Multicomponent access to novel dihydroimidazo[1′,5′:1,2] pyrido[3,4-b]indol-2-ium salts and indoles by means of Ugi/Bischler-Napieralski/ heterocyclization two step strategy

Article abstract of DOI:10.1016/j.tet.2014.04.081

A simple, efficient and general two step procedure, through a sequential Ugi reaction followed by a Bischler-Napieralski/heterocyclization tandem closure, to give novel 6,11-dihydro-5H-imidazo[1′,5′:1,2]pyrido[3,4- b]indol-2-ium salt derivatives, is described. By changing the amine and the acid components with ammonium formate, the same procedure affords 6,11-dihydro-5H-imidazo[1′,5′:1,2]pyrido[3,4-b]indole derivatives.

Full text of DOI:10.1016/j.tet.2014.04.081

Accepted Manuscript
Multicomponent access to novel dihydroimidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium
salts and indoles by means of Ugi/Bischler–Napieralski/heterocyclization two step
strategy
Alessandra Silvani, Giordano Lesma, Sergio Crippa, Vito Vece
PII:
S0040-4020(14)00615-2
10.1016/j.tet.2014.04.081
TET 25531
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 4 March 2014
Revised Date: 8 April 2014
Accepted Date: 25 April 2014
Please cite this article as: Silvani A, Lesma G, Crippa S, Vece V, Multicomponent access to novel
dihydroimidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium salts and indoles by means of Ugi/Bischler–Napieralski/
heterocyclization two step strategy, Tetrahedron (2014), doi: 10.1016/j.tet.2014.04.081.
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Multicomponent access to novel
dihydroimidazo[1',5':1,2]pyrido[3,4-b]indol-
2-ium salts and indoles by means of
Ugi/Bischler–Napieralski/heterocyclization
two step strategy
Leave this area blank for abstract info.
Alessandra Silvani, Giordano Lesma, Sergio Crippa, and Vito Vece
Dipartimento di Chimica, Università degli Studi di Milano, via C. Golgi, 19, 20133 Milano (Italy)

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Tetrahedron
journal homepage: www.elsevier.com
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Multicomponent access to novel dihydroimidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium
salts and indoles by means of Ugi/Bischler–Napieralski/heterocyclization two step
strategy
Alessandra Silvani, Giordano Lesma, Sergio Crippa, and Vito Vece
Dipartimento di Chimica, Università degli Studi di Milano, via C. Golgi, 19, 20133 Milano (Italy)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple, efficient and general two step procedure, through a sequential Ugi reaction followed
by a Bischler–Napieralski/heterocyclization tandem closure, to give novel 6,11-dihydro-5H-
imidazo[1',5':1,2] pyrido[3,4-b]indol-2-ium salt derivatives, is described. By changing the amine
and the acid components with ammonium formate, the same procedure affords 6,11-dihydro-
5H-imidazo[1',5':1,2]pyrido[3,4-b]indole derivatives.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
multicomponent reaction
Ugi reaction
isonitrile
carboline
imidazolium salt
1. Introduction
heterocyclic skeleton, THBC-based compounds are known to
bind with high affinity to various receptor sites, such as the
benzodiazepine (BzR), serotonin, and dopamine sites6 and to
inhibit monoamine oxidase A.7 Moreover, some tetracyclic β-
carbolines have been reported to act as selective inhibitors in the
anticancer field,8 or to be endowed with antimalarial properties.9
Multicomponent reactions (MCRs) have emerged as an
efficient and powerful tool in modern synthetic organic chemistry
due to their valued features to maximize structural complexity
and convergence, while saving synthetic operations.1 Since these
highly step-economic reactions are particularly appealing in the
context of diversity as well as target-oriented syntheses, they play
an important role in drug discovery and biological probe
chemistry. When coupled with post-MCR cyclizations, these
reactions can lead to interesting heterocyclic scaffolds, becoming
particularly useful for the construction of diverse arrays of drug-
like molecules in medicinal chemistry. Among the several
multicomponent protocols, the Ugi four-component reaction
(Ugi-4CR)2 has been, without any doubt, one of the most
investigated in pharmaceutical industry and in academic research
over the past two decades.3
Fig. 1. The 6,11-dihydro-5H-imidazo[1',5':1,2]pyrido[3,4-b]indole and
5,6-dihydroimidazo[5,1-a]isoquinoline frameworks.
In this context, we recently focused on tetrahydro-β-carboline
(THBC)-based compounds4 as privileged molecular targets, and
on the Ugi reaction, as a powerful tool for the synthesis of related
polycyclic structures.5 Natural and synthetic products containing
tryptophan-based pharmacophores exhibit a wide range of
important bioactivities, particularly concerning the central
Recently, dihydroimidazo-fused THBC derivatives, in which
the
6,11-dihydro-5H-imidazo [1',5':1,2]pyrido-[3,4-b]indole
framework 1 has been incorporated (Figure 1), have shown
particular interest because of their potential therapeutic
properties,10 mainly as agonists of 5HT-2 serotonin receptors,10a,b
nervous
In particular, due to their unique rigid
———system.
Corresponding author. Tel.: +039-02-50314079; e-mail: giordano.lesma@unimi.it

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and as inhibitors of Mitogen-activated protein-Kinase-2.11
dichloromethane at room temperature.18 It must be noted that any
attempt to dehydrate N-formyl tryptamine by means of
phosphoryl chloride19 at room temperature only led to a fast
decomposition of the starting material.
Generally, available methods for the synthesis of type 1
compounds capitalized upon a conventional amidation/Bischler-
Napieralski sequence which, however, do not allow for the rapid
introduction of different functional groups onto the core
structure. Yet, considerable recent progress has been represented
by Seganish’s synthesis12 of the related 5,6-dihydroimidazo[5,1-
a]isoquinolines 2,13 via an efficient Ugi/Bischler–Napieralski
reaction sequence.
The Ugi reaction was undertaken following a general
procedure, consisting of the sequential addition of aldehyde 6
(1.1 equiv), amine 7 (1.1 equiv), carboxylic acid 8 (1.1 equiv)
and, finally, isocyanide 5 (1.0 equiv) in methanol. The mixture
was stirred for 24-120 hours at 40 °C to provide intermediates 9
in moderate to good yields (Table 1). An investigation on
temperature and solvent revealed that the use of methanol at 40
°C gave the optimal results both in terms of yields and reaction
rates. When other solvents, such as CH2Cl2, CF3CH2OH or
toluene, or higher reaction temperatures were applied, yields
decreased significantly. This first multicomponent step was
tolerant with a variety of aromatic (entries 1, 4-6) and aliphatic
(entries 2-3, 7-10) aldehydes, having different electronic
properties. Acid sensible furfural afforded smoothly the Ugi
adduct in 77%. Notably, the steric hindrance of amine (entries 7,
8 and 10) as well as of acid (entries 3, 9) components does not
play a determinant role in terms of reactivity and product yields.
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Imidazolium salts, which are made up of a discrete cation and
anion pair, have found widespread utility as ionic liquids.14
Several areas of bio-applications, including antitumor,
antibacterials, antimicrobial, antioxidant activities and
bioengineering applications, have also been reported.15 Both
imidazoles and imidazolium salts are ubiquitous in nature and
play a critical role in many structures and functions due to their
ability to interact electrostatically with biological systems.16
2. Results and discussion
As part of our ongoing interest in the development of MCRs-
based heterocycles, we herein report the synthesis of diverse
1,2,3-trisubstituted
[3,4-b]indol-2-ium salts 3 and 1-substituted 6,11-dihydro-5H-
imidazo[1',5':1,2] pyrido[3,4-b]indoles 4, via an Ugi/Bischler-
Napieralski /heterocyclization two steps sequence (Scheme 1).
6,11-dihydro-5H-imidazo[1',5':1,2]pyrido
The subsequent Bischler-Napieralski/ heterocyclization of
Ugi-adducts 9 was carried out in toluene under nitrogen
atmosphere at 80-110 °C, using a large excess of phosphoryl
chloride (15 mol equiv) as dehydrating reagent for 60-360
minutes. Following this double dehydration protocol, we
obtained the target products 3, which could be easily isolated by
standard aqueous work-up, followed by conventional flash
chromatography as hydrochloride salts.
Notably, starting from a tryptamine-derived isocyanide, and
aldehydes, carboxylic acids and amines as Ugi components, a
non-conventional degree of chemical diversity could be
introduced at the N-2 nitrogen atom of 1, to afford imidazolium
salts structures.
It should be noted that the reaction time and yields somewhat
depend on the starting components of the Ugi step, which
determine the structure of the R1-3 residues. In general, as for the
Ugi reaction step, also in this case both aliphatic and aromatic
residues, having different electronic properties, as well as those
bearing bulky substituents showed to be suitable for the reaction.
Then, by a careful selection of starting materials, this two step
strategy can, potentially, give access to a multitude of diversified
molecules for testing of biological assays and catalytic ligand
properties,17 with improved synthetic efficiency. To the best of
our knowledge, this represents the first protocol which allows to
achieve unique indole-imidazolium structures, by means of a
multicomponent approach.
An exception is the Ugi adduct 9f containing a furan moiety:
due to the acidic reaction conditions, we observed only a rapid
degradation of the starting material with the production of
unidentified by-products. Importantly, the reaction proceeded
smoothly in the presence of electron-donating groups on the
The 3-(2-isocyano-ethyl)-1H-indole precursor 5 was prepared
in 82% overall yield, by formylation of tryptamine followed by
dehydration using triphenylphosphine and carbon tetrachloride in
benzene
ring
(entries
7,8,10),
where
competition

