Shielding Effect of Micelle for Highly Effective and Selective Monofluorination of Indoles in Water

Article abstract of DOI:10.1002/cssc.201900316

Highly selective direct monofluorination of indoles and arenes was developed through an approach that allows site-specific solubility of substrate and fluorine source in the micelle. This approach was highly selective for a broad range of substrates with excellent functional group tolerance. Differences in binding constant and solubility of indoles and arenes in the micelle allowed the fine-tuning of selectivity. Control experiments suggested a radical pathway and provided insight into the role of micelles of the environmentally benign amphiphile PS-750-M. Dynamic light scattering experiments strongly indicated the site-specific solubility of the substrate and fluorine source. The methodology was successfully adapted to gram scale, and the E-factor established from a recycle study indicated that the process is environmentally responsible and sustainable.

Full text of DOI:10.1002/cssc.201900316

Accepted Article
Title: Shielding Effect of Micelle for Highly Effective and Selective
Monofluorination of Indoles in Water
Authors: Pranjal Bora, Manisha Bihani, Scott Plummer, Fabrice Gallou,
and Sachin Handa
This manuscript has been accepted after peer review and appears as an
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To be cited as: ChemSusChem 10.1002/cssc.201900316
Link to VoR: http://dx.doi.org/10.1002/cssc.201900316
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10.1002/cssc.201900316
ChemSusChem
COMMUNICATION
Shielding Effect of Micelle for Highly Effective and Selective
Monofluorination of Indoles in Water
Pranjal P. Bora,[a] Manisha Bihani,[a] Scott Plummer,[b] Fabrice Gallou,[c] Sachin Handa*[a]
We dedicate this work to Prof. Gerald B. Hammond on the occasion of his upcoming 67th birthday
Abstract: Using an approach which allows site-specific solubility of
substrate and fluorine source in the micelle, highly-selective direct
monofluorination of indoles and arenes is developed. This approach
is highly selective on a broad range of substrates with excellent
functional group tolerance. Differences in binding constant and
solubility of indoles and arenes in the micelle allowed the fine-tuning
of selectivity. Control experiments suggested a radical pathway and
provided insight into the role of micelles of environmentally benign
amphiphile PS-750-M. DLS experiments strongly indicated the site-
specific solubility of the substrate and fluorine source. The
methodology is successfully adapted to gram-scale, and the E factor
established from a recycle study indicates that the process is
environmentally responsible and sustainable.
have applications in drug discovery.[8] To access such molecules,
fluorination is typically either performed prior to the indolization[7j-
k]
or achieved via gold-catalyzed cyclization of alkynylanilines[7l]
.
Both approaches need multi-step pre-functionalization, expensive
metal catalysts, and toxic organic solvents. These methods
employ electrophilic fluorine sources such as NFSI and selectfluor.
Fluorination with these reagents could also follow radical
pathway;[9,10] indeed, both the radical and ionic pathway could
proceed simultaneously.[10] Occurrence of both reaction pathways
causes formation of difluorinated and other side products, instead
monofluorinated indole.[7e]
Our approach to solve this issue is based on i) shielding the indole
substrate in a micellar environment; ii) controlling reactivity by
harnessing the high solubility of indoles inside the micelle and
better solubility of fluorination source at the inner-outer core
interface; and iii) leveraging the high solubility of monofluorinated
product inside the micelle and low solubility of oxygen to prevent
further oxidation (Scheme 1). When indoles are highly soluble in
the micelle, they can only react with the F-source during the
exchange process,[11] and the resulting product becomes
relatively more soluble in the micelle, which prevents further side
reactions. This process could provide high selectivity without use
of base and excess F-source.
