N-Halogeno compounds. Part 20. Vicarious electrophilic fluorodemethylation of 1,3,5-trimethoxybenzene and 2,4,6-trimethoxytoluene with 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor reagent F-TEDA-BF4</su

Article abstract of DOI:10.1016/S0022-1139(99)00064-0

Treatment of 1,3,5-trimethoxybenzene with one molar equivalence of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF₄) under mild conditions (-40 to +20°C) in acetonitrile gave mainly 2-fluoro-1,3,5-trim

Full text of DOI:10.1016/S0022-1139(99)00064-0

Journal of Fluorine Chemistry 96 (1999) 129±133
N-Halogeno compounds. Part 20. Vicarious electrophilic ¯uorodemethy-
lation of 1,3,5-trimethoxybenzene and 2,4,6-trimethoxytoluene with
1-chloromethyl-4-¯uoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetra¯uoroborate) (Select¯uorTM reagent F-TEDA-BF4)
*
Â
R. Eric Banks , Mohamed K. Besheesh, Romuald W. Gorski,
Nicholas J. Lawrence, Amanda J. Taylor
Chemistry Department, The University of Manchester Institute of Science and Technology, Manchester M60 1QD, UK
Received 28 August 1998; accepted 10 February 1999
Abstract
Treatment of 1,3,5-trimethoxybenzene with one molar equivalence of 1-chloromethyl-4-¯uoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetra¯uoroborate) (F-TEDA-BF4) under mild conditions ( 40 to ‡208C) in acetonitrile gave mainly 2-¯uoro-1,3,5-trimethoxybenzene
(62% yield; all product yields quoted refer to isolated pure materials, unless otherwise stated) and some 4,4-di¯uoro-3,5-
dimethoxycyclohexa-2,5-dien-1-one (13% yield), the structural parameters of which were determined by X-ray crystallography. Evidence
that the minor product arose via ¯uorodemethylation of the 2-¯uoro-1,3,5-trimethoxybenzene formed ®rst was obtained in a separate
experiment involving this ¯uoroaromatic compound and F-TEDA-BF4 as the sole reactants. Treatment of 1,3,5-trimethoxybenzene with a
two molar equivalence of F-TEDA-BF4 in acetonitrile (at 20 to ‡208C) produced only 4,4-di¯uoro-3,5-dimethoxycyclohexa-2,5-dien-1-
one (>50% yield), a conversion which was unaffected by carrying out the reaction in either aqueous acetonitrile (20 vol% H2O) or neat
water. Treatment of 2,4,6-trimethoxytoluene with a two-molar equivalence of F-TEDA-BF4 in acetonitrile between 20 and ‡208C gave
the ¯uorodemethylation product 4-¯uoro-3,5-dimethoxy-4- methylcyclohexa-2,5-dien-1-one in 81% yield. # 1999 Elsevier Science S.A.
All rights reserved.
Keywords: Electrophilic aromatic ¯uorination; 1-Chloromethyl-4-¯uoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetra¯uoroborate); Fluorodemethylation;
Fluorodienones; X-ray crystallography
*Corresponding author. Tel.:+44-161-200-4505; fax: +44-161-228-7040.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 6 4 - 0

130
R.E. Banks et al. / Journal of Fluorine Chemistry 96 (1999) 129±133
1. Introduction
lished conclusively by X-ray crystallographic analysis [11].
With a 1 : 1 molar ratio of reactants (1 to 4), the mono-
¯uoroaromatic product 15 can be isolated chromatographi-
cally in at least 62% yield; based on the stoichiometry
2 Â 1 ! 1 Â 10, the yields of the 2,5-dienone (10) formed
in the same vessel is appreciable (26%), and the correspond-
ing 2,4-dienone (14) does not appear to be produced. That
the mono¯uoroaromatic product 15 can undergo attack by
F-TEDA-BF4 (1) to give 10 under such reaction conditions
was established by treating 15 with a molar equivalence of 1
in wet (2 vol.% H2O) acetonitrile at 08C, then leaving the
mixture at 208C for 2 h before work-up, providing the 2,5-
dienone 10 in 72% yield.
