The role of F-N reagent and reaction conditions on fluoro functionalisation of substituted phenols

Article abstract of DOI:10.1016/j.tet.2006.02.051

The effect of steric interactions on the regioselectivity of fluorination of para alkyl substituted phenols was investigated and the strong effect of size of the alkyl substituent, the structure of the F-N reagent and the solvent on the site of fluorination was established. The course of reaction obeyed a second order rate equation, while the fluorination process required higher ΔH^≠ activation than oxidation or oxidative demethylation. Solvent polarity variations had a small effect on the rate of functionalisation, while an excellent Hammett correlation with ρ⁺=-2.3 was determined.

Full text of DOI:10.1016/j.tet.2006.02.051

Tetrahedron 62 (2006) 4474–4481
The role of F–N reagent and reaction conditions on fluoro
functionalisation of substituted phenols
a
a
a
a,b
Igor Pravst, Maja Papez Iskra, Marjan Jereb, Marko Zupan and Stojan Stavberb,
*
ˇ
a
ˇ
ˇ
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Askerceva 5, 1000 Ljubljana, Slovenia
bLaboratory for Organic and Bioorganic Chemistry, ‘Jozef Stefan’ Institute, Jamova 39, 1000 Ljubljana, Slovenia
Received 18 November 2005; revised 26 January 2006; accepted 16 February 2006
Abstract—The effect of steric interactions on the regioselectivity of fluorination of para alkyl substituted phenols was investigated and the
strong effect of size of the alkyl substituent, the structure of the F–N reagent and the solvent on the site of fluorination was established. The
course of reaction obeyed a second order rate equation, while the fluorination process required higher DHs activation than oxidation or
oxidative demethylation. Solvent polarity variations had a small effect on the rate of functionalisation, while an excellent Hammett
correlation with rCZK2.3 was determined.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
molecules2 and is also very effective in the bioisosterism
strategy.3 The mild and selective introduction of a fluorine
atom into organic molecules has been a specialised field of
investigation in the last three decades, and various types of
reagents were developed. Hydroxy substituted benzene
derivatives have been used as model substrates in
fluorination studies on several occasions,4 but the effective-
ness of preparation of fluoro substituted molecules also
varies with the other substituents present. The course of
fluorination is greatly dependent on the strong oxidation
capacity of this family of reagents. In the field of mild
fluorination, studies have been mainly connected with the
effect of the structure of the F–L reagent4 on the type of
transformation of the organic molecule, its regioselectivity,
the effect of solvent, inhibitors, etc.
Hydroxy substituted aromatic molecules are important
compounds in the chemistry of life and consequently in health
chemistry, today being very popular as antioxidising, antic-
arcinogenic molecules, etc.1 These molecules bear at least one
hydroxy group, but the second and third substituents play
important roles in their chemical reactivity. Usually at least
one alkoxy group is present while the third substituent
modulates the electron density of the aromatic ring. They can
be classified into one of three major classes: class A, the most
electron-rich molecules withatleast one additionalhydroxy or
alkoxy group, preferably para to the hydroxyl group, have a
very low oxidising potential and are very strong radical
inhibitors. In class B, the molecule bears an sp3 hybridized
carbon atom in the para position, while in class C an sp2
carbon atom is present at the para position. On the other hand,
the important role of the alkoxy group (usually methoxy in the
position ortho to the hydroxyl group) has been shown in
modulation of the biological activity of various types of
phenols, connected with the possibility of hydrogen bond
formation between the methoxy and hydroxy groups and
consequentlyinthe geometryofthe molecule anditshydrogen
atom donation properties.
Valuable information about the mechanism involved that
could be provided from kinetic data (rate of reaction,
activation parameters, Hammett correlations, etc.) are rare,
due to the high reactivity and high sensitivity of F–L
reagents (CF3OF, CF3COOF, CsSO4F, XeF2) to the reaction
conditions (small amounts of HF, presence of water, solvent
polarity, reaction of the solvent with the reagent, etc.). This
type of investigation is possible with the class of F–N
reagents,5 as they are quite reactive, stable, non-explosive
and selective in their fluorination of organic molecules.
