Polycyclic Indoline-Benzodiazepines through Electrophilic Additions of α-Imino Carbenes to Tr?ger Bases

Article abstract of DOI:10.1002/anie.201803756

Polycyclic indoline-benzodiazepines can be accessed through the intermolecular reaction of Tr?ger bases with N-sulfonyl-1,2,3-triazoles. Under Rh^II catalysis, α-imino carbenes are generated and a subsequent cascade of [1,2]-Stevens, Friedel–Cra

Full text of DOI:10.1002/anie.201803756

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Accepted Article
Title: Polycyclic Indoline-Benzodiazepines by Electrophilic Additions of
α-Imino Carbenes to Tröger Bases
Authors: Alessandro Bosmani, Alejandro Guarnieri-Ibáñez, Sébastien
Goudedranche, Céline Besnard, and Jerome Lacour
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Polycyclic Indoline-Benzodiazepines by Electrophilic Additions of
α-Imino Carbenes to Tröger Bases
Alessandro Bosmani,‡,[a] Alejandro Guarnieri-Ibáñez,‡,[a] Sébastien Goudedranche,[a] Céline Besnard,[b]
Jérôme Lacour*[a]
Abstract: Polycyclic indoline-benzodiazepines are afforded by the
intermolecular reaction of Tröger bases with -sulfonyl-1,2,3-
primary anilines with formaldehyde, react with α-keto carbenes to
afford ethano-TB, after aminal bridge expansion.[12] Drawing from
the direct analogy that exists between α-keto and α-imino
carbenes, the reactivity of 2 with intermediates A was tested.
Initial experiments were performed using Tröger base 2a (R3 =
Me) and N-tosyl-4-phenyltriazole 1A under dirhodium catalysis
(Rh2(oct)4, 1 mol%). While the reaction was mostly unproductive,
a product was isolated in low yield (8%).
N
triazoles. Under Rh(II)-catalysis, α-imino carbenes are generated and
a subsequent cascade of [1,2]-Stevens, Friedel-Crafts, Grob and
aminal formation reactions yield the polycyclic heterocycles as single
isomers (d.r.>49:1, four stereocenters incl. two bridgehead N-atoms).
Further ring-expansion by insertion of a second α-imino carbene leads
to elaborated polycyclic 9-membered ring triazonanes.
N
-Sulfonyl-1,2,3-triazoles 1 are structural motifs used regularly in
synthetic, biological and medicinal chemistry.[1] Significantly,
triazoles 1 are in equilibrium with α-diazo imines of type 1’ that
decompose under metal catalysis to afford α-imino carbenes A
(Scheme 1, top).[2] In recent years, many synthetically useful and
original processes have been developed using these electrophilic
intermediates, from migrations to ylide forming reactions and
subsequent transformations.[3],[4] In term of ammonium ylide
chemistry[5], few studies have been reported.[6] Of interest to the
current study, the synthesis of tetrasubstituted indolines by
reactions of o-vinylanilines is noteworthy.[7] Herein, in a new
development, the intermolecular reactivity of N-sulfonyl-1,2,3-
triazoles 1 with Tröger bases (TB) 2 is reported (Scheme 1,
bottom). Under Rh(II) catalysis (2 mol%),[8] densely functionalized
polycyclic heterocycles 3 are obtained (yields up to 85%).The
transformation involves, after the initial addition of carbenes A to
TB, a cascade of [1,2]-Stevens, Friedel-Crafts, Grob and aminal
formation reactions. Resulting chalice-like products
3 are
generated with high stereoselectivity (d.r.> 49:1, four
stereocenters incl. two bridgehead nitrogen atoms). When the
aminal nitrogen is protected by a nosyl group, insertion of a
second α-imino carbene is possible leading to nine-membered
triazonanes 4, albeit in moderate yields (29-34%). In view of their
unusual heterocyclic structures, products 3 and 4 should be of
interest in a variety of fields, and medical chemistry in particular.
In fact, these derivatives combine in a single framework both
indoline and benzodiazepine skeletons, which are privileged
motifs in natural product and medical chemistry (Figure 1).[9],[10]
Recently, it was shown that TB 2 (Scheme 1, bottom),[11] classical
diaza heterocycles prepared in one step by condensation of
Scheme 1. Generation of α-diazo carbenes and application to the synthesis of
elaborated polycyclic indoline-benzodiazepines.
