A new flexible strategy for the synthesis of gem-difluoro-bisarylic derivatives and heterocyclic analogues

Article abstract of DOI:10.1016/j.tet.2011.03.073

A new strategy has been designed for the preparation of gem-difluoro-bisarylic derivatives. It starts from easily accessible and reactive gem-difluoro-propargylic intermediates and elaborates the aromatic rings by a Diels-Alder-aromatization sequence. Het

Full text of DOI:10.1016/j.tet.2011.03.073

Tetrahedron 67 (2011) 3881e3886
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A new flexible strategy for the synthesis of gem-difluoro-bisarylic derivatives and
heterocyclic analogues
,
b
a
b
b
b
,
a,
*
Ali Khalaf a , Danielle Gree , Hassan Abdallah , Nada Jaber , Ali Hachem , Rene Gree
*
ꢀ
ꢀ
ꢀ
a
ꢀ
ꢀ ꢀ
Universite de Rennes 1, Laboratoire Sciences Chimiques de Rennes, CNRS UMR 6226, Avenue du General Leclerc, 35042 Rennes Cedex, France
b Laboratory for Medicinal Chemistry and Natural Products, Lebanese University, Faculty of Sciences (I) and PRASE-EDST, Hadath, Beyrouth, Lebanon
a r t i c l e i n f o
a b s t r a c t
Article history:
A new strategy has been designed for the preparation of gem-difluoro-bisarylic derivatives. It starts from
easily accessible and reactive gem-difluoro-propargylic intermediates and elaborates the aromatic rings
by a DielseAlder-aromatization sequence. Heterocyclic systems can be also obtained by 1,3 dipolar
cycloadditions, affording mixed aromatic/heteroaromatic derivatives with CF2 as a linker. Since this motif
is a bioisostere of O and CO, corresponding bisarylic scaffolds could be of use to prepare chemical
libraries of fluorinated analogues of bioactive natural products and/or drugs.
Received 20 February 2011
Received in revised form 17 March 2011
Accepted 22 March 2011
Available online 30 March 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
Propargylic fluorides
gem-Difluoro compounds
Cycloaddition reactions
gem-Difluoro-bisaryl derivatives
Fluorinated linkers
1. Introduction
and/or reagents.6 Moreover, direct fluorination of benzophenones
using nucleophilic fluorinating agents, such as DeoxofluorÒ, has im-
Diaryl ethers are recognized as important moieties since they
are key parts of many natural products,1 and also very often used in
bioorganic and medicinal chemistry.2 Similarly, diarylketones are
also frequently found in the core structures of natural products,
drugs or agrochemicals.3 On the other hand, it is well known that
introduction of fluorine in organic molecules strongly modifies
their physical, chemical and biological activities and this has been
also of much use in fluorobiorganic chemistry.4 Since CF2 is usually
considered as a bioisostere of the oxygen atom, as well as of a car-
bonyl group,5 it would be of much interest to have easy access to
gem-difluoro-bisarylic derivatives (Scheme 1).
portant limitations since it is very sensitive to the nature of sub-
stituentsonthearomaticsystems.6 Thereforeitappearedofinterestto
develop new strategies to access such attractive molecules. Towards
this goal, our design was to build one of the aromatic rings starting
from a propargylic gem-difluoride as a key intermediate (Scheme 2).
R1
F
F
F
F
EtO2C
Het
F
F
EtO2C
R2
Br
R3
Br
R2
key intermediate
O
F
F
O
O
EtO2C
R1
R2
R1
R2
R1
R2
Br
Scheme 2. A new synthetic strategy towards gem-difluoro-bisarylic derivatives and
mixed aryl-heteroaryl systems.
Scheme 1. Diaryl ethers, benzophenones and gem-difluoro-bisarylic derivatives.
However, the gem-difluorination of benzophenones is a difficult
operation, involving usually two-step processes through some in-
termediates (thioketones or thioketals) and harsh reaction conditions
This new approach takes advantage of the easy access and the
good reactivity of such intermediates7,8 and, further, should allow
the preparation of many other carbo- and hetero-cycles through
cycloaddition reactions. Moreover, provided appropriate sub-
stituents and/or functional groups are introduced on these skele-
tons, it should also allow the preparation of designed chemical
libraries of new fluorinated molecules.
