Asymmetric Dearomatizing Fluoroamidation of Indole Derivatives with Dianionic Phase-Transfer Catalyst

Article abstract of DOI:10.1021/acs.orglett.0c02026

Asymmetric dearomatizing fluorocyclization of indole derivatives was investigated using a dicarboxylate phase-transfer catalyst. This reaction proceeds under mild reaction conditions to provide fluoropyrroloindoline derivatives in a highly enantioselective manner. Various substitution patterns on the indole ring are well tolerated. To facilitate the reaction and ensure reproducibility, the addition of water is essential, and its possible role is discussed.

Full text of DOI:10.1021/acs.orglett.0c02026

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Letter
Asymmetric Dearomatizing Fluoroamidation of Indole Derivatives
with Dianionic Phase-Transfer Catalyst
Hiromichi Egami, Ryo Hotta, Minami Otsubo, Taiki Rouno, Tomoki Niwa, Kenji Yamashita,
and Yoshitaka Hamashima*
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ABSTRACT: Asymmetric dearomatizing fluorocyclization of indole derivatives was investigated using a dicarboxylate phase-transfer
catalyst. This reaction proceeds under mild reaction conditions to provide fluoropyrroloindoline derivatives in a highly
enantioselective manner. Various substitution patterns on the indole ring are well tolerated. To facilitate the reaction and ensure
reproducibility, the addition of water is essential, and its possible role is discussed.
We are interested in the synthesis and applications of
fluorine-containing molecules.12 As part of our continuing
research program on asymmetric halogenation reactions,13 we
recently developed chiral dicarboxylic acid precatalyst 1 for
asymmetric fluorination reactions.14 The in situ generated
dicarboxylate ion can serve as an anionic phase-transfer catalyst
to bring Selectfluor (2), which is insoluble in nonpolar organic
solvents, into the liquid phase, enabling highly enantioselective
fluorofunctionalization of alkenes and dearomative fluorination
of 2-naphthols.
Anticipating wide applicability of our dicarboxylate catalyst,
we became interested in using it for dearomatizing fluorination
of indole derivatives. With reference to previous reports,9a,10
we initially examined the reaction of an N-sulfonyl tryptamine
derivative. However, the desired product was obtained in a low
yield and the enantioselectivity was quite low (10%).15 In
contrast, promising enantioselectivity was observed when an
N-sulfonyl indole acetamide was used as a substrate, the
fluorination of which has not been examined before (vide
infra). Here, we present asymmetric dearomatizing fluorocyc-
lization of N-sulfonyl indole acetamides, affording easy access
to chiral fluoropyrroloindoline derivatives (Scheme 1b).
earomatizing intramolecular cyclization of indole de-
Drivatives with a pendant nucleophile is a representative
method for the construction of the pyrroloindoline framework.
Because this framework is often found in both natural and
unnatural bioactive compounds,1,2 various dearomatizing
reactions for its preparation have been investigated and
applied to the total synthesis of indole alkaloids.3
Reflecting the utility of the fluorine atom in pharmaceuticals
and agrochemicals,4 fluoropyrroloindolines would be of great
interest in drug development. Although tremendous efforts
have been devoted to the development of efficient fluorination
reactions,5 dearomatizing fluorination of indole derivatives has
been less well studied.6 In 2001, Shibata and co-workers
reported the fluorocyclization of tryptophan-derived diketopi-
perazines with FP-T300, albeit with moderate diastereoselec-
tivity.7 The same method was also applied to tryptamine
derivatives, but the enantioselective version was not exam-
ined.8 To date, there are only a few reports for enantioselective
fluorocyclization of tryptamine derivatives. Gouverneur applied
a cinchona alkaloid to develop a catalytic asymmetric variant in
2011 (Scheme 1a),9a and Yeung recently achieved excellent
enantioselectivity using a fluorinating reagent in situ generated
from an amino acid derived phthalazine.9b In 2017, You
demonstrated a similar reaction using Toste’s phosphate
phase-transfer catalysis conditions.10,11 However, these reac-
tions normally require extremely low temperature and/or an
appropriate substituent at a specific position of the indole ring
to achieve high asymmetric induction, and therefore a more
general reaction system with broad substrate scope is still
required.
Received: June 18, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02026
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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a
Scheme 1. Asymmetric Fluorocyclizations of Indole
Derivatives
Table 1. Optimization of the Reaction Conditions
b
entry
precat.
base
yield (%)
ee (%)
1
2
3
4
5
1
5
6
7
1
1
Na3PO4
Na3PO4
Na3PO4
Na3PO4
Na2HPO4
Na2HPO4
49
22
28
58
56
53
62
−2
−13
5
70
18
c
6
a
The reactions were carried out with precatalyst (10 mol %), base
(1.5 equiv), 2 (1.5 equiv), and Na2SO4 (50 mg) on a 0.1 mmol scale,
b
unless otherwise mentioned. Determined by 1H NMR analysis using
c
1,2-dibromoethane as an internal standard. Run with Selectfluor II
instead of Selectfluor.
