Elemental fluorine Part 12. Fluorination of 1,4-disubstituted aromatic compounds

Article abstract of DOI:10.1016/S0022-1139(99)00238-9

Direct fluorination of a series of 1,4-disubstituted benzene derivatives in acid reaction media at convenient temperature leads, in many cases, to selectively fluorinated aromatic products in preparatively useful conversions and yields.

Full text of DOI:10.1016/S0022-1139(99)00238-9

Journal of Fluorine Chemistry 102 (2000) 169±173
Elemental ¯uorine Part 12. Fluorination of 1,4-disubstituted
aromatic compounds$
Richard D. Chambersa,*, John Hutchinsona,b, Matthew E. Sparrowhawka,
Graham Sandforda, John S. Moillietb,c, Julie Thomsonb,c
aDepartement of Chemistry, University of Durham, Science Laboratories, South Road, Durham DH1 3LE, UK
bF2 Chemicals, Durham DH1 3LE, UK
cLea Lane, Lea Town, Preston PR4 ORZ, UK
Received 24 June 1999; received in revised form 24 June 1999; accepted 28 July 1999
Dedicated to our dear and valued friend, Professor Paul Tarrant, on the occasion of his 85th birthday
Abstract
Direct ¯uorination of a series of 1,4-disubstituted benzene derivatives in acid reaction media at convenient temperature leads, in many
cases, to selectively ¯uorinated aromatic products in preparatively useful conversions and yields. # 2000 Elsevier Science S.A. All rights
reserved.
Keywords: Fluorination; Halex; Aromatic
1. Introduction
paration of selectively ¯uorinated organic compounds [4±6]
and reactions between molecular ¯uorine and aromatic
compounds have been investigated by several groups of
workers. In most cases, the reaction between ¯uorine and
monosubstituted aromatic derivatives gave products that
were mixtures of regioisomers whose composition, although
in¯uenced by reaction conditions (e.g. solvent, temperature,
the presence of Lewis acid), was consistent with an electro-
philic substitution process [7±13]. A few examples of the
direct ¯uorination of disubstituted aromatic compounds
have also been reported. Where the ring substituents were
1,2- or 1,3- to one another, mixtures of regioisomers were
obtained but where the substituents were disposed 1,4, only
the hydrogen atom adjacent to the more electron donating
group, i.e. meta with respect to the electron withdrawing
group, was replaced by ¯uorine [9,10,12].
In the ®rst paper in this series [14], we discussed the
importance of the nature of the solvent on the direct ¯uor-
ination of aromatic compounds and, in particular, demon-
strated that solvents with high acidity and high dielectric
constant promoted a controlled electrophilic ¯uorination
process. We now report on a systematic investigation of
the ¯uorination of 1,4-disubstituted aromatic compounds
with a view to identifying compounds which might reason-
ably be prepared and, after suitable process development and
optimisation, manufactured by a direct ¯uorination process.
The importance of ¯uorinated compounds, and ¯uori-
nated aromatic compounds in particular, to the agrochemical
[1] and pharmaceutical [2] industries is well established.
Industrially, ¯uoroaromatic compounds having ¯uorine
attached directly to an aromatic ring are generally prepared
by either a halogen exchange reaction (Halex) in which an
`activated' chlorine atom on an aromatic ring is replaced by
¯uorine using ¯uoride ion in a suitable solvent, or by a
diazotization/¯uorodiazoniation sequence carried out on an
aromatic amine (Balz-Schiemann) [3]. However, the neces-
sary halo- and amino-aromatic precursors are not always
readily available so there is a continuous search for other
methods of introducing ¯uorine into speci®c sites of an
aromatic ring. The synthesis of ¯uoro-aromatic compounds
from the corresponding parent substrate by direct replace-
ment of hydrogen by ¯uorine offers an alternative approach
to the two established methodologies. There is currently
much interest in the use of molecular ¯uorine in the pre-
$ See R.D. Chambers, A.K. Joel, A.J. Rees, J. Fluorine Chem., 101
(1999) 97±105.
* Corresponding author. Tel.: ‡44-191-374-3120; fax: ‡44-191-384-
4737.
E-mail address: r.d.chambers@durham.ac.uk (R.D. Chambers).