We have already demonstrated that the reactions of
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
bis(tetrafluoroborate) (Selectfluore F-TEDA-BF4), a repre-
sentative of the F–N class of reagent, could be easily
monitored by iodometric titration.6 F–N reagents have been
The fluorine atom has several times been used as a
convenient substituent or modulator in the field of bioactive
Keywords: Fluorination; F–N reagents; Selectfluor F-TEDA-BF4;
Substituted phenols; Kinetics; Solvent effects; Substituent effects.
Corresponding author. Tel.: C386 1 477 3660; fax: C386 1 251 9385;
e-mail: stojan.stavber@ijs.si
*
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.02.051

I. Pravst et al. / Tetrahedron 62 (2006) 4474–4481
4475
used for fluorination of aromatic molecules; however, the
OH
R
7a: R=Me
b: R=CH(CH3)2
c: R=C(CH3)3
type of functionalisation strongly depends on the structure
of the F–N reagent, the functional groups attached to the
aromatic molecule and the reaction conditions (solvent e.g.,
acetonitrile, methanol, water, trifluoroacetic acid; catalyst
and reaction temperature). The types of ring transformations
observed include ring substitution, ipso substitution, the
addition process and oxidation.4–11
d: R=C(CH3)2CH2C(CH3)3
F-TEDA-BF4
CH2Cl
-
+ (BF4 )2
N
In order to obtain further information about the course of
functionalisation of aromatic molecules with the F–N type
of reagents, we decided to study the effect of substituents
and solvent polarity on mild functionalisation of substituted
phenols with Selectfluore F-TEDA-BF4, Accufluore
NFTh (1-hydroxy-4-fluoro-1,4-diazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate)) and FP-B800 (N-fluoro-2,6-
dichloropyridinium tetrafluoroborate). Because of the
importance of the substituent on the phenol in the para
position on the course of the functionalisation with F–N
reagents, we studied the effect of the alkyl group in the
context of steric interactions on the one hand and leaving
group properties on the other (Scheme 1).
N+
CH3CN MeOH
FP-B800
Cl
Cl
F
S
F-N
OH
N+
N+
BF4
H2O
-
F
-
N+(BF4 )2
F
NFTh
RING
FLUORINATION
OH
F
8a-d
R
H
H
O
OH
Y
R
Y
R
O
R
O
Y
F-N
S
F
F
R
9a-c
F
10
IPSO
SUBSTITUTION
ADDITION
2
1:Y=O, R=H
2:Y=O, R=OH
3:Y=O, R=OCH3
Scheme 2.
4:Y=O, R=COOCH3
5:Y=O, R=CN
Table 1. Effect of the structure of 4-substituted phenols, fluorination agents
and solvents on reaction channels in fluoro functionalisationa
6:Y=S, R=H
Scheme 1.
R subst.
Reagent
Product distribution 8:9:10 (yield
(%)) inb
MeCN
MeOH
2. Results and discussion
Me (7a)
iPr (7b)
tBu (7c)
tOct (7d)
F-TEDA-BF4
NFTh
FP-B800
F-TEDA-BF4
NFTh
FP-B800
F-TEDA-BF4
NFTh
FP-B800
34:66:0 (55)
41:59:0 (53)
(!5)
40:60:0 (78)
47:52:0 (87)
100:0:0 (22)
60:0:40 (84)
61:0:39 (92)
63:0:36 (43)
88:0:12 (55)
100:0:0 (52)
100:0:0 (60)
We started by investigating the effect of the bulk
substituent, the structure of the reagent and the solvent
on the course of functionalisation of para substituted
phenols (Scheme 2); the effect of these three parameters
is presented in Table 1. Fluorination with F-TEDA-BF4
in acetonitrile at reflux temperature resulted in three
types of product: 2-fluoro-4-alkyl-phenoles (8) as a result
of ortho fluorination, 4-alkyl-4-fluoro-cyclohexa-2,5-di-
enone addition products (9) and ipso substituted 4-fluoro-
phenol (10). The alkyl substituent has an important effect
on the reaction path, bulky alkyl substituents increasing
ortho fluorination (Me: 34%, iPr: 40%, tBu: 60%,
tOct(1,1,3,3-tetramethyl-butyl): 88%) and reducing para
attack. The structure of the alkyl group (tertiary,
secondary, primary carbon atom) also has an important
role in the competition between two types of functiona-
lisation at the para position and is graphically presented
in Figure 1.
