Aromatization via a dibromination-double dehydrobromination sequence: A facile and convenient synthetic route to 2,6-bis(trifluoroacetyl)phenols

Article abstract of DOI:10.1055/s-2008-1067080

An efficient and reliable method to synthesize 2,6-bis(trifluoroacetyl) phenols bearing various substituents in the 4-po-sition was developed. These valuable fluorinated building blocks were obtained from the corresponding cyclohexanones in a facile and convenient procedure, demonstrated to be superior to the traditional approaches. The application of this methodology to cyclohex-ane-1,4-dione opened access to 2,5-bis(polyfluoroacyl)-1,4- hydroquinones. Structural peculiarities of the obtained phenols as well as their 1,3-dicarbonyl or 1,3,5-tricarbonyl precursors are discussed on the basis of multinuclear NMR spectroscopy.

Full text of DOI:10.1055/s-2008-1067080

PAPER
1867
Aromatization via a Dibromination–Double Dehydrobromination Sequence:
A Facile and Convenient Synthetic Route to 2,6-Bis(trifluoroacetyl)phenols1
S
ynthetic Route to
m
2,6-Bis(trifluoroa
c
i
t
Gerd-Volker Röschenthaler*a
a
Institute of Inorganic & Physical Chemistry, University of Bremen, Leobener Str., 28334 Bremen, Germany
Fax +49(421)2208409; E-mail: sevenard@hfc-chemicals.com; fax +49(421)2184267; E-mail: gvr@chemie.uni-bremen.de
Institute of Organic Synthesis, Russian Academy of Sciences Ural Branch, S. Kovalevskoy Str. 22, GSP-147, 620041 Ekaterinburg,
b
Russian Federation
Received 21 November 2007; revised 20 March 2008
only product isolated.6 To circumvent the problem, a mul-
Abstract: An efficient and reliable method to synthesize 2,6-
tistep procedure in which 2,6-dibromo-4-methylphenol
was used as the starting compound was employed
bis(trifluoroacetyl)phenols bearing various substituents in the 4-po-
sition was developed. These valuable fluorinated building blocks
were obtained from the corresponding cyclohexanones in a facile
(Scheme 1). In contrast to the related data of Ansong et
and convenient procedure, demonstrated to be superior to the tradi- al.,7 double metalation and subsequent trifluoroacetyla-
tional approaches. The application of this methodology to cyclohex-
ane-1,4-dione opened access to 2,5-bis(polyfluoroacyl)-1,4-
hydroquinones. Structural peculiarities of the obtained phenols as
well as their 1,3-dicarbonyl or 1,3,5-tricarbonyl precursors are dis-
cussed on the basis of multinuclear NMR spectroscopy.
tion produced 3a (Scheme 1).
Me
Me
i, ii
iii, iv
Key words: fluorinated compounds, arenes, ketones, aromatiza-
tion, phenols
Br
Br
Br
Br
OH
OMe
1 92%
Me
OH
The incorporation of polyfluoroalkyl moieties, especially
the trifluoromethyl group, into organic molecules often
results in remarkable changes in the physical properties,
chemical reactivity, and biological activity of the derived
compounds, thereby making them more attractive for di-
verse practical applications. In fact, fluorinated substan-
ces have already become indispensable in many fields of
modern agrochemistry, pharmaceutical industry, and ma-
terials science.3 Therefore, methods for the synthesis of
fluorinated compounds that are simultaneously efficient,
economically feasible, and suitable for scale-up remain a
significant challenge for organic chemists.4 For other
work currently in progress in our laboratories, we required
phenols bearing two fluoroacyl moieties in the aromatic
ring. After extensive experimentation we succeeded in de-
veloping a facile, convenient, and reliable method to syn-
thesize these previously unknown compounds. Our
experimental findings and observations are summarized
here.
Me
v
F3C
CF3
F3C
CF3
O
O
O
OMe O
3a 70%
2 55%
Scheme 1 Synthesis of phenol 3a starting from 2,6-dibromo-4-
methylphenol. Reagents and conditions: (i) aq NaOH (1.6 equiv); (ii)
Me2SO4 (1 equiv), 40–100 °C, 30 min; (iii) BuLi (2 equiv), THF–
hexane, –78 °C, 1 h; (iv) CF3CO2Et (2 equiv), –78 °C to r.t., 1 h; (v)
BCl3 (1.5 equiv), CH2Cl2, –196 °C to r.t., 1 h.
Apart from the need for several steps because of the re-
quired protection/deprotection, as well as the only moder-
ate overall yield of 3a (35%), there is an additional serious
limitation to this synthetic protocol. Obviously, it is not
applicable to phenols with substituents in positions 3–5
that are sensitive towards nucleophilic attack. As for the
second classical route to 2,6-diacylphenols, namely
Prelog-type condensation,8 the putative starting com-
pound, 1,1,1,7,7,7-hexafluoroheptane-2,4,6-trione was
synthesized only very recently.9 Our first tests of its reac-
tivity gave only disappointing results, and we therefore
question the feasibility of this approach.
The methodology to synthesize our first target compound,
4-methyl-2,6-bis(trifluoroacetyl)phenol (3a, Scheme 1),
involved double acylation of p-cresol, promoted by a
Lewis acid. 2,6-Diacetyl-4-methylphenol can be obtained
easily in this way when an excess of acetyl chloride is
used in the presence of aluminum trichloride.5 Unfortu-
nately, this method does not work for trifluoroacetyl chlo-
ride: instead, 2-trifluoroacetyl-4-methylphenol was the
At the same time, there are some reports dealing with phe-
nol formation via consecutive dehydrohalogenations in
the cyclohexanone framework.10 Indeed, in the course of
recent work we observed that the 2,4-dibrominated 1,3,5-
triketone 4b underwent double dehydrobromination under
basic conditions to afford phenol 3b in 31% isolated yield
(Table 1, entry 1).11 Given the ease of the preparation of
SYNTHESIS 2008, No. 12, pp 1867–1878
x
x.
x
x
.
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0
0
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Advanced online publication: 16.05.2008
DOI: 10.1055/s-2008-1067080; Art ID: T18307SS
© Georg Thieme Verlag Stuttgart · New York

1868
D. V. Sevenard et al.
PAPER
both compound 4b and its precursor 2,6-bis(trifluoro-
acetyl)cyclohexanone (5b, Table 2),12 we became inter-
ested to know whether related reactions could be
developed into a general method to synthesize the target
2,6-bis(trifluoroacetyl)phenols 3 (Table 2). Attempts to
directly convert 5b into 3b when conventional oxidants
such as elemental sulfur or 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone were used failed. On the other hand, we
were pleased to find that the 1,3,5-triketone 4b, pre-gen-
erated from 5b, transformed into phenol 3b spontaneously
(Table 1, entry 2). There is no need to use any auxiliary re-
agents, although the dehydrobromination appeared to be
sluggish at ambient temperature: the conversion is com-
plete after 12 days, as indicated by 19F NMR monitoring
of the reaction mixture (Table 1, entry 2). Increase of the
temperature accelerated the aromatization considerably,
delivering compound 3b in 82% yield after reflux for 40
hours in chloroform as reaction solvent (Table 1, entry 3).
It is noteworthy that a further increase in reaction temper-
ature did not lead to better results. When xylene was used
instead of chloroform, the desired reaction was complicat-
ed by the formation of several unidentified side products.
Table 2 Synthesis of Phenols 3a–f Starting from the Corresponding
Cyclohexanonesa
R
R
i
ii
F3C
CF3
O
O
O
O
5
R
R
Br
O
Br
iii
F3C
CF3
F3C
CF3
O
OH
O
O
O
4
3
R
5
Yieldb
Intermediate Product Yieldb
of 5 (%)
4
3
of 3 (%)
Me
5a
5b
5c
5d
5e
5f
82
70
73
77
90
86
85
4a
4b
4c
4d
4e
4f
3a
3b
3c
3dc
3e
3f
92
H
82
Pr
95
Table 1 Dehydrobromination of Compound 4b
t-Bu
Ph
61
51
Br
O
Br
O
i
F3C
CF3
F3C
CF3
CO2Et
CO2H
51
O
OH
O
O
d
5g
4g
3g
–
4b
3b
a Reagents and conditions: (i) LiH (2 equiv; 4 equiv for 5g), CF3CO2Et
(3 equiv), THF, reflux, 48–50 h; (ii) Br2 (2 equiv), CHCl3, r.t., 24–60
h; (iii) reflux, 20–60 h (except for 3d).
Entry
1
Reagents and conditions (i)
Isolated yield of 3b (%)
3111
67
b Isolated yield.
Et3N, CH2Cl2, –50 °C to r.t.
CH2Cl2, r.t., 12 d
c Dehydrobromination step iii was carried out at r.t. (44 h).
d Formation of complex reaction mixtures, with product 3g not de-
tected at all.14
2a
3a
CHCl3, reflux, 40 h
82
a Starting compound 4b was pre-generated from 5b,11 and converted
into 3b without isolation.
warming; product 3d was obtained in 93% yield (by 19F
NMR) after 44 hours at ambient temperature.
Dilution appears to play an important role in the course of
this reaction. For instance, the attempted reaction of 5f
carried out in a reduced amount of chloroform as reaction
medium gave the bridged compound 613 repeatedly after
workup (Scheme 2). When the amount of solvent was in-
creased, it was possible to obtain 3f in 51% yield
(Table 2). The reason for this behavior of 4f is not clear.
Since only complex reaction mixtures14 formed when we
tried to aromatize compound 5g (Table 2), we sought to
prepare acid 3g from ester 3f (Table 3). Potassium bicar-
With these results in hand and using the principles estab-
lished earlier,11 we were able to synthesize a range of phe-
nol derivatives 3 with various substituents in the 4-
position, starting from commercially available cyclohex-
anones. The corresponding synthetic sequence is depicted
in Table 2. Double Claisen condensation with ethyl tri-
fluoroacetate and with lithium hydride as the base provid-
ed the corresponding 1,3,5-triketones 5 in 70–90% yields
(Table 2, step i). Treatment of 5 with excess elemental
bromine furnished compounds 4 (Table 2, step ii),11
which could be dehydrobrominated readily without isola-
tion (step iii). This formal oxidation, or rather two-step
aromatization of 5, allowed the preparation of phenol de-
rivatives 3 in a simple and convenient one-pot procedure
in 51–95% yields (Table 2).
O
COOEt
Br
Br
OH
OH
Br
O
ii
Br
i
F3C
5f
F3C
CF3
O
CF3
O
O
Within the substrates studied, the tert-butyl-substituted
compound 4d turned out to be the most reactive (Table 2).
In this case, the dehydrobromination step did not require
4f
6 43%
COOEt
Scheme 2 Formation of 6 from 5f. Reagents and conditions: (i) Br2
(2 equiv), CHCl3, r.t., 20 h; (ii) reflux, 48 h.
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

