Copper (II) as catalyst for intramolecular cyclization and oxidation of (1,4-phenylene)bisguanidines to benzodiimidazole-diylidenes

Article abstract of DOI:10.1016/j.jcat.2019.12.002

A synthetically useful approach of catalytic intramolecular cyclization and oxidation of 2′,2′-(1,4-phenylene)bis(1,3-dialkyl)guanidines (Alkyl = isopropyl 1 or cyclohexyl 2) catalyzed by copper acetate in acetonitrile under air was studied by on line mon

Full text of DOI:10.1016/j.jcat.2019.12.002

Journal of Catalysis 382 (2020) 150–154
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Priority Communication
Copper (II) as catalyst for intramolecular cyclization and oxidation of
(1,4-phenylene)bisguanidines to benzodiimidazole-diylidenes
Angela Mesias-Salazar a,1, Oleksandra S. Trofymchuk b,1, Constantin G. Daniliuc c, Antonio Antiñolo d,
Fernando Carrillo-Hermosilla d, Fabiane M. Nachtigall e, Leonardo S. Santos f, René S. Rojas a,
⇑
a Laboratorio de Química Inorgánica, Facultad de Química, Pontificia Universidad Católica de Chile, Casilla 306, Santiago 22, Chile
b Núcleo Científico Multidisciplinario-DI, University of Talca, P.O. Box 747, Talca, Chile
c Chemisches Institut der Universität Münster, Corrensstrasse 40, 48149 Münster, Germany
d Centro de Innovación en Química Avanzada (ORFEO-CINQA), Departamento de Química Inorgánica, Orgánica y Bioquímica, Facultad de Ciencias y Tecnologías Químicas,
Universidad de Castilla-La Mancha, 13071 Ciudad Real, Spain
e Instituto de Ciencias Químicas Aplicadas – Universidad Autónoma, 3467987 Talca, Chile
f Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
a r t i c l e i n f o
a b s t r a c t
A synthetically useful approach of catalytic intramolecular cyclization and oxidation of 20,20-(1,4-pheny
lene)bis(1,3-dialkyl)guanidines (Alkyl = isopropyl 1 or cyclohexyl 2) catalyzed by copper acetate in ace-
tonitrile under air was studied by on line monitoring of the reaction by ESI-MS. All-important interme-
diates organic species were intercepted during the experiment confirming for the first time the stepwise
(1,4-phenylene)bisguanidines cyclization and oxidation mechanism. Moreover, performed collision-
induced dissociation (CID) experiments were also applied as a structure elucidation tool. Bimetallic cop-
per intermediates Cu1 ([C28H48Cu2N6O10 + H]+) of m/z 755 and Cu2 [C22H36Cu2N6O4 + H]+ of m/z 575 were
documented. The plausible key mechanistic steps involving the formation of organic and inorganic inter-
mediates detected by in situ monitoring of the reaction are presented.
Article history:
Received 9 October 2019
Revised 28 November 2019
Accepted 2 December 2019
Keywords:
Guanidines
Copper acetate
ESI-MS
Ó 2019 Elsevier Inc. All rights reserved.
Catalysis
Cyclization
1. Introduction
Furthermore, guanidino-functionalized aromatic compounds
are strong electron donors and the 1,4 isomers are particularly
Guanidines are considered a versatile class of organic molecules
that show a wide range of interesting applications, for instance, as
organic superbases [1–3] or as N-donor ligands in coordination
chemistry [4–6]. Molecules, containing the guanidine structural
motif are also important pharmacophores, [7] for example, Verube-
cestat, an inhibitor of b-secretase, has been evaluated for the treat-
ment of Alzheimer’s disease [8]. Among the various small organic
activators that were tested, cyclic guanidines display catalytic
activities [9]. Over the last years the preparation of cyclic guanidi-
nes was improved greatly via the use of thioureas or formami-
dinium salts as guanylating agents [10,11] (Scheme 1a).
Alternatively, intramolecular N-arylation of haloaryl guanidines
were accomplished by palladium or copper mediated syntheses
(Scheme 1b) [12], or by consecutive guanylation and cyclization
reactions of amines using copper (Scheme 1c) [13] or titanium cat-
alysts (Scheme 1d) [14].
redox-active ligands, [11e] they are of great interest for several
applications, which span from catalysis [15] to optical devices,
and also are of importance in bioinorganic chemistry [16].
2. Results and discussion
Despite the reported methodologies to build up to benzimida-
zole type structures via aromatic guanidine cyclizations, there is
still a lack of atom-economic routes to accomplish efficient
bisguanidine aromatic motifs. Exploring (1,4-phenylene)
bisguanidines cyclization in a more general context we aimed at
the consecutive cyclization and oxidation of 20,20-(1,4-phenylene)
bis(1,3-dialkyl)guanidine (Alkyl = isopropyl 1 or cyclohexyl 2)
yielding the novel class of N-heterocyclic bisguanidines N,N’-(1,
5-diisopropylbenzodiimidazole-2,6-diylidene)bis(propan-2-amine)
5 and N, N’-(1,5-dicyclohexyl-benzodiimidazole-2,6-diylidene)dicy
clo hexanamine 6 (Scheme 2).
Moreover, the reaction mechanism was intended to be studied
by electrospray-mass spectrometry technique known for its sensi-
tivity and softness [17,18]. Though, the identification of various
⇑
Corresponding author.
E-mail address: rrojasg@uc.cl (R.S. Rojas).
These authors contributed equally.
1
https://doi.org/10.1016/j.jcat.2019.12.002
0021-9517/Ó 2019 Elsevier Inc. All rights reserved.