62:38:0 (84)
67:33:0 (88)
81:0:19 (83)
90:0:10 (91)
F-TEDA-BF4
88:0:12 (60)
a Reaction conditions: substrate (1 mmol), fluorinating reagent (1 mmol),
solvent (10 mL), reflux temperature, 2 h.
b Relative distribution in percentage determined from 19F NMR spectra of
isolated reaction mixtures; total yield of fluorinated products was
determined from 19F NMR spectra of isolated reaction mixtures using
octafluoronaphthalene as internal standard.
In fluoro functionalisation the regioselectivity and type of
transformation were found to be dependent on both the
solvent and the substituent. Methanol in comparison to
acetonitrile completely changed the regioselectivity in the
case of 4-methyl phenol (7a) where exclusive ortho

4476
I. Pravst et al. / Tetrahedron 62 (2006) 4474–4481
100
100
90
80
70
60
50
40
30
20
10
0
10
10c
OH
90
OH
80
70
F
F
60
9
50
O
9c
O
40
30
R
F
F
20
10
0
8
8c
OH
OH
F
F
20
30
35
40
50
55
80
Me (7a) iPr (7b) tBu (7c) tOct (7d)
R
T [˚C]
R
Figure 1. Effect of the alkyl substituent on reaction channels in fluorination
of 4-alkyl phenols (7a–d) with F-TEDA-BF4 in acetonitrile. Relative
distribution in % determined from 19F NMR spectra of isolated reaction
mixtures. Reaction conditions: substrate (1 mmol), F-TEDA-BF4 (1 mmol),
acetonitrile (10 mL), 2 h.
Figure 2. Effect of temperature on competition between the electrophilic
substitution process, ipso substitution and addition functionalisation of
4-tert-butyl phenol (7c) with NFTh in acetonitrile. Relative distribution in
percentage determined from 19F NMR spectra of isolated reaction mixtures.
Reaction conditions: substrate (1 mmol), fluorinating reagent (1 mmol),
solvent (10 mL), 2–24 h (2 h for at 80 8C, 8 h at 50 and 55 8C, 24 h at 20, 30
and 35 8C).
fluorination was observed, but the effect was less
pronounced with other phenols (Table 1).
(60% 8c, 40% 9c) was heated for another hour at 80 8C,
the dienone product 9c was completely converted to
4-fluorophenol (10). This conversion was also indepen-
dently confirmed recently.12 These experiments indicate
that 4-fluorophenol (10) was probably formed from
cyclohexadienone derivative 9 under the given reaction
conditions and not by the ipso substitution process from the
precursor carbonium ion (CB, Scheme 3).
Further, we investigated the effect of reagent structure on the
course of functionalisation of phenols and found that the
structurally similar NFTh is a comparable reagent but with
higher ortho regioselectivity, as evident from Table 1. The
pyridinium fluorinating reagent proved to be much less
reactive; conversions achieved after 2 h reflux were also
dependent on the substituent (5, 22, 43% for 7a, 7b, 7c,
respectively) with similar selectivity to F-TEDA-BF4 and
NFTh in the case of tert-butyl derivative 7c, but exclusive
ortho fluorination with iso-propyl derivative 7b. As evident
from Table 1 the alkyl group not only has an effect on the
regioselectivity, but also on the further transformation of the
intermediateformedafterparaattack. Inthecaseofthemethyl
group, the hydroxyl group lost a proton and the dienone
derivative 9a was formed exclusively, but in the case of the
tert-butyl derivative the alkyl group left the molecule giving
4-fluoro phenol (10). This reaction channel could be explained
by the stability of the tert-butyl cation as a leaving group from
the intermediate formed after para attack, or by the instability
of 4-tert-butyl-4-fluoro-cyclohexa-2,5-dienone. To clarify the
reaction pathways yielding addition or ipso substitution
products at the para position, we studied the effect of
temperature on fluorination of 4-tert-butyl phenol (7c) with
NFTh in acetonitrile and found that the product distribution
was significantly dependent on the temperature used. As
evident from Figure 2, at room temperature 60% of ortho
attack was accompanied by 40% of the addition process,
yielding cyclohexadienone product 9c.
