Efficient synthesis of α,α-difluoro ketones using selectfluor F-TEDA-BF4

Article abstract of DOI:10.1055/s-2005-918424

Selective and efficient synthesis of α,α-difluoro ketones was achieved following a protocol which includes the transformation of α-methylene ketones to the corresponding n-butylimine derivatives and their further treatment with Selectfluor F-TEDA-BF₄

Full text of DOI:10.1055/s-2005-918424

3140
PAPER
Efficient Synthesis of a,a-Difluoro Ketones Using SelectfluorTM F-TEDA-BF4
E
fficient
g
S
ynthesis of
o
a
,
a
-
Difluoro
r
Ketone
s
Pravst,a Marko Zupan,a,b Stojan Stavber*b
a
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, 1000 Ljubljana, Slovenia
Laboratory for Organic and Bioorganic Chemistry, ‘Jozef Stefan’ Institute, Jamova 39, 1000 Ljubljana, Slovenia
E-mail: stojan.stavber@ijs.si
b
Received 30 May 2005; revised 4 July 2005
various protocols of electrophilic fluorination,22–27 mono-
carbonyl compounds are usually monofluorinated when-
ever fluorination proceeds directly from ketones,28 as well
as indirectly via enol acetates, silyl enol ethers or metal
enolates.25,29 Transformations of ketones with N-fluoro-
1,4-diazoniabicyclo[2.2.2]octane dication salts were
found to be solvent dependent30 while further fluorination
of thus obtained a-fluoro ketones to a,a-difluoro deriva-
tives was unsuccessful using this methodology.28 To our
knowledge three methods for the transformation of the a-
methylene to the a,a-difluoro carbonyl functionality have
been reported. Nakano’s procedure follows low tempera-
ture reaction of N-fluorobenzensulfonimide (Accufluor
NFSi) in the presence of a large excess of MnBr2 with the
corresponding enolate anions, obtained by treatment of
ketones with an excess of the strong base N,N-bis(tri-
methylsilyl)amide.31 According to DesMarteau the
fluorination of imines with N-fluorobis[(trifluoro-
methyl)sulfonyl]imide followed by an acidic work-up re-
sulted in the formation of a,a-difluoro ketones,32 while
very recently, Shreeve reported low-temperature transfor-
mation of enamines to a,a-difluoroketones using Select-
fluor in the presence of weak base or molecular sieves.33
Abstract: Selective and efficient synthesis of a,a-difluoro ketones
was achieved following a protocol which includes the transforma-
tion of a-methylene ketones to the corresponding n-butylimine de-
rivatives and their further treatment with SelectfluorTM F-TEDA-
BF4 in acetonitrile solution at 80 °C.
Key words: halogenation, fluorination, imines, ketones, a,a-di-
fluoro ketones, Selectfluor F-TEDA-BF4
The introduction of a fluorine atom or fluorine-containing
groups into organic molecules often dramatically perturbs
their physical, chemical and biological properties1 and af-
fects their application in comprehensive areas covered by
the material and life sciences.2,3 Site-selective synthesis of
fluorine-substituted organic compounds is therefore of
wide interest to the research community.3,4
The carbonyl site in a-fluorinated ketones is a much better
electrophile than in the corresponding nonfluorinated ke-
tones since fluorine, as the most electronegative atom,
when bond to carbon, always acts inductively as an elec-
tron-withdrawing moiety. This causes not only changes in
reactivity but in biological activity as well. As long as
twenty years ago it has been shown that a,a-difluoro ke-
tones are good inhibitors of hydrolactic enzymes and by a
range of 104–105-fold better inhibitors than the corre-
sponding nonfluorinated ketones, as established in the
case of acetyl cholinesterase, pepsin and renin.5 Increased
inhibition of difluoro ketone derivatives was later estab-
lished for many other enzymes including renin,6–8 chy-
motripsin,9,10 porcine pancreatic elastase,11 interleukin-1b
converting enzyme,12 HIV protease,13 Alzheimer’s g-
secretase,14–16 matrix metalloproteases17 and others.18 It is
known that a,a-difluoro ketones tend to exist in hydrated
form and thus mimic closely the tetrahedral transition
state involved in enzyme inhibition.7
In our continuing interest in selective fluorination of or-
ganic compounds we now report a method for efficient
synthesis of a,a-difluoro ketones by fluorination of
imines with some commercially available N-F reagents:
SelectfluorTM F-TEDA-BF4 (1) and AccufluorTM NFTh
(2) as representatives of N-fluoro-1,4-diazoniabicy-
clo[2.2.2]octane dication salts, AccufluorTM NFSi (3) as
one of the N-fluoroamines, and N-fluoro-2,6-dichloropy-
ridinium tetrafluoroborate FP-B800 (4) as the most sel-
dom-used N-F reagent from the N-fluoropyridinium salt
family.
Synthesis of imines from ketones and primary amines us-
ing catalytic amounts of trifluoroacetic acid and azeotro-
pic removal of water is a known and routine procedure,34
but the ordinarily applied corresponding protocols include
the use of very toxic solvents such as benzene or toluene.
We found that cyclohexane could be used as solvent for
efficient synthesis of imines.
