Synthesis of 4-fluorophenols from 4-tert-butylphenols and fluoride sources under oxidative conditions

Article abstract of DOI:10.1135/cccc20021467

4-tert-Butylphenols can be easily transformed into 4-fluorophenols, provided that no coordinating moiety is present in 2-position, in a two step procedure under mild and safe conditions. The first step leads to 4-tert-butyl-4-fluorocyclohexa-2,5-dien-1-ones through an oxidative fluorination with [bis(trifluoroacetoxy)iodo]benzene and triethylamine tris(hydrofluoride), and is followed by an acid catalyzed aromatization with loss of isobutene. When extended to 4-tert-butylacetanilide, this method delivers 4-fluoroacetanilide in a single step but in a modest yield.

Full text of DOI:10.1135/cccc20021467

Synthesis of 4-Fluorophenols
1467
SYNTHESIS OF 4-FLUOROPHENOLS FROM 4-tert-BUTYLPHENOLS
AND FLUORIDE SOURCES UNDER OXIDATIVE CONDITIONS
1
Antoine BIENVENU, Audrey BARTHELEMY, Sarah BOICHUT, Bernard MARQUET ,
2
3,
Thierry BILLARD and Bernard R. LANGLOIS *
Laboratoire SERCOF, UMR CNRS 5622, Université Claude Bernard-Lyon I, Bâtiment E. Chevreul,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne cedex, France;
1
2
3
e-mail: marquet@univ-lyon1.fr, billard@univ-lyon1.fr, bernard.langlois@univ-lyon1.fr
Received April 26, 2002
Accepted October 7, 2002
Dedicated to the memory of Professor Miloš Hudlický.
4-tert-Butylph en ols can be easily tran sform ed in to 4-fluoroph en ols, provided th at n o coordi-
n atin g m oiety is presen t in 2-position , in a two step procedure un der m ild an d safe con di-
tion s. Th e first step leads to 4-tert-butyl-4-fluorocycloh exa-2,5-dien -1-on es th rough an
oxidative fluorin ation with [bis(trifluoroacetoxy)iodo]ben zen e an d trieth ylam in e tris(h ydro-
fluoride), an d is followed by an acid catalyzed arom atization with loss of isobuten e. Wh en
exten ded to 4-tert-butylacetan ilide, th is m eth od delivers 4-fluoroacetan ilide in a sin gle step
but in a m odest yield.
Keyw ord s: Fluoroarom atics; Fluorin ated com poun ds; 4-Fluoroph en ols; 4-tert-Butylph en ols;
4-Fluoroacetan ilide; 4-tert-Butylacetan ilide; Oxidation s; [Bis(trifluoroacetoxy)iodo]ben zen e;
Trieth ylam in e tris(h ydrofluoride); Fluorin ation s.
4-Fluoroph en ol is th e precursor of n um erous biologically active com poun ds
available on th e in dustrial scale: Butofilolol, Nebivolol, Cisapride,
Progabide, Sabeluzole, Sorbin il, Flum iclorac, Flum ipropyn , Quin oxyph en ,
etc.1 It can be prepared, as a m ixture with its 2-isom er, by fluorin ation of
ph en ol with fluorin e at low tem perature2. As th is tech n ique is difficult to
scale up, diazotization of 4-fluoroan ilin e in aqueous sulfuric acid is rou-
tin ely preferred3. Th e latter substrate arises from 1-fluoro-4-n itroben zen e,
wh ich is obtain ed eith er by n itration of fluoroben zen e or by h alogen ex-
ch an ge (“Halex” process) with alkalin e fluorides from 4-ch loron itro-
ben zen e2,3 (Sch em e 1).
Th ese two path ways to 4-fluoroph en ol suffer from several drawbacks. Th e
first route from an ilin e n eeds two diazotization steps wh ich are difficult to
scale up an d fluorin e is in troduced very early; m oreover, n itration of
Collect. Czech. Chem. Commun. (Vol. 67) (2002)
doi:10.1135/cccc20021467

1468
Bienvenu et al.:
fluoroben zen e is n ot totally para-regioselective (para/ortho = 91 : 9). In th e
secon d route, a h igh tem perature is required for h alogen exch an ge wh ich is
typically carried out in a h igh -boilin g aprotic solven t th e recyclin g of
wh ich could be troublesom e.
