Palladium/Norbornene-Catalyzed C?H Alkylation/Alkyne Insertion/Indole Dearomatization Domino Reaction: Assembly of Spiroindolenine-Containing Pentacyclic Frameworks

Article abstract of DOI:10.1002/anie.201801894

Reported is a highly chemoselective intermolecular annulation of indole-based biaryls with bromoalkyl alkynes by using palladium/norbornene (Pd/NBE) cooperative catalysis. This reaction is realized through a sequence of Catellani-type C?H alkylation, alkyne insertion, and indole dearomatization, by forming two C(sp²)?C(sp³) and one C(sp²)?C(sp²) bonds in a single chemical operation, thus providing a diverse range of pentacyclic molecules, containing a spiroindolenine fragment, in good yields with excellent functional-group tolerance. Preliminary mechanistic studies reveal that C?H bond cleavage is likely involved in the rate-determining step, and the indole dearomatization might take place through an olefin coordination/insertion and β-hydride elimination Heck-type pathway.

Full text of DOI:10.1002/anie.201801894

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Accepted Article
Title: Palladium/Norbornene-Catalyzed C-H Alkylation/Alkyne Insertion/
Indole Dearomatization Threefold Domino Reaction: Rapid
Assembly of Spiroindolenine-Containing Pentacyclic Frameworks
Authors: Lu Bai, Jingjing Liu, Wenjie Hu, Kunyu Li, Yao-Yu Wang, and
Xinjun Luan
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201801894
Angew. Chem. 10.1002/ange.201801894
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10.1002/anie.201801894
Angewandte Chemie International Edition
COMMUNICATION
Palladium/Norbornene-Catalyzed C-H Alkylation/Alkyne
Insertion/Indole Dearomatization Threefold Domino Reaction: Rapid
Assembly of Spiroindolenine-Containing Pentacyclic Frameworks
Lu Bai†, Jingjing Liu†, Wenjie Hu, Kunyu Li, Yaoyu Wang, Xinjun Luan*
Abstract: Herein we report a highly chemoselective intermolecular
annulation of indole-based biaryls with bromoalkyl alkynes by using
palladium/norbornene (Pd/NBE) cooperative catalysis. This threefold
domino process is realized through a sequence of Catellani-type C-
H alkylation, alkyne insertion, and indole dearomatization, by forming
two C(sp2)-C(sp3) and one C(sp2)-C(sp2) bonds in a single chemical
operation, thus providing a diverse range of pentacyclic molecules
containing a spiroindolenine fragment in good yields with excellent
functional group tolerance. Preliminary mechanistic studies reveal
that C-H bond cleavage is likely involved in the rate-determining step,
and the indole dearomatization might take place through an olefin
coordination/insertion and -hydride elimination Heck-type pathway.
The rapid and controlled generation of complex and diverse
molecular architectures from readily available starting materials
in a minimum number of steps is a highly appealing goal in
organic synthesis. One important strategy is the use of domino
reactions, which allow for the sequential construction of various
chemical bonds by a single-step manipulation.[1] Among them,
Pd/NBE-catalyzed reactions,[2] which were originally discovered
by Catellani[3] and further developed by Lautens[4] and others,[5]
represents a powerful approach for the expeditious synthesis of
highly substituted arenes through vicinal bisfunctionalization of
aryl iodides with various electrophiles and terminating reagents
by using NBE as a transient mediator (Scheme 1a). Notably, a
pre-existing R group, which remained intact in the transformation,
was commonly indispensable for facilitating the NBE excursion
to generate an arylpalladium AIV from intermediate AIII. From the
Scheme 1. Design plan for a new [Pd0]/NBE-catalyzed threefold domino
viewpoint of synthetic efficiency, it is highly desirable to decorate
this often neglected moiety simultaneously, and the envisioned
trisfunctionalization processes might be useful for building up
some frameworks that are inaccessible by traditional methods.