A. Mesias-Salazar et al. / Journal of Catalysis 382 (2020) 150–154
151
Scheme 1. Selected methods for guanidine cyclization.
Scheme 2. Synthetic design to achieve benzodiimidazole-diylidene-diamines 5 and 6.
transition metal catalysts in condensed phase reactions is often
very challenging, the ESI-MS tool has been successfully applied in
many cases due to the requirement of very low analyte concentra-
tions, which is often difficult to achieve with other types of analyt-
ical experiments, therefore compromising the direct on line ESI-MS
monitoring of the reaction.
starting compounds at 3.72 ppm for 1 and at 3.58 ppm for 2
confirmed the reaction courses via the respective cyclization and
oxidation reactions.
Slow crystallization of 5 and 6 from petroleum ether gave
single crystals suitable for X-ray crystal structural analysis.
The ORTEP drawings are shown in Fig. 1a-b. The structures con-
firmed the presence of isopropyl groups in 5 possessing large
dihedral angles of 114.7° (for C1N1C11C13) and of 125.4° (for
C1N3C14C16) (see wire model for 5 on Fig. 1). The dihedral
angles between the benzodiimidazole-diylidene core and cyclo-
hexyl substituents in 6 are of 100.7° (for C1N1C11C16) and of
121.5° (for C1N3C21C22), respectively (see wire model for 6
on Fig. 1). The CAC and CAN bond lengths (1.318–1.479 Å for
5 and 1.313–1.484 Å for 6) of the benzodiimidazole-diylidene
core indicate insignificant bond length alternation and charge
delocalization within the core structure (see Table S1,
Table S2 and Fig. 1).
The reaction mechanism for the catalytic cyclization of 1 was
studied using electrospray ionization connecting the mass spec-
trometer directly to the catalytic reaction vessel. This setup
enabled screening of intermediate species that had formed during
the first five hours of the reaction course (see Scheme S1 in Sup-
porting Information, for the experiment setup description).
A first experiment was carried out using 1 and 20% of copper
acetate as the catalyst at 70 °C in acetonitrile by coupling to a
PEEK-T microreactor (see Scheme S1). As the reaction solution
was out of the concentration range allowed to accomplish ESI-
MS data, it was applied the dilution of the reaction solution with
acetonitrile before MS analysis. Dilution of the solution with ace-
tonitrile on-line using a microreactor [21] resulted in a clean spec-
trum displaying Cu-containing cationic species that were easily
identified by their isotopic pattern, and allowed the on line contin-
uous flow analysis of the reaction mixture (see Scheme S1) [22].
Very clean MS spectra resulted displaying the cationic Cu species
Cu1 and Cu2 identified by their isotopic patterns during the first
five hours of the reaction course. With the given experimental
setup we accomplished appropriate sample concentrations for
the ESI-MS (see SI) [21].
In this paper we would like to present an alternative monitoring
of the copper catalyzed consecutive 1,4-bisguanidino aromatic
cyclization and oxidation to benzodiimidazole-diylidene-diamines
using a microreactor coupled directly to the ESI source, which pro-
vided the option of immediate detection of the active transient
species.
The starting bisguanidines 20,20-(1,4-phenylene)bis(1,3-diisopro
pyl guanidine)
1
and 20,20-(1,4-phenylene)bis(1,3-dicyclohexyl
guanidine) 2 were prepared by coupling of p-phenylene diamine
with 2 equivalents of the respective carbodiimides in presence of
diethyl zinc as catalyst, which proceeded via nucleophilic addition
of a zinc intermediate to the carbodiimides. Subsequent amine
protonolysis of the resultant guanidinato species [19] led to 1
and 2 in 95% and 99% yield, respectively (see Supporting Informa-
tion, Page S4).
The 2-aminobenzimidazole could be prepared directly by a Cu
(OAc)2/O2 catalyzed reaction of the diarylcarbodiimides with ami-
nes through a cascade of CH activation and C–H addition function-
alization [20].
Therefrom, we decided to test Cu(OAc)2 as catalyst inducing the
1,4-bisguanidino aromatic compounds 1 and 2 to form the tricyclic
N2,N6,1,5-tetraalkyl-1,5-dihydrobenzo[1,2-d:4,5-d’]diimidazole-2,
6-diamine (Alkyl = isopropyl 3 or cyclohexyl 4) intermediates. The
reaction involved the second step oxidation with the same catalyst
producing novel conjugated N-heterocyclic benzodiimidazole-diy
lidene-diamine 5 and 6 as purple solids in 67% and 62% yields,
respectively (Scheme 2).
1H NMR characterization of 5 and 6 confirmed the proposed
structures with CH-iPr heptets at 5.99 and 5.01 ppm for 5 (com-
pared to 3.73 (CH-iPr) ppm for 1) and heptets at 4.85 and 4.63
for 6 (compared to 3.37 (CHcyclohexyl) ppm for 2). Moreover, the
disappearence of NH protons from the guanidine groups of the