Efficient synthetic methods for the preparation of a,a-di-
fluoro ketones starting from alkynes19,20 or phenols21 have
been developed using various electrophilic fluorinating
reagents, while selective difluorination of carbonyl com-
pounds remains troublesome in those cases when the a-
methylene carbon atom is not additionally activated. As
some 1,3-dicarbonyl compounds (a-diketones, a-keto es-
ters, malonates) could be smoothly difluorinated using
We first tested this modification in order to synthesize te-
tralone imines 7 (Scheme 1) from tetralone (6) and n-bu-
tylamine or ( )-phenylethylamine. We were very
successful in both cases as the crude reaction mixtures
were pure enough to continue with fluorination without
further purification. According to the literature34–36 the
orientation of N-alkyl group is expected to be anti to the
aromatic ring.
SYNTHESIS 2005, No. 18, pp 3140–3146
x
x.
x
x
.
2
0
0
5
Advanced online publication: 06.10.2005
DOI: 10.1055/s-2005-918424; Art ID: T07205SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
Efficient Synthesis of a,a-Difluoro Ketones
3141
R
fluorination of ketones with N-F reagents, we first tried
reactions in methanol at reflux temperature, but as evident
from the results collected in Table 1 (entries 1,5,10), se-
lectivity of the transformation was poor. Fluorination with
1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]oc-
tane bis(tetrafluoroborate) (1, SelectfluorTM F-TEDA-
BF4), 1-fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]oc-
tane bis(tetrafluoroborate) (2, AccufluorTM NFTh) and N-
fluorobenzenesulfonimide (3, AccufluorTM NFSi) fol-
lowed by a hydrolysis with aqueous HCl resulted in the
formation of a mixture of monofluoro 8 and difluoro 9 de-
rivatives.
N
O
R-NH2
cyclohexane
TFAcat, reflux
7a: R = nBu (95%)
7b: R = ( )-CHMePh (71%)
6
Scheme 1
In order to determine optimal reaction conditions for high-
ly selective and efficient synthesis of a,a-difluoro ketones
using electrophilic fluorination reagents, we selected
imines 7 as test compounds. Since according to our previ-
ous work28 methanol was the best choice of solvent for
Table 1 Fluorination of Derivatives of Tetralone Imine 7 with Electrophilic Fluorination Reagentsa
R
O
O
N
F
F
+
1) 2 F-reagent
MeCN
F
2) HCl/H2O
7a: R = nBu
8
9
7b: R = ( )-CHMePh
Entry
Reagent
R1
Solvent
8:9b
Yield (%)c
1
2
3
4
CHMePh
CHMePh
CHMePh
n-Bu
MeOH
MeCN
MeCNd
MeCNd
73:27
25:75
0:100
0:100
88
92
93
95
F
N+
N+
-
(BF4
)
2
Cl2HC
F-TEDA-BF4
1
5
6
7
8
9
CHMePh
CHMePh
CHMePh
n-Bu
MeOH
MeCN
56:44
58:42
40:60
40:60
32:68
87
92
88
91
90
F
N+
N+
MeCNd
MeCNd
MeCNd,e
–
(BF4
)
2
HO
n-Bu
NFTh
2
10
11
12
13
CHMePh
CHMePh
CHMePh
n-Bu
MeOH
MeCN
MeCNd
MeCNd
31:69
21:79
13:87
12:88
84
94
90
89
F
O
O
S
S
Ph
Ph
O O
NFSi
3
14
15
n-Bu
n-Bu
MeCNd
CH2Cl2
100:0
100:0
67
65
–
BF4
F
d
Cl
N+
Cl
FP-B800
4
F
16
CHMePh
MeCNd
79:21
39
O
O
S
O
O–Cs+
CsSO4F
5
a Reaction conditions: 1) imine (1 mmol), fluorinating reagent (2 mmol), solvent (10 mL), reflux temperature; 2) hydrolysis with 37% aq HCl
solution (0.5 mL).
b Relative distribution in % determined from19F NMR spectra of isolated reaction mixtures.
c Total yield of fluorinated products was determined from 19F NMR spectra of isolated reaction mixtures using octafluoronaphthalene as internal
standard.
d Anhyd MeCN in dry atmosphere was used.
e Pure NFTh 2 was used (not in mixture with Al2O3 as commercially available).
Synthesis 2005, No. 18, 3140–3146 © Thieme Stuttgart · New York

3142
I. Pravst et al.
PAPER
The use of acetonitrile as reaction solvent improved the tion conditions resulted in the formation of a complex re-
selectivity of the reaction considerably (entries 2,6,11). action mixture of products among which at least two
Imines are very sensitive to the presence of nucleophiles different a,a-difluoro carbonyl derivatives could be de-
and therefore acetonitrile is expected to be a better reac- tected. On the other hand, 1-acetyladamantane (22, entry
tion medium than methanol, while moisture in the reac- 11) was via its imine selectively fluorinated to 1-adaman-
tion components would also lower the selectivity of the tan-1-yl-2,2-difluoroethanone (23) in acceptable yield.
transformation. Freshly distilled acetonitrile, additionally
dried by reaction with anhydrous Na2SO4, seems to be the
In conclusion, we can claim that SelectfluorTM F-TEDA-
BF4 (1), otherwise one of the most versatile reagents for
best choice for selective transformation of imines to a,a-
difluoro ketones, and among the reagents tested Selectflu-
orTM F-TEDA-BF4 (1) gave the best results (entries 3 and
4, Table 1). AccufluorTM NFSi (3) also gave good results
(entries 12,13), while AccufluorTM NFTh (2) was less suc-
cessful (entries 7–9). The use of N-fluoro-2,6-dichloropy-
ridinium tetrafluoroborate FP-B800 (4) was inefficient
because the transformation stopped at the stage of a-fluo-
ro ketone 8 (entries 14,15). Cesium fluoroxysulfate (5)
was also found to be unsuitable reagent for the transfor-
mation of imines to a,a-difluoro ketones (entry 16). The
alkyl group R had a very low influence on the selectivity
of the reaction as the results were very similar for n-butyl
(7a) and phenylethyl (7b) derivatives.
selective fluorination38 and many other function-
alizations39 of organic compounds, is an excellent choice
as the mediator for the transformation of ketones to a,a-
difluoromethylene ketones after prior activation of the
starting material by imine formation. Regioselective
transformation could be achieved in the case of aryl alkyl
ketones, benzocyclanones and alkyl tert-alkyl ketones,
while poor regioselectivity was observed in the case of di-
alkyl ketones.