However, up to date, the progress in this area is very limited. To
our knowledge, the only example concerning Pd/NBE-catalyzed
trisfunctionalization was realized by the Lautens group, through
an elegant threefold domino process, which was eventually
terminated by a C-H vinylation of heterocyclic R group.[6]
Transition-metal-catalyzed dearomatization reactions allow
the direct conversion of easily accessible planar molecules to
many synthetically valuable three-dimensional scaffolds.[7-9] With
our persistent enthusiasm on the exploration of cooperative C-H
reaction being terminated with indole dearomatization.
activation/arene dearomatization reactions,[10] we endeavored to
combine Catellani-type C-H functionalization with the disruption
of -system of arenes for enabling more efficient and economical
transformations.[11] Very recently, we found that aryl iodides with
an adjacent phenol species underwent spiroannulation with 2,5-
norbornadiene (NBD) and N-benzoyloxyamines (Scheme 1b).[12]
Remarkably, this Pd-catalyzed NBD-involved process rendered
the ortho-C-H amination and subsequent dearomatization of the
phenolic R group. This observation implied that key intermediate
BIII favored the phenol dearomatization pathway to generate a
NBD-embraced spiroindene, rather than giving rise to a AIV–type
of arylpalladium species via NBD excursion. Presumably, if the
rates of these two pathways are reversed, it might be possible to
trap such NBD-free intermediate with an alkyne.[8l] In this context,
we postulated a new Pd/NBE-catalyzed trisfunctionalization plan
through a cascade of C-H alkylation, alkyne insertion and indole
dearomatization, for the rapid assembly of attractive pentacyclic
scaffolds containing a spiroindolenine fragment,[13] by reacting
ortho-indole substituted aryl iodides with tethered bromoalkyl
alkynes that were designed by Lautens.[4d-e,6] A brief description
of our proposal, using 1a and 2a for illustrative purposes, is
depicted in Scheme 1c. Besides the obvious risk of direct N-
[*]
L. Bai,[†] J. Liu,[†] W. Hu, K. Li, Prof. Dr. Y. Wang, Prof. Dr. X. Luan
Key Laboratory of Synthetic and Natural Functional Molecule
Chemistry of the Ministry of Education, College of Chemistry &
Materials Science, Northwest University, Xi’an, 710127 (China)
E-mail: xluan@nwu.edu.cn
Prof. Dr. X. Luan
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin, 300071 (China)
These authors contributed equally to this work.
[†]
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201801894
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COMMUNICATION
alkylation and inherent challenge in typical Catellani reactions,[14]
the prerequisites for successful execution of this proposal are
that: 1) aryl/NBE palladacycle CII must be selectively formed by
avoiding the interruption of indole moiety;[15] 2) NBE excursion of
CIII should be more favorable than its intramolecular cyclizations;
3) intermediate CV has to undergo dearomative spiroannulation
but not [4+2] annulation through a C-H bond vinylation.[6] Herein,
we wish to report our results on this subject.
Stimulated by the aforementioned challenges, we began the
studies with 1a and 2a to explore the reaction conditions (Table
1). Initial attempts with PPh3 and PCy3 didn’t give the anticipated
product 3a, but N-alkylated cyclobutane adduct 5a was obtained
in high yields (entries 1-2). To our delight, electron-rich P(2-furyl)3
led to the formation of 3a in 52% yield, albeit with concomitant
generation of byproduct 4a (entry 3). Base screening proved that
K3PO4 was the better choice, providing 3a as the only product in
67% yield (entry 6). Replacing Pd(OAc)2 with several palladium
precursors didn’t show any superior results (entries 7-9). Further
optimization revealed that no other solvent provided comparable
efficiency as DMF (entries 10-13), but a THF/DMF mixed system
could greatly enhance the process to yield 3a in 79% (entry 14).
More gratifyingly, the reaction performance was further improved
at lower temperature (65 ºC) by using 50 mol% NBE (entry 15).
nitro (1i), formyl (1j), acetyl (1j), and ester (1l) groups. Notably,
C-H alkylation took place smoothly with the substrates (1m-n)
bearing a substituent adjacent to the C-H activation site to give
the desired products 1m-n in 70% and 82% yield, respectively.
Moreover, the process proceeded smoothly with sterically
congested substrates 1o-p, leading to the formation of 3o-p with
crowded scaffolds in high yields. Gratifyingly, further studies
demonstrated that the indole ring could be diversely substituted
at different positions with various functional groups such as
methoxy (1q), fluoro (1r), chloro (1s), ester (1t), and methyl (1u)
groups, and the products 3q-u were obtained in 71-85% yields.