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Table 1. Ugi-Components, Products and Yields of Ugi-4CR and of the Bischler– Napieralski/Heterocyclization.
entry R1CHO(6)
R2NH2 (7)
R3CO2H (8)
Ugi product (9)a
(yield %)b
Cyclization product (3)c
(yield %)b
4
5
6
7
9a
(76)
3ad
(94)
1
AcOH
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9b
(71)
3bd
(70)
2
3
AcOH
9c
(64)
3ce
(76)
9d
(84)
3d
(83)
4
9e
(81)
3ee
(88)
5
6
7
AcOH
AcOH
9f
(77)
3f
(nd)
9g
(73)
3g
(92)
9h
(69)
3h
(76)
8
(CHO)n
(CHO)n
(CHO)n
9i
(66)
3if
(77)
9
9j
(68)
3jg
(84)
10
aReaction condition: see text and supporting informations.
bIsolated yields.
cReaction conditions: 9, POCl3 (15 mol equiv), toluene, 60 min, 80 °C, (if not otherwise indicated).
dReaction time: 180 min.
eReaction time: 90 min.
fConditions: 300 min, 110 °C.
gConditions: 360 min, 110 °C

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Table 2. Aldehyde Ugi-Component, Products and Yields of Ugi-3CR and of the Bischler–Napieralski/Heterocyclization.
entry
R1CHO (6)
Ugi product (10)a
( yield %)b
Cyclization product (4)c
(yield %)b
4
5
6
d
1
HCO2NH4
10a (54)
4a (62)
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d
2
HCO2NH4
10b (58)
4b (74)
aReaction condition: see text and supporting informations.
bIsolated yields.
cReaction conditions: 10, POCl3 (15 mol equiv), toluene, 60 min, 80 °C.
dTwo equiv of the salt HCO2NH4 were used for the reaction.
of the electron-rich benzene ring to capture the transient Bischler-
Napieralski iminium salt, can, in principle, occur. On the other
hand, bulkiness seems to play a role in the rate of the tandem
reaction, as highlighted by the higher temperature and longer
reaction times required in the presence of an ortho substituent on
the aniline-derived ring (entries 9,10).
applied to the synthesis of libraries of heterocyclic compounds,
bearing up to three points of facile chemical diversity.
4. Experimental section
4.1. General
All solvents were distilled and properly dried, when
necessary, prior to use. All chemicals were purchased from
commercial sources and used directly, unless indicated otherwise.
All reactions were monitored by thin layer chromatography
(TLC) on precoated silica gel 60 F254; spots were visualized
with UV light or by treatment with 1% aqueous KMnO4 solution.
Products were purified by flash chromatography (FC) on silica
gel 60 (230 - 400 mesh). IR spectra were recorded in the FTIR
We envisioned that the transformation of 9 to 3 might occur
affording firstly mono-cyclized products 11 (Scheme 2) which,
subsequently, could further cyclize to provide final compounds 3.
To gain support for this mechanistic proposal, on selected Ugi-
products 9 the reaction was performed using a minor excess of
phosphoryl chloride (5 mol equiv) at 50 °C. No cyclic
intermediates 11 were observed, except for the cases of 9i and 9j,
which afforded separable amounts of the corresponding 11i and
11j, as stable compounds. 11i and 11j were then cleanly
converted to 3i and 3j by treatment with phosphoryl chloride, in
toluene, at 80°C.
1
mode. H NMR and 13C NMR spectra were recorded with 300
and 400 MHz (1H NMR) and 75 or 100 MHz (13C NMR)
spectrometers. Chemical shifts (δ) are expressed in ppm relative
1
to TMS at δ = 0 ppm for H NMR and relative to CDCl3 at δ =
By employing ammonium formate as a solid source of
ammonia in a three component Ugi reaction, we were able to
obtain formamide derivatives 10a and 10b (entries 1 and 2, Table
2), albeit in moderate yields. The above described Bischler-
Napieralski/heterocyclization protocol allowed to convert 10a
and 10b into the imidazole derivatives 4a and 4b, thus endorsing
this approach as a valid alternative for the synthesis of 1-
substituted dihydroimidazo[1',5':1,2]pyrido[3,4-b]indoles.
77.16 ppm for 13C NMR. 13C NMR spectra have been recorded
using the APT pulse sequence; the signals of CH and CH3 are
positive while CH2 and quarternary carbons are negative. High-
resolution MS spectra were recorded with a FT-ICR (Fourier
Transform Ion Ciclotron Resonance) instrument, equipped with
an ESI source, or a standard MS instrument, equipped with an EI
source.
4.2. Synthetic procedure for compound 5
A mixture of tryptamine (1.6 g, 10 mmol) in ethyl formate (8
mL) was refluxed for 18 hr. After concentration, the resulting
crude residue was dissolved in anhydrous dichloromethane (20
mL) and triphenylphospine (14.41 g, 55 mmol), carbon
tetrachloride (5.38 mL, 55 mmol) and triethylamine (15.4 mL,
110 mmol) were added in sequence. After being stirred at rt for
4h, the mixture was concentrated and the residue was purified by
FC with 30% ethyl acetate-hexane, for elution, to give 3-(2-
isocyanoethyl)-1H-indole 5 as an off-white solid (1.39 g, 82%):
mp 74-75 °C (lit. 73-74.5 °C).18b Melting point and spectral
properties (1H and 13C NMR) of the product are in agreement
with the reported data.18b
Scheme 2. Plausible Mechanism.
3. Conclusion
In summary, we have described a two step Ugi/Bischler–
Napieralski/heterocyclization sequence, providing a protocol for
4.3. General procedure for multicomponent isocyanide-based
synthesis of compounds 9a-j
the
synthesis
of
novel
trisubstituted
5,6-
salt
dihydroimidazo[1',5':1,2]-pyrido[3,4-b]indol-2-ium
To a solution of the aldehyde (6) (2.59 mmol) in MeOH (4.7
mL), the amine (7) (2.59 mmol) and the carboxylic acid (8) (2.59
mmol) were added, followed by addition of 3-(2-isocyanoethyl)-
1H-indole (5) (400 mg, 2.35 mmol). The resulting mixture was
derivatives and substituted dihydroimidazo-[1',5':1,2]pyrido[3,4-
b]indoles, from readily available starting materials. The proposed
sequence, which could be developed on multigram scale, can be