OH
OH
R
F-N L
F-N L
R
7
OH
OH
H
F
CA
CB
F R
R
O
OH
OH
F
At higher temperature (80 8C) the regioselectivity was
unchanged, the amount of ortho attack remaining
unchanged, while the cyclohexadienone product is no
longer found and 40% of 4-fluoro phenol (10) was formed
with comparably high conversions in all experiments (85–
95%). Further, we studied the stability of 4-tert-butyl-4-
fluoro-cyclohexa-2,5-dienone (9c) in acetonitrile or metha-
nol under reflux and after 2 h no conversion to 10 was
observed. On the other hand, when the reaction mixture
obtained after fluorination of 7c at room temperature
F R
R
F
8
9
10
Scheme 3.
In continuation, we investigated the kinetics of the reaction
of phenol (1) with F-TEDA-BF4 in water and acetonitrile,
monitoring the process of transformation by iodometric
titration and found that the rates of fluorination obey the

I. Pravst et al. / Tetrahedron 62 (2006) 4474–4481
4477
As evident from Table 2, reaction was faster in water than in
acetonitrile. Oxidation of p-hydroquinone (2) with
F-TEDA-BF4 to p-quinone8 also obeyed a second order
rate equation, but the process was much faster than
fluorination of the aromatic ring in 1 and the effect of
solvent polarity less pronounced than in the fluorination
process (k2water/k2acetonitrileZ1.9 for oxidation and 3.6 for
fluorination). The reactivity of the p-methoxy derivative (3),
which is also converted to p-quinone,8 lay in between that of
hydroquinone and phenol and the effect of solvent polarity
on the oxidation–demethylation process was less pro-
nounced than in the case of the above mentioned processes
(Table 2) (kw2 ater/k2acetonitrileZ1.5). However, transformation
in methanol–water mixture (9/1) was almost twice as fast
than in water alone. Introduction of a methyl group at the
para position enhanced functionalisation in acetonitrile by a
factor of 7.6 while no substantial increase was observed
when the methyl group is replaced by iso-propyl (Table 2).
A further increase in reactivity was achieved when one or
two additional alkyl groups were introduced into the
aromatic ring, that is, 3-methyl-4-iso-propylphenol (11a)
or 3,4,5-trimethylphenol (11b).
OH
OH
60
40
20
0
F-TEDA
H2O
F
CH3CN
0
4000
8000
t [s]
12000
16000
Figure 3. Effect of solvent on the reaction of phenol (1) with F-TEDA-BF4
at 40 8C.
simple rate equation (Fig. 3):
v Z d½F–Nꢀ=dt Z k2½F–Nꢀ½Y-C3H4–OHꢀ
Table 2. Effect of solvent and reaction temperature on the second order rate
constants for the functionalisation of phenol (1), p-hydroquinone (2),
p-methoxyphenol (3), 4-methylphenol (7a), 4-iso-propylphenol (7b),
3-methyl-4-iso-propylphenol (11a) and 3,4,5-trimethylphenol (11b) with
F-TEDA-BF4
Important information about the course of functionalisation
of aromatic molecules with the F–N type of reagents could
be obtained from the activation parameters, but up to now
no such data were available for this kind of reagent. We
therefore investigated the activation parameters for all three
types of transformations on the phenyl ring and also studied
the effect of solvent. It is evident that the highest activation
enthalpy is required for fluorination, while for oxidation and
oxidative demethylation almost the same DHs was
established, the activation enthalpy increasing in methanol–
water solution for the transformation of 3. As also evident
from Table 2, differences in activation entropies that were
observed in both the type of functionalisation and in the
effect of solvent on the geometry of the process are
important. In the fluorination process, a decrease of solvent
polarity was reflected in a lowering of activation entropy,
while the opposite effect was observed in oxidation (K68G
8 J/mol K for water and K39G4 J/mol K for acetonitrile).
The most interesting case is the oxidation–demethylation
process where differences between water and acetonitrile
were not so pronounced, but the transition state in the
presence of methanol must be much less ordered than in the
case of water. Introduction of a methyl group in phenyl ring
increased the activation enthalpy of fluoro functionalisation
in acetonitrile and caused significant changes in activation
entropies (K49 J/mol K for 1, K10 for 7a; Table 2). Further
introduction of alkyl groups (11a, 11b) decreased activation
enthalpies and changed activation entropies.