Table 2. Scope with respect to indole-derived aryl iodides.
Table 1. Optimization of the reaction conditions.[a]
Yield (%)[a]
Entry [Pd]
Ligand
Base
Solvent
3a
4a
5a
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
PPh3
PCy3
Cs2CO3 DMF
Cs2CO3 DMF
0
0
0
0
62
89
0
3
P(2-furyl)3 Cs2CO3 DMF
P(2-furyl)3 Na2CO3 DMF
52
59
35
67
10
21
15
42
9
21
0
4
0
5
P(2-furyl)3 K2CO3
P(2-furyl)3 K3PO4
P(2-furyl)3 K3PO4
DMF
0
0
6
DMF
0
0
7
DMF
11
0
0
8
[Pd(allyl)Cl]2 P(2-furyl)3 K3PO4
DMF
24
0
9
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
P(2-furyl)3 K3PO4
P(2-furyl)3 K3PO4
P(2-furyl)3 K3PO4
P(2-furyl)3 K3PO4
P(2-furyl)3 K3PO4
P(2-furyl)3 K3PO4
P(2-furyl)3 K3PO4
DMF
0
10
11
12
13
14[b]
15[b,c]
DMA
0
0
1,4-dioxane
THF
69
25
46
0
0
18
42
79
86
0
DME
0
THF/DMF
THF/DMF
0
0
0
[a] Isolated yield. [b] THF/DMF = 4:1. [c] Run at 65 ºC with 50 mol% NBE.
To further survey the scope of this domino reaction, a variety
of tethered bromoalkyl alkynes (2b-u) were evaluated (Table 3).
The experimental results showed that the phenyl substituent on
the alkyne terminus of 2a could be replaced with diversified aryls
bearing an electron-donating methoxy group (2b), an EWG such
as a fluoro (2c), chloro (2d), ester (2e), and nitro (2f) group, or a
heterocyclic group such as N-Ts-3-indolyl (2g) and 2-thienyl (2h),
and the desired products 3a'-g' were obtained in 63-85% yields.
Notably, substrate 2i bearing a vinylic substituent behaved quite
well to give compound 3h' in 90% yield. Moreover, a series of
alkyl-substituted substrates containing a methyl (2j), allyl (2k),
cyclopropyl (2l), or silyl ether groups were found to be suitable
With the optimal reaction conditions in hand, the scope with
respect to the aryl iodides was first examined (Table 2). Overall,
a broad range of indole-derived biaryls (1b-u) behaved very well
in the domino reaction, affording the corresponding pentacyclic
products 3b-u in 69-92% yields. Regarding the upper phenyl
ring, it is tolerable with electron-donating groups (EDGs) such as
methyl (1b,o), methoxy (1c), and methylenedioxy (1m) groups,
and electron-withdrawing groups (EWGs) such as fluoro (1d,n),
chloro (1e), trifluoromethyl (1f), trifluoromethoxy (1g), cyano (1h),
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10.1002/anie.201801894
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for the title transformation. Upon treatment with TBAF, 3l'
underwent TBS deprotection followed by stereospecific alkoxide
addition to furnish a fascinating hexacyclic framework 6. Much to
our delight, substrate 2n being featured with an electron-
deficient alkyne moiety underwent the insertion/dearomatization
cascade efficiently to generate product 3m' in 76% yield.
Moreover, the alkyne termini could be directly linked with a
heteroatom such as silicon (2o-p) and nitrogen (2q), and the
corresponding reactions were achieved with extremely high
efficiency. More importantly, substrate 2r, which contains a
stereogenic center next to the alkyne fragment, was proven to
results implied that NBE possessed far better affinity than
alkynes toward the Pd(II) center of intermediate CI. Otherwise,
such direct [3+2] spiroannulation byproduct like 8 would be
preferentially formed in the Pd/NBE-catalyzed reactions of 1 with
2. Treatment of 1a with the alkyne 7 and alkyl bromide 9 under
standard conditions afforded the anticipated product 10 in 76%
yield, together with the generation of NBE-embraced 11, and
possible byproduct 8 was not detected at all (Scheme 2c). The
success of this three-component trisfunctionalization reaction
indicated that the di-ortho-substituted arylpalladium species CIV
favored the migrative insertion of alkynes in comparison with
be effective for the stereocontrol of our threefold domino process, electron-rich NBE, which was due to the steric bulkiness of NBE.