PAPER
Synthetic Route to 2,6-Bis(trifluoroacetyl)phenols
1869
Table 3 Synthesis of Compounds 3g–j from 3b and 3f
R
i
g R = COOH
h R = COOMe
F3C
CF3
3b,f
i
j
R = NO2
R = Br
O
OH
O
3g–j
Entry
Starting
material
Reagents and conditions (i)
Product
Isolated
yield (%)
1
2
3
4
5
6
3f
aq KOH, MeOH, r.t., 48 h
3h
3g
3i
53
32
73
23
37
57
3f
concd HCl, reflux, 10 h
3b
HNO3, H2SO4, –5 °C to 0 °C, 1 h
3b
NBS (1.5 equiv), TFA, H2SO4, 0 °C to r.t., 2 h
py (1.1 equiv), CH2Cl2, 0 °C, then Br2 (1.1 equiv), r.t., 20 h
py (1.1 equiv), CH2Cl2, –78 °C, then Br2 (1.1 equiv), –78 °C, 30 min, then r.t., 16 h
3ja
3ja
3ja
3b
3b
a 2,4-Dibromo-6-(trifluoroacetyl)phenol and 2,4,6-tribromophenol were detected as byproducts (see experimental section).
bonate in aqueous methanol15 was investigated to no protection group from cyclohexanone,17 did not work at
avail. Somewhat unexpectedly, when potassium bicar- all in our case. To our surprise, treatment of 5k with hy-
bonate was replaced by potassium hydroxide, trans-ester- drochloric acid gave 1,4-hydroquinone 3k directly
ification of 3f occurred to give methyl ester 3h as the sole (Scheme 3). One can assume that the deprotection step is
isolable product (Table 3, entry 1). The saponification of followed by oxidation of the intermediary tetraketone 7
3f could be achieved under harsh acidic conditions, fur- with air oxygen in this case. It is worth mentioning that the
nishing acid 3g in moderate yield (Table 3, entry 2).
formation of the corresponding 1,4-benzoquinone was not
detected. When subjected to bromination, 5k yielded a
yellow crystalline material only poorly soluble in deuter-
ated chloroform and deuterated acetonitrile. Unfortunate-
ly, when dissolved in more polar solvents (acetone-d6,
DMSO-d6, THF-d8), it appeared to be unstable, and all at-
tempts to grow single crystals suitable for X-ray diffrac-
tion analysis failed. Nevertheless, on the basis of
elemental analysis data as well as 1H and 19F NMR spectra
recorded in various solvents, the macrocyclic structure 8
could be suggested (Scheme 3). The probable mechanism
of aromatization involves a bromination–dehydrobromi-
nation–elimination–tautomerization sequence (Scheme 4).
The driving force of the dimerization into bis-hemiketal 8
is obviously the increased electrophilicity of the trifluoro-
acetyl moieties: the ability of the strong electron-
withdrawing trifluoromethyl group18 to stabilize the adja-
cent hemiketal center is well known.9,11
To achieve further functionalization of the 4-position in
the 2,6-bis(trifluoroacetyl)phenol molecule, we studied
the behavior of parent compound 3b in aromatic electro-
philic substitution reactions (Table 3, entries 3–6). Nitra-
tion of 3b proceeded smoothly, yielding 3i in 73% yield
(Table 3, entry 3). The bromination reaction appeared to
be more delicate, and we therefore examined several reac-
tion conditions for it (Table 3, entries 4–6). Under neutral
conditions, phenol 3b showed no reactivity towards bro-
mine. This can be explained by the electron-withdrawing
influence of the two trifluoroacetyl groups, which reduces
the nucleophilicity of the phenol ring. An attempt with a
bromonium reagent, pre-generated from N-bromosuccin-
imide in trifluoroacetic acid–sulfuric acid,16 delivered 4-
bromophenol 3j in 23% yield (Table 3, entry 4). The bet-
ter results were obtained from the reaction between a py-
ridinium salt of 3b and bromine, performed at –78 °C to
20 °C (Table 3, entries 5 and 6). It should be noted that the As an extension of these studies, the synthesis of 1,4-hyd-
products of a further bromination, namely 2,4-dibromo-6- roquinones 11 bearing the fluoroacyl moieties in positions
(trifluoroacetyl)phenol and 2,4,6-tribromophenol, were 2 and 5 was undertaken. On the basis of published data
detected in small amounts in these reactions (Table 3, en- concerning closely related succinyl succinates,19 and the
tries 4–6).
results above, tetraketones 9 were chosen as precursors of
11 (Scheme 5). Double trifluoroacetylation of cyclohex-
ane-1,4-dione with ethyl trifluoroacetate and sodium
methoxide as base yielded 9a in 56% yield (Scheme 5).
Application of this procedure for double Claisen conden-
sation with methyl 2,2,3,3-tetrafluoropropionate gave
tetraketone 9b in only 3% yield. When lithium diisopro-
With 1,3,5-triketone 5k obtained from mono-protected
cyclohexane-1,4-dione (Scheme 3), the synthesis of 2,6-
bis(trifluoroacetyl)-1,4-benzoquinone and 2,6-bis(trifluo-
roacetyl)-1,4-hydroquinone (3k) was envisaged. Aqueous
formic acid in toluene, which had been reported to be an
extremely efficient reagent to remove the ethylene glycol
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

1870
D. V. Sevenard et al.
PAPER
OH
O
O
[O]
ii
CF3
F3C
F3C
CF3
O
OH
O
O
O
3k 19%
O
O
7
O
O
i
F3C
CF3
CF3
O
O
O
O
O
O
O
CF3
5k 78%
HO
OH
OH
iii
1/2
HO
F3C
O
O
O
CF3
8 50%
Scheme 3 Synthesis and aromatization of 1,3,5-triketone 5k. Reagents and conditions: (i) LiH (2.2 equiv), CF3CO2Et (3 equiv), THF, reflux,
48 h; (ii) concd HCl, MeOH, reflux, 2 h, then r.t., 15 h; (iii) Br2 (2.2 equiv), CHCl3, r.t., 48 h.
O
O
O
+
HO
O
O
O
CF2X
iii
i or ii
1) – HBr
2) H+
H
O
Br2
XCF2
Br
5k
CF3
F3C
F3C
CF3
O
O
O
O
O
O
O
O
9a 56% (i),
9b 3% (i), 18% (ii)
OH
O
1) tautomerization
2) dimerization
OH
O
O
O
O
– H+
8
F3C
CF3
CF2X
CF2X
Br
XCF2
XCF2
– HBr
O
O
O
O
Scheme 4 Possible mechanism of the formation of dimer 8 from 5k
HO
O
10
11a 88%
11b 86%
a X = F
b X = CF2H
pylamide was used as the base instead of sodium methox-
ide, the yield of 9b could be somewhat improved to 18%
(Scheme 5). The aromatization of compounds 9 proceed-
ed smoothly: upon treatment with elemental bromine, 1,4-
hydroquinones 11a and b were obtained in 88% and 86%
yield, respectively (Scheme 5). In contrast to the reaction
of 5 (Scheme 3), one equivalent of bromine is sufficient
for the aromatization of 9 (Scheme 5). Indeed, the elimi-
nation of hydrogen bromide from the mono-a-brominated
intermediate 10 followed by redistribution of the double
bonds in the ring via keto enol and dienone–phenol tau-
tomerism gave rise to the aromatic ring, as shown in
Scheme 5.
Scheme 5 Synthesis of 1,4-hydroquinones 11. Reagents and condi-
tions: (i) NaOMe (2.2 equiv), XCF2CO2R (2.1 equiv), Et2O, 24 h; (ii)
LDA (2 equiv), HCF2CF2CO2Me (2 equiv), THF, –78 °C, then r.t., 12
h; (iii) Br2 (1 equiv), CHCl3, r.t., 10 h.
and B (Scheme 6) seems to be low, and, therefore, the hy-
droxy proton ‘jumps’ between the two carbonyl oxygens
giving rise to a ‘bifurcate’ hydrogen-bonded structure
(Scheme 6). This process is rapid on the NMR timescale
at room temperature, resulting in an averaged spec-
trum.20,21
Analogously to other fluorinated 1,3,5-triketones,12,22 the
bis-enol is the predominant species for compounds 5 in
deuterated chloroform, acetone-d6, and tetrahydrofuran
solutions at room temperature, as confirmed by 1H and 19F
NMR spectroscopy. Due to the fast ‘enol–enol’ tautomer-
ism C ' D ' E (Scheme 6)12,20,22 only an averaged set of
signals is evident for this tautomer. The less abundant
mono-enol form F as well as monohydrate (gem-diol) G
were also observed (Scheme 6).
The structural features of the di-, tri-, and tetracarbonyl
compounds obtained require special comments
(Scheme 6). According to the NMR spectroscopy data
collected for deuterated chloroform and acetone-d6 solu-
tions at room temperature (see experimental section), phe-
nols 3 have a symmetrical structure, although the dH range
(11.1–12.4) of the phenolic hydroxy proton verifies the
presence of the hydrogen bond. Presumably, this hydro-
gen bond simultaneously involves two trifluoroacetyl
functions with the single phenolic hydroxy group
(Scheme 6). The energy barrier between the two forms A
In deuterated chloroform solution at room temperature,
complete enolization was established for both compounds
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