0022-1139/00/$ ± see front matter # 2000 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 2 3 8 - 9

170
R.D. Chambers et al. / Journal of Fluorine Chemistry 102 (2000) 169±173
Table 1
Table 3
Fluorination of nitrobenzene derivatives
Fluorination of phenol derivatives
a
X
Conversion (%)
Yield (%)
a
X
Conversion (%)
Yield (%)
b
c
b
c
NOÃ2
75
84
70
64
12
41
55
28
22
18
8
1
2
3
4
5
6
OH*
OMe*
NHAc
Me*
F
75
100
100
63
70
50
60
50
53
44
8
1
7
CN*
10
22
7
20
12
13
14
15
16
17
CF3
100
83
8
COMe
COOH
COOMe
Br
Trace
Trace
Trace
50
20
17
4
36
100
90
Cl
47
Cl
100
13
Table 2
Fluorination of benzonitrile derivatives
Table 4
Fluorination of anisole derivatives
a
X
Conversion (%)
Yield (%)
a
X
Conversion (%)
Yield (%)
b
c
OH*
OMe*
NHAc
Me*
84
90
86
86
67
64
35
66
60
40
10
b
c
7
8
9
2
8
NOÃ2
CN*
COOMe*
Br
100
50
35
51
43
49
53
19
10
9
10
10
90
92
10
11
<5
18
19
20
21
22
F*
Trace
92
15
7
Cl
80
Me
NHAc
48
Complex mixture
<5
2. Results and discussion
Reactions of ¯uorine with a series of nitrobenzene
(Table 1), benzonitrile (Table 2), phenol (Table 3) and
anisole (Table 4) derivatives were carried out under com-
parable experimental conditions. In each reaction, ¯uorine
(10% v/v in nitrogen) was passed through a stirred, cooled
(108C) solution of the substrate in formic acid. After
passage of ¯uorine, the reaction vessel was purged with
nitrogen, the reaction mixture was poured into water and
organic material was extracted into dichloromethane. High
vacuum distillation (Kugelrohr) of the residue gave a crude
product, free from any tarry material, which was analysed
by GCMS and 19F NMR. Generally, the ¯uorinated products
were not isolated from the crude product mixture but their
identity, and the yields and conversions, were determined by
19F NMR and GCMS analysis with reference to authentic
samples. However, ¯uorinations of certain substrates
(marked * in Tables 1±4) were repeated and the products
were subsequently isolated and characterised.
From the results outlined in Tables 1±4, the main con-
clusions are that:
1. By suitable choice of substituents in 1,4-disubstituted
benzenes, high yields of selectively fluorinated products
can be obtained at reasonable rates;
2. Where one substituent is a powerful deactivating group
e.g. NO2 or CN, the other substituent is preferably
significantly activating for the fluorination to proceed at
a reasonable rate (Table 1, Entries 1, 2, 3 and Table 2,
Entries 7, 8, 9, 10);
3. Where both groups are very much deactivating, as in
1,4-dinitrobenzene and 1,4-dicyanobenzene, the sub-
strates are resistant to fluorination;

R.D. Chambers et al. / Journal of Fluorine Chemistry 102 (2000) 169±173
171
Table 5
4. Where both groups are activating, as in 4-methoxyace-
Fluorinations in concentrated sulphuric acid
tanilide (Table 4, Entry 22) and para-cresol, fluorination
is very rapid and complex mixtures of products are
obtained. In the para-cresol case, quinone derived
compounds [9] and polymers seem to be the main
products;
5. During the fluorination of methoxy- compounds, other
than 4-nitroanisole (Table 1, Entry 2), protonation of the
ether oxygen occurs due to the acidity of the medium
and this leads to significant demethylation and to the
formation of substituted phenols, fluorophenols and
quinone derived structures.
