Regioselective electrolytic 5,8-difluorination of quinolines

Article abstract of DOI:10.1016/j.tetlet.2019.151474

Electrochemical anodic oxidation method for the incorporation of fluorine atom into quinoline ring is described. Our method involves a regioselective 5,8-difluorination of quinolines using HF:pyridine as a reagent/supporting electrolyte in an undivided electrochemical cell equipped with platinum anode and cathode. Various quinoline derivatives were subjected to electrolytic fluorination at room temperature to obtain moderate to good yields in short reaction time.

Full text of DOI:10.1016/j.tetlet.2019.151474

Journal Pre-proofs
Regioselective Electrolytic 5,8-Difluorination of Quinolines
Sean Spurlin, Mark Blocker, James LoBue, Ji Wu, Clifford Padgett, Abid Shaikh
PII:
S0040-4039(19)31273-0
DOI:
https://doi.org/10.1016/j.tetlet.2019.151474
TETL 151474
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Tetrahedron Letters
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Revised Date:
Accepted Date:
8 October 2019
26 November 2019
1 December 2019
Please cite this article as: Spurlin, S., Blocker, M., LoBue, J., Wu, J., Padgett, C., Shaikh, A., Regioselective
Electrolytic 5,8-Difluorination of Quinolines, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.
2019.151474
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Regioselective Electrolytic 5,8-Difluorination of Quinolines
Sean Spurlina, Mark Blockera, James LoBuea, Ji Wua, Clifford Padgettb and Abid Shaikha,*
aDepartment of Chemistry, Georgia Southern University, 521 College of Education Drive
Statesboro, GA 30458, USA
bDepartment of Chemistry, Georgia Southern University, Armstrong Campus, 11935 Abercorn
Street, Savannah, GA 31419, USA
*Corresponding author. Email: malnu@georgiasouthern.edu
Declarations of interest: none
Highlights:
 A regioselective incorporation of fluorine atoms on the benzenoid ring of quinolines has been
developed using Olah’s reagent.
 This method provides a direct access to difluorinated quinolines using electrolysis and
ambient reaction conditions.
 Products obtained in moderate to good yields in short reaction time.
Abstract:
Electrochemical anodic oxidation method for the incorporation of fluorine atom into quinoline
ring is described. Our method involves a regioselective 5,8-difluorination of quinolines using
1

HF:pyridine as a reagent/supporting electrolyte in an undivided electrochemical cell equipped
with platinum anode and cathode. Various quinoline derivatives were subjected to electrolytic
fluorination at room temperature to obtain moderate to good yields in short reaction time.
Graphical Abstract:
Keywords: Difluorination; electrolysis; quinolines; Olah’s reagent
1.
Introduction
Electrochemical anodic oxidation of aromatic compounds is a powerful technique in
synthesizing fine chemicals [1]. Electrochemistry offers selective generation of radical species at
variable current density resulting in high product regioselectivity [2]. Application of
electrochemical oxidation for the replacement of a hydrogen atom with a fluorine seems
attractive as compared to the traditional methods of fluorine incorporation to the organic
heterocyclic molecules [3]. The first account of electrochemical fluorination was reported by
Simons [4] using hydrogen fluoride (HF) as reagent to form various fluorocarbons as breakdown
products of a substrate carbon chain. At higher voltage (>7 V), formation highly oxidant fluorine
2