PAPER
Synthetic Route to 2,6-Bis(trifluoroacetyl)phenols
1871
R
R
3
F3C
CF3
F3C
CF3
O
O
O
O
O
O
H
H
A
B
R1
R2
R1
R2
R2
R1
CF3
F3C
F3C
CF3
CF3
F3C
5
O
O
O
O
O
O
O
O
O
H
H
H
H
H
H
C
D
E
R1
R2
R2
R1
CF3
F3C
F3C
CF3
OH
O
O
HO
O
O
O
H
H
G
F
H
H
O
O
O
H
O
O
O
O
CF2X
9
CF2X
CF2X
XCF2
XCF2
XCF2
O
O
O
H
O
H
O
H
H
I
J
Scheme 6 Hydrogen bonding and enolization features of compounds 3, 5, and 9
9a,b by 1H and 19F NMR spectroscopy, within the limits pounds were studied by multinuclear NMR spectroscopy;
of detection. The fast ‘enol–enol’ tautomerism20,22,23 man- this established the presence of a ‘bifurcate’ intramolecu-
ifests itself by the sole averaged set of signals, including lar hydrogen bond in 2,6-bis(trifluoroacetyl)phenols as
resonances of two hydroxy protons [dH = 14.57 (9a), well as predominant U-bis-enolization of their 1,3,5-tri-
15.04 (9b)] and C(3,6)H2 groups [dH = 3.60 (9a), 3.68 carbonyl precursors and 2,5-bis(polyfluoroacyl)cyclohex-
(9b)], as well as resonances of polyfluoroalkyl moieties. ane-1,4-diones.
The 3JH,F coupling constant of CF2H in 9b is 5.3 Hz; this
suggests that the bis-endo-enol form H is a predominant
tautomeric form in deuterated chloroform solution,24 rath-
er than exo-endo-bis-enol I or bis-exo-enol J (Scheme 6).
Melting and boiling points are uncorrected. 1H (200 MHz), 13C (50
MHz), and 19F (188 MHz) NMR spectra were recorded at 22 °C on
a Bruker DPX-200 spectrometer scaled to TMS (1H and 13C) and
CCl3F (19F). NMR chemical shifts are referenced with respect to the
residual solvent signals (1H: d = 7.25, 2.05, 1.73 for CDCl3, ace-
tone-d6, THF-d8, respectively; 13C: d = 77.0 and 29.9 for CDCl3 and
An additional NMR feature of compounds 3, 5, 9, and 11
should be mentioned, namely that 4JC,F and 5JH,F splitting
is observed. This splitting, probably resulting from
through-space coupling, is in good accordance with the U-
acetone-d6, respectively). Reaction progress was monitored by 19
F
NMR spectroscopy for samples from the reaction mixtures dis-
type structure25 of the intramolecularly hydrogen-bonded solved in CHCl3 containing hexafluorobenzene as an internal refer-
ence (without lock). Signals in the 13C NMR spectra of compounds
species under discussion.
3c,e,j,k were assigned on the basis of DEPT135 experiments, as
To summarize, a simple, efficient, and convenient method
to synthesize 2,6-bis(trifluoroacetyl)phenols was devel-
oped, involving aromatization of 2,6-bis(trifluoro-
acetyl)cyclohexanones by a one-pot dibromination–
double dehydrobromination procedure. Application of
this approach to cyclohexane-1,4-dione as well as 4-posi-
tion functionalization of the parent 2,6-bis(trifluoro-
acetyl)phenol opened access to valuable fluoroacylated
phenols and 1,4-hydroquinones, which are not easily ob-
well as on 4JC,F splitting. Signals of the CF2 moieties in the 13C NMR
spectrum of compound 11b were assigned on the basis of an HSQC
experiment. MS was carried out by EI (70 eV) on a Finnigan MAT-
8200 and MAT-95 spectrometers, and by CI (NH3 as reactant gas)
on a MAT-8200 spectrometer. HRMS was carried out by the peak
matching method on a Finnigan MAT-95 spectrometer. Elemental
analyses were carried out by the Microanalytisches Beller Labor,
Göttingen, Germany. CHCl3 for brominations was purchased from
Fisher Scientific and used without further purification. 4-Oxocyclo-
hexanecarboxylic acid was prepared according to a literature meth-
tained by other methods. Structural features of these com- od.26 2,6-Dibromo-4-methylanisole (1) was prepared by methyl-
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

1872
D. V. Sevenard et al.
PAPER
ation of sodium 2,6-dibromo-4-methylphenolate with dimethyl sul-
fate according to a published procedure.27 Other chemicals are com-
mercially available and were used as purchased unless otherwise
specified. Reactions in anhyd solvents (CHCl3 and CH2Cl2 from
P2O5; Et2O and THF from sodium/benzophenone ketyl) were per-
formed in oven-dried glassware under a static N2 atmosphere. Silica
gel grade 60, 320–630 mesh (MP Biomedicals Germany GmbH)
was used for column chromatography.
(dd, 2 H, 3,5-H, 2JH,H = 15.4, 3JH,H = 10.4 Hz), 2.64–2.71 (m, 2 H,
3,5-H), 14.6 (br s, 2 H, 2 × OH).
19F NMR (188 MHz, CDCl3): d = –68.70 (dt, 4JF,H = 1.6, 5JF,H = 0.5
Hz, CF3).
Mono-enol F Form of 5c
3
3
1H NMR (200 MHz, CDCl3): d = 4.05 (dd, JH,H = 5.9, JH,H = 3.4
Hz, 1 H, 2-H), 14.3 (br s, 1 H, OH), other signals are overlapped by
more intensive signals of the most abundant tautomer.
2,6-Bis(trifluoroacetyl)cyclohexanones 5a–f,k; General Proce-
dure
19F NMR (188 MHz, CDCl3): d = –77.39 [s, 3 F, C(O)CF3], –73.91
(dt, 5JF,H = 1.1 Hz, 3 F, =CCF3).
A soln of the appropriate cyclohexanone (86 mmol) and CF3CO2Et
(36.7 g, 256 mmol) in anhyd THF (100 mL) was added dropwise to
a well-stirred suspension of finely powdered LiH (1.5 g, 189 mmol)
in THF (150 mL). After complete addition, the mixture was heated
at reflux for 48 h and then cooled to r.t.; ca. 100 mL of solvent was
evaporated. Then 10% aq H2SO4 (190 mL) was added carefully to
the residue, and the mixture was stirred for 10 min and then extract-
ed with Et2O (5 × 50 mL). The combined extracts were dried
(MgSO4) and concentrated, and the residue was distilled in vacuo.
1,3,5-Triketones 5b (70%),12 5d (77%),11 and 5e (90%),22 obtained
according to this general procedure, are known compounds.
Mono-hydrate G Form of 5c
1H NMR (200 MHz, CDCl3): d = 4.10–4.15 (m, 1 H, 2-H), 14.5 (br
s, 1 H, OH), other signals are overlapped by more intensive signals
of the most abundant tautomer.
19F NMR (188 MHz, CDCl3): d = –78.49 [s, 3 F, C(OH)2CF3],
–73.65 (m, 3 F, =CCF3).
Ethyl 4-Oxo-3,5-bis(trifluoroacetyl)cyclohexanecarboxylate
(5f)
Yield: 86%; yellow liquid; boiling interval 90–105 °C/0.5 Torr.
4-Methyl-2,6-bis(trifluoroacetyl)cyclohexanone (5a)
Yield: 82%; yellow liquid; bp 128–132 °C/20 Torr.
Exists in CDCl3 soln as a mixture of bis-enol, mono-enol F, and
mono-hydrate (gem-diol) G (89:6:5; by NMR).28
Exists in CDCl3 soln as a mixture of bis-enol, mono-enol F, and
mono-hydrate (gem-diol) G (88:6:6; by NMR).28
MS (EI, 70 eV): m/z (%) = 362 (54) [M+], 342 (59) [M – HF]+, 317
(10) [M – OC2H5]+, 293 (12) [M – CF3]+, 289 (56) [M – CO2C2H5]+,
269 (35) [M – HF – CO2C2H5]+, 219 (100) [M – CF3 – CO2C2H5 –
MS (EI, 70 eV): m/z (%) = 304 (52) [M]+, 235 (100) [M – CF3]+,
165 (10) [M – 2 CF3 – H]+.
+
+
H]+, 69 (20) [CF3 ], 29 (50) [C2H5 ].
HRMS: m/z [M]+ calcd for C11H10F6O3: 304.0534; found: 304.0537;
–1.0 ppm, –0.3 mu, R ≈ 10000.
HRMS: m/z [M]+ calcd for C13H12F6O5: 362.0589; found: 362.0583;
1.8 ppm, 0.6 mu, R ≈ 10000.
Bis-enol Form of 5a
Bis-enol Form of 5f
1H NMR (200 MHz, CDCl3): d = 1.07 (d, 3JH,H = 6.4 Hz, 3 H, CH3),
1.70–1.96 (m, 1 H, 4-H), 2.06–2.19 (m, 2 H, 3,5-H), 2.62–2.70 (m,
2 H, 3,5-H), 14.6 (br s, 2 H, 2 × OH).
1H NMR (200 MHz, CDCl3): d = 1.24 (t, 3JH,H = 7.3 Hz, 3 H, CH3),
3
2.68–2.91 (m, 5 H, 1,2,6-H), 4.16 (q, JH,H = 7.3 Hz, 2 H, OCH2),
14.68 (q, 4JH,F = 2.1 Hz, 2 H, 2 × OH).
19F NMR (188 MHz, CDCl3): d = –68.75 (dt, 4JF,H = 2.0, 5JF,H = 1.4
Hz, CF3).
19F NMR (188 MHz, CDCl3): d = –68.87 (m, CF3).
Mono-enol F Form of 5f
1H NMR (200 MHz, CDCl3): d = 14.25 (s, 1 H, OH), other signals
are overlapped by more intensive signals of the most abundant tau-
tomer.
Mono-enol F Form of 5a
3
3
1H NMR (200 MHz, CDCl3): d = 4.05 (dd, JH,H = 7.1, JH,H = 2.4
Hz, 1 H, 2-H), other signals are overlapped by more intensive sig-
nals of the most abundant tautomer.
19F NMR (188 MHz, CDCl3): d = –78.11 [s, 3 F, C(O)CF3], –74.08
19F NMR (188 MHz, CDCl3): d = –77.52 [s, 3 F, C(O)CF3], –73.99
(t, 5JF,H = 1.0 Hz, 3 F, =CCF3).
(unresolved td, 5JF,H ≈ 0.9, 4JF,H ≈ 0.5 Hz, =CCF3).
Mono-hydrate G Form of 5f
1H NMR (200 MHz, CDCl3): d = 14.42 (s, 1 H, OH), other signals
are overlapped by more intensive signals of the most abundant tau-
tomer.
Mono-hydrate G Form of 5a
19F NMR (188 MHz, CDCl3): d = –78.53 [s, 3 F, C(OH)2CF3],
–73.68 (m, 3 F, =CCF3).
19F NMR (188 MHz, CDCl3): d = –78.42 [s, 3 F, C(OH)2CF3],
–73.94 (m, 3 F, =CCF3).
4-Propyl-2,6-bis(trifluoroacetyl)cyclohexanone (5c)
Yield: 73%; yellow liquid; boiling interval 140–146 °C/12 Torr.
Exists in CDCl3 soln as a mixture of bis-enol, mono-enol F, and
mono-hydrate (gem-diol) G (53:24:23; by NMR).28
7,9-Bis(trifluoroacetyl)-1,4-dioxaspiro[4.5]decan-8-one (5k)
Yield: 78%; yellow liquid which solidified quickly; boiling interval
101–108 °C/1 Torr, melting interval 41–46 °C.
MS (EI, 70 eV): m/z (%) = 332 (52) [M+], 313 (9) [M – F]+, 289 (11)
[M – C3H7]+, 263 (100) [M – CF3]+, 236 (18) [M – CF3CO + H]+, 69
Exists in CDCl3 soln as a mixture of bis-enol and mono-enol F
+
+
(87:13; by NMR).28
(22) [CF3 ], 41 (33) [C3H5 ].
HRMS: m/z [M]+ calcd for C13H14F6O3: 332.0847; found: 332.0848;
–0.4 ppm, –0.1 mu, R ≈ 10000.
MS (EI, 70 eV): m/z (%) = 348 (55) [M+], 330(10) [M – H2O]+, 279
+
(40) [M – CF3]+, 251 (15) [M – CF3CO]+, 86 (100) [C4H6O2 ].
HRMS: m/z [M]+ calcd for C12H10F6O5: 348.0432; found 348.0437;
–1.3 ppm, –0.4 mu, R ≈ 10000.
Bis-enol Form of 5c
1H NMR (200 MHz, CDCl3): d = 0.93 (t, 3JH,H = 6.4 Hz, 3 H, CH3),
1.24–1.46 (m, 4 H, CH2CH2CH3), 1.63–1.76 (m, 1 H, 4-H), 2.15
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

