Synthesis of polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones via a one-pot (Ugi-3CR/aza diels-alder/N-acylation/aromatization/SN2) process. A suitable alternative towards novel Aza-analogues of falipamil

Article abstract of DOI:10.3390/molecules23040763

We describe the one-pot synthesis of twenty polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones via a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) in 20 to 95% overall yields, as well as four pharmacologically promising analogues via an improved cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/S_N2): two piperazine-linked pyrrolo[3,4b]pyridin-5-ones in 33 and 34%, and a couple of Falipamil aza-analogues in 30 and 35% overall yields. It is worth highlighting the good substrate scope found, because final products are furnished with alkyl, aryl, and heterocyclic substituents. The use of chain-ring tautomerizable isocyanides (as key reagents for the Ugi-type three component reaction) allowed for a rapid and efficient assembly of the polysubstituted oxindoles, which were used in situ toward the complex products, conferring features like robustness, sustainability, and the one-pot approach to this synthetic methodology.

Full text of DOI:10.3390/molecules23040763

molecules
Article
Synthesis of Polyheterocyclic Pyrrolo[3,4-b]pyridin-5-
ones via a One-Pot (Ugi-3CR/aza Diels-Alder/N-
acylation/aromatization/SN2) Process. A Suitable
Alternative towards Novel Aza-Analogues
of Falipamil
Angel Zamudio-Medina 1, Ailyn N. García-González 2, Genesis K. Herrera-Carrillo 2,
Daniel Zárate-Zárate 2, Adriana Benavides-Macías 3, Joaquín Tamariz 3, Ilich A. Ibarra 4,*,
Alejandro Islas-Jácome 2,
*
and Eduardo González-Zamora 2,
*
ID
ID
1
Unidad Profesional Interdisciplinaria de Biotecnología, Instituto Politécnico Nacional, Av. Acueducto de
Guadalupe S/N, Barr. La Laguna Ticomán, C.P. 07340, Del. Gustavo A Madero, Ciudad de México, Mexico;
angelzamu2015@hotmail.com
2
3
4
Departamento de Química, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186,
Col. Vicentina, C.P. 09340, Del. Iztapalapa, Ciudad de México, Mexico; natgg@outlook.com (A.N.G.-G.);
purpulove-@live.com.mx (G.K.H.-C.); danzarate_286@hotmail.com (D.Z.-Z.)
Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Prol. Manuel Carpio y Plan de
Ayala S/N, Col. Santo Tomás, C.P. 11340, Del. Miguel Hidalgo, Ciudad de México, Mexico;
a_benavides@prodigy.net.mx (A.B.-M.); jtamarizm@gmail.com (J.T.)
Laboratorio de Fisicoquímica y Reactividad de Superficies, Instituto de Investigaciones en Materiales,
Universidad Nacional Autónoma de México, Circuito Exterior S/N, Ciudad Universitaria, C.P. 04510,
Del. Coyoacán, Ciudad de México, Mexico
*
Correspondence: argel@unam.mx (I.A.I.); aij@xanum.uam.mx (A.I.-J.); egz@xanum.uam.mx (E.G.-Z.);
Tel.: +52-55-5622-4595 (I.A.I.); +52-55-5804-4913 (A.I.-J. & E.G.-Z.)
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 20 February 2018; Accepted: 23 March 2018; Published: 27 March 2018
Abstract: We describe the one-pot synthesis of twenty polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones
via a cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) in 20 to 95% overall
yields, as well as four pharmacologically promising analogues via an improved cascade process
(Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2): two piperazine-linked pyrrolo[3,4-
b]pyridin-5-ones in 33 and 34%, and a couple of Falipamil aza-analogues in 30 and 35% overall yields.
It is worth highlighting the good substrate scope found, because final products are furnished with
alkyl, aryl, and heterocyclic substituents. The use of chain-ring tautomerizable isocyanides (as key
reagents for the Ugi-type three component reaction) allowed for a rapid and efficient assembly of the
polysubstituted oxindoles, which were used in situ toward the complex products, conferring features
like robustness, sustainability, and the one-pot approach to this synthetic methodology.
Keywords: one-pot procedures; cascade processes; multicomponent reactions; Ugi-3CR; aza Diels-Alder
Cycloadditions; microwave assisted synthesis; Pyrrolo[3,4-b]pyridin-5-ones; Falipamil; piperazine-linker
1. Introduction
Falipamil (
its bradycardic, vagolytic, and anti-ischemic properties [
view, the compound is an isoindolin-1-one, a benzo[d]fused heterocycle found in many natural and
1) is a calcium-channel-blocker of high interest in the medicinal chemistry due to
1–3] (Figure 1). From a structural point of
1
synthetic products exhibiting biological activity [4]. Moreover, the pyrrolo[3,4-b]pyridin-5-one is a
Molecules 2018, 23, 763; doi:10.3390/molecules23040763
www.mdpi.com/journal/molecules

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pyrrolo[b]fused polyheterocyclic system that can be considered an aza-analogue of the isoindolin-1-one
core, because the fused benzene is replaced by a pyridine. Similarly, various bioactive products
contain the pyrrolo[3,4-b]pyridin-5-one system within their structures. Besides, piperazine is a
common structural motif in bioactive products, and thus it is considered a privileged linker in
medicinal chemistry [
the isoindolin-1-one system that are piperazine-linked to other heterocycles exhibit strong binding
affinity to the 5-hydroxytryptamine 1A receptor [ ]. In the same way, Couture et al. synthesized
various piperazine-linked isoindolin-1-ones like the compound (Figure 1), bearing in mind its
possible use for further SAR studies [ ]. It is worthy to note that in the same work, Falipamil (
and various related analogues, such as the product (Figure 1), were synthesized successfully via a
5]. For example, Kung et al. described that various compounds containing
6
2
7
1)
3
stepwise (multistep) strategy. Indeed, almost all reports describing the synthesis of isoindolin-1-ones
and pyrrolo[3,4-b]pyridin-5-ones, including those piperazine-linked to other heterocyclic systems,
have been synthesized using stepwise methodologies [8].
Figure 1. Isoindolin-1-one and one of its aza-analogues (pyrrolo[3,4-b]pyridin-5-one).
We have investigated new one-pot synthetic strategies, mainly based on multicomponent
reactions (MCR) to construct novel polyheterocyclic compounds with potential applications in
different fields of knowledge such as agrochemistry, materials and polymers science, optics, and
medicinal chemistry [9]. In this context, we have reported some one-pot syntheses on a series of
novel, fused, polyheterocyclic pyrrolo[3,4-b]pyridin-5-one-based compounds via an Ugi-3CR/aza
Diels-Alder/N-acylation/aromatization cascade sequence combined with further cyclization processes
like free-radical mediated [10], Pummerer [11], Pictet-Spengler [12], and Pomeranz-Fritsch [13]. In the
same way, we developed an oxidative [14] and a repetitive version [15] of this robust one-pot
cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization). Additionally, by using this
methodology (one-pot approach), diverse aza-analogues of natural products, such as (
±
)-Nuevamine,
(
±
)-Lennoxamine, and Magallanesine, were synthesized successfully [13]. On the other hand, to the
best of our knowledge, the synthesis of Falipamil aza-analogues (or its piperazine-linked analogues)
has not been previously reported either via stepwise, or one-pot cascade, or via Multicomponent
Reactions (MCR)-based strategies.
Thus, it can be found in the literature of our own reports [10
present one, and in the above-mentioned methodology from the Couture’s group [
to the present one, in which Falipamil ( ) and some of its analogues ( ) are synthesized efficiently, but via
a stepwise strategy, resulting in larger times and generally using harsh conditions. Moreover, pioneering
works from Bienaymé and Zhu [16 17] allowed the synthesis of pyrrolo[3,4-b]pyridin-5-ones via a
cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) in good yields, short reaction
–15], which are previous works to the
7], which is a close work
1
2–3
,

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times, and under relatively milder conditions with respect to stepwise methods. Thus, the main
hypothesis behind the present work is that novel polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones,
including some piperazine-linked and Falipamil aza-analogues, can be synthesized efficiently via a
cascade process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization) followed by a SN2 reaction
under a new and robust MW-assisted one-pot process. Hence, this synthetic approach is in line with
the idea extracted from the remarkable work by Danishefsky et al. “the development of novel synthetic
strategies toward analogues of natural products with potential application in medicinal chemistry will
always be worthy to be investigated” [18].
2. Results and Discussion
The synthesis of the desired pyrrolo[3,4-b]pyridin-5-ones 11a–i was performed using our
previously optimized conditions [10]: scandium(III) triflate as the Lewis-acid catalyst (3% mol) [19],
microwaves (MW) as heat source to reduce reaction times [20], and benzene as the solvent.
Thus, 1.0 equiv. of the corresponding benzylamines 4a
–
c
(R1 =
a
H,
b
4-OMe,
c
b
3,4-[-O-CH2-O-])
2-BrPh, 4-FPh,
were combined with 1.0 equiv. of the corresponding aldehydes 5a
–
f
(R2 =
a
Ph,
c
d
4-OMePh,
e
4-AcPh,
f
n-Hex) in benzene [0.5 M] at 65 ◦C under MW heating conditions (55 W) to
give the Schiff bases 6a
–i
, which were activated in situ by scandium (III) triflate as Lewis-acid catalyst
to produce the iminium-like intermediates 7a
three steps from the racemic phenylalanine [21]) were added sequentially to provide the corresponding
5-aminooxazoles 9a in quantitative yields. These intermediates used as in situ were prepared to
access to the polyheterocycles 11a in one-pot manner. Consequently, when intermediates 9a were
detected by TLC (by typical features such as Rf and spot nature [22]), 1.4 equiv. of the maleic anhydride
10) [23] was added to give the desired products 11a-i via a cascade triple process: N-acylation/aza
–i. Then, 1.2 equiv. of the isocyanide 8a (prepared in
–
i
–i
–i
(
Diels-Alder cycloaddition/aromatization (decarboxylation-dehydration) (Scheme 1).
Scheme 1. Cont.