* Corresponding authors. E-mail addresses: ahachem@ul.edu.lb (A. Hachem),
ꢀ
rene.gree@univ-rennes1.fr (R. Gree).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.073

3882
A. Khalaf et al. / Tetrahedron 67 (2011) 3881e3886
2. Results and discussion
the stilbene-type product 8 in 53% yield while Stille cross
coupling,14 afforded styrene-type derivative 9 in 82% yield.
These data indicate that this bromide can be of much use to build
designed chemical libraries around this skeleton.15 However it was
of interest to examine the possibility of using the ester group as
a second point of molecular diversity. This was performed in several
ways, as indicated in Scheme 6. Since saponification of ester group in
compound 5 was unsuccessful under various reaction conditions,
the acid 11 was prepared in a two steps sequence: reduction with
LiBEt3H affording alcohol 10 in 97% yield, followed by oxidationwith
Jones reagent gave desired acid 11 in 87% yield. A classical coupling
reaction with DCC and DMAP and aniline afforded model amide 12
in 53% yield. Then oxidation of alcohol 10 by 2-iodoxybenzoic acid
(IBX) furnished, in 92% yield, the key aldehyde 13, which was used
for several transformations: reductive amination with aniline gave
amino derivative 14 in 87% yield. On the other hand, reaction with
alkynyl Grignard and phenyl lithium afforded the adducts 15 and 16
in 73% and 81% yields, respectively. Finally, a Wittig reaction with
carbomethoxymethylenetriphenylphosphorane gave the alkenes
17a and 17b as an 8/1 mixture in 81% overall yield. These isomers
were easily separated by silica gel chromatography. These results
demonstrate that, on such gem-difluoro-bisarylic derivatives, both
the bromo substituent and the ester function can be used to in-
troduce new groups and/or functions and therefore such scaffolds
are of interest regarding the preparation of chemical libraries for
biological studies.
The synthesis of the key gem-difluoro intermediate 3 is reported
in Scheme 3. Metallation of ethylpropiolate at strictly controlled
temperature (ꢀꢁ80 ꢂC)9 followed by trapping with p-bromo-
benzaldehyde and then by TMSCl, afforded propargylic alcohol 1 in
71% yield. Oxidation with Jones reagent gave ketone 2 in 89% yield.
Due to the presence of the propargylic system10 and the ester
function, this ketone reacted efficiently with diethylaminosulfur-
trifluoride (DAST) to afford 3 in 68% yield. Therefore this new gem-
difluoro-propargylic key intermediate was obtained in three steps
and 43% overall yield from ethylpropiolate.
OH
1) n-BuLi
Jones reagent
89 %
EtO2C
EtO2C
2) p-bromobenzaldehyde,
Br
1
TMSCl
71 %
F
F
O
DAST
68 %
EtO2C
EtO2C
Br
Br
3
2
Scheme 3. Synthesis of gem-difluoro intermediate 3.
Starting from intermediate 3 two representative aromatic de-
rivatives have been obtained by a classical DielseAlder-aromatiza-
tion sequence, as indicated in Scheme 4. Reaction with excess
dimethylbutadiene at reflux giving 4, followed by 2,3-dichloro-5,6-
dicyanobenzoquinone (DDQ)mediatedaromatizationaffordeda first
gem-difluoro-bisaryl derivative 5 in 96% overall yield. On the other
hand, reaction with Danishefsky’s diene,11 followed by DDQ aroma-
tization gave the second gem-difluoro-bisarylic molecule 6 in 83%
overall yield. In this cycloaddition a single isomer was obtained and
theregioselectivity was easilyestablished byextensive NMR analysis.
HO
O
HO
F
F
F
F
Jones reagent
LiBHEt3 (2.5 equiv)
5
THF, 0 °C
97%
Acetone, RT
87%
Br
Br
10
11
O
PhHN
PhNH2,
F
F
DCC (2 equiv)
DMAP (0.5 equiv)
EtO2C
EtO2C
F
F
F
F
CH2Cl2, RT
53%
Br
12
DDQ
3
Br
Toluene, 40°C
99%
PhHN
Br
O
F
F
4
5
F
F
1) PhNH2, ZnCl2
IBX (1.5 equiv)
MeO
1)
2) NaBH3CN
87%
10
Br
Br
DMSO/THF
40 °C
EtO2C
14
F
F
92%
13
PhLi
OSiMe3
MgBr
73%
81%
Ph
THF,
THF, -78 °C
3
-78 °C
OH
F
Br
2) DDQ
83%
F
OH
F
OH
F
6
Scheme 4. Synthesis of gem - difluoro-bisarylic derivatives 5 and 6.