PAPER
Synthetic Route to 2,6-Bis(trifluoroacetyl)phenols
1873
Bis-enol Form of 5k
2,6-Bis(trifluoroacetyl)phenols 3a–c,f from the Corresponding
2,6-Bis(trifluoroacetyl)cyclohexanones 5a–c,f; General Proce-
dure
1H NMR (200 MHz, CDCl3): d = 2.69 (s, 4 H, 3,5-H), 4.00 (s, 4 H,
OCH2CH2O), 14.59 (q, 4JH,F = 1.9 Hz, 2 H, 2 × OH).
A soln of Br2 (16.0 g, 100 mmol) in CHCl3 (30 mL) was added drop-
wise to a well-stirred soln of the appropriate 5 (50 mmol) in CHCl3
(200 mL) at r.t. The resulting red soln was stirred for 24 h (3f), 42 h
(3b), or 60 h (3a,c) at r.t., and then heated at reflux for an additional
20 h (3a), 40 h (3b), or 60 h (3c,f), depending on the reaction
progress, as determined by 19F NMR monitoring of the reaction
mixture. After the volatile materials had been removed in vacuo, the
residue was purified by recrystallization or distillation.
19F NMR (188 MHz, CDCl3): d = –68.90 (td, 5JF,H = 1.9, 4JF,H = 1.6
Hz, CF3).
Mono-enol F Form of 5k
1H NMR (200 MHz, CDCl3): d = 14.6 (br s, 1 H, OH), other signals
are overlapped by more intensive signals of the most abundant tau-
tomer.
19F NMR (188 MHz, CDCl3): d = –77.52 [s, 3 F, C(O)CF3], –73.85
(t, 5JF,H = 1.2 Hz, 3 F, =CCF3).
4-Methyl-2,6-bis(trifluoroacetyl)phenol (3a)
Yield: 92%; yellowish crystals; mp 51–52 °C (hexane).
1H NMR (200 MHz, CDCl3): d = 2.42 (s, 3 H, CH3), 7.88 (s, 2 H,
3,5-H), 11.74 (s, 1 H, OH).
4-Oxo-3,5-bis(trifluoroacetyl)cyclohexanecarboxylic Acid (5g)
A soln of 4-oxocyclohexanecarboxylic acid (0.56 g, 3.9 mmol) and
CF3CO2Et (1.70 g, 11.8 mmol) in anhyd THF (10 mL) was added
dropwise to a well-stirred suspension of finely powdered LiH (0.13
g, 15.8 mmol) in THF (20 mL). The mixture was heated at reflux for
50 h and cooled to r.t.; the precipitated solid was collected by filtra-
tion, washed with PE, and dried. To a well-stirred suspension of this
solid in Et2O (10 mL) was added 10% aq H2SO4 (16 mL). The mix-
ture was stirred for 10 min, and the organic layer was separated. Af-
ter additional extraction of the mixture with Et2O (2 × 10 mL), the
combined organic phases were dried (MgSO4) and concentrated;
this gave a brown liquid, which solidified. Recrystallization from
toluene gave 5g as yellowish crystals. The bis-enol, mono-enol F,
and mono-hydrate (gem-diol) G forms were detected in acetone-d6
and THF solns by NMR spectroscopy [88:6:6 (acetone-d6), 91:5:4
(THF)].28
13C NMR (200 MHz, CDCl3): d = 20.3 (s, CH3), 115.9 (q,
1JC,F = 290.1 Hz, CF3), 118.5 (s, 2,6-C), 129.8 (s, 4-C), 138.9 (q,
2
4JC,F = 2.4 Hz, 3,5-H), 162.2 (s, 1-C), 182.8 [q, JC,F = 37.0 Hz,
C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –72.75 (s, CF3).
MS (EI, 70 eV): m/z (%) = 300 (25) [M+], 281 (1) [M – F]+, 231
(100) [M – CF3]+, 161 (38) [M – 2 CF3 – H]+.
Anal. Calcd for C11H6F6O3: C, 44.02; H, 2.01; F 38.0. Found: C,
44.24; H, 2.01; F, 38.1.
2,6-Bis(trifluoroacetyl)phenol (3b)
Yield: 82%; yellow liquid; boiling interval 118–130 °C/12 Torr.
In contrast to 3b described earlier,11 the mono-hydrate (i.e., gem-di-
ol) was not detected by NMR spectroscopy. Alternatively, 3b could
be prepared in 67% yield (Table 1, entry 2). Performed in CH2Cl2 at
r.t., dehydrobromination of 2,4-dibromo-1,3,5-triketone 4b (pre-
generated from 5b and 2 equiv Br2) was complete after 12 d, as de-
termined by 19F NMR monitoring of the reaction mixture. Aqueous
workup followed by column chromatography (CHCl3) gave 3b as a
mixture with its mono-hydrate (68:32; by NMR).
Yield: 1.1 g (85%); mp 142–144 °C.
MS (EI, 70 eV): m/z (%) = 334 (100) [M+], 316 (32) [M – H2O]+,
289 (16) [M – CO2H]+, 265 (44) [M – CF3]+, 219 (80) [M – CO2H
– CF3 – H]+, 191 (89) [M – CF3CO – CO2H – H]+.
HRMS: m/z [M]+ calcd for C11H8F6O5: 334.0276; found 334.0283;
–2.2 ppm, –0.7 mu, R ≈ 10000.
Bis-enol Form of 5g
1H NMR (200 MHz, acetone-d6): d = 2.76–3.01 (m, 5 H, 1,2,6-H),
11.1 (br s, 1 H, CO2H), 14.6 (br s, 2 H, 2 × OH).
4-Propyl-2,6-bis(trifluoroacetyl)phenol (3c)
Yield: 95%; red liquid; boiling interval 82–94 °C/1 Torr.
1H NMR (200 MHz, CDCl3): d = 0.96 (t, 3JH,H = 7.3 Hz, 3 H, CH3),
1.56–1-75 (m, 2 H, CH2CH3), 2.64 (t, 3JH,H = 7.6 Hz, 2 H, ArCH2),
7.87 (s, 2 H, 3,5-H), 11.75 (s, 1 H, OH).
19F NMR (188 MHz, acetone-d6): d = –69.53 (s, CF3).
19F NMR (188 MHz, THF, without lock): d = –70.0 (s, CF3).
Mono-enol F Form of 5g
13C NMR (200 MHz, CDCl3): d = 13.4 (s, CH3), 24.2 (s, CH2CH3),
36.7 (s, ArCH2), 116.0 (q, 1JC,F = 290.6 Hz, CF3), 118.5 (s, 2,6-C),
134.5 (s, 4-C), 138.3 (s, 3,5-C), 162.3 (s, 1-C), 182.8 [q, 2JC,F = 37.2
Hz, C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –72.73 (s, CF3).
MS (EI, 70 eV): m/z (%) = 328 (24) [M+], 299 (22) [M – C2H5]+,
259 (100) [M – CF3]+, 229 (19) [M – C2H5 – CF3]+, 189 (10) [M –
2 CF3 – H]+.
1H NMR (200 MHz, acetone-d6): d = 4.59 (t, 3JH,H = 6.6, Hz, 1 H, 5-
H), other signals are overlapped by more intensive signals of the
most abundant tautomer.
19F NMR (188 MHz, acetone-d6): d = –78.64 [s, 3 F, C(O)CF3],
–74.20 (s, 3 F, =CCF3).
19F NMR (188 MHz, THF, without lock): d = –79.3 [s, 3 F,
C(O)CF3], –74.8 (s, 3 F, =CCF3).
HRMS: m/z [M]+ calcd for C13H10F6O3: 328.0534; found: 328.0524;
3.1 ppm, 1.0 mu, R ≈ 10000.
Mono-hydrate G Form of 5g
3
1H NMR (200 MHz, acetone-d6): d = 4.73 (dd, JH,H = 10.8,
3JH,H = 6.4 Hz, 1 H, 2-H), 6.64 (s, 2 H, 2 × OH), other signals are
overlapped by more intensive signals of the most abundant tau-
tomer.
4-Ethyl 4-Hydroxy-3,5-bis(trifluoroacetyl)benzoate (3f)
Yield: 51%; yellow crystals; mp 68–69 °C (heptane–toluene, 5:1).
1H NMR (200 MHz, CDCl3): d = 1.42 (t, 3JH,H = 7.1 Hz, 3 H, CH3),
4.43 (q, 3JH,H = 7.2 Hz, 2 H, CH2), 8.74 (s, 2 H, 2,6-H), 12.17 (s, 1
H, OH).
19F NMR (188 MHz, acetone-d6): d = –79.04 [s, 3 F, C(OH)2CF3],
–73.81 (m, 3 F, =CCF3).
19F NMR (188 MHz, THF, without lock): d = –79.7 [s, 3 F,
C(O)CF3], –74.6 (s, 3 F, =CCF3).
13C NMR (200 MHz, CDCl3): d = 14.2 (s, CH3), 62.2 (s, CH2),
1
115.7 (q, JC,F = 289.6 Hz, CF3), 118.7 (s, 3,5-C), 123.0 (s, 1-C),
139.3 (unresolved q, 4JC,F ≈ 2.8 Hz, 2,6-C), 163.3 (s, 4-C), 166.3 (s,
CO2C2H5), 182.7 [q, 2JC,F = 38.1 Hz, C(O)CF3].
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

