Insertion of Isocyanides into N?Si Bonds: Multicomponent Reactions with Azines Leading to Potent Antiparasitic Compounds

Article abstract of DOI:10.1002/anie.201604109

Trimethylsilyl chloride is an efficient activating agent for azines in isocyanide-based reactions, which then proceed through a key insertion of the isocyanide into a N?Si bond. The reaction is initiated by N activation of the azine, followed by nucleophilic attack of an isocyanide in a Reissert-type process. Finally, a second equivalent of the same or a different isocyanide inserts into the N?Si bond leading to the final adduct. The use of distinct nucleophiles leads to a variety of α-substituted dihydroazines after a selective cascade process. Based on computational studies, a mechanistic hypothesis for the course of these reactions was proposed. The resulting products exhibit significant activity against Trypanosoma brucei and T. cruzi, featuring favorable drug-like properties and safety profiles.

Full text of DOI:10.1002/anie.201604109

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201604109
German Edition: DOI: 10.1002/ange.201604109
Multicomponent Reactions
Hot Paper
À
Insertion of Isocyanides into N Si Bonds: Multicomponent Reactions
with Azines Leading to Potent Antiparasitic Compounds
Kranti G. Kishore+, Ouldouz Ghashghaei+, Carolina Estarellas+, M. Mar Mestre,
Cristina Monturiol, Nicola Kielland, John M. Kelly, Amanda Fortes Francisco,
Shiromani Jayawardhana, Diego MuÇoz-Torrero, Belꢀn Pꢀrez, F. Javier Luque, Rocꢁo Gꢂmez-
MontaÇo,* and Rodolfo Lavilla*
Abstract: Trimethylsilyl chloride is an efficient activating agent
for azines in isocyanide-based reactions, which then proceed
reagents and isocyanides gives the MCR adduct 2, following
the typical mechanism of N activation and isocyanide attack
at the a-position (Scheme 1A).[5] However, interaction with
trifluoroacetic anhydride (TFAA), a stronger electrophilic
agent, gives rise to mesoionic acid fluorides 3 (Scheme 1B).[6]
Interestingly, strong Brønsted acid activation (TfOH,
p-TsOH) of the isoquinoline enables an ABB’ reaction[7]
with isocyanides (Scheme 1C), leading to isoquinoline-fused
imidazolium salts.[8] The latter reactions were productive, but
mechanistic and selectivity issues have remained unsolved.
Furthermore, the harsh reactions conditions required for
these MCRs prevent the use of sensitive substrates.
À
through a key insertion of the isocyanide into a N Si bond. The
reaction is initiated by N activation of the azine, followed by
nucleophilic attack of an isocyanide in a Reissert-type process.
Finally, a second equivalent of the same or a different
À
isocyanide inserts into the N Si bond leading to the final
adduct. The use of distinct nucleophiles leads to a variety of
a-substituted dihydroazines after a selective cascade process.
Based on computational studies, a mechanistic hypothesis for
the course of these reactions was proposed. The resulting
products exhibit significant activity against Trypanosoma bru-
cei and T. cruzi, featuring favorable drug-like properties and
safety profiles.
In this context, we investigated the use of trimethylsilyl
chloride (TMSCl) as a new activating agent in these trans-
I
socyanides hold a central role in several fields of chemis-
try.[1] Their formally divalent character makes them ideal
partners for multicomponent reactions (MCRs).[2] However,
their mild nucleophilicity, together with their affinity to
metals, complicates their activation for many MCRs, which
hence often require harsh reaction conditions. Transition-
metal-catalyzed processes that involve isocyanides are syn-
thetically useful,[3] but complex, which is in part due to the
metal coordination. In this context, the development of new
facilitated MCR transformations is actively pursued, partic-
ularly those involving heterocycles, owing to their relevance
in biological and medicinal chemistry.
As a testing ground for developing new activation modes,
we selected isocyanide variants of the Reissert MCR.[4] The
interaction of isoquinoline with chloroformates or similar
Scheme 1. Reissert-type isocyanide multicomponent reactions.
p-TsOH=para-toluenesulfonic acid, Tf=trifluoromethanesulfonyl,
TFAA=trifluoroacetic anhydride, TMS=trimethylsilyl.