1-(Chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis-
(tetrafluoroborate) (1, SelectfluorTM F-TEDA-BF4) was purchased
from Aldrich and N-fluoro-2,6-dichloropyridinium tetrafluorobo-
rate (4, FP-B800) was purchased from Apollo. Both were used as
received.
1-Fluoro-4-hydroxy-1,4-diazoniabicyclo[2.2.2]octane
In order to determine the limitations of the method, we
further studied the effect of the structure of the ketone on
the selectivity and efficiency of its transformation to a,a-
difluoro derivatives with F-TEDA-BF4 (1) and the results
are collected in Table 2. Following the optimal reaction
protocol established after the experiments shown in
Table 1, acetophenone (10a, entry 1, Table 2) was readily
transformed to 2,2-difluorophenylethan-1-one (11a), as
well as 4-methoxyacetophenone (12, entry 5) to its a,a-di-
fluoro substituted derivative 13. Since no ring fluorinated
products were observed, evidently the selectivity of the
transformation was not interfered by the strong activation
of the aromatic ring, which was also confirmed in the case
of reaction of the imine prepared from 5-methoxy-1-te-
tralone (18, entry 9) which was also fluorinated only at the
a to carbonyl position, thus yielding 19. The correspond-
ing imines obtained from some derivatives of acetophe-
none functionalized with alkyl (10b), phenyl (10c) or
benzyl (10d) substituent at the methylene carbon atom
were readily transformed to the corresponding a,a-difluo-
ro ketones 11b–d, as well as imines from 1-indanone
(16a, entry 7) or benzosuberone (16b, entry 8) to 2,2-di-
bis(tetrafluoroborate) (2, AccufluorTM NFTh, 50% w/w on Al2O3)
and N-fluorobenzenesulfonimide (3, AccufluorTM NFSi) were re-
ceived as gifts from Allied Signal and used as obtained. Cesium flu-
oroxysulfate (CsSO4F, 5) was prepared from aqueous solution of
Cs2SO4 and a fluorine–nitrogen mixture as described in the litera-
ture.40 Starting materials were from Sigma-Aldrich and were used
as received. The following ACS grade solvents were used: CH2Cl2,
tert-butyl methyl ether, MeOH, hexane, petroleum ether (bp 40–
60 °C) (all from Carlo Erba Reagenti), cyclohexane and MeCN
(Merck). Other chemicals used were purchased from Sigma-Ald-
rich (trifluoroacetic acid, amines), Merck (Na2SO4, NaHCO3, HCl)
and Carlo Erba Reagenti (NaCl).
Melting points were determined on a Büchi 535 apparatus. 1H NMR
spectra were recorded on a Varian INOVA 300 spectrometer at 300
MHz and 13C NMR spectra on the same instrument at 76 MHz.
Chemical shifts are reported in ppm from TMS as the internal stan-
dard. 19F NMR spectra were recorded on a Varian EM 360L at 56.4
MHz and chemical shifts are reported in ppm from CCl3F as the in-
ternal 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 Au-
tospec Q instrument under electron impact (EI) conditions at 70 eV.
Elemental analyses were carried out on a Perkin-Elmer 2400 CHN
fluoro-1-indanone (17a) or 6,6-difluoro-6,7,8,9-tetra- analyzer or obtained from Mikroanalytisches Labor Pascher, Ger-
many.
hydrobenzocyclohepten-5-one (17b), respectively. The
presence of a sulfur atom in the target ketone did not in-
terfere with the selectivity or the efficiency of the fluori-
nation process, although one would expect some
interference due to the considerable oxidation power of F-
TEDA-BF4.37 3-Acetylthiophene (20, entry 10) was thus
selectively transformed to 2,2-difluoro-1-thiophen-3-yl-
ethanone (21) in high yield.
Imines 7a,b (and Table 1); General Procedure
A modified literature procedure was used.34 To a solution of ketone
(10 mmol) in cyclohexane (20 mL), were added amine (12 mmol)
and CF3CO2H (5 drops). The mixture was refluxed with azeotropic
removal of H2O using a Dean–Stark apparatus until the expected
amount of H2O was eliminated, but not longer than 24 h. The sol-
vent was removed under reduced pressure and the crude mixture
dissolved in tert-butyl methyl ether. The organic solution was
washed with a sat. aq solution of NaHCO3 and with 10% aq NaCl
solution, dried (Na2SO4) and the solvent evaporated. Crude imines
The fluorination protocol was also tested on some dialkyl
ketones and unfortunately complete loss of selectivity was
observed in the case of substrates containing two a-meth- were pure enough to continue with fluorination without previous
purification. Some imines, on which we tested this procedure, were
ylene groups. Treatment of imines derived from 5-
analyzed and compared with literature data.
