Electrolytic partial fluorination of organic compounds. Part 45: Highly regioselective anodic monofluorination of (E)-3-benzylidene-2,3-dihydrochroman-4-ones

Article abstract of DOI:10.1016/S0040-4039(01)00216-7

Anodic monofluorination at the position α to the oxygen atom of chroman-4-one derivatives was successfully carried out: this is the first selective electrochemical fluorination of fused-type, oxygen-containing heterocyclic compounds.

Full text of DOI:10.1016/S0040-4039(01)00216-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2513–2515
Electrolytic partial fluorination of organic compounds. Part 45:
Highly regioselective anodic monofluorination of
(E)-3-benzylidene-2,3-dihydrochroman-4-ones†
Kamal M. Dawooda,b and Toshio Fuchigamia,*
aDepartment of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan
bDepartment of Chemistry, Faculty of Science, Cairo University, Giza, Egypt
Received 9 January 2001; revised 29 January 2001; accepted 2 February 2001
Abstract—Anodic monofluorination at the position a to the oxygen atom of chroman-4-one derivatives was successfully carried
out: this is the first selective electrochemical fluorination of fused-type, oxygen-containing heterocyclic compounds. © 2001
Elsevier Science Ltd. All rights reserved.
Chroman-4-one derivatives have been known as
inhibitors of HIV-1 that causes AIDS.2 They have also
drawn much attention due to their broad range of
pharmacological activities.3 Moreover, the biological
potency of fluorinated heterocycles has been widely
documented.4 Therefore, considerable efforts have been
made to explore new synthetic routes to fluorinated
heterocycles. The electrochemical method was found
to be more applicable than the conventional, hazar-
dous chemical methods.5 Recently, we developed sel-
ective anodic fluorination of flavones6 and
arylthioethylenecarbonates7 as examples of oxygen-con-
taining heterocycles. Crown ethers were also anodically
fluorinated; however, a,v-difluoro products were
formed due to ring opening.8 On the other hand, furan,
benzofuran,9 and morpholines10 were anodically fluori-
Table 1. Anodic fluorination of (E)-3-benzylidene-2,3-dihydrochroman-4-ones (1a–c)
H
H
O
O
-2e, -H+
F-
Ar
Ar
O
O
F
2a-c
1a-c
1,2; a: Ar = C6H5; b: Ar = 4-ClC6H4; c: Ar = 4-BrC6H4
Run
Substrate
Supporting electrolyte/solvent
Charge passed (F/mol)
Yield (%)a
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1b
1c
Et4NF·4HF/DME
Et4NF·4HF/DMEb,c
Et4NF·4HF/MeCN
Et4NF·3HF/DME
Et3N·4HF/DME
Et3N·3HF/DME
Et4NF·4HF/DME
Et4NF·4HF/DME
6.5
5.5
3.0
7.0
8.5
8.5
7.0
6.5
72 (64)
17
21
68
52
35
60 (56)
59 (58)
a Calculated on the basis of 19F NMR spectra and the figures in parentheses are isolated yields.
b An undivided cell was used.
c A considerable amount of an unidentified, insoluble white polymeric product was formed.
* Corresponding author. Tel./fax: +81-45-924-5406; e-mail: fuchi@echem.titech.ac.jp
†
For Part 44, see: Ref. 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00216-7

2514
K. M. Dawood, T. Fuchigami / Tetrahedron Letters 42 (2001) 2513–2515
nated; however, their fluorinated products were either
not isolable due to their instability or were isolable in
very low yields with less selectivity. Therefore, a suc-
cessful selective anodic direct fluorination at position a
to a ring-oxygen atom has not yet been reported.
readily when the migrating double bond moves into
conjugation with an aromatic benzene nucleus.12 There-
fore, it is conceivable that intermediate B isomerizes
into C, followed by preferential attack of a fluoride ion
to the cationic intermediate C to give 2a. Benzylic
nucleophilic substitution takes place easily; however,
there was no evidence for the formation of the benzylic
fluorinated product 3a.
In this work, we successfully performed, for the first
time, a highly regioselective anodic direct fluorination
at the position a to the ring-oxygen atom of the biolog-
ically active chroman-4-one derivatives 1a–c. Anodic
fluorination of (E)-3-benzylidene-2,3-dihydrochroman-
4-one (1a), as a typical example, was conducted with
platinum plate electrodes (2×2 cm2) in a 0.3 M solution
of a fluoride salt in dimethoxyethane (30 ml) using a
divided cell under a nitrogen atmosphere at room tem-
perature. A constant current (6 mA/cm2) was applied
until the starting material was completely consumed.
The electrolysis results are summarized in Table 1. Only
one fluorinated product was obtained and it was iden-
tified as (E)-3-benzylidene-2,3-dihydro-2-fluorochro-
man-4-one (2a) on the basis of its elemental analysis
and spectral data.11
To generalize this interesting finding, we extended the
anodic fluorination to other chroman-4-one derivatives
1b,c and similar results were obtained, as shown in
Table 1 (runs 7 and 8). In both cases, a fluorine atom
was inserted selectively at the position a to the ring-
oxygen atom of 1b,c to afford the corresponding 2-
fluorochroman-4-ones 2b,c in moderate yields.13,14
Furthermore, anodic fluorination of 3-(4-chloroben-
zyl)chromone (4) was similarly attempted as shown in
Scheme 2. Interestingly, 2b was obtained in a reason-
able yield, but the corresponding fluorinated product 5
was not formed. This result is in sharp contrast to our
previous report for the anodic fluorination of flavones.6
In the case of flavones, 3-fluoroflavones were formed.
Thus, anodic fluorination of chromanone 1b and
As shown in Table 1, a highly regioselective anodic
monofluorination of 1a took place regardless of the
electrolytic conditions. It was found that a fluorine
atom attacked selectively the position a to the ring-oxy-
gen atom of 1a to furnish 2a in moderate to good
yields. Among various electrolytic conditions,
Et4NF·4HF/DME using a divided cell (run 1) was the
most effective for the formation of the fluorinated
product 2a.
homoisoflavone
4 provided the same fluorinated
product 2b. This result is quite interesting from a
mechanistic point of view. A proposed mechanism for
the anodic formation of 2b from 4 is outlined in
Scheme 3. A fluoride ion is assumed to attack the
radical cation D to form E, which is further oxidized to
give the fluorocarbocation F, followed by elimination
of a proton from the benzylic methylene group of F to
afford the thermodynamically more stable15 2-
fluorochroman-4-one derivative 2b rather than its iso-
mer 5.
An undivided cell (run 2) was not suitable for anodic
synthesis of 2a. In this case, the fluorination yield
decreased drastically due to the formation of an unde-
sirable, insoluble white polymeric product. Acetonitrile
(run 3) and Et3N·3HF (run 6) were also not effective.
The regioselective monofluorination of 1a is depicted in
Scheme 1. It was reported that isomerization occurs
In conclusion, we have successfully conducted anodic
fluorination at the position a to the ring-oxygen atom
of chroman-4-ones. This is the first report of successful
H
H
O
H
O
O
O
O
O
F
1a
F-
C
2a
-e
H
O
F
H
O
F-
O
-H+, -e
O
H
O
O
B
3a
A
Scheme 1.
H
C
O
O
O
CH2-C6H4Cl-p
-2e, -H+
C6H4Cl-p
Et4NF•4HF/DME
12F/mol
F
O
4
2b, 20% yield
Scheme 2.