1874
D. V. Sevenard et al.
PAPER
19F NMR (188 MHz, CDCl3): d = –72.90 (s, CF3).
HRMS: m/z [M]+ calcd for C16H8F6O3: 362.0378; found: 322.0376;
0.6 ppm, 0.2 mu, R ≈ 10000.
MS (EI, 70 eV): m/z (%) = 358 (6) [M+], 313 (18) [M – C2H5O]+,
289 (100) [M – CF3]+, 261 (40) [M – CF3CO]+, 243 (13) [M –
C2H5O – CF3 – H]+, 216 (7) [M – C2H5O – CF3CO]+, 191 (40) [M –
CF3CO – CF3 + H]+, 165 (6) [M – 2 CF3CO + H]+, 119 (8) [M –
C2H5O – 2 CF3CO]+, 91 (17) [M – 2 CF3CO – CO2C2H5]+, 73 (2)
4-Bromo-2,6-bis(trifluoroacetyl)phenol (3j) by Aromatization
of 1,3,5-Triketone 5g
Br2 (0.71 g, 4.5 mmol) was added dropwise to a well-stirred soln of
5g (0.48 g, 1.4 mmol) in CHCl3 (10 mL) at r.t. The resulting red soln
was stirred for 36 h at r.t. and then heated at reflux for an additional
40 h. 19F NMR monitoring of the reaction mixture revealed a com-
plex mixture of several aromatic products in approximately equal
concentrations. The mixture was cooled to r.t., and H2O (5 mL) was
added. After the mixture had stirred for 2 h at r.t., additional H2O
(20 mL) was added and the organic layer was separated. The aque-
ous phase was extracted with EtOAc (3 × 15 mL), and the combined
organic layer was dried (MgSO4) and evaporated under reduced
pressure to leave a yellow semi-solid. Column chromatography
(EtOAc) allowed the isolation of bis(trifluoroacetyl)phenol 3j as a
mixture with the corresponding mono-hydrate (47:53,28 by NMR),
and 2,4-dibromo-6-(trifluoroacetyl)phenol.
+
+
+
[CO2C2H5 ], 69 (9) [CF3 ], 29 (10) [C2H5 ].
HRMS: m/z [M]+ calcd for C13H8F6O5: 358.0276; found: 358.0276;
0.1 ppm, 0.0 mu, R ≈ 10000.
4-(tert-Butyl)-2,6-bis(trifluoroacetyl)phenol (3d)
Br2 (0.51 g, 3.2 mmol) was added dropwise to a well-stirred soln of
the 1,3,5-triketone 5d (0.50 g. 1.4 mmol) in CHCl3 (5 mL) at r.t. The
resulting red soln was stirred for 44 h at r.t. After the reaction was
complete (19F NMR monitoring), the volatile materials were re-
moved in vacuo to leave a yellow semi-solid. Column chromatog-
raphy (CHCl3) yielded the product. Besides 3d, its mono-hydrate
(13%)28 was detected by NMR spectroscopy.
Yield: 0.30 g (61%); yellow oil.
4-Bromo-2,6-bis(trifluoroacetyl)phenol (3j)
Yield: 60 mg (13%); yellow solid; melting interval 71–78 °C.
MS (CI, positive): m/z (%) = 364 (66) [M+], 344 (100) [M – HF]+.
MS (EI, 70 eV): m/z = 382 (1) [M + H2O]+, 364 (27) [M+], 295
(100) [M – CF3]+, 275 (8) [M – CF3 – HF]+, 225 (48) [M – 2 CF3 –
H]+, 197 (6) [M – CF3 – CF3CO – H]+, 28 (24) [CO+].
HRMS: m/z [M]+ calcd for C10H379BrF6O3: 363.9170; found:
363.9173; –0.9 ppm, 0.3 mu, R ≈ 10000.
MS (EI, 70 eV): m/z (%) = 342 (12) [M+], 327 (100) [M – CH3]+,
273 (20) [M – CF3]+.
HRMS: m/z [M]+ calcd for C14H12F6O3: 342.0691; found: 342.0695;
–1.3 ppm, –0.4 mu, R ≈ 9000.
3d (A ' B)
1H NMR (200 MHz, CDCl3): d = 1.35 (s, 9 H, t-Bu), 8.10 (s, 2 H,
3,5-H), 11.72 (s, 1 H, OH).
13C NMR (200 MHz, CDCl3): d = 30.8 (s, CH3), 34.5 [s, C(CH3)3],
116.0 (q, 1JC,F = 290.1 Hz, CF3), 118.3 (s, 2,6-C), 135.7 (s, 3,5-C),
143.2 (s, 4-C), 162.0 (s, 1-C), 183.0 [q, 2JC,F = 37.2 Hz, C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –72.72 (s, CF3).
3j (A ' B)
1H NMR (200 MHz, CDCl3): d = 8.15 (s, 2 H, 3,5-H), 11.8 (br s, 1
H, OH).
13C NMR (200 MHz, CDCl3): d = 115.7 (q, 1JC,F = 289.9 Hz, CF3),
4
120.3 (s, 2,6-C), 126.6 (s, 4-C), 140.6 (q, JC,F = 2.9 Hz, 3,5-C),
Mono-hydrate Form of 3d
162.5 (s, 1-C), 182.1 [q, 2JC,F = 38.0 Hz, C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –72.95 (s, CF3).
1H NMR (200 MHz, CDCl3): d = 1.33 (s, 9 H, t-Bu), 4.9 (br s, 2 H,
2 × OH), 7.89–7.96, 8.12–8.18 (both m, 2 × 1 H, 3,5-H), 12.07 (s, 1
H, 1-OH).
19F NMR (188 MHz, CDCl3): d = –86.10 [s, 3 F, C(OH)2CF3],
Mono-hydrate Form of 3j
1H NMR (200 MHz, CDCl3): d = 4.9 (br s, 2 H, 2 × OH), 8.01–8.06
–70.49 [d, 3 F, 5JF,H = 2.0 Hz, 3 F, C(O)CF3].
4
(m, 1 H, 3-H), 8.19 (d, JH,H = 2.6 Hz, 1 H, 5-H), 12.1 (s, 1 H, 1-
OH).
4-Phenyl-2,6-bis(trifluoroacetyl)phenol (3e)
2
13C NMR (200 MHz, CDCl3): d = 97.1 [q, JC,F = 34.7 Hz,
A soln of Br2 (14.9 g, 92 mmol) in CHCl3 (30 mL) was added drop-
wise to a well-stirred soln of the 1,3,5-triketone 5e (17.0 g. 46
mmol) in CHCl3 (250 mL) at r.t. The resulting red soln was stirred
for 60 h at r.t., and then heated at reflux for 20 h (19F NMR moni-
toring of the reaction mixture). The mixture was cooled to r.t., and
another portion of Br2 (3.7 g, 23 mmol) was added. After further
stirring of the mixture for 20 h at r.t., the volatile materials were re-
moved in vacuo. The orange oily residue was dissolved in hexane
and cooled to –30 °C; this caused a precipitate to form. The product
was collected by filtration and recrystallized from hexane.
C(OH)2CF3], 112.9, 115.4 (both s, 2-C, 6-C), 115.9 [q, 1JC,F = 289.5
Hz, C(O)CF3], 122.6 [q, 1JC,F = 289.0 Hz, C(OH)2CF3], 126.6 (s, 4-
C), 135.0 (q, JC,F = 3.7 Hz, 3-C), 142.5 (s, 5-C), 160.0 (s, 1-C),
4
184.6 [q, 2JC,F = 36.8 Hz, C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –85.81 [s, 3 F, C(OH)2CF3],
–70.79 [d, 5JF,H = 1.8 Hz, 3 F, C(O)CF3].
2,4-Dibromo-6-(trifluoroacetyl)phenol
Yield: 10 mg (2%); yellow solid; mp 69–73 °C.
Yield: 8.5 g (51%); yellow crystals; mp 76–77 °C.
1H NMR (200 MHz, CDCl3): d = 7.40–7.60 (m, 5 H, C6H5), 8.28 (s,
2 H, 3,5-H), 11.86 (s, 1 H, OH).
1H NMR (200 MHz, CDCl3): d = 7.86–7.93 (m, 1 H, 5-H), 8.01 (d,
4JH,H = 2.4 Hz, 1 H, 3-H), 11.5 (br s, 1 H, OH).
13C NMR (200 MHz, CDCl3): d = 111.7, 114.0, 115.3 (s, 2-C, 4-C,
6-C), 115.9 (q, 1JC,F = 289.6 Hz, CF3), 131.9 (q, 4JC,F = 4.2 Hz, 5-C),
144.1 (s, 3-C), 159.9 (s, 1-C), 183.7 [q, 2JC,F = 36.7 Hz, C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –70.76 (d, 5JF,H = 1.9 Hz, CF3).
MS (EI, 70 eV): m/z (%) = 346 (67) [M+], 277 (100) [M – CF3]+.
HRMS: m/z [M]+ calcd for C8H379Br2F3O2: 345.8452; found:
345.8424; 7.9 ppm, 2.7 mu, R ≈ 10000.
13C NMR (200 MHz, CDCl3): d = 116.0 (q, 1JC,F = 290.1 Hz, CF3),
119.1 (s, 2,6-C), 126.8, 128.6, 129.4, 133.8 (s, C6H5), 137.4 (s, 4-
4
C), 136.8 (q, JC,F = 1.9 Hz, 3,5-C), 163.0 (s, 1-C), 183.9 [q,
2JC,F = 37.2 Hz, C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –72.68 (s, CF3).
MS (EI, 70 eV): m/z (%) = 362 (88) [M+], 293 (100) [M – CF3]+,
223 (28) [M – 2 CF3 – H]+, 168 (10) [M – 2 CF3CO]+, 77 (3)
+
+
[C6H5 ], 69 (8) [CF3 ].
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