The introduction of fluorine atoms onto aromatic and
heteroaromatic rings induces significant changes in the
physiochemical properties[1] of the resulting molecule; e.g., i)
enhancement of lipophilicity and metabolic stability in drug
molecules;[2] ii) alteration of structural properties of organometallic
catalysts for better enantioselectivity;[3] and iii) exertion of control
on the overall reactivity of molecule.[4] The uniquely tuned
properties of fluorinated molecules are often far superior to their
non-fluorinated analogues, making them highly valuable
entities.[5] Among the many methods for their preparation, direct
C–H fluorination is considered one of the most valuable in
pharmaceutical, agrochemical, and fine-chemical industry.[6]
Many methods for direct C–H fluorination of indoles and other
heterocycles have been documented,[7] allowing facile access to
molecules of interest in drug discovery research.[8] Most notably,
these methods include: directing-group-assisted palladium
catalysis under microwave irradiation at elevated reaction
temperature;[7a] silver-mediated α-fluorination of pyridines,
quinolines, and diazines;[7b] ortho directed fluorination via
magnesiation;[7c]
and
electrophilic
fluorination
of
heteroaromatics.[7d] All of these methods require elevated
temperature and toxic organic solvents. Methods for the direct
fluorination of indoles mostly generate 3,3-difluoro-2-oxindoles[7e]
and 3,3-difluoro-3H-indole.[7f] To obtain the latter, protection at the
indole 2-position is needed to inhibit further oxidation. Therefore,
direct monofluorination of indoles is challenging. Molecules
containing monofluorinated indoles are bioactive in nature and
Scheme 1. Shielding effect of micelle for selective and direct C–H
monofluorination.
[a]
Dr. P. P. Bora, Dr. M. Bihani, Prof. S. Handa*
2320 S. Brook St., Department of Chemistry
University of Louisville, Louisville, KY 40292, USA
*E-mail: sachin.handa@louisville.edu
Dr. S. Plummer, Novartis Institutes for BioMedical Research
250 Massachusetts Ave, Cambridge, MA 02139
Dr. F. Gallou
The proposed strategy can be achieved with the use of an
amphiphile which dissolve substrate in the inner core, does not
itself react with any reaction component, produces micelles with
moderately non-polar inner cores, and provides minimal oxygen
solubility inside the core. Our amphiphile, PS-750-M, is carefully
crafted to meet these criteria. Therefore, direct monofluorination
[b]
[c]
Novartis Pharma AG, Basel (Switzerland)
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/cssc.201900316
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COMMUNICATION
of indoles can be possibly conducted in water as a recyclable
reaction medium and at room temperature. Notably, in most of
today’s synthetic chemistry, water is just considered as a medium
for reaction work-up to remove inorganics and other water-soluble
impurities from the reaction mixture. With this single event, tons
of aqueous as well as organic waste is generated every year.[12]
So far, usage of water as a reaction medium for organic synthesis
and catalysis did not gain much attention as it deserves,
especially in academia.[13] The inherited insolubility and instability
of reagents and catalysts in aqueous media is also responsible
for a slow and sporadic progress of aqueous organic or
organometallic chemistry. The false perception of generation of
more aqueous waste in aqueous chemistry is also responsible for
it. Nonetheless, more aqueous waste is generated from work-up
of reactions conducted in organic solvents.[12]
Optimization studies revealed a dependence of the reaction on
several variables, i.e., nature of fluorine source and surfactant,
reaction temperature, global concentration, sequence of addition,
stoichiometry of indole and fluorine source, and absence of
dissolved oxygen. Oxygen dissolution in the micellar core of PS-
750-M is minimal and therefore transformation was clean even in
the absence of argon atmosphere (for details, see SI). NFSI was
found to be the optimal fluorine source (Table 1, entries 1, 4) while
selectfluor, HF in pyridine,[1d-f] and KF were not as effective
(entries 2, 3, 6). KF and HF•pyridine under suitable oxidizing
conditions were chosen as
a fluorine source since this
transformation can also proceed through a radical pathway.
Dissolving indole in a surfactant solution prior to NFSI provided
better yield (entries 1, 4), which may be due to low probability of
immediate exposure of indole to excessive NFSI. Other
surfactants as well as organic solvents were ineffective for this
transformation, and in most cases, 3-fluoro-2-oxindoles and
polymeric side product were observed (entries 7-12).
