Synthesis of new 1,2-diaryl[2]benzopyrano[3,4-d]imidazol-5(1H)-one derivatives mediated by ceric ammonium nitrate

Full text of DOI:10.1016/j.tetlet.2017.02.087

Accepted Manuscript
Synthesis of new 1,2-diaryl[2]benzopyrano[3,4-d]imidazol-5(1H)-one deriva-
tives mediated by ceric ammonium nitrate
Ricaurte Rodríguez, Daniel E. Vicentes, Justo Cobo, Manuel Nogueras
PII:
S0040-4039(17)30273-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.02.087
TETL 48698
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
4 February 2017
26 February 2017
27 February 2017
Please cite this article as: Rodríguez, R., Vicentes, D.E., Cobo, J., Nogueras, M., Synthesis of new 1,2-
diaryl[2]benzopyrano[3,4-d]imidazol-5(1H)-one derivatives mediated by ceric ammonium nitrate, Tetrahedron
Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.02.087
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Synthesis of new 1,2-diaryl[2]benzopyrano[3,4-d]imidazol-5(1H)-one derivatives
mediated by ceric ammonium nitrate
Ricaurte Rodrígueza*, Daniel E. Vicentesb*, Justo Coboc, Manuel Noguerasc
aDepartamento de Química, Universidad Nacional de Colombia, Ciudad Universitaria, Carrera 30, No.
45-03, Edificio 451, Bogotá, Colombia
bDepartamento de Química, Universidad de Ciencias Aplicadas y Ambientales, Calle 222, No. 55-37,
Bogotá, Colombia
cDepartamento de Química inorgánica y Orgánica, Universidad de Jaén, 23071 Jaén, Spain
Introduction
From the synthetic point of view the construction of 1H-2-benzopyran-1-ones (1) (isochromen-1-ones or
isocoumarins) framework has been a challenge to the synthetic and medicinal chemists. To this end different
synthetic strategies have been developed (Scheme 1).1-10
Br O
O
O
R2
OH
H
OH
R2
R1
Ref. 4
Ref. 3
O
O
RNC RNH2
Ref. 2
RNC
O
R2
O
O
O
O
OR
H
R2
X
I
R2
Ref. 5
Ref. 1
1
R1
X = Br, I
O
OR
O
O
O
X
O
O
OH
R2
R1
R2
Ref. 8
O
Ref. 7
X = Br, I
Ref. 6
Scheme 1. Synthetic approximations to different isocoumarin derivatives
The isocoumarin nucleus is of special interest because of its wide bioactive spectrum; some derivatives have
been screening as herbicidal, insecticidal and fungicidal,2b DNA-Dependent Protein Kinase inhibitors,6 anti
HIV-1,11 anti-allergic,12 anticoagulants,13 among others.
Some years ago, Opatz and Ferenc developed a strategy for the synthesis of new diaminoisocoumarin
derivatives (Scheme 2).14 This reaction is a combination between the Strecker and Ugi reactions, in fact the
diaminoisocoumarin derivatives which are obtained by a Strecker procedure are actually a stable intermediates
in the Ugi reaction3. Following this strategy, Marcaccini et al have obtained others diaminoisocoumarin
derivatives by using isocyanide derivatives instead of an inorganic cyanide.
Ar
O
HN
NH2
KCN / AcOH
MeOH / relux
OH
H
+
Ar NH2
O
O
O
1a-d
2
3a-d
Scheme 2. Synthesis of 3,4-diaminoisocoumarin derivatives 1a-d
Despite the reports found in the literature concerning to the instability of compounds 1 under different reaction
conditions3,15-16 they have attracted our attention since they could be used as starting substrate in the synthesis
of new heterocyclic compounds which in turn could be explored for their biological activity.
On the other hand, Ceric Ammonium Nitrate (CAN) has proved to be very useful in organic synthesis for over
45 years and it plays an important role as mediator in different chemical transformations in the field of
heterocyclic chemistry.17 Recently, it has been used in the synthesis or modification of: (a). Substituted
phenanthrenes and dihyroquinoline derivatives by a carbon-carbon bond formation,18a-c (b). Disubstituted-1,3,4-
oxadiazoles, 4,5-dihydrofuran and pterin derivatives by a carbon-oxygen bond formation,18d-f (c).
*Corresponding authors:
E-mail addresses: rrodrigueza@unal.edu.co (R.R); dvicentes@udca.edu.co (D.E.V).