Subst. Solvent
T
(8C)
k2
DHs
(kJ/mol) (J/mol K)
DSs
(10K3 MK1 sK1 a
)
1
35
40
45
2.3
3.9
6.5
83G1
80G3
59G3
68G4
58G3
60G7
73G4
86G2
85G2
76G2
70G2
K27G1
K49G3
K68G8
K39G4
K74G5
K70G12
K18G1
K10G0.4
K14G0.5
K21G0.4
K17G0.5
H2O
35
40
45
0.63
1.0
1.7
MeCN
2
7
12
17
21
36
51
H2O
7
12
17
11
19
30
MeCN
3
17
22
26
38
54
81
H2O
19
22
25
22
36
41
MeCN
19
22
26
75
102
137
MeOH/
H2O
9:1
7a
35
40
46
4.8
8.7
14
MeCN
7b
35
40
46
5.1
8.6
15
Important information about the nature of the intermediate
in the functionalisation of the aromatic molecule could be
obtained by using solvents with various dielectric constants
or by using mixtures of solvents for which the Grunwald–
Winstein Y values have already been determined;13 very
large variations were observed for acetonitrile–water
solutions.14 Unfortunately, reactions with F–N type of
reagents are solvent dependent, where small changes could
completely halt the process or alter its course. Functiona-
lisation of substituted phenols with F-TEDA-BF4 proceeded
very well in acetonitrile or water, and fortunately
MeCN
11a
15
20
25
7.9
15
24
MeCN
11b
0
2
5
22
28
50
MeCN
a An average from at least three measurements with no more than 3%
relative error.

4478
I. Pravst et al. / Tetrahedron 62 (2006) 4474–4481
As evident from Figure 4 an excellent correlation with spC
with a value of rCZK2.3 was established. It is interesting
that the correlation was excellent in spite of the fact that
different types of phenyl ring functionalisation were
involved. The similar behaviour of para substituted phenols
on functionalisation as in the case of nitration and
hydroxylation could be explained by the formation of
cation radicals after one electron transfer from the aromatic
nucleus to the F–N reagent, while further reactions resulted
in various types of product. Formation of cation radicals has
also been confirmed by UV and ESR spectroscopy in
halogenations with N–X reagents (NBS, NCS, .) of
electron-rich aromatic molecules.17,18 Effective transfor-
mation of cation radicals to fluoro substituted products in
our case was best achieved when alkyl groups (7, 11) are
present at position four.
Table 3. Effect of solvent polarity (Ybenzyl) on the second order rate
constants for the reactions of phenol (1), p-hydroquinone (2), p-
methoxyphenol (3) and 3-methyl-4-iso-propyphenol (11a) with F-TEDA-
BF4 in acetonitrile–water solutionsa
c
Solventb
Ybenzyl
k2 (10K3 MK1 sK1
)
1
2
3
11a
90An
80An
60An
40An
20An
K1.45
K0.35
0.81
1.74
2.72
1.8
1.5
1.3
1.7
2.8
63
51
42
38
43
40
29
19
23
35
29
20
15
a Reactions at 40 8C for 1, at 17 8C for 2, at 22 8C for 3 and at 25 8C for 11a.
b % v/v of acetonitrile in water solution.
c Values from Ref. 14.
acetonitrile–water mixtures have a very large range of Y
values.14 However, as evident from Table 3, variation of Y
in the range of 4.17 units had only a small effect on second
order rate processes for functionalisation of phenol (1),
p-hydroquinone (2), p-methoxyphenol (3) and 3-methyl-4-
iso-propylphenol (11a). The small effect of solvent polarity
on the second order rate constants indicated a small change
in the polarity of the rate determining transition state in
comparison to the reactants.
Two reaction channels resulting after fluorine attack at
position 2 or 4 giving fluoro carbonium ions are presented in
Scheme 3 (CA and CB). As evident from an independent
experiment, 4-fluorophenol (10) was formed from cyclo-
hexadienone derivative 9 at higher temperature as was
observed with substrates bearing a substituted tertiary
carbon atom (i.e., in the case of the tert-butyl derivative 7c).
