Preparation of Indolenines via Nucleophilic Aromatic Substitution

Article abstract of DOI:10.1021/acs.orglett.9b00489

An unusual aromatic substitution to access indolenines is described. 2-(2-Methoxyphenyl)acetonitrile derivatives are reacted with various alkyl and aryl Li reagents to furnish the corresponding indolenine products, constituents of natural products, and cyanine dyes such as indocyanine green. This new method was used to synthesize 41 indolenines with large functional group tolerance, and selected examples were further converted to the corresponding indolenine dyes. Key experiments provide insight into the mechanism of this nucleophilic aromatic substitution.

Full text of DOI:10.1021/acs.orglett.9b00489

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Preparation of Indolenines via Nucleophilic Aromatic Substitution
Florian Huber,† Joel Roesslein,† and Karl Gademann*
Department of Chemistry, University of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland
S
* Supporting Information
ABSTRACT: An unusual aromatic substitution to access
indolenines is described. 2-(2-Methoxyphenyl)acetonitrile deriva-
tives are reacted with various alkyl and aryl Li reagents to furnish
the corresponding indolenine products, constituents of natural
products, and cyanine dyes such as indocyanine green. This new
method was used to synthesize 41 indolenines with large functional
group tolerance, and selected examples were further converted to
the corresponding indolenine dyes. Key experiments provide
insight into the mechanism of this nucleophilic aromatic
substitution.
he indolenine or 3-H-indole structure can be found in
Scheme 1. Approaches Towards the Indolenine Structure
T
many natural products (Figure 1) and is often used to
access other indole derivatives such as the reduced indolines.1
Figure 1. Indolenine-type natural products and indolenine-based
dyes.
Besides their appearance in natural products and in indole
synthesis, indolenines are also employed as precursors for
various indolenine-based dyes like indocyanine green.2 These
dyes find applications in nonlinear optics,3 solar energy
conversion,4 imaging of diseases,5 molecular sensors,6 and in
vivo and ex vivo imaging.7 Recently, photochromic molecules
or molecular photoswitches based on an indolenine core
structure received significant interest in the fields of medicine
and smart materials, due to their property of changing color
upon light exposure.8 For the synthesis of the indolenine
scaffold, there are numerous methods (Scheme 1) reported in
the literature,1e which can be divided into three major groups:
(1) interrupted Fischer indolization,9 (2) dearomatization of
indoles,10 and (3) intramolecular condensation of an aniline
derivative with a carbonyl species to form the C−N bond.11
Among the different approaches, only the Fischer indolization
is used for the synthesis of indolenine-based dyes, a result of
the availability of the starting materials. Although this method
works well for a variety of indolenines, it is limited to
substituents in the 5-position.12 Otherwise, unsymmetrically
substituted hydrazones result in low yields and product
mixtures.13 The group of Ong published another approach
toward indolenines starting from fluoronitriles.14 However, the
indolenine could only be isolated in poor yields. A similar
observation was reported by the group of Chiba, applying
Received: February 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
reductive conditions to the anisol analogs with a poor yield for
the indolenine.15 During our work on benzyl nitriles, we
serendipitously discovered their unique reactivity toward
organolithium compounds. Upon treatment of 2-methoxyphe-
nylacetonitrile (1) with phenyllithium, the formation of an
indolenine was observed at higher temperatures. Intrigued by
this discovery, the reaction was further optimized (Table 1).
Scheme 2. Variation of the Organolithium Reagent
Table 1. Optimization for the Indolenine Cyclization
a
b
entry
PhLi (equiv)
T (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
9
10
1.2
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
80
80
80
1
1
1
1
1
1
2
2
4
71
26
90
51
93
93
94
90
91
92
82
60
100
120
100
100
100
100
100
100
c
d
18
2
2
e
11
12
f
g
0
indolenine. Beside donor substituents, electron-withdrawing
substituents are tolerated as well and give the corresponding
indolenines in high yields. Surprisingly the cyclization method
tolerates chloride substituents, giving access to further
modifications. Next, the benzylic position was modified with
various ring sizes, leading to the spiroindolenines. The 4-
membered ring gave the indolenine in poor yields. All larger
ring sizes delivered the cyclization product in very good yield.
Oxygen-, nitrogen-, and sulfur-containing rings are tolerated
and give the spiroindolenines in high yields. Unsymmetric
substituted nitriles showed high yields for the cyclization,
tolerating benzyl, allyl groups, and TBS-protected alcohols.
Furthermore, various aryl substituents, an alkyne moiety, as
well as an acetal-protected aldehyde did not affect the
cyclization, showing the broad application of this method.
The transfer of the cyclization method to the corresponding
pyridylnitriles gives access to azaindolenines, which are used as
precursors for near-infrared fluorescent dyes (Figure 1).16
Through the cyclization of various dinitriles the cyclic
bisindolenines were obtained in good yields. Bisindolenine
32 was synthesized starting from (S)-BINOL, and its use as a
new ligand for metal catalysis is currently under investigation
in our group.
Due to the unusual reactivity of the described trans-
formation, the mechanism of the reaction was further
investigated. It is well-known that nitriles react with organo-
lithium reagents to form the corresponding imines.17 Imine 33
