Synthesis of Indolines and Derivatives by Aza-Heck Cyclization

Article abstract of DOI:10.1002/anie.201907758

For the first time, an aza-Heck cyclization that allows the preparation of indoline scaffolds is described. Using N-hydroxy anilines as electrophiles, which can be easily accessed from the corresponding nitroarenes, this method provides indolines bearing pendant functionality and complex ring topologies. Synthesis of challenging indolines, such as those bearing fully substituted carbon atoms at C2, is also possible using this method.

Full text of DOI:10.1002/anie.201907758

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Accepted Article
Title: Synthesis of Indolines and Derivatives via Aza-Heck Cyclization
Authors: Feiyang Xu, Katerina Korch, and Donald Watson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201907758
Angew. Chem. 10.1002/ange.201907758
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10.1002/anie.201907758
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Indolines and Derivatives via Aza-Heck Cyclization
Feiyang Xu, Katerina M. Korch, and Donald A. Watson*
substituted C2 carbon.[4i][5] In general, access to indolines bearing
Abstract: For the first time, an aza-Heck cyclization that allows the
full substitution at C2 is challenging, and most often requires
preparation of indoline scaffolds is described. Using N-hydroxy
manipulation of a preformed indole core.[1a] Tsuji-Trost and
anilines as electrophiles, which can be easily accessed from the
related allylation reactions are capable of accessing such
corresponding nitroarenes, this method provides indolines bearing
molecules;[6] however, they require more highly functionalized
pendant functionality and complex ring topologies. Synthesis of
allylic electrophiles, which introduces difficulty in starting material
challenging indolines, such as those bearing fully substituted carbons
at C2 is also possible using this method.
preparation and limits the accessible product ring topologies.
Thus, there is a clear need to develop a cyclization technology
that can produce a wide range of indoline topologies, including
more challenging product structures, from easily available starting
materials.
The indoline scaffold is found in numerous natural products and
biologically
active
complex
molecules.[1]
Synthetic
Previous work: Aza-Wacker Cyclizations
pharmaceuticals containing this ring system are used to treat a
wide variety of diseases, including migraines, hypertension,
cancer, and chronic inflammatory and neurodegenerative
conditions.[2] Notable examples of indoline-containing natural
products and drugs are shown in Figure 1,[3] many of which bear
a fully substituted carbon at C2 and/or unsaturation adjacent to
the indoline nitrogen.
SO2R
SO2R
• difficult nitrogen deprotection
• limited substrate scope
• no tolerance with highly
substituted alkene
cat. PdII
NH Me
N
H
H
This work: Aza-Heck Cyclizations
MeO
O
O
O
OMe
• broad substrate scope and
functional group tolerance
• acessible to indolines
bearing fully substituted
carbon center
cat. Pd0
N
O
H
O
OMe
R
N
Me
Me
MeO
N
H
H
Me
N
H
Me
Me
OH
O
O
H
H
N
N
O
H
R
N
O
H
H
R = H, alkyl, aryl, ester, nitrile
H
OMe
rupicoline
acetylcholinesterase inhibitor
polyveoline
schizozygine
antimicrobial agent
aldolase inhibitor
N
O
N
Figure 2. Prior Art and Our Method.
OMe
N
Me
N
H
O
Me
H
MeO
H
Me
N
N
CO2Me
Over the past several years, the discovery of Heck-type
reactions using heteroatomic electrophiles has greatly enhanced
carbon-heteroatom bond construction.[7] Within the context of
alkaloid synthesis, aza-Heck cyclizations employing nitrogen
electrophiles has proven to be a powerful strategy for nitrogen-
containing heterocycle synthesis.[8] To date, we and others have
described a few classes of such electrophiles that allow access to
pyrroles and pyridines,[9] cyclic imines,[10] saturated pyrrolidines
and piperidines,[11] lactams,[12] and imidazolidinones.[13] However,
the use of nitrogen electrophiles bearing aromatic substitution has
not been demonstrated. Moreover, only two prior examples of
aniline electrophiles have been shown in cross-coupling reactions,
making this a highly underdeveloped area of study.[14],[15]
Herein, we report that N-aryl-N-hydroxy carbamates undergo
facile palladium-catalysed cyclization onto pendant alkenes to
deliver indolines, and related heterocycles, bearing allylic
unsaturation. Unlike earlier methods, broad scope of alkene
substitution and functional group compatibility are observed,
allowing the preparation of indolines with complex ring topologies
and substitution patterns and making this a general approach to
this important ring system.
