Rapid Assembly of Diversely Functionalized Spiroindenes by a Three-Component Palladium-Catalyzed C?H Amination/Phenol Dearomatization Domino Reaction

Article abstract of DOI:10.1002/anie.201708310

A novel palladium-catalyzed three-component reaction of phenol-derived biaryls with N-benzoyloxyamines and norbornadiene (NBD) has been developed for the assembly of highly functionalized spiroindenes. This domino process was realized through NBD-assisted C?H amination and phenol dearomatization by forming one C?N bond and two C?C bonds in a single step. Preliminary studies indicated that asymmetric control of this transformation was feasible with chiral ligands. Moreover, the potential synthetic utility of this methodology was highlighted by a series of further transformations.

Full text of DOI:10.1002/anie.201708310

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Accepted Article
Title: Rapid Assembly of Diversely Functionalized Spiroindenes by a
Three-Component Palladium-Catalyzed C-H Amination/Phenol
Dearomatization Domino Reaction
Authors: Liangxin Fan, Jingjing Liu, Lu Bai, Yaoyu Wang, and Xinjun
Luan
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10.1002/anie.201708310
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COMMUNICATION
Rapid Assembly of Diversely Functionalized Spiroindenes by a
Three-Component Palladium-Catalyzed C-H Amination/Phenol
Dearomatization Domino Reaction
Liangxin Fan†, Jingjing Liu†, Lu Bai, Yaoyu Wang, Xinjun Luan*
Abstract: A novel palladium-catalyzed three-component reaction of
phenol-derived biaryls with N-benzoyloxyamines and norbornadiene
(NBD) has been developed for the assembly of highly functionalized
spiroindenes. This domino process was realized through NBD-
assisted C-H amination and phenol dearomatization by forming one
C-N bond and two C-C bonds in a single step. Preliminary studies
indicated that asymmetric control of this transformation was feasible
with chiral ligands. Moreover, the potential synthetic utility of this
methodology was highlighted by a series of further transformations.
underwent C-H palladation to form five-membered palladacycle
C,[5] rather than giving rise to spirocyclic intermediate B by
disrupting -system of phenol.[2-3,6] Noteworthy, an electron-rich
NBE-bridged palladacycle I, analogous to the intermediate C,
played an important role in the Catellani reaction, which was first
discovered in 1997.[7] Seminal work by Catellani and Lautens,[8]
together with the recent studies by other groups[9] showed that I
could react with various carbon electrophiles (X-FG1), followed
by NBE excursion to give arylpalladium species II, being trapped
wtih many different termination reagents (Y-FG2) (Scheme 2b).
In 2013, Dong identified the successful capture of palladacycle I
with nitrogen electrophiles such as N-benzoyloxyamines to form
intermediate II, which was then reduced with isopropanol to
afford formal meta-C-H amination products.[10] Further studies by
other groups demonstrated that aminated species II was able to
couple with a wide variety of nucleophiles and olefins as well.[11]
Intrigued by these elegant reports, we decided to investigate the
feasibility of merging the C-H amination of palladacycle C[12] with
a subsequent phenol dearomatization in the intermediate D, for
building up diversely functionalized spiroindenes 4 (Scheme 2c).
The key issue for such a process is if palladium-induced phenol
dearomatization can compete with NBD excursion via -carbon
elimination. In this paper, we present our efforts on this subject.
The rapid assembly of complex and diverse frameworks is an
important objective in organic synthesis. As a result, the domino
reactions, in which multiple bonds are formed in a sequential
manner, have thus emerged as powerful tools for creating highly
functionalized, architecturally complex molecules from simple
substrates in a single operation.[1] Among them, special attention
has been paid to palladium-catalyzed domino processes due to
their high compatibility of various functional groups and reaction
pathways. Herein, we disclose a novel palladium-catalyzed
three-component domino reaction for the one-step assembly of
polyfunctionalized spiroindenes through a potent NBD-assisted
C-H amination and phenol dearomatization cascade (Scheme 1).
Scheme 1. Palladium-catalyzed C-H amination/phenol dearomatization.
Transition-metal-catalyzed dearomatization of phenols has
been recognized as a straightforward and efficient strategy for
accessing a wide range of valuable spirocyclic scaffolds.[2-3] In
our attempts to develop a Pd(0)-catalyzed [3+2] spiroannulation
of 1a with strained olefin 2, the desired dearomatized product 5a
was only formed in low yield (<10%), with benzocyclobutene 6a
being isolated as the major outcome (up to 99% yield) (Scheme
2a).[4] This observation implied that intermediate A preferentially
[*]
L. Fan,[†] Dr. J. Liu,[†] L. Bai, 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
Scheme 2. Design plan for the C-H amination/phenol dearomatization reaction.