a
Substituents
X
Conversion (%)
Yield (%)
Y
b
c
1
OH
NO2
30
63
75
87
64
23
74
24
50
81
75
65
31
60
8
2
OCH3
CH3
F
NO2
NO2
11
2
Given that methyl and methoxy groups both activate a
benzene ring to electrophilic attack, the ¯uorination of 4-
methylanisole was surprising in that the conversion was
only 48% (Table 4, 21) whereas the conversion of the
nominally less reactive 4-nitroanisole (Table 1, 2), 4-cya-
noanisole (Table 2, 8) and 4-nitrotoluene (Table 1, 4) were
100%, 90% and 63%, respectively. This led us to examine,
under the conditions outlined above, the ¯uorination of
para-xylene which showed that, like 4-methylanisole, this
compound has a surprisingly low reactivity (conversion,
35%) compared to 4-nitroanisole, 4-cyanoanisole or 4-
nitrotoluene. We have also examined the ¯uorination of
mesitylene which, because it is highly activated towards
electrophilic attack, would be expected to be very reactive
(give a high conversion) towards ¯uorine. In this case,
sulphuric and formic acid could not be used as reaction
media because of competing sulphonation and immiscibilty
of the substrate, respectively. Consequently, reaction of
mesitylene with ¯uorine in tri¯uoroacetic acid was carried
out, and repeated several times, but only 5% conversion of
the mesitylene, to a single ring-¯uorinated product, was
observed. The reason for the unexpectedly low reactivity of
mesitylene (and xylene) towards ¯uorine in acidic media
remains uncertain, given the successful ¯uorination of ``less
4
5
NO2
10
±
6
Cl
OCH3
CH3
NO2
CO2Me
CHO
18
23
10
±
to the reaction medium should lead to enhanced reactivity of
the electron-rich aromatic substrates towards ¯uorination.
In an earlier paper [15], it was demonstrated that an
increase in the acidity of the reaction medium, for example,
changing the medium from formic to sulphuric acid,
resulted in an increase in conversion of the deactivated
aromatic substrate, 4-¯uorobenzoic acid, into products.
Against this background we investigated the use of con-
centrated sulphuric acid as a solvent for the ¯uorination of
other 1,4-disubstituted benzenes and the results are sum-
marised in Table 5.
By comparing results included in Tables 1±5, we see that
conversion of the nitrobenzene derivatives (Y ˆ NO2,
X ˆ F, Cl, CH3; Tables 1 and 5, entries 1, 2, 4) is higher
when ¯uorination is carried out in the more acidic medium,
thus con®rming that ¯uorine behaves as a more powerful
electrophile in such a solvent. However, for substituted
nitrobenzenes where X ˆ OH, OCH3 (Tables 1 and 5,
entries 1, 2) and in methoxy methylbenzoate (Tables 4
and 5 entry 18) the conversions of the aromatic substrates
to products are lower in sulphuric acid than in formic. This
could be due to a greater degree of protonation of the oxygen
atoms in the OH and OMe groups by the stronger acid
leading to reduced susceptibility of the molecule to electro-
philic ¯uorination.
1
activated'' substrates (Tables 1±4). The H and 13C NMR
spectra of mesitylene in CF3COOH demonstrated that the
low reactivity of the compound towards ¯uorine could not
be accounted for by protonation of the aromatic ring.
A competition reaction involving ¯uorination of an equi-
molar mixture of mesitylene and 4-nitrotoluene in
CF3COOH gave a totally unexpected result. The conversion
of mesitylene increased to 20%, but the 4-nitrotoluene was
recovered unchanged. We considered whether p-complexes,
formed by the interaction of the p-electron rich mesitylene
with the relatively electron poor 4-nitrotoluene, could be the
cause of increased susceptibility of mesitylene and
decreased reactivity of nitrotoluene towards ¯uorination.
However, cyclic voltammetry studies of a solution of mesi-
tylene in CF3COOH showed no change in oxidation poten-
tial after the addition of an equivalent of nitrotoluene. At this
stage, we have no clear evidence to indicate the reasons why
mesitylene and xylene are relatively unreactive towards
¯uorine or why the addition of a more deactivated aromatics
3. Conclusions
In principle, after suitable process development and
optimisation, it is now reasonable to consider direct ¯uor-
ination as a potential route to certain 1,4-disubstituted
benzenes on a large scale, and this methodology is com-
plimentary to current industrial processes like `Halex'
(halogen exchange) and diazotisation routes. Generally,
molecules with an activating and a deactivating group in

172
R.D. Chambers et al. / Journal of Fluorine Chemistry 102 (2000) 169±173
the 1 and 4 positions give practical reaction rates and good
yields of products in direct ¯uorination reactions but it is
currently unclear why certain compounds, such as 1,4-
xylene and mesitylene, have unexpectedly low reactivity.