(F2) was observed which causes destruction of carbon framework. Further investigations
revealed that substrates containing heteroatoms could be protonated under HF to form salts to
increase conductivity of the solution [5]. Fluorination of benzo[h]quinolines and
benzo[f]quinolines was reported by Saeki using an ionic liquid tetrabutylammonium hydrogen
difluoride (nBu4N.HF2) as reagent, solvent and supporting electrolyte (Scheme 1a) [6]. This
method resulted 5-fluoro, 5,6-difluoro and 7,10-difluoro products with a very low product
selectivity and yields. Chambers and co-workers showed that it was feasible to incorporate
fluorine at the benzenoid ring of a quinoline using elemental fluorine (F2) (Scheme 1b) [7].
However a mixture of products indicated that fluorination occurred at 5, 6 and 8-positions of
quinoline and a 5,8-difluoroquinoline product was also obtained. This approach enabled the
synthesis of 5,8-difluoroquinoline in 32% yield, however, due to the use of highly oxidant
elemental fluorine gas, poor product selectivities were observed. Recent studies reported use of
N-F reagent Selectflour to obtain mono, di and trifluorination across alkene located on benzylic
carbons of enamides [8] to carry out electrophilic fluorination of activated alkenes which
provided good to excellent yields under acidic or basic conditions. Ideally, the most
straightforward approach to the synthesis would involve the transformation of an aryl Csp2-H to
Csp2-F bond by using well known and commonly used fluorinating reagents. Herein, we
describe the use of HF-pyridine (Olah’s reagent) [9] for the synthesis of 5,8-difluoroquinolines
starting from various substituted quinolines. Our synthetic strategy involves electrolysis using
Olah’s reagent as both a solvent and a supporting electrolyte. It’s a straightforward protocol for
the rapid access of various 5,8-difluoroquinolines. This work demonstrates the successful
extension of an electrolytic fluorination of quinolines as described by Saeki [6] and
electrochemical fluorination of p-nitrotoluene developed by Savett (Scheme 1c) [10].
3

Scheme 1. Literature overview of various fluorine incorporation methods
Fluorinated organic molecules often exhibit unusual biological activity due to differences
in their physical and chemical properties [11]. Introduction of a fluorine substituent into organic
molecules enhances their lipophilicity and bioavailability as compared to their hydrogen
analogues [12]. As a result, incorporation of fluorine atom to organic molecules is considered a
valuable tool in drug discovery, and development of new methodologies for the synthesis of
fluorinated molecules is in great demand [13]. Quinoline represents an important heterocyclic
core that is responsible for a wide range of biological activity in various natural and synthetic
4

compounds [14], Fluorinated quinoline derivatives such as 5,8-difluoroquinoline was reported to
possess in vivo mutagenic activity, on the other hand, 5-fluoro and 7-fluoroquinolines were
found to be carcinogens in rats [15].
2.
Results and discussion
Our original goal was to achieve the acid-catalyzed C-H functionalization of quinaldine
to incorporate fluorine atom at the methyl group. We started our investigation by choosing the
reaction between quinaldine 1 with HF:pyridine (70:30) as the model substrates. To our surprise,
the fluorination product 3 at the 2-methyl position of quinoline was not observed; instead, an
unexpected 5,8-difluoro product 2 was obtained in 68% yield. The protonation of nitrogen at the
pyridine moiety inhibits the electron transfer at the methyl carbon making it less susceptible for
fluorination. Surprised by this result, we further investigated the reaction yields with time. The
reaction proceeded rapidly at room temperature in higher yield. There was no significant
improvement in the product yield observed even after the extended time of 6 h and increasing the
electron density from 2.4 to 5 V. In contrast, no desired product formation was observed at
potential lower than 2.4 V at a specified duration of 2 hours.
With the optimized conditions in hand, the scope and limitations of this method were
then investigated with various substituted quinolines. Results showed that a wide range of
substituted quinolines reacted smoothly to form the corresponding 5,8-difluoro products 4-8
(Scheme 2). The substrates bearing a methyl group on the pyridinyl ring could afford the
products in good yields. In addition, 2-methylpyrazine and 1-methylisoquinoline substrates also
afforded the expected products 10 and 11 respectively in good yields. An important observation
worth mentioning is that reactions with halogenated quinolines provided the expected products
5

without the loss of halogens. Mono-fluorinated product 9 was obtained when 8-chloro-2-
methylquinoline was subjected to electrolysis. In all cases, selective fluorination occurred on the
benzenoid ring only and there were no other by-products including mono-fluorinated product
formation was observed. To further investigate the validity of this method, we carried out
fluorination of acridine providing a 1,4,5,8-tetrafluoro product 12.
Scheme 2. Regioselective difluorination of quinoline and its derivatives.a
aReaction conditions: 2-methylquinoline (100 mg, 0.7 mmol), HF:pyridine (4 mL), 2.4 V, 2 h
To gain the mechanistic insight of the reaction pathway, a control experiment using
radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was carried out. When
TEMPO was added to the electrochemical cell, we did not observe the formation of the desired
6