Hammett correlations have several times been used in
investigating the effect of substituents on the transformation
of aromatic molecules.15 A very good kinetic correlation
with sCp has been demonstrated in the reactions of para
substituted phenols with peroxynitrite (ONOOK), in spite of
the fact that functionalisation (nitration or hydroxylation)
occurred at the position meta to the substituent.16 We
undertook a similar investigation, although reactions with
phenols bearing electron withdrawing groups give complex
reaction mixtures, fluoro substituted products not being the
major ones, while in the case of a hydroxyl substituent, a
high yield oxidation process took place and oxidation
followed by demethoxylation giving p-quinone was
observed with p-methoxyphenol (3).
3. Conclusion
In summarizing our observations, we can state that steric
interactions and reaction conditions strongly influenced the
regioselectivity of fluorination of para alkyl substituted
phenols with F–N reagents. The site of fluorination
depended on the size of the substituent, the structure of
the F–N reagent and the solvent. In MeCN, the methyl group
favoured attack at the para position (66%), while bulky
alkyl substituents like tBu or the 1,1,3,3-tetramethyl-butyl
(tOct) group caused a change of the regioselectivity and
ortho fluorination (60 and 88%) was found to be dominant.
On the other hand, analogous reactions in MeOH resulted in
exclusive fluorination of the position two in the case of
4-methylphenol, and predominant fluorofunctionalisation at
the same position in the case of other 4-alkyl-substituted
phenols. The structure of the alkyl substituents also
influenced the type of fluorofunctionalisation, since attack
at the para position resulted in the addition process thus
forming 4-fluoro-4-alkyl-cyclohexa-2,5-dienone derivatives
9, while the substitution process resulting in formation of
2-fluoro-4-alkylphenol derivatives 8 followed ortho attack.
Reactions of F-TEDA-BF4 with phenol derivatives bearing
electron withdrawing substituents (4, 5) resulted in complex
reaction mixtures, while p-hydroquinone (2) and
p-methoxyphenol were transformed to p-quinone. Kinetic
studies on the transformation of para substituted phenols
with F-TEDA-BF4 carried out in water, acetonitrile
or water–acetonitrile mixtures at various temperatures
established that the course of the reaction obeyed the
simple rate equation nZd[F–N]/dtZk2[F–N][Y-C6H4–OH]
for all types of transformations. Higher DHs activation was
required for the fluorination process (DHs: 80–83 kJ/mol)
than for oxidation (DHs: 59–68 kJ/mol) or oxidative
demethylation (DHs: 58–73 kJ/mol). A very pronounced
effect of solvent polarity on activation entropies was
observed in all three types of functionalisation (fluorination,
log k
3.0
rel
ρ+
= -2.3
p-OH
2.0
1.0
p-OMe
R=0.99
+
σ p
H
0.0
-1
-0.6
-0.2
0.2
0.6
p-COOMe
p-CN
1
-1.0
-2.0
Figure 4. Hammett correlation plot (log krel./sCp ) for the functionalisation
of para substituted phenols (1–5) with F-TEDA-BF4 at 70 8C in
acetonitrile.

I. Pravst et al. / Tetrahedron 62 (2006) 4474–4481
4479
oxidation, oxidative demethylation), but the effect depended
on the type of transformation. In order to obtain more
insight into the nature of the rate determining step in
transformations of para substituted phenols with F-TEDA-
BF4, Grunwald–Winstein correlation analysis carried out
and since only a small effect of solvent polarity variation on
reaction rates was established we can presume that the
polarity of the rate determining state is not so different from
the reactants. On the basis of the excellent Hammett
correlation plot obtained for reactions of para substituted
phenols with with F-TEDA-BF4 (rCZK2.3; RZ0.99) we
can also anticipate similar nature of the key intermediate of
these reactions, although the type of products strongly
depended on the substituents.
chromatography and identified on the basis of spectroscopic
data and elemental combustion analysis or high resolution
MS spectroscopy, while in the case of known compounds
comparison with literature data was made. Sufficient purity
of all compounds was determined by 1H NMR
spectroscopy.
4.1.1. 2-Fluoro-4-methyl-phenol (8a).20 Reaction con-
ditions: F-TEDA-BF4/MeOH/reflux/2 h: 120 mg crude
reaction mixture (contained 65 mg of 8a, determined by
OFN), column chromatography (SiO2/CH2Cl2) gave 43 mg
(34%) of oily product.
