insertion into Pd-amide bond took place, ii)
methyl valinate (g) gave a mixture of 5g and 6g with the prevailance of the carboxamide (5g) (entries 10, 11).
It is worth noting that close to an equimolar mixture of carbonylated products was obtained using 7-iodoindole
(1) as the substrate with this N-nucleophile (Table 1, entries 18, 19), the formation of 2-ketocarboxamide (3g)
is slightly favoured in this case.
O
O
HNR'R"
I
R'R''N
+
CO (1-40 bar), 50 oC R'R''N
O
Pd(OAc)2 / PPh3
N
N
N
H
H
H
5
6
4
Scheme 2. Aminocarbonylation of 5-iodoindole (for the N-nucleophiles used see Scheme 1)
7

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Table 2. Aminocarbonylation of 5-iodoindole (4) in the presence of Pd(OAc)2 + 2 PPh3 'in situ' catalyst a)
Entry
Amine
Reaction
time
Conv. b)
[%]
Ratio of the carbonylated products b);
(isolated yield c)) [%]
[h]
Carboxamide
Ketocarboxamide
(5)
(6)
1
2
t-BuNH2 (a)
aniline (b)
24
24
48
24
24
24
140
24
48
24
96
24
72
95
90
21 (5a); (11)
>99 (5b)
>99 (5b); (47)
14 (5c); (15)
6 (5d)
79 (6a); (46)
<1 (6b)
3
aniline (b)
>98
95
<1 (6b)
4
piperidine (c)
morpholine (d)
GlyOMe (e)
GlyOMe (e)
AlaOMe (f)
AlaOMe (f)
ValOMe (g)
ValOMe (g)
ProOMe (h)
ProOMe (h)
86 (6c); (66)
94 (6d); (50)
90 (6e)
5
95
6
51
10 (5e)
7
>98
63
10 (5e)
90 (6e); (74)
80 (6f)
8
20 (5f)
9
94
36 (5f)
64 (6f); (46)
35 (6g)
10
11
12
13
77
65 (5g)
>98
70
60 (5g); (25)
17 (5h)
40 (6g); (24)
83 (6h)
>98
21 (5h)
79 (6h); (36)
a) Reaction conditions (unless otherwise stated): 1 mmol substrate (4), amine nucleophile: 3 mmol of a (or 2
mmol of b / 1.5 mmol of c, d / 1.1 mmol of e, f, g, h), 0.025 mmol of Pd(OAc)2 (2.5 mol%), 0.05 mmol of
PPh3 (5 mol%), 0.5 mL of Et3N, 10 mL of DMF, 50 oC, 40 bar of CO.
b) determined by GC-MS
c) yields of the isolated target compound (based on the substrate (4))
d) 1 bar of CO
2.3. Aminocarbonylation of 5-bromo-7-iodoindole (7) in the presence of various N-nucleophiles
As a part of the systematic functionalization of the indole ring, the aminocarbonylation of 5-bromo-7-
iodoindole (7) was carried out. As above (see reactions in Scheme 1 and 2), a mixture of the corresponding
carboxamide (8) and 2-ketocarboxamide (9) was obtained (Scheme 3). It has been determined by MS and
NMR investigations that the bromoaryl moiety remained intact under the conditions used. This behaviour is of
practical importance, since the bromoarene functionality can potentially be further reacted in other cross-
coupling reactions, enabling further selective functionalization of the parent indole.
Although aminocarbonylation can be carried out even at atmospheric carbon monoxide pressure (Table
3, entries 1,2), giving rise to the formation of 2-ketocarboxamde (9a), in general, high selectivities (>98%)
8

ACCEPTED MANUSCRIPT
towards ketoamides (9) can be achieved at high CO pressure (entries 3, 6, 7, 10). Even under these conditions,
methyl alaninate (f) and methyl valinate (g) gave lower chemoselectivities (entries 8 and 9, respectively).
Based on the aforementioned results, the almost exclusive formation of carboxamide (8b) was observed with b
as nucleophile (entry 4).
HNR'R"
Br
Br
Br
CO (1-40 bar), 50 oC
+
Pd(OAc)2 / PPh3
N
N
N
H
H
H
O
I
R'R''N
O
O
NR'R''
8
9
7
Scheme 3. Aminocarbonylation of 5-bromo-7-iodoindole (for the N-nucleophiles used see Scheme 1)
Table 3. Aminocarbonylation of 5-bromo-7-iodoindole (7) in the presence of Pd(OAc)2 + 2 PPh3 'in situ'
catalyst a)
Entry
Amine
Reaction
time
Pressure
[bar]
Conv. b)
[%]
Ratio of the carbonylated products b);
(isolated yield c)) [%]
[h]
Carboxamide
Ketocarboxamide
(8)
(9)
1
2
t-BuNH2 (a)
t-BuNH2 (a)
t-BuNH2 (a)
aniline (b)
24
48
24
48
24
24
70
24
96
24
1
65
>98
>98
>98
>98
94
13 (8a)
16 (8a)
3 (8a)
87 (9a)
1
84 (9a) (53)
97 (9a) (53)
<2 (9b)
3
40
40
40
40
40
40
40
40
4
>98 (8b) (68)
8 (8c)
5
piperidine (c)
morpholine (d)
GlyOMe (e)
AlaOMe (f)
ValOMe (g)
ProOMe (h)
92 (9c) (54)
>98 (9d) (66)
>98 (9e) (45)
82 (9f) (38)
74 (9g) (46)
>98 (9h) (66)
6
<2 (8d)
<2 (8e)
18 (8f)
7
95
8
82
9
>98
>98
26 (8g)
<2 (8h)
10
a) Reaction conditions (unless otherwise stated): 1 mmol substrate (7), amine nucleophile: 3 mmol of a (or 2
mmol of b / 1.5 mmol of c, d / 1.1 mmol of e, f, g, h), 0.025 mmol of Pd(OAc)2 (2.5 mol%), 0.05 mmol of
PPh3 (5 mol%), 0.5 mL of Et3N, 10 mL of DMF, 50 oC.
b) determined by GC-MS
c) yields of the isolated target compound (based on the substrate (7))
9

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2.4. Aminocarbonylation of 7-iodoindole (1) in the presence of chiral diamines as N-nucleophiles
In order to obtain new chiral bis-indole derivatives bearing carboxamide moieties, the scope of the
aminocarbonylation reaction of 7-iodoindole (1) was expanded to the use of several chiral diamines as N-
nucleophiles: (S)-propane-1,2-diamine (i), (1S,2S)-(+)-1,2-diaminocyclohexane(j) and the axially chiral
aromatic (S)-1,1'-binaphthyl-2,2'-diamine (k) (Scheme 4). The reactions were carried out under 10 bar CO, at
100 °C for 24 h. After work-up, the conversions were calculated based on NMR analysis of crude mixtures,
and the dimeric-indole derivatives (10i, 10j, 10k) were purified by column chromatography. In all cases, the
substrate was fully converted, with the dimeric indole derivatives being the main products. It should be noted
that the monomeric product (11) was only observed and isolated when the less nucheophilic aromatic diamine
(k) was used (Table 4, entry 3).
i, j, k
H2N
NH2
NH2
O
NH HN
O
O
NH
CO (10 bar), 100 oC
H
N
H
N
H
N
Pd(OAc)2 / PPh3
N
H
I
10
11
1
NH2
NH2
=
H2N
NH2
H2N
NH2
H2N
NH2
j
i
k
Scheme 4. Aminocarbonylation of 7-iodoindole using chiral diamines (i, j, k) as N-nucleophiles
Table 4. Synthesis of 7-carboxamide indole dimers via aminocarbonylation of 7-iodoindole (1), using chiral
diamines as nucleophiles, in the presence of Pd(OAc)2 + 2 PPh3 'in situ' catalyst a
Entry
Diamine
Conv. b)
Dicarboxamide Monoarboxamide
(10) (isolated
yields)
46b (10i) (39)
(11) (isolated
yields)
-
>97
>98
>96
1
2
3
i
j
31 b (10j) (16)
40 b (10k) (32)
-
34b (11k) (29)
k
a) Reaction conditions: 0.9 mmol substrate (1), 0.45 mmol amine nucleophile (i-k), 0.025 mmol Pd(OAc)2
(2.8 mol%) 0.05 mmol PPh3 (5.6 mol%), 0.5 mL Et3N, 9 mL DMF, 100°C, 10 bar of CO; 24 h.
b) determined by NMR on the crude mixture.
10