product 2, which confirms that the reaction involves a single electron transfer (SET) pathway.
Based on the literature reports [16], a plausible difluorination mechanism is described in scheme
3. Anodic oxidation of quinaldine 1 via a single electron transfer produced a radical cation
species 13. Later, nucleophilic substitution (SNAr) with a fluorine anion to afford radical 14
having fluorine atom placed at benzylic C-5 position. On further oxidation, a cationic
intermediate 15 is formed which on deprotonation of the most acidic proton at C-5 with pyridine
forms a stable product 5-fluoro-2-methylquinoline 16. We anticipate a similar mechanism to take
place at the benzylic C-8 position to afford the required 5,8-difluorinated product 2. Formation of
fluorine gas F2 was not observed at a potential of 2.4 V under HF, eliminating the role of F2 as
fluorinating agent [4], Also, during anodic oxidation, generation of radical cation is facilitated at
the stable benzylic positions C-5 and C-8 making it attractive for the fluoride attack to form the
expected difluorination product 2.
Scheme 3. A plausible mechanism for 5-8-difluorination of 2-methylquinoline
7

1H NMR spectra of product 2 showed a unique pattern of signals in the aromatic range
confirming the 5,8-difluorination occurred of the benzenoid ring (see supporting information for
details). In order to characterize the new product and to further gain information about 5,8-
difluorination, the regioselectivity of compound 2 has been determined by X-ray crystallography.
Compound 2 was obtained with almost 99.5% purity by successive application of column
chromatography and recrystallization with dichloromethane. The X-ray crystal structure of
compound 2 is shown in Figure 1. The analysis of the structure leads to an unambiguous
assignment of 5,8-regioslectivity of the product formation.
Figure 1. X-ray crystal structure of product 2 for the regioselectivity determination
3.
Conclusion
In summary, we have developed a novel highly regioselective direct 5,8-difluorination of
quinolines with the HF:pyridine reagent under electrolysis. Moderate to good yields were
obtained with various quinoline derivatives under mild reaction conditions and short reaction
8

time. Product regioselectivity was determined using x-ray crystal structure analysis.
4.
Experimental
General experimental procedure: The electrochemical cell was assembled from a 5 mL
polypropylene vial using platinum electrodes (1 cm x 1 cm). Quinaldine (100 mg, 0.7 mmol) was
transferred into the reaction cell along with a stir bar. 4 mL of HF:Pyridine (70:30) mixture was
then added and the solution was stirred. The cell voltage of 2.4 V was applied with a current
density of 100-60 mA/cm2 for 2h. After the satisfactory conversion, as indicated by thin layer
chromatography TLC using hexane/ethyl acetate 80:20 mixture as eluent, the excess acid was
neutralized by adding the solution drop-wise into a 10% sodium bicarbonate solution (250 mL).
The product was then extracted in ethyl acetate, filtered through anhydrous sodium sulfate and
concentrated. The crude product mixture was purified using normal phase flash chromatography
(hexane/ethyl acetate 90:10 to 80:20) to get a white solid in 68% isolated yield along with the
recovered starting material.
Acknowledgments
Financial support provided by Georgia Southern University, College Office of Undergraduate
Research (COUR) award and GSU-honors program are gratefully acknowledged.
Supplementary data
Detailed experimental procedure and characterization of all the products associated with this
article is enclosed.
9

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12

Regioselective Electrolytic 5,8-Difluorination of Quinolines
Sean Spurlina, Mark Blockera, James LoBuea, Ji Wua, Clifford Padgettb and Abid Shaikha,*
aDepartment of Chemistry, Georgia Southern University, 521 College of Education Drive
Statesboro, GA 30458, USA
bDepartment of Chemistry, Georgia Southern University, Armstrong Campus, 11935 Abercorn
Street, Savannah, GA 31419, USA
Declarations of interest: none
13

Graphical Abstract:
14

Highlights:
 A regioselective incorporation of fluorine atoms on the benzenoid ring of quinolines has been
developed using Olah’s reagent.
 This method provides a direct access to difluorinated quinolines using electrolysis and
ambient reaction conditions.
 Products obtained in moderate to good yields in short reaction time.
15