nonanone or 1-phenylacetone under the mentioned reac-
Synthesis 2005, No. 18, 3140–3146 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of a,a-Difluoro Ketones
3143
Table 2 Synthesis of a,a-Difluoro Ketones from Ketones by Reaction of Imines with Selectfluor F-TEDA-BF4 (1)a
1) 2 F-TEDA-BF4
anhyd MeCN
1
O
Bun
O
N
R''
R''
R'
R''
R'
2) HCl/H2O
R'
F
F
Entry
Ketone
Reaction time (h) a,a-Difluoro ketone
Yield (%)b
1
2
3
4
O
a: R1 = H
4
4
4
4
77
76
73
85
O
b: R1 = C8H17
c: R1 = Ph
CF2
R1
d: R1 = CH2Ph
R1
10
11
5
4
70
O
O
O
Me
Me
CHF2
MeO
MeO
12
13
6
4
82
O
CF2H
15
17
14
16
7
8
a: n = 1
b: n = 3
4
4
89
81
O
O
O
O
CF2
(CH2)n
(CH2)n
9
4
80
CF2
OMe
OMe
18
19
10
11
8
76
61
S
S
O
O
Me
CF2H
CF2H
20
21
12
O
Me
O
22
23
a Reaction conditions: 1) imine (1 mmol), SelectfluorTM F-TEDA-BF4 (1; 2 mmol), anhyd MeCN (10 mL), reflux temperature, 4–12h;
2) hydrolysis with 37% aq HCl solution (0.5 mL).
b Refer to pure products and calculated on the basis of the starting imine.
Butyl-(3,4-dihydro-2H-naphthalen-1-ylidene)amine (7a)35
Yield: 95%; brown oil.
MS (EI, 70 eV): m/z (%) = 201 (10, M+), 158 (35), 135 (99), 105
(100), 77 (76).
IR (neat): 1670, 1610, 1580, 1435, 1285, 755, 720 cm–1.
( )-(3,4-Dihydro-2H-naphthalen-1-ylidene)(1-phenyleth-
yl)amine (7b)34,36
Yield after crystallization from n-hexane: 71%; pale yellow crys-
tals; mp 51 °C.
1H NMR (300 MHz, CDCl3): d = 0.97 (t, J = 7.3 Hz, 3 H, CH3), 1.46
(m, 2 H, CH2), 1.73 (m, 2 H, CH2), 1.93 (m, 2 H, CH2), 2.56 (t,
J = 6.6 Hz, 2 H, CH2), 2.80 (t, J = 6.1 Hz, 2 H, CH2), 3.44 (t, J = 7.1
Hz, 2 H, CH2), 7.11 (m, 1 H, ArH), 7.18–7.29 (m, 2 H, ArH), 8.17
(m, 1 H, ArH).
13C NMR (76 MHz, CDCl3): d = 14.0, 20.8, 22.6, 27.6, 29.8, 33.2,
50.7, 125.6 (ArCH), 126.3 (ArCH), 128.2 (ArCH), 129.4 (ArCH),
135.0 (ArC), 140.2 (ArC), 163.9 (C=N).
IR (KBr): 3050, 3005, 2960, 2870, 1620, 1590, 1490, 1450, 1360,
1295, 1230, 1295, 1230, 1190, 1065, 1025, 760, 730, 695 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.52 (d, J = 6.5 Hz, 3 H, CH3),
1.90 (m, 2 H, CH2), 2.60 (m, 2 H, CH2), 2.79 (t, J = 6.0 Hz, 2 H,
Synthesis 2005, No. 18, 3140–3146 © Thieme Stuttgart · New York

3144
I. Pravst et al.
PAPER
CH2), 4.86 (q, J = 6.5Hz, 1 H), 7.10 (m, 1 H, ArH), 7.17–7.33 (m, 5
(ArCH), 130.1 (ArCH), 132.2 (ArC), 134.2 (ArCH), 189.7 (t,
H, ArH), 7.45 (m, 2 H, ArH), 8.36 (m, 1 H, ArH).
J = 31.0 Hz, C=O).
13C NMR (76 MHz, CDCl3): d = 22.7, 25.2, 27.7, 29.8, 58.4, 126.0
(ArCH), 126.3 (ArCH), 126.4 (ArCH), 126.6 (ArCH), 128.2
(ArCH), 128.3 (ArCH), 129.5 (ArCH), 135.1 (ArC), 140.4 (ArC),
146.5 (ArC), 162.6 (C=N).
19F NMR (56.4 MHz, CDCl3): d = –101.0 (t, J = 18.1 Hz, CF2).
MS (EI, 70 eV): m/z = 268 (2, M+), 156 (2), 105 (100), 77 (40).
Anal. Calcd for C16H22F2O: C, 71.61; H, 8.26. Found: C, 72.03; H,
8.43.
MS (EI, 70 eV): m/z (%) = 249 (65), 234 (68), 105 (100), 77 (27).
2,2-Difluoro-1,2-diphenylethanone (11c)19,20
Yield: 73%; colorless liquid.
IR (neat): 3015, 2995, 1680, 1575, 1430, 1240, 1115, 990, 875 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.4–7.5 (m, 5 H, ArH), 7.58 (m, 1
H, ArH), 7.60 (m, 2 H, ArH), 8.06 (d, J = 7.5 Hz, 2 H, ArH).
13C NMR (76 MHz, CDCl3): d = 116.9 (t, J = 252.9 Hz, CF2), 125.6
(t, J = 5.8 Hz, ArCH), 128.6 (ArCH), 128.8 (ArCH), 130.2 (ArCH),
130.9 (ArCH), 132.1 (ArC), 133.1 (ArC), 134.2 (ArCH), 188.9
(C=O).