Prof. Dr. X. Luan
State Key Laboratory of Elemento-organic Chemistry, Nankai
University, Tianjin, 300071 (China)
These authors contributed equally to this work.
[†]
We began the studies by employing phenol-based biaryl 1a,
NBD (2) and morpholino benzoate 3a as the standard substrates
to explore the catalytic system for the potential domino reaction
Supporting information for this article is given via a link at the end
of the document.
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10.1002/anie.201708310
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COMMUNICATION
(Table 1). To our delight, the envisaged transformation could be
realized by heating the mixture of 1a, 2 and 3a in a variety of
solvents at 100 ºC , in the presence of 10 mol% of Pd(OAc)2, 25
mol% of PPh3, and 3.0 equivalents of Cs2CO3 (entries 1-5). In
particular, the use of DME led to the formation of product 4a in
higher yield (69%), albeit with concomitant generation of 25%
unwanted 6a. Further examinations on the palladium sources
revealed that Pd(OAc)2 was crucial for this process (entires 6-7).
Moreover, replacing Cs2CO3 with bases such as Na2CO3 and
K2CO3 dramatically shut down the anticipated reaction pathway
(entries 8-9). Thereby, a wide range of monophosphine ligands
featuring different electronic and steric properties were tested for
enhancing the reaction performance (entries 10-14), and the
electron-rich P(p-MeO-C6H4)3 was found to be the better ligand,
affording 4a in 81% yield. Unfortunately, it was still impossible to
prevent the formation of unwanted 6a. Noteworthy, the outcome
of the control experiment without adding 3a clearly illustrated the
difficulties of the oxidative addition of C with amination agent 3a,
by avoiding a rather competitive side reaction pathway for the
generation of 6a (entry 15). Additionally, potential dearomatized
byproduct 5a was not detected during the whole optimization
studies, suggesting that the evolution of phenol dearomatization
should be accelerated by that newly introduced amino group.
substituents, including both alkyl and phenyl groups (1b-e,m),
electron-donating methoxy group (1f), and electron-withdrawing
groups (EWGs) such as fluoro (1g), trifluoromethyl (1h), chloro
(1i), ester (1j), cyano (1k), and nitro (1l) groups were tolerated.
Moreover, substrate 1n with another fused-ring was compatible
as well. When the electron-deficient biaryls (1e,g-l) were used,
P(p-F-C6H4)3 was found to be the more effective ligand for the
desired transformations. Remarkably, two sterically congested
substrates (1m-n) behaved quite well in this domino process,
leading to products 4m-n with more crowded architectures in
good yields. Unfortunately, attempts with heteroaromatic rings
were unsuccessful. Next, some representative variations on the
phenol ring were performed, and it revealed that doubly methyl-
substituted substrate 1o could be converted into 4o in 75% yield.
Unsymmetrical 1p was able to participate in the title reaction,
giving rise to a diastereomeric mixture of 4p in 63% yield with
5:1 dr. The structure of its major diastereomer was assigned by
X-ray analysis.[13] Additionally, naphthol-derived 1q reacted
efficiently to give product 4q in 62% yield with 3:1 dr.
Table 2. Scope with respect to the phenol-derived biaryls.
Table 1. Optimization of the reaction conditions.[a]
Yield (%)[a]
Entry [Pd]
Ligand
Base
Solvent
4a 6a
24 19
50 41
25 22
64 28
69 25
25 69
1
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Na2CO3 DME
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMF
2
3
4
5
6
7
8
9
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
[Pd(allyl)Cl]2 PPh3
PdCl2
MeCN
toluene
dioxane
DME
DME
DME
PPh3
PPh3
PPh3
P(2-furyl)3
PCy3
DavePhos
P(p-F-C6H4)3
P(p-MeO-C6H4)3 Cs2CO3
P(p-MeO-C6H4)3 Cs2CO3
17
0
76
4
Pd(OAc)2
Pd(OAc)2
DME
DME
DME
DME
DME
DME
DME
0
11
10 Pd(OAc)2
11 Pd(OAc)2
11 Pd(OAc)2
13 Pd(OAc)2
14 Pd(OAc)2
15[b] Pd(OAc)2
68 21
50 23
0
6
65 18
81 10
NA 94
[a] Isolated yield. [b] No 3a added. NA = not applicable.