These latter results demonstrate that, although ¯uorine acts
in many situations as a simple electrophile, there is clearly
much yet to learn about the range of mechanistic prefer-
ences.
priate 19F NMR resonances gave the yield of ¯uoro-aro-
matic, based upon the conversion obtained above.
Selected reactions were repeated and the ¯uorinated
products were isolated by column chromatography over
silica gel using hexane/dichloromethane (2:1) as eluent.
Analytical and spectroscopic data for 1b, 2b, 4b±8b,
10b, 18b, 2c, 8c and 18c, prepared by the direct ¯uorination
process, are given below.
2-Fluoro-4-nitrophenol 1b: white crystals; m.p. 118.5±
1208C (lit. [15] 120±1228C); (Found: C, 45.6; H, 2.5; N, 8.7.
C6H4FNO3 requires: C, 45.9%; H, 2.5%; N, 8.9%); dH 7.22
(1H, dd, JH5,H6 8.8, JH6,F 8.8, H-6), 8.0 (2H, m, H-3,5),
10.15 (1H, br s, OH); dC 112.2 (d, 2JCF 22.9, C-3), 117.2 (d,
4. Experimental
NMR spectra were recorded in deuteriochloroform unless
otherwise stated on either a Varian Gemini 200, a Varian
VXR 400S or a Bruker AC250 NMR spectrometer (1H,
250 MHz; 19F, 235 MHz) with chemical shifts being mea-
sured from tetramethylsilane and trichloro¯uoromethane
in ppm. Coupling constants are given in Hz. Mass spectra
were recorded on either a Fissons VG Trio 1000 spectro-
meter coupled with a Hewlett Packard 5890 series II gas
chromatograph. Elemental analyses were obtained on
either a Perkin-Elmer 240 or a Carlo Erba Elemental
Analyser. Melting points and boiling points were recorded
at atmospheric pressure and are uncorrected. Column
chromatography was carried out using silica gel (Merck
No. 9385) and silica plates (Merck) were used for TLC
analysis.
4
3JCF 1.9, C-6), 121.5 (d, JCF 3.1, C-5), 140.8 (m, C-4),
1
2
149.7 (d, JCF 242.6, C-2), 149.8 (d, JCF 14.0, C-1); dF
133.9 (m); m/z (EI ) 157 (M , 100%), 127 (46), 83 (95),
57 (94).
‡
‡
2-Fluoro-4-nitroanisole 2b: white crystals; m.p. 102±
1038C (from ethanol) (lit. [15] 103.6±104.68C); (Found:
C, 49.3; H, 3.65; N, 8.0. Calc. for C7H6FNO3: C, 49.1%; H,
3.5%; N, 8.2%); dH 4.0 (3H, s, OCH3), 7.0 (1H, dd, 3JH5;H6
8.8, 4JH6;F 8.4, H-6), 7.95 (1H, dd, 3JH3;F 10.6, 4JH3;H5 2.4,
3
4
5
H-3), 8.06 (1H, ddd, JH5;H6 8.8, JH3;H5 2.4, JH5;F 1.5,
3
H-5); dC 56.6 (s, OCH3), 112.0 (d, JCF 2.3, C-6), 112.1
(d, 2JCF 27.4, C-3), 120.9 (d, 4JCF 3.1, C-5), 141.5 (s, C-4),
1
2
151.1 (d, JCF 251.4, C-2), 153.3 (d, JCF 10.7, C-1); dF
131.4 (m); m/z (EI ) 171 (M , 100%), 141 (38), 125 (9),
110 (18).