as a possible intermediate was treated with various bases
(Scheme 4). Sodium hydride showed no formation of the
indolenine. Switching from sodium hydride to the lithium base
tert-butyllithium, a high yield for the indolenine was achieved.
The weaker base LiHMDS gave similar results. This confirms
the observation made during the optimization (Table 1),
which underlines the crucial role of the Li counterion for the
indolenine cyclization.
a
General conditions: sealed tube, 0.3 mmol nitrile, 3.0 mL toluene.
b
c
1
Yield was determined by H NMR with internal standard. Isolated
d
e
f
yield. 1 mmol scale. THF as solvent. PhMgBr instead of PhLi.
g
Imine formation observed.
Equimolar amounts of phenyllithium gave the best results,
whereas an excess of lithium reagent only lead to a lower yield
for the indolenine (entries 1−3). Further optimization
demonstrated that the ideal temperature is 100 °C, at which
the reaction is completed after 2 h (entry 7). Longer reaction
times only lead to lower yields (entries 9 and 10). Although
THF constitutes a suitable solvent, the yield is higher for
toluene. Exchanging phenyllithium with phenylmagnesium
bromide gave the corresponding imine, and no formation of
the indolenine could be observed (entry 12). Under the
optimized conditions the desired indolenine 2a was isolated in
excellent 94% yield.
With an optimized procedure in hand, the possible
modification of the organolithium reagent was investigated at
first (Scheme 2). Various aryllithium reagents were employed
for the cyclization, giving high yields independent from donor
or acceptor substituents and the substitution pattern on the
aryllithium. Fluorides and a tetrahydropyran-protected phenol
did not have any effect on the cyclization and gave the
indolenines in high yields. Fortunately, alkyllithium reagents
such as methyllithium result in indolenine formation in good
yield, which are ideal precursors for the synthesis of indolenine
dyes.
Next the scope of the indolenine cyclization was evaluated
(Scheme 3). The cyclization works well with donor
substituents on the aromatic core. Furthermore, it is possible
to install the methoxy substituents at every possible position
on the aromatic ring in high yields. With the currently known
methods, only compound 5 is accessible in good yields. As can
be seen with indolenine 8, the cyclization works well with a
very electron-rich benzyl nitrile, delivering a highly substituted
With these results in hand, a possible mechanism was
proposed (Scheme 5). First the nitrile is attacked by
B
DOI: 10.1021/acs.orglett.9b00489
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Organic Letters
Letter
Scheme 3. Scope of the Indolenine Cyclization
a
b
2.0 equiv of PhLi. 4 h, 100 °C.
phenyllithium, and the intermediary imine is formed. Via
coordination of the lithium cation with the imine and the
aromatic oxygen the methoxy group is activated as a leaving
group. This activation enables the intramolecular attack of the
nitrogen to the aromatic system followed by the cleavage of
lithium methoxide. Other pathways via an aryne or a radical
intermediate appear rather unlikely. The allylic substrates 20
and 22 both formed the indolenine in a high yield, and no
products resulting from a radical 5-exo-cyclization with the
terminal double bond were observed. Furthermore, the
substrates 3 and 7 with substituents ortho to the methoxy
group strongly disfavor an aryne-type mechanism.
As mentioned before, the main advantage of the Fischer
indolization is the availability of the starting materials. The
nitriles required for the indolenine cyclization either are
accessible in one step from the corresponding arylfluorides via
a nucleophilic aromatic substitution or are already commer-
cially available.18
As an application of this new method, the synthesis of
indolenine-based dyes was carried out.5b,19 Methylindolenines
34, 36, and 38 were prepared, employing the described
C
DOI: 10.1021/acs.orglett.9b00489
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Conversion of Imine 33 to Indolenine 2a with
Various Bases
Scheme 7. Synthesis of Indolenine-Based Poylmethine Dye
40 and Squaraine Dye 41
a
The yield was determined with 1H NMR and 1,3,5-trimethox-
ybenzene as the internal standard.
Scheme 5. Possible Mechanism for the Indolenine
Cyclization
In summary, a new method for the synthesis of indolenines
based on an aromatic substitution was developed. The method
tolerates a variety of substituents and gives high yields
independent of the position of the substituents on the
aromatic ring. Further modification of the lithium reagent
allows access to a broader scope of indolenines. Mechanistic
investigations suggest an aromatic substitution facilitated by Li
reagents. Furthermore, three indolenines were used to access
new indolenine-based dyes.
ASSOCIATED CONTENT
* Supporting Information
■
S
method in this work. The indolenines were further converted
into the N-methyl iodine salts, except for indolenine 34, which
was reacted with 1,3-propane sultone to sulfonate 35 (Scheme
6). The salts 35 and 37 were used to synthesize the
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00489.
Detailed experimental procedures, analytical data, and
1H NMR, 13C NMR, and 19F-NMR spectra (PDF)
a
Scheme 6. Synthesis of Indolenine-Based Salts
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: karl.gademann@uzh.ch.
ORCID
Karl Gademann: 0000-0003-3053-0689
Author Contributions
†F.H. and J.R. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank C. Lu
̈
thi (University of Zurich) for skillful technical
assistance and the Swiss National Science Foundation for
financial support (200020_163151).
a
o-DCB = 1,2-dichlorobenzene, MW = microwave.
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DOI: 10.1021/acs.orglett.9b00489
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