Tetrahedron Letters 57 (2016) 3496–3500

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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet

Selective reaction route in the construction of the pyrrolo[3,4-b]

pyridin-5-one core from a variety of 5-aminooxazoles and maleic
anhydride. A DFT study
Alejandro Islas-Jácome a, Angel Rentería-Gómez a, Manuel A. Rentería-Gómez a,
Eduardo González-Zamora b, J. Oscar C. Jiménez-Halla a,⇑, Rocío Gámez-Montaño a,⇑
a
Departamento de Química, División de Ciencias Naturales y Exactas, Universidad de Guanajuato, Noria Alta S/N, Col. Noria Alta, C. P. 36000 Guanajuato, Guanajuato, Mexico
b
Departamento de Química, División de Ciencias Básicas e Ingeniería, Universidad Autónoma Metropolitana-Iztapalapa, San Rafael Atlixco 186, Col. Vicentina, C. P. 09340, Iztapalapa,
CDMX, Mexico

a r t i c l e i n f o a b s t r a c t

Article history: Density Functional Theory (DFT) based calculations were performed at the PCM (toluene)-M06-2X/6-311
Received 19 May 2016 +G(d)//M06-2X/6-31G(d) level of theory to rationalize the construction of the pyrrolo[3,4-b]pyridin-5-
Revised 15 June 2016 one core from a variety of 5-aminooxazoles and maleic anhydride because there are two possible reaction
Accepted 22 June 2016
pathways; A = N-acylation/aza Diels–Alder/aromatization and B = aza Diels–Alder/N-acylation/aromati-
Available online 23 June 2016
zation. After analyzing the nineteen energy profiles, we concluded that the reaction route depends on
the stereoelectronic nature of substituents of the 5-aminooxazole. Two examples followed Path A
Keywords:
whereas the others seventeen preferred Path B.
Pyrrolo[3,4-b]pyridin-5-ones
5-Aminooxazoles
Ó 2016 Elsevier Ltd. All rights reserved.
Maleic anhydride
Aza Diels–Alder
N-acylation
Aromatization

Pyrrolo[3,4-b]pyridin-5-one is the core of several products
exhibiting a variety of very interesting biological properties, for
example antiepileptic (1),1 antipsychotic (2),2 as well as antihypo-
glycemic (3).3 This heterocyclic framework is an aza-analog of the
isoindolin-1-one core because the terminal benzene ring is replaced
by a pyridine. In the same context, various natural products with
high interest in medicinal chemistry such as the (±)-nuevamine
(4a),4 (±)-lennoxamine (4b),5 (±)-chilenine (4c)6 and the magal-
lanesine (4d)7 have the isoindolin-1-one moiety in their structures
(Fig. 1).
As a part of our ongoing program to synthesize novel poly-hete-
rocyclic compounds and having in mind that synthetic analogs of
natural bioactive products may exhibit higher or different biological
activity respect to the formers,8 we recently developed several
methodologies using the U-3CR9 as key synthetic tool for preparing
⇑ Corresponding authors. Tel.: +52 473 732 0006x1433; fax: +52 473 732
0006x8120 (J.O.C.J.-H.); tel.: +52 473 732 0006x8191; fax: +52 473 732 0006x8168
(R.G.-M.).
E-mail addresses: jjimenez@ugto.mx (J. Oscar C. Jiménez-Halla), rociogm@ugto.
mx (R. Gámez-Montaño).
series of novel pyrrolo[3,4-b]pyridin-5-ones fused with various
heterocyclic frameworks of interest in medicinal chemistry.
Thus, in 2010 the novel aza-analogs of the natural product (±)-
nuevamine 15a–d were synthesized in moderate yields (12–71%)
by a sequence U-3CR/aza Diels–Alder/N-acylation/aromatization/
free radical cyclization.10 Then, in 2011 the novel tetrahydroiso-
quinolin-pyrrolo[3,4-b]pyridin-5-ones 15e–g were prepared in
moderate yields (27–59%) by a sequence U-3CR/aza Diels–Alder/
N-acylation/aromatization/Pummerer.11 In 2012, novel aza-ana-
logs of the natural alkaloid (±)-nuevamine 15h–k were synthesized
in moderate yields (22–63%) via U-3CR/aza Diels–Alder/N-acyla-
tion/aromatization/Pictet-Spengler.12 More recently, in 2014 novel
aza-analogs of the (±)-nuevamine 14l–o were synthesized quickly
in moderate yields (29–57%) via the one pot oxidative U-3CR/aza
Diels–Alder/N-acylation/aromatization process.13 Finally, in 2015
novel cyclic analogs of the hexamethylenebis(3-pyridine)amide
(HMBPA) 14p–s were prepared in modest yields (6–12%) by a
one pot U-3CR/aza Diels–Alder/N-acylation/aromatization pro-
cess14 (Scheme 1).
These methodologies start with an U-3CR to construct the
5-aminooxazole core, which reacts in situ with maleic anhydride
via a tandem aza Diels–Alder cycloaddition/N-acylation/