PAPER
Synthetic Route to 2,6-Bis(trifluoroacetyl)phenols
1875
Ethyl (1RS,2SR,4RS,5SR)-1,5-Dibromo-2,4-dihydroxy-9-oxo-
2,4-bis(trifluoromethyl)-3-oxabicyclo[3.3.1]nonane-7-carboxy-
late (6)
Br2 (1.38 g, 8.6 mmol) was added dropwise to a well-stirred soln of
5f (1.56 g, 4.3 mmol) in CHCl3 (25 mL). The resulting red soln was
stirred for 20 h at r.t., and then heated at reflux for an additional 48
h. The mixture was cooled to r.t. and evaporated to leave a brown
oily residue which solidified in several days. Recrystallization of
the solid from toluene yielded 6.
19F NMR (188 MHz, CDCl3): d = –85.73 [s, 3 F, C(OH)2CF3],
–70.80 [s, 3 F, C(O)CF3].
4-Nitro-2,6-bis(trifluoroacetyl)phenol (3i)
Phenol 3b (1.0 g, 3.5 mmol) was dissolved in concd aq H2SO4 (2
mL) at –10 °C. A mixture of 65% HNO3 (0.25 mL) and concd aq
H2SO4 (0.5 mL) was added dropwise to this soln at –5 °C. The re-
sulting soln was stirred for 1 h at 0 °C, poured into ice water (100
g), and extracted with Et2O (4 × 10 mL). The combined extracts
were washed with brine (5 mL) and dried (Na2SO4). Removal of the
solvent gave a solid residue, which was recrystallized (heptane–
toluene, 1:1); this furnished 3i as a mixture with the corresponding
monohydrate (67:33,28 by NMR).
Yield: 1.0 g (43%); white crystals; mp 113–115 °C.
3
1H NMR (200 MHz, acetone-d6): d = 1.23 (t, JH,H = 7.1 Hz, 3 H,
CH3), 2.63–2.80 (m, 2 H, 6,8-H), 3.00–3.21 (m, 2 H, 6,8-H), 3.58
(tt, 3JH,H = 13.2, 3JH,H = 4.6 Hz, 1 H, 7-H), 4.14 (q, 3JH,H = 7.2 Hz, 2
H, OCH2), 7.7 (br s, 2 H, 2 × OH).
Yield: 0.84 g (73%); pale yellow crystals; melting interval 92–
97 °C.
19F NMR (188 MHz, acetone-d6): d = –78.81 (s, CF3).
MS (EI, 70 eV): m/z (%) = 331 (6) [M+], 262 (100) [M – CF3]+, 216
MS (EI, 70 eV): m/z (%) = 518 (1) [M – H2O]+, 343 (44) [M – H2O
– CF3CO – Br + H]+, 269 (100) [M – H2O – CF3CO – Br –
CO2C2H5]+, 191 (44) [M – H2O – CF3CO – 2 Br – CO2C2H5 + H]+,
(32) [M – CF3 – NO2]+, 192 (16) [M – 2 CF3 – H]+, 69 (3) [CF3 ].
+
HRMS: m/z [M]+ calcd for C9H3F3NO5: 261.9963; found:
261.9959; 1.6 ppm, 0.4 mu, R ≈ 10000.
+
69 (38) [CF3 ].
HRMS: m/z [M – H2O]+ calcd for C13H1079Br2F6O5: 517.8799;
found: 517.8815; –3.1 ppm, –1.6 mu, R ≈ 10000.
3i (A ' B)
1H NMR (200 MHz, CDCl3): d = 8.97 (unresolved t, 5JH,F ≈ 0.7 Hz,
2 H, 3,5-H), 12.4 (br s, 1 H, OH).
4-Hydroxy-3,5-bis(trifluoroacetyl)benzoic Acid (3g)
A soln of 3f (0.20 g, 0.56 mmol) in concd aq HCl (5 mL) was heated
at reflux for 10 h. The mixture was cooled to r.t. and evaporated to
dryness. The solid residue was washed with warm CHCl3 (15 mL),
and the organic phase was evaporated. Column chromatography of
the solid residue (EtOAc) yielded 3g.
19F NMR (188 MHz, CDCl3): d = –72.98 (s, CF3).
Monohydrate Form of 3i
1H NMR (200 MHz, CDCl3): d = 4.9 (br s, 2 H, 2 × OH), 8.85–8.90
[m, 1 H, 5(3)-H], 8.95 [s, 1 H, 3(5)-H], 12.4 (br s, 1 H, 1-OH).
19F NMR (188 MHz, CDCl3): d = –85.52 [s, 3 F, C(OH)2CF3],
Yield: 60 mg (32%); yellow crystals; melting interval 136–143 °C.
1H NMR (200 MHz, CDCl3): d = 8.79 (s, 2,6-H).
–71.00 [d, 5JF,H = 1.4 Hz, 3 F, C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –72.90 (s, CF3).
Compound 3j by Bromination of 3b (Table 3, entry 4)
To a well-stirred soln of 3b (2.9 g, 10 mmol) in TFA (5 mL) was
added concd aq H2SO4 (1.5 mL) at 0 °C. To the resulting brown soln
maintained at 0 °C was added NBS (2.7 g, 15 mmol) in several por-
tions within 10 min. The mixture was allowed to warm and stirred
for 2 h at r.t., then poured into H2O (300 mL), and extracted with
CH2Cl2 (4 × 25 mL). The combined extracts were washed with brine
(25 mL) and dried (Na2SO4). Removal of the solvent gave an oily
residue, which was distilled in vacuo; this gave a yellow liquid
(boiling interval 80–110 °C/1 Torr). Column chromatography
(CHCl3, then EtOAc) furnished two fractions. The first one (0.5 g
of yellow semi-solid after evaporation) consisted of 2,4-dibromo-6-
(trifluoroacetyl)phenol, 2,4,6-tribromophenol,29 and 3j (1:1:1, by
NMR). The second fraction [0.85 g (23%) of yellow semi-solid]
was found to be 3j in mixture with the corresponding mono-hydrate
(87:13,28 by NMR).
MS (EI, 70 eV): m/z (%) = 330 (8) [M+], 261 (100) [M – CF3]+, 191
(64) [M – 2 CF3 – H]+, 69 (4) [CF3]+.
HRMS: m/z [M]+ calcd for C11H4F6O5: 329.9963; found: 329.9969;
–1.9 ppm, –0.6 mu, R ª 10000.
Methyl 4-Hydroxy-3,5-bis(trifluoroacetyl)benzoate (3h)
A 5% aq KOH soln (7 mL) was added dropwise to a stirred soln of
3f (0.30 g, 0.83 mmol) in MeOH (10 mL) at ca. 18 °C. The resulting
soln was left for 48 h at r.t., and then diluted with H2O (50 mL). The
mixture was acidified with 12% aq HCl to pH 1, and extracted with
EtOAc (4 × 10 mL). The combined extracts were dried (MgSO4)
and concentrated. Column chromatography of the residue (CHCl3)
yielded a yellow oil which solidified slowly to afford methyl ester
3h as a mixture with the corresponding monohydrate (65:35,28 by
NMR).
Compound 3j by Bromination of 3b (Table 3, entry 5)
Py (50 mg, 0.62 mmol) was added to a well-stirred soln of 3b (0.16
g, 0.56 mmol) in CH2Cl2 (3 mL) at 0 °C. The mixture was allowed
to reach r.t., and Br2 (100 mg, 0.62 mmol) was added. The resulting
yellow soln was stirred for 20 h at r.t., poured into H2O (50 mL), and
acidified with 12% aq HCl to pH 1. The organic layer was separat-
ed, and the aqueous phase was extracted with CH2Cl2 (5 × 5 mL).
The combined organic layer was dried (Na2SO4) and the solvent
was evaporated; this left a yellow oil. Column chromatography
(CHCl3, then EtOAc) furnished two fractions. The first one (50 mg
of yellow solid after evaporation) consisted of 2,4-dibromo-6-(tri-
fluoroacetyl)phenol and 2,4,6-tribromophenol29 (1:1, by NMR).
The second fraction [80 mg (37%) of yellow semi-solid] was found
to be 3j in mixture with the corresponding mono-hydrate (65:35,28
by NMR).
Yield: 0.15 g (53%); yellow semi-solid.
MS (EI, 70 eV): m/z (%) = 344 (8) [M+], 313 (20) [M – CH3O]+, 275
(100) [M – CF3]+, 205 (40) [M – 2 CF3 – H]+, 216 (2) [M – CH3O –
CF3CO]+.
Anal. Calcd for C12H6F6O5: C, 41.88; H, 1.76. Found: C, 41.59; H,
1.85.
3h (A ' B)
1H NMR (200 MHz, CDCl3): d = 3.98 (s, 3 H, CH3), 8.74 (s, 2 H,
2,6-H), 12.1 (br s, 1 H, OH).
19F NMR (188 MHz, CDCl3): d = –72.86 (s, CF3).
Monohydrate Form of 3h
1H NMR (200 MHz, CDCl3): d = 3.95 (s, 3 H, CH3), 4.8, 5.1 (2 br
s, 2 × 1 H, 2 × OH), 8.64, 8.73 (2 s, 2 × 1 H, 2-H, 6-H), 12.1 (br s,
1 H, 1-OH).
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