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Scheme 1.
Synthesis of pyrrolo[3,4-b]pyridin-5-ones via a cascade process (Ugi-3CR/aza
Diels-Alder/N-acylation/aromatization).
Although some yields of products 11 were moderate, these results can be considered satisfactory
due to the molecular complexity of final products and the fact that they were synthesized in one-pot
manner. This methodology was also demonstrated to have highly atomic economy, since various new
C-C and C-N bonds were created, and only two molecules of water and one of carbon dioxide were lost
in all the process. In addition, compounds 11c and 11d contain a fluorine atom in their structures. It is
well known that the incorporation of fluorine atoms into the structure of potentially bioactive molecules
often enhances their pharmacokinetic properties such as lipophilicity, oral bioavailability, and metabolic
resistance [24]. Interestingly, the product 11h was synthesized in 95% yield (the highest among all the
products), probably due to the high nucleophilicity of the piperonyl amine (doubly activated by the
di-oxamethylene group in its 3,4-positions) combined with the highly activated 2-bromobenzaldehyde.
Continuing with our efforts to gain substrate scope, we synthesized the series of morpholine-containing
analogues 11j
aldehydes 5a,c
CH2) and maleic anhydride 10 via an Ugi-3CR/aza Diels-Alder/N-acylation/aromatization cascade
process (Scheme 2).
It is worth highlighting the structural versatility of the products, because they are provided
–
–
o
. Thus, the 3-morpholinopropan-1-amine (4d) was combined sequentially with the
d,f,g (R1 =
a
Ph, 4-FPh, 4-OMePh, n-Hex, 4-ClPh), isocyanides 8a (X = O,
c
d
f
g
–
b
a
b
with alkyl, aryl, and heterocyclic substituents. The use of the piperidine-containing isocyanide 8b to
synthesize the analogues 11n (45%) and 11o (47%) appears not to alter the efficiency of the reactions,
since their yields remained close to those of the other analogues 11j–m (47–54%).
A further example (in which the amino component of the MCR is modified) was performed
by utilizing the tryptamine (4e) to prepare the polyheterocyclic analogue 11p in 65% yield.
Thus, the tryptamine (4e) was combined sequentially with 2-bromobenzaldehyde (5b), isocyanide 8a,
and maleic anhydride (10) via an Ugi-3CR/aza Diels-Alder/N-acylation/aromatization cascade
process (Scheme 3).

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Scheme 2. Synthesis of morpholine-based polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones via a cascade
process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization).
Scheme 3. Synthesis of a tryptamine-based polyheterocyclic pyrrolo[3,4-b]pyridin-5-one via a cascade
process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization).

Molecules 2018, 23, 763
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Having in mind the idea of functionalizing the amine moiety of the pyrrolo[3,4-b]pyridin-5-ones
to construct more complex polyheterocycles, the alcohol-containing analogues 11q were synthesized
in 43 and 20 % yields, respectively. Thus, 2-aminoethan-1-ol (4f) was combined sequentially with the
corresponding aldehydes 5f n-Hex, 3-OMePh), the isocyanide 8a and maleic anhydride (10),
(R1 =
–
r
,
h
f
h
using the previously detailed methodology to afford the expected products 11q–r (Scheme 4).
Scheme 4. Synthesis of N-alcohol-functionalized pyrrolo[3,4-b]pyridin-5-ones via a cascade process
(Ugi-3CR/aza Diels-Alder/N-acylation/aromatization).
Then, with the aim of evaluating the introduction of an additional step in the one-pot process,
a further SN2 reaction was adapted to our cascade process. The first objective was to prepare the
bromine-containing analogue 11s as a common precursor to introduce a variety of amines through a
sequential SN2 reaction. Thus, 2-bromoethan-1-amine 4g was used as starting material, which reacted
sequentially with the benzaldehyde (5a), isocyanide 8a, and maleic anhydride (10) to furnish the
product 11s in 31% yield (Scheme 5).
Subsequently, the availability of the SN2 reaction was tested by treatment of 11s with a mixture of
morpholine (12a) and triethylamine in acetonitrile as the solvent using MW as heat source (80 ◦C) for
30 minutes to synthesize the morpholine-containing polyheterocyclic pyrrolo[3,4-b]pyridin-5-one 11t
in 35% yield (Scheme 6). Since the chain length between the two heterocyclic systems was shortened
by one methylene, the product 11t is a shorter analogue of the morpholine-containing polyheterocyclic
pyrrolo[3,4-b]pyridin-5-ones 11j–o (Scheme 2).

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Scheme 5. Synthesis of the bromide-functionalized pyrrolo[3,4-b]pyridin-5-one via a cascade process
(Ugi-3CR/aza Diels-Alder/N-acylation/aromatization).
Scheme 6. Synthesis of a morpholine-containing pyrrolo[3,4-b]pyridin-5-one via an improved one-pot
process (Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2).
Following the proposed cascade process, the more complex polyheterocyclic pyrrolo[3,4-
b]pyridin-5-ones 11u
bromine-containing analogues 11s’. Then, strongly inspired by the work from Couture et al. [
we synthesized the pair of piperazine-linked analogues 11u in 34 and 33% yields, respectively,
–
x
were synthesized from 11s or from other of its in situ prepared
7],
–
v
through the same one-pot procedure. It is noteworthy that the secondary amine used for the SN2
reaction (last step) was 1-(2-methoxyphenyl)piperazine (12b), which contains one of the most valued
linkers in medicinal chemistry (piperazine). Finally, we synthesized the Falipamil aza-analogues

Molecules 2018, 23, 763
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11w–x in 30 and 35% yields, respectively, by following the procedure of preparation of the analogues
11u . The secondary amine used for both derivatives was N-methyl-3,4,-dimethoxyphenethylamine
12c) (Scheme 7). It is worthy to note that the products 11w present morpholine and benzyl groups
attached to the pyrrolo[3,4-b]pyridin-5-one scaffold, which may be interpreted as a little loss of
structural analogy to falipamil. However, both morpholine [25 26] and benzyl [27] are substituents
–v
(
–x
,
that are relatively easy to remove from aromatic rings just to recover certain analogy to falipamil.
Scheme 7. Synthesis of polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones via an improved one-pot process
(Ugi-3CR/aza Diels-Alder/N-acylation/aromatization/SN2).

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All the products herein reported 11a
–
x
were fully characterized using IR, NMR, and HRMS or EA
techniques (See the Supplementary Materials for further details). Thus, the compound 11a was selected
to discuss briefly the 1H and 13C-NMR spectra. The pyridine proton (position 4) appears at 7.97 ppm
due to the mesomeric effect coming from the N-sp2. Besides, the CH in which the three components of
the MCR converge has a peak value of 5.30 ppm. As seen, this proton is alkylic. However, it belongs
to a pyrrolidinone system. With respect to 13C, there are two key peaks worth highlighting. The first
one is the peak at 167.1 ppm, which belongs to a γ-lactam-carbonyl carbon. The second one is just the
CH in which all the reagents converge. That peak appears at 64.5 ppm, a non-typic shift for an alkylic
carbon atom. It is important to mention that despite several attempts to obtain adequate crystals for
X-ray analysis for at least one product were conducted; these were unsuccessful.
A plausible reaction mechanism is depicted in Scheme 8, which is supported on computational
calculations previously reported [28]. Thus, a condensation between amines
aldehydes occurs to give the Schiff bases , which are nucleophilically attacked by the respective
isocyanides to afford the nitrilium ions 13. The later undergo a chain-ring tautomerization to give the
5-aminooxazoles as products of the Ugi-3CR, which react with maleic anhydride (10) in two possible
4 and the corresponding
5
6
8
9
pathways: (a) intermolecular N-acylation/intramolecular aza Diels-Alder cycloaddition (through 14) or
(b) intermolecular aza Diels-Alder cycloaddition/intramolecular N-acylation (through 15) to provide the
O-bridged intermediate 16. The latter undergoes a decarboxylation to give 17, followed by a dehydration
to provide the pyrrolo[3,4-b]pyridin-5-ones 11 (Scheme 6). It is worth noting that a close DFT-based
study was reported recently by Gámez-Montaño et al. to support a plausible reaction mechanism for
the construction of the isoinsolin-1-one core via an Ugi-type reaction [29]. Besides, as was discussed,
the pyrrolo[3,4-b]pyridin-5-one is the ‘aza-version’ of the isoinsolin-1-one core.
Scheme 8. Plausible reaction mechanism (adapted from Ref. [9] with permission from the Royal Society
of Chemistry).
3. Experimental Section
3.1. General Information, Instrumentation, Software, and Chemicals
1H and 13C Nuclear Magnetic Resonance (NMR) spectra were acquired on a Bruker Advance
III spectrometer (500 MHz, Fällande, Uster, Switzerland). The solvent used for NMR samples
was deuterated chloroform (CDCl3). Chemical shifts are reported in parts per million (
δ/ppm).
Coupling constants are reported in Hertz (J/Hz). Internal reference for NMR spectra was

Molecules 2018, 23, 763
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tetramethylsilane (TMS) at 0.00 ppm. Multiplicities of the signals are reported using the standard
abbreviations: singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). NMR spectra were
analyzed using the MestreNova software (Ver. 10.0.1–14719). Infrared (IR) spectra were acquired
on a Perkin Elmer GX spectrometer (Norwalk, CT, USA) using the Attenuated Total Reflectance
(ATR) method. The absorbance peaks are reported in reciprocal centimeters (υ
max/cm−1). IR spectra
were analyzed using the Report Builder software (Ver. 2.01). Elemental analyses (CHNS) were
determined in a Perkin Elmer 2400 Series II Analyzer (Norwalk, CT, USA). High Resolution Mass
Spectroscopy (HRMS) spectra were acquired on a Jeol JMS–GC Mate II spectrometer (Akishima, Tokyo,
Japan). HRMS samples were injected directly (direct probe) and analyzed by the Electron Impact (EI)
method. HRMS spectra were analyzed using the Jeol-data analysis software. Melting points were
determined on a Fisher-Johns apparatus (Suwanee, GA, USA) and are uncorrected. Microwave assisted
reactions were performed in closed vessel mode on a CEM Discover MW-reactor (Matthews, NC,
USA). Reaction progress was monitored by Thin Layer Chromatography (TLC) on precoated plates
with Kieselgel 60 (F254), and the spots were visualized under Ultraviolet (UV) light (254 or 365 nm).
Flash columns packed with silica-gel Merck 60 (230–400 nm) and glass preparative plates (20
×
20 cm)
coated with Kieselgel 60 (F254) doped with UV indicator were used to purify the products. Mixtures
in different proportions (v/v) of hexanes (Hex) with ethyl acetate (EtOAc) or ethyl acetate (EtOAc)
with ethanol (EtOH) were used to run TLC, silica-gel columns, preparative plates, and to measure the
Retention Factors (Rf) (using the same mobile phase for all these experiments per product). All starting
materials and solvents were used as received without further purification, distillation, or dehydration.
Chemical structures were drawn using the ChemBioDraw software (Ver. 13.0.2.3020). The purity for
all synthesized products (up to 98%) was assessed by NMR.
3.2. Synthesis and Characterization of the Polysubstituted Pyrrolo[3,4-b]pyridin-5-ones 11a–s
General procedure 1 (GP-1): The corresponding amines (0.1 mmol, 1.0 equiv.) and the
corresponding aldehydes (1.0 equiv.) were placed in a 10 mL sealed CEM Discover microwave
◦
reaction tube and diluted in benzene [0.5 M]. The mixture was stirred and irradiated (MW, 65 C,
55 W) for◦15 min, and then Sc(OTf)3 (0.03 equiv.) was added. The mixture was stirred and irradiated
(MW, 65 C, 55 W) for 15 min, and then the corresponding isocyanides (1.2 equiv.) were added.
The mixture was stirred and irradiated (MW, 80 ◦C, 100 W) for 30 min, and then maleic anhydride
◦
(1.4 equiv.) was added. Finally, the new reaction mixture was stirred and irradiated (MW, 80 C,
100 W) for 30 min. Then, the solvent was removed to dryness under vacuum. The crude was diluted
in dichloromethane (5.0 mL), washed with a concentrated aqueous solution of NaHCO3 (3 × 25 mL),
and then washed with brine (3
×
25 mL). The organic layer was dried using anhydrous Na2SO4 and
then filtered over a celite pad. The solvent was removed to dryness under vacuum. The residue was
purified immediately using a silica-gel column chromatography followed by preparative TLC using
mixtures of Hex–EtOAc or EtOAc-EtOH (v/v) in different proportions as mobile phase to afford the
corresponding polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones 11a–s.
3.2.1. 2,6-Dibenzyl-3-morpholino-7-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (11a)
According to GP-1, benzylamine (10.7 mg), benzaldehyde (10.2
µL), scandium (III) triflate
(1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride (13.7 mg)
were reacted together in PhH (0.2 mL) to afford the product 11a (23.3 mg, 49%) as a yellow solid;
mp = 128–130 ◦C; Rf = 0.54 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR) max/cm−1 921, 1114, 1263, 1442,
υ
1695; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
1H), 4.31 (d, J = 13.9 Hz, 1H), 5.30 (s, 1H), 5.45 (d, J = 14.8 Hz, 1H), 7.13–7.18 (m, 7H), 7.22–7.23 (m, 2H),
7.29–7.34 (m, 3H), 7.38–7.41 (m, 3H), 7.97 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
40.0 (CH2),
δ 2.81–2.88 (m, 4H), 3.79–3.84 (m, 5H), 4.19 (d, J = 13.9 Hz,
δ
43.9 (CH2), 53.0 (CH2), 64.5 (CH), 67.1 (CH2), 123.9 (Cqar), 124.1 (CHar), 126.1 (CHar), 127.7 (CHar),
128.1 (CHar), 128.2 (CHar), 128.5 (CHar), 128.7 (CHar), 128.8 (2 CHar), 129.0 (CHar), 135.3 (Cqar),