Figure 1. Typical examples of indoline (left) and benzodiazepines (right)
[]
A. Bosmani, A. Guarnieri-Ibáñez, Dr. S. Goudedranche, Prof. J.
Lacour
Département de Chimie Organique, Université de Genève
quai Ernest Ansermet 30, 1211 Geneva 4 (Switzerland)
Fax: (+41) 22-379-3215
E-mail: jerome.lacour@unige.ch
Homepage: http://www.unige.ch/sciences/chiorg/lacour/
Dr. C. Besnard,
Laboratoire de Cristallographie, Université de Genève
quai Ernest Ansermet 24, 1211 Geneva 4 (Switzerland)
These authors contributed equally to this work.
1
This compound 3aA presented interesting characteristics in H
and 13C-NMR spectroscopy and an additional mass of 271 Da
compared to 2a (equivalent to one carbene moiety). The structure
of 3aA was determined with certainty after X-ray diffraction
analysis (Figure 2). It presents an interesting chalice-like
geometry with 5-, 6- and 7-membered rings forming a rigid bowl-
shape motif footed by substituent R1 (here Ph) that extends from
[‡]
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the center of the cup in an apical fashion. In Figure 2, both top
and lateral views of 3aA are represented; the geometry of
a treatment with thiophenol/K2CO3 to afford 5 in 74% yield
(Scheme 2).[17] Care was also taken to verify that the process can
occur under metal-free conditions. Using Davies’ N-sulfonyl-4-
phthalimido triazole 1P,[18] product 3aP was formed under thermal
activation only albeit in 31% yield. Finally, 3lA and 3mA were also
prepared; these compounds formed as single regioisomers are of
importance for the mechanistic discussion (vide infra).
compounds
3 being difficult to appreciate with a single
representation.[13] Overall, the interesting fusion of indoline and
benzodiazepine motifs is revealed.
a)
b)
Figure 2. Representations of indoline-benzodiazepine 3aA and stick views of
the crystal structure. [a] View from above the rim (top). [b] Lateral view. Part of
the tosyl group is removed for clarity in the stick models. The apical phenyl
group is indicated in red and replaced by a single ball in the top right
representation.
With this result and characterization in hand, optimization studies
were conducted to improve the synthesis of 3aA and the results
are reported in Table S1. Improved conditions use CHCl3 as
solvent and Rh2(Piv)4 (2 mol%) as catalyst. Complete
consumption of 2a is achieved after 48 h at 80 °C using a slight
excess of 1A (1.5 equiv, 0.25 M). Product 3aA is then formed in
70% yield as a single stereoisomer.[14] With these conditions,
disubstituted and naphthyl derivatives 3bA and 3cA were
obtained in 30% and 64% yields respectively. In the first case, the
lower yield might be due to the strain created by the methyl groups
at immediate proximity to the central bicyclic core.[15] Modulation
of the substituents at the para-position to the nitrogen atoms of
TB substrates led to products 3dA to 3kA in moderate to good
yields (45-75%). Clearly, reactions proceed more effectively with
electron donating substituents (3dA-3fA) than with electron-
withdrawing groups (3gA-3kA). A higher nucleophilic character of
the nitrogen atoms is beneficial for the first elemental step of the
mechanism (vide infra, Scheme 3, A → B).[16]
Scheme 2. Scope of the reaction. [a] Reaction performed at 100 °C. [b] PhSH,
The reaction was also performed with a series of N-sulfonyl
triazoles 1B to 1P and TB 2a as substrate. An inverse electronic
demand is now beneficial. In fact, with electron donating
substituents on the triazole precursors, products 3aB-3aD are
obtained in low to moderate yields (34-55%) while higher yields
(74-83%) are afforded in the presence of electron withdrawing
groups (3aF-3aH). This electronic preference was confirmed with
four other derivatives (3aI-3aL); thiophene and methyl ester
substituents promoting the reaction effectively while n-propyl and
6-methoxynaphthalene residues leading to lower yields.
In this study, the influence of the sulfonyl group substituent was
further investigated. Dimethylsulfamoyl, mesyl (Ms) and p-nosyl
(Ns) substituted triazoles were reacted and afforded products
3aM, 3aN and 3aO in 56%, 61% and 47% yields respectively.
