Domino Carbopalladation/C-H Activation as a Quick Access to Polycyclic Frameworks

Article abstract of DOI:10.1021/acs.orglett.7b03843

A new type of domino reaction for synthesis of heterocycles fusing the important bioactive cores, such as oxindole, indoline, and isoquinoline, is presented. Upon exposure to the very common palladium catalyst, the conceptually designed N-alkenyl iodobiaryls undergo a sequential carbopalladation/C-H activation to build polycyclic frameworks. These novel unique frameworks may provide structure sources in fragment-based drug discovery.

Full text of DOI:10.1021/acs.orglett.7b03843

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Domino Carbopalladation/C−H Activation as a Quick Access to
Polycyclic Frameworks
Nemai Saha,†,‡,§ Haiwen Wang,†,§ Shengyi Zhang,† Yongliang Du,† Daqian Zhu,† Yumin Hu,†
Peng Huang,*,†,‡ and Shijun Wen*,†,‡
†State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University
Cancer Center, 651 Dongfeng East Road, Guangzhou 510060, China
‡School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan Road, Guangzhou 510006, China
S
* Supporting Information
ABSTRACT: A new type of domino reaction for synthesis of
heterocycles fusing the important bioactive cores, such as
oxindole, indoline, and isoquinoline, is presented. Upon
exposure to the very common palladium catalyst, the
conceptually designed N-alkenyl iodobiaryls undergo a
sequential carbopalladation/C−H activation to build polycyclic
frameworks. These novel unique frameworks may provide
structure sources in fragment-based drug discovery.
fficient synthesis of heterocyclic frameworks are in demand
as they are widely present in natural products and
offer a great avenue toward synthesis of oxindole derivatives
mediated by palladium catalysis.8 Oxindole constitutes an
essential core in natural products and biological useful
compounds,9 and it may provide a structural basis in FBDD.
Numerous synthetic methods are developed to build up the
oxindole framework.10 The majority of the reported methods
often involve external nucleophilic trapping of transient σ-alkyl
PdII I-a arising from an intramolecular Heck reaction,11 resulting
in several seminal synthetic pathways to oxindole derivatives II
(Scheme 1a). In this regard, cyanides,12 hydrazones,13 CO,14
allenes,15 isocyanides,16 and others17 might be used. While R is
an aryl group, I-a might also undergo another intramolecular C−
H activation ready for further transformation.18
E
pharmaceuticals.1 Recently, fragment-based drug discovery
(FBDD) has become a powerful strategy to generate drug-hits
toward the development of potential clinical drugs.2 Key features
of FBDD require high-quality fragments with reasonable
molecular weights, hydrogen bond donors/acceptors, and
rigidity/flexibility. The development of novel frameworks is of
importance to provide fragment sources in FBDD. In this regard,
heterocyclic fragments are good candidates. We are interested in
seeking compounds exhibiting antiproliferative ability against
malignant cancers by targeting tumorigenic pathways.3 In the
past, a series of heterocycles containing a biaryl system were
made in our laboratory.4 Thus, we envisioned that some novel
alkaloid-like scaffolds could be constructed by incorporating a
biaryl with naturally important heterocycles like oxindole and
isoquinoline (Figure 1).
Scheme 1. Directed Cascade Pathways Initiated by an
Intramolecular Heck Reaction
Figure 1. Heterocyclic frameworks fusing oxindole or isoquinoline
motifs.
Domino reactions are able to construct modular molecular
frameworks by forming multiple bonds in a single operation.5
Synthetic chemists continue to develop novel protocols to
prepare heterocycles, especially employing transition-metal-
mediated domino transformations.6 Among them, the well-
known Heck reaction has received great attention.7 Haloarenes
with a pendant olefin motif are useful substrates for potential
intramolecular cascade reactions. For example, ortho-haloanilides
Received: December 8, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03843
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Since 2-iodobiaryls were often used to prepare cyclic
diaryliodoniums in our laboratory,19 we became interested in
the construction of alkaloid-like polycyclic scaffolds from 2-
iodobiaryl III (Scheme 1b). It was our hypothesis that
installation of an aryl ortho to the iodine in III would provide a
potential C−H activation site for in situ generated palladium
species III-a. Finally, reductive elimination of III-b would furnish
tetracycle IV. With this strategy, several series of novel polycyclic
frameworks could be obtained by using an approach of diversity-
oriented synthesis, providing chemical libraries for biological
interrogation.20
smoothly even at 60 °C, with 60% yield. This high spontaneity of
the domino process was encouraging because C−H activation
often demands high temperature.21 Notably, the reaction did not
need additional ligands. Solvent had a pronounced effect on this
cascade reaction. Protic methanol suppressed C−H activation
and favored protonolysis of III-a to form 3,3-dimethyl oxindole.