1876
D. V. Sevenard et al.
PAPER
Compound 3j by Bromination of 3b (Table 3, entry 6)
MS (CI, positive): m/z (%) = 364 (100) [0.5M + NH4]+, 363 (95)
A soln of 3b (2.0 g, 7.0 mmol) in anhyd CH2Cl2 (30 mL) was cooled
to –78 °C, and anhyd py (0.61 g, 7.7 mmol) and Br2 (1.1 g, 7.7
mmol) were added sequentially. The resulting soln was stirred for
30 min at –78 °C, then for 16 h at r.t. The soln was poured into H2O
(200 mL), the organic layer was separated, and the aqueous phase
was extracted with CH2Cl2 (4 × 40 mL). The combined organic lay-
er was dried (Na2SO4) and the solvent was evaporated to leave a yel-
low oil. Column chromatography (CHCl3, then EtOAc) furnished
two fractions. The first one (0.2 g of yellow oil after evaporation)
consisted of starting 3b, 2,4-dibromo-6-(trifluoroacetyl)phenol, and
2,4,6-tribromophenol29 (1:1:1, by NMR). The second fraction [1.4
g (57%); yellow semi-solid] was found to be 3j in mixture with the
corresponding mono-hydrate (90:10,28 by NMR).
[0.5M + NH3]+, 346 (30) [0.5M]+.
MS (CI, negative): m/z (%) = 346 (100) [0.5M]–, 326 (98) [0.5M –
HF]–.
MS (EI, 70 eV): m/z (%) = 346 (44) [0.5M]+, 302 (10) [0.5M –
CH2CH2O]+, 277 (20) [0.5M – CF3]+, 233 (100) [0.5M – CH2CH2O
– CF3]+, 163 (12) [0.5M – CH2CH2O – 2 CF3 – H]+, 45 (18)
[C2H5O]+.
HRMS: m/z [0.5M]+ calcd for C12H8F6O5: 346.0276; found:
346.0279; –0.9 ppm, –0.3 mu, R ≈ 10000.
Anal. Calcd for C24H16F12O10: C, 41.64; H, 2.33; F, 32.9. Found: C,
41.56; H, 2.40; F, 32.7
2,5-Bis(trifluoroacetyl)cyclohexane-1,4-dione (9a)
2,6-Bis(trifluoroacetyl)-1,4-hydroquinone (3k)
CF3CO2Et (10.5 g, 74 mmol) was added to an ice-cooled suspension
of NaOMe (4.4 g, 80 mmol) in anhyd Et2O (100 mL) under stirring,
after which cyclohexane-1,4-dione (3.9 g, 35 mmol) was added in
several portions. The mixture was stirred for 24 h at r.t. After treat-
ment with 10% aq H2SO4 (80 mL), the mixture was stirred for 10
min and extracted with Et2O (3 × 15 mL). The combined extracts
were dried (MgSO4) and concentrated. The solid residue was re-
crystallized (heptane–toluene, 2:1).
Concd aq HCl (3 mL) was added to a soln of 5k (3.0 g, 8.6 mmol)
in MeOH (40 mL). The resulting soln was heated at reflux for 2 h,
cooled to r.t., and stirred for 15 h. The soln was poured into H2O
(250 mL), and extracted with EtOAc (3 × 40 mL). The combined
extracts were dried (Na2SO4) and evaporated; this left an orange oil,
which solidified. The solid was recrystallized (heptane–toluene,
4:1) to give 3k.
Yield: 0.50 g (19%); orange crystals; mp 140 °C.
1H NMR (200 MHz, acetone-d6): d = 7.66 (s, 2 H, 3,5-H), 9.08 (s, 1
H, 4-OH), 11.13 (s, 1 H, 1-OH).
Yield: 6.1 g (56%); orange crystals; melting interval 115–120 °C.
1H NMR (200 MHz, CDCl3): d = 3.60 (s, 4 H, 2,5-H), 14.57 (s, 2 H,
2 × OH).
1
13C NMR (200 MHz, acetone-d6): d = 117.1 (q, JC,F = 289.6 Hz,
19F NMR (188 MHz, CDCl3): d = –74.61 (t, 5JF,H ≈ 0.9 Hz, CF3).
MS (EI, 70 eV): m/z (%) = 304 (100) [M+], 235 (40) [M – CF3]+,
CF3), 120.3 (s, 2,6-C), 125.4 (s, 3,5-C), 150.7 (s, 4-C), 157.6 (s, 1-
C), 183.4 [q, 2JC,F = 36.7 Hz, C(O)CF3].
+
207 (34) [M – CF3CO]+, 97 [26] [CF3CO+], 69 (48) [CF3 ].
19F NMR (188 MHz, acetone-d6): d = –72.92 (s, CF3).
HRMS: m/z [M]+ calcd for C10H6F6O4: 304.0170; found: 304.0153;
5.7 ppm, 1.7 mu, R ≈ 10000.
MS (EI, 70 eV): m/z (%) = 302 (47) [M+], 233 (100) [M – CF3]+,
163 (52) [M – 2 CF3 – H]+, 135 (14) [M – CF3 – CF3CO – H]+, 108
+
(10) [M – 2 CF3CO]+, 69 (10) [CF3 ].
2,5-Bis(2,2,3,3-tetrafluoropropionyl)cyclohexane-1,4-dione
(9b)
HRMS: m/z [M]+ calcd for C10H4F6O4: 302.0014; found: 302.0025;
–3.6 ppm, –1.1 mu, R ≈ 10000.
Method A: HCF2CF2CO2Me (3.0 g, 18.5 mmol) was added to an
ice-cooled suspension of NaOMe (1.0 g, 18.5 mmol) in anhyd Et2O
(30 mL) under stirring, after which cyclohexane-1,4-dione (1.0 g,
8.9 mmol) was added in several portions. The mixture was stirred
for 24 h at r.t. After treatment with 10% aq H2SO4 (20 mL), the mix-
ture was stirred for 10 min and then extracted with Et2O (4 × 15
mL). The combined extracts were dried (MgSO4) and concentrated.
The oily residue was dissolved in CHCl3 and filtered through a bed
of silica gel, and the filter pad was washed with CHCl3. The filtrate
was evaporated, and the solid residue was recrystallized from hep-
tane.
5,7,16,18-Tetrahydroxy-8,19-bis(trifluoroacetyl)-5,16-bis(tri-
fluoromethyl)-1,4,12,15-tetraoxa[5,5]metacyclophane (8)
Br2 (0.51 g, 3.2 mmol) was added dropwise to a well-stirred soln of
5k (0.50 g, 1.45 mmol) in CHCl3 (20 mL). The resulting red soln
was stirred in a stoppered flask for 48 h. After opening of the flask
(caution: slight internal pressure due to HBr vapors), the precipitate
was collected by filtration and air-dried; this yielded product 8.
Yield: 0.25 g (50%); yellow powder; mp 153 °C.
1H NMR (200 MHz, acetone-d6): d = 3.99–4.24 (m, 6 H, 2 CH2, 2 ×
2
3
3
Yield: 100 mg (3%); yellow needles; mp 83–85 °C.
CH), 4.54 (ddd, JH,H = 10.6, JH,H = 8.9, JH,H = 1.6 Hz, 2 H, 2 ×
CH), 7.35 [d, 3JH,H ≈ 2 Hz, 2 H, 11,22(9,20)-H], 7.66 [d, JH,H ≈ 3
3
Method B: A soln of cyclohexane-1,4-dione (1.0 g, 8.9 mol) in an-
hyd THF (10 mL) was added dropwise to a mixture of a 1.8 M soln
of (commercially obtained) LDA in heptane–THF–ethylbenzene
(10 mL) and THF (20 mL) maintained at –78 °C. After the mixture
had stirred for 40 min, HCF2CF2CO2Me (2.9 g, 18.0 mmol) was
added via cannula. The reaction mixture was warmed to r.t. and
stirred for 12 h. After treatment with 10% aq H2SO4 (20 mL), the
mixture was stirred for 10 min and then extracted with Et2O (4 × 15
mL). The combined extracts were washed with brine (15 mL), dried
(Na2SO4), and concentrated. The residue was purified by column
chromatography (CHCl3).
Hz, 2 H, 9,20(11,22)-H], 8.0 (br s, 2 H, 5,16-OH), 10.4 (br s, 2 H,
7,18-OH). The two last signals disappeared after the addition of
deuterated acetic acid.
1H NMR (200 MHz, THF-d8): d = 3.90–4.10 (m, 6 H, 2 CH2, 2 ×
CHH), 4.40–4.51 (m, 2 H, 2 × CHH), 7.25 [d, 3JH,H ≈ 2.4 Hz, 2 H,
11,22(9,20)-H], 7.61 [d, 3JH,H ≈ 2.9 Hz, 2 H, 9,20(11,22)-H], 8.2 (br
s, 2 H, 5,16-OH), 10.2 (br s, 2 H, 7,18-OH).
19F NMR (188 MHz, acetone-d6): d = –85.53 [s, 6 F, 2 ×
C(OH)2CF3], –73.87 [s, 6 F, 2 × C(O)CF3].
19F NMR (188 MHz, THF-d8): d = –85.86 [s, 6 F, 2 × C(OH)2CF3],
–74.35 [s, 6 F, 2 × C(O)CF3].
19F NMR (188 MHz, CDCl3): d = –85.80 [s, 6 F, 2 × C(OH)2CF3],
–70.71 [s, 6 F, 2 × C(O)CF3].
Yield: 0.60 g (18%).
5
1H NMR (200 MHz, CDCl3): d = 3.68 (t, JH,F = 1.5 Hz, 4 H, 2,5-
H), 6.18 (tt, 2JH,F = 52.6, 3JH,F = 5.3 Hz, 2 H, 2 × CF2H), 15.04 (s, 2
H, 2 × OH).
19F NMR (188 MHz, CD3CN): d = –85.81 (s, 6 F, 2 × C(OH)2CF3],
–73.00 (s, 6 F, 2 × C(O)CF3].
2
19F NMR (188 MHz, CDCl3): d = –139.41 (dt, JF,H = 52.6,
3JF,F = 7.2 Hz, 4 F, 2 × CF2CF2H), –122.01 (m, 4 F, 2 × CF2CF2H).
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