152
A. Mesias-Salazar et al. / Journal of Catalysis 382 (2020) 150–154
Fig. 1. ORTEP drawings of 5 (a) and 6 (b) at 105 (a) and 100 (b) K. Displacement ellipsoids are drawn at the 50% probability level. Hydrogen atoms are omitted for clarity.
Thus, during the first couple of minutes of reaction time we
were able to observe only the starting material [1 + H]+ of m/z
361, see Fig. 2a. During the first hour of the reaction time we inter-
cepted the formation the species [1* + H]+ of m/z 359 (Fig. 2b),
which corresponds to the product of the cyclization of 1 at one
side. Next, 97 min since the reaction started the species [3 + H]+
of m/z 357 that corresponds to the second side cyclization product
was revealed. During the first five hours of an experiment no other
organic species were detected. The reaction was left overnight and
finally, after 12 h of the reaction time the formation of the species
[5 + H]+ of m/z 355 was observed (Fig. 3d) confirming the mecha-
nism of a stepwise cyclization and subsequent oxidation reaction.
The catalytic formation of one- and second-side cyclization
products 1* and 3 was confirmed through an experiment per-
formed in J. Young NMR tube under air after a reaction time of
24 h (for details see SI).
able up to 74 min of reaction time. The formation of the [copper]
intermediate Cu1 ([C28H48Cu2N6O10 + H]+ of m/z 755) became
detectable after 3 min (Fig. 3a-b). After 74 min of reaction time,
the copper species Cu2 ([C22H36Cu2N6O4 + H]+ of m/z 575) was
observed, which remained present during the next 5 h (see Fig. 3-
c-f). Moreover, after 250 min of reaction time, the purely organic
species 2L [C40H68N12 + 2H]+ of m/z 722 was formed corresponding
to the dimer of 1 (see Fig. 3f). The isotopic patterns of all ions
matched the calculated ones, in particular those containing the
[Cu] species. For the catalytic cyclization and oxidation reactions
of 1,4-aromatic bisguanidines we propose the reaction pathway
shown in Scheme 3. The catalytic reaction commences in presence
of 20% of copper acetate in acetonitrile transforming 1,4-aromatic
bisguanidine 1 (Scheme 3a) under air generating the bimetallic
copper intermediate Cu1 complex (Fig. 3a-b). An aromatic CAH
bond activation was promoted with H+ elimination that achieved
copper complex Cu2 (Scheme 3b) [21]. Cu2 is the main species that
remains throughout the reaction course of the ESI-MS analysis (see
Fig. 3c-f).
Regarding the [Cu] intermediates that were detected during the
reaction course (Fig. 3) the analysis confirmed the presence of cop-
per acetate catalyst Cu(OAc)2 ([C4H6CuO4 + H]+ of m/z 182) observ-
Fig. 2. In situ ESI-MS monitoring of the catalytic cyclization of 1. (a), (b), (c) and (d) represent 7, 58, 97 min and 12 h respectively after the reaction started.