K. M. Dawood, T. Fuchigami / Tetrahedron Letters 42 (2001) 2513–2515
2515
Cl
Cl
F-
Cl
O
O
O
O
O
CH2
CH2
CH2
F
-e
O
4
D
E
H
F
O
Cl
Cl
Cl
H
O
2b
O
-e
-H+
C
H
O
O
F
CH2
F
F
O
5
Scheme 3.
regioselective electrochemical direct fluorination of
fused-type, oxygen-containing heterocyclic compounds
where the methodology is of potential synthetic value.
7. Ishii, H.; Yamada, N.; Fuchigami, T. Chem. Commun.
2000, 1617.
8. (a) Hou, Y.; Fuchigami, T. Tetrahedron Lett. 1999, 40,
7819; (b) Ishii, H.; Hou, Y.; Fuchigami, T. Tetrahedron
2000, 56, 8877.
Acknowledgements
9. Meurs, J. H.; Eilenberg, W. Tetrahedron 1991, 47, 705.
10. Gambaretto, G. B.; Napoli, M.; Franccaro, C.; Conte, L.
J. Fluorine Chem. 1982, 19, 427.
The authors would like to thank the Japan Society for
the Promotion of Science (JSPS) for financial support
(Grant-in-Aid for Scientific Research No. 1299307).
They are also grateful to the Kato Foundation for
financial support.
11. Compound 2a: mp 69–70°C (AcOEt/hexane); 1H NMR
(CDCl3) l 6.76 (d, 1H, J=45.20 Hz), 7.33–7.49 (m, 7H),
7.63 (dd, 1H, J=8.58, 7.26 Hz), 7.96 (s, 1H), 8.17 (d, 1H,
J=7.92 Hz); 13C NMR (CDCl3) l 87.75 (d, J=173.3
Hz), 118.06, 123.77, 124.06, 125.33, 125.71, 126.19,
128.44, 128.68, 133.87, 137.48, 137.79, 153.53, 153.69,
156.15, 175.54; 19F NMR l −101.40 (d, J=45.04 Hz);
MS (m/z) 254 (M+). Anal. calcd for C16H11FO2: C, 75.58;
H, 4.36. Found: C, 75.92, H, 4.55.
References
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13. Compound 2b: mp 93–94°C (AcOEt/hexane); 1H NMR
(CDCl3) l 6.69 (d, 1H, J=45.19 Hz), 7.29–7.42 (m, 6H),
7.62 (dd, 1H, J=8.58, 6.93 Hz), 7.98 (s, 1H), 8.14 (d, 1H,
J=7.91 Hz); 13C NMR (CDCl3) (DEPT) l 87.25 (d,
J=173.3 Hz), 118, 125.33, 125.53, 127.6, 127.7, 128.53,
133.89, 153.15, 153.33 (CH’s), 123.29, 123.6, 134.44,
136.17, 156.04, 175.33 (C’s); 19F NMR l −102.50 (d,
J=45.04 Hz); MS (m/z) 288 (M+). Anal. calcd for
C16H10ClFO2: C, 66.56; H, 3.49. Found: C, 66.74, H,
3.77.
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14. Compound 2c: mp 80–81°C (AcOEt/hexane); 1H NMR
(CDCl3) l 6.69 (d, 1H, J=45.19 Hz), 7.34–7.52 (m, 6H),
7.67 (dd, 1H, J=7.91, 6.93 Hz), 7.99 (s, 1H), 8.17 (d, 1H,
J=7.92 Hz); 19F NMR l −102.76 (d, J=45.04 Hz); MS
(m/z) 333 (M+). Anal. calcd for C16H10BrFO2: C, 57.68;
H, 3.03. Found: C, 57.59, H, 3.25.
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