‡
‡
2,6-Di¯uoro-4-nitroanisole 2c: pale yellow crystals;
(Found: C, 44.2; H, 2.6; N 7.1. C7H5F2NO3 requires: C,
44.4%; H, 2.6%; N, 7.4%); dH 4.17 (3H, t, 5JHF 2.0, OCH3),
5. Fluorination reactions Ð general procedure
4
A glass reaction vessel ®tted with a mechanical stirrer, an
FEP thermocouple well, an FEP gas delivery tube and an
exit tube to a scrubber ®lled with soda lime was charged
with substrate (25 mmol) and either formic or concentrated
sulphuric acid (100 ml) before being cooled to ca. 108C. The
vessel was purged with nitrogen and then ¯uorine
(50 mmol) diluted to 10% v/v with nitrogen was passed
through the stirred solution over 1.75 h. When the ¯uorine
supply had been turned off, the reaction vessel was purged
with nitrogen. The reaction mixture was then poured into
water and extracted with dichloromethane. The extracts
were dried, the solvent was removed at reduced pressure
and the residue was distilled at reduced pressure to remove
all the volatile material from the tarry residue. The weighed
distillate was then analysed by GC and NMR spectroscopy,
and the main products were identi®ed by GCMS and 19F
NMR spectroscopy, with reference to authentic samples
(purchased from either the Aldrich, Fluorochem or Lan-
caster synthesis). The composition of a weighed crude
reaction mixture was determined by GCMS analysis and
the conversion of start material was calculated from GC
peak intensities. The amount of ¯uoro-aromatic in the crude
product was determined by adding a known amount of
¯uorobenzene to a weighed amount of the crude product
mixture. Comparison of the relative intensities of the appro-
7.8 (2H, m, H-3,5); dC 61.8 (t, JCF 4.2, OCH3), 109.0 (m,
C-3), 140.9 (m, C-4), 142.5 (t, 2JCF 12.9, C-1), 153.97 (dd,
‡
3
1JCF 252.2, JCF 6.4, C-2); dF 125.1 (m); m/z (EI ) 189
‡
(M , 100%), 159 (45), 143 (14), 128 (20), 100 (12).2-
Fluoro-4-nitrotoluene 4b: pale yellow crystalline solid;
m.p. 33.0±34.38C (from ethanol) (lit. [16] 34±358C);
(Found: C, 53.9; H, 3.8; N, 8.9. C7H6FNO2 requires: C,
54.2%; H, 3.9%; N, 9.0%); dH 2.17 (3H, s, CH3), 7.20 (1H,
dd, JH5,H6 7.7, JH6,F 7.7, H-6), 7.47 (1H, dd, JH3,F 10.5,
JH3,H5 2.0, H-3), 7.65 (1H, m, H-5); dC 15.9 (s, CH3), 112.0
(d, 2JCF 27.4, C-3), 120.7 (s, C-5), 133.7 (d, 3JCF 5.3, C-6),
135.1 (d, 2JCF 17.3, C-1), 148.6 (d, 3JCF 8.4, C-4), 162.2 (d,
‡
‡
1JCF 248.7, C-2); dF 113.4 (m); m/z (EI ) 155 (M ,
100%), 125 (20), 109 (77), 83 (56).
3,4,-Di¯uoro-nitrobenzene 5b: yellow oil; (Found: C,
45.4; H, 1.8; N, 8.6. C7H3F2NO2 requires: C, 45.3%; H,
1.9%; N, 8.8 %); dH 7.3 (1H, m, H-5), 8.1 (2H, m, H-2,6); dC
113.9 (d, 2JCF 21.3, C-2), 117.8 (dd, 2JCF 19.4, C-5), 120.7
(dd, 3JCF 7.99, 4JCF 3.77, C-6), 144.0 (s, C-1), 149.8 (d, 1JCF
2
1
2
254.5, JCF 14.1, C-3), 154.6 (dd, JCF 260.3, JCF 12.8,
‡
C-4); dF 126.6 (1F, m, F-4), 133.0 (1F, m, F-3); m/z (EI )
159 (M , 86%), 129 (28), 113 (100), 101 (26), 63 (77).
‡
3-Fluoro-4-chloro-nitrobenzene 6b: pale yellow crystals;
m.p. 63.5±64.28C (from ethanol) (lit. [17] 63±648C);
(Found: C, 40.9; H, 1.6; N, 7.7. C6H3ClFNO2 requires:

R.D. Chambers et al. / Journal of Fluorine Chemistry 102 (2000) 169±173
173
‡
C, 41.0%; H, 1.7%; N, 8.0 %); dH 7.6 (1H, m, H-5), 8.0 (2H,
m, H-2,6); dC 112.3 (d, 2JCF 25.9, C-2), 119.9 (d, 4JCF 4.2,
C-6), 128.7 (d, JCF 17.6, C-4), 131.2 (s, C-5), 147.0 (s,
247, C-3), 165.8 (s, C=O); dF 135.2 (m); m/z (EI ) 184
(M , 36%), 153 (100), 125 (15), 110 (20), 82 (30).