With 3aO in hand, removal of the p-nosyl group was possible by
K2CO3, CH3CN/DMSO (49 : 1), 50 °C, 2 h. [c] Thermal activation only.
A rationale for the observed reactivity is outlined in Scheme 3. In
the presence of Rh(II) catalysts and Rh2(Piv)4 in particular, N-
sulfonyl triazoles 1 generate α-imino carbenes A by nitrogen
extrusion.[2] These electrophilic intermediates react with Tröger
bases 2 to form nitrogen ylides B. The quaternization of the
nitrogen atom leads to a ring opening of the aminal bridge and
form intermediates of type C. These species react
intramolecularly in an aza-Mannich reaction and cyclize to form
sulfonyl imines D. The overall process from 1 to D corresponds to
a formal [1,2]-Stevens rearrangement.[12a] Then, induced by the
spatial proximity between the electrophilic imine and the electron-
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rich aniline,
a
Friedel-Crafts cyclization occurs to form
suggests that, once formed, intermediates D react rapidly in the
Friedel-Crafts and subsequent reactions to form products 3.
intermediate E. In this rigid moiety, the alignment of the nitrogen
lone pair with the * orbital of the adjacent C-C bond (highlighted
in red) leads to a Grob fragmentation[19] and the formation of
intermediates F. A final intramolecular trapping of the new iminium
species by the nitrogen of the sulfonamide group leads to final
aminal formation and products 3.
Scheme 4. Top [a]: reversible ylide formation under metal-catalyzed conditions
and preferred formation of electronically-stabilized iminium CII. Bottom [b]:
formation of iminium intermediates CI and CII under (kinetic) metal free-
conditions. EDG = Electron Donating Group (OMe or Me), NPG = N-Phthalimido
Group
Scheme 3. Mechanistic rationale
In the above rationale, the ylide formation (A → B) is presented
as a reversible step. This was established by the regioselective
formation of 3lA and 3mA in which nitrogens para to the nitro
group of 2l and 2m – the more electron poor and less nucleophilic
N-atoms – have reacted with carbenes A.[20] This result, in
contradiction with the general reactivity (Scheme 2),[16] can be
however rationalized by a Curtin-Hammet analysis.[12a] It is
proposed that carbenes A react preferentially with the more
electron-rich nitrogen atoms (para to the MeO or Me groups, step
A → BI) but the subsequent aminal opening is disfavored as it
would lead to electronically unstable intermediates CI (Scheme 4,
top). Opportunely, upon ylide equilibration, reaction of A with the
less nucleophilic (disfavored) nitrogen occurs (→ BII). The
subsequent aminal opening forms intermediates CII and their
higher stability constitutes the kinetic and thermodynamic driving
force of the process. Importantly, in the reactions with 1P
performed under thermal activation,[18] TB 2l and 2m react to
afford 1:1 mixtures of regioisomers (see Scheme S1-S2). In these
metal-free processes, intermediates BIII and BIV are probably
formed in equimolar ratio and do not interconvert (Scheme 4,
bottom). The presence of the Rh(II) catalyst is thus essential to
ensure the reversibility of the ylide formation.
Finally, with p-nosyl-substituted derivative 3aO in hand, the
possibility to form benzodiazepine-indoline adducts containing, in
addition, a 9-membered 1,3,6-triazonane ring was recognized
(Scheme 5).[22] In fact, treatment of 3aO with an excess of 1A, 1B
or 1O (3 equiv) in CHCl3 (0.25 M) at 80 °C (48 h) and Rh2(Piv)4
as catalyst (2 mol%) afforded products 4A, 4B and 4O in
moderate yields (29-34%). The structure of compounds 4 was
unambiguously
determined
by
X-ray
crystallography.
Mechanistically, the most nucleophilic and less-hindered tertiary
nitrogen atom of 3O reacts with carbenes A (generated in situ) to
yield ylides G (Scheme 5, bottom). Then, aminal opening
(formation of iminium intermediates H) and intramolecular
nucleophilic closures lead to products 4.