Br
Br
16
15
The next step was to demonstrate the possibility of using the
CO2Me
p-bromo substituent in some palladium-catalyzed reactions. Three
representative examples, using gem-difluoro-bisaryl derivative 5 as
a model substrate, are indicated in Scheme 5. First a Suzu-
kieMiyaura coupling,12 with phenylboronic acid, afforded bi-
phenyl-type compound 7 in 80% yield. Then Heck reaction,13 gave
MeO2C
F
F
F
F
Ph3P=CHCO2Me
+
13
PhH, 50 °C
Br
Br
81% (overall)
17a
17b
Scheme 6. Synthesis of gem-diaryl derivatives 10e17.
The next step was to demonstrate the possibility of using the
same propargylic intermediates for the preparation of mixed aro-
matic/heteroaromatic derivatives with a CF2 group as linker. This
was performed on two representative examples of 1,3 dipolar cy-
cloadditions (Scheme 7). Reaction of 3 with benzyl azide afforded in
90% overall yield a 1/2 mixture of triazoles 18a and 18b, separated by
silica gel chromatography. The regioselectivity was established
based on 13C NMR data: for 18b there is a small JCF coupling constant
(4.5 Hz) between the carbon of the CH2Ph group with the two
fluorine atoms, coupling which do not exist for 18a. On the other
hand, nitrile oxide cycloaddition, using nitroethane under
Scheme 5. Palladium-catalyzed reactions on aromatic intermediate 5.

A. Khalaf et al. / Tetrahedron 67 (2011) 3881e3886
3883
Mukaiyama’s conditions,16 gave an inseparable (2/1) mixture of
isoxazoles 19a and 19b in 97% overall yield. The regioselectivity of
the cycloaddition was also established by NMR: for 19b there is
a small JHF coupling constant (1.9 Hz) between the two fluorine
atoms and the protons of the CH3 group together with a small JCF
coupling constant (3.1 Hz) with the carbonof this CH3. Such coupling
constants are not present in 19a.
a concentrated (5.4 M) solution of Jones reagent until disappear-
ance of the starting material (TLC analysis). After addition of iso-
propanol (5 equiv), the reaction mixture was filtered and the
residues were washed with ether. The combined organic phases
were dried over MgSO4, filtered and concentrated in vacuo. After
purification by flash chromatography on silica gel ketone 2 was
obtained as yellow crystals. Mp: 32e34 ꢂC. (2.48 g, 89% yield).
Rf¼0.26 (Et2O/pentane, 2/98). 1H NMR (CDCl3, 300 MHz)
d, ppm:
1.36 (t, 3H, J¼7.1 Hz); 4.34 (q, 2H, J¼7.1 Hz); 7.63e7.68 (m, 2H);
7.93e7.98 (m, 2H). 13C NMR (CDCl3, 75 MHz)
d, ppm: 13.9; 63.1;
F
F
F
F
EtO2C
N
EtO2C
N
79.2; 80.8; 130.8; 130.9; 132.2; 134.3; 152.0; 175.0. HRMS (ESI)
calcd for C12H9O379BrNa: [MþNa]þ: m/z 302.9633. Found: m/z
302.9636 (1 ppm).
PhCH2N3
+
N
N
N
60 °C, 6 h
Ph
N
Br
Br
90% (overall)
Ph
F
18a
18b
3
4.3. 4-(4-Bromophenyl)-4,4-difluorobut-2-ynoicacid
ethylester 3
F
EtO2C
O
F
F
EtO2C
C2H5NO2 (3 equiv)
PhNCO (3 equiv)
+
To propargylic ketone 2 (2.18 g, 7.76 mmol) were added three
drops of 95% ethanol and DAST (8.14 mL, 8 equiv). The reaction
mixture was stirred at 65 ꢂC for 8 h. After coming back to room
temperature, pentane (50 mL) was added, followed byslowaddition
of a 1% HCl solution. The organic layers were separated, washed with
water (3ꢃ5 mL), dried over MgSO4 and concentrated under vacuum
at 300 mbar pressure. After purification bychromatographyon silica
gel, ester 3 was obtained as a colourless oil (1.6 g, 68% yield). Rf¼0.46
Et3N, Toluene
50 °C, 3h
97% (overall)
O
N
Br
N
Br
19a
19b
Scheme 7. Synthesis of mixed gem-difluoro aromatic/heteroaromatic derivatives
18 and 19.