PAPER
Synthetic Route to 2,6-Bis(trifluoroacetyl)phenols
1877
MS (EI, 70 eV): m/z (%) = 368 (100) [M+], 267 (100) [M –
CF2CF2H]+, 239 (68) [M – HCF2CF2CO]+, 110 (30) [M – 2
HCF2CF2CO]+, 101 (36) [CF2CF2H+], 51 (16) [CF2H]+.
HRMS: m/z [M]+ calcd for C12H8F8O4: 368.0295; found: 368.0295;
–0.1 ppm, 0.0 mu, R ≈ 10000.
MS (EI, 70 eV): m/z (%) = 314 (28) [M+], 245 (100) [M – CF3]+, 69
(4) [CF3]+.
Anal. Calcd for C12H8F6O3: C, 45.88; H, 2.57; F, 36.3. Found: C,
45.68; H, 2.61; F, 35.8.
Deprotection of 2
2,5-Bis(fluoroacyl)-1,4-hydroquinones 11; General Procedure
Br2 (0.54 g, 2.1 mmol) was added dropwise to a well-stirred soln of
the appropriate 9 (2.1 mmol) in CHCl3 (5 mL) at r.t. The resulting
red soln was stirred in a stoppered flask for 10 h. After opening of
the flask (caution: slight internal pressure due to HBr vapors), the
volatile materials were evaporated, and the residue was recrystal-
lized from heptane.
A soln of 2 (18.0 g, 57 mmol) in anhyd CH2Cl2 (10 mL) was placed
in a thick-walled glass ampule equipped with a Teflon tap, and then
BCl3 (10.0 g, 86 mmol) was condensed into the evacuated ampule
at liquid N2 temperature. The mixture was gradually allowed to
warm and stirred for 1 h at r.t. After the volatile materials had been
removed in vacuo, the content of the ampule was carefully treated
with an ice–water mixture (20 mL). The resulting mixture was par-
titioned between H2O (100 mL) and CH2Cl2 (100 mL). The organic
layer was separated, washed with H2O (4 × 50 mL), dried (Na2SO4),
and concentrated. Recrystallization of the residue from hexane at
–50 °C gave 3a.
2,5-Bis(trifluoroacetyl)-1,4-hydroquinone (11a)
Yield: 88%; orange crystals; mp 131–134 °C.
1H NMR (200 MHz, CDCl3): d = 7.59 (q, 5JH,F = 2.0 Hz, 2 H, 3,5-
H), 10.04 (s, 2 H, 2 × OH).
Yield: 12.0 g (70%).
13C NMR (200 MHz, CDCl3): d = 115.8 (q, 1JC,F = 289.8 Hz, CF3),
4
120.1 (s, 2,5-C), 120.1 (q, JC,F = 3.8 Hz, 3,6-C), 154.6 (s, 1,4-C),
Acknowledgment
184.4 [q, 2JC,F = 36.7 Hz, C(O)CF3].
We are grateful to Dr. M. Braun, Solvay Organics GmbH, Bens-
berg, Germany, for the generous gift of chemicals. Mrs. D. Kemken
and Dr. T. Dülcks, Institute of Organic Chemistry, University of
Bremen, Germany, are thanked for recording mass spectra, and Mr.
P. Brackmann, Institute of Inorganic & Physical Chemistry, Univer-
sity of Bremen, Germany, is thanked for the X-ray diffraction mea-
surements. We are indebted to Dr. A. A. Kolomeitsev for helpful
discussions.
19F NMR (188 MHz, CDCl3): d = –71.41 (d, 5JF,H = 1.9 Hz, CF3).
MS (EI, 70 eV): m/z (%) = 302 (56) [M+], 233 (100) [M – CF3]+,
+
205 (2) [M – CF3CO]+, 69 (12) [CF3 ].
HRMS: m/z [M]+ calcd for C10H4F6O4: 302.0014; found: 302.0008;
2.1 ppm, 0.6 mu, R ≈ 10000.
2,5-Bis(2,2,3,3-tetrafluoropropionyl)-1,4-hydroquinone (11b)
Yield: 86%; orange crystals; mp 116–117 °C.
2
3
1H NMR (200 MHz, CDCl3): d = 6.27 (tt, JH,F = 52.3, JH,F = 5.1
Hz, 2 H, 2 × CF2H), 7.73 (t, 5JH,F = 2.0 Hz, 2 H, 3,5-H), 10.1 (br s,
2 H, 2 × OH).
References
(1) This work was presented in part at the 18th International
Symposium on Fluorine Chemistry, Bremen, Germany, 30
July–4 August 2006.
(2) Present address: Hansa Fine Chemicals GmbH, BITZ,
Fahrenheit Str. 1, 28359 Bremen, Germany.
13C NMR (200 MHz, CDCl3): d = 108.4 (tt, JC,F = 252.2,
1
2JC,F = 31.6 Hz, CF2H), 110.1 (tt, JC,F = 264.9, JC,F = 27.3 Hz,
1
2
4
3
CF2CO), 120.4 (t, JC,F = 6.8 Hz, 3,6-C), 121.3 (t, JC,F = 2.5 Hz,
2,5-C), 154.5 (s, 1,4-C), 190.2 [t, 2JC,F = 28.5 Hz, C(O)CF2].
(3) (a) Welch, J. T. Tetrahedron 1987, 43, 3123. (b) Lin, P.;
Jiang, J. Tetrahedron 2000, 56, 3635. (c) Welch, J. T.;
Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
Wiley: New York, 1991. (d) Organofluorine Chemistry –
Principles and Commercial Applications; Banks, R. E.;
Smart, B. E.; Tatlow, J. C., Eds.; Plenum: New York, 1994.
(e) Bégué, J.-P.; Bonnet-Delpon, D. Chimie bioorganique et
médicinale du fluor; CNRS Editions: Paris, 2005.
(4) (a) Hiyama, T. Organofluorine Compounds. Chemistry and
Application; Springer: Berlin, 2000. (b) Kirsch, P. Modern
Fluoroorganic Chemistry, Synthesis, Reactivity,
Applications; Wiley-VCH: Weinheim, 2004. (c) Chambers,
R. D. Fluorine in Organic Chemistry; Blackwell: Oxford,
2004.
2
19F NMR (188 MHz, CDCl3): d = –138.38 (dt, JF,H = 52.5,
3JF,F = 6.4 Hz, 4 F, 2 × CF2H), –117.09 (m, 5JF,H = 2.0 Hz, 4 F, 2 ×
CF2CO).
MS (EI, 70 eV): m/z (%) = 366 (64) [M+], 265 (100) [M –
CF2CF2H]+.
HRMS: m/z [M]+ calcd for C12H6F8O4: 366.0138; found: 366.0138;
0.2 ppm, 0.1 mu, R ≈ 10000.
4-Methyl-2,6-bis(trifluoroacetyl)anisole (2)
A 1.6 M soln of BuLi in hexane (73 mL, 117 mmol) was added
dropwise to a soln of 1 (16.0 g, 57 mmol) in anhyd THF (100 mL)
maintained at –78 °C. After the mixture had stirred for 1 h at this
temperature, CF3CO2Et (17.0 g, 120 mmol) was added dropwise.
The reaction mixture was allowed to reach r.t. and stirred for 1 h.
After successive treatment of the mixture with 10% aq NH4Cl (30
mL) and 10% aq HCl (100 mL), the aqueous layer was saturated
with NaCl and the organic layer was separated. After extraction
with Et2O (4 × 30 mL), the combined organic phases were washed
successively with brine (30 mL) and H2O (30 mL), dried (Na2SO4),
and concentrated. Distillation of the residue gave the product.
(5) Mandal, S. K.; Nag, K. J. Chem. Soc., Dalton Trans. 1983,
2429.
(6) Schoth, R.-M. PhD Thesis; University of Bremen:
Germany, 1996.
(7) Ansong, O.; Antoine, M. D.; Nwokogu, G. C.; Hergenrother,
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(8) (a) Prelog, V.; Metzler, O.; Jeger, O. Helv. Chim. Acta 1947,
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1842. (c) Bertz, S. H. Synthesis 1980, 708. (d) Nishiwaki,
N.; Tohda, Y.; Ariga, M. Synthesis 1997, 1277.
(9) Sevenard, D. V.; Kazakova, O.; Chizhov, D. L.;
Röschenthaler, G.-V. J. Fluorine Chem. 2006, 127, 983.
(10) (a) Openshaw, H. T.; Robinson, R. J. Chem. Soc. 1946, 912.
(b) Coumbarides, G. S.; Dingjan, M.; Eames, J.;
Weerasooriya, N. J. Chem. Res., Synop. 2000, 328.
Yield: 9.8 g (55%); yellow liquid; bp 52 °C/1 Torr.
1H NMR (200 MHz, CDCl3): d = 2.27 (s, 3 H, ArCH3), 3.69 (s, 3 H,
OCH3), 7.67 (s, 2 H, 3,5-H).
19F NMR (188 MHz, CDCl3): d = –77.93 (s, CF3).
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York

1878
D. V. Sevenard et al.
PAPER
(11) Sevenard, D. V.; Kazakova, O.; Chizhov, D. L.; Yachevskii,
D. S.; Lork, E.; Poveleit, J.; Charushin, V. N.;
Röschenthaler, G.-V. Helv. Chim. Acta 2007, 90, 369.
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(b) Chizhov, D. L.; Pashkevich, K. I.; Röschenthaler, G.-V.
J. Fluorine Chem. 2003, 123, 267.
(13) For the synthesis of related bridged dibromoketones from
fluorinated 1,3,5-triketones, as well as for the stereochemis-
try of 4, see ref. 11.
(23) (a) Koltsov, A. I.; Kheifets, G. M. Russ. Chem. Rev. (Engl.
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Prevrashcheniya b-Dikarbonil’nykh Soedineniy (in
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(14) 2,4-Dibromo-6-(trifluoroacetyl)phenol and 4-bromophenol
3j and its monohydrate could be identified (see experimental
procedure), whereas the targeted acid 3g was not detected at
all.
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(16) Duan, J.; Zhang, L. H.; Dolbier, W. R. Jr. Synlett 1999, 1245.
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79.
(27) Kohn, M.; Segel, A. Monatsh. Chem. 1925, 46, 661.
(28) For freshly prepared CDCl3 (3d,h,i,j and 5a,c,f,k), acetone-
d6, or THF (5g) solns. It is notable that if the CDCl3 soln of
5c is maintained at r.t. for 20 h, the [bis-enol]/[F]/[G] molar
ratio changes from 53:24:23 to 89:6:5 (by NMR
(19) (a) Herrman, F. Liebigs Ann. Chem. 1882, 211, 306.
(b) Guha, P. C. Chem. Ber. 1939, 72, 1359. (c) Bagrov, F.
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(20) The Chemistry of Enols; Rappoport, Z., Ed.; Wiley:
Chichester, 1990.
(21) For the hydrogen bonding and equilibria in related non-
fluorinated phenols, see: Koelle, U.; Forsén, S. Acta Chem.
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(22) Sevenard, D. V.; Kazakova, O.; Lork, E.; Dülcks, T.;
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spectroscopy). Contact with silica gel leads to hydration of
phenols 3. When a mixture of 3j is stirred with silica gel in
CHCl3, the concentration of the hydrate form increases from
11% to 70% after 14 h at r.t. Dehydration can be achieved if
the substance is maintained in anhyd CHCl3: for 3j the
hydrate content changed from 70% to 11% after 7 d at r.t.
The use of 4-Å MS accelerates dehydration. In this case, the
content of the hydrate form decreases to 7% after 17 h at r.t.
(by 19F NMR). Anhyd MgSO4 appeared to be inefficient.
(29) Okada, Y.; Yokozava, M.; Akiba, M.; Oishi, K.; Okawa, K.;
Akeboshi, T.; Kawamura, Y.; Inokuma, S.; Nakamura, Y.;
Nishimura, J. Org. Biomol. Chem. 2003, 1, 2506.
Synthesis 2008, No. 12, 1867–1878 © Thieme Stuttgart · New York