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stirred at 40 °C, for 24 to 120 h until the completion of the
reaction, as indicated by TLC. The reaction mixture was cooled
to room temperature and concentrated, and the residue was
purified via FC as indicated below.
acetate-hexane, 3:7); νmax(CHCl3) 3432, 3310, 1678, 1631,
1
1513, 1457, 1418 cm-1; H NMR (300 MHz, CDCl3) δ 8.27 (s,
1H), 7.51 (d, J = 7.8 Hz, 1H), 7.32 (d, J = 7.8 Hz, 1H), 7.19 (d, J
= 7.8 Hz, 2H), 7.14 (t, J = 7.6 Hz, 1H), 7.05 (t, J = 7.6 Hz, 1H),
6.91 (br, s, 1H), 6.77 (d, J = 7.8 Hz, 2H), 5.88 (br, s, 2H), 5.44
(m, 1H), 4.97-4.90 (m, 2H), 3.93 (br, m, 2H), 3.77 (s, 3H), 3.57
(m, 2H), 2.91 (t, J = 6.8 Hz, 2H), 2.75 (hept, J = 6.6 Hz, 1H),
1.11 (d, J = 6.5 Hz, 3H), 1.09 (d, J = 6.6 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 179.0, 170.1, 159.5, 136.4, 134.8, 130.9 (2C),
127.3, 122.5, 121.8, 119.1, 118.5, 116.0 (2C), 114.0 (2C), 112.3,
111.4, 61.3, 55.2, 48.4, 40.0, 31.0, 25.1, 19.7, 19.6; HRMS (ESI)
calculated for C26H32N3O3 [MH+] 434.2444, found 434.2453.
4.3.1. N-(2-(1H-Indol-3-yl)ethyl)-2-(N-isopropyl cetamido)-2-
(pyridin-3-yl)acetamide (9a). Prepared according to the general
procedure above from nicotinaldehyde, isopropylamine and
acetic acid, for 48 h; FC: ethyl acetate-dichloromethane, 2:1;
yield: 676 mg (76%); off-white solid; mp 129-131 °C; Rf = 0.46
(ethyl acetate-dichloromethane, 7:3); νmax(CHCl3) 3334, 3309,
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1669, 1642, 1516, 1456, 1422, 1373 cm-1; H NMR (300 MHz,
CDCl3) δ 8.47-8.41 (m, 2H), 8.30 (br, m, 1H), 7.56 (br, d, J = 8.0
Hz, 1H), 7.55 (d, J = 7.8 Hz, 1H), 7.31 (d, J = 7.9 Hz, 1H), 7.16
(br, t, J = 7.7 Hz, 1H), 7.11 (dd, J = 7.5 and 4.9 Hz, 1H), 7.07 (br,
t, J = 7.7 Hz, 1H), 6.95 (d, J = 2.3 Hz, 1H), 6.54 (m, 1H), 4.76 (s,
1H), 4.08 (hept, J = 6.7 Hz, 1H), 3.58 (m, 2H), 2.94 (t, J = 7.0
Hz, 2H), 2.11 (s, 3H), 1.30 (d, J = 6.7 Hz, 3H), 1.11. (d, J = 6.7
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.2, 169.7, 149.0,
148.7, 136.5, 135.9, 132.9, 127.3, 123.4, 122.7, 121.7, 119.0,
118.5, 112.0, 111.4, 60.0, 50.9, 40.2, 24.8, 22.6, 21.4, 20.8;
HRMS (ESI) calculated for C22H27N4O2 [MH+] 379.2134, found
379.2145.
4.3.5 N-(2-(1H-Indol-3-yl)ethyl)-2-(N-isopropylacetamido)-2-
(thiophen-3-yl)acetamide (9e). Prepared according to the general
procedure above from thiophene-3-carbaldehyde, isopropylamine
and acetic acid, for 24 h; FC: ethyl acetate; yield: 730 mg (81%);
off-white solid; mp 159-162 °C; Rf = 0.12 (ethyl acetate-
dichloromethane, 1.5:1); νmax(CHCl3) 3426, 3335, 1668, 1639,
1518, 1452 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.21 (br, m, 1H),
7.58 (d, J = 7.7 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.22 (m, 2H),
7.20 (t, J = 7.7 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 7.02 (m, 1H),
6.99 (br, s, 1H), 6.26 (br, m, 1H), 4.84 (br, s, 1H), 4.11 (hept, J =
6.7 Hz, 1H), 3.62 (dq, J = 12.9 and 6.4 Hz, 1H), 3.51 (dq, J =
12.9 and 6.4 Hz, 1H), 2.96 (m, 2H), 2.18 (s, 3H), 1.37 (d, J = 6.7
Hz, 3H), 1.10 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
170.6, 169.9, 138.0, 136.5, 128.2, 127.3, 126.1, 124.4, 122.6,
121.7, 119.1, 118.6, 112.4, 111.4, 57.4, 50.6, 40.2, 24.9, 22.5,
21.6, 21.0; HRMS (ESI) calculated for C21H26N3O2S [MH+]
384.1746, found 384.1738.
4.3.2.
N-(2-(1H-Indol-3-yl)ethyl)-2-cyclopropyl-2-(N-
isopropylacetamido)acetamide (9b). Prepared according to the
general procedure above from cyclopropanecarbaldehyde,
isopropylamine and acetic acid, for 24 h; FC: ethyl acetate-
dichloromethane, 2:1; yield: 569 mg (71%); white solid; mp 115-
116 °C; Rf = 0.16 (ethyl acetate-hexane, 1:1.5); νmax(CHCl3)
1
3470, 3300, 1660, 1644, 1519, 1456, 1358 cm-1; H NMR (300
MHz, CDCl3) δ 8.33 (br, s, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.34 (d,
J = 7.7 Hz, 1H), 7.32 (br, m, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.09
(t, J = 7.7 Hz, 1H), 7.06 (br, s, 1H), 3.93 (hept, J = 6.6 Hz, 1H),
3.59 (m, 2H), 2.97 (t, J = 6.9 Hz, 2H), 2.78 (br, m, 1H), 2.09 (s,
3H), 1.16 (d, J = 6.6 Hz, 3H), 1.14 (d, J = 6.6 Hz, 3H), 0.55-0.48
(m, 1H), 0.34-0.28 (m, 2H), 0.19-0-15 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 171.7, 171.3, 136.6, 127.4, 124.6, 121.6, 118.9,
118.6, 112.2, 111.5, 63.7, 49.6, 40.1, 25.1, 22.9, 22.1, 21.0, 11.2,
5.5, 5.2; HRMS (ESI) calculated for C20H28N3O2 [MH+]
342.2182, found 342.2173.
4.3.6.
N-(2-(1H-Indol-3-yl)ethyl)-2-(furan-2-yl)-2-(N-
isopropylacetamido)acetamide (9f). Prepared according to the
general procedure above from furfural, isopropylamine and
acetic acid, for 48 h; FC: ethyl acetate-dichloromethane, 1:1;
yield: 664 mg (77%); white solid; mp 98-101 °C; Rf = 0.28
(ethyl acetate-dichloromethane, 1.5:1); νmax(CHCl3) 3429, 3333,
1674, 1642, 1520, 1456, 1372 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.24 (br, m, 1H), 7.67 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 7.8 Hz,
1H), 7.27 (br, m, 1H), 7.17 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.7
Hz, 1H), 7.04 (br, s, 1H), 6.58 (br, m, 1H), 6.39 (br, d, J = 3.9
Hz, 1H), 6.27 (br, m, 1H), 4.87 (br, s, 1H), 4.04 (hept, J = 6.7
Hz, 1H), 3.63 (dq, J = 13.2 and 6.6 Hz, 1H), 3.51 (dq, J = 13.2
and 6.6 Hz, 1H), 2.95 (t, J = 6.6 Hz, 2H), 2.11 (s, 3H), 1.30 (d, J
= 6.7 Hz, 3H), 1.12 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 170.6, 168.6, 150.5, 136.5 (2C), 127.4, 122.8, 121.7,
119.0, 118.6, 112.2, 111.5, 111.0, 109.9, 55.4, 50.4, 40.4, 25.0,
22.3, 21.2, 21.0; HRMS (ESI) calculated for C21H26N3O3 [MH+]
368.1974, found 368.1982.
4.3.3. N-(1-((2-(1H-Indol-3-yl)ethyl)amino)-1-oxopentan-2-
yl)-N-isopropyl-3,5-dimethoxybenzamide
(9c).
Prepared
according to the general procedure above from n-butyraldehyde,
isopropylamine and 3,5-dimethoxybenzoic acid, for 96 h; FC:
ethyl acetate-hexane, 1:1; yield: 700 mg (64%); pale yellow
solid; mp 118-122 °C; Rf = 0.22 (ethyl acetate-dichloromethane,
1
7:3); νmax(CHCl3) 3475, 3294, 1656, 1594, 1543, 1458 cm-1; H
NMR (400 MHz, CDCl3) δ 8.25 (br, m, 1H), 8.14 (br, m, 1H),
7.66 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.19 (ddd, J =
7.8, 7.4 and 1.2 Hz, 1H), 7.14 (ddd, J = 7.8, 7.4 and 1.2 Hz, 1H),
7.12 (br, s, 1H), 6.51 (br, m, 1H), 6.39 (d, J = 2.1 Hz, 2H), 3.93
(br, m, 1H), 3.80 (s, 6H), 3.83-3.72 (m, 1H), 3.66 (q, J = 6.6 Hz,
2H), 3.03 (t, J = 6.6 Hz, 2H), 2.32-2.09 (br, m, 2H), 1.49-1.30
(br, m, 2H), 1.18 (br, m, 3H), 1.10 (br, m, 3H), 0.97 (br, t, J = 7.2
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 174.4, 173.4, 161.7 (2C),
139.6, 137.1, 128.1, 122.9, 122.5, 119.9, 119.4, 113.5, 111.9,
105.4, 104.8, 102.1, 62.1, 56.2 (2C), 53.1, 40.4, 32.8, 26.0, 21.6,
21.2, 21.0, 14.6; HRMS (ESI) calculated for C27H36N3O4 [MH+]
466.2706, found 466.2694.
4.3.7.
N-(2-(1H-Indol-3-yl)ethyl)-2-(N-(3,4-
dimethoxyphenyl)isobutyramido)-3,3-dimethylbutanamide (9g).
Prepared according to the general procedure above from
pivalaldehyde, 3,4-dimethoxyaniline and isobutyric acid, for 24
h; FC: ethyl acetate-dichloromethane, 4:1; yield: 925 mg (73%);
off-white solid; mp 148-149 °C; Rf = 0.83 (ethyl acetate-
dichloromethane, 3:1); νmax(CHCl3) 3310 (br), 1674, 1632, 1513,
1
1465, 1418, 1386 cm-1; H NMR (300 MHz, CDCl3) δ 8.19 (s,
1H), 7.62 (d, J = 7.8 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 7.18 (t, J
= 7.7 Hz, 1H), 7.11 (t, J = 7.7 Hz, 1H), 7.07 (br, s, 1H), 6.85-6.67
(m, 3H), 4.86 (br, s, 1H), 3.88 (br, s, 3H), 3.85(s, 1H), 3.80 (s,
3H), 3.67-3.53 (m, 2H), 2.99 (t, J = 7.1 Hz, 2H), 2.60-2.46 (m,
1H), 1.02 (t, J = 6.9 Hz, 3H), 0.97 and 0.93 (two singlets, 9H),
0.84 (d, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 171.9,
171.6, 149.8, 149.4, 137.1, 134.7, 127.8, 122.7, 122.6, 119.8,
119.2(2C), 113.2, 112.0, 111.9, 111.0, 56.6 and 56.5 (2C), 40.1,
4.3.4.
N-(2-((2-(1H-Indol-3-yl)ethyl)amino)-1-(4-
methoxyphenyl)-2-oxoethyl)-N-allylisobutyramide
dimethylbutanamide (9d). Prepared according to the general
procedure above from anisaldehyde, allylamine and isobutyric
acid, for 24 h; FC: ethyl acetate-dichloromethane, 1:1; yield: 855
mg (84%); off-white solid; mp 86-88 °C; Rf = 0.63 (ethyl