19F NMR (56.4 MHz, CDCl3): d = –99.3 (s, CF2).
MS (EI, 70 eV): m/z = 232 (15, M+), 213 (20), 183 (45), 165 (50),
Difluoro Ketones 9,11,13,15,17,19,21,23; General Procedure
To a solution of imine (1 mmol) in freshly distilled MeCN (10 mL),
were added anhyd Na2SO4 (100 mg) and SelectfluorTM F-TEDA-
BF4 (208 mg, 2 mmol). The suspension was mixed and heated under
reflux for 4–12 h, until the fluorinating agent was consumed as in-
dicated by KI starch paper. Aq HCl (0.5 mL, 37%) was then added
to the mixture and the stirring was continued for 10 min. The sol-
vent was removed under reduced pressure and the crude mixture
dissolved in tert-butyl methyl ether. The organic solution was
washed with aq sat. solution of NaHCO3 and with 10% aq NaCl so-
lution, dried (Na2SO4) and the solvent evaporated. Pure products
were obtained by flash chromatography (SiO2, CH2Cl2) and many
of them were found to be highly hygroscopic (Table 2). Isolated
pure compounds were fully characterized by NMR, MS and IR
spectroscopy and the new ones were additionally verified by ele-
mental microanalysis.
127 (15), 105 (100), 77 (63).
2,2-Difluoro-1,3-diphenylpropan-1-one (11d)
Yield: 85%; colorless highly hygroscopic crystals; mp 45 °C.
IR (KBr): 1700, 1600, 1450, 1280, 1180, 1030, 900 cm–1.
2,2-Difluoro-3,4-dihydro-2H-naphthalen-1-one (9)33
Yield: 91%; yellow crystals; mp 31 °C.
IR (KBr): 1710, 1595, 1440, 1320, 1220, 1140, 920 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.50 (m, 2 H, CH2CF2), 3.18 (t,
J = 6.3 Hz, CH2), 7.30 (m, ArH), 7.39 (m, ArH), 7.58 (m, ArH), 8.1
(m, ArH).
13C NMR (76 MHz, CDCl3): d = 25.5 (t, J = 5.5 Hz, CH2), 32.3 (t,
J = 22.9 Hz, CH2), 113.6 (t, J = 248.3 Hz, CF2), 127.4 (ArCH),
128.6 (ArCH), 128.9 (ArCH), 130.0 (ArC), 135.0 (ArCH), 142.8
(ArC), 185.0 (t, J = 25.9 Hz, C=O).
1H NMR (300 MHz, CDCl3): d = 3.50 (t, J = 17.8 Hz, 2 H, CH2),
7.29 (m, 5 H, ArH), 7.43 (m, 2 H, ArH), 7.58 (t, J = 7.4 Hz, 1 H,
ArH), 8.01 (dd, J = 7.4 Hz, J = 1.0 Hz, 2 H, ArH).
13C NMR (76 MHz, CDCl3): d = 40.1 (t, J = 23.2 Hz, CH2), 118.4
(t, J = 254.7 Hz, CF2), 127.6 (ArCH), 128.4 (ArCH), 128.6 (ArCH),
130.1 (ArCH), 130.8 (ArCH), 131.2 (ArC), 132.1 (ArC), 134.2
(ArCH), 189.5 (t, J = 31.2 Hz, C=O).
19F NMR (56.4 MHz, CDCl3): d = –99.0 (t, J = 17.8 Hz, CF2).
MS (EI, 70 eV): m/z (%) = 246 (1, M+), 105 (100), 77 (42).
19F NMR (56.4 MHz, CDCl3): d = –112.0 (t, J = 12.7 Hz, CF2).
MS (EI, 70 eV): m/z (%) = 182 (70, M+), 118 (100), 90 (70).
Anal. Calcd for C15H12F2O·1/10 H2O: C, 72.63; H, 4.96. Found: C,
72.55; H, 5.03.
2,2-Difluoro-1-(4-methoxyphenyl)ethanone (13)33
Yield: 70%; colorless liquid.
2,2-Difluorophenylethan-1-one (11a)20
Yield: 77%; colorless liquid.
IR (neat): 1670, 1575, 1490, 1300, 1230, 1160, 1120, 1040, 970,
850 cm–1.
IR (neat): 1690, 1590, 1440, 1540, 1380, 1340, 1130, 1060, 970,
860 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.89 (s, 3 H, CH3), 6.26 (t, J = 53.7
Hz, 1 H, CF2H), 6.98 (d, J = 9.0 Hz, 2 H, ArH), 8.05 (d, J = 8.8 Hz,
2 H, ArH).
1H NMR (300 MHz, CDCl3): d = 6.29 (t, J = 53.5 Hz, 1 H, CF2H),
7.55 (t, J = 7.7 Hz, 2 H, ArH), 7.68 (t, J = 6.8 Hz, 1 H, ArH), 8.08
(d, J = 8.2 H, 2 H, ArH).
13C NMR (76 MHz, CDCl3): d = 55.5 (CH3), 111.4 (t, J = 253.7 Hz,
CHF2), 114.2 (ArCH), 132.1 (ArCH), 164.9 (ArC), 186.0 (t,
J = 25.0 Hz, C=O).
19F NMR (56.4 MHz, CDCl3): d = –122.7 (d, J = 52 Hz, CHF2).
MS (EI, 70 eV): m/z (%) = 186 (15, M+), 135 (95), 105 (100), 92
(20), 77 (76).