NaNO2 / HF
NH2
F
0 to 60 oC
HNO3
H2SO4
KF
H2
Cl
NO2
NH2
F
F
NO2
sulfolane
180 - 200 oC
Raney Ni
EtOH
60 oC
NaNO2
F
OH
H2SO4 / H2O
SCHEME 1
It m ust be n oticed th at, in con trast to oth er fluoroarom atics, 4-fluoro-
ph en ol can n ot be prepared by stan dard diazotization of 4-am in oph en ol in
an h ydrous h ydrogen fluoride (Balz–Sch iem an n reaction ) because of exten -
sive form ation of side-products4.
An efficien t m odification h as been proposed by Yon eda et al., wh o used
pyridin ium poly(h ydrogen fluoride) (Olah ’s reagen t, Py/HF = 30 : 70 w/w)
in stead of h ydrogen fluoride as solven t, but good yields of fluoroph en ol
can be reach ed un der very strictly con trolled con dition s on ly5. Th us, a
m ore ch em o- an d regioselective access to 4-fluoroph en ol un der m ild con di-
tion s h as to be foun d.
Som e years ago, Jacquesy et al. described an in terestin g oxidative fluori-
n ation of 4-alkylph en ols in to 4-alkyl-4-fluorocycloh exa-2,5-dien -1-on es,
usin g [bis(trifluoroacetoxy)iodo]ben zen e (also called ph en yliodin e bis-
trifluoroacetate, PIFA) as oxidizin g agen t an d Olah ’s reagen t as th e fluoride
source6 (Sch em e 2). Apart from th e fact th at th e resultin g product can n ot
be rearom atized in to a fluoroben zen e derivative, th is reaction was carried
out in an agressive m edium wh ich is n ot com patible with a glass apparatus.
Moreover, in our h an ds th is tech n ique prove n ot to be suitable for th e oxi-
dative fluorin ation of 4-tert-butylph en ol.
More recen tly, 4-alkyl-4-fluorocycloh exa-2,5-dien -1-on es were also ob-
tain ed from 4-alkylph en ols an d 1-(ch lorom eth yl)-4-fluoro-1,4-diazon ia-
bicyclo[2.2.2]octan e bis(tetrafluoroborate) (Selectfluor™ or F-TEDA-BF4)
or its 1-h ydroxy an alogue (Accufluor™), actin g as oxidizers an d fluorin at-
in g agen ts7. Good yields (> 80%) an d com plete regioselectivities were usu-
ally reach ed, except for 4-tert-butylph en ol wh ich led to two regioisom ers
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of 4-Fluorophenols
1469
OH
O
PhI(OCOCF3)2
C5H5N, HF, (30 : 70 w/w)
CH2Cl2, r.t.
R
F
R
O
O
R
R
PhI(OCOCF3)2
F
C5H5N, HF, (30 : 70 w/w)
CH2Cl2, r.t.
HO
O
SCHEME 2
(Sch em e 3). Such a process is m ore realistic th an th e previous oxidative flu-
orin ation of ph en ols with CF3OF 8, ClO3F 9, N-fluoro bis(perfluoroalkan e)-
11
sulfon im ides10, F2 or Pb(IV)/F– sources (Olah ’s reagen t, Et3N·3HF)12; n ev-
erth eless, it n eeds an expen sive reagen t wh ich is n ot yet available on a large
scale.
R1
N
(BF4 )2
O
O
OH
N
F
R1= CH2Cl, OH
MeCN, r.t.
R = Me, i-Pr
R
F
F
R
OH
O
F
F-TEDA-BF4
+
MeCN or MeOH
r.t.
major
minor
SCHEME 3
Th e com parative an alysis of Jacquesy’s an d Stavber’s works led us to pro-
posal of a n ew two-step route to 4-fluoroph en ol (3a). Havin g in m in d th e
easy protosubstitution of tert-butylated arom atics, 4-tert-butylph en ol (1a)
was ch osen as startin g m aterial on wh ich oxidative fluorin ation sh ould be
first applied. Th e form ed 4-tert-butyl-4-fluorocycloh exa-2,5-dien -1-on e (2a)
sh ould be th en subm itted to acid-catalyzed arom atization . In th is secon d
step, isobuten e would be expelled an d could be recycled for th e preparation
of 4-tert-butylph en ol (Sch em e 4).