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Conclusions
The synthesis of ketocarboxamide-functionalised indoles with double CO insertion at C-7 and C-5 was
achieved using a highly reactive, low-ligated Pd(0) catalyst generated from Pd(OAc)2/2PPh3. The coordination
of the PPh3(O) in the catalytically active intermediate to form Pd(PPh3)(P(O)Ph3) species cannot be excluded.
The importance of the coordination of strong and weak donor ligands was emphasized in the
aminocarbonylation of 2-bromopyridine derivatives using Bedford palladacycle and dppf (1,1’-
bis(diphenylphosphinoferrocene) as catalyst.31
The formation of indole-2-ketocarboxamides is of particular note. The 2-ketocarboxamides were
obtained as major products for most N-nucleophiles, with the only exception being aniline of low basicity. In
the latter case, the corresponding carboxamides formed via simple carbon monoxide insertion, prevailed under
o
the reaction conditions used (50 C, 1-40 bar CO). The aminocarbonylation reaction enabled the facile
preparation of the target compounds.
Considering the high relevance and large bio-aplications of dimeric indole-derivatives the bis-
aminocarbonylation reaction herein described provides an efficient and versatile synthetic methodology to
obtain a new family of chiral bis-indole carboxamide in a one-pot reaction.
3. Experimental
3.1. General procedures
13
1H and C NMR spectra were recorded in CDCl3 on a Bruker Avance III 500 spectrometer at 500 and
125.7 MHz, respectively. Chemical shifts δ are reported in ppm relative to CHCl3 (7.26 and 77.00 ppm for 1H
and 13C, respectively). Elemental analyses were measured on a 1108 Carlo Erba apparatus. Samples of the
catalytic reactions were analysed with a Hewlett Packard 5830A gas chromatograph fitted with a capillary
column coated with OV-1 (internal standard: naphthalene; injector temp 250 ˚C, oven: starting temp 50 ˚C
(hold-time 1 min), heating rate 15 ˚C min-1, final temp 320 ˚C (hold-time 11 min); detector temp 280 ˚C,
carrier gas: helium (rate: 1 mL min-1)). The FT-IR spectra were taken in KBr pellets using an IMPACT 400
spectrometer (Nicolet) applying a DTGS detector in the region of 400-4000 cm-1, the resolution was 4 cm-1.
The amount of the samples was ca. 0.5 mg.
The iodoarene substrates, 7-iodoindole, 5-iodoindole, 5-bromo-7-iodoindole, as well as the amine
nucleophiles were purchased from Sigma-Aldrich and were used without further purification.
3.2. Aminocarbonylation of 7-iodoindole in the presence of various amines as N-nucleophiles under
atmospheric carbon monoxide pressure
In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.1 mg, 0.05 mmol), 7-
iodoindole (243 mg, 1 mmol) or 5-bromo-7-iodindole (322 mg, 1mmol), amine nucleophile (3 mmol of a / 2
mmol of b / 1.5 mmol of c, d / 1.1 mmol of e, f, g, h) and triethylamine (0.5 mL) were dissolved in DMF (10
mL) under argon in a three-necked flask equipped with a gas inlet, reflux condenser with a ballon (filled with
11

ACCEPTED MANUSCRIPT
argon) at the top. The atmosphere was changed to carbon monoxide. The reaction was conducted for the given
reaction time upon stirring at 50 ˚C and analysed by GC-MS (internal standard: naphthalene). The mixture was
then concentrated and evaporated to dryness. The residue was dissolved in chloroform (20 mL) and washed
with water (3 20 mL). the organic phase was dried over Na2SO4, filtered and evaporated to a crystalline
material or a waxy residue. All compounds were subjected to column chromatography (Silicagel 60 (Merck),
0.063-0.200 mm), EtOAc/CHCl3, or EtOAc/toluene, or hexane/EtOAc/MeOH (the exact ratios are specified in
Section Characterization (3.4) for each compound).
3.3. Aminocarbonylation of 7-iodoindole in the presence of various amines as N-nucleophiles under high
carbon monoxide pressure
In a typical experiment, Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.1 mg, 0.05 mmol), 7-
iodoindole (243 mg, 1 mmol) or 5-bromo-7-iodindole (322 mg, 1mmol), amine nucleophile (3 mmol of a / 2
mmol of b / 1.5 mmol of c, d / 1.1 mmol of e, f, g, h) and triethylamine (0.5mL) were dissolved in DMF (10
mL) under argon in a 100 mL autoclave. The atmosphere was changed to carbon monoxide and the autoclave
was pressurized to the given pressure by carbon monoxide. The reaction was conducted for the given reaction
time upon stirring at 50 ˚C and analysed by GC-MS (internal standard: naphthalene). The mixture was then
concentrated and evaporated to dryness and worked-up as described in Section 3.2.
The analogous procedures (same molar ratios, identical reaction conditions, similar work-up) were used
in the aminocarbonylation of 5-iodoindole and 5-bromo-7-iodoindole.
3.4. Carbonylation of 7-iodoindole using chiral diamines as N-nucleophiles
In a typical experiment, Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.1 mg, 0.05 mmol), 7-
iodoindole (224 mg, 0.9 mmol), the desired diamine nucleophile (0.45 mmol) were placed in a stainless steel
autoclave. After degassing the autoclave, triethylamine (0.5 ml) and DMF (9 mL) were added via cannula. The
autoclave was then pressurized with 10 bar CO and the reaction was conducted for 24 h at 100 °C. The
1
mixture was then concentrated and evaporated to dryness, with the crude being analysed by H-NMR
spectroscopy. The residue was dissolved in chloroform (20 ml) and washed with water (3x20 mL) and BRINE
(3x20 mL). The organic phase was dried over Na2SO4, filtered and the solvent was evaporated. All compounds
were subjected to column chromatography (Silicagel 60 (Merck), 0.063-0.200 mm) using EtOAc/CHCl3 (the
exact ratios are specified in Section Characterization (3.5) for each compound).
3.5. Characterization of the products
7-(N-tert-Butylcarboxamido)indole (2a). Yield: 54 mg (25 %); brown viscous material [Found: C,
72.26; H, 7.58; N, 12.65; C13H16N2O requires C, 72.19; H, 7.46; N, 12.95 %]; Rf (20 % toluene, 80 % CHCl3)
0.72; δH (500 MHz, CDCl3) 10.37 (1 H, brs, indole-NH), 7.80 (1 H, d, 7.8 Hz, Ar-H), 7.34-7.31 (2 H, overlap,
m, Ar-H and indole-H), 7.12 (1 H, t, 7.7 Hz, Ar-H), 6.58 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 6.21 (1 H, brs,
12

ACCEPTED MANUSCRIPT
NH), 1.55 (9 H, s, (CH3)3). δC (125.7 MHz, CDCl3) 167.5, 135.5, 129.6, 125.5, 124.4, 118.6, 118.5, 117.2,
101.8, 51.5, 29.01. IR (KBr, ν (cm-1)): 3422 (indole-NH), 3336 (NH), 1632 (CON); MS m/z (rel int.): 216 (58,
M+), 201 (2), 185 (2), 160 (33), 144 (100), 116 (31), 89 (16), 63 (4).
7-(N-tert-Butylglyoxylamido)indole (3a). Yield: 142 mg (58 %); off-white solid material, mp. 104 ˚C;
[Found: C, 68.70; H, 6.75; N, 11.25; C14H16N2O2 requires C, 68.83; H, 6.60; N, 11.47 %]; Rf (20 % toluene,
80 % CHCl3) 0.58; δH (500 MHz, CDCl3) 10.44 (1 H, brs, indole-NH), 8.79 (1 H, d, 7.8 Hz, Ar-H), 7.98 (1 H,
d, 7.8 Hz, Ar-H), 7.86 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 7.23 (1 H, t, 7.8 Hz, Ar-H), 6.99 (1 H, brs, NH),
6.65 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 1.52 (9 H, s, (CH3)3). δC (125.7 MHz, CDCl3) 188.8, 162.1, 135.9,
129.4, 129.3, 129.2, 125.4, 119.3, 116.7, 103.1, 51.7, 29.01. IR (KBr, ν (cm-1)): 3381 (indole-NH), 3246 (NH),
1656 (CO), 1640 (CON); MS m/z (rel int.): 244 (36, M+), 144 (100), 116 (36), 89 (14), 57 (14).
7-(N-Phenylcarboxamido)indole (2b). Yield: 120 mg (51 %); brown solid material, mp. 145 ˚C;
[Found: C, 76.16; H, 5.30; N, 11.69; C15H12N2O requires C, 76.25; H, 5.12; N, 11.86 %]; Rf (5 % EtOAc, 95
% CHCl3) 0.53; δH (500 MHz, CDCl3) 10.33 (1 H, brs, indole-NH), 8.11 (1 H, brs, NH), 7.89 (1 H, d, 7.5 Hz,
Ar-H), 7.68 (2H, d, 8.0 Hz, Ph (ortho)), 7.55 (1 H, d, 7.5 Hz, Ar-H), 7.68 (2H, d, 8.0 Hz, Ph (meta)), 7.36 (1
H, dd, 3.0 Hz, 2.3 Hz, indole-H), 7.21 (2 H, overlap, m, Ar-H and Ph(para)), 6.64 (1 H, dd, 3.0 Hz, 2.3 Hz,
indole-H). δC (125.7 MHz, CDCl3) 166.1, 137.7, 135.6, 129.8, 129.2, 125.9, 125.4, 124.7, 120.6, 119.0, 118.8,
116.1, 102.1. IR (KBr, ν (cm-1)): 3418 (indole-NH), 3295 (NH), 1643 (CON); MS m/z (rel int.): 236 (64, M+),
206 (3), 144 (100), 116 (47), 89 (19), 63 (5).
7-(N,N-Pentane-1,5-diylcarboxamido)indole (2c). Yield: 76 mg (33 %); pale brown solid material,
mp. 121 ˚C; [Found: C, 73.49; H, 7.14; N, 12.05; C14H16N2O requires C, 73.66; H, 7.06; N, 12.27 %]; Rf (5 %
EtOAc, 95 % CHCl3) 0.46; δH (500 MHz, CDCl3) 9.29 (1 H, brs, indole-NH), 7.71 (1 H, d, 7.8 Hz, Ar-H),
7.26 (1 H, s, indole-H), 7.22 (1 H, d, 7.3 Hz, Ar-H), 7.11 (1 H, t, 7.6 Hz, Ar-H), 6.56 (1 H, s, indole-H), 3.69
(4 H, brs, 2x N-CH2), 1.73-1.66 (6 H, m, 3x CH2). δC (125.7 MHz, CDCl3) 169.4, 134.9, 129.1, 125.2, 122.8,
120.9, 118.5, 117.6, 102.4, 47.0, 26.3, 24.7. IR (KBr, ν (cm-1)): 3244 (indole-NH), 1623 (CON); MS m/z (rel
int.): 228 (87, M+), 144 (100), 116 (60), 89 (22), 84 (16), 63 (5).
7-(N,N-Pentane-1,5-diylglyoxylamido)indole (3c). Yield: 170 mg (66 %); beige solid material, mp.
125 ˚C; [Found: C, 70.16; H, 6.41; N, 10.75; C15H16N2O2 requires C, 70.29; H, 6.29; N, 10.93 %]; Rf (5 %
EtOAc, 95 % CHCl3) 0.71; δH (500 MHz, CDCl3) 10.34 (1 H, brs, indole-NH), 7.97 (1 H, d, 7.8 Hz, Ar-H),
7.68 (1 H, d, 7.6 Hz, Ar-H), 7.38 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 7.22 (1 H, t, 7.7 Hz, Ar-H), 6.66 (1 H,
dd, 3.0 Hz, 2.3 Hz, indole-H), 3.82-3.76 (2 H, m, N-CH2), 3.38-3.33 (2 H, m, N-CH2), 1.79-1.70 (4 H, m, 2x
13