To optimize the reaction conditions, N-methylindole
acetamide derivative 3a was chosen as a test substrate (Table
1). Encouragingly, the initial experiment using the standard
reaction conditions established in the previous report14a gave
the desired product 4a in 49% yield with 62% ee (entry 1). In
contrast, other carboxylic acid precatalysts such as our hydroxy
carboxylic acid 513a and chiral binaphthyldicarboxylic acid 6
did not work well (entries 2 and 3). Although chiral
phosphoric acid 7 could promote the reaction in moderate
yield, the ee value was unsatisfactory (entry 4). These results
are suggestive of the superiority of the linked dicarboxylic acid
precatalyst 1. Further screening of the reaction conditions
revealed the combination of toluene and Na2HPO4 to be
optimal in terms of the chemical yield and the enantiose-
lectivity (entry 5).15 Because the use of Selectfluor II instead of
2 afforded 4a with only 18% ee (entry 6), the structure of the
fluorinating reagent is presumed to be important to form a
reactive species with a well-defined chiral environment.
We next examined the effect of protective groups and found
that protection at the N1 position of the indole ring had a
marked impact on the reaction performance (Table 2). For
example, an electron-withdrawing tert-butoxylcarbonyl (Boc)
group was totally ineffective (entry 1), and the nonprotected
substrate 3c gave a low yield and enantioselectivity (entry 2). A
benzyl group retarded the reaction, probably due to the lower
solubility of 3d, but a para-methoxybenzyl (PMB) group gave
comparable results to those observed in the case of N-methyl-
protected 3a (entries 3 and 4). When silyl groups were
incorporated to examine steric and hydrophobic effects, a great
improvement of the asymmetric induction was observed
(entries 5 and 6). N-Methanesulfonyl amide reduced the
reaction efficiency (entry 7), but a benzenesulfonyl group gave
a better chemical yield (entry 8). The best enantioselectivity
a
Table 2. Effect of Protective Groups
b
entry
R1
R2
4
yield (%)
ee (%)
1
2
3
4
5
6
7
8
Boc
H
Bn
PMB
TBS
TIPS
TIPS
TIPS
TIPS
TIPS
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Me
Ph
Ph
Ph
b
c
d
e
f
g
h
i
N.R.
24
20
64
68
74
20
99
−
11
43
73
81
86
43
86
93
94
c
9
10
i
i
quant.
quant.
cd
,
e
a
The reactions were carried out with 1 (10 mol %), Na2HPO4 (1.5
equiv), 2 (1.5 equiv), and Na2SO4 (50 mg) in toluene (1 mL) at
room temperature on a 0.1 mmol scale, unless otherwise mentioned.
Determined by H NMR analysis using 1,2-dibromoethane as an
internal standard. Run at 0 °C. Run with 10 μL of H2O in the
absence of Na2SO4. Isolated yield. Boc = tert-butoxycarbonyl, Bn =
benzyl, PMB = para-methoxybenzyl, TBS = tert-butyldimethylsilyl,
TIPS = triisopropylsilyl, N.R. = no reaction. quant. = quantitative
yield.
b
1
c
d
e
(93%) was observed when the reaction was carried out at 0 °C
(entry 9). However, we encountered poor reproducibility; the
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reaction sometimes halted completely under the reaction
conditions shown in entry 9. After a series of experiments, we
found that the addition of an appropriate amount of H2O was
crucial to ensure reproducibility, and in this case, Na2SO4 was
no longer necessary for the reaction (entry 10).15 The reaction
could be carried out on a 1 mmol scale, and comparable results
(82%, 94% ee) were obtained.15 The reasons for this will be
discussed later. Moreover, when the previously reported
methods that worked well for tryptamine derivatives9a,10
were applied to the present substrate, unsatisfactory results
were obtained (Supporting Information, section 3.3),15
indicating that the present system is the first solution for
indole acetic acid derivatives and complementary to those for
tryptamine substrates.
Scheme 2. Asymmetric Dearomatizing Fluoocyclization of
3w
Deprotection of the product 4i with 94% ee was successfully
achieved as shown in Scheme 3. The TIPS group could be
Scheme 3. Transformations of Fluorinated Pyrroloindoline
4i
Having optimized the reaction conditions, we investigated
the generality of the reaction (Table 3). 4-Substituted indole
a
Table 3. Substrate Scope
b
entry
R
4
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
10
11
4-Me
4-F
j
k
l
m
n
o
p
q
r
s
t
u
v
87
90
63
75
86
75
76
90
68
76
65
66
50
93
74
96
97
81
81
80
78
78
93
92
92
95
4-Cl
4-Br
5-Me
5-MeO
5-Cl
5-Br
5-I
6-Me
6-F
6-Cl
6-Br
c
removed easily under acidic conditions to give 8i in 88% yield
without any loss of optical purity. The N-benzenesulfonyl
amide could also be deprotected without difficulty when 4i was
treated with Li/naphthalene, affording lactam 9i in good yield.