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1470
Bienvenu et al.:
OH
O
OH
[O] / F
H
cat.
+
F
F
1a
2a
3a
Phenol / H cat.
SCHEME 4
For th e first step, [bis(trifluoroacetoxy)iodo]ben zen e was ch osen as oxi-
dizer but in stead of Olah ’s reagen t, th e h an dlin g of wh ich is troublesom e,
oth er sources of m ore n ucleoph ilic fluorides were tested. Prelim in ary results
in dicated th at dich lorom eth an e was th e m ost appropriate solven t sin ce th e
n ucleoph ilic on es, such as dibutyl eth er, sulfolan e, or aceton itrile probably
com pete with fluoride. Th e results are listed in Table I.
TABLE I
Oxidative fluorin ation of 4-tert-butylph en ol with Ph I(OCOCF3)2 an d fluorides to 4-tert-
butyl-4-fluorocycloh exa-2,5-dien -1-on es (Ph I(OCOCF3)2, 1.3 eq., CH2Cl2, room tem perature)
No. of
equivalen ts
Tem perature
°C
Isolated yield
%
En try
F– Sources
1
2
Et3N·3HF
Et3N·3HF
1
2
3
3
3
3
3
3
3
3
3
25
25
25
0
10
36
62
62
40
46
(27)c
22
0
3
Et3N·3HF
4
Et3N·3HF
5
Et3N·3HFa
25
25
25
25
25
25
25
6
Et3N·2HFb
7
KHF2
8
KF/18-crown -6
KF/cryptan d[2.2.2]
Me4NF·4H2O
an h ydrous Me4NF
9
10
11
3
3
a
b
In CH2Cl2/H2O (50 : 1 v/v), p-ben zoquin on e observed as by-product. Form ed in situ from
Et3N·3HF an d Et3N (1 : 1). Crude yield from 19F NMR with Ph OCF3 as in tern al stan dard.
c
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of 4-Fluorophenols
1471
–
Table I clearly shows that the Et3N·3HF complex (equivalent to Et3NH+H2F3 )
beh aves as th e best fluoride source, provided th at 3 equivalen ts are used, ei-
th er at room tem perature (en try 3) or at 0 °C (en try 4). In terestin gly, th is
solvated fluoride is advan tageous over Olah ’s reagen t because it is m ore sta-
ble, less h ygroscopic an d m ore n ucleoph ilic, it does n ot em it an y HF fum es
(even un der h eatin g or distillation ), it is n ot acidic an d can be used in glass-
ware. It can be n oticed th at com parative yields were obtain ed from
Et3N·3HF an d 4-tert-butylph en ol (62%) on on e h an d, an d from Olah ’s re-
agen t an d 4-eth ylph en ol (61%) or 4-m eth ylph en ol (68%)6a on th e oth er
h an d. In th e latter case, electroph ilic dim erization of th e substrate occurred
as a side-reaction 6a. Because of th e bulkin ess of th e tert-butyl group, such a
dim erization was n ot observed for 4-tert-butylph en ol. However, oth er
n ucleoph ilic species, such as water (en try 5) or eth ers (e.g. crown eth ers, en -
try 8) in terfere with fluoride an ion an d m ust be avoided, as well as oxidiz-
able com poun ds such as trieth ylam in e (en try 6) or cryptan d [2.2.2] (en try 9).
Such a sen sitivity to com petitin g n ucleoph iles stron gly suggests th at in -
term ediate cation ic species were form ed. Several m ech an ism s, reported in
Sch em e 5, can be con sidered: eith er two con secutive sin gle-electron tran s-
Route A
Route B + C
R
OH
- CF3COOH
+ Ph-I(OCOCF3)2
R
OH
R
O
OCOCF3
I
Ph
OCOCF3
Ph
I
Route C
- PhI
- CF3COO
F
OCOCF3
Route B
R
OH
R
O
Ph-I-OCOCF3
CF3COO
- H
- PhI
- 2 CF3COO
R
R
R
F
O
O
O
F
Ph-I-OCOCF3
CF3COO
SCHEME 5
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1472
Bienvenu et al.:
fers leadin g first to a radical-cation th en to a cation , as suggested by
Eberson et al.13 an d Kita et al.14 (route A), or form ation of a cation ic
com plex from iodin e(III) wh ich could be tran sform ed in a con certed way
(route B) or deliver a ph en oxylen ium cation (route C)15,16
.