3. Conclusion
(Et2O/pentane, 2/98). 1H NMR (CDCl3, 300 MHz)
d
, ppm: 1.34 (t, 3H,
In conclusion, this study confirms the versatility of propargylic
fluorides in the synthesis of useful building blocks for further appli-
cations in organic and medicinal chemistry. A functionalized gem-
difluoro-propargylic intermediate 3, with a CF2Ar group, has been
prepared for the first time. Through cycloadditions, it afforded ver-
satile scaffolds, which could be developed in many different ways. In
particular intermediates of this type could easily generate chemical
librariesof bisaromatic or mixed aromatic/heteroaromatic molecules
with fluorinated linkers, of interest in bioorganic and medicinal
chemistry. Development of this chemistry, as well as preparation of
other heterocycles starting from propargylic fluorides, are under
active study in our group and will be reported in due course.
J¼7.1 Hz); 4.29 (q, 2H, J¼7.1 Hz); 7.50e7.53 (m, 2H); 7.60e7.63 (m,
2H). 13C NMR (CDCl3, 75 MHz)
d, ppm: 13.9; 63.1; 76.3 (t,
2JCF¼43.9 Hz); 78.7 (t, 3JCF¼5.9 Hz); 111.1 (t, 1JCF¼235.5 Hz); 126.0 (t,
3
2
5JCF¼2.3 Hz); 126.9 (t, JCF¼4.8 Hz); 132.1; 133.4 (t, JCF¼27.5 Hz);
151.7 (t, 4JCF¼2.3 Hz). 19F NMR (CDCl3, 282 MHz)
, ppm: ꢁ79.69 (s).
d
HRMS (ESI) calcd for C12H9O2F279BrNa: [MþNa]þ: m/z 324.9652.
Found: m/z 324.9652 (0 ppm).
4.4. 2-[(4-Bromophenyl)-difluoromethyl]-5-
methylcyclohexa-1,4-dienecarboxylicacid ethylester 4
The difluoro-propargylic ester 3 (1.75 g, 1 equiv) and 2,3-dime-
thylbutadiene (6.5 mL, 10 equiv) were refluxed neat at 80 ꢂC over-
night. After purification by flash chromatography on silica gel,
cyclohexadiene 4 was isolated as a colourless oil (2.18 g, 98% yield).
4. Experimental section
4.1. 4-(4-Bromophenyl)-4-hydroxybut-2-ynoicacid ethyl ester 1
Rf¼0.68 (Et2O/pentane, 4/96).1H NMR (CDCl3, 300 MHz)
d, ppm: 1.25
To a solution of ethylpropiolate (2.1 mL, 0.02 mmol) in anhydrous
THF (25 mL) cooled at ꢁ90 ꢂC, was added, dropwise under nitrogen,
a solution of n-BuLi in hexanes (15.3 mL, 1.6 M, 1.2 equiv). The mix-
ture was stirred for 30 min at tꢀꢁ80 ꢂC before dropwise addition, of
p-bromobenzaldehyde (4.26 g, 1.2 equiv) in anhydrous THF (15 mL).
After 20 min additional stirring at the same temperature, TMSCl
(6.1 mL, 2.5 equiv) was added dropwise. The reaction mixture was
stirred for additional 90 min at tꢀꢁ80 ꢂC and then in an ice bath for
additional 1 h. The mixture was treated with a saturated NH4Cl so-
lution, extracted by ether (3ꢃ80 mL). The combined organic phases
were washed with water, dried over MgSO4 and concentrated in
vacuo. After purification by chromatography on silica gel, using as
eluent a 15/85 ether/pentane mixture, compound 1 was obtained as
a yellow oil (4.08 g, 71% yield). Rf¼0.16 (Et2O/pentane, 2/8). 1H NMR
(t, 3H, J¼7.1 Hz); 1.58 (s, 3H); 1.64 (s, 3H); 2.53 (m, 2H); 2.92 (m, 2H);
4.20 (q, 2H, J¼7.1 Hz); 7.49e7.57 (m, 4H). 13C NMR (CDCl3, 75 MHz)
d,
3
ppm: 13.9; 17.7; 18.0; 31.6 (t, JCF¼3.2 Hz); 35.5; 61.1; 120.1
1
5
(t, JCF¼243.5 Hz); 121.2; 121.6; 124.5 (t, JCF¼2.3 Hz); 127.6
(t, 3JCF¼5.6 Hz); 128.5 (t, 2JCF¼25.6 Hz); 130.1 (t, 3JCF¼4.7 Hz); 131.6;
134.7 (t, JCF¼28.5 Hz); 169.9 (t, JCF¼0.9 Hz). 19F NMR (CDCl3,
2
4
282 MHz)
d
, ppm: ꢁ92.42 (s). HRMS (ESI) calcd for C18H19O2F279BrNa:
[MþNa]þ: m/z 407.0434. Found: m/z 407.0435 (0 ppm).