Interestingly, the ee value of 9i was found to be 98%,
suggesting that self-disproportionation of the enantiomers
might occur during purification by silica gel column
chromatography.16 Fortunately, we were able to obtain an
enantio-pure single crystal of 9i, the X-ray structural analysis of
which established its absolute and relative stereochemistry.17
Accordingly, the absolute stereochemistry of 4i was deter-
mined to be 3aR, 8aS.
While Na3PO4 can deprotonate the precatalyst 1 rapidly in
toluene, less basic Na2HPO4 reacted reluctantly with 1.
However, the 1H NMR spectrum of 1 in toluene-d8
dramatically changed in the presence of a small amount of
water (10 μL of H2O per 1 mL of toluene).15 This observation
indicated that the precatalyst 1 is quickly converted to its
anionic form. Thus, the concentration of the actual phase-
transfer catalyst would be increased considerably, facilitating
the phase transfer of 2 to give the putative chiral fluorinating
reagent. Additionally, the 1H NMR experiment clearly showed
that the substrate undergoes facile deprotonation under basic
conditions,15 which is in accord with the expected lower pKa
value of the N-sulfonyl amide unit. The high stereoselectivity
observed in this reaction can be rationalized in terms of
hydrogen bonding between the catalyst and the substrate anion
mediated by water molecule(s), resulting in an associative
interaction that defines the structure of the transition state,
although the details remain to be elucidated.
c
12
13
a
The reactions were carried out with 1 (10 mol %), Na2HPO4 (1.5
equiv), 2 (1.5 equiv), and H2O (10 μL) in toluene (1 mL) at 0 °C on
a 0.1 mmol scale. Isolated yield. Run for 48 h. Bs = benzenesulfonyl.
b
c
derivatives were good substrates irrespective of the electronic
properties of the substituent, affording the corresponding
products in high yields with up to 97% ee (4j−4m). Although
substituents at the 5 position had some negative influence on
the stereoselectivity, the desired products were formed at
synthetically useful levels (4n−4r). As for the substituent at
the 6 position, methyl and halogen groups were well tolerated
and the desired products were formed in a highly
enantioselective manner (4s−4v). Halogen groups anywhere
at the 4−6 positions are expected to be useful handles for
further structural modification.
A further example is shown in Scheme 2. Because 7-
substituted indole substrate could not be protected with a
TIPS group, N-PMB-protected indole derivative 3w was
subjected to the reaction. The dearomatizing fluorocyclization
proceeded to give 4w in 50% isolated yield with 90% ee. These
results clearly indicate that the present catalytic system is
compatible with various substitution patterns on the indole
ring, which is still difficult to achieve with other catalytic
systems.
In summary, we have developed asymmetric dearomatizing
fluoroamidation of indole acetamide derivatives using a
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dicarboxylate phase-transfer catalyst. Indole substrates with
various substitution patterns were available, and excellent
enantioselectivity of up to 97% was achieved. We also found
that water efficiently promotes the reaction, which might
provide a useful clue to developing other types of reactions.
Further study of the present reaction system is underway in
our laboratory.
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02026.
Optimization of the reaction conditions, NMR experi-
ments concerning H2O effect, experimental procedure,
characterization data (PDF)
Accession Codes
CCDC 1989933 contains 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 Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
Yoshitaka Hamashima − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka 422-8526, Japan;
orcid.org/0000-0002-6509-8956; Email: hamashima@u-
shizuoka-ken.ac.jp
Authors
Hiromichi Egami − School of Pharmaceutical Sciences,
University of Shizuoka, Shizuoka 422-8526, Japan;
orcid.org/0000-0002-7784-4987
Ryo Hotta − School of Pharmaceutical Sciences, University of
Shizuoka, Shizuoka 422-8526, Japan
Minami Otsubo − School of Pharmaceutical Sciences, University
of Shizuoka, Shizuoka 422-8526, Japan
Taiki Rouno − School of Pharmaceutical Sciences, University of
Shizuoka, Shizuoka 422-8526, Japan
Tomoki Niwa − School of Pharmaceutical Sciences, University of
Shizuoka, Shizuoka 422-8526, Japan
Kenji Yamashita − School of Pharmaceutical Sciences, University
of Shizuoka, Shizuoka 422-8526, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02026
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grant-in-Aid for Scientific
Research (Nos. 19H03353 and 18K06585), a grant from the
Uehara Memorial Foundation, Nagase Science and Technol-
ogy Foundation, Basis for Supporting Innovative Drug
Discovering and Life Science Research (BINDS) from Japan
Agency for Medical Research and Development (AMED). We
are grateful to Dr. Tomoyuki Kimura of Institute of Microbial
Chemistry for X-ray analysis.
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̃
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(17) The ORTEP diagram of 9i (CCDC 1989933) with 50%
probability of thermal ellipsoid is shown in the Supporting
Information.
E
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Org. Lett. XXXX, XXX, XXX−XXX