Table 1. Reaction optimization for selective monofluorination of indole[a]
F
solvent
+
[F]
N
N
rt, 5 h
Table 2. Substrate scope for C–H monofluorination of indoles[a]
1
2
F
O
O
0.62 mmol NFSI
O
O
R/Ar
R/Ar
S
2BF4
S
N
N
3 wt % aq. PS-750-M
rt
Cl
N
R
R
x(HF)•pyridine
F
N
N
F
0.5 mmol
OC(O)Me
N-Fluorobenzenesulfonimide Selectfluor (F-TEDA)
(NFSI)
HF in pyridine
(Olah reagent)
F
F
F
F
F
MeO
Br
O2N
N
N
N
N
N
entry
[F] source
solvent
% 2[b]
2
5 h, 82%
3
6 h, 80%
4
12 h, 65%
F
5
60 h, 50%*
6
8 h, 70%
1
2
3
NFSI
3 wt % aq. PS-750-M
3 wt % aq. PS-750-M
3 wt % aq. PS-750-M
80
F
F
F
F
F
40[c]
O
Selecfluor
F3C
traces[d]
N
Me
N
70% HF in pyridine
(Olah reagent)
N
N
7
6 h, 65%
F
8
8 h, 70%
9
12 h, 62%
10 12 h, 65%
4
5
NFSI[e]
NFSI[g]
KF
3 wt % aq. PS-750-M
3 wt % aq. PS-750-M
3 wt % aq. PS-750-M
3 wt % aq. Nok
3 wt % aq. TPGS-750-M
water
90 (82)[f]
5[h]
N
F
F
F
F
N
6
traces[d]
45
O2N
Me(O)C
OMe
N
N
N
N
7
NFSI
NFSI
NFSI
NFSI
NFSI
NFSI
Me
8
51
11 12 h, 70%
12 10 h, 71%
13 12 h, 65%
14 60 h, 45%*
9
27[h]
51
F
F
F
F
Br
MeO
10
11
12
THF
N
N
N
N
DMSO
32
Br
acetonitrile
38
16 12 h, 60%
17 8 h, 72%
18 18 h, 72%
15 4 h, 50%
[a]Reaction conditions: 1 (0.25 mmol), [F] (0.31 mmol), solvent (1 mL), rt. [b]Yields
based on GCMS using mesitylene as an internal standard. [c]Unidentified
polymeric side product(s) was also detected. [d]30% aq. H2O2 (0.5 mmol) was
used as additive.[e]Sequence of addition was reversed, i.e., 1 was first dissolved
in aq. PS-750-M followed by addition of [F] source.[f] Isolated yield. [g]0.5 mmol
NaHCO3 was also used as a base. [h]55% mixture of 2-oxindoles and unknown
side products were in GCMS analysis using mesitylene as an internal standard.
F
F
MeO
MeO
F
F
N
CF3
N
N
N
CF3
OMe
19 13 h, 57%
20 5 h, 56%
21 12 h, 80%
22 12 h, 65%
F
Here we disclose the results of our strategy: a general, highly
efficient, scalable, mild, greener, and sustainable method for
monofluorination of indoles, which can be also applied to
monofluorination of arenes with further fine-tuning of arene
solubility with optimal temperature. Our study began with a model
reaction of 1 with different fluorine sources in environmentally
benign, non-toxic surfactant PS-750-M to obtain monofluorinated
product 2 (Table 1). When dissolved in water, PS-750-M
spontaneously forms nanomicelles with moderately polar-inner
core which mimic polar-aprotic organic solvents, while relatively
highly polar interface assists in dissolving the fluorinating reagent.
When mixed with indole, these micelles exponentially increase in
size as 1 is accommodated into in the micellar core (see
Supporting Information and Scheme 3a).
Me
O
N
F
F
F
N
O2S
Me
CHO
N
N
N
23 14 h, 68%
24 14 h, 71%
25 11 h, 66%
[a]Reaction conditions: Indole (0.5 mmol) in1.6 mL 3 wt % PS-750-M, NFSI (0.62
mmol) in 0.4 mL THF, rt. All yields are isolated. Reaction temperature 45 oC
*
and remaining starting material was recovered (85% yield based on recovered
starting material). GCMS yields in all cases except 5 and 14 were 100%.