As th e replacem en t of PIFA by several oth er oxidizers (ceric am m on ium
n itrate (CAN), CuCl/Fe(NO3)3/H2O2, CuCl/t-BuOOH, CuCl/t-BuOOH/Fe(NO3)3,
FeCl3, K2S2O8/(NH4)2FeSO4), kn own to oxidize ph en ols th rough a sin gle-
electron tran sfer, failed in our h an ds to afford dien on e 2a from ph en ol 1a
an d Et3N·3HF, it can be suggested th at route A was n ot in volved in th e oxi-
dative fluorin ation . Our experim en ts did n ot allow an y ch oice between
route B an d route C but stron g eviden ces h ave been recen tly brough t in fa-
vour of route C 15,16
.
Con cern in g th e replacem en t of PIFA by an oth er oxidizer, it m ust be also
m en tion ed th at th e use of lead tetraacetate was disappoin tin g: dien on e 2a
was obtain ed in a 7% yield on ly.
Oxidative fluorin ation with PIFA an d Et3N·3HF was th en applied to
2,4-di-tert-butylph en ol (1b) an d 2-tert-butylph en ol (1c) (Sch em e 6). Th e ex-
pected com poun d 2b was obtain ed in a satisfactory yield from ph en ol 1b as
a sin gle regioisom er; in deed, fluorin ation occurred exclusively at th e
para-position , probably because of steric factors. Surprisin gly, ph en ol 1c
was also fluorin ated at th e 4-position in stead of th e expected 2-position , on
wh ich a cation ic ch arge sh ould h ave been stabilized. Moreover, as th e
m on ofluorin ated in term ediate can be arom atized, oxidative fluorin ation
occurred twice. Th e resultin g 2-tert-butyl-4,4-difluoro-2,5-cycloh exadien -
1-on e (4), wh ich bears water-sen sitive allylic fluorin e atom s, was con tam i-
n ated with tert-butyl-p-ben zoquin on e after work-up. In th e sam e way,
OH
O
PhI(OCOCF3)2 (1.3 eq.)
Et3N·3HF (3 eq.)
CH2Cl2, r.t.
F
1b
2b 68%
OH
O
O
PhI(OCOCF3)2 (1.3 eq.)
+
Et3N·3HF (3 eq.)
CH2Cl2, r.t.
F
F
O
1c
4, 15%
28%
SCHEME 6
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of 4-Fluorophenols
1473
3-tert-butylph en ol afforded 3-tert-butyl-4,4-difluoro-2,5-cycloh exadien -
1-on e on ly in a 8% yield, alon g with tert-butyl-p-ben zoquin on e again .
4-tert-Butylben zen e-1,2-diol, 4-tert-butyl-2-m eth oxyph en ol an d 2-tert-
butyl-4-m eth oxyph en ol failed to afford fluorin ated products but tert-butyl-
ben zoquin on es were form ed in all cases, probably alon g with som e poly-
m eric m aterials (Sch em e 7). In fact, oxidative fluorin ation probably occured
on 4-tert-butylben zen e-1,2-diol but th e fluorin ated in term ediate obviously
lost h ydrogen fluoride. Th e tran sform ation of th e two oth er substrates
could brin g argum en ts for th e occuren ce of ph en oxylen ium cation s, as al-
ready proposed15,16
.
OH
OH
O
O
O
O
O
[O] / F
- HF
H
F
OH
O
O
OCH3
O
- MeF
CH3
F
OH
O
O
O
O
- MeF
F
OCH3
CH3
SCHEME 7
To obtain th e target 4-fluoroph en ols 3 th rough th e rearran gem en t de-
scribed in Sch em e 8, 4-tert-butyl-4-fluorocycloh exa-2,5-dien -1-on es 2a an d
2b were subjected to an acidic treatm en t, eith er with trifluoroacetic acid or
with solution of an h ydrous h ydrogen ch loride in dieth yl eth er. Th ese two
acidic m edia were used as solven ts. Th e results are reported in Table II.