‡
2
Methyl 3,5-di¯uoro-4-methoxy-benzoate 18c: a white
crystalline solid; m.p. 69.8±70.98C (lit. [19] 70±718C);
dH 3.82 (3H, s, OCH3), 4.01 (3H, s, OCH3), 7.5 (2H, d,
‡
C-1), 157.6 (d, 1JCF 254, C-3); dF 110.4 (m); m/z (EI ) 177
‡
‡
(M , 32.3%), 175 (M , 100), 147 (11), 145 (33), 131 (24),
129 (76), 117 (27), 109 (21), 93 (19), 74 (14).
3JHF 8.4, H-2,6); dC 52.5 (s, ±COOCH3), 61.6 (t, JCF 4.0,
4
3
2-Fluoro-4-cyanophenol 7b: white crystals; m.p. 133.5±
134.68C (lit. [18] 134±1358C); (Found: C, 61.1; H, 2.9; N,
10.0. C7H4FNO requires: C, 61.3%; H, 2.9%; N, 10.2%); dH
7.2 (1H, m, H-6), 8.0 (2H, m, H-3,5), 10.15 (1H, br s, OH);
dC 104.0 (d, 3JCF 8.35, C-4), 117.8 (s, CN), 118.4 (s, C-6),
OCH3), 113.8 (m, C-2), 124.1 (t, JCF 8.45, C-1), 140.5 (t,
2JCF 13.2, C-4), 154.6 (dd, 1JCF 249, 3JCF 6.1, C-3), 164.9 (t,
4JCF 3.0, C=0); dF 127.7 (m); m/z (EI ) 202 (M , 57%),
171 (100), 143 (20), 128 (22), 100 (48).
‡
‡
2
4
119.6 (d, JCF 20.9, C-3), 130.0 (d, JCF 3.4, C-5), 148.1
(d, 2JCF 14.1, C-1), 150.3 (d, 1JCF 242, C-2); dF 137.5 (m);
m/z (EI ) 137 (M , 100%), 117 (14), 89 (32).
Acknowledgements
‡
‡
3-Fluoro-4-methoxy-benzonitrile 8b: white crystals; m.p.
95.6±97.08C (lit. [18] 98±998C); (Found: C, 62.9; H, 3.9; N,
9.1. C8H6FNO requires C, 63.6%; H, 4.0%; N, 9.3%); dH
3.95 (3H, s, OCH3), 7.01 (1H, dd, JH5;H6 8.4, JH5;F 8.4,
H-5), 7.36 (1H, dd, 3JH2;F 10.4, 4JH2;H6 1.8, H-2), 7.43 (1H,
We thank F2 Chemicals for funding (GS and MES), the
Royal Society (University Research Fellowship to GS) and
Dr. Maurice Medebielle (for Cyclic Voltammetry experi-
ments).
3
4
3
4
4
ddd, JH5;H6 8.4, JH2;H6 1.8, JH6;F 1.6, H-6); dC 56.3 (s,
OCH3), 103.9 (d, JCF 8.4, C-1), 113.5 (s, C-5), 118.0 (s,
3
References
2
4
CN), 119.5 (d, JCF 20.9, C-2), 129.7 (d, JCF 3.8, C-6),
2
1
[1] D. Cartwright, in: R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.),
Organofluorine Chemistry: Principles and Commercial Applications,
Plenum Press, New York, 1994, p. 237.
151.7 (d, JCF 250, C-3), 151.8 (d, JCF 10.7, C-4); dF
‡
‡
131.9 (m); m/z (EI ) 151 (M , 100%), 136 (50), 108 (78).
3,5-Di¯uoro-4-methoxy-benzonitrile 8c: white crystals;
m.p. 83.9±85.48C; (Found: C, 56.3%; H, 3.0%; N, 7.9%.
C8H5F2NO requires: C, 56.8%; H, 3.0%; N, 8.2%); dH 4.1
[2] P.N. Edwards, in: R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.),
Organofluorine Chemistry: Principles and Commercial Applications,
Plenum Press, New York, 1994, p. 501.
5
[3] J.S. Moilliet, in: R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.),
Organofluorine Chemistry: Principles and Commercial Applications,
Plenum Press, New York, 1994, p. 195.