http://dx.doi.org/10.1016/j.tetlet.2016.06.099
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
 A. Islas-Jácome et al. / Tetrahedron Letters 57 (2016) 3496–3500 3497

Cl
O NH 2
O
pyrrol o[3,4-b]pyridine-5 -one iso indolin-1- one
O O N
N Cl
N O
N
HN HN
MeO F NH 2
N 1 MeO N
MeO N Me
MeO
2
3

O O OMe O OMe
OMe OMe O
N N N
OMe N
OH OMe
OMe
4b O OMe
4a 4c O
O O O O
O O O 4d
O

Figure 1. Selected examples of bioactive pyrrolo[3,4-b]pyridin-5-ones (1–3) and the natural isoindolin-1-ones (4a–d).

Ug i-3CR / Aza Diels-Ald er / Fr ee r adical cycli zation10

NH2
5a O
R1 R
R2 O
R 1
CHO N
O R
O N Bn
NH N Me
O
R2 Br N Bn
6a-d Br
Sc(OTf)3 N O B u3SnH /
Br
MW (6 5 °C) R1 ACN R2 R1
P hH
O Bn R P hH
PhH
R2 15a : R 1 = H, R 2 = H ( 62%)
CN 14a-d
R 15b : R1 = OH, R2 = H (12%)
10a-d
Bn N 15c : R 1 = OMe, R 2 = H (40% )
7a R= 15d : R1,R 2 = OCH2O (71% )
O

Ugi-3CR / A za Diels-Alder / Pu mmere r11

R1
NH 2 R2
R2 R
5b-d SPh R1 R O
NH Bn
P hS CHO O O O Bn N N
Sc(OTf)3 O N
6e N O N m-CPB A
P hMe SPh
O Bn R MW (68 °C) SPh TMS OTf / R1
DIPEA
CN Ph Me R2
R DCM
10 e-g R1 15e : R 1,R 2 = O CH 2O (59%)
Bn 1 4e-g
7a N R2 15f : R1 = H, R2 = OMe (46%)
R=
O 15g : R 1 = H, R2 = H (27%)

R1 Ug i-3CR / Aza Diels-Ald er / Pictet-Speng ler12

R2 NH2 O
R3
R3 R
R4 R2 R2
3
R 5 e-h N
R4
R4 R1 N Bn
R1 Me
O 1 R4
Ph S CHO SP h O m-CPBA R
O O
Sc(OTf)3 NH N
6e TFAA R2 R3
PhMe DCM
PhS
O N O MW (80 °C)
PhMe
N 15h : R 1 = R 4 = H, R2 = R3 = OMe (63%)
CN R 15i : R1 = R2 = OMe, R 3 = R 4 = H (54% )
R Ph R Bn
15j : R 1 = R 4 = H, R 2 = R 3 = OH (25%)
Bn N
7a R = 10h-k 1 4h-k 15k : R 1 = R 4 = OMe, R 2 = R 3 = H (22 %)
O

