Csp2-Csp2 and Csp2-N Bond Formation in a One-Pot Reaction between N-Tosylhydrazones and Bromonitrobenzenes: An Unexpected Cyclization to Substituted Indole Derivatives

Article abstract of DOI:10.1021/acs.orglett.7b03422

A novel, sequential, palladium-catalyzed, cross-coupling reaction using N-tosylhydrazone and bromonitrobenzene derivatives followed by reductive cyclization has been developed. This transformation providing an efficient route to unexpected N-arylindole derivatives involves, in a one-pot reaction, the formation of one Csp²-Csp² bond and two Csp²-N bonds together with the cleavage of one Csp²-heteroatom bond. Evaluation of the biological activity led to the identification of compound 5a, which displays potent activity at nanomolar concentrations against human colon carcinoma cell line.

Full text of DOI:10.1021/acs.orglett.7b03422

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Csp2−Csp2 and Csp2−N Bond Formation in a One-Pot Reaction
between N‑Tosylhydrazones and Bromonitrobenzenes: An
Unexpected Cyclization to Substituted Indole Derivatives
Tourin Bzeih,†,‡ Diana Lamaa,† Gilles Frison,§ Ali Hachem,‡ Nada Jaber,‡ Jerome Bignon,∥
Pascal Retailleau,∥ Mouad Alami,† and Abdallah Hamze*,†
†BioCIS, Univ. Paris-Sud, CNRS, Universite
́
Paris-Saclay, 92290 Chatenay-Malabry, France
‡Laboratory for Medicinal Chemistry,Faculty of Sciences (1) and PRASE-EDST, Lebanese University, Beirut, Lebanon
§LCM, CNRS, Ecole Polytechnique, Universite
́
Paris-Saclay, 91128 Palaiseau, France
∥Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, 91198 Gif-sur-Yvette, France
S
* Supporting Information
ABSTRACT: A novel, sequential, palladium-catalyzed, cross-
coupling reaction using N-tosylhydrazone and bromonitro-
benzene derivatives followed by reductive cyclization has been
developed. This transformation providing an efficient route to
unexpected N-arylindole derivatives involves, in a one-pot
reaction, the formation of one Csp2−Csp2 bond and two
Csp2−N bonds together with the cleavage of one Csp2−
heteroatom bond. Evaluation of the biological activity led to
the identification of compound 5a, which displays potent
activity at nanomolar concentrations against human colon
carcinoma cell line.
-Tosylhydrazones have captured great interest among
scientists in the past decade as versatile coupling partners
N
in both transition-metal-catalyzed and metal-free cross-coupling
reactions for the construction of carbon−carbon and carbon−
heteroatom bonds.1 Therefore, N-tosylhydrazones are used as
versatile synthons in the synthesis of a wide range of heterocyclic
compounds. Our involvement in the chemistry of 1,1-diaryl-
ethylene derivatives, combined with our endeavor to develop
novel isocombretastatin A-4 analogues2 as interesting antitumor
compounds, led us to explore a series of Pd- or Cu-catalyzed
cross-coupling reactions of N-tosylhydrazones with various
partners to generate a library of potentially active compounds.3
On the other hand, nitrogen heterocycles are common fragments
of a large number of FDA-approved drugs and in medicinal
chemistry.4 Some of them are routinely used as potential
bioisosteres for a variety of functional groups in drug
optimization processes.5 Recently, we developed a one-pot
two-step reaction of N-tosylhydrazones and ortho-nitrobenzenes
for the synthesis of variously substituted 3-arylindole and 2,3-
diarylindole derivatives (Figure 1, eq 1).6 The process involves
the formation of an olefin intermediate A, obtained through
palladium-catalyzed carbene coupling reaction followed by
reductive cyclization pursuing a Cadogan mechanism in the
presence of PPh3. This method was also successfully applied to
the synthesis of (1-arylvinyl)carbazoles by reaction between
hydrazones and bromonitrobiphenyl substrates. Due to the
generality of the method, we aimed to apply it to synthesize new
building blocks while showing their efficacy in the context of our
Figure 1. Palladium-catalyzed one-pot reaction of N-tosylhydrazones
and 2-nitrobromoarenes.
medicinal chemistry program. Consequently, we attempted at
first to prepare new isoCA-4 analogues bearing eight-membered
ring heterocycles by coupling the N-tosylhydrazone 1 with the
corresponding electrophilic coupling partners 2, then mediating
the reductive cyclization in the presence of PPh3 (Figure 1, eq 2).