ACCEPTED MANUSCRIPT
1
2
3
6
Tetrahedron
34.8, 31.8, 28.5 (3C), 26.1, 20.3 (2C); HRMS (ESI) calculated
residue, which was purified by FC with dichloromethane–ethyl
acetate, 1:3.5, for elution.
for C28H38N3O4 [MH+] 480.2862, found 480.2854.
4
5
6
7
8
9
4.3.8.. N-(2-((2-(1H-Indol-3-yl)ethyl)amino)-2-oxoethyl)-N-
(3,4-dimethoxyphenyl)isobutyramide (9h). Prepared according to
the general procedure above from paraformaldehyde, 3,4-
dimethoxyaniline and isobutyric acid, for 48 h; FC: ethyl acetate-
dichloromethane, 7:3; yield: 686 mg (69%); white solid; mp 116-
4.4.1.
N-(2-(1H-Indol-3-yl)ethyl)-2-formamido-2-(4-
methoxyphenyl)acetamide (10a). Prepared according to the
general procedure above from anisaldehyde. Yield: 670 mg
(54%); off-white solid; mp 152-154 °C; Rf = 0.25 (ethyl acetate-
dichloromethane, 7:3); νmax(CHCl3) 3479, 3409 (br), 2937, 1674,
1671, 1611, 1512, 1486, 1457 cm-1; 1H NMR (300 MHz, DMSO-
d6) δ 10.82 (s, 1H), 8.79 (d, J= 8.3 Hz, 1H), 8.42 (t, J = 5.6 Hz,
1H), 8.06 (s, 1H), 7.53 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 7.8 Hz,
1H), 7.30 (d, J = 7.8 Hz, 2H), 7.10-7.01 (m, 2H), 6.98 (t, J = 7.8
Hz, 1H), 6.91 (d, J = 7.8 Hz, 2H), 5.45 (d, J = 8.3 Hz, 1H), 3.75
(s, 3H), 3.34 (br, m, 2H), 2.81 (t, J= 7.3 Hz, 2H); 13C NMR (75
MHz, DMSO-d6) δ 169.6, 160.4, 158.7, 136.2, 130.9, 128.2 (2C),
127.1, 122.8, 120.9, 118.3 (2C), 113.8 (2C), 111.6, 111.4, 55.1,
54.1, 39.9, 25.0; HRMS (ESI) calculated for C20H22N3O3 [MH+]
352.1661, found 351.1668.
118 °C;
Rf
=
0.33 (ethyl acetate-dichloromethane,
4:1); νmax(CHCl3) 3434, 3347, 1668, 1514, 1464, 1419 cm-1; H
NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.57 (d, J = 7.8 Hz, 1H),
7.34 (d, J = 7.8 Hz, 1H), 7.19 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 7.8
Hz, 1H), 7.05 (s, 1H), 6.75-6.55 (m, 3H), 6.38 (br, t, J = 6.5 Hz,
1H), 4.16 (s, 2H), 3.85 (s, 3H), 3.77 (s, 3H), 3.61 (q, J = 6.6 Hz,
2H), 2.96 (t, J = 6.7 Hz, 2H), 2.51 (hept, J = 6.7 Hz, 1H), 0.97 (d,
J = 6.7 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 178.8, 169.0,
149.6, 148.8, 136.4, 135.6, 127.3, 122.3, 122.1, 119.8, 119.3,
118.6, 111.3 (2C), 112.5, 110.7, 56.0 (2C), 54.2, 39.5, 30.9, 25.2,
19.6 (2C); HRMS (ESI) calculated for C24H30N3O4 [MH+]
424.2236, found 424.2228.
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
4.4.2.
N-(2-(1H-Indol-3-yl)ethyl)-2-formamido-3,3-
dimethylbutanamide (10b). Prepared according to the general
procedure above from pivalaldehyde. Yield: 616 mg (58%);
amorphous white solid; Rf = 0.31 (ethyl acetate-dichloromethane,
7:3); νmax(CHCl3) 3475, 3400, 3332, 2887, 1670 (br), 1614, 1523,
1458 cm-1; 1H NMR (300 MHz, CD3OD) δ 8.10 (s, 1H), 7.55 (d,
J = 7.8 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 7.09-7.04 (m, 2H), 7.00
(t, J = 7.8 Hz, 1H), 4.24 (s, 1H), 3.49 (m, 2H), 2.95 (t, J = 7.4 Hz,
2H), 0.95 (s, 9H); 13C NMR(75 MHz, CD3OD) δ 173.0, 169.6,
139.1, 129.6, 124.4, 123.2, 120.5, 120.1, 114.0, 113.1, 61.8, 42.1,
36.0, 28.0 (3C), 27.1; HRMS (ESI) calculated for C17H24N3O2
[MH+] 302.1869, found 302.1876.
4.3.9. N-(2-((2-(1H-Indol-3-yl)ethyl)amino)-2-oxoethyl)-N-(2-
bromophenyl)isobutyramide (9i). Prepared according to the
general procedure above from paraformaldehyde, 2-bromoaniline
and isobutyric acid, for 96 h; FC: ethyl acetate-hexane, 1:1.5;
yield: 686 mg (66%); pale yellow solid mp 159-161 °C; Rf = 0.75
(ethyl acetate-dichloromethane, 7:3); νmax(CHCl3) 3430, 3345,
1668, 1525, 1473, 1423 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.16
(br, m, 1H), 7.65 (br, d, J = 7.7 Hz, 1H), 7.62 (d, J = 7.8 Hz, 1H),
7.40 (d, J = 7.8 Hz, 1H), 7.28-7.20 (m, 4H), 7.14 (t, J = 7.7 Hz,
1H), 7.11 (br, s, 1H), 6.47 (br, m, 1H), 4.68(d, J = 15.3 Hz, 1H),
3.74 (dq, J = 13.2 and 6.6 Hz, 1H), 3.60 (dq, J = 13.2 and 6.6 Hz,
1H), 3.59 (d, J = 15.3 Hz, 1H), 3.03 (t, J = 6.6 Hz, 2H), 2.25
(hept, J = 6.7 Hz, 1H), 1.08 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.7
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 178.5, 168.7, 141.5,
136.5, 133.7, 130.7, 130.1, 129.0, 127.3, 123.3, 122.4, 122.1,
119.4, 118.7, 112.6, 111.3, 53.0, 39.5, 31.6, 25.1, 19.8, 19.2;
HRMS (ESI) calculated for C22H25BrN3O2 [MH+] 442.1130,
found 442.1136.
4.5. General procedure for preparation of compounds 3a-j
and 4a,b by tandem Bischler-Napieralski/heterocyclization
To a solution of the Ugi product (9 or 10) (1.0 mmol) in
anhydrous toluene (10 mL) was added POCl3 (1.37 mL, 15
mmol). Depending on the substrate, the reaction mixture was
stirred at 80-110 °C for 60 to 360 min until the completion of
the reaction as indicated by TLC. After cooling at rt, a 5%
solution of Na2CO3 (10 mL) was added and the mixture extracted
with dichloromethane (2 x 25 mL). The combined organic
extracts were washed with brine (10 mL) and then dried
(Na2SO4) and filtered. The solvent was removed under reduced
pressure and the residue was purified by FC to yield the pure
compound (3 or 4) as indicated below.
4.3.10. N-(2-((2-(1H-Indol-3-yl)ethyl)amino)-2-oxoethyl)-N-
(2-bromo-4,5-dimethoxyphenyl)isobutyramide (9j). Prepared
according
to
the
general
procedure
above
from
paraformaldehyde, 2-bromo-4,5-dimethoxyaniline and isobutyric
acid, for 120 h; FC: ethyl acetate-dichloromethane, 7:3; yield:
803 mg (68%); off-white solid mp 198-200 °C (dec.); Rf = 0.62
(ethyl acetate); νmax(CHCl3) 3435, 3347, 1666, 1506, 1462, 1441
cm-1; 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 8.03 (bt, J
= 6.5 Hz, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.35 (br, s, 1H), 7.34 (d,
J = 7.8 Hz, 1H), 7.31 (br, s, 1H), 7.13 (br, s, 1H), 7.07 (t, J = 7.5
Hz, 1H), 6.96 (d, J = 7.6 Hz, 1H), 4.76 (d, J = 15.6 Hz, 1H), 3.84
(s, 3H), 3.74 (s, 3H), 3.45-3.34 (m, 3H), 2.81 (t, J = 7.2 Hz, 2H),
2.30 (hept, J = 6.6 Hz, 1H), 0.97 (d, J = 6.6 Hz, 6H); 13C NMR
(100 MHz, DMSO-d6) δ 176.8, 168.2, 149.7, 148.9, 136.7,
134.4, 127.7, 123.1, 121.4, 118.7 (2C), 115.7, 114.6, 113.6,
112.2, 111.8, 56.6, 56.4, 51.3, 40.2, 31.0, 25.6, 20.3, 19.6;
HRMS (ESI) calculated for C24H29BrN3O4 [MH+] 502.1341,
found 502.1352.
4.5.1. 2-Isopropyl-3-methyl-1-(pyridin-3-yl)-6,11-dihydro-5H-
imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium
Prepared according to the general procedure above from 9a, for
180 min at 80 °C; FC: dichloromethane-ethyl acetate-methanol,
chloride
(3a).
1:1.5:2.5; yield: 356 mg (94%); foam; Rf
=
0.82
(dichloromethane-methanol, 4:1); νmax(CHCl3) 3155, 1641,
1586, 1533, 1456, 1432 cm-1; H NMR (300 MHz, CD3OD) δ
1
8.88 (br, d, J = 3.9 Hz, 1H), 8.77 (br, s, 1H), 8.10 (br, d, J = 7.8
Hz, 1H), 7.75 (dd, J = 7.8, 5.0 Hz, 1H), 7.57 (d, J = 7.8 Hz, 1H),
7.27 (d, J = 7.8 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.08 (t, J = 7.7
Hz, 1H), 4.56 (hept, J = 7.2 Hz, 1H), 4.47 (t, J = 6.9 Hz, 2H),
3.35 (t, J = 6.9 Hz, 2H), 2.90 (s, 3H), 1.51 (d, J = 7.2 Hz, 6H);
13C NMR (75 MHz, CD3OD) δ 153.1, 152.6, 146.0, 141.8, 139.8,
135.6, 133.3, 129.8, 126.9, 126.5, 125.3, 124.8, 122.8, 120.1,
113.5, 113.1, 53.2, 45.0, 22.0 (2C), 20.9, 12.2; HRMS (ESI)
calculated for C22H23N4+ [M+] 343.4443, found 343.4435.
4.4. General procedure for multicomponent isocyanide-based
synthesis of compounds 10a,b
To a solution of 3-(2-isocyanoethyl)-1H-indole (5) (600 mg,
3.53 mmol) and aldehyde (6) (3.88 mmol) in MeOH (7 mL),
ammonium formate (7.06 mmol) was added in one portion and
the solution was stirred for 24 to 48 h until the completion of the
reaction as indicated by TLC (eluent: ethyl acetate-hexane, 1:1).
The solvent was evaporated under reduced pressure to give a
4.5.2. 1-Cyclopropyl-2-isopropyl-3-methyl-6,11-dihydro-5H-
imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium
Prepared according to the general procedure above from 9b, for
180 min at 80 °C; FC: dichloromethane-methanol, 9:1; yield: 239
mg (70%); pale yellow foam; Rf = 0.15 (dichloromethane-
chloride
(3b).

ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
9
7
methanol, 4:1); νmax(CHCl3) 3299 (br), 1647, 1503, 1458, 1388
yield: 442 mg (92%); pale yellow wax; Rf = 0.40 (ethyl acetate-
1
cm-1; H NMR (300 MHz, CD3OD) δ 7.58 (d, J = 7.8 Hz, 1H),
methanol, 4:1); νmax(CHCl3) 3138, 1655, 1576, 1563, 1455, 1413
1
7.51 (d, J = 7.8 Hz, 1H), 7.22 (t, J = 7.7 Hz, 1H), 7.12 (t, J =
7.7 Hz, 1H), 5.25 (hept, J = 6.8 Hz, 1H), 4.28 (t, J = 6.8 Hz,
2H), 3.23 (t, J = 6.8 Hz, 2H), 2.79 (s, 3H), 2.01 (m, 1H), 1.69 (d,
J = 6.8 Hz, 6H), 1.37 (m, 2H), 0.84-0.74 (m, 2H); 13C NMR (75
MHz, CD3OD) δ 144.5, 139.9, 128.7(2C), 127.0, 125.0, 123.6,
121.6, 120.0, 113.4, 111.4, 52.1, 44.7, 21.9, 21.6 (2C), 20.9, 12.3,
cm-1; H NMR (300 MHz, CDCl3) δ 10.83 (s, 1H), 7.82 (d, J =
7.8 Hz, 1H), 7.51 (d, J = 7.8 Hz, 1H), 7.19 (br, t, J = 7.7 Hz, 1H),
7.11 (t, J = 7.7 Hz, 1H), 7.08 (m, 1 H), 6.98 (br, s, 2H), 4.17 (m,
2H), 3.97 (s, 3H), 3.90 (s, 3H), 3.18 (m, 2H), 3.06 (hept, J = 7.0
Hz, 1H), 1.38 (d, J = 7.0 Hz, 3H), 1.37 (s, 9H), 1.34 (d, J = 7.0
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 151.1, 149.7 (2C), 138.7,
136.5, 127.5 (2C), 124.8, 123.4, 122.8, 121.3, 120.2, 118.3,
113.9, 112.1, 111.4, 111.0, 56.7, 56.3, 45.1, 31.5 (3C), 29.6,
+
9.1 (2C); HRMS (ESI) calculated for C20H24N3 [M+] 306.1965,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
found 306.1973.
+
25.9, 20.4, 19.0 (2C); HRMS (ESI) calculated for C28H34N3O2
4.5.3.
3-(3,5-Dimethoxyphenyl)-2-isopropyl-1-propyl-6,11-
[M+] 444.2646, found 444.2640.
dihydro-5H-imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium chloride
(3c). Prepared according to the general procedure above from 9c,
for 90 min at 80 °C; FC: dichloromethane-methanol, 9:1; yield:
354 mg (76%); pale yellow solid; mp 248-250 °C (dec.); Rf =
0.72 (ethyl acetate-methanol, 4:1); νmax(CHCl3) 3164, 1635,
1597, 1541, 1460, 1424, 1368 cm-1; 1H NMR (400 MHz, CDCl3)
δ 12.0 (br, m, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.46 (br, d, J = 7.8
Hz, 1H), 7.19 (ddd, J = 7.8, 7.6 and 1.1 Hz, 1H), 7.08 (ddd, J =
7.8, 7.6 and 1.1 Hz, 1H), 6.77 (t, J = 2.2 Hz, 1H), 6.68 (d, J = 2.2
Hz, 2H), 4.58 (hept, J = 6.9 Hz, 1H), 3.97 (t, J = 6.9 Hz, 2H),
3.93 (s, 6H), 3.39 (br, t, J = 7.5 Hz, 2H), 3.11 (t, J = 6.9 Hz, 2H),
1.72 (sext, J = 7.5 Hz, 2H), 1.52 (d, J = 6.9 Hz, 6H), 1.14 (t, J =
7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7 (2C), 145.7,
142.5, 139.6, 132.0, 131.5, 124.8, 124.0, 122.6, 120.6, 118.6,
114.5, 110.1, 109.3 (2C), 105.0, 56.6 (2C), 52.4, 45.2, 26.3, 23.8,
4.5.7. 2-(3,4-Dimethoxyphenyl)-3-isopropyl-6,11-dihydro-5H-
imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium
chloride
(3h).
Prepared according to the general procedure above from 9h, for
60 min at 80 °C; FC: ethyl acetate-methanol, 9:1; yield: 295 mg
(76%); off-white solid; mp 271-273 °C (dec.); Rf = 0.68 (ethyl
acetate-methanol, 4:1); νmax(CHCl3) 3122, 1601, 1516, 1463,
1421, 1334 cm-1; 1H NMR (300 MHz, CDCl3) δ 12.41 (s, 1H),
8.27 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H),
7.14 (t, J = 7.6 Hz, 1H), 7.06 (br, s, 1H), 6.98 (t, J = 7.7 Hz, 1H),
6.88 (dd, J = 8.8 and 2.0 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.37
(t, J = 6.8 Hz, 2H), 3.92 (s, 3H), 3.84 (s, 3H), 3.35 (hept, J = 6.7
Hz, 1H), 3.11 (t, J = 6.8 Hz, 2H), 1.40 (d, J = 6.7 Hz, 6H); 13C
NMR (75 MHz, CDCl3) δ 151.4, 150.1, 149.6, 137.9, 127.8,
126.2, 125.3, 123.5 (2C), 121.5, 120.0, 119.3, 118.9, 112.6,
111.5, 110.4, 108.4, 56.6, 56.6, 45.0, 26.3, 20.2, 20.0 (2C);
+
23.2 (2C), 20.7,14.7; HRMS (ESI) calculated for C27H32N3O2
[M+] 430.2489, found 430.2495.
HRMS (ESI) calculated for C24H26N3O2 [M+] 388.2020, found
+
388.2029.
4.5.4. 2-Allyl-3-isopropyl-1-(4-methoxyphenyl)-6,11-dihydro-
5H-imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium chloride (3d).
Prepared according to the general procedure above from 9d, for
60 min at 80 °C; FC: dichloromethane-methanol, 4:1; yield: 360
mg (83%); white foam; Rf = 0.42 (dichloromethane-methanol,
4.5.8.
2-(2-Bromophenyl)-3-isopropyl-6,11-dihydro-5H-
chloride (3i).
imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium
Prepared according to the general procedure above from 9i, for
300 min at 110 °C; FC: dichloromethane-methanol, 3:1; yield:
341 mg (77%); pale yellow solid; mp 280-282 °C (dec.); Rf =
0.10 (ethyl acetate-methanol, 4:1); νmax(CHCl3) 3178, 1645,
1597, 1541, 1460, 1427, 1375 cm-1; 1H NMR (400 MHz, CDCl3)
δ 12.7 (s, 1H), 8.36 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.53 (br, d,
J = 7.8 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H), 7.36 (d, J = 7.8 Hz,
1H), 7.33 (t, J = 7.6 Hz, 1H), 7.19 (t, J = 7.7 Hz, 1 H), 7.07 (t, J
= 7.7 Hz, 1H), 4.53 (t, J = 7.2 Hz, 2H), 3.24 (t, J = 7.2 Hz, 2H),
3.18 (hept, J = 7.0 Hz, 1H), 1.44 (d, J = 7.0 Hz, 3H), 1.42 (d, J =
7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 159.6, 149.1, 148.3,
138.0, 134.0, 132.8, 132.1, 129.7, 129.3, 129.2, 123.6, 121.2,
119.9, 118.5, 115.9, 113.0, 108.0, 45.0, 26.3, 20.1, 19.3, 19.2;
1
4:1); νmax(CHCl3) 3156, 1643, 1567, 1512, 1457, 1328 cm-1; H
NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.49 (d, J = 7.8 Hz, 3H),
7.26 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.13-7.04 (m,
3H), 5.81 (ddt, J = 16.6, 10.7 and 4.9 Hz, 1H), 5.26 (d, J = 10.7
Hz, 1H), 4.97 (d, J = 16.6 Hz, 1H), 4.81 (br, d, J = 4.9 Hz, 2H),
4.50 (t, J = 6.8 Hz, 2H), 3.88 (s, 3H), 3.70 (hept, J = 7.2 Hz, 1H),
3.28 (t, J = 6.8 Hz, 2H), 1.53 (d, J = 7.2 Hz, 6H); 13C NMR (75
MHz, CDCl3) δ 162.3, 150.3, 137.8 (2C), 132.7 (2C), 132.0,
125.7, 124.6, 123.4, 122.0, 121.2, 119.3, 119.0, 116.7, 116.0
(2C), 112.6, 110.7, 55.6, 48.1, 45.5, 26.3 20.6, 19.7 (2C); HRMS
(ESI) calculated for C26H28N3O+ [M+] 398.2227, found 398.2222.
+
HRMS (ESI) calculated for C22H21BrN3 [M+] 406.0919, found
4.5.5. 2-Isopropyl-3-methyl-1-(thiophen-3-yl)-6,11-dihydro-
5H-imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium chloride (3e).
Prepared according to the general procedure above from 9e, for
90 min at 80 °C; FC: dichloromethane-methanol, 4:1; yield: 338
mg (88%); light yellow solid; mp 195-198 °C (dec.); Rf = 0.22
(ethyl acetate-methanol, 9:1); νmax(CHCl3) 3301 (br), 1660, 1513,
1454, 1373, 1313 cm-1; 1H NMR (400 MHz, CD3OD) δ 7.87 (dd,
J = 2.9 and 1.2 Hz, 1H), 7.72 (d, J = 5.0 and 2.9 Hz, 1H), 7.56 (d,
J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.29 (dd, J = 5.0 and
1.2 Hz, 1 H), 7.17 (br, t, J = 7.6 Hz, 1H), 7.09 (br, t, J = 7.6 Hz,
1H), 4.59 (hept, J = 7.0 Hz, 1H), 4.36 (t, J = 7.1 Hz, 2H), 3.28 (t,
J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.49 (d, J = 7.0 Hz, 6H); 13C NMR
(100 MHz, CD3OD) δ 144.4, 138.9, 131.1, 129.7, 129.1, 128.3,
127.7, 126.1, 125.9, 124.2, 121.1, 120.8, 119.0, 112.6, 112.2,
52.2, 44.0, 21.0 (2C), 19.9, 11.0; HRMS (ESI) calculated for
C21H22N3S+ [M+] 348.1529, found 348.1522.
406.0928.
4.5.9.
2-(2-Bromo-4,5-dimethoxyphenyl)-3-isopropyl-6,11-
dihydro-5H-imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium chloride
(3j). Prepared according to the general procedure above from 9j,
for 360 min at 110 °C; FC: dichloromethane-methanol, 4:1;
yield: 422 mg (84%); off-white solid; mp 298-301 °C (dec.); Rf =
0.38 (ethyl acetate-methanol, 4:1); νmax(CHCl3) 3122, 1656,
1
1599, 1560, 1511, 1461, 1442, 1390 cm-1; H NMR (400 MHz,
CD3OD) δ 7.66 (d, J = 7.8 Hz, 1H), 7.59 (s, 1H), 7.46 (br, s, 1H),
7.45 (d, J = 7.8 Hz, 1H), 7.44 (s, 1H), 7.28 (br, t, J = 7.7 Hz,
1H), 7.17 (br, t, J = 7.7 Hz, 1H), 4.73 (m, 2H), 3.98 (s, 3H), 3.90
(s, 3H), 3.43 (t, J = 7.1 Hz, 2H), 3.37 (hept, J = 7.0 Hz, 1H), 1.53
(d, J = 7.0 Hz, 3H), 1.44 (d, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CD3OD) δ 153.5, 151.8, 150.9, 139.0, 127.1 (2C), 126.2,
124.5, 121.5, 120.8, 119.3, 117.1, 115.7, 113.7, 112.3, 112.2,
110.9, 56.9, 56.8, 45.6, 26.9, 20.2, 18.7, 18.1; HRMS (ESI)
calculated for C24H25BrN3O2+ [M+] 466.1125, found 466.1116.
4.5.6. 1-(tert-Butyl)-2-(3,4-dimethoxyphenyl)-3-isopropyl
6,11-dihydro-5H-imidazo[1',5':1,2]pyrido[3,4-b]indol-2-ium
-
chloride (3g). Prepared according to the general procedure above
from 9g, for 60 min at 80 °C; FC: ethyl acetate-methanol, 9:1;
4.5.10.
1-(4-Methoxyphenyl)-6,11-dihydro-5H-
imidazo[1',5':1,2]pyrido[3,4-b]indole (4a). Prepared according