N
CO2Me
N
H
MeO
MeO
prunifoline B
vasorelaxant agent
CN
H
H
O
O
MeO
grandilodine A
cytotoxic agent
winchinie B
cytotoxic agent
stobadine
antiarrhythmia agent
Figure 1. Notable Natural Products and Drugs Containing Indoline Scaffolds.
Because of the prevalence of indolines in bioactive molecules,
the discovery of new methods to prepare this heterocycle has
attracted substantial research interest.[1] One attractive strategy
involves cyclization of an aniline equivalent onto a pendant alkene.
Aza-Wacker approaches to indoline synthesis using this general
strategy have been previously described;[4] however, in general
they are highly limited in terms of alkene substitution of the
substrate. The vast majority of such cyclizations require
substrates bearing either a terminal or 1,2-disubstituted alkene
and result in mono-cyclic indolines or related heterocycles. Using
aza-Wacker approaches, there has been only one isolated
example of the formation of a fused bicyclic indoline,[4f] and one
example of the cyclization to form an indoline bearing a fully
Towards development of the aza-Heck reaction, our initial
studies investigated the cyclization of 1 bearing an ester leaving
group, which has been widely utilized in cross-couplings of
nitrogen electrophiles (including those of anilines). We focused on
the easily reduced palladium pre-catalyst (COD)Pd(CH2SiMe3)2,
and selected P(OCH2CF3)3 as ligand, as it has shown success in
previous aza-Heck reactions (Table 1, Entry 1). Disappointingly,
under these and other conditions, only trace conversion and none
of the desired aza-Heck product 3a was observed. We then
sought a leaving group that might favor greater reactivity. We
[*]
F. Xu, K. M. Korch and Prof. Dr. D. A. Watson
Department of Chemistry and Biochemistry
University of Delaware
Newark, DE 19716 (USA)
E-mail: dawatson@udel.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201907758
Angewandte Chemie International Edition
COMMUNICATION
speculated that a carbonate leaving group might serve such as
role, as decarboxylation might lead to irreversible oxidation
addition.[16]
Previously, the single-step semi-reduction of nitroarenes to N-
aryl-N-hydroxy carbamates had been reported.[17] Although these
products have not been explored in cross-coupling reactions, we
envisioned that these might make outstanding substrates, not
only for their potential carbonate leaving group, but also for their
ease of preparation. Moreover, substrate assembly would be
aided by the vast chemistry of nitroarene synthesis.[18] Gratifyingly,
we found that known protocols were well-suited to substrates
bearing pendant alkenes,[17a] allowing for a ready entry into the
required substrate class (Scheme 1).[19]
Table 1. Reaction Optimization.
Me
O
O
MeO
O
O
O
O
O
Pd catalyst
ligand
R
N
N
N
Me
OMe
MeCN, 80 °C
RO
O
O
NO2
N
NH4Cl, ClCO2R, Zn
THF/H2O, 0 °C
1
2
3a, R = Me
3b, R = OMe
O
OR
Entry
1 [b]
2
Pd Catalyst [mol %]
Ligand [mol %]
Yield [%, 3] [a]
22 examples, yields up to 86%
Scheme 1. Synthesis of N-aryl-N-hydroxy Carbamate Substrates.
(COD)Pd(CH2SiMe3)2 [5]
(COD)Pd(CH2SiMe3)2 [5]
(COD)Pd(CH2SiMe3)2 [5]
(COD)Pd(CH2SiMe3)2 [5]
(COD)Pd(CH2SiMe3)2 [5]
(COD)Pd(CH2SiMe3)2 [5]
(COD)Pd(CH2SiMe3)2 [5]
Pd2dba3•CHCl3 [1.5]
P(OCH2CF3)3 [12.5]
P(OCH2CF3)3 [12.5]
P[3,5-(CF3)2-C6H3]3 [12.5]
P(4-CF3-C6H4)3 [12.5]
P(4-F-C6H4)3 [12.5]
PPh3 [12.5]
0
25
53
85
65
61
0
Excitingly, and in validation of our hypothesis, using a substrate
bearing the carbonate leaving group (2), the desired product 3b
was observed in 25% yield (Table 1, Entry 2). Ligand optimization
revealed that P[3,5-(CF3)2-C6H3]3 provided 3b in 53% yield (Entry
3).[11b] Ultimately, the related ligand to P(4-CF3-C6H4)3 proved to
have the optimal balance of electronic and steric properties,
providing product 3b in 85% yield (Entry 4). Other similarly sized,
but electronically varied ligands proved inferior (Entries 5–7).