4.5. 2-[(4-Bromophenyl)difluoromethyl]-4,5-
dimethylbenzoicacid ethylester 5
A solution of the cyclohexadiene 4 (790 mg, 1 equiv) and DDQ
(559 mg, 1.2 equiv) in toluene (2 mL) was stirred at 40 ꢂC for 2 h.
The reaction mixture was filtered on silica gel and the residues
were washed with ether. The organic phase was concentrated in
vacuo and the product 5 was isolated by flash chromatography on
silica as yellow crystals (776 mg, 99% yield). Mp: 83e85 ꢂC. Rf¼0.60
(CDCl3, 300 MHz)
d
, ppm: 1.29 (t, 3H, J¼7.1 Hz); 4.22 (q, 2H,
J¼7.1 Hz); 5.50 (s, 1H); 7.47e7.49 (m, 2H); 7.50e7.52 (m, 2H). 13C
NMR (CDCl3, 75 MHz) d, ppm: 13.9; 62.4; 63.4; 77.9; 85.7; 122.8;
128.3; 131.8; 137.5; 153.3. HRMS (ESI) calcd for C12H11O379BrNa:
[MþNa]þ: m/z 304.9789. Found: m/z 304.9792 (1 ppm).
(Et2O/pentane, 4/96). 1H NMR (CDCl3, 300 MHz)
d, ppm: 1.10 (t, 3H,
J¼7.1 Hz); 2.33 (s, 3H); 2.34 (s, 3H); 4.12 (q, 2H, J¼7.1 Hz); 7.33e7.36
4.2. 4-(4-Bromophenyl)-4-oxo-but-2-ynoicacid ethylester 2
(m, 2H); 7.42 (s, 1H); 7.46 (s, 1H); 7.49e7.53 (m, 2H). 13C
NMR (CDCl3, 75 MHz)
d, ppm: 13.7; 19.4; 19.8; 61.2; 120.3
1
5
3
To alcohol 1 (2.78 g, 9.82 mmol) in acetone (30 mL) was
added dropwise under magnetic stirring at room temperature,
(t, JCF¼241.5 Hz); 124.2 (t, JCF¼2.5 Hz); 127.9 (t, JCF¼4.9 Hz);
3
3
128.5 (t, JCF¼7.7 Hz); 129.0 (t, JCF¼3.4 Hz); 130.8; 131.2; 131.8

3884
A. Khalaf et al. / Tetrahedron 67 (2011) 3881e3886
2
2
4
(t, JCF¼26.8 Hz); 137.1 (t, JCF¼28.5 Hz); 139.0 (t, JCF¼1.5 Hz);
132.3 (t, 2JCF¼27.1 Hz); 136.9; 137.0 (t, 2JCF¼28.0 Hz); 138.7; 138.8 (t,
139.7; 167.9. 19F NMR (CDCl3, 282 MHz)
d
, ppm: ꢁ81.93 (s). HRMS
5JCF¼2.0 Hz); 139.5; 168.2. 19F NMR (CDCl3, 282 MHz)
d, ppm:
(ESI) calcd for C18H17O2F279BrNa: [MþNa]þ: m/z 405.02778. Found:
m/z 405.0278 (0 ppm).