ACCEPTED MANUSCRIPT
CH2), 1.62-1.55 (2 H, m, CH2). δC (125.7 MHz, CDCl3) 193.9, 165.3, 134.7, 129.7, 128.9, 127.1, 126.1, 119.4,
116.7, 102.85, 47.2, 42.2, 26.2, 25.5, 24.4. IR (KBr, ν (cm-1)): 3359 (indole-NH), 1661 (CO), 1630 (CON);
MS m/z (rel int.): 256 (42, M+), 144 (100), 116 (35), 89 (30), 84 (3), 69 (30), 63 (3).
7-(N,N-Pentane-3-oxa-1,5-diylcarboxamido)indole (2d). Yield: 28 mg (12 %); brown solid material,
mp. 107 ˚C; [Found: C, 67.76; H, 6.30; N, 12.01; C13H14N2O2 requires C, 67.81; H, 6.13; N, 12.17 %]; Rf (5 %
EtOAc, 95 % CHCl3) 0.36; δH (500 MHz, CDCl3) 9.27 (1 H, brs, indole-NH), 7.75 (1 H, d, 7.8 Hz, Ar-H),
7.28 (1 H, s, indole-H), 7.23 (1 H, d, 7.3 Hz, Ar-H), 7.11 (1 H, t, 7.3 Hz, Ar-H), 6.59 (1 H, s, indole-H), 3.81-
3,76 (8 H, overlap, m, 2x O-CH2 and 2x N-CH2), 1.73-1.66 (6 H, m, 3x CH2). δC (125.7 MHz, CDCl3) 169.6,
135.0, 129.3, 125.4, 123.4, 121.2, 118.5, 116.3, 102.6, 67.1, 45.6. IR (KBr, ν (cm-1)): 3253 (indole-NH), 1615
(CON); MS m/z (rel int.): 230 (65, M+), 215 (3), 186 (5), 144 (100), 116 (45), 89 (17), 63 (5).
7-(N,N-Pentane-3-oxa-1,5-diylglyoxylamido)indole (3d). Yield: 170 mg (65 %); beige solid material,
mp. 166 ˚C; [Found: C, 65.16; H, 5.40; N, 10.66; C14H14N2O3 requires C, 65.11; H, 5.46; N, 10.85 %]; Rf (5 %
EtOAc, 95 % CHCl3) 0.63; δH (500 MHz, CDCl3) 10.32 (1 H, brs, indole-NH), 7.99 (1 H, d, 5.6 Hz, Ar-H),
7.70 (1 H, d, 5.6 Hz, Ar-H), 7.39 (1 H, s, indole-H), 7.23 (1 H, t, 5.6 Hz, Ar-H), 6.67 (1 H, s, indole-H), 3.85
(4 H, brs, 2x O-CH2), 3.66 (2 H, brs, N-CH2), 3.42 (2 H, brs, N-CH2). δC (125.7 MHz, CDCl3) 193.0, 165.3,
134.7, 129.8, 129.3, 127.1, 126.3, 119.4, 116.5, 103.0, 66.8, 66.7, 46.4, 41.7. IR (KBr, ν (cm-1)): 3360 (indole-
NH), 1661 (CO), 1634 (CON); MS m/z (rel int.): 258 (30, M+), 144 (100), 116 (35), 89 (12), 63 (4).
7-(N-(1’-Methoxycarbonylmethyl)carboxamido)indole (2e) (identified as minor component in 3e).
MS m/z (rel int.): 232 (76, M+), 200 (6), 185 (4), 173 (4), 144 (100), 116 (50), 89 (22), 63 (7). δH (500 MHz,
CDCl3) 10.28 (1 H, brs, indole-NH), 7.83 (1 H, d, 7.8 Hz, Ar-H), 7.48 (1 H, d, 7.8 Hz, Ar-H), 7.33 (1 H,
overlapping brs, indole-H), 7.15 (1 H, t, 7.8 Hz, Ar-H), 6.95 (1 H, brs NH), 6.59 (1 H, dd, 3.0 Hz, 2.3 Hz,
indole-H), 4.31 (2 H, d, 5.6 Hz, N-CH2), 3.83 (3 H, s, O-CH3).
7-(N-(1’-Methoxycarbonylmethyl)glyoxylamido)-indole (3e). Yield: 176 mg (68 %); yellow solid
material, mp. 98 ˚C; [Found: C, 60.14; H, 4.77; N, 10.55; C13H12N2O4 requires C, 60.00; H, 4.65; N, 10.76 %];
Rf (5 % EtOAc, 95 % CHCl3) 0.62; δH (500 MHz, CDCl3) 10.42 (1 H, brs, indole-NH), 8.77 (1 H, d, 7.7 Hz,
Ar-H), 7.98 (1 H, d, 7.7 Hz, Ar-H), 7.72 (1 H, brs NH), 7.34 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 7.21 (1 H, t,
7.7 Hz, Ar-H), 6.67 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 4.24 (2 H, d, 5.6 Hz, N-CH2), 3.83 (3 H, s, O-CH3). δC
(125.7 MHz, CDCl3) 186.9, 169.6, 162.7, 135.8, 129.6, 129.4, 129.3, 125.6, 119.4, 116.5, 103.2, 52.6, 41.1. IR
(KBr, ν (cm-1)): 3434 (indole-NH), 3302 (NH), 1771 (COO), 1663 (CO), 1636 (CON); MS m/z (rel int.): 260
(33, M+), 201 (2), 144 (100), 116 (46), 89 (15), 63 (4).
14