Dihydropyrimidine-coumarin analogues by a carbon nitrogen bond formation,18g (d). 1,3-dicarbonyl
compounds by a carbon-sulfur bond formation18h and (e). Spiro indeno[1,2-b]quinolin] derivatives by a
combination of carbon-carbon and carbon-nitrogen bond formation,17i among others. The reasons for its wide
use is due to it has two special chemical characteristics, in the first place it can act as a Lewis acid catalyst and,
in the second place it can act as an oxidizing agent since it accepts an electron.
In this paper we present the use of CAN as key mediator in the synthesis of new 1,2-diaryl[2]benzopyrano[3,4-
d]imidazol-5(1H)-one derivatives under mild reaction conditions.
Results and Discussions
Our route to prepare compounds 6a-j starts with the synthesis of 3,4-diaminocoumarin derivatives 1a-d which
are obtained in good yield (Table 1) by the strategy developed by Opatz and Ferenc (Scheme 2)14. Then,
compounds 1a and 4a were used as a model to set up the reaction conditions. Therefore, they were reacted
together under diverse reaction conditions affording the results shown in Schem 3.
Table 1. Yields for the products 1a-d.
Compound Ar
Yield
86
81
1a
1b
1c
1d
C6H5
4-MeC6H4
4-BrC6H4
4-ClC6H4
84
80
O
O
Entry 1-6
X
N
N
Cl
6
Ph
O
H
Cl
O
NHPh
N
Conditions
O
Entry 1
+
5, 82 %
O
NH2
1a
NHPh
Cl
O
O
NH2
Entry 2
N
7, 88 %
O
Entry
Solvent
AcOHa
AcOEtb
THFb,c
Catalyst
AcOH
I2
PTSA
PTSA
Product(s)
5a
1
2
3
4
5
6
7
5a + 7
5a + 7
AcOEta,c
ClCH2CH2Clb
AcOEtb
BF3.OEt2 Complex Mixture
BF3.OEt2 Complex Mixture
a. 50 oC. b. Room temperature. c. Low yield for both compounds
Scheme 3. Different attemps to obtain compound 6a from 1a and 4a.
Initially, we used acetic acid (entry 1), which resulted in the formation of the Schiff base 5a in high yield (82
%); then, molecular iodine was used as catalyst in a non-protic solvent like ethyl acetate, and under these
conditions the ring opening-closure, like the Dimroth rearrangement took place to afford compound 7 also in
high yield (88 %). This result is in agreement with a previous report.15 In contrast, the use of p-toluensulfonic
acid as catalyst (entries 3 and 4) with different solvents and temperatures did not afford the desired compound
6a, instead a mixture consisting mainly of compounds 5a and 7 was obtained in low yields. Furthermore, the
use of a strong Lewis acid as boron trifluoride etherate (entries 5 and 6) afforded a more complex mixture even.
Beacuse of our one-step methodology of cyclocondensation did not work (Scheme 3) and taking into account
the instability of compound 1a (and its analogues 1b-d) under the explored reaction conditions (Scheme 3), we
decided to develop a two-step sequence, firstly isolating compound 5a, and afterwards inducing it to the
corresponding cyclization to yield compound 6a. Scheme 4 shows the different reaction conditions explored to
this end. So, when p-toluensulfonic acid was used (in ethyl acetate, entries 1 and 2) as a catalyst either at room
temperature or under reflux compound 5a demonstrated to be stable (in contrast to the starting compounds 1a-
d) but did not form the desired compound 6a. Then, we used Cu(AcO)2 as a Lewis catalyst but this strategy did
*Corresponding authors:
E-mail addresses: rrodrigueza@unal.edu.co (R.R); dvicentes@udca.edu.co (D.E.V).