ꢁ81.47 (s). HRMS (ESI) calcd for C26H24O2F2Na: [MþNa]þ: m/z
429.1642. Found: m/z 429.1638 (1 ppm).
4.6. 2-[(4-Bromo-phenyl)-difluoro-methyl]-4-hydroxy-
4.9. 2-[Difluoro-(4-vinyl-phenyl)-methyl]-4,5-dimethyl
benzoic acid ethyl ester 6
benzoic acid ethyl ester 9
A mixture of difluoro-propargylic ester 3 (100 mg, 0.33 mmol)
and Danishefsky’s diene (0.19 mL, 3 equiv), was stirred neat over-
night at 70 ꢂC. After addition of DDQ (90 mg, 1.2 equiv) and toluene
(1 mL), the mixture was stirred for 3 h at 40 ꢂC. The reaction mixture
was filtered and the residues were washed with ether. The combined
organic phases were concentrated in vacuo. After purification by
flash chromatography on silica gel, the product 6 was isolated as
yellow crystals (101 mg, 83% yield). Mp: 130e132 ꢂC. Rf¼0.34 (Et2O/
A solution of bromo-ester 5 (100 mg, 0.26 mmol), vinyl-
tributylstannane (0.15 mL, 2 equiv), palladium dichlorobis-
(triphenylphosphine) (18 mg, 10 mol %) in dioxane (2 mL), was
stirred under argon, at 90 ꢂC for 24 h. After filtration, the residues
were washed with Et2O and the solution was concentrated in
vacuo. After purification by chromatography on silica gel the
product 9 was isolated as white crystals (71 mg, 82% yield). Mp:
62e64 ꢂC. Rf¼0.26 (Et2O/pentane, 5/95). 1H NMR (CDCl3, 300 MHz)
pentane, 30/70). 1H NMR (acetone-d6, 300 MHz)
d, ppm: 1.06 (t, 3H,
d
, ppm: 1.08 (t, 3H, J¼7.1 Hz); 2.32 (s, 3H); 2.33 (s, 3H); 4.10 (q, 2H,
J¼7.1 Hz); 3.19 (br s,1H); 4.05 (q, 2H, J¼7.1 Hz); 7.08 (dd,1H, J¼8.5 Hz,
J¼7.1 Hz); 5.30 (d, 1H, J¼10.9 Hz); 5.78 (d, 1H, J¼17.6 Hz); 6.72 (dd,
J¼2.5 Hz); 7.25 (d, 1H, J¼2.5 Hz); 7.42e7.45 (m, 2H); 7.63e7.66 (m,
1H, J¼17.6, 10.9 Hz); 7.42e7.44 (m, 6H). 13C NMR (CDCl3, 75 MHz)
2H); 7.70 (d, 1H, J¼8.5 Hz). 13C NMR (acetone-d6, 75 MHz)
d
, ppm:
d
, ppm: 13.6; 19.4; 19.9; 61.2; 115.2; 120.7 (t, JCF¼240.8 Hz);
1
3
5
3
3
15.0; 62.4; 116.2 (t, JCF¼8.7 Hz); 118.6 (t, JCF¼1.3 Hz); 122.1
125.8; 126.4 (t, JCF¼5.0 Hz); 128.6 (t, JCF¼7.6 Hz); 129.2
(t, 1JCF¼241.0 Hz); 124.4 (t, 3JCF¼3.3 Hz); 125.5 (t, 5JCF¼2.5 Hz); 129.9
(t, JCF¼3.3 Hz); 130.6; 132.6 (t, JCF¼27.1 Hz); 136.1; 137.3 (t,
3
2
3
2
5
5
(t, JCF¼5.0 Hz); 133.1; 134.4; 138.4 (t, JCF¼26.8 Hz); 139.0 (t,
2JCF¼27.9 Hz); 138.8 (t, JCF¼1.4 Hz); 138.9 (t, JCF¼2.1 Hz); 139.5;
J¼28.0 Hz); 161.6; 168.3. 19F NMR (acetone-d6, 282 MHz)
d, ppm:
168.2. 19F NMR (CDCl3, 282 MHz)
d
, ppm: ꢁ81.63 (s). HRMS (ESI)
ꢁ82.73 (s). HRMS (ESI) calcd for C16H13O3F279BrNa: [MþNa]þ: m/z
392.9914. Found: m/z 392.9911 (1 ppm).
calcd for C20H20O2F2Na: [MþNa]þ: m/z 353.1329. Found: m/z
353.1328 (0 ppm).
4.7. 2-(Biphenyl-4-yl-difluoro-methyl)-4,5-dimethyl-benzoic
4.10. {2-[(4-Bromophenyl)difluoromethyl]-4,
acid ethyl ester 7
5-dimethylphenyl}methanol 10
A solution of bromo-ester 5 (150 mg, 0.39 mmol), phenylboronic
acid (96 mg, 2 equiv), palladium dichlorobis(triphenylphosphine)
(14 mg, 5 mol %) and potassium carbonate (108 mg, 2 equiv) in a 5/
1 mixture of dioxane and water (3 mL) was stirred at 90 ꢂC for 22 h.