From th ese data, it appears th at 4-fluorocycloh exa-2,5-dien -1-on es 2a
an d 2b can yield th e correspon din g 4-fluoroph en ols 3a an d 3b in trifluoro-
acetic acid at room tem perature (en tries 1 an d 5); th e yields were satisfac-
tory but th e reaction s were slow (on e day). Heatin g to reflux in creased
dram atically th e rate but decreased th e yield because of growin g role of side
reaction s (en try 2).
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1474
Bienvenu et al.:
H
O
O
OH
R
R
R
+ H
- H
+
H3C
H3C
F
F
F
2, 3
R
H2C
H
a
b
H
2
3
t-Bu
SCHEME 8
In con trast, n o arom atization occurred in HCl·Et2O at room tem perature
an d reflux was n eeded to obtain fluoroph en ols 3 in th is m edium . Con se-
quen tly, th e reaction h ad to be carried out in a sealed vessel to preven t HCl
loss. HCl con cen tration was also a crucial param eter: with a 0.71 M solu-
tion , th e reaction was slow an d 4-fluoroph en ol (3a) form ed alon g with its
tert-butyl eth er (en try 3), wh ereas with a 2.0 M solution , th e reaction was
com plete in 8 h , th e yield was n ot affected an d 4-fluoroph en ols 3 were ob-
tain ed as th e sole products (en tries 4 an d 6).
Like 4-fluoroph en ol (3a), 4-fluoroan ilin e is an im portan t buildin g block
for th e preparation of biologically active com poun ds. Th us, we decided to
exten d our successful two-step syn th esis of 4-fluoroph en ol (3a) to th e prep-
aration of 4-fluoroan ilin e from 4-tert-butylan ilin e. 4-tert-Butylan ilin e itself
was, h owever, too oxidizable to react clean ly an d was probably proton ated
TABLE II
Arom atization of 4-tert-butyl-4-fluorocycloh exa-2,5-dien -1-on es 2a an d 2b
Tim e
h
Tem perature
°C
Isolated yield
%
En try Substrate
Acid
Eq. H+
1
2
3
2a
2a
2a
CF3CO2H
CF3CO2H
5
10
5
24
1
25
3a 57
3a 48
3a 62b
72 (reflux)
40
HCl/Et2O
(0.71 M)a
71
4
2a
HCl/Et2O
(2.0 M)a
5
7
40
3a 57
5
6
2b
2b
CF3CO2H
2
5
22
8
25
40
3b 52
3b 61
HCl/Et2O
(2.0 M)a
a
b
Carried out in a sealed vessel; p-FC6H4OH (35%) + p-FC6H4O-t-Bu (27%).
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of 4-Fluorophenols
1475
durin g reaction with PIFA. Con sequen tly, n o fluorin ated product was
form ed, eith er at room tem perature or upon h eatin g. So, 4-tert-butylacet-
an ilide was ch osen as an oth er startin g m aterial. No reaction occurred at
room tem perature am on g th is substrate, PIFA an d Et3N·3HF in dich loro-
m eth an e but, at reflux for on e day, 4-fluoroacetan ilide was directly ob-
tain ed, th ough in a m odest yield, in stead of th e expected 4-tert-butyl-
4-fluorocycloh exa-2,5-dien -1-im in e. Th e yield was sligh tly im proved wh en
th e reaction was carried out in 1,2-dich loroeth an e at reflux (Sch em e 9).
NHC(O)CH3
NHC(O)CH3
PhI(OCOCF3)2 (1.3 eq.)
Et3N·3HF (3 eq.)
24 h
F
CH2Cl2, 40 oC
C2H4Cl2, 80 oC
19%
21%
SCHEME 9
Th e differen ce in reactivity between 4-tert-butylph en ol an d 4-tert-butyl-
acetan ilide could be explain ed by th e lower n ucleoph ilicity of th e latter
substrate towards iodin e(III) on on e h an d, an d th e fact th at th e n itrogen
equivalen t of a ph en oxylium ion could be n ot form ed on th e oth er h an d.