Molecules 2018, 23, 763
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136.8 (Cqar), 139.2 (Cqar), 147.8 (Cqar), 160.5 (Cqar), 162.1 (Cqar), 167.1 (Cq); HRMS (EI): calcd. for
C31H30N3O2+ 476.2338, found 476.2341.
3.2.2. 2,6-Dibenzyl-7-(2-bromophenyl)-3-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 11b
According to GP-1, benzylamine (10.7 mg), 2-bromobenzaldehyde (11.7 µL), scandium (III) triflate
(1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride (13.7 mg)
were reacted together in PhH (0.2 mL) to afford the product 11b (42.0 mg, 76%) as a white solid;
mp = 109–111 ◦C; Rf = 0.53 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR) max/cm−1 940, 1015, 1112, 1441,
υ
◦
1694; 1H-NMR (500 MHz, CDCl3, 25 C):
4.12 (d, J = 13.7 Hz, 1H), 4.27 (d, J = 13.7 Hz, 1H), 5.32 (d, J = 14.7 Hz, 1H), 5.99 (s, 1H), 6.74–6.76 (m, 1H),
7.12–7.28 (m, 12H), 7.65–7.67 (m, 1H), 7.89 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
39.8 (CH2),
δ 2.81–2.84 (m, 4H), 3.00–3.82 (m, 4H), 3.86 (d, J = 14.8 Hz, 1H),
δ
44.3 (CH2), 53.0 (CH2), 63.2 (CH), 67.1 (CH2), 123.6 (Cqar), 123.8 (CHar), 125.6 (Cqar), 126.1 (CHar),
127.7 (CHar), 127.9 (2 CHar), 128.1 (CHar), 128.6 (CHar), 128.7 (CHar), 128.9 (CHar), 129.9 (CHar),
133.5 (CHar), 134.8 (Cqar), 136.5 (Cqar), 139.1 (Cqar), 147.7 (Cqar), 160.3 (Cqar), 162.2 (Cqar), 167.4 (Cq);
Elemental analysis: calcd. for C31H28BrN3O2 C 67.15, H 5.09, N 7.58%, found C 66.65, H 5.29, N 7.34%.
3.2.3. 2,6-Dibenzyl-7-(4-fluorophenyl)-3-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 11c
According to GP-1, benzylamine (10.7 mg), 4-fluorobenzaldehyde (10.7 µL), scandium (III) triflate
(1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride (13.7 mg)
were reacted to◦gether in PhH (0.2 mL) to afford the product 11c (18.8 mg, 38%) as a yellow solid;
mp = 152–154 C; Rf = 0.54 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR) υ
max/cm−1 920, 1114, 1220,
◦
1441, 1696; 1H-NMR (500 MHz, CDCl3, 25 C):
δ 2.79–2.85 (m, 4H), 3.76–3.81 (m, 5H), 4.17 (d,
J = 3.9 Hz, 1H), 4.27 (d, J = 13.9 Hz, 1H), 5.24 (s, 1H), 5.41 (d, J = 14.9 Hz, 1H), 7.05–7.17 (m,
10H), 7.24–7.31 (m, 4H), 7.92 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
δ 40.0 (CH2), 43.8 (CH2),
53.0 (CH2), 63.7 (CH), 67.1 (CH2), 116.0 (d, oJCF = 21.0 Hz, CF), 123.7 (Cqar), 123.9 (CHar), 126.2 (CHar),
m
127.8 (CHar), 128.1 (CHar), 128.4 (CHar), 128.7 (CHar), 128.8 (CHar), 129.8 (d, JCF = 8.3 Hz, CF),
131.1 (d, pJCF = 2.6 Hz, CF), 136.6 (Cqar), 139.1 (Cqar), 147.9 (Cqar), 160.3 (Cqar), 162.1 (Cqar), 162.8 (d,
iJCF = 247.5 Hz, CF), 166.9 (Cq); Elemental analysis: calcd. for C31H28FN3O2 C 75.44, H 5.72, N 8.51%,
found C 75.10, H, 5.75, N 8.42%.
3.2.4. 2-Benzyl-7-(4-fluorophenyl)-6-(4-methoxybenzyl)-3-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]
pyridin-5-one 11d
According to GP-1, (4-methoxyphenyl)methanamine (13.1 µL), 4-fluorobenzaldehyde (10.7 µL),
scandium (III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic
anhydride (13.7 mg) were reacted together in dry PhH (0.2 mL) to afford the product 11d (31.4 mg,
60%) as a white solid; mp = 145–147 ◦C; Rf = 0.52 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR)
υ
max/cm−1
917, 1114, 1221, 1246, 1441, 1509, 1694, 2852; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
δ 2.78–2.85 (m, 4H),
3.72 (d, J = 14.7 Hz, 1H), 3.75 (s, 3H), 3.79 (t, J = 4.6 Hz, 4H), 4.16 (d, J = 13.9 Hz, 1H), 4.27 (d, J = 13.9 Hz,
1H), 5.24 (s, 1H), 5.35 (d, J = 14.7 Hz, 1H), 6.81–6.83 (m, 2H), 7.05–7.14 (m, 11H), 7.91 (s, 1H); 13C-NMR
◦
o
(126 MHz, CDCl3, 25 C):
δ 39.9 (CH2), 43.2 (CH2), 53.0 (CH2), 55.2 (CH3), 63.6 (CH), 67.1 (CH2),
114.1 (CHar), 115.9 (d, JCF = 21.7 Hz, CF), 123.8 (CHar), 123.9 (CHar), 126.1 (CHar), 128.1 (CHar),
p
128.7 (CHar), 129.8 (CHar), 131.2 (d, JCF = 2.5 Hz, CF), 139.2 (Cqar), 147.8 (Cqar), 159.2 (Cqar),
160.3 (Cqar), 162.0 (Cqar), 162.8 (d, JCF = 247.4 Hz, CF), 166.8 (Cq); Elemental analysis: calcd. for
i
C32H30FN3O3 C 73.40, H 5.78, N 8.03%, found C 73.45, H 6.13, N 8.15%.
3.2.5. 2-Benzyl-6-(4-methoxybenzyl)-7-(4-methoxyphenyl)-3-morpholino-6,7-dihydro-5H-pyrrolo
[3,4-b]pyridin-5-one 11e
According to GP-1, (4-methoxyphenyl)methanamine (13.1 µL), 4-methoxybenzaldehyde (12.2 µL),
scandium (III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic
anhydride (13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11e (24.6 mg, 46%)