4.1.2. 2-Fluoro-4-isopropyl-phenol (8b). Reaction con-
ditions: F-TEDA-BF4/MeOH/reflux/2 h: 135 mg crude
reaction mixture (contained 80 mg of 8b, determined by
OFN), column chromatography (SiO2/CHCl3) gave 65 mg
(42%) of brown oily product. 1H NMR (300 MHz, CDCl3) d
1.20 (d, JZ6.9 Hz, 6H, Me), 2.83 (heptet, JZ6.9 Hz, 1H,
CH), 3.79 (d, JZ2.3 Hz, 1H, OH), 6.87–6.89 (m, 1H, ArH),
6.90–6.92 (m, 1H, ArH), 6.94–6.95 (m, 1H, ArH); 13C NMR
(76 MHz, CDCl3) d 24.0 (CH3), 33.3 (CH), 113.3 (d, JZ
17.4 Hz, ArCH), 116.9 (d, JZ1.3 Hz, ArCH), 122.4 (d, JZ
2.3 Hz, ArCH), 141.2 (d, JZ14.2 Hz, ArCOH), 142.0 (d,
JZ4.9 Hz, ArC), 150.9 (d, JZ237.2 Hz, ArCF); 19F NMR
(56.4 MHz, CDCl3) d K141.0 (m); MS (EI, 70 eV) m/z 154
(30, MC), 139 (100), 109, 91; high resolution MS: m/z
154.079503 (calcd for C9H11FO m/z 154.079393).
4. Experimental
Melting points were determined on a Bu¨chi 535 apparatus. 1H
NMR spectra were recorded on a Varian EM 360L at 60 MHz
or on a Varian INOVA 300 spectrometer at 300 MHz, and 13C
NMR spectra on the same instrument at 76 MHz. Chemical
shiftsarereportedinpartspermillionfromTMSastheinternal
standard. 19F NMR spectra were recorded on a Varian EM
360L at 56.4 MHz and chemical shifts are reported in parts per
million from CCl3F as internal standard. IR spectra were
recorded on a Perkin-Elmer 1310 spectrometer. Standard KBr
pellet procedures were used to obtain IR spectra of solids,
while a film of neat material was used to obtain IR spectra of
liquid products. Mass spectra were obtained on an Autospec Q
instrument under electron impact (EI) conditions at 70 eV.
Elemental analyses were carried out on a Perkin-Elmer
2400 CHN analyzer or obtained from Mikranalytisches
Labor Pascher, Germany. 1-Chloromethyl-4-fluoro-1,4-
diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate)19 (Select-
fluore F-TEDA-BF4; Air Products) was crystallised
from an acetonitrile–methanol mixture and dried in a vacuum
at 20 8C. 1-Fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]-
octane bis(tetrafluoroborate) (Accufluore NFTh, 50% w/w
onAl2O3)wasreceivedasa giftfromAlliedSignalandusedas
obtained. N-Fluoro-2,6-dichloropyridinium tetrafluoroborate
(FP-B800) was received from Chichibu Onoda Cement Corp.,
Japan, and also used as obtained. Other starting materials were
obtained from commercial sources. Acetonitrile and methanol
were purified by distillation and stored over molecular sieves.
4.1.3. 2-Fluoro-4-tert-butyl-phenol (8c)8 Reaction con-
ditions: F-TEDA-BF4/MeOH/reflux/4 h: 141 mg crude
reaction mixture (contained 113 mg of 8c, determined by
OFN), column chromatography (SiO2/CHCl3) gave 75 mg
(45%) of oily product.
4.1.4. 2-Fluoro-4-(1,1,3,3-tetramethyl-butyl)-phenol
(8d). Reaction conditions: F-TEDA-BF4/MeOH/reflux/4 h:
177 mg crude reaction mixture (contained 118 mg of 8d,
determined byOFN), columnchromatography(SiO2/CH2Cl2)