In deed, th e reaction m ech an ism could be m odified wh en m ovin g from
oxygen to n itrogen , for exam ple in such a way th at th e n itrogen atom
could be proton ated th rough out all process, a fact wh ich could explain th e
direct form ation of fluoroan ilin e (Sch em e 10).
Ph
CF3CO2
I
O
O
OCOCF3
HN
HN
PhI(OCOCF3)2
Et3N·3HF
F
O
O
H
HN
F
N
CF3CO2
- CF3CO2H
F
H
SCHEME 10
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1476
Bienvenu et al.:
In con clusion , 4-tert-butylph en ols 1 can be easily tran sform ed in to
4-fluoroph en ols 3, provided th at n o coordin atin g m oiety is presen t in th e
2-position , in a two step procedure un der m ild an d safe con dition s. Th e
first step leads to 4-tert-butyl-4-fluorocycloh exa-2,5-dien -1-on es 2 th rough
oxidative fluorin ation with [bis(trifluoroacetoxy)iodo]ben zen e an d trieth yl-
am in e tris(h ydrofluoride), an d is followed by an acid catalyzed arom atiza-
tion with loss of isobuten e. Wh en exten ded to 4-tert-butylacetan ilide, th is
m eth od affords 4-fluoroacetan ilide in a sin gle step, avoidin g th e arom a-
tization step, but, so far, th e yield is m odest an d work is in progress to im -
prove th is result.
Fin ally, th is two-step syn th esis of fluoroph en ols correspon ds form ally to
electroph ilic fluorin ation of ph en ols an d an ilin es.
EXPERIMENTAL
Prior to use, solven ts were stored over 3 Å m olecular sieves un der n itrogen , KF an d KHF2
were dried by azeotropic distillation of th eir suspen sion s in toluen e, an d 4-tert-butylph en ol,
as well as 2,4-di-tert-butylph en ol were purified by sublim ation . Oth er reagen ts were used as
received. 4-tert-Butylacetan ilide was prepared by acetylation of 4-tert-butylan ilin e with acetic
an h ydride. TLC an alyses were carried out on Kieselgel 60F 254 deposited on alum in ium
plates, detection bein g don e by UV (254 n m ). Flash ch rom atograph y was perform ed on sil-
ica gel Geduran SI 60 (230–400 m esh ). Un corrected m eltin g poin ts were determ in ed in capil-
lary tubes. Un less stated oth erwise, NMR spectra were recorded in CDCl3. 1H NMR spectra
were recorded at 200 or 300 MHz an d 13C NMR spectra at 50 or 75 MHz. Substitution pat-
tern s of differen t carbon s were determ in ed by a DEPT 135 sequen ce. 19F NMR spectra were
recorded at 188 MHz. Ch em ical sh ifts (δ) are given in ppm vs TMS (1H, 13C) or CFCl3 19F)
(
used as in tern al referen ces. Couplin g con stan ts (J) are given in Hz. Crude yields were deter-
m in ed by 19F NMR vs Ph OCF3 used as in tern al stan dard. GC was carried out on an apparatus
fitted with a sem i capillary colum n (len gth 15 m , i.d. 0.53 m m , film th ickn ess (DB1) 1 µm )
an d a cath arom etric detector. Mass spectrom etry, coupled with gas ch rom atograph y, was
carrried out un der electron im pact at 70 eV.
Oxidative Fluorin ation of 4-tert-Butylph en ol (1a) an d 2,4-Di-tert-butylph en ol (1b).
Gen eral Procedure
A flam e-dried th ree-n ecked vessel was successively ch arged, un der n itrogen , with th e ph en ol
1a or 1b (4 m m ol), dich lorom eth an e (50 m l) an d th e fluoride source (3 eq.). Th e resultin g
m ixture was stirred at room tem perature for 30 m in , th en cooled to 0 °C with an ice bath
before dropwise addition , with in 1 h , of [bis(trifluoroacetoxy)iodo]ben zen e (1.3 eq.), dis-
solved in dich lorom eth an e (30 m l). Th e reaction m edium was warm ed to room tem perature
an d kept un der stirrin g for 24 h . Th en , it was wash ed with a 12.5% aqueous solution of am -
m on ia un til n eutral an d decan ted. Th e organ ic ph ase was dried over MgSO4 an d evaporated
in vacuo. Th e crude residue was separated an d purified by colum n ch rom atograph y.