After establishing optimal reaction conditions for this highly
selective pathway, substrate scope was explored to find out
whether this methodology is general or not. To our delight, it was
remarkably general, reproducible at variable scales, and tolerant
of many functional groups which are sensitive to either
electrophilic or radical mechanisms. Notably, under optimized
conditions, only indole’s heteroaryl ring was fluorinated while
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10.1002/cssc.201900316
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other aromatic residues were remained unaffected. Both the other
heteroaromatic and aromatic moieties were well tolerated (Table
2; 2-25). Functional groups such as bromo (4, 18), fluoro (8, 9, 11,
24), ester (6), nitro (5, 14), ether (3, 12, 15, 21, 22), aldehyde (24),
ketone (11), and sulfonyl (25) easily survived without any
detrimental effect on the reaction outcome. However, the
presence of an electron withdrawing group on indole ring lowers
its reactivity towards fluorination, and require comparatively
longer reaction time (4, 18). The strong –inductive effect by
deactivating nitro group caused incomplete conversion in 5 and
14. The acidic pH of the reaction mixture (see SI for pH
measurement experiments) due to the inherited acidic nature of
aqueous PS-750-M could possibly cause aldol-type side
reactions in the substrates containing aldehyde and ketone
functional groups. However, no such side reaction was observed,
and transformations cleanly proceeded for the formation of 11 and
24. Although GCMS yields were excellent in most cases, isolated
yields in some cases were moderate due to reaction scale and
poor product solubility in eluent used in chromatography. Notably,
a bisindole compound selectively mono fluorinated (25), and
fluorination only occurred at the more electron-rich indole ring.
Other electron-rich heteroaromatics such as pyrazole (13) and
isoxazole (23) also remained intact and no fluorination was
observed on these residues. Different types of N-benzyl residues
were also well tolerated. Substrates with N-aryl and alkyl residues
also displayed good-to-excellent reactivity.
Control experiments were conducted to confirm the possibility of
radical mechanism. In the first set of experiments, arene 33 was
subjected to the reaction conditions in the presence of either 0.8
equivalent TEMPO or BHT (Scheme 2a). Only 21% conversion
was obtained when TEMPO was used as an additive while 71%
was obtained in the presence of BHT. Notably, selectivity was lost
in both the cases. This may be due to interference in the radical
pathway for formation of desired product. To further confirm this
inhibition or interference, indole substrate 1 was subjected to the
similar conditions strictly under argon atmosphere, and only fully
oxidized product N-benzylisatin 34 was obtained. Indole radical
was also detected via mass analysis of a reaction mixture at the
start of reaction, which clearly shows the existence of such radical
with mass 206.1 (Scheme 2b). Radical trapping was also
attempted using BHT, which clearly cannot participate in the ionic
mechanism. Reaction of 33 in the presence of BHT allowed the
formation of 35 in about 25% yield, which is a strong evidence for
the formation of radical species during monofluorination (Scheme
2c). Therefore, radical pathway is responsible for the loss of
selectivity when transformations were conducted in organic
solvent since no such shielding effect of micelles exist there.
Table 3. C–H monofluorination of arenes – substrate scope[a]
H
F
0.62 mmol NFSI
R
R
3 wt % aq. PS-750-M
60 o
C
0.5 mmol
O
O
O
NH
OMe
OMe
O
NH
F
F
F
F
MeO
MeO
OMe
MeO
26 44 h, 55%
27 24 h, 65%
28 36 h, 62%
29 36 h, 52%
O
F
O
O
NH
H
F
F
H
H
MeO
30 44 h, 53%
Me
31 48 h, 55%
32 60 h, 55%
[a]Reaction conditions: Arene (0.5 mmol), 1.6 mL 3 wt % PS-750-M, NFSI (0.62
mmol) in 0.4 mL THF, 60 oC. All yields are isolated. In all cases, yields based
on recovered starting material was > 90%.
To test our hypothesis on another substrates class, the strategy
was further applied to the monofluorination of arenes. With slight
increase in reaction temperature, a variety of challenging arenes
displayed good-to-excellent reactivity (Table 3, 26-32). Since PS-
750-M has moderately non-polar inner cores, the higher reaction
temperature may be needed to enhance the solubility of non-polar
arenes in the micellar core without significantly affecting the
exchange process. Excellent regioselectivity was observed in all
these cases (26, 28-32) without formation of side products.
Functional groups such as Cbz (28-30) and ketone (32) were well
tolerated. In the substrates containing Cbz residue, fluorination
was exceptionally selective, i.e., ortho to this residue, which
possibly occurred due to the delivery of fluorine atom via
hydrogen bonding.[14] Notably, with the reported methods, 31 can
be only synthesized via
a
multi-step functional group
Scheme 2. Control experiments for evidence of radical pathway.
interconversion strategy, which produces overall low yield and an
enormous amount of waste.[15] Comparatively, our methodology is
straightforward, user-friendly, and proceeds in a single-step.