Molecules 2018, 23, 763
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as a yellow solid; mp = 166–168 ◦C; Rf = 0.42 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR)
υ
max/cm−1 701,
1
◦
940, 1015, 1112, 1441, 1694, 2842; H-NMR (500 MHz, CDCl3, 25 C):
δ 2.76–2.84 (m, 4H), 3.70 (d,
J = 14.7 Hz, 1H), 3.80–3.92 (m, 10H), 4.15 (d, J = 13.8 Hz, 1H), 4.29 (d, J = 13.8 Hz, 1H), 5.21 (s, 1H),
5.34 (d, J = 14.7 Hz, 1H), 6.82–6.83 (m, 2H), 6.◦88–6.90 (m, 2H), 7.02–7.04 (m, 2H), 7.10–7.15 (m, 7H),
δ 40.0 (CH2), 43.0 (CH2), 53.0 (CH2), 55.2 (CH3),
7.91 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 C):
55.3 (CH3), 63.9 (CH), 67.1 (CH2), 114.1 (CHar), 114.4 (CHar), 123.9 (CHar), 124.0 (Cqar), 126.1 (CHar),
127.1 (Cqar), 128.1 (CHar), 128.7 (CHar), 129.0 (Cqar), 129.3 (CHar), 129.8 (CHar), 139.3 (Cqar),
147.7 (Cqar), 159.1 (Cqar), 159.8 (Cqar), 160.8 (Cqar), 161.9 (Cqar), 166.7 (Cq); HRMS (EI): calcd. for
C33H34N3O4+ 536.2549, found 536.2611.
3.2.6. 7-(4-Acetylphenyl)-2-benzyl-6-(4-methoxybenzyl)-3-morpholino-6,7-dihydro-5H-pyrrolo
[3,4-b]pyridin-5-one 11f
According to GP-1, (4-methoxyphenyl)methanamine (13.1 µL), 4-acetylbenzaldehyde (14.8 mg),
scandium (III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic
anhydride (13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11f (16.4 mg, 30%)
as a yellow solid; mp = 149–151 ◦C; Rf = 0.34 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR) max/cm−1 917,
υ
1
◦
1035, 1114, 1247, 1441, 1687, 2852; H-NMR (500 MHz, CDCl3, 25 C):
δ 2.62 (s, 3H), 2.79–2.86 (m,
4H), 3.72 (d, J = 14.8 Hz, 1H), 3.78 (s, 3H), 3.79–3.82 (m, 4H), 4.12 (d, J = 14.0 Hz, 1H), 4.27 (d,
J = 13.9 Hz, 1H), 5.29 (s, 1H), 5.39 (d, J = 14.7 Hz, 1H), 6.81–6.83 (m, 2H), 7.07–7.13 (m, 7H),
7.24–7.26 (m, 2H), 7.91 (s, 1H), 7.96–7.97 (m, 2H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
δ 126.7 (CH3),
40.0 (CH2), 43.5 (CH2), 53.0 (CH2), 55.3 (CH3), 63.8 (CH), 67.1 (CH2), 114.2 (CHar), 123.8 (Cqar),
124.0 (CHar), 126.2 (CHar), 128.2 (2 CHar), 128.5 (Cqar), 128.7 (Cqar), 129.0 (CHar),129.8 (CHar),
137.3 (Cqar),139.1 (Cqar), 140.9 (Cqar),148.0 (Cqar), 159.2 (Cqar), 159.8 (Cqar), 162.1 (Cqar), 167.0 (Cq),
197.5 (Cq); Elemental analysis: calcd. for C34H33N3O4 C 74.57, H 6.07, N 7.67%, found C 74.55, H 6.26,
N 7.49%.
3.2.7. 6-(benzo[d][1,3]dioxol-5-ylmethyl)-2-benzyl-3-morpholino-7-phenyl-6,7-dihidro-5H-pyrrolo
[3,4-b]pyridin-5-one 11g
According to GP-1, piperonylamine (12.5 µL), benzaldehyde (10.2 µL), scandium (III) triflate
(1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride (13.7 mg)
were reacted together in PhH (0.2 mL) to afford the product 11g (24.4 mg, 47%) as a yellow solid;
mp = 126–128 ◦C; Rf = 0.51 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR) max/cm−1 927, 1036, 1114, 1243,
υ
1442, 1694; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
δ 2.77–2.84 (m, 4H), 3.68 (d, J = 14.8 Hz, 1H), 3.78–3.80
(m, 4H), 4.15 (d, J = 13.9 Hz, 1H), 4.28 (d, J = 13.9 Hz, 1H), 5.27 (s, 1H), 5.32 (d, J = 14.7 Hz, 1H), 5.90 (d,
J = 1.5 Hz, 1H), 5.92 (d, J = 1.5 Hz, 1H), 6.62 (dd, J = 1.5, 7.8 Hz, 1H), 6.71–6.72 (m, 2H), 7.12–7.15
(m, 7H), 7.35–7.38 (m, 3H), 7.90 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
δ 40.0 (CH2), 43.6 (CH2),
53.0 (CH2), 64.3 (CH), 67.1 (CH2), 101.1 (CH2), 108.3 (CHar), 108.9 (CHar), 121.9 (CHar), 123.8 (Cqar),
123.9 (CHar), 126.1 (CHar), 128.1 (2 CHar), 128.6 (CHar), 128.8 (CHar), 129.0 (CHar), 130.7 (Cqar),
135.3 (Cqar), 139.2 (Cqar), 147.1 (Cqar), 147.8 (Cqar), 148.0 (Cqar), 160.5 (Cqar), 162.0 (Cqar), 166.9 (Cq);
HRMS (EI): calcd. for C32H30N3O4+ 520.2236, found 520.2208.
3.2.8. 6-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-benzyl-7-(2-bromophenyl)-3-morpholino-6,7-dihydro-5H-
pyrrolo[3,4-b]pyridin-5-one 11h
According to GP-1, piperonylamine (12.5 µL), 2-bromobenzaldehyde (11.7 µL), scandium (III)
triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride
(13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11h (56.7 mg, 95%) as a yellow
solid; mp = 109–111 ◦C; Rf = 0.51 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR)
υ
max/cm−1 701, 940, 1015,
1
1112, 1441, 1694; H-NMR (500 MHz, CDCl3, 25 ◦C):
δ 2.83–2.85 (m, 4H), 3.79 (d, J = 14.7 Hz, 1H),
3.83–3.85 (m, 4H), 4.12–4.16 (m, 1H), 4.31 (d, J = 13.7 Hz, 1H), 5.24 (d, J = 14.7 Hz, 1H), 5.93 (dd,
J = 1.5, 6.1 Hz, 2H), 6.01 (s, 1H), 6.65 (dd, J = 1.7, 7.9 Hz, 1H), 6.71–6.77 (m, 4H), 7.13–7.24 (m,

Molecules 2018, 23, 763
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◦
6H), 7.69–7.71 (m, 1H), 7.90 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 C):
δ
39.9 (CH2), 44.1 (CH2),
53.0 (CH2), 63.1 (CH), 67.1 (CH2), 101.0 (CH2), 108.3 (CHar), 109.1 (CHar), 122.2 (CHar), 123.6 (Cqar),
123.8 (CHar), 125.6 (Cqar), 126.1 (CHar), 127.9 (CHar), 128.0 (CHar), 128.1 (CHar), 129.0 (CHar),
129.9 (CHar), 130.3 (Cqar), 133.5 (CHar), 134.9 (Cqar), 139.1 (Cqar), 147.1 (Cqar), 147.7 (Cqar),
+
147.9 (Cqar), 160.3 (Cqar), 162.2 (Cqar), 167.3 (Cq); HRMS (EI): calcd. for C32H29BrN3O4 598.1341,
found 598.1360.
3.2.9. 6-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-benzyl-7-hexyl-3-morpholino-6,7-dihydro-5H-pyrrolo
[3,4-b]pyridin-5-one 11i
According to GP-1, piperonylamine (12.5 µL), heptanal (14.0 µL), scandium (III) triflate (1.5 mg),
2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride (13.7 mg) were
reacted together in PhH (0.2 mL) to afford the product 11i (31.3 mg, 59%) as a yellow viscous liquid;
Rf = 0.53 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR)
υ
max/cm−1 701, 928, 1038,1115, 1243, 1441, 1691;
1H-NMR (500 MHz, CDCl3, 25 ◦C):
δ
0.72–0.78 (m, 1H), 0.85 (t, J = 7.16 Hz, 3H), 1.10–1.22 (m, 7H),
1.84–1.93 (m, 1H), 2.01–2.15 (m, 1H), 2.83–2.89 (m, 4H), 3.83–3.86 (m, 4H), 4.11 (d, J = 14.9 Hz, 1H),
4.29 (d, J = 14.0 Hz, 1H), 4.39–4.42 (m, 2H), 5.26 (d, J = 14.9 Hz, 1H), 5.94 (dd, J = 1.4, 3.7 Hz, 2H),
6.76 (d, J = 7.8 Hz, 2H), 6.78–6.82 (m, 2H), 7.16–7.19 (m, 1H), 7.23–7.28 (m, 5H), 7.88 (s, 1H); 13C-NMR
(126 MHz, CDCl3, 25 ◦C):
δ 14.0 (CH3), 22.3 (CH2), 22.5 (CH2), 29.1 (2 CH2), 31.6 (CH2), 40.0 (CH2),
43.7 (CH2), 53.1 (CH2), 59.8 (CH), 67.2 (CH2), 101.1 (CH2), 108.3 (CHar), 108.7 (CHar), 121.5 (Cqar),
123.6 (Cqar), 124.7 (Cqar), 126.2 (CHar), 128.2 (CHar), 128.8 (CHar), 130.9 (Cqar), 139.5 (Cqar),
147.1 (Cqar), 147.5 (Cqar), 148.0 (Cqar), 160.4 (Cqar), 161.3 (Cqar), 167.1 (Cq); Elemental analysis:
calcd. for C32H37N3O4 C 72.84, H 7.07, N 7.96%, found C 72.76, H 7.31, N 7.76%.
3.2.10. 2-Benzyl-3-morpholino-6-(3-morpholinopropyl)-7-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]
pyridin-5-one 11j
According to GP-1, 3-morpholinopropan-1-amine (14.6 µL), benzaldehyde (10.2 µL), scandium
(III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride
(13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11j (27.7 mg, 54%) as a yellow
viscous liquid; Rf = 0.20 (Hex–AcOEt = 1/◦1, v/v); FT–IR (ATR)
υ
max/cm−1 698, 1031, 1115, 1252, 1443,
δ 1.67–1.73 (m, 1H), 1.77–1.82 (m, 1H), 2.29–2.37 (m, 6H),
1512, 1689; 1H-NMR (500 MHz, CDCl3, 25 C):
2.76–2.83 (m, 4H), 2.99–3.05 (m, 1H), 3.58–3.66 (m, 4H), 3.76–3.79 (m, 4H), 3.94–3.99 (m, 1H), 4.20 (d,
J = 13.9 Hz, 1H), 4.28 (d, J = 13.9 Hz, 1H), 5.49 (s, 1H), 7.08–7.11 (m, 1H), 7.14–7.15 (m, 4H), 7.16–7.18
(m, 2H), 7.32–7.35 (m, 3H), 7.87 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
δ 25.0 (CH2), 38.7 (CH2),
40.0 (CH2), 53.0 (CH2), 53.6 (CH2), 56.0 (CH2), 65.6 (CH), 66.8 (CH2), 67.1 (CH2), 123.7 (CHar), 124.2
(Cqar), 126.1 (CHar), 128.0 (CHar), 128.1 (CHar), 128.6 (CHar), 128.7 (CHar), 128.9 (CHar), 135.7 (Cqar),
139.3 (Cqar), 147.8 (Cqar), 160.4 (Cqar), 161.8 (Cqar), 167.2 (Cq); HRMS (EI): calcd. for C31H36N4O3
512.2787, found 512.2795.
3.2.11. 2-Benzyl-7-(4-fluorophenyl)-3-morpholino-6-(3-morpholinopropyl)-6,7-dihydro-5H-pyrrolo
[3,4-b]pyridin-5-one 11k
According to GP-1, 3-morpholinopropan-1-amine (14.6 µL), 4-fluorobenzaldehyde (10.7 µL),
scandium (III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic
anhydride (13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11k (26.0 mg, 49%) as
a yellow viscous liquid; Rf = 0.32 (Hex–AcOEt = 1/1, v/v); F◦T–IR (ATR)
υ
max/cm−1 699, 862, 1032,
1.69–1.74 (m, 1H), 1.77–1.83 (m,
1
1115, 1221, 1443, 1508, 1692; H-NMR (500 MHz, CDCl3, 25 C):
δ
1H), 2.32–2.38 (m, 6H), 2.79–2.85 (m, 4H), 2.96–3.02 (m, 1H), 3.61–3.64 (m, 4H), 3.79–3.82 (m, 4H),
4.00–3.95 (m, 1H), 4.22 (d, J = 13.9 Hz, 1H), 4.29 (d, J = 13.9 Hz, 1H), 5.48 (s, 1H), 7.03–7.08 (m, 2H),
◦
7.13–7.18 (m, 7H), 7.87 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 C):
δ
25.2 (CH2), 38.7 (CH2), 40.1 (CH2),
o
53.1 (CH2), 53.7 (CH2), 56.1 (CH2), 64.9 (CH), 67.0 (CH2), 67.2 (CH2), 116.1 (d, JCF = 21.8 Hz, CF),
123.8 (CHar), 124.2 (Cqar), 126.3 (CHar), 128.3 (CHar), 128.8 (CHar), 129.7 (d, mJCF = 8.3 Hz, CF), 131.5