ACCEPTED MANUSCRIPT
7-(N-(1’-Methoxycarbonylethyl)carboxamido)indole (2f) (isolated in a 2/8 mixture of 2f/3f). δH (500
MHz, CDCl3) 10.29 (1 H, brs, indole-NH), 7.83 (1 H, d, 7.8 Hz, Ar-H), 7.48 (1 H, d, 7.8 Hz, Ar-H), 7.34 (1 H,
dd, 3.0 Hz, 2.3 Hz, indole-H), 7.15 (1 H, t, 7.8 Hz, Ar-H), 6.98 (1 H, d, 5.7 Hz, NH), 6.59 (1 H, dd, 3.0 Hz, 2.3
Hz, indole-H), 4.87 (1 H, qi, 7.2 Hz, N-CH) 3.83 (3 H, s, O-CH3), 1.58 (3 H, d, 7.2 Hz, CHCH3). δC (125.7
MHz, CDCl3) 173.7, 167.4, 135.8, 129.6, 129.3, 125.1, 119.3, 118.7, 115.3, 102.0, 52.6, 48.3, 18.6. MS m/z
(rel int.): 246 (48, M+), 187 (9), 171 (5), 144 (100), 116 (33), 102 (2), 89 (14), 63 (4).
7-(N-(1’-Methoxycarbonylethyl)glyoxylamido)indole (3f) (isolated in a 2/8 mixture of 2f/3f). Rf (5 %
MeOH, 20 % EtOAc, 75 % hexane) 0.40; δH (500 MHz, CDCl3) 10.43 (1 H, brs, indole-NH), 8.78 (1 H, d, 7.8
Hz, Ar-H), 7.98 (1 H, d, 7.8 Hz, Ar-H), 7.72 (1 H, d, 6.1 Hz, NH), 7.34 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H),
7.21 (1 H, t, 7.8 Hz, Ar-H), 6.65 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 4.76 (1 H, qi, 7.3 Hz, N-CH) 3.83 (3 H,
s, O-CH3), 1.57 (3 H, d, 7.3 Hz, CHCH3). δC (125.7 MHz, CDCl3) 187.1, 167.4, 162.1, 135.9, 129.6, 129.4,
129.3, 125.1, 119.4, 116.6, 103.2, 52.7, 48.1, 18.2. IR (KBr, ν (cm-1)): 3402 (indole-NH), 3261 (NH), 1745
(COO), 1664 (CO), 1636 (CON); MS m/z (rel int.): 274 (31, M+), 215 (4), 144 (100), 116 (36), 102 (6), 89
(15), 63 (4).
7-(N-(1’-Methoxycarbonyl-2’-methylpropyl)carboxamido)indole (2g), Yield: 107 mg (39 %); pale
yellow viscous material; [Found: C, 65.46; H, 6.47; N, 10.05; C15H18N2O3 requires C, 65.68; H, 6.61; N, 10.21
%]; Rf (5 % MeOH, 15 % EtOAc, 80 % hexane) 0.64; δH (500 MHz, CDCl3) 10.28 (1 H, brs, indole-NH), 7.84
(1 H, d, 7.8 Hz, Ar-H), 7.51 (1 H, d, 7.8 Hz, Ar-H), 7.34 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 7.16 (1 H, t, 7.7
Hz, Ar-H), 6.91 (1 H, d, 8.3 Hz, NH), 6.59 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 4.84 (1 H, dd, 8.6 Hz, 5.1 Hz,
N-CH) 3.82 (3 H, s, O-CH3), 2.37-2.30 (1 H, m, CH(CH3)2), 1.06 (3 H, d, 6.9 Hz, CHCH3), 1.04 (3 H, d, 6.9
Hz, CHCH3). δC (125.7 MHz, CDCl3) 172.7, 167.7, 135.4, 129.6, 125.6, 125.1, 119.2, 118.7, 115.5, 102.0,
57.2, 52.3, 31.7, 19.1, 18.1. IR (KBr, ν (cm-1)): 3427 (NH), 1734 (COO), 1646 (CON); MS m/z (rel int.): 274
(29, M+), 215 (7), 171 (11), 160 (17), 144 (100), 130 (2), 116 (37), 89 (13), 63 (2).
7-(N-(1’-Methoxycarbonyl-2’-methylpropyl)glyoxylamido)indole (3g), Yield: 136 mg (45 %); yellow
solid material, mp. 71 ˚C; [Found: C, 63.46; H, 6.12; N, 9.03; C16H18N2O4 requires C, 63.56; H, 6.00; N, 9.27
%]; Rf (5 % MeOH, 15 % EtOAc, 80 % hexane) 0.52; δH (500 MHz, CDCl3) 10.46 (1 H, brs, indole-NH), 8.77
(1 H, d, 7.7 Hz, Ar-H), 7.98 (1 H, d, 7.7 Hz, Ar-H), 7.69 (1 H, d, 8.8 Hz, NH), 7.36 (1 H, dd, 3.0 Hz, 2.3 Hz,
indole-H), 7.21 (1 H, t, 7.7 Hz, Ar-H), 6.59 (1 H, dd, 3.0 Hz, 2.3 Hz, indole-H), 4.71 (1 H, dd, 9.1 Hz, 5.1 Hz,
N-CH) 3.82 (3 H, s, O-CH3), 2.39-2.30 (1 H, m, CH(CH3)2), 1.06 (3 H, d, 6.9 Hz, CHCH3), 1.03 (3 H, d, 6.9
Hz, CHCH3). δC (125.7 MHz, CDCl3)187.3 171.7, 162.4, 135.9, 129.6, 129.4, 129.3, 125.6, 119.4, 116.6,
15

ACCEPTED MANUSCRIPT
103.2, 57.3, 52.4, 61.5, 19.1, 17.8. IR (KBr, ν (cm-1)): 3427 (overlap indole-NH and NH), 3284 (NH), 1742
(COO), 1665 (CO), 1636 (CON); MS m/z (rel int.): 302 (29, M+), 243 (4), 144 (100), 130 (9), 116 (35), 89
(13), 63 (2).
7-(N-(2’-Methoxycarbonylbutane-1,4-diyl)glyoxylamido)indole (3h), (ca. 1/3 mixture of two C(O)N
rotamers). Yield: 171 mg (57%); beige solid material, mp. 94 ˚C; [Found: C, 64.12; H, 5.40; N, 9.12;
C16H16N2O4 requires C, 63.99; H, 5.37; N, 9.33 %]; Rf (5 % EtOAc, 95 % CHCl3) 0.68; δH (500 MHz, CDCl3)
10.33/10.28 (major/minor) (1 H, brs, indole-NH), 7.99-7.94 (major + minor) (2 H, overlap, m, 2x Ar-H),
7.38/7.35 (major/minor) (1 H, dd, 3.00 Hz, 2.34 Hz, indole-H), 7.26/7.21 (major/minor) (1 H, t, 7.70 Hz, Ar-
H), 6.66/6.64 (major/minor) (1 H, dd, 3.00 Hz, 2.34 Hz, indole-H), 4.73/4.69 (major/minor) (1 H dd, 8.82 Hz,
4.15 Hz, N-CH), 3.89/3.43 (major/minor) (3 H, s, O-CH3), 3.84-3.78/3.64-3.55 (minor/major) (2 H, m, N-
CH2), 2.39-1.94 (major/minor) (4 H, m, 2x CH2). δC (125.7 MHz, CDCl3) 192.7/191.9 (major/minor), 172.0,
165.3/164.5 (major/minor), 135.2/134.9 (minor/major), 129.5/129.4 (major/minor), 129.1/128.9
(major/minor), 128.3/127.9 (minor/major), 126.0/125.8 (major/minor), 119.7/119.2 (major/minor),
116.5/116.3 (minor/major), 102.9, 59.5/58.3 (minor/major), 52.6/52.3 (major/minor), 47.3/46.4 (major/minor),
31.1/29.2 (minor/major), 24.7/22.4 (major/minor). IR (KBr, ν (cm-1)): 3410 (indole-NH), 3410 (indole-NH),
1745 (COO), 1653 (CO), 1636 (CON); MS m/z (rel int.): 300 (35, M+), 241 (4), 144 (100), 128 (33), 116 (37),
89 (15), 63 (4).
5-(N-tert-Butylcarboxamido)indole (5a). Yield: 25 mg (11 %); brow viscous material, [Found: C,
72.01; H, 7.30; N, 12.75; C13H16N2O requires C, 72.19; H, 7.46; N, 12.95 %]; Rf (5 % EtOAc, 95 % CHCl3)
0.28; δH (500 MHz, CDCl3) 9.11 (1 H, brs, indole-NH), 8.04 (1 H, s, Ar-H), 7.6 (1 H, d, 8.5 Hz, Ar-H), 7.38 (1
H, d, 8.5 Hz, Ar-H), 7.26 (1 H, s, indole-H), 6.59 (1 H, s, indole-H), 6.1 (1 H, brs, indole-NH), 1.52 (9 H, s,
(CH3)3). δC (125.7 MHz, CDCl3) 168.5, 137.5, 132.1, 127.5, 125.8, 120.7, 119.6, 111.1, 103.1, 51.5, 29.0. IR
(KBr, ν (cm-1)): 3357 (indole-NH and NH (overlapping)), 1638 (CON); MS m/z (rel int.): 216 (20, M+), 201
(2), 160 (20), 144 (100), 116 (34), 89 (14), 63 (4).
5-(N-tert-Butylglyoxylamido)indole (6a). Yield: 113 mg (46 %); beige solid material, mp. 175 ˚C;
[Found: C, 68.96; H, 6.40; N, 11.25; C14H16N2O2 requires C, 68.83; H, 6.60; N, 11.47 %]; Rf (5 % EtOAc, 95
% CHCl3) 0.60; δH (500 MHz, CDCl3) 8.90 (1 H, s, Ar-H), 8.73 (1 H, brs, indole-NH), 8.12 (1 H, dd, 8.7 Hz,
1.5 Hz, Ar-H), 7.40 (1 H, d, 8.68 Hz, Ar-H), 7.24 (1H, dd, 3.02 Hz, 2.35 Hz, indole-H), 7.01 (1 H, brs, NH),
6.67 (1 H, d, 1.97 Hz, indole-H), 1.51 (9 H, s, (CH3)3). δC (125.7 MHz, CDCl3) 188.3, 162.5, 139.1, 127.4,
16