The user-friendly site-selective commercial electrophilic
¯uorinating agent 1-chloromethyl-4- ¯uoro-1,4-diazoniabi-
cyclo[2.2.2]octane bis(tetra¯uoroborate) (1; Select¯uorTM
reagent F-TEDA-BF4) discovered by Banks and Sharif [1,2]
has been reported recently [3,4] to convert 9-methoxyphe-
nanthrene (2) in acetonitrile to 9-¯uoro-10-hydroxyphenan-
threne (3) and thence 9,9-di¯uoro-10-oxo-9,10-
dihydrophenanthrene (4); oxidative demethylation of 4-
methoxyphenol (5) with (1) in the same solvent gave p-
benzoquinone (6) [5]. We ®rst encountered vicarious aro-
matic ¯uorodemethylation in 1993 [6] while searching for a
more suitably activated aromatic substrate than methoxy-
benzene [2,7] with which to rank F-TEDA-BF4 (1) and its
Use of a 2 : 1 molar ratio of F-TEDA-BF4 (1) to 1,3,5-
trimethoxybenzene (7) in acetonitrile promotes the com-
plete conversion of 1-¯uoro-2,4,6-trimethoxybenzene (15)
formed ®rst to the di¯uoro-2,5-dienone 10, which can be
isolated chromatographically in at least 51% yield. Use
of wet acetonitrile (2 vol.% H2O) or aqueous acetonitrile
(20 vol% H2O) as the reaction solvent improved the yield
of 10 marginally (to 56% and 58%, respectively), but use
of water alone gave the best result (63% yield). Note that
F-TEDA-BF4 (1) is quite soluble in water (176 g/l at 208C
[2]) and we have often found it useful to employ wet
solvents to enhance the concentration of this reagent (under
appropriate substrate/reaction mechanism circumstances,
of course). Use of pure water as the solvent in the present
case, while disadvantageous from the viewpoint of reaction
mixture homogeneity (7 is an insoluble solid) simpli®es the
product work-up procedure, since the spent ¯uorinating
agent occurs as the known [2] water-soluble proton salt
‡
congeners as `F ' delivery agents. The reactions encoun-
tered involved conversion of 1,3,5-trimethoxybenzene (7),
4-methoxytoluene (8) and 2-methoxynaphthalene (9) to,
inter alia, 4,4-di¯uoro-3,5-dimethoxycyclohexa-2,5-dien-
1-one (10), 4-¯uoro-4-methylcyclohexa-2,5-diene-1-one
(11), and 1,1-di¯uoro-2-oxo-1,2- dihydronaphthalene
(12), respectively. The object of this paper is to provide
details of our work on the electrophilic ¯uorination of 1,3,5-
trimethoxybenzene (7) with F-TEDA-BF4 (1) and on the
analogous reaction involving 2,4,6-trimethoxytoluene (13).
Note that ¯uorodealkylation (including ¯uorodemethyla-
tion) of 1- and 2-alkoxynaphthalenes with caesium ¯uoro-
xysulphate at room temperature in acetonitrile in the
presence of boron tri¯uoride was reported more than a
decade ago [8], the reactions proceeding via initial `normal'
electrophilic mono¯uorination of these activated sub-
strates. Much earlier (1962) [9], perchloryl ¯uoride was
used to convert 3,5-dimethoxyphenol to a mixture of
4,4-di¯uoro-3,5-dimethoxycyclohexa-2,5-dien-1-one (10)
and its positional isomer 6,6-di¯uoro-3,5-dimethoxy-
cyclohexa-2,4-diene-1-one (14), the latter being used
as the precursor (via zinc-acetic acid reduction) of
2-¯uoro-3,5-dimethoxyphenol needed for the synthesis of
7-¯uoro-7-dechlorogriseofulvin [10]. Our work on the
use of F-TEDA-BF4 (1) to convert phenols to ¯uorodie-
‡
‡
ClCH2± N(CH2CH2)3N ±H (BF4 )2 (16).