Molecules 2018, 23, 763
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(d, pJCF = 3.2 Hz, CF), 139.3 (Cqar), 148.0 (Cqar), 160.3 (Cqar), 162.0 (Cqar), 162.8 (d, iJCF = 247.6 Hz,
CF), 167.2 (CO); HRMS (EI): calcd. for C31H35FN4O3 530.2693, found 530.2694.
3.2.12. 2-Benzyl-7-(4-methoxyphenyl)-3-morpholino-6-(3-morpholinopropyl)-6,7-dihydro-5H-
pyrrolo[3,4-b]pyridin-5-one 11l
According to GP-1, 3-morpholinopropan-1-amine (14.6 µL), 4-methoxybenzaldehyde (12.2 µL),
scandium (III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic
anhydride (13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11l (25.5 mg, 47%) as
a yellow viscous liquid; Rf = 0.17 (AcOEt–EtOH = 10/1, v/v); FT–IR (ATR)
υ
max/cm−1 1115, 1252, 1443,
1512, 1689, 2852; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
δ
1.67–1.73 (m, 1H), 1.77–1.83 (m, 1H), 2.30–2.39
(m, 6H), 2.85–2.76 (m, 4H), 2.98–3.03 (m, 1H), 3.62–3.65 (m, 4H), 3.78–380 (m, 7H), 3.91–3.96 (m, 1H),
4.21 (d, J = 13.9 Hz, 1H), 4.30 (d, J = 13.9 Hz, 1H), 5.45 (s, 1H), 6.88–6.89 (m, 2H), 7.07–7.09 (m, 2H),
◦
7.13–7.18 (m, 5H), 7.87 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 C):
δ 25.1 (CH2), 38.5 (CH2), 40.1 (CH2),
53.1 (CH2), 53.6 (CH2), 55.3 (CH3), 56.1 (CH2), 65.2 (CH), 66.9 (CH2), 67.1 (CH2), 114.4 (CHar), 123.7
(CHar), 124.3 (Cqar), 126.1 (CHar), 127.4 (Cqar), 128.2 (CHar), 128.7 (CHar), 129.3 (CHar), 139.4 (Cqar),
147.8 (Cqar), 159.9 (Cqar), 160.7 (Cqar), 161.8 (Cqar), 167.0 (CO); HRMS (FAB): calcd. for C32H38N4O4
542.2893, found 542.2890.
3.2.13. 2-Benzyl-7-hexyl-3-morpholino-6-(3-morpholinopropyl)-6,7-dihydro-5H-pyrrolo[3,4-b]
pyridin-5-one 11m
According to GP-1, 3-morpholinopropan-1-amine (14.6 µL), heptanal (14.0 µL), scandium (III)
triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride
(13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11m (25.5 mg, 49%) as a yellow
viscous liquid; Rf = 0.40 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR) υ
max/cm−1 700, 1031, 1115, 1399, 1446,
◦
1648; 1H-NMR (500 MHz, CDCl3, 25 C):
δ 0.71–0.79 (m, 1H), 0.84 (d, J = 7.1 Hz, 3H), 1.10–1.25 (m, 8H),
1.79–1.91 (m, 3H), 2.23–2.17 (m, 1H), 2.39–2.43 (m, 6H), 2.80–2.87 (m, 4H), 3.23–3.27 (m, 1H), 3.65–3.70
(m, 4H), 3.82 (t, J = 4.6 Hz, 4H), 4.05 (m, 1H), 4.28 (d, J = 14.0 Hz, 1H), 4.43 (d, J = 14.0 Hz, 1H), 4.56
(dd, J = 3.2, 5.7 Hz, 1H), 7.15–7.19 (m, H), 7.22–7.28 (m, 4H), 7.82 (s, 1H); 13C-NMR (126 MHz, CDCl3,
◦
25 C):
δ
14.1 (CH3), 22.5 (2 CH2), 25.4 (CH2), 29.2 (CH2), 29.4 (CH2), 31.6 (CH2), 38.1 (CH2), 40.0 (CH2),
53.1 (CH2), 53.7 (CH2), 56.2 (CH2), 60.5 (CH), 67.0 (CH2), 67.2 (CH2), 123.4 (CHar), 125.0 (Cqar), 126.2
(CHar), 128.3 (CHar), 128.8 (CHar), 139.6 (Cqar), 147.5 (Cqar), 160.3 (Cqar), 161.1 (Cqar), 167.1 (CO);
HRMS (EI): calcd. for C31H44N4O3 520.3413, found 520.3414.
3.2.14. 2-Benzyl-7-(4-chlorophenyl)-6-(3-morpholinopropyl)-3-(piperidin-1-yl)-6,7-dihydro-5H-
pyrrolo[3,4-b]pyridin-5-one 11n
According to GP-1, 3-morpholinopropan-1-amine (14.6 µL), 4-chlorobenzaldehyde (14.1 mg),
scandium (III) triflate (1.5 mg), 2-benzyl-3-oxo-3-(piperidin-1-yl)propanenitrile (29.1 mg), and maleic
anhydride (13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11n (24.5 mg, 45%)
as a yellow viscous liquid; Rf = 0.33 (AcOEt–EtOH = 10/1, v/v); FT–IR (ATR)
υ
max/cm−1 680, 755,
1.54–1.60 (m,
781, 833, 982, 1036, 1168, 1250, 1385, 1515, 1759; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
δ
2H), 1.68–1.73 (m, 5H), 1.76–1.82 (m, 1H), 3.31–3.40 (m, 6H), 2.75–2.81 (m, 4H), 2.94–3.00 (m, 1H),
3.62–3.65 (m, 4H), 3.94–4.00 (m, 1H), 4.16 (d, J = 13.8 Hz, 1H), 4.25 (d, J = 13.9◦Hz, 1H), 5.43 (s, 1H),
7.09–7.20 (m, 7H), 7.32–7.33 (m, 2H), 7.80 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 C):
δ 24.1 (CH2), 25.2
(CH2), 26.5 (CH2), 38.8 (CH2), 39.9 (CH2), 53.7 (CH2), 54.4 (CH2), 56.2 (CH2), 64.9 (CH), 67.0 (CH2),
123.2 (CHar), 123.9 (Cqar), 126.1 (CHar), 128.2 (CHar), 129.0 (CHar), 129.2 (CHar), 129.4 (CHar), 134.6
(2 Cqar), 139.6 (Cqar), 149.7 (Cqar), 159.2 (Cqar), 162.2 (Cqar), 167.6 (CO); HRMS (EI): calcd. for
C32H38ClN4O2+ 545.2683, found 545.2639.

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3.2.15. 2-Benzyl-7-(4-methoxyphenyl)-6-(3-morpholinopropyl)-3-(piperidin-1-yl)-6,7-dihydro-5H-
pyrrolo[3,4-b]pyridin-5-one 11o
According to GP-1, 3-morpholinopropan-1-amine (14.6 µL), 4-methoxybenzaldehyde (12.2 µL),
scandium (III) triflate (1.5 mg), 2-benzyl-3-oxo-3-(piperidin-1-yl)propanenitrile (29.1 mg), and maleic
anhydride (13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11o (25.4 mg, 47%) as
a yellow viscous liquid; Rf = 0.28 (AcOEt–EtOH = 10/1, v/v); FT–IR (ATR) υ
max/cm−1 1115, 1252, 1443,
◦
1512, 1689, 2852; 1H-NMR (500 MHz, CD3OD, 25 C):
δ 1.67–1.74 (m, 1H), 1.77–1.84 (m, 1H), 2.35–2.49
(m, 10H), 2.81–2.88 (m, 4H), 3.06–3.11 (m, 1H), 3.61–3.65 (m, 5H), 3.76–3.78 (m, 2H), 3.79 (s, 3H), 4.24 (d,
J = 14.2 Hz, 1H), 4.32 (d, J = 14.1 Hz, 1H), 5.62 (s, 1H), 6.93–6.95 (m, 2H), 7.08–7.16 (m, 7H), 7.98 (s, 1H);
◦
13C-NMR (126 MHz, CD3OD, 25 C):
δ 25.5 (CH2), 39.8 (CH2), 40.7 (CH2), 54.1 (CH2), 54.4 (CH2), 55.8
(CH3), 57.0 (CH2), 66.7 (CH), 67.4 (CH2), 68.1 (CH2), 115.5 (CHar), 125.2 (CHar), 125.6 (Cqar), 127.2
(CHar), 128.3 (Cqar), 129.2 (CHar), 129.7 (CHar), 130.7 (CHar), 140.6 (Cqar), 149.7 (Cqar), 161.7 (Cqar),
162.1 (Cqar), 163.6 (Cqar), 168.9 (CO); HRMS (EI): calcd. for C33H40N4O3 540.3100, found 540.2995.
3.2.16. 6-(2-(1H-Indol-3-yl)ethyl)-2-benzyl-7-(2-bromophenyl)-3-morpholino-6,7-dihydro-5H-pyrrolo
[3,4-b]pyridin-5-one 11p
According to GP-1, tryptamine (16.0 mg), 2-bromobenzaldehyde (11.7 µL), scandium (III) triflate
(1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride (13.7 mg)
were reacted together in PhH (0.2 mL) to afford the product 11p (39.4 mg, 65%) as a yellow solid; mp
◦
= 99–101 C; Rf = 0.33 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR)
υ
max/cm−1 420, 695, 738, 1112, 1440,
1674, 3287; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
δ
2.81–2.83 (m, 4H), 3.01–3.07 (m, 1H), 3.17–3.21 (m,
2H), 3.78–3.81 (m, 1H), 3.83–3.84 (m, 4H), 4.21 (d, J = 13.8 Hz, 1H), 4.32 (d, J = 13.9 Hz, 1H), 6.23 (s,
1H), 6.71–6.73 (m, 1H), 7.01 (d, J = 2.1 Hz, 1H), 7.06–7.09 (m, 1H), 7.15–7.23 (m, 8H), 7.28–7.29 (m, 1H),
7.55 (d, J = 7.9 Hz, 1H), 7.69–7.71 (m, 1H), 7.89 (s, 1H), 8.64 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25
◦C):
δ 29.4 (CH2), 40.0 (CH2), 41.2 (CH2), 53.0 (CH2), 63.9 (CH), 67.1 (CH2), 111.3 (CHar), 112.2 (Cqar),
118.6 (CHar), 119.2 (CHar), 121.9 (CHar), 122.1 (CHar), 123.6 (CHar), 124.3 (Cqar), 125.7 (Cqar), 126.2
(CHar), 127.4 (Cqar), 128.0 (CHar), 128.2 (CHar), 128.9 (CHar), 130.1 (CHar), 133.4 (CHar), 135.1 (Cqar),
136.4 (Cqar), 139.2 (Cqar), 147.9 (Cqar), 160.3 (Cqar), 162.0 (Cqar), 167.4 (CO); HRMS (EI): calcd. for
C34H32BrN4O2 607.1708, found 607.1710.
3.2.17. 2-Benzyl-7-hexyl-6-(2-hydroxyethyl)-3-morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-
one 11q
According to GP-1, 2-aminoethan-1-ol (6.0 µL), heptanal (14.0 µL), scandium (III) triflate (1.5 mg),
2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride (13.7 mg) were
reacted together in PhH (0.2 mL) to afford the product 11q (8.7 mg, 20%) as a yellow viscous liquid; Rf
= 0.22 (AcOEt); FT–IR (ATR)
0.73–0.78 (m, 1H), 0.84 (t, J = 7.1 Hz, 3H), 1.15–1.21 (m, 7H), 1.83–1.90 (m, 2H), 2.19–2.24 (m, 1H),
υ
max/cm−1 1115, 1399, 1447, 1672; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
δ
2.82–2.85 (m, 4H), 3.44–3.47 (m, 1H), 3.81–3.83 (m, 4H), 3.86–3.89 (m, 2H), 3.96–3.99 (m, 1H), 4.28 (d,
J = 14.0 Hz, 1H), 4.42 (d, J = 14.0 Hz, 1H), 4.64–4.66 (m, 1H), 7.16–7.18 (m, 1H), 7.23–7.25 (m, 4H), 7.82
(s, 1H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
δ 14.4 (CH3), 22.6 (2 CH2), 29.3 (CH2), 29.6 (CH2), 31.7
(CH2), 40.1 (CH2), 44.3 (CH2), 53.2 (CH2), 62.0 (CH2), 62.3 (CH), 67.3 (CH2), 123.6 (CHar), 124.7 (Cqar),
126.3 (CHar), 128.4 (CHar), 128.9 (CHar), 139.6 (Cqar), 147.7 (Cqar), 160.5 (Cqar), 161.6 (Cqar), 168.7
(CO); HRMS (EI): calcd. for C26H36N3O3+ 438.2757, found 438.2777.
3.2.18. 2-Benzyl-6-(2-hydroxyethyl)-7-(3-methoxyphenyl)-3-morpholino-6,7-dihydro-5H-pyrrolo
[3,4-b]pyridin-5-one 11r
According to GP-1, 2-aminoethan-1-ol (6.0 µL), 3-methoxybenzaldehyde (12.2 µL), scandium (III)
triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride
(13.7 mg) were reacted together in PhH (0.2 mL) to afford the product 11r (19.4 mg, 43%) as a yellow
−1
viscous liquid; Rf = 0.11 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR)
υ
max/cm 1114, 1261, 1393, 1444, 1680,