Finally, we found that the more readily available and bench-stable
pre-catalyst (Pd2dba3•CHCl3) provided similar yields at lower
catalyst loading (Entry 8), making this a highly practical method
for indoline synthesis. Notably, although acyl, sulfonyl, or phenoxy
leaving groups have been previously used in aza-Heck
cyclizations, this is the first reported example of using a carbonate
leaving group in a heteroatomic cross-coupling.
3
4
5
6
7
P(C6F5)3 [12.5]
8
P(4-CF3-C6H4)3 [7.5]
84 [c]
[a] Yield calculated by 1H NMR with 1,3,5-trimethoxybenzene as internal
standard. [b] 1 as starting material instead of 2. [c] Isolated Yield.
These conditions enabled synthesis of a broad scope of
indolines. The model product 3b was isolated in 84% yield. Using
R1O
O
O
O
O
OR1
R2
1.5 mol % Pd2dba3•CHCl3
7.5 mol % P(4-CF3-C6H4)3
N
OR1
N
MeCN, 80 °C
R2
O
O
O
O
R =
Me
Ph
O
O
OMe
OMe
Me
OMe
OMe
OMe
OMe
Me
5, 73%
6, 67% (gram scale)[b]
N
N
R
N
N
N
N
CO2Et 7, 39%,[c] 57%[d]
CN]
8, 41%,[c] 53%[d]
Me
O
a3b, 84%a
4, 89%[a]
9, 73%[b] (dr = 85:15)
10, 65%[b]
11, 65%[b], [e]
O
N
O
O
O
O
N
O
N
OMe
O
OMe
OMe
Me
OMe
OMe
OMe
Me
OMe
Me
MeO
Br
N
N
N
N
Cl
Me
O
O
Me
12, 45%[b], [e]
13, 57%[b], [e]
14, 39%[b], [e]
15, 57%[b]
16, 77% (gram scale)[b]
17, 67%[b]
[18, 0%[
O
O
O
OMe
O
O
OMe
O
Me
OMe
OMe
OMe
OBn
N
N
N
O
N
N
N
N
S
O
O
a19, 69%a
20, 61%[b]
21, 56%[b]
]22, 65%[a]
23, 31% (51%)[b], [f]
]24, 78%]
(gram-scale, X-Ray)
(X-Ray)
[a] Average of two runs. [b] Run with 5 mol % Pd2dba3•CHCl3, 25 mol % P(4-CF3-C6H4)3. [c] Run with 5 mol % Pd2dba3•CHCl3, 25 mol % P(4-CF3-C6H4)3, DCE. [d] Run with 7.5
mol % Pd2dba3•CHCl3, 37.5 mol % P(4-CF3-C6H4)3, DCE. [e] Run at 100 °C. [f] Parenthetical yield calculated by 1H-NMR with 1,3,5-trimethoxybenzene as internal standard.
Scheme 2. Scope of the Indoline-Forming Aza-Heck Cyclizations.
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a substrate bearing a larger cyclohexene ring, 4 was produced in
89% yield. More substituted alkenes can also be utilized. These
include
both
trisubstituted
alkenes
(10-12),
tetrasubstitutedalkenes (13), and those bearing a range of
groups, including alkyl, aryl, ester, and nitrile (5-8). Many of these
examples provide indolines bearing fully substituted C2 carbons
adjacent to nitrogen.[20] As mentioned, this is a motif that appears
widely in bioactive natural products but is often challenging to
prepare (Figure 1).[1a] Benzylic substitution is also well tolerated.