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6
7
8
9
8
Tetrahedron
to the general procedure above from 10a, for 60 min at 80 °C;
(d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 180.2, 157.7,
150.2, 149.3, 137.1, 132.5, 127.9, 125.7, 125.0, 120.5, 120.2,
116.9, 116.0, 114.2, 113.0 (2C), 56.7, 56.5, 53.0, 49.2, 32.3, 30.1,
FC: ethyl acetate-methanol, 9:1; yield: 195 mg (62%); white
foam; Rf = 0.48 (ethyl acetate-methanol, 4:1); νmax(CHCl3) 3337,
1646, 1529, 1455, 1412, 1319 cm-1; 1H NMR (300 MHz, CDCl3)
δ 8.29 (br, s, 1H), 7.75-7.62 (m, 3H), 7.51 (d, J = 7.8 Hz, 1H),
7.29 (d, J = 7.8 Hz, 1H), 7.19-7.09 (m, 2H), 7.02 (br, d, J = 7.1
Hz, 2H), 4.24 (t, J = 6.8 Hz, 2H), 3.86 (s, 3H), 3.20 (t, J = 6.8
Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 159.8, 138.6, 129.0,
128.0 (2C), 126.8, 123.0, 120.8 (2C), 118.6, 115.1 (2C), 111.9
(2C), 111.7 (2C), 107.9, 55.4, 43.6, 21.8; HRMS (ESI) calculated
for C20H18N3O+ [MH+] 316.1450, found 316.1462.
20.5, 19.8; HRMS (ESI) calculated for C24H27BrN3O3 [MH+]
484.1236, found 484.1229.
+
References and notes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
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1. For an overview, see: (a) Zhu, J.; Bienaymé, H. Eds.,
Multicomponent reactions, Wiley-VCH, Weinheim, 2005. For
recent reviews, see: (b) Ruijter, E.; Scheffelaar, R.; Orru, R. V. A.
Angew. Chem., Int. Ed. 2011, 50, 6234–6246. (c) Domling, A.
Chem. Rev. 2006, 106, 17–89. (d) Ramón, D. J.; Yus, M. Angew.
Chem. Int. Ed. 2005, 44, 1602–1634.
4.5.11.
1-(tert-Butyl)-6,11-dihydro-5H-
imidazo[1',5':1,2]pyrido[3,4-b]indole (4b). Prepared according
to the general procedure above from 10b, for 60 min at 80 °C;
FC: ethyl acetate-hexane, 9:1; yield: 196 mg (74%); white foam;
Rf = 0.68 (ethyl acetate-methanol, 9:1); νmax(CHCl3) 3298, 1638,
1533, 1437, 1424, 1327 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.56
(br, s, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 7.7 Hz, 1H),
7.40 (s, 1H), 7.15 (td, J = 7.7 and 1.2 Hz, 1H), 7.10 (td, J = 7.7
and 1.2 Hz, 1H), 4.13 (t, J = 6.7 Hz, 2H), 3.07 (t, J = 6.7 Hz, 2H),
1.48 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 145.3, 136.5, 134.5,
126.7, 126.3, 122.0, 120.2, 118.5, 118.0, 111.3, 107.3, 43.6, 32.4,
2. Ugi, I.; Steinbrückner, C. Angew. Chem. 1960, 72, 267–268.
3. (a) Evans, C. G.; Smith, M. C.; Carolan, J. P.; Gestwicki, J. E.
Bioorg. Med. Chem. Lett. 2011, 21, 2587–2590. (b) De Moliner,
F.; Crosignani, S.; Banfi, L.; Riva, R.; Basso, A. J. Comb. Chem.
2010, 12, 613–616. (c) Riva, R.; Banfi, L.; Basso, A.; Cerulli, V.;
Guanti, G.; Pani, M. J. Org. Chem. 2010, 75, 5134–5143. (d)
Isambert, N.; Lavilla, R. Chem. Eur. J. 2008, 8444–8454. (e)
Beaumont, S.; Retailleau, P.; Dauban, P.; Dodd, R. H. Eur. J. Org.
Chem. 2008, 5162–5175. (f) Constantino, L.; Barlocco, D. Curr.
Med. Chem. 2006, 13, 65–85. (g) Kalinski, C.; Umkehrer, M.;
Schmidt, J.; Ross, G.; Kolb, J.; Burdack, C.; Hiller, W.;
Hoffmann, S. D. Tetrahedron Lett. 2006, 47, 4683–4686. (h)
Weber, L. Drug Discov.Today 2002, 7, 143–147. (i) Endo, A.;
Yanagisawa, A.; Abe, M.; Tohma, S.; Kan, T.; Fukuyama, T. J.
Am. Chem. Soc. 2002, 124, 6552–6554.
4. (a) Dominguez, G.; Pérez-Castells, J. Eur. J. Org. Chem. 2011,
7243–7253. (b) Singh, V.; Hutait, S.; Biswas, S.; Batra, S. Eur. J.
Org. 2010, 531–539. (c) Danieli, B.; Giovanelli, P.; Lesma, G.;
Passarella, D.; Sacchetti, A.; Silvani, A. J. Comb. Chem. 2005, 7,
458–462. (d) Danieli, B.; Lesma, G.; Passarella, D.; Silvani, A.
Curr. Org. Chem. 2000, 4, 231–261.
5. Lesma, G.; Cecchi, R.; Crippa, S.; Giovanelli, P.; Meneghetti, F.;
Musolino, M.; Sacchetti, A.; Silvani, A. Org. Biomol. Chem.
2012, 10, 9004–9012.
31.0 (3C), 20.9; HRMS (ESI) calculated for C17H20N3 [MH+]
266.1657, found 266.1661.
+
4.6. General procedure for preparation of compounds 11i,j
To a solution of the Ugi product (9) (1.0 mmol) in anhydrous
toluene (10 mL) was added POCl3 (0.46 mL, 5 mmol). The
reaction mixture was stirred at 50 °C, under a nitrogen
atmosphere, until the complete consumption of the starting
material. After cooling to rt, a 5% solution of Na2CO3 (10 mL)
was added and the mixture extracted with dichloromethane (2 x
25 mL). The combined organic extracts were washed with brine
(10 mL) and then dried (Na2SO4) and filtered. The solvent was
removed under reduced pressure and the residue was purified by
FC to yield the pure intermediate (11) as indicated below.
6. (a) Khorana, N.; Smith, C.; Herrick-Davis, K.; Purohit, A.; Teitler,
M.; Grella, B.; Dukat, M.; Glennon, R. A. J. Med. Chem. 2003,
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Moyer, J. A.; Andree, T. H.; Muth, E. A. J. Med. Chem. 1987, 30,
1818–1823. (c) Oakley, N.; Jones, B. Eur. J. Pharmacol. 1980, 68,
381.
4.6.1.
N-(2-Bromophenyl)-N-((4,9-dihydro-3H-pyrido[3,4-
b]indol-1-yl)methyl)isobutyramide (11i). Prepared according to
the general procedure above from 9i; FC: ethyl acetate-hexane,
1:1.5; yield: 59 mg (14%); thick syrup; Rf = 0.54 (ethyl acetate-
dichloromethane, 7:3); νmax(CHCl3) 3318, 1628, 1607, 1526,
7. Callaway, J. C.; Gyntber, J.; Poso, A.; Airaksinen, M. M.;
Vepsäläinen J. J. Heterocycl. Chem. 1994, 31, 431–435.
8. Jenkins, P. R.; Wilson, J.; Emmerson, D.; Garcia, M. D.; Smith,
M. R.; Gray, S. J.; Britton, R. G.; Mahale, S.; Chaudhuri, B.;
Bioorg. Med. Chem. 2008, 16, 7728–7739.
1434, 1325 cm-1; H NMR (300 MHz, CDCl3) δ 10.15 (br, m,
1
1H), 7.70 (dd, J = 7.9 and 1.8 Hz, 1H), 7.63 (br, d, J = 7.9 Hz,
1H), 7.51 (br, d, J = 7.9 Hz, 1H), 7.37-7.24 (m, 3H), 7.18 (br, t, J
= 7.8 Hz, 1H), 6.88 (br, d, J = 7.6 Hz, 1H), 5.38 (d, J = 14.3 Hz,
1H), 4.50-4.36 (br, m, 1H), 3.91 (dt, J = 15.8 and 7.3 Hz, 1H),
3.73 (br, ddd, J = 15.8, 11.4 and 7.6 Hz, 1H), 3.01-2.81 (m, 2H),
2.28 (hept, J = 6.7 Hz, 1H), 1.20 (d, J = 6.7 Hz, 3H), 0.96 (d, J =
6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 179.9, 157.9, 141.4,
135.0, 133.1, 130.8, 129.5, 127.7, 127.5, 123.8, 123.5, 119.8,
119.0, 117.8, 114.4, 111.8, 52.9, 49.7, 32.1, 25.1, 19.8, 19.6;
HRMS (ESI) calculated for C22H23BrN3O+ [MH+] 424.1024,
found 424.1029.
9. Gupta, L.; Srivastava, K.; Singh, S.; Puri, S. K.; Chauhan P. M. S.
Bioorg. Med. Chem. Lett. 2008, 18, 3306–3309.
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2008101824 A1 20080828. (b) Fourtillan, J.-B.; Fourtillan, M.;
Jacquesy, J.-C; Karam, O.; Tafani, J.-P; Zunino, F.; PCT Int.
Appl. (2002), WO 2002092598 A1. (c) Ostresh, J.M.; PCT Int.
Appl. (1998), WO 9834112 A1 19980806. (d) Blondelle, S.: et al.;
Peptides 2000, Proceedings of the 26th European Peptide
Symposium, Montpellier (Fr).
11. (a) Trujillo, J. I.; Meyers, M. J.; Anderson, D. R.; Hegde, S.;
Mahoney, M. W.; Vernier, W. F.; Buchler, I. P.; Wu, K. K.; Yang,
S; Hartmann, S. J.; Reitz, D. B. Bioorg. Med. Chem. Lett. 2007,
17, 4657–4663. (b) Meyers, M. J.; Trujillo, J. I.; Vernier, W. F.;
Anderson, D. R.; Reitz, D. B.; Buchler, I. P.; Hedge, S. G.;
Mahoney, M. W.; Wu, K. K. PTC Int. Appl. (2005), WO
2005009370 A2 20050203.
12. Seganish, W. M.; Bercovici, A.; Ho, G. D.; Loozen, H. J. J.;
Timmers, C. M.; Tulshian, D. Tetrahedron Lett. 2012, 53, 903–
905.
13. (a) Ho, G. D.; Seganish, W. M.; Bercovici, A.; Tulshian, D.;
Greenlee, W. J.; Van Rijn, R.; Hruza, A.; Xiao, L.; Rindgen, D.;
Mullins, D.; Guzzi, M.; Zhang, X.; Bleickardt, C.; Hodgson, R.
Bioorg. Med. Chem. Lett. 2012, 22, 2585–2589. (b) Knueppel, D.;
Martin, S. F. Tetrahedron 2011, 67, 9765–9770.
4.6.2 N-(2-Bromo-4,5-dimethoxyphenyl)-N-((4,9-dihydro-3H-
pyrido[3,4-b]indol-1-yl)methyl)isobutyramide (11j). Prepared
according to the general procedure above from 9j; FC: ethyl
acetate-hexane, 1:1.5; yield: 111.5 mg (23%); thick oil; Rf = 0.41
(ethyl acetate-dichloromethane, 7:3); νmax(CHCl3) 3278 (br),
1632, 1618, 1512, 1466, 1376 cm-1; 1H NMR (300 MHz, CDCl3)
δ 10.00 (br, m, 1H), 7.59 (br, d, J = 7.9 Hz, 1H), 7.47 (br, d, J =
7.8 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.25 (br, s, 1H), 7.13 (t, J =
7.7 Hz, 1H), 7.07 (br, s, 1H), 5.31 (d, J = 13.7 Hz, 1H), 4.22 (d, J
= 13.7 Hz, 1H), 3.88 (s, 3H), 3.86 (m, 2H), 3.68 (s, 3H), 2.87 (m,
2H), 2.83 (hept, J = 6.6 Hz, 1H), 1.18 (d, J = 6.6 Hz, 3H), 0.93
14. Zhang, Y. G.; Chan, J. Y. G. Energy Environ. Sci., 2010, 3, 408–
417.