Attempts to effect conventional electrophilic aromatic
substitution of ring hydrogen with ¯uorine in 2,4,6-tri-
methyoxytoluene (13) using a molar equivalence of F-
TEDA-BF4 (1) in acetonitrile provided only the vicarious
¯uorodemethylation product 4-¯uoro-3,5-dimethoxy-4-
methylcyclohexa-2,5-dien-1-one (17) in 81% yield. The
structure of this new dienone was established beyond doubt
by X-ray analysis [11].
nones,
e.g.
p-cresol ! 2-¯uoro-4-methylphenol ‡ 4-
The fate of the methyl group lost in the conversion of 2-
¯uoro-1,3,5-trimethoxybenzene (15) to 4,4-di¯uoro-3,5-
dimethoxycyclohexa-2,5-dienone (10) or of 2,4,6-tri-
methoxytoluene (13) to 4-¯uoro-3,5-dimethoxy-4-methyl-
cyclohexa-2,5-dienone (17) remains obscure at present.
Several potential direct nucleophilic demethylating agents
(Nu:) can be envisaged (see Scheme 1): the mono-cationic
residue 19 derived from F-TEDA-BF4 (1), acetonitrile and
water (the solvent systems), and the activated aromatic
substrates (7, 13) or even the mono¯uoro derivative 15.
No evidence for the intervention of 19 could be found by 1H
NMR analysis, examination of crude products failing to
reveal the presence of the mono-methylated di-cation
¯uoro-4-methylcyclohexa-2,5-dienone, will be presented
elsewhere.
2. Results and discussion
As expected, the `activated' aromatic substrate 1,3,5-
trimethoxybenzene (7) readily undergoes electrophilic
¯uorination by F-TEDA-BF4 (1) in acetonitrile at room
temperature or below (reaction mixtures prepared at 408C
were allowed to warm to 208C and left for 2 h before work-
up) to give 2-¯uoro-1,3,5-trimethoxybenzene (15). How-
ever, once formed, 15 readily suffers attack by 1 to yield the
¯uorodemethylation product 4,4-di¯uoro-3,5-dimethoxycy-
clohexa-2,5-dienone (10), the structure of which was estab-
‡
‡
ClCH2± N(CH2CH2)3N ±CH3 [an authentic sample of
the new bis(tetra¯uoroborate) 18 was prepared from 19
‡
and the oxonium salt (CH3)3O BF4 for comparative

R.E. Banks et al. / Journal of Fluorine Chemistry 96 (1999) 129±133
131
Scheme 1. Possible `direct' fluorodemethylation mechanism. (a) Candidates: 7, 13, 15, 19, CH3CN and/or H2O (note that even when no H2O was
deliberately added to the acetonitrile, ingress of moisture under the low-temperature reaction conditions employed could have provided the water required).
(b) No evidence was obtained to support the proposal that Nu ˆ 7, 13, 15 or 19 (see the text).
purposes]. Likewise, no NMR evidence was found for
the ring-methylation of substrates 7, 13 or 15. The
possibility that 18 formed initially but, subsequently, was
de-methylated by attack of water can be discounted,
since the 1H NMR spectrum of a solution of 18 in
D2O underwent no change during seven days at ambient
temperature. An alternative plausible mechanism is outlined
in Scheme 2. Work planned on vicarious electrophilic
¯uorodemethylation of methoxyarenes of interest in the
study of bioactive molecules, including the use of H218O
as the reaction solvent, may enable us to resolve this
mechanistic issue.
3. Experimental details
3.1. General
Melting points were determined using an Electrothermal
9200 apparatus, and are uncorrected. TLC analysis was
performed with Al back plates pre-coated with silica
(0.2 mm, 60 F254) and examined under UV ¯uorescence
(254 nm); dry-column ¯ash chromatographic (DCFC)
separations were executed on silica gel (Fluka H 5±
40 mm). IR, NMR and MS analyses were carried out on
Perkin±Elmer (783 spectrophotometer), Bruker [AC-300
Scheme 2. Possible `indirect' fluorodemethylation mechanism.