With stereogenic benzylic substitution, good levels of
diastereoselectivity are observed (9); with benzylic ketones,
pseudoindoxyls arise (including those bearing fully substituted
carbon centers, 11-13). These oxidized heterocycles appear in
many natural products, but typically must be prepared by the
oxidative rearrangement of indoles.[21] It is also notable that these
cyclizations proceed via 5-exo cyclization onto an electron-
deficient alkene opposite to its inherent electronic bias.
A
range of functional groups are compatible with this
cyclization, including ethers (16, 19, 22), carbonyls (7, 11–13, 20),
nitrile (8), aryl chloride (17), and various appended heterocycles
(19–22). Unfortunately, aryl bromide is not tolerated (18). N-
hydroxy aniline bearing an allylic ether can also cyclize under
these conditions, resulting in the fused vinyl ether 19 on gram
scale.
A range of bicyclic ring topologies can also be prepared,
including fused (3b, 4–8, 15–17, 19–21, 24), spirocyclic (12), and
bridged (22) systems. Again, this starkly contrasts aza-Wacker
cyclizations, where most examples result in mono-cyclic products
(see above). There are no reported examples of bridged indolines
formed by aza-Wacker cyclization. 6-exo cyclization is also
possible. For example, bridged bicyclic hemiaminal 22 can be
prepared in this fashion; this is the first metal-catalyzed approach
to access such a scaffold. Similarly, dihydrophenanthridine 23
can be prepared via 6-exo cyclization of a biaryl substrate.[22]
Finally, the carbamate group can be varied. For example, the
Cbz-protected indoline (24) was prepared in good yield, indicating
that other protecting and leaving groups can be utilized in this
chemistry.
In summary, we have developed a general method for the
synthesis of indoline derivatives using an aza-Heck approach.
This marks the first use of aniline electrophiles and carbonate
leaving groups in such a cyclization. This reaction offers distinct
advantages over existing methods, particularly with respect to
functional group compatibility, accessible ring topologies, and
tolerance of alkene substitution. The ease of access to the
required substrates by semi-reduction of nitroarenes, along with
the highly adaptable nature of the reaction, should make this
process highly applicable to the synthesis of indoline-containing
natural products and bioactive molecules.
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Acknowledgements
The University of Delaware (UD) and the NIH NIGMS (NIH P20
GM104316) are gratefully acknowledged for support of this work.
Dr. Glenn P. A. Yap (UD) is thanked for X-ray Crystallography.
Data was acquired at UD on instruments obtained with the
assistance of NSF and NIH funding (NSF CHE-0421224, CHE-
0840401, CHE-1229234, and CHE-1048367; NIH P20
GM104316, P30 GM110758, S10 RR026962, and S10
OD016267).
Keywords: catalysis • palladium • indolines • aza-Heck •
[12] S. A. Shuler, G. Yin, S. B. Krause, C. M. Vesper, D. A. Watson, J. Am.
Chem. Soc. 2016, 138, 13830-13833.
cyclization
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COMMUNICATION
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other aza-Heck processes, see reference 11b.
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[18] N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH, New York,
2001.
[19] See Supporting Information.
[20] For products 7 and 8, higher catalyst loading is required to achieve good
yields due to the instability of the starting material in solution.
[21] a) X.-Y. Zhou, X. Chen, L.-G. Wang, Synlett 2016, 27, 2742-2746; b) X.
Zhang, C. S. Foote, J. Am. Chem. Soc. 1993, 115, 8867-8868; c) E.
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[22] In this case, the isolated yield was suppressed due to product instability.
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10.1002/anie.201907758
Angewandte Chemie International Edition
COMMUNICATION
Layout 2:
COMMUNICATION
Feiyang Xu, Katerina M. Korch and
Donald A. Watson
Synthesis of Indolines and Derivatives via Aza-Heck Cyclization
Page No. – Page No.
MeO
O
O
O
• easily prepared substrates
• broad substrate scope and
functional group tolerance
OMe
Synthesis of Indoline Derivatives via
Aza-Heck Cyclizations
N
cat. Pd0
R
N
O
OMe
• acessible to indolines bearing fully
substituted carbon center
Text for Table of Contentsdf
R
21 examples
yields up to 89%
R = H, alkyl, aryl,
ester, nitrile
This article is protected by copyright. All rights reserved.