(3H, s, OCH3), 7.2 (2H, m, H-2); dC 61.7 (t, JCF 4.0,
OCH3), 105.1 (t, 3JCF 11.1, C-1), 116.7 (s, CN), 116.8 (dd,
2JCF 17.9, JCF 8.3, C-2), 141.1 (t, JCF 12.6, C-4), 154.8
4
2
[4] S.T. Purrington, B.S. Kagen, T.B. Patrick, Chem. Rev. 86 (1986)
997.
‡
(dd, 1JCF 252, 3JCF 6.49, C-3); dF 125.8 (m); m/z (EI ) 169
(M , 100%), 154 (45), 126 (48), 75 (26).
‡
[5] G.G. Furin, G.P. Gambaretto, Direct Fluorination of Organic
Compounds, Cleup, Padova, 1996.
[6] J. Hutchinson, G. Sandford, Top. Curr. Chem. 193 (1997) 1.
3-Fluoro-4-methyl-benzonitrile 10b: white crystals;
(Found: C, 70.6; H, 4.2; N, 10.2. C8H6FN requires: C,
71.0%; H, 4.4%; N, 10.1%); dH 2.3 (3H, s, CH3), 7.3
[7] V. Grakauskaus, J. Org. Chem. 35 (1970) 723.
[8] N.B. Kaz0mina, L.S. German, I.D. Rubin, I.L. Knunyants, Dokl.
Acad. Nauk. SSSR-Khimiya 194 (1970) 1329.
3
(3H, m, H-2,5,6); dC 14.7 (d, JCF 3.4, CH3), 110.7 (d,
3JCF 9.1, C-1), 117.7 (d, 4JCF 2.7, CN), 118.4 (d, 2JCF 25.5,
[9] S. Misaki, J. Fluorine Chem. 17 (1981) 159.
4
2
[10] S. Misaki, J. Fluorine Chem. 21 (1982) 191.
C-2), 127.7 (d, JCF 3.8, C-6), 131.2 (d, JCF 17.1, C-4),
132.3 (d, 3JCF 5.7, C-5), 160.5 (d, 1JCF 248, C-3); dF 114.5
(m); m/z (EI ) 135 (M , 100%), 134 (86), 108 (32), 107
[11] H.H. Coenen, K. Franken, S. Metwally, G. Stocklin, J. Labelled
Compd. RadioPharm. 23 (1986) 1179.
‡
‡
[12] S.T. Purrington, D.L. Woodward, J. Org. Chem. 56 (1991) 142.
[13] L. Conte, G.P. Gambaretto, M. Napoli, C. Fraccaro, E. Legnaro, J.
Fluorine Chem. 70 (1995) 175.
(23).
Methyl 3-¯uoro-4-methoxy-benzoate 18b: white crystals;
m.p. 36.5±37.88C (lit. [19] 37.58C); dH 3.8 (3H, s, OCH3),
3.9 (3H, s, OCH3), 6.97 (1H, dd, JH5;H6 8.4, JH5;F 8.4,
[14] R.D. Chambers, C.J. Skinner, J. Hutchinson, J. Thomson, J. Chem.
Soc. Perkin Trans. 1 (1996) 605.
3
4
[15] G. Schiemann, T.B. Miau, Chem. Ber. 66 (1933) 1179.
[16] F.C. Schmelkes, M. Rubin, J. Am. Chem. Soc. 66 (1944) 1632.
[17] C.K. Ingold, C.N.N. Vass, J. Chem. Soc. (1928) 422.
[18] S.M. Kelly, Helv. Chim. Acta 67 (1984) 1572.
[19] B. Niemann, J. Am. Chem. Soc. 63 (1941) 2204.
H-5), 7.36 (1H, dd, 3JH2;F 10.4, 4JH2;H6 1.8, H-2), 7.43 (1H,
3
4
5
ddd, JH5;H6 8.4, JH2;H6 1.8, JH6;F 1.6, H-6); dC 52.0
(s, ±COOCH3), 56.1 (s, ±OCH3), 112.1 (d, JCF 1.5, C-
3
5), 117.0 (d, 2JCF 19.8, C-2), 122.7 (d, 3JCF 6.4, C-1), 126.5
(d, 4JCF 3.4, C-6), 151.5 (d, 2JCF 10.6, C-4), 151.5 (d, 1JCF