With the optimized reaction conditions in hand, we first
surveyed the scope of this domino process by reacting a number
of biaryls (1b-q) with 2 and 3a, and the experimental data are
given in Table 2. Generally, these reactions proceeded smoothly,
leading to the formation of highly functionalized spiroindenes 4b-
p in 62-87% yields. Regarding the upper aromatic ring, various
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10.1002/anie.201708310
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COMMUNICATION
To further investigate the scope of this reaction, diversified
N-benzoyloxyamines were evaluated (Table 3). Overall, a series
with a readily available TADDOL ligand L1 demonstrated that
product 4m could be formed in 56% yield with a promising
of secondary cyclic amine moieties were successfully introduced, enantiomeric excess of 84%, and the asymmetric transformation
affording the anticipated aminated spiroindenes 4a'-k' in 45-72%
yields. Similar to the standard substrate, compound 3b that was
prepared from 2,6-dimethylmorpholine proceeded smoothly for
the generation of product 4a', and its structure was assigned by
X-ray.[13] Moreover, substrates 3c-i, derived from the medicinally
important piperidine building block, served as effective aminating
reagents for accessing a variety of spirocyclic products 4b'-h'.
Various functional groups were well tolerated on the piperidine
moiety including methyl (3d,i), silyl ether (3e), hydroxyl (3f),
ester (3g) and ketal (3h) groups. Satisfactorily, Boc-protected
piperazine (3j) could be incorporated as the amine source for
the synthesis of compound 4i' (72% yield). It is worth noting that
N-benzoyloxylamines (3k-l) with seven-membered amines such
as azepane and Boc-protected diazepane behaved well to yield
4j'-k'. However, the limitation of this method became apparent
since the aminating agents based on pyrrolidine and linear
amines were not applicable under the reaction conditions.
of biaryl 1p, NBD (2) and 3a was realized to produce 4p, which
contains three contiguous stereocenters, as a diastereomeric
mixture (5:1 dr) in 70% yield with 85% ee for 4pmajor (Scheme 3).
Table 3. Scope with respect to N-benzoyloxyamines.
Scheme 3. Preliminary asymmetric studies.
Scheme 4. Synthetic transformations of 4a.
To showcase the potential utility of this newly developed
method, several transformations of product 4a were performed
towards all the three units of the spirocyclic scaffold (Scheme 4).
Hydrogenation of 4a by using Pd/C as the catalyst under 1 atm
H2 led to 7a in 96% yield. When 4a was treated with m-CPBA,
epoxide 8a was obtained in 81% yield. Moreover, the electron-
rich C-C double bond of 4a underwent dihydroxylation to give 9a,
which could be further converted into a tetracyclic 10a bearing
Next, we turned our attention to the development of an
asymmetric version of this domino reaction. Preliminary studies
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10.1002/anie.201708310
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[4]
[5]
For the experimental details, see the supporting information.
two aldehyde units. Adapting Wittig reaction conditions, 4a could
be transferred into 11a with an exocyclic olefin species. Luche
reduction of 4a and followed by subsequent treatment with p-
toluenesulfonic, allowed to deliver a rearranged product 12a in
84% yield. Next, phenanthrene 13a could be accessed from 12a
by a retro-Diels-Alder reaction. Notably, subjecting 4a to
bromination conditions, product 14a was isolated 78% yield.
In summary, we have developed an unprecedented Pd(0)-
catalyzed NBD-assisted C-H amination/phenol dearomatization
domino reaction, which allows the rapid assembly of a new class
of highly functionalized spiroindenes from phenol-derived biaryls,
NBD and N-benzoyloxyamines. Notably, this transformation was
realized through the formation of one C-N and two C-C bonds in
a single chemical operation, and represents a rare example of
transition-metal-catalyzed intermolecular processes for the one-
step construction of some rather complex molecular frameworks
from three readily available starting materials.
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Acknowledgements
This work was supported by NSFC (21672169) and the Science
and Technology Department of Shaanxi Province (2017KCT-37).
Keywords: C-H amination • dearomatization • spiroannulation •
homogeneous catalysis • palladium
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[13] CCDC 1560775 (4pmajor
)
and 1560774 (4a') contains 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.
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10.1002/anie.201708310
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COMMUNICATION
L. Fan, J. Liu, L. Bai, Y. Wang, X. Luan*
Page No. – Page No.
Rapid
Assembly
of
Diversely
Functionalized Spiroindenes by a Three-
Component Palladium-Catalyzed C-H
Amination/Phenol
Domino Reaction
Dearomatization
A novel palladium-catalyzed three-component reaction of phenol-derived biaryls
with N-benzoyloxyamines and norbornadiene (NBD) has been developed for the
assembly of highly functionalized spiroindenes. This domino process was realized
through NBD-assisted C-H amination and phenol dearomatization by forming one
C-N bond and two C-C bonds in a single step. Preliminary studies indicated that
asymmetric control of this transformation was feasible with chiral ligands. Moreover,
the potential synthetic utility of this methodology was highlighted by a series of
further transformations.
This article is protected by copyright. All rights reserved.