affording 3q' as a diastereomeric mixture (4:1 dr). The relative
stereochemistry of 3q'major was confirmed by X-ray studies.[16]
Finally, it is worth mentioning that the tether for linking the alkyl
bromide and alkyne fragments could be extended with one more
carbon, oxygen, or nitrogen, thus enabling the rapid construction
of three types of unprecedented pentacyclic frameworks (3r'-t')
bearing a seven-membered carbo- or heterocyclic ring unit.
Moreover, this observation revealed that the use of tethered
bromoalkyl alkynes 2 was crucial for the reaction with 1, allowing
preventing the formation of any undesired byproducts like 11.
By not adding the base, the reaction of 1a with 7 was carried
out, and product 8 was isolated in 8% yield (Scheme 2d). This
outcome revealed that 8 should not be generated through the
deprotonation/tautomerization of indole moiety, and followed by
the reductive elimination of a spirocyclic palladacycle. Most likely,
this two-component process, and the titled threefold domino
reaction, were all terminated by a dearomatizing Heck-type
annulation through olefin coordination/insertion and -hydride
elimination. To testify our assumption, benzofuran derivative 12,
which couldn’t be deprotonated by K3PO4, was examined, and
the Heck product 13 was obtained in 68% yield (Scheme 2e).
Table 3. Scope with respect to bromoalkyl alkynes.
To gain more insights into the mechanism of this reaction, a
series of exploratory experiments were carried out (Scheme 2).
Parallel experiments with 1b and [D6]-1b demonstrated a kinetic
isotope effect (kH/kD = 2.3; Scheme 2a), suggesting that the C-H
bond cleavage was likely involved in the rate-determining step.
Control experiment between 1a and NBE led to the
formation of 4a in 5% yield, and the reaction of 1a with alkyne 7
gave a spirocyclic product 8 in 91% yield (Scheme 2b). These
Scheme 2. Mechanistic studies.
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Chem. 2017, 129, 7272; m) R. Li, G. Dong, Angew. Chem. Int. Ed. 2018,
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In summary, we have developed a new type of Pd/NBE-
catalyzed threefold domino reaction, wherein ortho-indole aryl
iodides and tethered bromoalkyl alkynes were used to build up
spiroindolenine-containing pentacyclic scaffolds through controlled
formation of three C-C bonds in a single step. Notably, this new
protocol, using NBE as a transient mediator, was featured by
terminating the trisfunctionalization domino process with indole
dearomatization, and represents a rare example of transition-
metal-catalyzed intermolecular reactions for the rapid assembly
of polycyclic frameworks from easily accessible starting materials.
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Acknowledgements
Financial support was provided by the Key Science and
Technology Innovation Team of Shaanxi Province (2017KCT-
37), the National Science Foundation of China (21672169), and
the Northwest University (YYB17007).
Keywords: C-H activation • dearomatization • norbornene •
domino reactions • palladium
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[16] CCDC 1822106 (3q'major) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre.
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10.1002/anie.201801894
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
L. Bai, J. Liu, W. Hu, K. Li, Y. Wang, X.
Luan*
Page No. – Page No.
Palladium/Norbornene-Catalyzed
C-H
Insertion/Indole
Threefold Domino
Rapid Assembly of
Alkylation/Alkyne
Dearomatization
Reaction:
A novel palladium/norbornene-catalyzed intermolecular annulation of ortho-indole
substituted aryl iodides with tethered bromoalkyl alkynes has been developed for
Spiroindolenine-Containing Pentacyclic
Frameworks
the rapid construction of diversified pentacyclic scaffolds containing
a
spiroindolenine fragment. This threefold domino process was realized through a
sequence of C-H alkylation, alkyne insertion, and indole dearomatization.
This article is protected by copyright. All rights reserved.