13C NMR (76 MHz, CDCl3): d = 111.1 (t, J = 253.7 Hz, CHF2),
128.9 (ArCH), 129.6 (ArCH), 131.5 (ArC), 134.8 (ArCH), 187.5 (t,
J = 25.6 Hz, C=O).
19F NMR (56.4 MHz, CDCl3): d = –124.2 (d, J = 53.5 Hz, CHF2).
MS (EI, 70 eV): m/z = 156 (1, M+), 105 (100), 84 (13), 77 (92).
2,2-Difluoro-1-phenyldecan-1-one (11b)
Yield: 76%; colorless liquid.
IR (neat): 3060, 2920, 2850, 1700, 1600, 1450, 1175, 710 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.89 (t, J = 7.0 Hz, 3 H, CH3), 1.30
(m, 10 H, 5 CH2), 1.50 (m, 2 H, CH2), 2.18 (m, 2 H, CH2CF2), 7.50
(m, 2 H, ArH), 7.63 (tt, J = 7.4, 2.0 Hz, 1 H, ArH), 8.11 (dd,
J = 7.4, 1.0 Hz, 2 H, ArH).
2,2-Difluoro-1-naphthalen-2-ylethanone (15)
Yield: 82%; yellow highly hygroscopic crystals; mp 47 °C.
IR (KBr): 1705, 1460, 1140, 1120, 1060, 820 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.40 (t, J = 53.6 Hz, 1 H, CF2H),
7.56-7.68 (m, 2 H, ArH), 7.87–8.20 (m, 4 H, ArH), 8.63 (s, 1 H,
ArH).
13C NMR (76 Hz, CDCl3): d = 111.4 (t, J = 253.8 Hz, CHF2), 124.0
(ArCH), 127.2 (ArCH), 127.9 (ArCH), 129.0 (ArCH), 129.6
(ArCH), 130.0 (ArCH), 132.3 (ArC), 132.5 (t, J = 3.4 Hz, ArC),
136.3 (ArC), 187.50 (t, J = 25.2 Hz, C=O).
13C NMR (76 MHz,CDCl3): d = 14.1 (CH3), 21.4 (t, J = 4.0 Hz,
CH2), 22.7 (CH2), 29.1 (CH2), 29.3 (CH2), 29.4 (CH2), 31.8 (CH2),
34.1 (t, J = 22.8 Hz, CH2CF2), 119.9 (t, J = 252.4 Hz, CF2), 128.7
Synthesis 2005, No. 18, 3140–3146 © Thieme Stuttgart · New York

PAPER
Efficient Synthesis of a,a-Difluoro Ketones
3145
19F NMR (56.4 MHz, CDCl3): d = –122.0 (d, J = 53.6 Hz, CHF2).
MS (EI, 70 eV): m/z (%) = 206 (35, M+), 155 (100), 127 (90), 84
1H NMR (300 MHz, CDCl3): d = 6.15 (t, J = 53.7 Hz, 1 H, CHF2),
7.40 (dd, J = 2.8 Hz, J = 5.2 Hz, 1 H), 7.65 (m, 1 H, ArH), 8.37 (m,
1 H, ArH).
13C NMR (76 MHz, CDCl3): d = 111.1 (t, J = 253.5 Hz, CF2), 126.8
(ArCH), 127.4 (ArCH), 135.5 (t, J = 2.0 Hz, ArC), 136.1 (t, J = 4.3
Hz, ArCH), 182.1 (t, J = 26.0 Hz, C=O).
(25).
Anal. Calcd for C12H8F2O·1/4H2O: C, 68.41; H, 4.07. Found: C,
68.21; H, 3.94.
2,2-Difluoro-1-indanone (17a)
Yield: 89%; yellow highly hygroscopic crystals; mp 26–27 °C.
IR (KBr): 1770, 1640, 1350, 1270, 1100, 970, 780 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.57 (t, J = 12.7 Hz, 2 H), 7.48 (m,
2 H, ArH), 7.74 (m, 1 H, ArH), 7.85 (m, 1 H, ArH).
19F NMR (56.4 MHz, CDCl3): d = –122.0 (d, J = 53.7 Hz, CHF2).
MS (EI, 70 eV): m/z (%) = 20 (23, M+), 111 (100), 83 (40).
Anal. Calcd for C6H4F2O·1/5H2O: C, 43.48; H, 2.68. Found: C,
43.53; H, 2.68.
1-Adamantan-1-yl-2,2-difluoroethanone (23)
Yield: 61%; colorless liquid.
IR (neat): 2860, 2810, 1710, 1440, 1330, 1110, 1150, 990 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.78 (m, 6 H, CH2), 1.96 (m, 6 H,
CH2), 2.10 (m, 3 H, CH), 5.99 (t, J = 53.0 Hz, 1 H, CH2F).
13C NMR (76 MHz, CDCl3): d = 37.3 (t, J = 25.3 Hz, C-3), 117.0 (t,
J = 256.3 Hz, C-2), 125.6 (ArCH), 127.0 (ArCH), 128.9 (ArCH),
132.4 (t, J = 3.0 Hz, ArC), 137.4 (ArCH), 147.7 (t, J = 6.1 Hz,
ArC), 191.5 (t, J = 26.4 Hz, C-1).
19F NMR (56.4 MHz, CDCl3): d = –112.0 (t, J = 12.7 Hz).
MS (EI, 70 eV): m/z = 168 (100, M+), 140 (35), 118 (23), 104 (27),
90 (31), 76 (25).
13C NMR (76 MHz, CDCl3): d = 27.5 (CH), 36.1 (t, J = 5.2 Hz, C),
36.3 (CH2), 37.1 (CH2), 109.3 (t, J = 253.1 Hz, CHF2), 201.9 (t,
J = 22.1 Hz, C=O).