Control experiments were also conducted to confirm the role of
micelles of PS-750-M. Reaction was totally non-selective when
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10.1002/cssc.201900316
ChemSusChem
COMMUNICATION
conducted in either neat water or organic solvents (See SI). N-
benzylisatin and oxidized products were the major side products.
To further confirm the accommodation of substrate in the micellar
core, dynamic light scattering (DLS) experiments were conducted
at room temperature (Scheme 3a). Average diameter was
increased to 643 nm when NFSI was dissolved in the aqueous
solution of PS-750-M, which means NFSI solubility is greater
either at the interface or inner core. On other hand, increase in
diameter was greater when indole was dissolved, i.e., 845 nm,
which clearly indicates its accommodation inside the micellar core.
Same trend in particle size growth was observed when 10% THF
was added to the indole as well as NFSI in aqueous solution of
PS-750-M. Notably, increase in size was more in the case where
indole is dissolved in surfactant solution containing 10% THF, i.e.,
1291 nm. Particle size distribution was also narrower in this case
was another indicative of accommodation of substrate in the
micelle and dissolution of NFSI at the interface. Furthermore,
swelling of micelle in the presence of both the indole and NFSI,
i.e., average particle size 1848 nm, was a stronger evidence of
their solubility at the inner core and interior-exterior interface
respectively.
In final remarks, based on the shielding effect, many other types
of transformations can be developed in a highly selective and
greener way. With our approach, more highly-complex
monofluorinated indoles can be developed, which could possibly
assist drug discovery, especially, when such products are found
highly stable.
Experimental Section
General procedure for fluorination of indoles: Indole (0.5
mmol) was taken in a 4 mL flame-dried reaction vial containing
PTFE-coated magnetic stir bar. Reaction vial was gently closed
with a rubber septum. Reaction vial was evacuated and back-filled
with argon or nitrogen for three times. Under the positive argon or
nitrogen pressure, 1.6 mL freshly degassed 3 wt % aqueous
solution of PS-750-M was added to the reaction mixture. Reaction
mixture was stirred for 2-3 minutes at ambient temperature. N-
fluorobenzenesulfonimide (NFSI) (97 mg, 0.31 mmol) in 0.4 mL
THF was added to the reaction mixture and mixture was stirred
for 10 minutes at rt. After 10 min, another fraction of NFSI (97 mg,
0.31 mmol) was added to the reaction mixture and mixture was
stirred under the argon or nitrogen atmosphere at rt. After reaction
completion as monitored by both TLC and GCMS, septum was
removed from reaction vial. 1 mL EtOAc or MTBE was added to
the reaction mixture and mixture was stirred for a minute. Stirring
was stopped and organic layer was allowed to separate from
aqueous layer. Organic layer was withdrawn with the aid of
syringe needle. Similar extraction procedure was repeated for 1-
2 times. Combined organic layer was dried over anhydrous
sodium sulfate. Volatiles were removed under reduced pressure
to obtain semi-pure product. Pure product was obtained by flash
chromatography over silica gel using EtOAc/hexanes as eluent.
(For detailed procedure of fluorination of indoles and arenes, see
SI).
Acknowledgements
We acknowledge the Novartis Institutes for Biomedical Research
and University of Louisville for financial support. High-resolution,
accurate mass spectra were recorded by Ms. Angela Hansen at
the Indiana University Mass Spectrometry Facility using a MAT-
95XP mass spectrometer purchased with NIH grant
1S10RR016657-01. We thank Mr. Anthony Ewurum for
assistance in MALDI-TOF experiment.
Keywords: Selective micellar catalysis 1 • Green Chemistry 2 •
Fluorination in water 3 • E factor 4 • Sustainability 5
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10.1002/cssc.201900316
ChemSusChem
COMMUNICATION
COMMUNICATION
P. P. Bora, M. Bihani, S. Plummer, F.
Gallou, S. Handa*
Page 1. – Page 5.
Shielding Effect of Micelle for Highly
Effective
and
Selective
Monofluorination of Indoles in Water
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