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2919; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
δ
2.83 (s, 1H), 2.77–2.82 (m, 4H), 3.16–3.19 (m, 1H), 3.40–3.43
(m, 1H), 3.56–3.59 (m, 1H), 3.74 (s, 3H), 3.77–3.79 (m, 4H), 3.95–3.99 (m, 1H), 4.2 (d, J = 14.0 Hz, 1H),
4.29 (d, J = 14.0 Hz, 1H), 5.61 (s, 1H), 6.70–6.71 (m, 1H), 6.77–6.78 (m, 1H), 6.86 (ddd, J = 0.9, 2.6, 8.3
Hz, 1H), 7.13–7.16 (m, 5H), 7.18–7.20 (m, 1H), 7.87 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
δ 40.0
(CH2), 43.8 (CH2), 53.0 (CH2), 55.3 (CH3), 61.2 (CH2), 66.6 (CH), 67.1 (CH2), 113.7 (CHar), 114.0 (CHar),
120.3 (CHar), 126.2 (CHar), 127.4 (Cqar), 128.2 (CHar), 128.8 (CHar), 129.5 (CHar), 130.0 (CHar), 136.9
(Cqar), 139.2 (Cqar), 147.9 (Cqar), 160.0 (Cqar), 160.4 (Cqar), 162.1 (Cqar), 168.2 (CO); HRMS (EI): calcd.
for C27H29N3O4 459.2158, found 459.2158.
3.2.19. 2-Benzyl-6-(2-bromoethyl)-3-morpholino-7-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-
one 11s
According to GP-1, 22-bromoethan-1-amina (20.5 mg), benzaldehyde (10.2 µL), scandium (III)
triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), and maleic anhydride
(13.7 mg) were reacted together in dry PhH (0.2 mL) to afford the product 11s (15.2 mg, 31%) as a
−1
yellow viscous liquid; Rf = 0.48 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR)
1443, 1696; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
1H), 3.78–3.80 (m, 4H), 4.21 (d, J = 14.0 Hz, 1H), 4.29 (d, J = 13.9 Hz, 1H), 4.30–4.33 (m, 1H), 5.72 (s, 1H),
υ
max/cm 699, 747, 1114, 1391,
δ
2.78–2.82 (m, 4H), 3.32–3.40 (m, 2H), 3.57–3.61 (m,
◦
7.11–7.18 (m, 8H), 7.36–7.38 (m, 2H), 7.92 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 C):
δ 29.6 (CH2), 40.1
(CH2), 42.3 (CH2), 53.0 (CH2), 66.3 (CH), 67.1 (CH2), 123.6 (Cqar), 124.0 (CHar), 126.2 (CHar), 128.0
(CHar), 128.2 (CHar), 128.7 (CHar), 128.9 (CHar), 129.1 (CHar), 135.1 (Cqar), 139.1 (Cqar),147.9 (Cqar),
160.4 (Cqar), 162.4 (Cqar), 167.5 (CO); HRMS (EI): calcd. for C26H26BrN3O2 491.1208, found 491.1208.
3.3. One-Pot Synthesis and Characterization of the Polysubstituted Pyrrolo[3,4-b]pyridin-5-ones 11t–x
General procedure 2 (GP-2): The 2-bromoethan-1-amine (0.1 mmol, 1.0 equiv.) and the
corresponding aldehydes (1.0 equiv.) were placed in a 10 mL sealed CEM Discover microwave
◦
reaction tube and diluted in benzene [0.5 M]. The mixture was stirred and irradiated (MW, 65 C,
55 W) for◦15 min, and then Sc(OTf)3 (0.03 equiv.) was added. The mixture was stirred and irradiated
(MW, 65 C, 55 W) for 15 min, and then the corresponding isocyanides (1.2 equiv.) were added.
The mixture was stirred and irradiated (MW, 80 ◦C, 100 W) for 30 min, and◦then maleic anhydride
(1.4 equiv.) was added. The mixture was stirred and irradiated (MW, 80 C, 100 W) for 30 min,
and then the solvent was removed to dryness under vacuum. Anhydrous acetonitrile [0.5 M] was
added. Finally, the corresponding secondary amine (1.0 equiv.) and triethylamine (1.1 equiv.) were
sequentially added, and then the new reaction mixture was stirred and irradiated (MW, 80 ◦C, 100 W)
for 30 min. Then, the solvent was removed to dryness under vacuum. The crude was diluted in
dichloromethane (5.0 mL), washed with a concentrated aqueous solution of NaHCO3 (3
×
25 mL),
and then washed with brine (3 25 mL). The organic layer was dried using anhydrous Na2SO4 and
×
then filtered over a celite pad. The solvent was removed to dryness under vacuum. The residue was
purified immediately using a silica-gel column chromatography followed by a preparative TLC using
mixtures of Hex–EtOAc or EtOAc-EtOH (v/v) in different proportions as mobile phase to afford the
corresponding polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones 11t–x.
3.3.1. 2-Benzyl-3-morpholino-6-(2-morpholinoethyl)-7-phenyl-6,7-dihydro-5H-pyrrolo[3,4-b]
pyridin-5-one 11t
According to GP-2, 2-bromoethan-1-amine (20.5 mg), benzaldehyde (10.2
triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), maleic anhydride (13.7 mg),
morpholine (8.7 L), and triethylamine (15.3 L) were reacted together first in PhH (0.2 mL) and then
in MeCN (0.2 mL) to afford the product 11t (17.4 mg, 35%) as a yellow solid; mp = 71–73 ◦C; Rf = 0.17
(AcOEt); FT–IR (ATR)
max/cm−1 1015, 1115, 1393, 1443, 1693; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
µL), scandium (III)
µ
µ
υ
δ
2.38–2.43 (m, 4H), 2.45–2.50 (m, 1H), 2.56–2.61 (m, 1H), 2.78–2.84 (m, 4H), 3.00–3.06 (m, 1H), 3.66–3.67
(m, 4H), 3.68–3.80 (m, 4H), 4.09–4.14 (m, 1H), 4.21 (d, J = 13.9 Hz, 1H), 4.28 (d, J = 13.9 Hz, 1H), 5.73 (s,