[*] K. G. Kishore,[+] Prof. R. Gꢀmez-MontaÇo
Departamento de Quꢁmica
Prof. J. M. Kelly, Dr. A. F. Francisco, S. Jayawardhana
Department of Pathogen Molecular Biology
London School of Hygiene and Tropical Medicine
Keppel Street, London WC1E 7HT (UK)
Universidad de Guanajuato
Noria Alta S/N, CP 36050 Guanajuato, Gto. (Mexico)
E-mail: rociogm@ugto.mx
O. Ghashghaei,[+] M. M. Mestre, C. Monturiol, Dr. N. Kielland,
Prof. R. Lavilla
Laboratory of Organic Chemistry, Faculty of Pharmacy
University of Barcelona and Barcelona Science Park
Baldiri Reixac 10-12, 08028 Barcelona (Spain)
E-mail: rlavilla@pcb.ub.es
Prof. D. MuÇoz-Torrero
Laboratori de Quꢁmica Farmacꢃutica, Facultat de Farmꢄcia, and
Institut de Biomedicina (IBUB), Universitat de Barcelona
Av. Joan XXIII, 27-31, 08028 Barcelona (Spain)
Prof. B. Pꢅrez
Departament de Farmacologia, de Terapꢃutica i de Toxicologia
Institut de Neurociꢃncies, Universitat Autꢆnoma de Barcelona
08193 Bellaterra, Barcelona (Spain)
Dr. C. Estarellas,[+] Prof. F. J. Luque
[+] These authors contributed equally to this work.
Departament de Nutriciꢂ, Ciꢃncia dels Aliments i Gastronomia
Facultat de Farmꢄcia, and IBUB, Universitat de Barcelona
Prat de la Riba 171, 08921, Santa Coloma de Gramenet (Spain)
Supporting information and the ORCID identification numbers for
the authors of this article can be found under http://dx.doi.org/10.
1002/anie.201604109.
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Figure 1. Reaction scope: azines and isocyanides. c-hex=cyclohexyl, PMP=para-methoxyphenyl.
formations, looking for milder conditions, wider synthetic
scope, and selective processes. Incidentally, TMSCl and
related derivatives have been used in MCRs almost exclu-
sively to activate carbonyl compounds,[9a,b] although Krasavin
and co-workers reported an elegant example with imines.[9c]
The interaction of isoquinoline and cyclohexyl isocyanide
with one equivalent of TMSCl in acetonitrile readily gen-
erated imidazolium salt 4a (65%; Scheme 1C, Figure 1),
which precipitated as the chloride salt, presumably after
spontaneous hydrolysis of the initial TMS adduct. Owing to
the relevance of this new activation mode, we further studied
this process.
To determine the scope of the reaction, we screened
a wide array of isocyanides and azines. Isoquinoline reacted
with aliphatic isocyanides (cyclohexyl, tert-butyl, and benzyl
isocyanides) to generate the expected adducts (4a–4c) in
good yields (Figure 1). Functionalized isocyanides (ethyl
isocyanoacetate and diethyl isocyanomethylphosphonate
(PhosMIC)) are compatible with the reaction conditions,
and the corresponding imidazolium salts (4d, 4e) were
obtained in slightly lower yields. Aromatic isocyanides, such
as 2,6-dimethylphenyl-, 2-naphthyl-, and 4-methoxyphenyli-
socyanide, also yielded the expected compounds (4 f–4h). We
then examined the azine component. Bromo-, carboxy-, and
hydroxy-substituted isoquinolines reacted to yield the salts
4i–4k and 4n. These adducts can be derivatized in conven-
tional post-transformation reactions. The acid 4i was thus
converted into ester 4l and amide 4m using standard
procedures. However, the halogenated salts 4j and 4k do
not react with boronic acids in standard Suzuki couplings,
probably because their imidazolium moieties form stable
NHC–Pd complexes.[10] Experimental support came from the
characterization of the Pd complex of 4s and the observation
of its low catalytic activity in Suzuki couplings (see the
Supporting Information).
excess of the same isocyanide to render the double imidazo-
lium salt 4u. 4-Methoxyphenylisocyanide, however, yielded
monoadduct 4t. Interestingly, the reaction with 2,2’-bipyri-
dine afforded the guanidinium salt 4v in high yield,
which is likely generated in a formal [4+1] cycloaddition
(Figure 1).[11,12]
Finally, we explored the possibility of introducing two
distinct isocyanide residues. When a mixture of two isocya-
nides of similar nucleophilicity[13] (cyclohexyl and para-
methoxyphenyl) was reacted with isoquinoline and TMSCl,
a roughly equimolecular mixture of the four possible products
was obtained (see the Supporting Information). However, the
use of one equivalent of an aliphatic isocyanide with another
one of reduced nucleophilicity (isocyanoacetate, toluenesul-
fonylmethyl isocyanide (TosMIC), or PhosMIC) dramatically
changed the outcome, and we observed the formation of
a single adduct in good yields. In this way, the isoquinoline-
imidazolium salts 4w–4z were obtained without detectable
amounts of the homoadducts. The residues arising from the
more nucleophilic species were attached to the azine
a-position, whereas the less nucleophilic ones ended up
linked to the heterocyclic nitrogen atom. Unequivocal
structural assignment was achieved by X-ray diffraction of
a monocrystal of salt 4x (Figure 1). These results represent
a breakthrough in the programmed synthesis of ABB’
adducts, which had thus far been restricted to the use of two
equivalents of the same input or required the separation of
complex mixtures. Furthermore, the connectivity pattern
outlined above was tested in other reactant combinations.