A. Mesias-Salazar et al. / Journal of Catalysis 382 (2020) 150–154
153
Fig. 3. In situ ESI-MS monitoring of the catalytic cyclization of 1. (a), (b), (c), (d), (e) and (f) represent 3, 74, 108, 172 and 250 min respectively after the onset of the reaction.
(Scheme 3g), 3 is oxidized by copper (II) acetate probably by an
outer-sphere mechanism [22b] to form N2,N6,1,5-tetraisopropyl
benzo[1,2-d:4,5-d’]diimidazole-2,6(1H,5H)-diimine. Finally, all
the Cu(I) species formed throughout the reaction are reoxidized
by the oxygen present in the air atmosphere regenerating the Cu
(II) catalyst (Scheme 3h) [23].
3. Conclusions
In this paper, a convenient ESI-MS study was used as structure
elucidation tool to unravel the reaction intermediates in the con-
secutive catalytic cyclization and oxidation of 1,4 aromatic bis-
guanidines catalyzed by copper acetate. The catalytic cyclization
and oxidation of 20,20-(1,4-phenylene)bis(1,3-dialkyl)guanidines
(Alkyl = isopropyl 1 or cyclohexyl 2) was studied through direct
connection of the microreactor to the reaction media, allowing
the screening of different species that had been formed during
the first five hours of the reaction. This procedure allowed to follow
the stepwise reaction mechanism, and in addition allowed us to
intercept and characterize the key copper-containing intermediate
Cu2 [C22H36Cu2N6O4 + H]+ of m/z 575, which remains present until
the next 5 h of the reaction. A series of organic intermediates were
intercepted and characterized during the course of the reaction,
Scheme 3. Key steps in the proposed catalytic cyclization of bisguanidines. The
and their compositions were ascertained via the detection of the
proposed structures for [Cu1 + H],+ [Cu2 + H]+ are compatible with the obtained
next ions: [1 + H]+ of m/z 361, [1* + H]+ of m/z 359 and [3 + H]+
mass spectra, other possible structures cannot be ruled out.
of m/z 357 that were confirmed by ESI-MS/MS and NMR studies.
Based on the ESI-MS experiments, it was possible to rationalize
the key steps in the catalytic cyclization and oxidation of 1,4 aro-
matic bisguanidines. The proposed mechanism is unique among
the reported organometallic catalytic cyclizations of guanidines
presenting the cleavage of the CAH bond, through Cu2 complex.
In the following step, the Cu2, undergoes a reductive elimina-
tion leading to the formation of a new CAN bond with the release
of a Cu(I) species (Scheme 3c). In this step, a new Cu3 intermediate
is formed (Scheme 3c) probably by interaction with oxygen gener-
ating another new copper activated complex (not observed by ESI-
MS) which promote the second aromatic CAH bond activation with
H+ elimination by reductive elimination from Cu3 to N2,N6,1,5-tet
raisopropyl-1,5-dihydrobenzo[1,2-d:4,5-d’]diimidazole-2,6-diami-
ne 3 (Scheme 3f) with release of a Cu(I) species. In addition, the
direct formation of 1* is also possible (identified by NMR,
Scheme 3d) by hydrolysis of Cu2 complex. In the last step
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.

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support from the Ministerio de Economia
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