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15. Riduan, S. N.; Zhang, Y. Chem. Soc. Rev. 2013, 42, 9055–9070
and references cited therein.
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2008, 73, 1983–1986.
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Magistris, E.; Paio, A.; Provera, S.; Seneci, P. Tetrahedron Lett.
2000, 41, 7271–7275. (b) Westling, M.; Smith, R.; Livinghouse,
T. J. Org. Chem. 1986, 51, 1159–1165.
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3210.
mling, A. and Ugi, I., Angew. Chem. Int. Ed. 2000, 39, 3168–
Supplementary Material
1H NMR and 13C NMR copies of all synthesized compounds.
Supplementary data associated with this article can be found in
the online version.

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Supporting information
Multicomponent Access to Novel Dihydroimidazo[1',5':1,2]pyrido[3,4-b]indol-2-
ium Salts and Indoles by means of Ugi/Bischler–Napieralski/Heterocyclization
Two Step Strategy
Alessandra Silvani, Giordano Lesma,* Sergio Crippa, and Vito Vece*
Dipartimento di Chimica, Università degli Studi di Milano, via C. Golgi, 19 20133 Milano (Italy)
email: giordano.lesma@unimi.it
Page n°
1H and 13C NMR spectra of compounds 9a-j
1H and 13C NMR spectra of compounds 10a,b
1H and 13C NMR spectra of compounds 3a-j
1H and 13C NMR spectra of compounds 4a,b
1H and 13C NMR spectra of compounds 11i,j
2 - 11
12 - 13
14 - 22
23 - 24
25 - 26
1

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Compound 9a: 1H NMR (300 MHz, CDCl3)
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 9a: 13C NMR (75 MHz, CDCl3)
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
2

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Compound 9b: 1H NMR (300 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Chemical Shift (ppm)
Compound 9b: 13C NMR (75 MHz, CDCl3)
03
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)

ACCEPTED MANUSCRIPT
Compound 9c: 1H NMR (400 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 9c: 13C NMR (75 MHz, CDCl3)
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
4

ACCEPTED MANUSCRIPT
Compound 9d: 1H NMR (300 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 9d: 13C NMR (75 MHz, CDCl3)
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
5

ACCEPTED MANUSCRIPT
Compound 9e: 1H NMR (400 MHz, CDCl3)
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Chemical Shift (ppm)
Compound 9e: 13C NMR (75 MHz, CDCl3)
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
86
Chemical Shift (ppm)

ACCEPTED MANUSCRIPT
Compound 9f: 1H NMR (300 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 9f: 13C NMR (75 MHz, CDCl3)
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
7

ACCEPTED MANUSCRIPT
Compound 9g: 1H NMR (300 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 9g: 13C NMR (75 MHz, CDCl3)
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
8
Chemical Shift (ppm)

ACCEPTED MANUSCRIPT
Compound 9h: 1H NMR (300 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 9h: 13C NMR (75 MHz, CDCl3)
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
9
Chemical Shift (ppm)

ACCEPTED MANUSCRIPT
Compound 9i: 1H NMR (400 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 9i: 13C NMR (75 MHz, CDCl3)
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
10

ACCEPTED MANUSCRIPT
Compound 9j: 1H NMR (300 MHz, DMSO-d6)
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
Chemical Shift (ppm)
Compound 9j: 13C NMR (100 MHz, DMSO-d6)
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
11

ACCEPTED MANUSCRIPT
Compound 10a: 1H NMR (300 MHz, DMSO-d6)
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
Chemical Shift (ppm)
Compound 10a: 13C NMR (75 MHz, DMSO-d6)
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
12
Chemical Shift (ppm)

ACCEPTED MANUSCRIPT
Compound 10b: 1H NMR (300 MHz, CD3OD)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 10b: 13C NMR (75 MHz, CD3OD)
184
176
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
13

ACCEPTED MANUSCRIPT
Compound 3a: 1H NMR (300 MHz, CD3OD)
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 3a: 13C NMR (75 MHz, CD3OD)
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
14

ACCEPTED MANUSCRIPT
Compound 3b: 1H NMR (300 MHz, CD3OD)
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0
-0.5
-1.0
Chemical Shift (ppm)
Compound 3b: 13C NMR (75 MHz, CD3OD)
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
0
Chemical Shift (ppm)
15

ACCEPTED MANUSCRIPT
Compound 3c: 1H NMR (400 MHz, CDCl3)
12.5
12.0
11.5
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 3c: 13C NMR (100 MHz, CDCl3)
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
16

ACCEPTED MANUSCRIPT
Compound 3d: 1H NMR (300 MHz, CDCl3)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 3d: 13C NMR (75 MHz, CDCl3)
168
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
17

ACCEPTED MANUSCRIPT
Compound 3e: 1H NMR (400 MHz, CD3OD)
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
Chemical Shift (ppm)
Compound 3e: 13C NMR (100 MHz, CD3OD)
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
18

ACCEPTED MANUSCRIPT
Compound 3g: 1H NMR (300 MHz, CDCl3)
11.0
10.5
10.0
9.5
9.0
8.5
8.0
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Chemical Shift (ppm)
Compound 3g: 13C NMR (75 MHz, CDCl3)
160
152
144
136
128
120
112
104
96
88
80
72
64
56
48
40
32
24
16
8
Chemical Shift (ppm)
19