ACCEPTED MANUSCRIPT
127.1, 125.8, 125.7, 124.6, 111.2, 104.9, 51.6, 28.5. IR (KBr, ν (cm-1)): 3357 (indoleNH), 3212 (NH), 1661
(CO), 1647 (CON); MS m/z (rel int.): 244 (7, M+), 144 (100), 116 (35), 89 (13), 57 (8).
5-(N-Phenylcarboxamido)indole (5b). Yield: 111 mg (47 %); brown solid material, mp. 180 ˚C;
[Found: C, 76.16; H, 5.30; N, 11.75; C15H12N2O requires C, 76.25; H, 5.12; N, 11.86 %]; Rf (20 % EtOAc, 80
% CHCl3) 0.53; δH (500 MHz, CDCl3) 8.55 (1 H, brs, indole-NH), 8.23 (1 H, s, Ar-H), 7.93 (1 H, s, NH), 7.77
(1H, dd, 8.51 Hz, 1.65 Hz, Ar-H), 7.70 (2H, d, 7.67 Hz, Ph (ortho)), 7.48 (1 H, d, 8.5 Hz, Ar-H), 7.45 (2H, t,
8.2 Hz, Ph (meta)), 7.32 (1 H, t, 3.0 Hz, indole-H), 7.16 (1 H, t, 7.4 Hz, Ph(para)), 6.68 (1 H, s, indole-H). δC
(125.7 MHz, CDCl3) 166.8, 138.4, 137.7, 129.1, 127.7, 126.9, 125.8, 124.2, 121.2, 120.3, 120.1, 111.3, 103.7.
IR (KBr, ν (cm-1)): 3418 (indole-NH), 3178 (NH), 1643 (CON); MS m/z (rel int.): 236 (26, M+), 144 (100),
116 (40), 89 (17), 63 (7).
5-(N,N-Pentane-1,5-diylcarboxamido)indole (5c). Yield: 35 mg (15 %); brown viscous material,
[Found: C, 73.50; H, 7.23; N, 12.01; C14H16N2O requires C, 73.66; H, 7.06; N, 12.27 %]; Rf (30 % EtOAc, 70
% CHCl3) 0.37; δH (500 MHz, CDCl3) 9.41 (1 H, brs, indole-NH), 7.67 (1 H, s, Ar-H), 7.35 (1 H, d, 8.3 Hz,
Ar-H), 7.23 (1 H, s, indole-H), 77.11 (1 H, d, 8.2 Hz, Ar-H), 6.52 (1 H, s, indole-H), 3.58-3.56 (2 H, m, N-
CH2), 3.38-3.29 (2 H, m, N-CH2), 1.67-1.59 (2H, m, CH2), 1.59-1.53 (4H, m, 2x CH2). δC (125.7 MHz,
CDCl3) 172.09, 136.52, 128.59, 127.3, 125.66, 120.92, 119.81, 111.19, 102.61, 47.19, 41.74, 26.39, 25.28,
24.37. IR (KBr, ν (cm-1)): 3487 (indole-NH), 1653 (CON); MS m/z (rel int.): 228 (68, M+), 144 (100), 116
(47), 89 (18), 63 (5).
5-(N,N-Pentane-1,5-diylglyoxylamido)indole (6c). Yield: 170 mg (66 %); beige solid material, mp.
198 ˚C; [Found: C, 70.16; H, 6.41; N, 10.70; C15H16N2O2 requires C, 70.29; H, 6.29; N, 10.93 %]; Rf (30 %
EtOAc, 70 % CHCl3) 0.52; δH (500 MHz, CDCl3) 9.03 (1 H, brs, indole-NH), 8.25 (1H, s, Ar-H), 7.80 (1H, d,
8.6 Hz, Ar-H), 7.40 (1H, d, 8.6 Hz, Ar-H), 7.28 (1 H, t, 3 Hz, indole-H), 6.65 (1 H, s, indole-H), 3.77-3.75 (2
H, m, N-CH2), 3.35-3.33 (2H, m, N-CH2), 1.73-1.71 (4H, m, 2x CH2), 1.56-1.55 (2H, m, CH2). δC (125.7
MHz, CDCl3) 192.5, 166.6, 139.5, 127.7, 126.4, 125.7, 125.1, 122.6, 111.8, 104.5, 47.2, 42.1, 26.2, 25.5, 24.4.
IR (KBr, ν (cm-1)): 3172 (indole-NH), 1656 (CO), 1625 (CON); MS m/z (rel int.): 256 (4, M+), 144 (100), 116
(35), 89 (14), 69 (7).
5-(N,N-Pentane-3-oxa-1,5-diylcarboxamido)indole (5d). MS m/z (rel int.): 230 (22, M+), 144 (100),
116 (43), 89 (17), 56 (5).
5-(N,N-Pentane-3-oxa-1,5-diylglyoxylamido)indole (6d). Yield: 129 mg (50 %); beige solid material,
mp. 187 ˚C; [Found: C, 65.19; H, 5.30; N, 10.71; C14H14N2O3 requires C, 65.11; H, 5.46; N, 10.85 %]; Rf (40
17

ACCEPTED MANUSCRIPT
% EtOAc, 60 % CHCl3) 0.40; δH (500 MHz, CDCl3) 8.81 (1 H, brs, indole-NH), 8.28 (1 H, s, Ar-H), 7.84 (1
H, dd, 8.61 Hz, 1.38 Hz, Ar-H), 7.45 (1 H, d, 8.58 Hz, Ar-H), 7.31 (1 H, t, 2.6 Hz, indole-H), 6.69 (1 H, s,
indole-H), 3.85 (4 H, s, 2x O-CH2), 3.67 (2 H, t, N-CH2), 3.43 (2 H, t, N-CH2). δC (125.7 MHz, CDCl3) 191.6,
166.6, 139.5, 127.7, 126.4, 125.6, 125.3, 122.8, 111.8, 104.7, 66.8, 66.7, 46.4, 41.6. IR (KBr, ν (cm-1)): 3260
(indole-NH), 1664 (CO), 1631 (CON); MS m/z (rel int.): 258 (3, M+), 144 (100), 116 (40), 89 (15), 63 (5).
5-(N-(1’-Methoxycarbonylmethyl)carboxamido)indole (5e) (identified as a minor component in 6e).
MS m/z (rel int.): 232 (42, M+), 200 (3), 144 (100), 116 (28), 89 (19), 63 (7). δH (500 MHz, CDCl3) 8.85 (1 H,
s, Ar-H), 8.65 (1 H, brs, indole-NH), 8.36 (1 H, d, 8.8 Hz, Ar-H), 8.31 (1 H, d, 8.7 Hz, Ar-H), 7.37 (1 H, brs
NH), 7.29 (1 H, s, indole-H), 6.70 (1 H, s, indole-H), 4.23 (2 H, d, 5.6 Hz, N-CH2), 3.84 (3 H, s, O-CH3).
5-(N-(1’-Methoxycarbonylmethyl)glyoxylamido)indole (6e). Yield: 196 mg (74 %); brown solid
material, mp. 117 ˚C; [Found: C, 60.17; H, 4.70; N, 10.55; C13H12N2O4 requires C, 60.00; H, 4.65; N, 10.76
%]; Rf (40 % EtOAc, 60 % CHCl3) 0.57; δH (500 MHz, CDCl3) 8.91 (1 H, s, Ar-NH), 8.58 (1 H, brs, indole-
NH), 8.15 (1 H, d, 8.7 Hz, Ar-H), 7.62 (1 H, brs NH), 7.43 (1 H, d, 8.7 Hz, Ar-H), 7.28 (1 H, s, indole-H),
6.70 (1 H, s, indole-H), 4.23 (2 H, d, 5.6 Hz, N-CH2), 3.83 (3 H, s, O-CH3). δC (125.7 MHz, CDCl3) 186.4,
169.5, 163.1, 139.3, 127.5, 127.3, 125.8, 125.5, 124.5, 111.3, 105.1, 52.5, 41.1. IR (KBr, ν (cm-1)): 3376
(indole-NH), 3337 (NH), 1739 (COO), 1670 (CO), 1652 (CON); MS m/z (rel int.): 260 (10, M+), 144 (100),
116 (49), 89 (19), 63 (5).
5-(N-(1’-Methoxycarbonylethyl)carboxamido)indole (5f). MS m/z (rel int.): 246 (12, M+), 187 (7),
144 (100), 116 (33), 89 (12), 63 (4).
5-(N-(1’-Methoxycarbonylethyl)glyoxylamido)indole (6f). Yield: 126 mg (46 %); brown solid
material, mp. 135 ˚C; [Found: C, 61.20; H, 5.41; N, 10.01; C14H14N2O4 requires C, 61.31; H, 5.14; N, 10.21
%];Rf (30 % EtOAc, 70 % CHCl3) 0.60; δH (500 MHz, CDCl3) 8.89 (1 H, s, Ar-H), 8.73 (1 H, brs, indole-
NH), 8.12 (1 H, dd, 8.70 Hz, 1.5 Hz, Ar-H), 7.63 (1 H, d, 7.02 Hz, NH), 7.41 (1 H, d, 8.7 Hz, Ar-H), 7.26 (1
H, t, 3.0 Hz, indole-H), 6.67 (1 H, s, indole-H), 4.73 (1 H, qi, 7.26 Hz, N-CH) 3.81 (3 H, s, O-CH3), 1.56 (3 H,
d, 7.2 Hz, CHCH3). δC (125.7 MHz, CDCl3186.7, 172.6, 162.6, 139.3, 127.5, 127.2, 125.9, 125.5, 124.5,
111.3, 104.9, 52.6, 48.2, 18.1. IR (KBr, ν (cm-1)): 3363 (indole-NH), 3289 (NH), 1733 (COO), 1664 (CO),
1646 (CON); MS m/z (rel int.): 274 (7, M+), 144 (100), 116 (37), 89 (14), 63 (4).
5-(N-(1’-Methoxycarbonyl-2’-methylpropyl)carboxamido)indole (5g), Yield: 70 mg (25 %); brown
viscous material; [Found: C, 65.77; H, 6.40; N, 10.05; C15H18N2O3 requires C, 65.68; H, 6.61; N, 10.21 %]; Rf
(20 % EtOAc, 80 % CHCl3) 0.47; δH (500 MHz, CDCl3) 9.52 (1 H, brs, indole-NH), 8.15 (1 H, s, Ar-H), 7.65
18