Molecules 2018, 23, 763
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◦
1H), 7.14–7.19 (m, 8H), 7.34–7.36 (m, 2H), 7.88 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 C):
δ
36.8 (CH2),
40.1 (CH2), 53.1 (CH2), 53.7 (CH2), 57.3 (CH2), 66.2 (CH), 67.0 (CH2), 67.2 (CH2), 123.8 (CHar), 126.2
(CHar), 127.8 (CHar), 128.2 (CHar), 128.6 (CHar), 128.8 (CHar), 129.0 (CHar), 129.6 (Cqar), 135.8 (Cqar),
139.3 (Cqar), 147.7 (Cqar), 160.8 (Cqar), 161.8 (Cqar), 167.2 (Cq); HRMS (EI): calcd. for C30H34N4O3
498.2631, found 498.2631.
3.3.2. 2-Benzyl-7-(4-methoxyphenyl)-6-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-3-morpholino-
6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 11u
According to GP-2, 2-bromoethan-1-amine (20.5 mg), 4-methoxybenzaldehyde (12.2
scandium (III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), maleic
anhydride (13.7 mg), 1-(2-methoxyphenyl)piperazine (19.2 mg), and triethylamine (15.3 L) were
reacted together first in PhH (0.2 mL) and then in MeCN (0.2 mL) to afford the product 11u (21.5 mg,
µL),
µ
34%) as a yellow viscous liquid; Rf = 0.71 (AcOEt–EtOH = ◦10/1, v/v); FT–IR (ATR)
υ
max/cm−1 1114,
δ 2.59–2.71 (m, 4H), 2.78–2.82 (m, 6H),
1241, 1444, 1504, 1689, 2821; 1H-NMR (500 MHz, CDCl3, 25 C):
3.05–3.08 (m, 4H), 3.78–3.79 (m, 5H), 3.80 (s, 3H), 3.84 (s, 3H), 4.07–4.13 (m, 1H), 4.22 (d, J = 13.9 Hz,
1H), 4.29 (d, J = 13.9 Hz, 1H), 5.73 (s, 1H), 6.86–6.91 (m, 6H), 7.11–7.16 (m, 7H), 7.89 (s, 1H); 13C-NMR
◦
(126 MHz, CDCl3, 25 C):
δ 36.9 (CH2), 40.1 (CH2), 50.5 (CH2), 53.0 (CH2), 53.4 (CH2), 55.3 (CH3), 55.4
(CH3), 56.9 (CH2), 65.8 (CH), 67.1 (CH2), 111.2 (CHar), 114.4 (CHar), 118.2 (CHar), 121.0 (CHar), 123.0
(CHar), 123.9 (CHar), 124.0 (Cqar), 126.1 (CHar), 127.5 (Cqar), 128.2 (CHar), 128.7 (CHar), 129.1 (CHar),
139.3 (Cqar), 141.2 (Cqar), 147.7 (Cqar), 152.2 (Cqar), 159.8 (Cqar), 161.1 (Cqar), 161.8 (Cqar), 167.0 (Cq);
HRMS (EI): calcd. for C38H43N5O4 633.3315, found 633.3317.
3.3.3. 2-Benzyl-7-(4-fluorophenyl)-6-(2-(4-(2-methoxyphenyl)piperazin-1-yl)ethyl)-3-morpholino-
6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 11v
According to GP-2, 2-bromoethan-1-amine (20.5 mg), 4-fluorobenzaldehyde (10.7
(III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), maleic anhydride
(13.7 mg), 1-(2-methoxyphenyl)piperazine (19.2 mg), and triethylamine (15.3 L) were reacted together
first in PhH (0.2 mL) and then in MeCN (0.2 mL) to afford the product 11v (20.5 mg, 33%) as a yellow
µL), scandium
µ
viscous liquid; Rf = 0.73 (AcOEt–EtOH = 10/1, v/v); FT–I◦R (ATR)
υ
max/cm−1 698, 748, 1027, 1114,
δ 2.52–2.73 (m, 6H), 2.80–2.83 (m, 4H),
1239, 1444, 1500, 1693, 2819; 1H-NMR (500 MHz, CDCl3, 25 C):
3.04–3.08 (m, 4H), 3.69–3.75 (m, 1H), 3.78–3.80 (m, 4H), 3.84 (s, 3H), 4.11–4.16 (m, 1H), 4.23 (q, J =13.9
Hz, 1H), 4.27 (q, J =14.0 Hz, 1H), 5.79 (s, 1H), 6.84–6.86 (m, 1H), 6.91–6.93 (m, 2H), 6.97–7.00 (m, 1H),
◦
7.03–7.07 (m, 3H), 7.11–7.19 (m, 6H), 7.89 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 C):
δ 37.0 (CH2), 40.1
(CH2), 50.6 (CH2), 53.1 (CH2), 53.4 (CH2), 55.4 (CH3), 57.0 (CH2), 65.6 (CH), 67.1 (CH2), 111.3 (CHar),
116.0 (d, oJCF = 21.7 Hz) (CHar), 118.2 (CHar), 121.0 (CHar), 123.0 (CHar), 123.9 (CHar), 126.2 (CHar),
128.2 (CHar), 128.8 (CHar), 129.5 (d, mJCF = 8.3 Hz) (CHar), 131.6 (d, pJCF = 3.1 Hz) (Cqar), 139.2 (Cqar),
141.2 (Cqar), 147.8 (Cqar), 152.3 (Cqar), 160.6 (Cqar), 161.9 (Cqar), 162.8 (d, iJCF = 247.4 Hz) (Cqar),
167.1 (Cq); HRMS (EI): calcd. for C37H40FN5O3 621.3115, found 621.3113.
3.3.4. 2-Benzyl-6-(2-((3,4-dimethoxybenzyl)(methyl)amino)ethyl)-3-morpholino-7-phenyl-6,7-
dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 11w
According to GP-2, 2-bromoethan-1-amine (20.5 mg), benzaldehyde (10.2
triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), maleic anhydride (13.7 mg),
2-(3,4-dimethoxyphenyl)-N-methylethan-1-amine (23.8 mg), and triethylamine (15.3 L) were reacted
together first in PhH (0.2 mL) and then in MeCN (0.2 mL) to afford the product 11w (18.2 mg, 30%)
µL), scandium (III)
µ
as a yellow viscous liquid; Rf = 0.35 (AcOEt–EtOH = 10/1, v/v); FT◦–IR (ATR)
υ
max/cm−1 700, 1028,
δ 2.31 (s, 3H), 2.54–2.64 (m,
1
1114, 1236, 1261, 1443, 1515, 1691; H-NMR (500 MHz, CDCl3, 25 C):
2H), 2.66–2.74 (m, 2H), 2.80–2.83 (m, 4H), 2.99–3.07 (m, 2H), 3.79–3.81 (m, 4H), 3.82 (s, 3H), 3.84 (s,
3H), 3.85–3.87 (m, 1H), 4.01–4.13 (m, 1H), 4.23 (d, J = 13.9 Hz, 1H), 4.28 (d, J = 14.0 Hz, 1H), 5.66 (s,
1H), 6.67–6.70 (m, 2H), 6.73–6.75 (m, 1H), 7.17–7.18 (m, 7H), 7.36–7.35 (m, 3H), 7.89 (s, 1H); 13C-NMR

Molecules 2018, 23, 763
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◦
(126 MHz, CDCl3, 25 C):
δ
33.2 (CH2), 37.8 (CH2), 40.1 (CH2), 42.1 (CH2), 53.1 (CH2), 55.5 (CH2), 55.9
(CH3), 56.0 (CH3), 59.7 (CH2), 66.2 (CH), 67.2 (CH2), 111.4 (CHar), 112.1 (CHar), 120.6 (CHar), 123.8
(CHar), 124.0 (Cqar), 126.2 (CHar), 128.0 (CHar), 128.2 (CHar), 128.7 (Cqar), 128.8 (CHar), 129.0 (CHar),
132.6 (Cqar), 135.8 (Cqar), 139.4 (Cqar), 147.4 (Cqar), 147.8 (Cqar), 148.9 (Cqar), 160.8 (Cqar), 161.8
(Cqar), 167.3 (Cq); HRMS (EI): calcd. for C37H42N4O4 [M] 606.3206, found 606.3208.
3.3.5. 2-Benzyl-6-(2-((3,4-dimethoxybenzyl)(methyl)amino)ethyl)-7-(4-methoxyphenyl)-3-
morpholino-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one 11x
According to GP-2, 2-bromoethan-1-amine (20.5 mg), 4-methoxybenzaldehyde (12.2
µL),
scandium (III) triflate (1.5 mg), 2-isocyano-1-morpholino-3-phenylpropan-1-one (29.3 mg), maleic
anhydride (13.7 mg), 2-(3,4-dimethoxyphenyl)-N-methylethan-1-amine (23.8 mg), and triethylamine
(15.3
product 11x (22.3 mg, 35%) as a yellow viscous liquid; Rf = 0.33 (Hex–AcOEt = 1/1, v/v); FT–IR (ATR)
max/cm−1 698, 749, 1027, 1114, 1241, 1444, 1504, 1689, 2849; 1H-NMR (500 MHz, CDCl3, 25 ◦C):
µL) were reacted together first in PhH (0.2 mL) and then in MeCN (0.2 mL) to afford the
υ
δ
2.29 (s, 3H), 2.52–2.54 (m, 1H), 2.59–2.61 (m, 1H), 2.66–2.67 (m, 2H), 2.79–2.82 (m, 4H), 2.97–3.02 (m,
1H), 3.77–3.80 (m, 9H), 3.81 (s, 3H), 3.82 (s, 3H), 4.05–4.08 (m, 1H), 4.23 (d, J = 13.9, Hz, 1H), 4.29 (d,
J = 13.9 Hz, 1H), 5.60 (s, 1H), 6.67–6.69 (m, 2H), 6.72–6.74 (m, 1H), 6.87–6.89 (m, 2H), 7.06–7.08 (m, 2H),
7.10–7.13 (m, 1H), 7.13–7.16 (m, 6H), 7.88 (s, 1H); 13C-NMR (126 MHz, CDCl3, 25 ◦C):
δ 33.3 (CH2),
37.7 (CH2), 40.0 (CH2), 42.1 (CH2), 53.1 (CH2), 55.3 (CH3), 55.6 (CH2), 55.8 (CH3), 55.9 (CH3), 59.8
(CH2), 65.6 (CH), 67.2 (CH2), 111.3 (CHar),112.0 (CHar), 120.5 (CHar), 123.7 (CHar), 124.1 (Cqar), 126.1
(CHar), 127.6 (CHar), 128.1 (CHar), 128.7 (CHar), 129.2 (CHar), 129.5 (Cqar), 132.8 (Cqar), 139.4 (Cqar),
147.3 (Cqar), 147.6 (Cqar), 148.8 (Cqar), 159.8 (Cqar), 161.0 (Cqar), 161.7 (Cqar), 167.0 (Cq); HRMS (EI):
calcd. for C38H44N4O5 [M] 636.3312, found 636.3315.
4. Conclusions
The herein described one-pot synthetic strategy, based on multicomponent reactions,
allowed for the rapid construction of various new polyheterocyclic compounds (for example,
pyrrolo[3,4-b]pyridine-5-ones linked with other heterocycles like morpholines, piperidines, and
piperazines). Hence, highly polysubstituted and polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones,
including some Falipamil aza-analogues and a pair of piperazine-linked analogues, were synthesized
through a robust one-pot process. Likewise, a novel and complex sequence Ugi-3CR/aza
Diels-Alder/N-acylation/aromatization (decarboxylation-dehydration) was carried out in a one-pot
manner including an additional final SN2 step to provide a wide diversity of polyheterocycles.
Despite the molecular complexity of the final products and the high number of formed bonds, modest to
good yields were obtained. The high atomic economy (-2H2O and -CO2) provides to this methodology
the category of ‘sustainable’. The final products could be considered for further SAR studies, since the
pyrrolo[3,4-b]pyridine-5-one scaffold, piperazine-linker, and the drug falipamil are of high interest in
medicinal chemistry.
1
Supplementary Materials: The following are available online: H and 13C-NMR spectra of all the products 11a
–x
Figures S1–S48.
Acknowledgments: A.N.G.-G (25741/CB-2014-236879), G.K.H.-C. (24741/CB-2014-236879), and D.Z.Z.
(23890/CB-2014-236879) thank CONACYT for their internships. J.T. acknowledges the financial support
provided by SIP-IPN (Grants 20170791 and 20170902) and CONACYT (Grant 178319). J.T. is a fellow of the
EDI-IPN and COFAA-IPN programs. I.A.I. acknowledges PAPIIT-UNAM-Mexico (IN101517) and CONACYT
(1789) for financial support. A.I.-J. acknowledges QI-DQ-CBI-UAMI for his visiting professor position (40966)
and PRODEP-SEP for financial support (12413143). E.G.-Z. acknowledges CONACyT (CB-2014-236879) and
PRODEP-SEP (Article Processing Charges and/or Publication Fees) for financial support.
Author Contributions: A.Z.-M. synthesized the polyheterocyclic pyrrolo[3,4-b]pyridin-5-ones herein described.
A.B.-M. synthesized the piperazine-containing analogues. D.Z.-Z. synthesized the aza-analogues of falipamil.
A.N.G.-G. and G.K.H.-K. integrated the supporting information file. J.T. characterized the products by
spectroscopic techniques. I.A.I., A.I.-J., and E.G.-Z. are the responsible researchers who wrote the manuscript and
to whom correspondence must be addressed.