Scheme 1. (A) Synthesis of poly-heterocyclic compounds having the pyrrolo[3,4-b]pyridin-5-one core from 5-aminooxazoles and maleic anhydride. (B) Synthesis of poly-
heterocyclic compounds having the pyrrolo[3,4-b]pyridin-5-one core from 5-aminooxazoles and maleic anhydride.

aromatization to give the pyrrolo[3,4-b]pyridin-5-one core. This the synthesis of pyrrolo[3,4-b]pyridin-5-ones from 5-aminooxa-
latter allowed the preparation of several kinds of linear poly- zole and maleic anhydride.
heterocyclic systems after a post-annulation process. In regard to Based on reports describing the synthesis of pyrrolo[3,4-b]pyr-
reaction mechanisms, both Ugi and those for the post-annulations idin-5-ones also from 5-aminooxazoles with maleic anhydride,15
are well known. However, there are no formal studies describing reaction mechanisms involving an aza Diels–Alder cycloaddition
3498 A. Islas-Jácome et al. / Tetrahedron Letters 57 (2016) 3496–3500

Scheme 1 (continued)

in any part of the reaction route have been proposed. The main
hypothesis of this work is that there are two possible pathways
by which the pyrrolo[3,4-b]pyridin-5-ones 14a–s can be formed
when 5-aminooxazoles 10a–s react with maleic anhydride. Path-
way A = N-acylation/aza Diels–Alder/aromatization and Pathway
B = aza Diels–Alder/N-acylation/aromatization (Scheme 2).
Therefore, in order to disclose the most kinetic and thermody-
namically favorable pathway that these reactions follow, we per-
formed a computational study based on Density Functional
Theory (DFT) at the PCM(toluene)-M06-2X/6-311+G(d)//M06-
2X/6-31G(d)16 level of theory employing the Gaussian09 software
package17 (see the Supporting Information for further details).
We have first calculated the total energy profile for the 5-
aminooxazole 10h (Scheme 1) according to the pathways shown
in Scheme 2. We chose derivative h among all of them for the con-
version from 10 to 14 because example h represented the first doubt
about this reaction mechanism; it can be found in the manuscript
published in 2012.12 Thus, Path B involves first an Aza Diels–Alder
cycloaddition producing 11hPB intermediate and then a N-acyla-
tion, whereas Path A goes in the inverse order through 11hPA spe-
cies. The Figure 2 shows a comparison between the two routes.
Since transition states TS10h?11hPB and TS11hPB?12h are both lower
in energy than the corresponding ones for Path A, clearly Path B is
the kinetically favored over Path A. The energy difference between
the two energy barriers for the first conversion is 2.3 kcal mol 1
whereas for the second reaction step is 1.4 kcal mol 1, which leads
to intermediate 12h. From here, a decarboxylation involving an
early migration of a proton and then a C–C bond break occurs via
TS12h?13h with an energy barrier of 8.2 kcal mol 1 conducting to
the intermediate 13h releasing CO2. We also located a transition
state involving the initial C–C bond breaking, but the subsequent
generation of HCO2, which transfers the proton lately is undesirable
and rises the energy barrier for ca. 32 kcal mol 1. The last calculated
step regarding the aromatization of 13h via a dehydration to get the
intermediate 14h is an exothermic reaction ( 11.2 kcal mol 1) as
well as all of the other reaction steps above mentioned (Fig. 2).
However, we did not calculate the associated energy barriers since
the proton abstraction along with the hydroxyl group (producing