ACCEPTED MANUSCRIPT
(1 H, dd, 8.53 Hz, 1.5 Hz, Ar-H), 7.38 (1 H, d, 8.52 Hz, Ar-H), 7.25 (1 H, t, 2.8 Hz, indole-H), 6.81 (1 H, d,
8.65 Hz, NH), 6.59 (1 H, s, indole-H), 4.84 (1 H, dd, 8.56 Hz, 5.17 Hz, N-CH) 3.77 (3 H, s, O-CH3), 2.27-2.34
(1 H, m, CH(CH3)2), 1.04 (3 H, d, 6.87 Hz, CHCH3), 1.03 (3 H, d, 6.9 Hz, CHCH3). δC (125.7 MHz, CDCl3)
173.9, 168.9, 137.9, 127.5, 126.1, 125.5, 120.8, 120.2, 111.3, 103.1, 57.6, 52.1, 31.6, 19.1, 18.1. IR (KBr, ν
(cm-1)): 3341 (indole-NH), 3217 (NH), 1737 (COO), 1634 (CON); MS m/z (rel int.): 274 (9, M+), 215 (3), 160
(28), 144 (100), 116 (37), 89 (12), 63 (3).
5-(N-(1’-Methoxycarbonyl-2’-methylpropyl)glyoxylamido)indole (6g), Yield: 74 mg (24 %); brown
viscous material; [Found: C, 63.78; H, 5.80; N, 9.05; C16H18N2O4 requires C, 63.56; H, 6.00; N, 9.27 %]; Rf
(20 % EtOAc, 80 % CHCl3) 0.68; δH (500 MHz, CDCl3) 10.04 (1 H, brs, indole-NH), 8.88 (1 H, s, Ar-H), 8.11
(1 H, dd, 8.69 Hz, 1.53 Hz, Ar-H), 7.61 (1 H, d, 9.3 Hz, NH), 7.39 (1 H, d, 8.7 Hz, Ar-H), 7.24 (1 H, t, 2.86
Hz, indole-H), 6.65 (1 H, s, indole-H), 4.67 (1 H, dd, 9.02 Hz, 5.08 Hz, N-CH) 3.80 (3 H, s, O-CH3), 2.37-
2.27 (1 H, m, CH(CH3)2), 1.05 (3 H, d, 6.86 Hz, CHCH3), 1.01 (3 H, d, 6.88 Hz, CHCH3). δC (125.7 MHz,
CDCl3)186.8 171.6, 163.0, 139.4, 127.5, 127.1, 126.0, 125.5, 124.4, 111.4, 104.9, 57.4, 52.3, 31.4, 19.1, 17.7.
IR (KBr, ν (cm-1)): 3332 (indole-NH and NH (overlapping)), 1742 (COO), 1652 (CO), 1636 (CON); MS m/z
(rel int.): 302 (9, M+), 144 (100), 116 (30), 89 (9), 63 (2).
5-(N-(2’-Methoxycarbonylbutane-1,4-diyl)carboxamido)indole (5h). MS m/z (rel int.): 272 (16, M+),
213 (12), 144 (100), 116 (30), 89 (11), 63 (3).
5-(N-(2’-Methoxycarbonylbutane-1,4-diyl)glyoxylamido)indole (6h) (ca. 1/3 mixture of two C(O)N
rotamers). Yield: 112 mg (36%); brown viscous material; [Found: C, 64.17; H, 5.40; N, 9.11; C16H16N2O4
requires C, 63.99; H, 5.37; N, 9.33 %]; Rf (20 % EtOAc, 80 % CHCl3) 0.34; δH (500 MHz, CDCl3) 9.78/9.71
(minor/major) (1 H, brs, indole-NH), 8.40/8.36 (major/minor) (1H, s, Ar-H), 7.86/7.84 (1 H, d, 8.5 Hz, Ar-H),
7.38/7.36 (1 H, d, 8.6 Hz, Ar-H), 7.20/7.15 (major/minor) (1 H, m, indole-H), 6.61/6.58 (major/minor) (1 H,
s, indole-H), 4.71/4.54 (major/minor) (1 H dd, 8.73 Hz, 4.24 Hz, N-CH), 3.82/3.75 (major/minor) (3 H, s, O-
CH3), 3.73-3.69/3.63-3.50 (major/minor) (2 H, m, N-CH2), 2.35-1.86 (minor/major) (4 H, m, 2x CH2). δC
(125.7 MHz, CDCl3) 191.7/190.9 (major/minor), 172.1, 166.8/165.9 (major/minor), 139.8/139.6
(major/minor), 127.8/127.5 (major/minor), 126.7/126.5 (major/minor), 126.0/125.7 (minor/major),
125.1/124.9 (minor/major), 123.2/122.27 (minor/major), 112.1/111.6 (major/minor), 104.3/102.6
(major/minor), 59.5/58.4 (minor/major), 52.5/52.4 (major/minor), 47.3/46.4 (major/minor), 31.2/29.5
(minor/major), 24.9/22.4 (major/minor). IR (KBr, ν (cm-1)): 3292 (indole-NH), 1744 (COO), 1661 (CO), 1636
(CON); MS m/z (rel int.): 300 (3, M+), 144 (100), 128 (11), 116 (31), 89 (11), 63 (3).
19

ACCEPTED MANUSCRIPT
5-Bromo-7-(N-tert-butylcarboxamido)indole (8a). MS m/z (rel int.): 294/296 (55, M+), 279/281 (5),
238/240 (59), 222/234 (100), 194/196 (19), 115 (53), 88 (9), 57 (12).
5-Bromo-7-(N-tert-butylglyoxylamido)indole (9a). Yield: 170 mg (53%); yellow solid material, mp.
120 ˚C; [Found: C, 52.17; H, 4.80; N, 8.55; C14H15N2O2Br requires C, 52.03; H, 4.68; N, 8.67 %]; Rf (2 %
EtOAc, 98 % CHCl3) 0.90; δH (500 MHz, CDCl3) 10.45 (1 H, brs, indole-NH), 8.95 (1 H, d, 1.60 Hz, Ar-H ),
8.06 (1 H, d, 1.60 Hz, Ar-H), 7.34 (1 H, dd, 3.00 Hz, 2.34 Hz, indole-H), 7.06 (1 H, brs, NH), 6.58 (1 H, dd,
3.00 Hz, 2.34 Hz, indole-H), 1.51 (9 H, s, (CH3)3). δC (125.7 MHz, CDCl3) 187.5, 161.3, 134.7, 131.3, 131.2,
131.0, 126.7, 117.6, 112.0, 102,6, 51.8, 28.4. IR (KBr, ν (cm-1)): 3313 (NH), 1661 (CO), 1649 (CON); MS
m/z (rel int.): 322/324 (34, M+), 222/224 (100), 194/196 (25), 115 (48), 88 (5), 57 (43).
5-Bromo-7-(N-phenylcarboxamido)indole (8b). Yield: 214 mg (68%); yellow solid material, mp. 187
˚C; [Found: C, 57.30; H, 3.40; N, 8.03; C15H11N2OBr requires C, 57.16; H, 3.52; N, 8.19 %]; Rf (10 % EtOAc,
90 % CHCl3) 0.90; δH (500 MHz, CDCl3) 10.28 (1 H, brs, indole-NH), 7.98 (2 H, brs, 1 Hz, overlap NH, Ar-
H), 7.67 (2H, dd, 8.39 Hz, 0,87 Hz, Ph (ortho)), 7.64 (1 H, d, 2 Hz, Ar-H), 7.43 (2H, t, 7.95 Hz, Ph (meta)),
7.36 (1 H, t, 2.7 Hz, indole-H), 7.23 (1H, t, 7.43 Hz, Ph (para)), 6.57 (1 H, dd, 3.07 Hz, 2.31 Hz, indole-H). δC
(125.7 MHz, CDCl3) 164.8, 137.3, 134.2, 131.3, 129.2, 127.5, 127.1, 125.0, 121.6, 120.7, 117.5, 111,5 101.8.
IR (KBr, ν (cm-1)): 3409 (indole-NH), 3342 (NH), 1653 (CON); MS m/z (rel int.): 314/316 (64, M+), 222/224
(100), 194/196 (30), 115 (69), 92 (9), 88 (7), 77 (3), 65 (9), 51 (3).
5-Bromo-7-(N-phenylglyoxylamido)indole (9b). MS m/z (rel int.): 342/344 (36, M+), 222/224 (100),
194/196 (26), 115 (60), 77 (12), 63 (7), 51 (3).
5-Bromo-7-(N,N-pentane-1,5-diyl-carboxamido)indole (8c). MS m/z (rel int.): 306/308 (100, M+),
222/224 (79), 194/194 (40), 115 (88), 88 (12), 84 (51), 63 (5), 56 (5).
5-Bromo-7-(N,N-pentane-1,5-diylglyoxylamido)indole (9c). Yield: 167 mg (54%); yellow solid
material, mp. 183 ˚C; [Found: C, 53.66; H, 4.40; N, 8.07; C15H15N2O2Br requires C, 53.75; H, 4.51; N, 8.36
%]; Rf (5 % EtOAc, 95 % CHCl3) 0.50; δH (500 MHz, CDCl3) 10.37 (1 H, brs, indole-NH), 8.07 (1 H, d, 1.25
Hz, Ar-H), 7.76 (1 H, d, 1.55 Hz, Ar-H), 7.39 (1 H, dd, 3.00 Hz, 2.34 Hz, indole-H), 6.66 (1 H, dd, 3.00 Hz,
2.34 Hz, indole-H), 3.76 (2 H, brs, N-CH2), 3.35-3.27 (2 H, m, N-CH2), 1.77-1.72 (4 H, m, 2x CH2), 1.58 (2
H, brs, CH2). δC (125.7 MHz, CDCl3) 192.8, 164.5, 133.5, 131.4, 131.0, 128.9, 127.4, 117.7, 111.9, 102.4,
47.3, 42.4, 26.2, 25.5, 24.4. IR (KBr, ν (cm-1)): 1653 (CO), 1629 (CON); MS m/z (rel int.): 334/336 (35, M+),
222/224 (56), 194/196 (19), 115 (50), 112 (100), 88 (7), 84 (13), 69 (43), 56 (9).
20