not work either (entry 3). As a last resort CAN was used as a catalyst and tetrahydrofuran as solvent. To our
delight, the compound 5a was transformed into the new desired product 6a in good yield (entry 4). Then, we
tried several reaction conditions in order to optimize the cyclization step mediated by CAN, finding that the
best yields were obtained when equimolar quantities of CAN and imine 5a were used.19
Cl
NHPh
O
O
N
N
N
Cl
Conditions
O
6a, 65 %
Ph
5a
O
Entry
Solvent
AcOEta
AcOEtb
Catalyst
PTSA
PTSA
Product(s)
1
2
3
4
5a
5a
AcOEta,b
Cu(AcO)2 5a
CAN 6a
THFa
Scheme 4. Different attemps to obtain compound 6a from 5a. a. Room temperature, b. Heating at 70 oC.
Encouraged by these results, we synthesized 10 new imine derivatives 5a-j which were cyclized to derivatives
6a-j (Table 2) using the above optimized conditions (entry 1 in Scheme 3, and entry 4 in Scheme 4,
respectively) and so, to prove the scope of this procedure with different aryl substituents.
Table 2.
Two-step synthesis of 1,2-diaryl[2]benzo-pyrano[3,4-d]imidazoles 6a-j via imines 5a-j.
Ar1
AcOH
O
O
N
O
O
NH2
O
O
CAN / THF
N
N
Ar1CHO
Ar1
+
NH
Ar
NH
Ar
70 o
C
rt
Ar
1a-d
4a-d
5a-j
6a-j
Comp.
Ar
Ar1
5 (%)
82
85
6 (%)
65
42
a
b
c
d
e
f
C6H5
C6H5
C6H5
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-ClC6H4
4-ClC6H4
C6H5
4-NO2C6H4
4-ClC6H4
4-NO2C6H4
4-MeOC6H4
C6H5
4-ClC6H4
4-NO2C6H4
4-NO2C6H4
82
77
67
52
90
80
71
44
g
h
i
87
84
63
56
93
92
69
74
j
Three facts are noteworthy, firstly the mixture takes an intense orange color due to CAN and, with the progress
of the reaction, the color of the solution turns into a light yellow. Secondly, after isolation of compound 6, the
inorganic salt is white which implies a change in the oxidation state of the cerium atom from Ce+4 to Ce+3 (it is
well known that cerium (III) salts are white). Thirdly, the addition of two drops of water reduce the reaction
time, as judged by faster change of color of the reaction mixture. With these evidences, we postulate the
following plausible mechanism for the formation of compounds 6.
+4
Ce
Ce+3
Ce+3
N+ Ar1
O
O
O
O
Ar1
N
O
O
N
H
Ar1
N+
NH
Ar
NH
Ar
H
Ar
H
Ce+3
O
H
H
O
O
N
O
O
O
O
+3
(CeOH)
N
N
H
-
H
- H2
Ar1
Ar1
Ar1
N
N
N
Ar
Ar
Ar
Scheme 5. An approximation to a plausible mechanism for oxidative cyclization.
Conclusion
In summary, we have implemented a simple two-step methodology for obtaining a new series of 1,2-
diaryl[2]benzopyrano[3,4-d]imidazol-5(1H)-one derivatives 6a-j in acceptable to good yields through a carbon-
nitrogen bond-forming reaction by using CAN as key mediator. Which constitutes a simple way to form this
*Corresponding authors:
E-mail addresses: rrodrigueza@unal.edu.co (R.R); dvicentes@udca.edu.co (D.E.V).

interesting tricyclic system that fused isocoumarin and imidazole rings, what is of interest to develop new
bioactive derivatives. The role of the CAN is important since it acts as Lewis catalyst, as it was proposed in the
mechanism (Scheme 5).
Acknowledgments
R.R. thanks Universidad Nacional de Colombia for the financial support to this investigation. J.C. and M.N.
thank the Consejería de Innovación, Ciencia y Empresa (Junta de Andalucía), Universidad de Jaén for the
financial support and Centro de Instrumentación Científico-Técnico” of Universidad de Jaén. D.E.V thanks
Universidad de Ciencias Aplicadas y Ambientales for the financial support.
A. Supplementary material
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org
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*Corresponding authors:
E-mail addresses: rrodrigueza@unal.edu.co (R.R); dvicentes@udca.edu.co (D.E.V).

Graphical Abstract
O
O
N
Ar1
O
O
NH2
O
O
CAN / THF
N
N
AcOH
Ar1
Ar1CHO
+
70 oC
rt
NH
Ar
NH
Ar
Ar
up to 93 %
up to 74 %
6a-j
1a-d
4a-d
5a-j
*Corresponding authors:
E-mail addresses: rrodrigueza@unal.edu.co (R.R); dvicentes@udca.edu.co (D.E.V).

Highlights:
Simple starting compounds like aromatic aldehydes and amine are used
Mild reaction conditions for obtaining stable and new heterocyclic compounds
The use of ceric ammonium nitrate as key catalyst under water tolerable conditions giving
excellen results
Compounds of the biological interest are obtain in good yields.
*Corresponding authors:
E-mail addresses: rrodrigueza@unal.edu.co (R.R); dvicentes@udca.edu.co (D.E.V).