19F NMR (56.4 MHz, CDCl3): d = –125.0 (d, J = 53.0 Hz, CHF2).
Anal. Calcd for C9H6F2O·1/10H2O: C, 63.61; H, 3.68. Found: C,
63.85; H, 4.07.
MS (EI, 70 eV): m/z (%) = 163 (2, AdCO+), 135 (100, Ad+), 93 (20),
6,6-Difluoro-6,7,8,9-tetrahydrobenzocyclohepten-5-one (17b)
Yield: 81%; colorless highly hygroscopic liquid.
IR (neat): 1710, 1450, 1175, 1140, 1100, 950, 900, 840 cm–1.
79 (20, HF2CO+).
Anal. Calcd for C12H16F2O: C, 67.27; H, 7.53. Found: C, 67.26; H,
7.59.
1H NMR (300 MHz, CDCl3): d = 2.00 (m, 2 H, CH2), 2.37 (m, 2 H,
CH2CF2), 3.02 (m, 2 H, CH2), 7.23 (dd, J = 7.6, 1.0 Hz, 1 H, ArH),
7.33 (ddd, J = 7.5, 7.4, 1.0 Hz, 1 H, ArH), 7.46 (ddd, J = 1.5, 7.1,
7.6 Hz, 1 H, ArH), 7.69 (dd, J = 7.7, 1.3 Hz, 1 H, ArH).
13C NMR (76 MHz, CDCl3): d = 21.9 (t, J = 5.4 Hz, CH2), 33.5
(CH2), 34.3 (t, J = 23.6 Hz, CH2), 118.8 (t, J = 249.7 Hz, CF2),
126.8 (ArCH), 129.8 (ArCH), 130.1 (ArCH), 132.8 (ArCH), 134.7
(ArC), 141.5 (ArC), 194.0 (t, J = 29.4 Hz, C=O).
Acknowledgment
The authors are grateful to K. Žmitek, J. Iskra, A. Gačeša and Dr. J.
Plavec for NMR spectra, T. Stipanovič and Prof. B. Stanovnik for
some elemental combustion analysis, and to the Ministry of Higher
Education, Science and Technology of the Republic of Slovenia for
financial support.
19F NMR (56.4 MHz, CDCl3): d = –100.5 (t, J = 16.2 Hz, CF2).
MS (EI, 70 eV): m/z = 196 (100, M+), 168 (86), 149 (30), 131 (65),
104 (95), 91 (25), 77 (30).
References
(1) Smart, B. E. J. Fluorine Chem. 2001, 109, 3.
(2) (a) Chemistry of Organic Fluorine Compounds II: A Critical
Review, ACS Monograph 187; Hudlicky, M.; Pavlath, A. E.,
Eds.; American Chemical Society: Washington, DC, 1995.
(b) Modern Fluoroorganic Chemistry. Synthesis, Reactivity,
Applications; Kirsch, P., Ed.; Wiley-VCH: Weinheim,
2004. (c) Chambers, R. D. Fluorine in Organic Chemistry;
Blackwell: Oxford, 2004. (d) ChemBioChem, Special Issue
on Fluorine in Life Sciences, Vol. 37; Royal Society of
Chemistry: Cambridge, 2004, 557–726.
(3) Methods of Organic Chemistry (Houben–Weyl),
Organofluorine Compounds; Baasner, B.; Hagemann, H.;
Tatlow, J. C., Eds.; Vol. E 10a-c: Thieme: Stuttgart, 1999.
(4) Shimizu, M.; Hiyama, T. Angew. Chem. Int. Ed. 2005, 44,
214.
Anal. Calcd for C11H10F2O·2/5H2O: C, 64.96; H, 5.35. Found: C,
64.48; H, 5.06.
2,2-Difluoro-5-methoxy-3,4-dihydro-2H-naphthalen-1-one (19)
Yield: 80%; yellow crystals; mp 79 °C.
IR (neat): 1705, 1580, 1470, 1430, 1250, 1060, 1000, 950, 740 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.53 (m, 2 H, CH2), 3.10 (t, J = 6.2
Hz, 2 H, CH2), 3.89 (s, 3 H, CH3), 7.11 (dd, J = 8.1, 1.0 Hz, 1 H,
ArH), 7.36 (t, J = 8.0 Hz, 1 H, ArH), 7.71 (dd, J = 7.9, 1.0 Hz, 1 H,
ArH).
13C NMR (76 MHz, CDCl3): d = 19.5 (t, J = 5.7 Hz, CH2), 31.5 (t,
J = 22.9 Hz, CH2), 55.8 (CH3), 113.7 (t, J = 248.2 Hz, CF2), 115.6
(ArCH), 119.9 (ArCH), 128.0 (ArCH), 131.1 (ArC), 131.9 (ArC),
156.7 (ArC), 185.4 (t, J = 26.0 Hz, C=O).
(5) Gelb, M. H.; Svaren, J. P.; Abeles, R. H. Biochemistry 1985,
24, 1813.
(6) Tarnus, C.; Jung, M. J.; Remy, J. M.; Baltzer, S.; Schirlin, D.
G. FEBS Lett. 1989, 249, 47.
19F NMR (56.4 MHz, CDCl3): d = –113.0 (t, J = 14 Hz, CF2).
MS (EI, 70 eV): m/z (%) = 212 (100, M+), 148 (85), 120 (75), 105
(35), 90 (70), 77 (40).
(7) Sham, H. L.; Stein, H.; Rempel, C. A.; Cohen, J.; Plattner, J.