ACCEPTED MANUSCRIPT
5-Bromo-7-(N,N-pentane-3-oxa-1,5-diylcarboxamido)indole (8d). MS m/z (rel int.): 308/310 (75,
M+), 293/295 (5), 264/266 (11), 222/224 (100), 194/196 (38), 115 (80), 88 (11), 86 (20), 63 (5), 56 (13).
5-Bromo-7-(N,N-pentane-3-oxa-1,5-diylglyoxylamido)indole (9d). Yield: 222 mg (66%); yellow solid
material, mp. 134 ˚C; [Found: C, 50.02; H, 3.70; N, 8.05; C14H13N2O3Br requires C, 49.87; H, 3.89; N, 8.31
%]; Rf (10 % EtOAc, 95 % CHCl3) 0.50; δH (500 MHz, CDCl3) 10.29 (1 H, brs, indole-NH), 8.09 (1 H, d, 1.23
Hz, Ar-H), 7.70 (1 H, d, 1.55 Hz, Ar-H), 7.39 (1 H, dd, 3.00 Hz, 2.34 Hz, indole-H), 6.61 (1 H, dd, 3.00 Hz,
2.34 Hz, indole-H), 3.85 (4 H, brs, 2x O-CH2), 3.74-3.68 (2 H, m, N-CH2), 3.48-3.42 (2 H, m, N-CH2). δC
(125.7 MHz, CDCl3) 191.8, 164.5, 133.5, 131.5, 131.4, 129.0, 127.5, 117.5, 111.9, 102.6, 66.7, 66.6, 46.4,
41.8. IR (KBr, ν (cm-1)): 1669 (CO), 1636 (CON); MS m/z (rel int.): 336/338 (30, M+), 222/224 (100),
194/196 (23), 115 (50), 88 (7), 70 (25), 63 (4), 56(4).
5-Bromo-7-(N-(1’-Methoxycarbonylmethyl)carboxamido)indole (8e). MS m/z (rel int.): 310/312 (89,
M+), 222/224 (100), 194/196 (34), 143 (17), 115 (96), 88 (18), 56 (9).
5-Bromo-7-(N-(1’-Methoxycarbonylmethyl)glyoxylamido)indole (9e). Yield: 152 mg (45 %); yellow
solid material, mp. 166 ˚C; [Found: C, 46.19; H, 3.40; N, 8.22; C13H11N2O4Br requires C, 46.04; H, 3.27; N,
8.36 %]; Rf (10 % EtOAc, 90 % CHCl3) 0.52; δH (500 MHz, CDCl3) 10.41 (1 H, brs, indole-NH), 8.96 (1 H, d,
1.69 Hz, Ar-H), 8.10 (1 H, d, 1.51 Hz, Ar-H), 7.66 (1 H, brs NH), 7.37 (1 H, t, 2.76 Hz, indole-H), 6.61 (1 H,
t, 2.91 Hz, indole-H), 4.24 (2 H, d, 5.54 Hz, N-CH2), 3.85 (3 H, s, O-CH3). δC (125.7 MHz, CDCl3) 185.8,
169.4, 161.8,134.7, 131.7, 131.3, 131.0, 126.8, 117.3, 112.1, 102.7, 52.6, 41.1. IR (KBr, ν (cm-1)): 3408
(indole-NH), 3293 (NH), 1746 (COO), 1663 (CO), 1637 (CON); MS m/z (rel int.): 338/340 (26, M+), 222/224
(100), 194/196 (34), 143 (7), 115 (76), 88 (26), 56 (12).
5-Bromo-7-(N-(1’-methoxycarbonyl-ethyl)carboxamido)indole (8f) (identified as a minor component
in 9f). MS m/z (rel int.): 324/326 (41, M+), 265/267 (12), 249/251 (6), 222/224 (100), 194/196 (24), 115 (49),
102 (2), 88 (6), 63 (2).δH (500 MHz, CDCl3) 10.24 (1 H, brs, indole-NH), 7.89 (1 H, d, 0.97 Hz, Ar-H), 7.55
(1 H, d, 1.43 Hz, Ar-H), 7.31 (1 H, dd, 3.00 Hz, 2.34 Hz, indole-H), 6.95 (1 H, d, 6.75 Hz, NH), 6.49 (1 H, dd,
3.00 Hz, 2.34 Hz, indole-H), 4.84 (1 H, qi, 7.14 Hz, N-CH), 3.84 (3 H, s, O-CH3), 1.57 (3 H, d, 7.20 Hz,
CHCH3).
5-Bromo-7-(N-(1’-methoxycarbonylethyl)glyoxylamido)indole (9f). Yield: 134 mg (38%); yellow
solid material, mp. 148 ˚C; [Found: C, 47.55; H, 3.80; N, 7.70; C14H13N2O4Br requires C, 47.61; H, 3.71; N,
7.93 %]; Rf (5 % EtOAc, 95 % CHCl3) 0.71; δH (500 MHz, CDCl3) 10.41 (1 H, brs, indole-NH), 8.89 (1 H, d,
1.62 Hz, Ar-H), 8.05 (1 H, d, 1.35 Hz, Ar-H), 7.75 (1 H, d, 7.25 Hz, NH), 7.35 (1 H, dd, 3.00 Hz, 2.34 Hz,
21