gave 75 mg (33%) of light brown crystalline product, mp 59–
60 8C, 1H NMR(300 MHz, CDCl3)d 0.72(s, 9H, tBu), 1.32(s,
6H, 2CH3), 1.68 (s, 2H, CH2), 5.12 (s, 1H, OH), 6.90 (m, 1H,
ArH), 7.01 (m, 1H, ArH), 7.06 (m, 1H, ArH); 13C NMR
(76 MHz,CDCl3)d31.6(CH3),31.7(CH3),32.3(C),38.1(C),
56.9 (CH2), 113.4 (d, JZ18.4 Hz, ArCH), 116.3 (d, JZ
2.1 Hz, ArCH), 122.2 (d, JZ3.0 Hz, ArCH), 140.7 (d, JZ
14.7 Hz, ArCOH), 143.5 (d, JZ4.7 Hz, ArC), 150.6 (d, JZ
235.6 Hz, ArCF); 19F NMR (56.4 MHz, CDCl3) d K141.6
(m);MS(EI, 70 eV) m/z 224 (5, MC), 153 (100), 57(35); high
resolution MS: m/z 224.158320 (calcd for C14H21FO m/z
224.157644). Anal. Calcd for C14H21FO$1/4H2O C, 73.49; H,
9.47. Found: C, 73.34; H, 9.26.
4.1. Fluorination of phenols (7) with ‘F–N’ reagents;
general procedure
To a solution of substrate 7 (1 mmol) in 10 mL of solvent
(MeCN, MeOH or CH2Cl2) 1 mmol of fluorinating agent
(F-TEDA-BF4, NFTh or FP-B800 was added, the reaction
mixture stirred at reflux temperature until the fluorinating
agent was consumed (KI starch paper). The reaction solvent
was removed under reduced pressure, the crude reaction
mixture dissolved in 50 mL of dichloromethane, washed
with water (20 mL), dried over Na2SO4, the solvent
4.1.5. 4-Fluoro-4-methyl-cyclohexa-2,5-dienone (9a).21
Reaction conditions: F-TEDA-BF4/MeCN/reflux/2 h:
102 mg crude reaction mixture (contained 46 mg of 9a,
determined by OFN), column chromatography (SiO2/
CH2Cl2) gave 33 mg (26%) of dense oily product.
1
evaporated, the reaction mixture analyzed by H and 19F
NMR spectroscopy and the relative distribution of products
was determined. The amount of fluorinated products present
in the reaction mixture was determined from 19F NMR
spectra using octafluoronaphthalene (OFN) as internal
standard. Pure compounds were isolated by column
4.1.6.
4-Fluoro-4-isopropyl-cyclohexa-2,5-dienone
(9b).10 Reaction conditions: F-TEDA-BF4/MeCN/reflux/
2 h: 125 mg crude reaction mixture (contained 72 mg of 9b,

4480
I. Pravst et al. / Tetrahedron 62 (2006) 4474–4481
determined by OFN), column chromatography (SiO2/
CH2Cl2) gave 48 mg (31%) of dense oily product.
0.6 mmol F-TEDA-BF4 was added and stirred. The progress
of F-TEDA-BF4 consumption was monitored by iodometric
titration. The results are presented in Table 3.
4.1.7. 4-tert-Butyl-4-fluoro-cyclohexa-2,5-dienone (9c).12
Reaction conditions: NFTh/MeCN/20 8C/24 h: 160 mg
crude reaction mixture (contained 59 mg of 9c, determined
by OFN), column chromatography (SiO2/CH2Cl2) gave
49 mg (29%) of yellow crystals, mp 63.1–63.4 8C; 1H NMR
(60 MHz, CCl4) d 1.1 (d, JZ19 Hz, 9H), 6.3 (d, JZ13 Hz,
2H), 7.0 (dd, JZ17, 13 Hz, 2H); 19F NMR (56.4 MHz,
CCl4) d K165.3 (m); MS (EI, 70 eV) m/z 168 (MC, 21%),
153 (75), 135 (65), 125 (35), 107 (25), 91 (12), 83 (15), 57
(100); high resolution MS: m/z 168.0957 (calcd for
C10H13FO: 168.0950).
Acknowledgements
ˇ
The authors are grateful to K. Zmitek, A. Gacesa and
ˇ ˇ
Dr. J. Plavec for NMR spectra and to the Ministry of Higher
Education, Science and Technology of the Republic of
Slovenia for financial support.
4.1.8. 4-Fluorophenol (10).22 Reaction conditions: 4-tert-
butyl-phenol/NFTh/MeCN/reflux/2 h: 170 mg crude
reaction mixture (contained 38 mg of 10, determined by
OFN), column chromatography (SiO2/CH2Cl2) gave 25 mg
(18%) of crystalline product, mp 46 8C (lit.22 43–45 8C).
References and notes
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