Acetonitrile, dioxane, and toluene gave low yields (Table S1).
Having the optimal condition in hand, we next focused on the
scope of substrates to explore the transformation generality
(Figure 2). The functionality on the N-atom, viz, methyl, ethyl,
and removable benzyl and 4-methoxybenzyl (PMB), was very
tolerable (2a−2e). Remarkably, N-allyl was also compatible,
providing an oxindole with an allyl untouched (2f). Substrates
1c−1g with more congested Ar1 containing additional Me and
Ph provided the desirable oxindoles in excellent yields.
Substituents on the Ar2 ring, including electron-donating groups
(Me, t-Bu, dimethyl, OMe) and electron-withdrawing groups (F,
CN, CO2Et), were also studied. When placed in the 4-position,
all the substrates underwent the domino process with high
efficiency (2h−2l). The substrate with a methyl at the ortho
position also underwent the transformation smoothly (2m).
Substrates containing a CN at the meta position led to
regioselective preference to the ortho-isomer (2n/2n′ or 2o/
2o′), likely attributed to the palladium chelation by ortho-CN in
the transition state III-b. The ethyl and phenyl exhibited a similar
result, generating the expected oxindoles (2q−2t) in excellent to
moderate yields. The substrate bearing an allyl instead of acryloyl
also underwent the domino process to afford indoline derivative
2u, of which the structure was confirmed by X-ray crystallog-
raphy (Figure 2). It is noteworthy that the intramolecular
carbopalladation was preferential to acryloyl in the presence of
allyl, as documented in the formation of 2f.
To test our concept, the study began with 1a for the survey of
reaction conditions. To our satisfaction, a tetracyclic oxindole 2a
was successfully obtained quantitatively using catalytic Pd-
(OAc)2 with Na2CO3 as base in DMF at 95 °C (Scheme 2). Both
Scheme 2. Domino Reaction under the Optimal Condition
NMR and mass spectroscopy unambiguously suggested the
skeleton of 2a, further validated by a single-crystal X-ray analysis
of its analogue 2c (Figure 2). The transformation also occurred
Increasing the number of heteroatoms at a proper range is of
great importance in fragment scaffolds of FBDD and
pharmaceuticals. Therefore, more heterocyclic moieties were
investigated (Figure 3). The new substrates containing thienyl
and pyridyl satisfactorily afforded the expected skeletons in good
to excellent yields (4a−4e). The pyridyl substrate required
additional Ph3P to achieve a good yield (4e) because
coordination of a transition metal by pyridyl often compromises
Figure 3. Substrate scope with phenyl−aryl/heteroaryl systems. a75 °C,
Figure 2. Substrate scope with biphenyl systems of 1.
2 h. bAdditional PPh3 (0.2 equiv).
B
DOI: 10.1021/acs.orglett.7b03843
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Organic Letters
Letter
the catalyst reactivity.22 Other biaryl acrylamides containing an
α- or a β-naphthyl moiety also underwent the transformation
smoothly (4f, 4g).
To gain more diversified fragments, different skeletons were
considered to incorporate the biaryls by C−N bond connection.
A pyrrole ring is present in a broad spectrum of biologically active
compounds.23 Thus, N-arylpyrroles 5a,b were synthesized to test
our domino reaction (Figure 4). Under the standard reaction
8c). Installation of an electron-donating or -withdrawing group
did not impact the domino transformation (8d−8f).
In our domino process, β-H elimination would compete with
intramolecular C−H activation if there was a β-H present in the
N-alkenyl motif of 1. Thus, two control experiments were then
performed (Scheme 3). The C−H activation was disrupted,
Scheme 3. Mechanistic Study
Figure 4. Transformation with the N-arylpyrrolyl system.
condition, the expected skeleton featuring a hybridized pyrrolyl/
piperidyl/oxindole was obtained in excellent yields (6a, 6b). The
new results demonstrated that intramolecular C−H activation
could proceed in the pyrrole ring at high efficacy.