Pathway A = N-acylati on / A za Diels-Alder / Aromatization

Pathway B = Aza Die ls-A lder / N-acylation / Aromatization

R1 11(a -s)PA
R2 N O

COOH R1 1 9 exa mpl es

R1 Path A N O N O
O O H O
R2 NH R3
N O R3
Bn R3 - CO2 R1 N - HOH
O R1 N
O N Bn
N O Bn R3 R 2 HO N Bn
R2 R1
O O R2
O NH H 13a-s
Bn R3 Path B O
N 12a-s 1 4a-s
10a-s
O
Bn R3
1 1(a-s)PB
O
Aromatization (decarboxylation and dehydration)
R 1 = al kyl-, Bn-, allyl -; R2 = aryl-, PhSCH 2-; R 3 = cyclic or acyclic secondary amines

Scheme 2. Two possible reaction pathways to construct the pyrrolo[3,4-b]pyridin-5-one core 14 from 5-amiooxazoles 10 and maleic anhydride.
 A. Islas-Jácome et al. / Tetrahedron Letters 57 (2016) 3496–3500 3499

1. N-acylation step
TS10h 11hPA
20.0 (16.45) 2. Diels-Alder Step
TS11hPA 12h
Relative Enthalpy (kcal mol-1) 10.0 TS10h 11hPB (14.14) (8.90)

(7.51) TS11hPB 12h

0.0 11hPA 3. Decarboxylation step
10h (-6.96) TS12h 13h Path A
(0.0) (-9.32)
-10.0 Path B
11hPB
(-10.72)
-20.0 12h
(-17.54)
-H2O
-30.0 13h
1. Diels-Alder Step + CO2
(-28.13)
-40.0
14h
(-39.35)
2. N -acylation step
-50.0
Reaction coordinate

Figure 2. Energy profile for the proposed reaction mechanism calculated at PCM(toluene)-M06-2X/6-311+G(d)//M06-2X/6-31G(d) level of theory. Relative energy values are
in parenthesis. Optimized geometries of the involved transition states are shown. Color code: nitrogen—blue, oxygen—red, sulfur—yellow, carbon—gray and hydrogen—white.

water) can be achieved either, assisted by a base or through an inter- reaction steps. Whereas reactions c–g, and h have a very exother-
molecular single proton transfer (SPT) between two molecules mic first reaction steps and a less exothermic second reaction steps
(reactions mechanisms involving at least two more steps). However, for Path B; the inverse trend is found for Path A. Moreover, reac-
these mechanistic details are not part of our target for the discussion tions a, b and j have an endothermic first reaction step (Path A).
of reaction pathways and therefore we ignored them in this work. This is noteworthy since these last two are allylamine instead of
More importantly, each reaction step is exothermic and the total cycloalkylamine derivatives, which drive the reaction to react
reaction energy for the reaction 10h?14h is 39.35 kcal mol 1 so exothermically toward the aza Diels–Alder cycloaddition step. This
this chemical transformation proceeds irreversibly. can be explained in terms of structure: a cycloalkylamine has less
Next, we calculated the transformation 10?12 for all the other movement whereas a chain amine is more fluxional and takes
reactions outlined in Scheme 1 with the aim of giving a quantita- more time for reacting with maleic anhydride making the aza
tive measurement on the preference between Paths A and B in Diels–Alder step more favorable to achieve.
these reactions. In Table 1, we report the relative reaction energies On the other hand, these reactions present a lower energy bar-
and the activation energies calculated with the already mentioned rier in the first reaction step favoring Path B (initial Aza Diels–Alder
theoretical methodology. cycloaddition) upon Path A (initial N-acylation step), with
We first note that reactions l–o present low exothermic reac- exception of reactions m and o (N-acylation is favored over Aza
tion steps in both initial Paths A and B, and very exothermic second Diels–Alder cycloaddition). Furthermore, the second reaction step

Table 1
Reaction energies DH0298 (kcal mol ) and the activation energy barriers DHà (kcal mol
1 1
) for all reactions were calculated at PCM(toluene)-M06-2X/6-311+G(d)//M06-2X/6-31G
(d) level