Iodoben zen e was first eluted with pure petroleum eth er, th en dien on es 2a or 2b were eluted
with a petroleum eth er/eth yl acetate m ixture (80 : 20).
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

Synthesis of 4-Fluorophenols
1477
4-tert-Butyl-4-fluorocyclohexa-2,5-dien-1-one (2a). Reaction accordin g to gen eral procedure
afforded dien on e 2a as a brown solid (62%, 410 m g). 1H NMR (200 MHz, CDCl3): 7.00 (dd,
3
3
3
2 H, JHH = 10.1 an d JHF = 7.0, H-3, H-5); 6.28 (d, 2 H, JHH = 10.1, H-2, H-6); 1.06 (s, 9 H,
t-Bu). 13C NMR (75 MHz, CDCl3): 184.69 (C=O); 145.06 (d, JCF = 22.6, C-3, C-5); 130.04
(C-2, C-6); 92.92 (d, JCF = 169, C-4); 38.98 (d, JCF = 23.2, C(CH3)3); 25.15 (d, JCF = 3.4,
CH3). 19F NMR (188 MHz, CDCl3): –162.54 (t, JFH = 7.0). MS, m/z: 112 (M• + – C4H8), 83, 63,
2
1
2
3
3
57, 55.
2,4-Di-tert-butyl-4-fluorocyclohexa-2,5-dien-1-one (2b). Reaction accordin g to gen eral proce-
dure afforded dien on e 2b as a deep green solid (68%, 616 m g). 1H NMR (300 MHz, CDCl3):
3
3
4
3
4
6.87 (ddd, 1 H, JHH = 10.4, JHF =7.4, JHH = 3.1, H-5); 6.74 (dd, 1 H, JHF4 = 8.6, JHH = 3.1,
3
H-3); 6.18 (d, 1 H, JHH = 10.4, H-6); 1.24 (s, 9 H, 2-t-Bu); 1.10 (d, 9 H, JHF = 1.1, 4-t-Bu).
13C NMR (75 MHz, CDCl3): 184.88 (C=O); 147.46 (d, JCF = 9.0, C-2); 142.79 (d, JCF = 22.6,
C-3 or C-5); 138.69 (d, JCF = 23.7, C-3 or C-5); 131.70 (d, JCF = 9.0, C-6); 94.10 (d, JCF
168, C-4); 39.35 (d, JCF = 23.7, 4-C(CH3)3); 34.83 (d, JCF = 1.1, 2-C(CH3)3); 29.11
(2-C(CH3)3); 25.32 (d, JCF = 3.9, 4-C(CH3)3). 19F NMR (188 MHz, CDCl3): –162.62.
3
2
3
3
1
=
2
4
3
2-tert-Butyl-4,4-difluorocyclohexa-2,5-dien-1-one (4). Th e sam e procedure was applied except
th at, after th e en d of th e reaction , th e m edium was stirred with solid K2CO3 (2 to 3 g) for
1 h , th en filtered an d dich lorom eth an e was evaporated in vacuo. Th e crude residue was puri-
fied by colum n ch rom atograph y in th e sam e way as for dien on es 2a an d 2b. tert-Butyl-
p-ben zoquin on e was th us separated to afford dien on e 4 as yellow solid (15%, 112 m g).
3
3
4
1H NMR (300 MHz, CDCl3): 6.72 (ddt, 1 H, JHH = 10.0, JHF = 6.3, JHH = 3.4, H-5); 6.56 (dt,
1 H, JHF = 6.3, JHH = 3.4, H-3); 6.22 (d, 1 H, JHH = 10.0, H-6); 1.25 (s, 9 H, t-Bu). 13C NMR
3
4
3
2
(75 MHz, CDCl3): 184.23 (C=O); 149.52 (C-2); 135.34 (t, JCF = 28.3, C-3 or C-5); 133.24 (t,
3JCF = 9.4, C-6); 131.49 (t, JCF = 28.3, C-3 or C-5); 111.32 (t, JCF = 207.0, C-4); 34.81 (s,
C(CH3)3); 28.90 (s, CH3). 19F NMR (188 MHz, CDCl3): –97.8. MS, m/z: 186 (M• +), 171, 151,
144, 143, 139, 109, 107, 103, 83, 77, 76, 75, 67, 65, 39, 29, 27.