In summary, polycyclic indoline-benzodiazepines
generated in a single step by the direct intermolecular reaction of
TB with -sulfonyl-1,2,3-triazoles. Initiated by the formation of α-
3
were
N
imino carbenes under Rh(II)-catalysis, cascades of [1,2]-Stevens,
Friedel-Crafts, Grob and aminal formation reactions are obtained
to yield the triaza polycycles as single isomers (d.r.>49:1, four
stereocenters incl. two bridgehead N-atoms). Mechanistic
insights were provided demonstrating, for instance, the
importance of metal-bound ylides to explain the regioselectivity of
Of importance for the mechanistic understanding, aldehyde
substituted ethano-TB 2’ was also prepared (see SI) and reacted
with tosyl amine in the presence of anthranilic acid (10 mol%).[21]
The corresponding iminium D could not be observed in 1H NMR
spectroscopy, but a slow and steady formation of polycyclic
product 3’ (32%) was evidenced (eq. 1). This experiment
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Scheme 5. Synthesis of benzodiazepine-indoline-triazonanes 4 and probable
intermediates G and H. [a] Part of the sulfonyl groups are removed for clarity;
the apical phenyl group is replaced by a red single ball.
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Synthetic procedures and spectral characterization of new
compounds are reported in the electronic supporting information.
CCDC 1832809 to 1832811, products 4O, 3aA and 3lA, contain
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgements
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In relation to compounds 3 and 4, vinblastine is an interesting example
as it contains not only the indoline skeleton but also a 9-membered ring
in the second fragment.
We thank the University of Geneva and the Swiss NSF for
financial support. We also acknowledge the contributions of the
Sciences Mass Spectrometry (SMS) platform at the Faculty of
Sciences, University of Geneva.
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Keywords: Benzodiazepine • Cascade Reactions • -Imino
Carbene • Indoline • Rhodium(II) Catalysis
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[12] The aminal opening is induced by the N-atom quaternization. See the
following references and discussion therein: a) A. Sharma, L. Guénée,
J.-V. Naubron, J. Lacour, Angew. Chem. Int. Ed. 2011, 50, 3677-3680;
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2012, 10, 966-969.
[13] In Scheme 3, a third stereochemical representation of compounds 3 is
provided.
[14] In TB and derivatives, the bridgehead nitrogen atoms are stereogenic
and configurationally stable under neutral conditions.
[15] With TB carrying substituents ortho to the nitrogen atoms, only traces of
the desired products were observed with very small conversion of
starting materials.
[16] With two p-nitro substituents, only traces of conversion are observed.
[17] T. Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-
6374.
[18] J. S. Alford, H. M. L. Davies, Org. Lett. 2012, 14, 6020-6023.
[19] C. A. Grob, W. Baumann, Helv. Chim. Acta 1955, 38, 594-610.
[20] Unsymmetrically substituted TB derivatives can be used as mechanistic
probes. See ref. 12a and A. Bosmani, S. A. Pujari, C. Besnard, L.
Guénée, A. I. Poblador-Bahamonde, J. Lacour, Chem. Eur. J. 2017, 23,
8678-8684.
[21] S. Morales, F. G. Guijarro, J. L. García Ruano, M. B. Cid, J. Am. Chem.
Soc. 2014, 136, 1082-1089.
[22] Compound 4O was first identified in the crude mixture of the reaction of
1O with 2a as a by-product.
[23] Y. Zhou, J. Li, X. Ji, W. Zhou, X. Zhang, W. Qian, H. Jiang, H. Liu, J. Org.
Chem. 2011, 76, 1239-1249.
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Entry for the Table of Contents
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A. Bosmani, A. Guarnieri-Ibáñez, S.
Goudedranche, C. Besnard, J. Lacour*
Page No. – Page No.
Polycyclic Indoline-Benzodiazepines
by Electrophilic Additions of α-Imino
Carbenes to Tröger Bases
Polycyclic indoline-benzodiazepines are afforded by the one-pot reaction of Tröger
bases with
N-sulfonyl-1,2,3-triazoles under Rh(II)-catalysis. After a cascade of
[1,2]-Stevens, Friedel-Crafts, Grob and aminal formation reactions, single isomers
are isolated (d.r.>49:1, four stereocenters incl. two N-atoms). Further ring-
expansion can be elaborated to lead to polycyclic 9-membered ring triazonanes.
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