132
R.E. Banks et al. / Journal of Fluorine Chemistry 96 (1999) 129±133
(1H at 300 MHz; 13C at 75.5 MHz) and AC-200 (13C at
50 MHz; 19F at 188.8 MHz)] and VG (70±70 EQ) or Kratos
(MS50) instruments, respectively. NMR chemical shifts are
quoted relative to Me4Si (1H; 13C) or CF3CO2H (19F),
positive values being assigned to down®eld absorptions.
X-Ray crystallographic data were recorded on a Rigaku
AFC6S instrument using monochromated MoKa radiation.
1-Chloromethyl-4-¯uoro-1,4-diazoniabicyclo[2.2.2]oc-
tane bis(tetra¯uoroborate) (1; F-TEDA-BF4) was prepared
by direct ¯uorination of the corresponding monoquat salt
but the structural transformations involved have not been
investigated yet.
3.2.2. In Water
F-TEDA-BF4 (1) (3.56 g, 10.1 mmol) was added portion-
wise to a vigorously stirred suspension of ®nely-powdered
1,3,5-trimethoxybenzene (7) (0.84 g, 5.0 mmol) in water
(80 cm3) at room temperature. After a 2-h reaction period,
the solid product present was recovered by ®ltration, washed
with water, dried in vacuo (over KOH pellets) and shown by
NMR analysis (1H, 19F) to be 4,4-di¯uoro-3,5-dimeth-
oxycyclohexa-2,5-dienone (10) (0.60 g, 3.2 mmol, 63%).
‡
ClCH2± N(CH2CH2)3N BF4 as described previously [2].
3.2. Electrophilic fluorination of 1,3,5-trimethoxybenzene
(7)
3.2.3. In aqueous acetonitrile
The reaction in water (Section 3.2.2) was repeated
exactly but water (20 cm3) was added to the solution of 7
in acetonitrile (80 cm3) just before F-TEDA-BF4 was intro-
duced. DCFC puri®cation of the product provided the
di¯uoro-2,5-dienone 10 in 58% yield.
3.2.1. In acetonitrile
Finely powdered F-TEDA-BF4 (1) (7.12 g, 20.1 mmol)
was added portion-wise to a cold ( 408C) stirred solution of
1,3,5-trimethoxybenzene (7) (3.36 g, 19.9 mmol) in HPLC-
grade acetonitrile (Aldrich; 250 cm3), no attempt being
made to prevent the ingress of atmospheric moisture. The
reaction mixture was stirred at room temperature for 2 h,
then evaporated (Rotavapor) and the solid residue puri®ed
by DCFC (1 : 3 ethyl acetate: hexane; 80 cm3 fractions
collected) to provide 2-¯uoro-1,3,5-trimethoxybenzene
(15) (2.30 g, 12.4 mmol, 62%). [3rd fraction. Analysis:
1H NMR (CDCl3) ꢀ 3.76 (s, 3H, 3-CH3O), 3.85 (s, 6H,
3.3. Ex-situ electrophilic fluorination of 1-fluoro-2,4,6-
trimethoxybenzene (15)
Powdered F-TEDA-BF4 (1, 1.82 g, 5.13 mmol) was
added portion-wise to a cold (ice bath) stirred solution of
1-¯uoro-2,4,6-trimethoxybenzene (15; 0.93 g, 5.00 mmol)
in wet (2 vol% H2O) acetonitrile (40 cm3). After 5 min, the
cooling bath was removed and the mixture stirred at room
temperature for 2 h before work-up (evaporation; DCFC
separation of the residue using 1 : 3 by vol. ethyl acetate-
hexane). The only product isolated was 4,4-di¯uoro-3,5-
dimethoxycyclohexa-2,5-dienone (10; 0.67 g, 3.60 mmol,
72%), m.p. 142±1438C, with correct NMR (1H, 19F) para-
meters.