Energy profile Reaction step Energy barrier

10 ? 11PB 10 ? 11PA 11PB ? 12 11PA ? 12 TS10?11PB TS10?11PA TS11PB?12 TS11PA?12
h 10.72 6.96 6.82 10.58 14.14 16.45 18.23 15.86
a 11.87 2.63 7.51 22.01 11.72 28.90 31.15 12.65
b 13.19 0.89 7.12 21.20 9.04 28.83 32.53 12.78
c 13.20 0.01 7.31 20.50 8.79 29.43 32.22 13.10
d 11.74 0.82 9.31 20.23 10.07 29.30 30.93 13.11
e 12.44 4.45 9.65 17.64 9.42 21.70 29.13 15.81
f 14.03 4.07 9.72 19.68 8.90 20.66 27.44 13.79
g 13.46 1.24 8.26 20.49 8.92 24.82 28.72 14.09
i 8.01 6.44 11.37 12.94 13.84 19.86 18.94 19.33
j 12.33 7.08 5.20 24.61 9.28 17.06 27.94 13.82
k 8.27 9.87 12.89 11.29 12.85 17.45 20.44 20.18
l 3.08 4.05 16.83 15.86 13.57 13.60 9.83 12.44
m 3.45 3.30 15.74 15.89 13.45 13.39 10.99 13.60
na 0.10 8.01 20.44 12.54 12.51 13.00 10.06 6.26
oa 3.20 9.63 9.49 3.07 13.58 12.42 10.71 7.86
p 5.24 2.71 9.11 11.64 7.42 18.66 14.49 4.52
q 12.12 4.92 5.19 12.39 7.11 16.69 12.47 3.66
r 8.69 5.00 5.28 8.97 7.76 14.98 12.09 4.04
s 9.10 4.38 4.71 9.43 7.26 19.52 9.95 4.32
a
Reactions that probably follow pathway A.
3500 A. Islas-Jácome et al. / Tetrahedron Letters 57 (2016) 3496–3500
of all reactions has a higher energy barrier for Path B compared
with Path A, except for i, l and m. Thus, undoubtedly reactions i,
k, l and m go through Path B and reaction o prefers Path A. We
noticed that the value of the energy barrier for the first reaction
step is higher for all the reactions except for n, for which the tran-
sition state energy of the second reaction step TS11PB exceed those
of both TS10?11. For example, compare with entry h in Figure 2.
Therefore, the first reaction step controls the kinetic of reaction
and thus, reactions a–h and j favor Path B whereas reaction n goes
through Path A like o. Finally, reactions p–s undoubtedly follow
Path B because the first reaction step presents a lower energy via
TS10?11PB, (initial Aza Diels–Alder cycloaddition upon N-acylation).
In summary, DFT calculations revealed that the majority of
reactions between the 5-aminooxazoles and maleic anhydride to
construct the pyrrolo[3,4-b]pyridin-5-one core (reactions a–m
and p–s) proceed through an initial aza Diels–Alder cycloaddition
followed by the N-acylation step (Path B), whereas reactions n
and o follow Path A. This behavior could be due to a stereoelec-
tronic effects coming from substituents of the 5-aminooxazole.
Thus, our calculations suggest that there is a selective reaction
route in the construction of the pyrrolo[3,4-b]pyridin-5-one core
using specific 5-aminooxazoles with maleic anhydride. This work
may help to solve the mechanistic doubts about this class of
reactions.
Acknowledgements
R.G.-M. thanks CONACYT – México for financial support (pro-
ject: CB-2011-166747-Q and DAIP project 009/2015) E.G.-Z. is
grateful for the CONACYT financial support (236879). A.I.-J. thanks
Universidad de Guanajuato for his contract (SG/015/16-employee
ID: 00247). J.O.C.J.-H. kindly acknowledges Supercomputer Center
of the Laboratorio Nacional de Caracterización de Propiedades
Fisicoquímicas y Estructura Molecular for the computation time
provided at Pipila cluster (CONACYT, Project: 123732).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.06.
099.
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