Initially, N-tosylhydrazone 1a, derived from (3,4,5-
trimethoxy)acetophenone, was treated with 1-bromo-2-(2-
nitrophenoxy)benzene 2a in the presence of Pd2(dba)3·
Received: November 2, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03422
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Letter
CHCl3/XPhos as the catalytic system and LiOtBu as the base in
dioxane (Figure 2). When the first coupling reaction is
Scheme 1. Pd-Catalyzed One-Pot Synthesis of N-
Phenylindolylphenols
Figure 2. Unexpected formation of N-arylindole from N-tosylhydrazone
and bromo(nitrophenoxy)benzene.
completed (monitoring by HPLC), the reductive cyclization
was realized in a one-pot sequence by the addition of PPh3
(Figure 2). Under these conditions, the eight-membered ring
heterocycle was not detected at all. We have discovered that the
reaction gives rise to an unexpected cyclization product 4a,
resulting from a sequence involving one Csp2−Csp2 and two
Csp2−N bond formations, together with a Csp2−O bond
cleavage. This new cyclization process appears to involve a
mechanistically fascinating nitrene rearrangement and rear-
omatization. The structure of this new N-arylindole 4a was
confirmed by NMR and X-ray analysis. These results were also
very promising and interesting as the indole moiety is one of the
most prevalent heterocycles in nature,7 and one-pot strategies for
the synthesis of indole derivatives have been a unique field of
study.8 In particular, N-arylindoles are displayed in a various
number of biologically and pharmaceutically significant com-
pounds.9 Hence, incorporating these N-arylindoles within the
structure of isoCA-4 can result in a novel series of interesting
compounds.
We then studied the scope of the reaction with respect to the
N-tosylhydrazones 1 and 2-bromo-2′-nitrodiphenyl ethers 2 or
2-bromo-N-(2-nitrophenyl)anilines 3 partners (Scheme 1). It
should be noted that compounds 2 and 3 were easily synthesized
by an aromatic nucleophilic substitution between ortho-nitro-
haloarenes and 2-bromophenol with the ability of diverse
substitution on both aryl units (see Supporting Information
(SI)). The reaction appears to be insensitive to electronic
properties of the N-tosylhydrazone partners: both electron-rich
(e.g., 4a and 4h) and electron-deficient (e.g., 4b and 4f) undergo
effective coupling in similarly good yields. Functional groups
such as nitrile (4b, 4k) and fluorine (4f, 4p) are conserved in the
reactions. Hydrazones bearing heterocycles are also competent
coupling partners (cf. 4d, 4m, 4o, 4s). Next, we explored
modifications on the electrophilic partners 2 and 3. The coupling
of building blocks containing different substituents (R2, R3, and
R4) using the novel reaction developed in this study yielded
products having skeletal complexity and diversity (cf. 4j−v).
Again, 2-bromo-2′-nitrodiphenyl ethers 2 having electron-
withdrawing or electron-donating groups on both aromatic rings
B and C were also tolerated. Structures of 4b and 4s were
characterized by X-ray analyses. Encouraged by the results above,
we envisioned widening the generality of this method to
substrates 3 having a nitrogen atom as the linker between rings
B and C. As expected, coupling with different N-tosylhydrazones
afforded the desired indole derivatives 5 in good yields
(compounds 5a−k, Scheme 2). To further explore the flexibility
of this cascade reaction, we attempted to react heterocyclic
electrophilic partners with N-tosylhydrazones. The coupling of
3-bromo-N-(3-nitrophenyl)pyridin-2-amine with the corre-
sponding N-tosylhydrazones was very applicable, giving rise to
Scheme 2. Pd-Catalyzed One-Pot Synthesis of N-
Phenylindolylanilines
B
DOI: 10.1021/acs.orglett.7b03422
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Organic Letters
Letter
new azaindole derivatives (compounds 5j−k). X-ray analysis of
5k showed that the same mechanism is followed while changing
the linker (O to NH).
Scheme 5. Proposed Mechanism
To get a comparative study between this method and currently
available process, we synthesized compound 4g starting from
commercially available 3-iodophenol and indole (Scheme 3A).
Scheme 3. Comparative Study for the Synthesis of 3-
Arylindole 4g
highly strained aziridine ring opens to give o-iminoquinone 8,
which upon subsequent 6π-electrocyclization delivers the 1,3-
diarylindole 4.