After addition of MgSO4 and filtration, the residues were washed
with ether and the solution concentrated in vacuo. After purifica-
tion by chromatography on silica gel, the product 7 was isolated as
white crystals (120 mg, 80% yield). Mp: 79e81 ꢂC. Rf¼0.27 (Et2O/
To the ester 5 (276 mg, 0.72 mmol) in anhydrous THF (3 mL) was
added, dropwise under magnetic stirring and under N2 at 0 ꢂC,
a 1 M solution of LiBEt3H in THF (1.8 mL, 2.5 equiv). The reaction
mixture was stirred at room temperature for 30 min and then
quenched by addition of a saturated NH4Cl solution and two drops
of 2 N HCl. The organic phase was separated, washed with a satu-
rated Na2CO3 solution, dried (MgSO4) and concentrated in vacuo.
After purification by flash chromatography on silica gel the alcohol
10 was isolated as white crystals (238 mg, 97% yield). Mp:
85e87 ꢂC. Rf¼0.27 (Et2O/pentane, 15/85). 1H NMR (acetone-d6,
pentane, 5/95). 1H NMR (CDCl3, 300 MHz)
d
, ppm: 1.09 (t, 3H,
J¼7.1 Hz); 2.34 (s, 3H); 2.36 (s, 3H); 4.14 (q, 2H, J¼7.1 Hz); 7.34e7.63
(m, 11H). 13C NMR (CDCl3, 75 MHz)
d
, ppm: 13.6; 19.4; 19.9; 61.2;
300 MHz)
d
, ppm: 2.30 (s, 3H); 2.32 (s, 3H); 4.14 (t, 1H, J¼5.6 Hz);
120.8 (t, 1JCF¼240.9 Hz); 126.6 (t, 3JCF¼4.9 Hz); 126.8; 127.2; 127.7;
4.50 (d, 2H, J¼5.6 Hz); 7.32 (s, 1H); 7.42e7.44 (m, 2H); 7.56 (s, 1H);
3
3
128.6 (t, JCF¼7.5 Hz); 128.8; 129.2 (t, JCF¼3.3 Hz); 130.6; 132.3 (t,
7.65e7.69 (m, 2H). 13C NMR (CDCl3, 75 MHz)
d, ppm: 19.4; 19.5;
2
5
2JCF¼27.1 Hz); 136.9 (t, JCF¼28.1 Hz); 138.8 (t, JCF¼1.5 Hz); 139.5;
62.0 (t, 4JCF¼3.4 Hz); 121.3 (t, 1JCF¼241.1 Hz); 124.6 (t, 5JCF¼2.4 Hz);
5
140.3; 142.6 (t, JCF¼2.0 Hz); 168.2. 19F NMR (CDCl3, 282 MHz)
d,
127.8 (t, 3JCF¼5.2 Hz); 127.9 (t, 3JCF¼7.9 Hz); 130.6 (t, 2JCF¼26.3 Hz);
ppm: ꢁ81.43 (s). HRMS (ESI) calcd for C24H22O2F2Na: [MþNa]þ: m/z
403.1485. Found: m/z 403.1483 (1 ppm).
130.9; 131.7; 135.7; 136.2 (t, JCF¼2.1 Hz); 136.5 (t, JCF¼28.8 Hz);
3
2
139.5 (t, 5JCF¼1.6 Hz). 19F NMR (CDCl3, 282 MHz)
, ppm: ꢁ83.13 (s).
d
HRMS (ESI) calcd for C16H15OF279BrNa: [MþNa]þ: m/z 363.0172.
4.8. 2-[Difluoro-(4-styryl-phenyl)-methyl]-4,5-dimethyl-
Found: m/z 363.0172 (0 ppm).
benzoic acid ethyl ester 8
4.11. 2-[(4-Bromophenyl)-difluoromethyl]-4,
DMF (2 mL) was first degassed by bubbling argon. Then were
added successively: bromo-compound 5 (100 mg, 0.26 mmol),
palladium (dichlorobistriphenylphosphine) (9 mg, 5 mol %), potas-
sium carbonate (72 mg, 2 equiv) and styrene (0.15 mL, 5 equiv). The
reaction mixture was stirred under argon at 120 ꢂC for 3 days. After
addition of ether (25 mL) the reaction mixture was washed with
water (3ꢃ5 mL), dried (MgSO4), filtered and concentrated in vacuo.
After purification by chromatography on silica gel the product 8
was isolated as white crystals (56 mg, 53% yield). Mp: 73e75 ꢂC.
5-dimethylbenzoic acid 11
To a solution of alcohol 10 (100 mg, 0.29 mmol) in acetone (1 mL)
was added dropwise at room temperature, a concentrated (5.4 M)
solution of Jones reagent until TLC showed the completion of re-
action. Then isopropanol (5 equiv) was added to the reaction mix-
ture, which was filtered and the residues were washed with ether.