When different nucleophiles (indole, dimedone) and one
equivalent of an isocyanide were reacted with isoquinoline in
TMSCl-promoted reactions,[14] the adducts 5a–5e (Figure 2)
were conveniently obtained in high yields.
Control experiments with a proton scavenger support the
participation of TMSCl as the activating agent (see the
Furthermore, aryl-substituted isoquinolines reacted to
generate the corresponding derivatives 4o and 4p. Remark-
ably, 4,4’-biisoquinoline underwent a double reaction to
generate salt 4q in a single step. Other azines were also
tested, and whereas pyridine was unreactive even under
forcing conditions, quinoline generated the corresponding
adduct 4r in good yields. Interestingly, phthalazine reacted
with two equivalents of cyclohexyl isocyanide to selectively
yield the salt 4s, with no trace of the double reaction product
being detected. Conversely, quinoxaline reacted with an
Figure 2. Interception of the MCR cascade with different nucleophilic
species.
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the likelihood of the insertion step was supported by the
generation of amidines 6a–6c through reaction of isocyanides
with N-silyl amines, albeit at higher temperatures (toluene,
1108C; Scheme 2B).[19] In agreement with the proposed
mechanism, deactivated or sterically hindered N-silyl deriv-
atives failed to undergo the insertion reaction (see the
Supporting Information). The course of the reaction was
followed by NMR spectroscopy; the silylated intermediates
À
were detected and evolved in situ into the C H amidines by
spontaneous hydrolysis with adventitious water. Although
GC/MS analysis of the crude reaction mixtures confirmed the
presence of silylated species and D2O quenching gave
amidine 6b with partial isotopic labeling (see the Supporting
Information), it was impossible to characterize the inter-
mediates or trap them with distinct electrophiles.
Pivotal to this chemistry is the novel isocyanide insertion
step, as contrary to the standard nucleophilic behavior
commonly exhibited by isocyanides, the isocyanide seems to
act as an electrophile in spite of the absence of metal cations
or strong bases. To gain insight into the insertion process
leading to amidines 6, quantum-mechanical calculations were
performed (see the Supporting Information). For the sake of
simplicity, computations were performed with methyl isocy-
anide and trimethylsilyl dimethylamine (DMA-TMS) as the
reagents. The reactive channel starts with the attack of the
DMA-TMS amine nitrogen atom at the isocyanide in
a process that involves the progressive loss of the sp hybrid-
ization of this latter reagent and the increased pyramidaliza-
tion of the amine nitrogen atom (Figure 3). These structural
changes are the major contribution to the reaction barrier.
Furthermore, they afford the geometrical arrangement
needed for the formation of the transition state (TS), where
the isocyanide C atom is located 1.54 ꢀ away from the amine
Scheme 2. Mechanistic proposal and control experiments. Ar=
4-MeOC6H4.
Supporting Information). We propose a novel mechanism
that accounts for the experimental outcome (Scheme 2A).
The reaction starts with the activation of the azine by TMSCl
to generate in situ N-silyl azinium ion A,[15] which is sub-
sequently attacked by an isocyanide (or another nucleophilic
species) to yield nitrilium cation B, likely stabilized by
a chloride counterion. A second (less nucleophilic) isocyanide
À
may insert into the N Si bond of this intermediate to yield
silylated amidine C, giving
rise to the fused imidazo-
lium salt 4 by intramolecu-
lar N addition to the nitri-
lium moiety and spontane-
ous hydrolysis of the result-
ing adduct. Although the
azine activation by electro-
philes and the isocyanide
attack upon formation of
the resulting intermediate
are known,[4] the N Si
isocyanide
À
insertion[16,17]
is unprecedented.[18] All
attempts to isolate the
silyl-substituted
imidazo-
lium salts under anhydrous
conditions were unsuccess-
ful, likely owing to the insta-
bility of the putative struc-
ture. Similarly, experiments
performed to trap this sily-
lated intermediate with
a variety of electrophiles
were unproductive, always
À =
Figure 3. Reactive pathway along the intrinsic reaction coordinate (IRC) for the insertion of Me N C into
DMA-TMS. Conversion of the pre-reactant (Pre-R) into the transition state (TS) occurs through a metastable
intermediate (I1) orienting the isocyanide C atom towards the Si atom, enabling the insertion between the
amine N and Si atoms in the final product (P). Inset: Changes in the distances between the isocyanide
leading to salts 4. However, C atom and DMA-TMS (Si and N) around the TS (IRC=0).