To gain better insight into the reaction mechanism, and to
obtain the preference for 4 and 5 over the expected products, we
have carried out a computational study at the DFT level (Scheme
6; see the SI for computational details). The nitrene species B (6a
Scheme 6. DFT Computation of the Mechanism
First, 3-phenyl-1H-indole was obtained in a 40% yield after a
metal-free C3-arylation of the indole.10 Then, a copper-catalyzed
coupling with the protected phenol was conducted, leading to
the arylindole in a 58% yield.11 The latter underwent a
deprotection step to afford 4g in an 86% yield. According to
this three-step strategy, 4g was obtained in a 20% overall yield.
On the other hand, using our method (Scheme 3B),
hydrazone 1 was obtained in a nearly quantitative yield (98%)
starting from acetophenone. Then, coupling was realized using
our standard conditions, thus leading to 4g in a 70% overall yield.
This clearly shows the advantage of this new method in terms of
the number of steps and the overall yield.
Finally, to obtain more molecular diversity on our scaffold, we
studied the oxidative C2 olefination of indoles via Pd-catalyzed
C−H bond activation. The reaction of 4c with ethyl acrylate in
the presence of the Pd(OAc)2/Cu(OAc)2 catalyst system12
(Scheme 4) proceeded efficiently even in the presence of the
hindered 3,5-dimethoxyphenyl group at C3-position, affording
the desired compound 4ca in a 63% yield.
in its triplet state, 6b in its singlet state) adds to CC double or
aromatic bonds to form 7 and 10, which include the aziridine
moiety, with the former being more easily formed. A rearrange-
ment from 7 followed by an electrocyclization and a proton
transfer leads easily to 4, whereas ring opening from 10 leading to
12 after proton transfer is energetically more difficult.
Furthermore, 4 is significantly more stable than 12, indicating
that 4 is both the kinetic and thermodynamic product, in
agreement with experiments.
Schematic potential energy surface for the cyclization reactions
leading to the expected (12) and observed (4) compounds from
the nitrene species obtained at the IEFPCM(1,4-dioxane)-
B3LYP-GD3BJ/6-311++G(2d,2p)//IEFPCM(1,4-dioxane)-
B3LYP/6-311G(d,p) level.
Scheme 4. Pd-Catalyzed C−H Olefination of Indoles
After the success of synthesizing these new compounds, their
potency was measured in cell viability studies using HCT-116
human colon cancer cells. A fluorimetry-based assay was used for
the determination of the drug concentration required to inhibit
cell growth by 50% after incubation in the culture medium for 72
h. IsoCA-4 was included as a positive control to validate the
quality of the experimental results.
The results are shown in Table 1. None of these 2-(3-aryl-1-
indol-1-yl)phenol analogues (4a,b, 4j, and 4k) exhibited
significant antiproliferative activity against HCT-116 cells.
However, indoles having aniline instead of phenol showed
interesting antiproliferative activity. The best activities were
obtained with compounds having the trimethoxyphenyl group
(cf. 5a and 5g vs 5k). The assay showed that compound 5a (IC50
To clarify the cascade reaction mechanism, the coupling
intermediate A (Scheme 5) was first isolated and identified, and
then the cyclization was conducted in a separate step to confirm
that it was mediated with the aid of PPh3 without the
incorporation of any reagent or the catalyst from the coupling
step. The mechanism was suggested as it first proceeded by
deoxgenation of the nitro group forming the nitrene species B.
Since the expected eight-membered ring was not formed, we can
rule out the insertion of nitrene into the terminal double bond.
On the other hand, a cyclization of nitrene B could lead to the
aziridination of the proximal electron-rich aryl ring 7.13 The
C
DOI: 10.1021/acs.orglett.7b03422
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Organic Letters
Letter
Laboratory of Excellence LERMIT supported by a grant from
ANR (ANR-10-LABX-33). This work was performed using HPC
resources GENCI-CINES/IDRIS (2017-A0020806894).
Table 1. Cytotoxic Activity of Selected Derivatives Against
HCT-116 Cells
a
b
b
compound
IC50 (nM)
compound
IC50 (nM)
2.0
c
4a
4b
4j
na
5a
5g
5k
8
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03422.
Experimental procedures, characterization data, X-ray
1
analysis and computational methods, H NMR and 13C
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O. Eur. J. Med. Chem. 2017, 134, 159.
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CCDC 1576649−1576652 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: abdallah.hamze@u-psud.fr.
ORCID
Gilles Frison: 0000-0002-5677-3569
Abdallah Hamze: 0000-0001-8425-1971
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the support of this project by CNRS,
Univ. Paris-Sud, and by La Ligue Contre le Cancer through an
■
́
Equipe Labellisee 2014 grant. BioCIS is a member of the
D
DOI: 10.1021/acs.orglett.7b03422
Org. Lett. XXXX, XXX, XXX−XXX