J. FEBS Lett. 1987, 220, 299.
Anal. Calcd for C11H10F2O2: C, 62.26; H, 4.75. Found: C, 61.95; H,
4.88.
(8) Thaisrivongs, S.; Pals, D. T.; Kati, W. M.; Turner, S. R.;
Thomasco, L. M.; Watt, W. J. Med. Chem. 1986, 29, 2080.
(9) Takahashi, L. H.; Radhakrishnan, R.; Rosenfield, R. E.;
Meyer, E. F.; Trainor, D. A. J. Am. Chem. Soc. 1989, 111,
3368.
(10) Imperiali, B.; Abeles, R. H. Biochemistry 1987, 26, 4474.
(11) Imperiali, B.; Abeles, R. H. Biochemistry 1986, 25, 3760.
2,2-Difluoro-1-thiophen-3-ylethanone (21)
Yield: 76%; colorless liquid.
IR (neat): 1690, 1510, 1420, 1250, 1135, 1060, 850 cm–1.
Synthesis 2005, No. 18, 3140–3146 © Thieme Stuttgart · New York

3146
I. Pravst et al.
PAPER
(12) Robinson, R. P.; Donahue, K. M. J. Org. Chem. 1992, 57,
7309.
(26) Banks, R. E.; Lawrence, N. J.; Popplewell, A. L. J. Chem.
Soc., Chem. Commun. 1994, 343.
(13) Sham, H. L.; Betebenner, D. A.; Wideburg, N. E.; Kempf, D.
J.; Plattner, J. J.; Norbeck, D. W. J. Fluorine Chem. 1995,
73, 221.
(14) Wolfe, M. S.; Xia, W. M.; Moore, C. L.; Leatherwood, D.
D.; Ostaszewski, B.; Rahmati, T.; Donkor, I. O.; Selkoe, D.
J. Biochemistry 1999, 38, 4720.
(27) Stavber, G.; Zupan, M.; Jereb, M.; Stavber, S. Org. Lett.
2004, 6, 4973.
(28) Stavber, S.; Jereb, M.; Zupan, M. Synthesis 2002, 2609.
(29) Tozer, M. J.; Herpin, T. F. Tetrahedron 1996, 52, 8619.
(30) Stavber, S.; Jereb, M.; Zupan, M. Chem. Commun. 2000,
1323.
(15) Moore, C. L.; Leatherwood, D. D.; Diehl, T. S.; Selkoe, D.
J.; Wolfe, M. S. J. Med. Chem. 2000, 43, 3434.
(16) Wolfe, M. S.; Citron, M.; Diehl, T. S.; Xia, W. M.; Donkor,
I. O.; Selkoe, D. J. J. Med. Chem. 1998, 41, 6.
(17) Reiter, L. A.; Martinelli, G. J.; Reeves, L. A.; Mitchell, P. G.
Bioorg. Med. Chem. Lett. 2000, 10, 1581.
(18) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.;
McCarthy, J. R.; Wolfe, M. S., Eds.; American Chemical
Society: Washington DC, 1996.
(31) (a) Nakano, T.; Makino, M.; Morizawa, Y.; Matsumura, Y.
Angew. Chem. Int. Ed. 1996, 35, 1019. (b) Thomas, M. G.;
Suckling, C. J.; Pitt, A. R.; Suckling, K. E. J. Chem. Soc.,
Perkin Trans.1 1999, 3191.
(32) Ying, W. W.; DesMarteau, D. D.; Gotoh, Y. Tetrahedron
1996, 52, 15.
(33) Peng, W.; Shreeve, J. M. J. Org. Chem. 2005, 70, 5760.
(34) Gutman, A. L.; Etinger, M.; Nisnevich, G.; Polyak, F.
Tetrahedron: Asymmetry 1998, 9, 4369.
(19) Stavber, S.; Zupan, M. J. Org. Chem. 1987, 52, 5022.
(20) Zupan, M.; Iskra, J.; Stavber, S. J. Org. Chem. 1995, 60, 259.
(21) Stavber, S.; Zupan, M. Synlett 1996, 693.
(22) Zajc, B.; Zupan, M. J. Org. Chem. 1982, 47, 573.
(23) Umemoto, T.; Fukami, S.; Tomizawa, G.; Harasawa, K.;
Kawada, K.; Tomita, K. J. Am. Chem. Soc. 1990, 112, 8563.
(24) Xu, Z. Q.; DesMarteau, D. D.; Gotoh, Y. J. Fluorine Chem.
1992, 58, 71.
(35) Johnson, G. P.; Marples, B. A. Tetrahedron Lett. 1984, 25,
3359.
(36) Warmuth, R.; Munsch, T. E.; Stalker, R. A.; Li, B.; Beatty,
A. Tetrahedron 2001, 57, 6383.
(37) Gilicinski, A. G.; Pez, G. P.; Syvret, R. G.; Lal, G. S. J.
Fluorine Chem. 1992, 59, 157.
(38) Singh, R. P.; Shreeve, J. M. Acc. Chem. Res. 2004, 37, 31.
(39) Stavber, S.; Zupan, M. Acta Chim. Slov. 2005, 52, 13.
(40) Appelman, E. H.; Basile, L. J.; Thompson, R. C. J. Am.
Chem. Soc. 1979, 101, 3384.
(25) Davis, F. A.; Han, W.; Murphy, C. K. J. Org. Chem. 1995,
60, 4730.
Synthesis 2005, No. 18, 3140–3146 © Thieme Stuttgart · New York