2
1
Acid Catalyzed Arom atization of Dien on es 2a an d 2b.
Gen eral procedure
Cycloh exadien on e 2a or 2b (1 m m ol) was placed in a on e-n ecked vessel with trifluoroacetic
acid (5 eq.) or a 2 M solution of h ydrogen ch loride in Et2O. After sealin g th e vessel, th e m ix-
ture was stirred at room tem perature for 24 h (CF3COOH) or at reflux for 8 h (HCl, Et2O).
Th en , th e acid was evaporated in vacuo an d th e crude residue was purified by colum n ch ro-
m atograph y with petroleum eth er/eth yl acetate (90 : 10) as eluen t.
4-Fluorophenol (3a). Reaction accordin g to gen eral procedure afforded ph en ol 3a as a
wh ite solid (57%, 64 m g). M.p. 46 °C (com m ercial sam ple: 48 °C).
2-tert-Butyl-4-fluoro-phenol (3b). Reaction accordin g to gen eral procedure afforded ph en ol
3
3b as a pale brown liquid (61%, 106 m g). 1H NMR (300 MHz, CDCl3): 6.98 (dd, 1 H, JHF
=
4
3
3
4
10.5, JHH = 3.1, H-3); 6.74 (ddd, 1 H, JHH = 8.5, JHF = 7.4, JHH = 3.1, H-5); 6.61 (dd, 1 H,
3JHH = 8.5, JHF = 5.3, H-2); 5.27 (s, 1 H, OH); 1.42 (s, 9 H, t-Bu). 13C NMR (50 MHz, CDCl3):
4
1
4
3
156.88 (d, JCF = 236, C-4); 150.68 (d, JCF = 2.1, C-1); 138.15 (d, JCF = 6.0, C-2); 116.83 (d,
3JCF = 8.2, C-6); 113.90 (d, JCF = 23.8, C-3 or C-5); 112.50 (d, JCF = 22.8, C-3 or C-5); 34.78
(s, C(CH3)3); 29.30 (s, CH3). 19F NMR (188 MHz, CDCl3): –124.56 (s). MS, m/z: 168(M• +),
153, 149, 133, 125, 109, 57.
2
2
Collect. Czech. Chem. Commun. (Vol. 67) (2002)

1478
Bienvenu et al.:
4-Fluoroacetan ilide
A
flam e-dried th ree-n ecked vessel was successively ch arged, un der n itrogen , with
4-tert-butylacetan ilide (765 m g, 4 m m ol), dich lorom eth an e (50 m l) an d Et3N·3HF (1.95 m l,
eq.). Th e resultin g m ixture was stirred at room tem perature for 30 m in an d th en
3
[bis(trifluoroacetoxy)iodo]ben zen e (2.24 g, 1.3 eq.), dissolved in dich lorom eth an e (30 m l),
was dropwise added. Th e reaction m ixture was th en kept un der reflux for 24 h , wash ed with
a 12.5% aqueous solution of am m on ia un til n eutral an d decan ted. Th e organ ic ph ase was
dried over MgSO4 an d evaporated in vacuo to afford a yellow solid (19%, 29 m g). M.p.
150 °C. 1H NMR (300 MHz, CDCl3): 7.43 (m , 2 H, H-2 an d H-6); 6.99 (m , 2 H, H-3 an d H-5);
2.16 (s, 3 H, CH3). 19F NMR (282 MHz, CDCl3): –118.43 (m ). (Th ese spectral features were in
com plete accordan ce with th ose of an auth en tic sam ple of 4-fluoroacetan ilide, prepared
from com m ercial 4-fluoroan ilin e an d acetic an h ydride).
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Collect. Czech. Chem. Commun. (Vol. 67) (2002)