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N atom, while it faces the Si atom (distance of 2.10 ꢀ;
Figure 3). Attack of the isocyanide C atom on the Si atom
and a computational justification for this novel process. We
have applied this activation mode to Reissert-type isocyanide
MCRs, which can now be conducted with improved selectivity
and benefit from an expanded scope. Some products dis-
played potent and selective in vitro activity against the
causative agents of the African sleeping sickness and
Chagas disease, paving the way for more detailed structure–
activity relationship studies towards the development of
convenient lead compounds.
À
then leads to insertion into the Namine Si bond, which is
À
enlarged to 2.84 ꢀ in the final product, whereas the C Namine
À
and C Si bond lengths are 1.41 and 1.94 ꢀ, respectively. The
product is energetically favored by approximately 3.7 kcal
molÀ1 with regard to the pre-reactant complex (see the
Supporting Information, Table S1). These calculations sup-
port the mechanistic proposal, which involves the nucleo-
philic addition of the amine lone pair on the isocyanide and
a transition state with a unique azasilaiminocyclopropane
connectivity.
Acknowledgements
Recently, Wipf, Robello, and co-workers reported the
activity of imidazolium salts against Trypanosoma cruzi.[20]
Inspired by their results, and considering the need for
effective medicines for neglected tropical diseases,[21] we
tested the bioactivity of the synthesized compounds against
the causative agents of two trypanosomiases, namely T. brucei
for African trypanosomiasis and T. cruzi for Chagas disease,
which infect several million people. The search for simple,
efficient hits is appealing,[22] particularly if they can simulta-
neously treat more than one parasitic infection. We evaluated
the in vitro trypanocidal activity of adducts 4 against blood-
stream forms of T. brucei and the epimastigote form of
T. cruzi. The results revealed an interesting spectrum of
activities across the whole series, with many compounds
having low micromolar (or even submicromolar) EC50 and
EC90 values (Figure 4; see also the Supporting Information)
We acknowledge support from DGICYT–Spain (CTQ-2015-
67870P, SAF2014-57094R), the Generalitat de Catalunya
(2014 SGR52, 137, 1189), and CONACyT–Mꢁxico (CB-2011–
166747-Q). K.G.K. thanks CONACYT for Ph.D. graduate
scholarships (481808/285150). F.J.L. is grateful to Icrea
Academia for financial support. The Consorci de Serveis
Universitaris de Catalunya (CSUC) is acknowledged for
providing computational facilities. J.M.K. acknowledges sup-
port from the Drugs for Neglected Diseases Initiative
(DNDi).
Keywords: azines · isocyanides · multicomponent reactions ·
silicon · trypanosomiasis
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Figure 4. Bioactivity data of selected compounds. SI=Selectivity
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In summary, we have described the insertion of isocya-
À
nides into N Si bonds, providing a mechanistic hypothesis
4
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À
À
[11] Remarkably, this compound was also synthesized by Berthet and
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À
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Received: May 3, 2016
Published online: && &&, &&&&
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Communications
Multicomponent Reactions
K. G. Kishore, O. Ghashghaei,
C. Estarellas, M. M. Mestre, C. Monturiol,
N. Kielland, J. M. Kelly, A. F. Francisco,
S. Jayawardhana, D. MuÇoz-Torrero,
B. Pꢁrez, F. J. Luque,
R. Gꢂmez-MontaÇo,*
R. Lavilla*
Insert here! Multicomponent reactions
(MCRs) with isoquinolines and other
azines that proceed through the insertion
reaction conditions. Some of the prod-
ucts showed in vitro activity against the
causative agents of trypanosomiasis.
TMS=trimethylsilyl.
&&&& — &&&&
À
À
Insertion of Isocyanides into N Si
Bonds: Multicomponent Reactions with
Azines Leading to Potent Antiparasitic
Compounds
of an isocyanide into a N Si bond are
described. This novel activation mode
enables a variety of transformations to
take place with high selectivity under mild
6
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