4
1,5-CH3O), 6.15 (d, JHF 6.2 Hz, 2H, ring C±H) ppm. 19F
NMR (CDCl3) ꢀ-91.05 (t, 4JHF 7.8 Hz). 13C NMR (CDCl3) ꢀ
1
56.2 (1, 5-CH3O), 92.0 (3-CH3O), 137.5 (d, JCF 236 Hz,
CF), 148.6 (2, 6-C), 161.7 (3, 5-C) ppm. MS (accurate
‡
mass): Calculated for (M ‡ H) m/z 191.0523. Found:
191.0523], 4,4-di¯uoro-3,5-dimethoxycyclohexa-2,5-dien-
1-one (10) (0.50 g, 2.63 mmol, 26%), m.p.140±1438C
(Ref. [9], m.p. 146±1488C). Product 10 was isolated from
the 6th and 7th DCFC fractions; UV (MeOH) 239.6 (",
16805), 298.0 (", 3773), nm [Ref. [9], 240 (", 16 900), 296
(", 4000) nm]; 1H NMR (CDCl3) 3.79 (s, 6H, CH3O), 5.42
3.4. Electrophilic fluorination of 2,4,6-trimethoxytoluene
(13)
4
(t, JHF 2.3 Hz, CHC=O) ppm; 19F NMR (CDCl3) 34.8
Finely-powdered F-TEDA-BF4 (1; 4.26 g, 12.0 mmol)
was added portion-wise to a cold ( 408C) stirred solution
of 2,4,6-trimethoxytoluene (13; 2.16 g, 11.9 mmol) in acet-
onitrile (90 cm3). The reaction mixture was removed from
the cooling bath (dry ice-methanol) after 5 min. then kept
(stirrer in motion) at room temperature for 2 h before work-
up (evaporation; DCFC of the yellow residue, 1 : 3 ethyl
acetate-hexane). This provided pale yellow 4-¯uoro-3,5-
dimethoxy- 4-methylcyclohexa-2,5-dien-1-one (17, n.c.)
(1.80 g, 9.7 mmol, 81%), m.p. 95±978C. [Analysis: UV
(methanol) 241.2 (", 18 430.5), 292.5 (", 4680) nm; 1H
NMR (CDCl3) ꢀ 1.75 (d, JHF 21.8 Hz, 3H, CH3), 3.78 (s,
6H, 3,5-CH3O), 5.40 (d, 4JHF 0.9 Hz) ppm; 19F NMR ꢀ 79.5
(m, JHF 2.3 Hz) ppm; 13C NMR (CDCl3) 56.7 (s, CH3O),
1
2
106.4 (t, JCF 242 Hz, CF2), 161.0 (t, JCF 22 Hz, C±CF2),
102.4 (s,C C=O), 184.5 (s, C=O) ppm. The structure was
con®rmed by X-ray analysis [11]. When the above reaction
was repeated using a 2 : 1 molar ratio of F-TEDA-BF4 (1;
3.56 g, 10.05 mmol) to 1,3,5-trimethoxybenzene (7; 0.84 g,
5.00 mmol) in 70 cm3 of acetonitrile, followed by DCFC
puri®cation of the crude product, only the di¯uorodienone
10 was isolated (0.49 g, 2.57 mmol, 51%). Deliberate use of
wet acetonitrile (2 vol.% of H2O was added to the solvent
before the ¯uorinating agent 1 was introduced) in a reaction
between 10 mmol of 1 and 5 mmol of 7 (initiated at 218C,
then allowed to warm to 208C) increased the yield of
isolated 10 to 56%.