Molecules 2018, 23, 763
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Conflicts of Interest: The authors declare no conflict of interest. The founding sponsors had no role in the design
of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the
decision to publish the results.
References
1.
Reiffen, M.; Eberlein, W.; Müller, P.; Psiorz, M.; Noll, K.; Heider, J.; Lillie, C.; Kobinger, W.; Luger, P.
Specific Bradycardic Agents. 1. Chemistry, Pharmacology, and Structure–Activity Relationships of
Substituted Benzazepinones, a New Class of Compounds Exerting Antiischemic Properties. J. Med. Chem.
1990, 33, 1496–1504. [CrossRef] [PubMed]
2.
Rieu, J.P.; Duflos, A.; Tristani, J.C.; Patoiseau, J.F.; Tisne-Versailles, J.; Bessac, A.M.; Bonnafous, R.;
Marty, A.; Verscheure, Y.; Bigg, D.C.H. Synthesis and bradycardic activity of a series of substituted
3-aminoalkyl-2,3-dihydro-4H-l,3-benzoxazin-4-ones as potent antiischemics. Eur. J. Med. Chem. 1993
28, 683–691. [CrossRef]
,
3.
4.
5.
Boucher, M.; Chassaing, C.; Chapuy, E. Cardiac electrophysiological effects of falipamil in the conscious dog:
Comparison with alinidine. Eur. J. Pharmacol. 1996, 306, 93–98. [CrossRef]
Speck, K.; Magauer, T. The chemistry of isoindole natural products. Beilstein J. Org. Chem. 2013, 9, 2048–2078.
[CrossRef] [PubMed]
Korch, K.M.; Eidamshaus, C.; Behenna, D.C.; Nam, S.; Horne, D.; Stoltz, B.M. Enantioselective Synthesis of
α
-Secondary and α-Tertiary Piperazin-2-ones and Piperazines by Catalytic Asymmetric Allylic Alkylation.
Angew. Chem. Int. Ed. 2015, 54, 179–183. [CrossRef] [PubMed]
6.
7.
Zhuang, Z.-P.; Kung, M.-P.; Mu, M.; Kung, H.F. Isoindol-1-one Analogues of 4-(20-methoxyphenyl)-1
[2 -[N-(2 -pyridyl)-p-iodobenzamido]ethyl]piperazine (p-MPPI) as 5-HT1A Receptor Ligands. J. Med. Chem.
1998, 41, 157–166. [CrossRef] [PubMed]
Lorion, M.; Couture, A.; Deniau, E.; Grandclaudon, P. Complementary Synthetic Approaches to
Constitutionally Diverse N-Aminoalkylated Isoindolinones: Application to the Synthesis of Falipamil
and 5-HT1A Receptor Ligand Analogues. Synthesis 2009, 11, 1897–1903. [CrossRef]
Sovic´, I.; Karminski-Zamola, G. Derivati izoindolina, sinteza i biološka aktivnost. I. Prirodni i sintetski
derivati izoindolina. Kem. Ind. 2014, 63, 173–182. [CrossRef]
0
00
8.
9.
Ibarra, I.A.; Islas-Jácome, A.; González-Zamora, E. Synthesis of polyheterocycles via multicomponent
reactions. Org. Biomol. Chem. 2018, 16, 1402–1418. [CrossRef] [PubMed]
10. Zamudio-Medina, A.; García-González, M.C.; Padilla, J.; González-Zamora, E. Synthesis of a tetracyclic
lactam system of Nuevamine by four-component reaction and free radical cyclization. Tetrahedron Lett. 2010
51, 4837–4839. [CrossRef]
,
11. Islas-Jácome, A.; González-Zamora, E.; Gámez-Montaño, R. A short microwave-assisted synthesis of
tetrahydroisoquinolinpyrrolopyridinones by a triple process: Ugi-3CR–aza Diels–Alder/S-oxidation/Pummerer.
Tetrahedron Lett. 2011, 52, 5245–5248. [CrossRef]
12. Islas-Jácome, A.; Cárdenas-Galindo, L.E.; Jerezano, A.V.; Tamariz, J.; González-Zamora, E.; Gámez-Montaño, R.
Synthesis of Nuevamine Aza-Analogues by a Sequence: I-MCR–Aza-Diels–Alder–Pictet–Spengler. Synlett
2012, 23, 2951–2956. [CrossRef]
13. Vázquez-Vera, O.; Sánchez-Badillo, J.S.; Islas-Jácome, A.; Rentería-Gómez, M.A.; Pharande, S.G.;
Cortes-García, C.J.; Rincón-Guevara, M.A.; Ibarra, I.A.; Gámez-Montaño, R.; González-Zamora, E. An efficient
Ugi-3CR/aza Diels–Alder/Pomeranz–Fritsch protocol towards novel aza-analogues of (
)-lennoxamine and magallanesine: A diversity oriented synthesis approach. Org. Biomol. Chem. 2017, 15,
2363–2369. [CrossRef] [PubMed]
±
)-nuevamine,
(
±
14. Islas-Jácome, A.; Gutierrez-Carrillo, A.; García-Garibay, M.A.; González-Zamora, E. One-Pot Synthesis of
Nuevamine Aza-Analogues by Combined Use of an Oxidative Ugi Type Reaction and Aza-Diels–Alder
Cycloaddition. Synlett 2014, 25, 403–406. [CrossRef]
15. Zamudio-Medina, A.; García-González, M.C.; Gutierrez-Carrillo, A.; González-Zamora, E. Synthesis of cyclic
analogues of hexamethylenebis(3-pyridine)amide (HMBPA) in a one-pot process. Tetrahedron Lett. 2015, 56,
627–629. [CrossRef]

Molecules 2018, 23, 763
20 of 20
16. Sun, X.; Janvier, P.; Zhao, G.; Bienaymé, H.; Zhu, J. A Novel Multicomponent Synthesis of Polysubstituted
5-Aminooxazole and Its New Scaffold-Generating Reaction to Pyrrolo[3,4-b]pyridine. Org. Lett. 2001, 3,
877–880. [CrossRef] [PubMed]
17. Janvier, P.; Sun, X.; Bienaymé, H.; Zhu, J. Ammonium Chloride-Promoted Four-Component Synthesis of
Pyrrolo[3,4-b]pyridin-5-one. J. Am. Chem. Soc. 2002, 124, 2560–2567. [CrossRef] [PubMed]
18. Wilson, R.M.; Danishefsky, S.J. On the Reach of Chemical Synthesis: Creation of a MiniPipeline from an
Academic Laboratory. Angew. Chem. Int. Ed. 2010, 49, 6032–6056. [CrossRef] [PubMed]
19. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W.E.-L. Rare-Earth Metal Triflates in Organic Synthesis.
Chem. Rev. 2002, 102, 2227–2302. [CrossRef] [PubMed]
20. Kappe, C.O.; Dallinger, D. Controlled microwave heating in modern organic synthesis: Highlights from the
2004–2008 literature. Mol. Divers. 2009, 13, 71–193. [CrossRef] [PubMed]
21. Fayol, A.; Housseman, C.; Sun, X.; Janvier, P.; Bienaymé, H.; Zhu, J. Synthesis of α-Isocyano-α-alkyl(aryl)acetamides
and their Use in the Multicomponent Synthesis of 5-Aminooxazole, Pyrrolo[3,4-b]pyridin-5-one and
4,5,6,7-Tetrahydrofuro[2,3-c]pyridine. Synthesis 2005, 1, 161–165. [CrossRef]
22. Rentería-Gómez, M.A.; Morales-Salazar, I.; García-González, N.; Segura-Olvera, D.; Sánchez-Serratos, M.;
Ibarra, I.A.; González-Zamora, E.; Gámez-Montaño, R.; Islas-Jácome, A. Ultrasound-assisted synthesis
of eight novel and highly functionalized 2-aminonitrile oxazoles via Ugi-3CR. In Proceedings of
the 21st International Electronic Conference on Synthetic Organic Chemistry, 1–30 November 2017;
Sciforum Electronic Conference Series 2017. Volume 21. [CrossRef]
23. González-López, M.; Shaw, J.T. Cyclic Anhydrides in Formal Cycloadditions and Multicomponent Reactions.
Chem. Rev. 2009, 109, 164–189. [CrossRef] [PubMed]
24. Purser, S.; Moore, P.R.; Sallow, S.; Gouverneur, V. Fluorine in Medicinal Chemistry. Chem. Soc. Rev. 2008, 37,
320–330. [CrossRef] [PubMed]
25. Yi, Y.-Q.-Q.; Yang, W.-C.; Zhai, D.-D.; Zhang, X.-Y.; Li, S.-Q.; Guan, B.-T. Nickel-catalyzed C–N bond reduction
of aromatic and benzylic quaternary ammonium triflates. Chem. Commun. 2016, 52, 10894–10897. [CrossRef]
26. Tobisu, M.; Nakamura, K.; Chatani, N. Nickel-Catalyzed Reductive and Borylative Cleavage of Aromatic
Carbon Nitrogen Bonds in N-Aryl Amides and Carbamates. J. Am. Chem. Soc. 2014, 136, 5587–5590.
−
[CrossRef] [PubMed]
27. Chambers, R.R., Jr.; Collins, C.J.; Maxwell, B.E. Reductive Debenzylation of 1-Benzylnaphtalene by a Na-K
Alloy. J. Org. Chem. 1985, 50, 4960–4963. [CrossRef]
28. Islas-Jácome, A.; Rentería-Gómez, A.; Rentería-Gómez, M.A.; González-Zamora, E.; Jiménez-Halla, J.O.C.;
Gámez-Montaño, R. Selective reaction route in the construction of the pyrrolo[3,4-b]pyridine-5-one core
from a variety of 5-aminooxazoles and maleic anhydride. A DFT study. Tetrahedron Lett. 2016, 57, 3496–3500.
[CrossRef]
29. Rentería-Gómez, A.; Islas-Jácome, A.; Cruz-Jiménez, A.E.; Manzano-Velázquez, J.C.; Rojas-Lima, S.;
Jiménez-Halla, J.O.C.; Gámez-Montaño, R. Synthesis of 2-Tetrazolylmethyl-isoindolin-1-ones via a One-Pot
UgiAzide/(N-Acylation/exo-Diels
−
Alder)/Dehydration Process. ACS Omega 2016, 1, 943–951. [CrossRef]
Sample Availability: Samples of the compounds 11a–x are available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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