ACCEPTED MANUSCRIPT
indole-H), 6.57 (1 H, dd, 3.00 Hz, 2.34 Hz, indole-H), 4.74 (1 H, qi, 7.27 Hz, N-CH) 3.84 (3 H, s, O-CH3),
1.57 (3 H, d, 7.20 Hz, CHCH3). δC (125.7 MHz, CDCl3) 186.1, 172.6161.4, 134.6, 131.6, 131.1, 131.0, 126.9,
117.3, 112.0, 102.7, 52.8, 48.2, 18.1. IR (KBr, ν (cm-1)): 3276 (NH), 1747 (COO), 1664 (CO), 1636 (CON);
MS m/z (rel int.): 352/354 (31, M+), 293/265 (4), 222/224 (100), 194/196 (36), 115 (55), 102 (28), 88 (8), 70
(8), 63 (6).
5-Bromo-7-(N-(1’-Methoxycarbonyl-2’-methylpropyl)carboxamido)indole (8g). MS m/z (rel int.):
352/354 (28, M+), 293/295 (13), 249/251 (13), 238/240 (25), 222/224 (100), 194/196 (29), 143 (7), 115 (61),
88 (6), 59 (4).
5-Bromo-7-(N-(1’-Methoxycarbonyl-2’-methyl-propyl)glyoxylamido)indole (9g). Yield: 176 mg
(46%); yellow solid material, mp. 115 ˚C; [Found: C, 50.19; H, 4.40; N, 7.15; C16H17N2O4Br requires C,
50.41; H, 4.49; N, 7.35 %]; Rf (5 % EtOAc, 95 % CHCl3) 0.81; δH (500 MHz, CDCl3) 10.45 (1 H, brs, indole-
NH), 8.92 (1 H, d, 1.6 Hz, Ar-H), 8.08 (1 H, d, 1.4 Hz, Ar-H), 7.70 (1 H, d, 8.84 Hz, NH), 7.37 (1 H, t, 2.8 Hz,
Ar-H), 6.59 (1 H, dd, 3.1 Hz, 2.2 Hz, indole-H), 4.68 (1 H, dd, 9.1 Hz, 4.9 Hz, N-CH), 3.83 (3 H, s, O-CH3),
2.41-2.28 (1 H, m, CH(CH3)2), 1.06 (3 H, d, 6.86 Hz, CHCH3), 1.05 (3 H, d, 6.89Hz, CHCH3). δC (125.7
MHz, CDCl3) 186.2, 171.6, 161.7, 134.6, 131.6, 131.2, 126.9, 121.8, 117.4, 112.0, 102.7, 57.3, 52.4, 31.5,
19.1, 17.8. IR (KBr, ν (cm-1)): 3393 (indole-NH), 3298 (NH), 1741 (COO), 1667 (CO), 1640 (CON); MS m/z
(rel int.): 380/382 (34, M+), 321/323 (6), 222/224 (100), 194/196 (34), 115 (67), 98 (15), 88 (9), 59 (9).
5-Bromo-7-(N-(2’-methoxycarbonylbutane-1,4-diyl)glyoxylamido)indole (9h). (ca. 2/5 mixture of
two C(O)N rotamers). Yield: 250 mg (66%); yellow viscous material; [Found: C, 50.70; H, 4.12; N, 7.12;
C16H15N2O4Br requires C, 50.61; H, 3.99; N, 7.39 %]; Rf (5 % EtOAc, 95 % CHCl3) 0.34; δH (500 MHz,
CDCl3) 10.32/10.25 (major/minor) (1 H, brs, indole-NH), 8.08 (major + minor) (1 H, overlap, d, 1.35 Hz, Ar-
H), 8.05/8.03 (minor/major) (1 H, d, 1.20 Hz, Ar-H), 7.39/7.35 (major/minor) (1 H, dd, 3.00 Hz, 2.34 Hz,
indole-H), 7.26/7.21 (major/minor) (1 H, t, 7.70 Hz, Ar-H), 6.60/6.58 (major/minor) (1 H, dd, 3.00 Hz, 2.34
Hz, indole-H), 4.74/4.70 (major/minor) (1 H dd, 8.85 Hz, 4.31 Hz, N-CH), 3.90/3.49 (major/minor) (3 H, s, O-
CH3), 3.82-3.76/3.64-3.54 (minor/major) (2 H, m, N-CH2), 2.39-1.96 (major/minor) (4 H, m, 2x CH2). δC
(125.7 MHz, CDCl3) 191.5/190.7 (major/minor), 171.9/171.7 (minor/major), 164.6/163.8 (major/minor),
134.0/133.7 (minor/major), 131.4/131.2 (major/minor), 131.1/129.9 (major/minor), 130.1/129.6
(minor/major), 127.4/127.1 (major/minor), 117.4/117.3 (minor/major), 112.1/111.8 (major/minor), 102.4,
59.6/58.5 (minor/major), 52.4/52.1 (major/minor), 47.3/46.6 (major/minor), 31.1/29.2 (minor/major),
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24.7/22.3 (major/minor). IR (KBr, ν (cm-1)): 1757 (COO), 1742 (CO), 1636 (CON); MS m/z (rel int.): 378/380
(23, M+), 222/224 (58), 194/196 (20), 156, (3); 128 (100), 115 (43), 88 (5), 59 (5).
(S)-N,N'-(propane-1,2-diyl)bis(1H-indole-7-carboxamide) (10i). Yield: 63 mg (39 %), beige solid,
20
m.p. 45-147 °C. [α]D = -20.0 (c 0.25, CH2Cl2). Rf (25 % CHCl3, 75 % EtOAc) 0.66. δH (400 MHz, CDCl3)
10.26 (1H, brs, indole-NH), 10.24 (1H, brs, indole-NH), 7.74–7.70 (2H, m, indole-H), 7.48-7.30 (4H, m,
indole-H), 7.22 (2H, brs, indole-H), 7.02–6.96 (2H, m, indole-Ar), 6.51 (2H, brs, NH), 4.42–4.40 (1H, m,
alkyl-CH2), 3.69–3.64 (1H, m, alkyl-CH2), 3.52–3.48 (1H, m, alkyl-CH2), 1.29 (3H, d, 6.6 Hz, CH3). δC (100.6
MHz, CDCl3) 169.5, 168.9, 135.40, 135.43, 129.61, 129.63, 125.7 (double intensity), 125.00, 125.02, 119.5
(double intensity), 118.80, 118.84, 115.8, 115.7, 102.11, 102.13, 47.1, 46.2, 18.5. HRMS (ESI): m/z calcd. for
C21H20N4O2Na [M+Na]+ 383.1478; found 383.1477.
N,N'-((1S,2S)-cyclohexane-1,2-diyl)bis(1H-indole-7-carboxamide) (10j). Yield: 39 mg (16 %),
yellow oil. [α]D20 = + 10.0 (c 0.5, CH2Cl2). Rf (75 % CHCl3, 25 % EtOAc) 0.45. δH (400 MHz, CDCl3) 10.13
(2H, brs, indole-NH), 7.73 (2H, d, 7.8 Hz, indole-H), 7.42 (2H, d, 7.4 Hz, indole-H), 7.24–7.20 (2H, m,
indole-H), 7.17–7.11 (2H, brs, indole-H), 7.04 (2H, t, 7.7 Hz, indole-H), 6.49–6.48 (2H, m, NH), 4.05 (2H,
brs, alkyl-(CH)2, 2.29 (2H, d, 7.6 Hz, alkyl-(CH)2), 1.86-1.84 (2H, m, alkyl-(CH)2), 1.45–1.44 (4H, m, alkyl-
(CH)2). δC (100.6 MHz, CDCl3) 168.9, 135.4, 129.6, 125.6, 125.0, 119.4, 118.8, 115.9, 102.0, 54.6, 32.6, 24.9.
HRMS (ESI): m/z calcd. for C24H24N4O2Na [M+Na]+ 423.1797; found 423.1797.
N,N'-(1,1'-binaphthyl-2,2'-diyl)bis(1H-indole-7-carboxamide) (10k). 82 mg (32 %), beige solid, m.p.
20
> 250 °C. [α]D = - 70.0 (c 1.0, CH2Cl2). Rf (90 % CHCl3, 10 % EtOAc) 0.92. δH (400 MHz, CDCl3) 10.04
(2H, brs, indole-NH), 8.72 (2H, d, 9.0 Hz,), 8.16 (2H, d, 9.0 Hz,), 8.04–8.00 (4H, m,), 7.68 (2H, d, 7.8 Hz,),
7.49 (2H, t, J = 7.6 Hz,), 7.35 (2H, t, J = 7.6 Hz,), 7.28 (2H, d, J = 8.7 Hz,), 7.23–7.20 (2H, m,), 6.82 (2H, t, J
= 7.7 Hz,), 6.49-6.45 (4H, m,). δC (100.6 MHz, CDCl3) 166.4, 135.5, 135.2, 132.5, 131.5, 130.3, 129.6, 128.7,
127.9, 125.9, 125.8, 125.5, 125.2, 121.7, 121.1, 119.1, 118.9, 115.8, 102.2. HRMS (ESI): m/z calcd. for
C38H27N4O2 [M+H]+ 571.2129; found 571.2131.
N-(2'-amino-1,1'-binaphthyl-2-yl)-1H-indole-7-carboxamide (11k). Yield: 55 mg (29 %), beige solid,
m.p 118-120 °C. [α]D20: - 50.0 (c 1.0, CH2Cl2). Rf (90 % CHCl3, 10 % EtOAc) 0.75. δH (400 MHz, CDCl3)
10.20 (1H, brs, indole-NH), 8.90 (1H, d, 9.0 Hz,), 8.18 (1H, brs, indole-NH), 8.09 (1H, d, 9.2 Hz,), 7.96 (1H,
d, 8.0 Hz,), 7.91 (1H, d, 8.7 Hz,), 7.85 (1H, d, 8.0 Hz,), 7.68 (1H, d, 7.8 Hz,), 7.48–7.43 (1H, m,), 7.33–7.27
(4H, m,), 7.24–7.16 (m, 2H), 7.02 (1H, d, 8.2 Hz,), 6.81 (1H, t, 7.7 Hz,), 6.51 (1H, brs, amide-NH), 6.44 (1H,
d, 7.5 Hz,), 3.75 (2H, s,). δC (100.6 MHz, CDCl3) 166.1, 156.5, 142.9, 135.5, 135.2, 133.7, 132.8, 131.4,
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130.8, 129.60, 129.64, 128.51, 128.53, 127.7, 127.1, 125.8, 125.7, 125.3, 125.2, 123.8, 123.1, 120.9, 120.5,
119.0, 118.9, 118.2, 116.4, 110.5, 102.2. HRMS (ESI): m/z calcd. for C29H22N3O [M+H]+ 428.1757; found
428.1756.
Acknowledgement: The authors thank the Hungarian Scientific Research Fund (K113177) and
Environmental industry related innovative trans- and interdisciplinary research team development in the
University of Pécs knowledge base (SROP-4.2.2.D-15/1/KONV-2015-0015) for the financial support, as well
as Johnson Matthey for the generous gift of Pd(OAc)2. This paper was supported by the János Bolyai Research
Scholarship of the Hungarian Academy of Sciences. A. T. thanks MTA Postdoctoral Research Programme for
the financial support. The authors also thank Fundação para a Ciência e a Tecnologia (FCT) for the financial
support to Coimbra Chemistry Centre (PEst-OE/QUI/UI0313/2014). R.M.B.C.; L.D. and F.M.S.R. thank FCT
for grants SFRH/BPD/100537/2014, PD/BD/106020/2014 and BIC QUI/00313, respectively. The present
scientific contribution is dedicated to the 650th anniversary of the foundation of the University of Pécs,
Hungary.
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