3
(q, JFH 21.8 Hz, CH3CF) ppm; 13C NMR (CDCl3) ꢀ 22.0
2
(d, JCF 28.6 Hz, CH3CF), 56.2 (d, CH3O), 87.2 (d, JCF
1
}
2
The pale-yellow dienone (10) slowly becomes brown
when exposed to Manchester daylight [the change is fairly
rapid under UVirradiation (TLC inspection lamp; 365 nm)],
179.0 Hz), 100.2 (C±C=O), 168.1 (d, JCF 16.2 Hz,
CH3OC±CF), 186.2 (C±O) ppm; MS (accurate mass) m/z:
‡
Calculated for (M ‡ H) 187.0770. Found: 187.0771]. Like

R.E. Banks et al. / Journal of Fluorine Chemistry 96 (1999) 129±133
133
its 4,4-di¯uoro analogue (10), 4-¯uoro-3,5-dimethoxy-4-
methylcyclohexa-2,5-dienone (17) is sensitive to UV light,
but the products have not been identi®ed yet. The structure
of 17 was con®rmed by X-ray analysis [11].
CH2CH2), 5.55 (s, 2H, CH2Cl) ppm. 19F NMR (D2O) ꢀTFA
72.5 (BF4 ) ppm. 13C NMR [(CD3)2SO] ꢀ 53.6 (CH3),
55.4 (CH2NCH2Cl), 56.1 (CH2NCH3), 71.9 (CH2Cl) ppm.
3.5. Preparation of 1-chloromethyl-4-methyl-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)
(18)
References
[1] R.E. Banks, U.S. Patent, 5, 086, 178/1992 (to Air Products and
Chemicals, Inc.).
[2] R.E. Banks, M.K. Besheesh, S.N. Mohialdin-Khaffaf, I. Sharif,
J. Chem. Soc., Perkin Trans. 1 (1996) 2069.
Trimethoxonium tetra¯uoroborate (Aldrich; 1.48 g,
0.01 mol) was added to a solution of 1-chloromethyl-4-
aza-1-azoniabicyclo[2.2.2]octane tetra¯uoroborate (19)
(2.48 g, 0.01 mol) [12] in nitromethane (10 cm3). The mix-
ture was stirred under nitrogen overnight, then evaporated
(Rotavapor); the white residual solid was washed with a
small volume of diethyl ether containing acetonitrile
(4 : 1 v/v), dried in vacuo at room temperature, and then
shown by NMR and MS analyses to be 1-chloromethyl-4-
methyl-1,4- diazoniabicyclo[2.2.2]octane bis(tetra¯uorobo-
rate) (18; n.c.) (3.33 g, 0.095 mol, 95%). Analysis: Found:
C, 27.5; H, 4.8; BF4 , 49.6; N, 7.9%. Calculated for
C8H17B2ClF8N2: C, 27.4; H, 4.9; BF4 , 49.6; N, 8.0%);
1H NMR [(CD3)2SO] ꢀ 3.26 (s, 3H, CH3), 3.93 (s, 12H,
[3] M. Zupan, J. Iskra, S. Stavber, J. Fluorine Chem. 70 (1995) 7.
[4] M. Zupan, J. Iskra, S. Stavber, Croat. Chem. Acta 69 (1996) 1437.
[5] M. Zupan, J. Iskra, S. Stavber, Bull. Chem. Soc. Jpn. 68 (1995) 1655.
[6] M. Moore, A.J. Taylor, UMIST Final-Year B.Sc. Project Reports,
MichaelmasTerm, 1993.
[7] R.E. Banks, S.N. Mohialdin-Khaffaf, G.S. Lal, I. Sharif, R.G. Syvret,
J. Chem. Soc., Chem. Commun. (1992) 595.
[8] S. Stavber, M. Zupan, J. Org. Chem. 50 (1985) 3609.
[9] D. Taub, Chem. and Ind. (London), (1962) 558.
[10] D. Taub, C.H. Kuo, N.L. Wendler, Chem. and Ind. (London), (1962)
557.
[11] R.G. Pritchard (UMIST), personal communication.
[12] R.E. Banks, M.K. Besheesh, S.N. Mohialdin-Khaffaf, I. Sharif,
J. Fluorine Chem. 78 (1996) 43.