Ring size variation is a general strategy to ensure exploitation
of the developed method. Thus, a new series of N-alkenyl
biphenyl carboxamides 7a−7f were designed to build isoquino-
line frameworks with a middle 6/6 ring system (Figure 5).
whereas β-H elimination was possible in substrate 9, leading
completely to the formation of 10. When 11 with a cycloalkene
motif was examined, a γ-H elimination was still dominant to
produce 12, although α-H was absent. To gain further
understanding of the kinetic pathways, we measured the kinetic
isotope effect (KIE) of this domino process by performing two
parallel reactions with either 1c or 1c-d5. The value of kH/kD
(KIE = 2.76) implied that the C−H activation might be rate
limiting in the domino process.
In summary, we have developed a new type of domino reaction
to access polycyclic frameworks catalyzed by a very common
palladium species. A α-halobiaryl system is designed to realize
domino Heck carbopalladation, C−H activation, and cyclization,
forming two cycles and a quaternary center. Applying this
approach, we have successfully constructed a series of novel ring-
fused heterocycles including oxindole, indoline, and isoquino-
line. Our constructed molecular frameworks may provide
fragment sources in FBDD. Moreover, preliminary biological
evaluation indeed found some hits with obvious anticancer
capacity (Figure S1).
ASSOCIATED CONTENT
* Supporting Information
■
S
Figure 5. Domimo transformation with substrates 7.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03843.
Experimental details, data characterization, and spectra
copies (PDF)
Compared to those of aryl acryloylamide 1, the reactions with N-
allyl aryl carboxamide 7 were sluggish and required more catalyst
loading to complete the conversion. The NMR spectra of 7
recorded at room temperature showed signal multiplication,
implying that 7 might have a torsional rotation to suppress the
reaction. Under modified conditions, the expected isoquinoline
skeletons were finally delivered in a good manner (8a−8f). As
demonstrated in Figure 5, functionalities on the N-atom were
well tolerated to give ring-fused isoquinoline derivatives (8a−
Accession Codes
CCDC 1557338 and 1557349 contain the supplementary
crystallographic 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 Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
C
DOI: 10.1021/acs.orglett.7b03843
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(11) Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am.
Chem. Soc. 2011, 133, 14916−14919.
AUTHOR INFORMATION
■
Corresponding Authors
(12) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. - Eur. J. 2007, 13, 961−
967.
*E-mail: huangpeng@sysucc.org.cn.
*E-mail: wenshj@sysucc.org.cn.
ORCID
(13) (a) Xia, Y.; Wang, J. Chem. Soc. Rev. 2017, 46, 2306−2362.
(b) Gao, Y.; Xiong, W.; Chen, H.; Wu, W.; Peng, J.; Gao, Y.; Jiang, H. J.
Org. Chem. 2015, 80, 7456−7467.
(14) (a) Liao, G.; Yin, X.-S.; Chen, K.; Zhang, Q.; Zhang, S.-Q.; Shi, B.-
F. Nat. Commun. 2016, 7, 12901−13000. (b) Frutos-Pedreno, R.;
Shijun Wen: 0000-0002-9347-8243
Author Contributions
§N.S. and H.W. contributed equally.
́
García-Lοpez, J.-A. Adv. Synth. Catal. 2016, 358, 2692−2700.
(15) (a) Elboray, E. E.; Gao, C.; Grigg, R. Tetrahedron 2012, 68, 3103−
3111. (b) Volla, C. M. R.; Backvall, J.-E. ACS Catal. 2016, 6, 6398−6402.
̈
Notes
(16) Kong, W.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55,
9714−9718.
The authors declare no competing financial interest.
(17) (a) Kong, W.; Wang, Q.; Zhu, J. J. Am. Chem. Soc. 2015, 137,
16028−16031. (b) Wang, M.; Zhang, X.; Zhuang, Y.-X.; Xu, Y.-H.; Loh,
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Weinstabl, H.; Peters, B.; Hou, X.; Lautens, M. Angew. Chem. 2014, 126,
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ACKNOWLEDGMENTS
■
This work was supported in part by National Natural Science
Foundation of China (81672952, 81430060), Guangdong
Science and Technology Program (2017A020215198), and
Guangzhou Science and Technology Program (201504010038,
201508020250, LCY201317).
(18) (a) Ye, J.; Shi, Z.; Sperger, T.; Yasukawa, Y.; Kingston, C.;
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