The organic phases were dried (MgSO4), filtered and concentrated in
vacuo. After purification by flash chromatography on silica gel, the
acid 11 was isolated as white crystals (90 mg, 87% yield). Mp:
Rf¼0.29 (Et2O/pentane, 1/9). 1H NMR (CDCl3, 300 MHz)
d, ppm: 1.10
(t, 3H, J¼7.1 Hz); 2.34 (s, 3H); 2.35 (s, 3H); 4.13 (q, 2H, J¼7.1 Hz); 7.11
188e190 ꢂC. 1H NMR (DMSO-d6, 300 MHz)
d, ppm: 2.28 (s, 3H); 2.30
(d, 1H, J¼16.4 Hz); 7.15 (d, 1H, J¼16.4 Hz); 7.27e7.54 (m, 11H). 13C
(s, 3H); 7.37e7.70 (m, 6H). 13C NMR (DMSO-d6, 75 MHz)
d, ppm:
5
NMR (CDCl3, 100 MHz)
d
, ppm: 13.7; 19.3; 19.8; 61.2; 120.7 (t,
18.8; 19.2; 120.4 (t, 1JCF¼241.5 Hz); 123.4 (t, JCF¼2.3 Hz); 127.6 (t,
3JCF¼7.7 Hz); 127.8 (t, 3JCF¼5.0 Hz); 129.6 (t, J¼3.3 Hz); 130.0; 130.7
(t, 2JCF¼27.0 Hz); 131.2; 136.6 (t, 2JCF¼28.5 Hz); 139.0 (t, 5JCF¼1.3 Hz);
3
1JCF¼240.9 Hz); 126.1; 126.5 (t, JCF¼5.0 Hz); 126.6; 127.7; 127.9;
3
23
128.6 (t, JCF¼7.5 Hz); 128.7; 129.3 (t,
J
CF
¼3.2 Hz); 130.0; 130.6;

A. Khalaf et al. / Tetrahedron 67 (2011) 3881e3886
3885
139.2; 168.6. 19F NMR (DMSO-d6, 282 MHz)
d
, ppm: ꢁ76.81 (s).
1JCF¼241.8 Hz); 124.6 (t, 2JCF¼2.5 Hz); 127.9 (t, 3JCF¼5.1 Hz), 127.9 (t,
HRMS (ESI) calcd for C16H13O2F279BrNa: [MþNa]þ: m/z 376.9965.
Found: m/z 376.9966 (0 ppm).
3JCF¼8.1 Hz); 129.2; 130.7; 131.3 (t, JCF¼26.1 Hz); 131.7; 134.8 (t,
2
2
5
3JCF¼2.3 Hz); 135.4; 136.6 (t, JCF¼28.6 Hz); 139.4 (t, JCF¼1.6 Hz);
147.9. 19F NMR (CDCl3, 376 MHz)
d
, ppm: ꢁ84.64 (s). HRMS (ESI)
4.12. 2-[(4-Bromo-phenyl)-difluoro-methyl]-4,5-dimethyl-N-
phenyl-benzamide 12
calcd for C22H20NF279BrNa: [MþNa]þ: m/z 438.0645. Found: m/z
438.0646 (0 ppm).
A solution of carboxylic acid 11 (37 mg, 0.10 mmol), DCC (43 mg,
4.15. 1-{2-[(4-Bromo-phenyl)-difluoro-methyl]-4,5-dimethyl-
2 equiv), DMAP (7 mg, 0.5 equiv) and aniline (12
m
L, 1.2 equiv) was
phenyl}-prop-2-yn-1-ol 15
stirred in CH2Cl2, at room temperature during 5 h. After addition of
a 1% HCl solution, the aqueous and organic phases were separated.
The organic phase was washed twice with water, dried (MgSO4)
and concentrated in vacuo. After purification by silica gel flash
chromatography, the amide 12 was isolated as white crystals
(24 mg, 53% yield). Mp: 171e173 ꢂC. Rf¼0.32 (Et2O/pentane, 25/75).
To a solution of aldehyde 13 (48 mg, 0.14 mmol) in anhydrous
THF (1 mL) was added dropwise at 0 ꢂC under nitrogen, a 0.5 M
solution of ethynyl magnesium bromide in THF (0.34 mL,
0.17 mmol, 1.2 equiv). The reaction mixture was stirred for 3 h, at
0 ꢂC, before quenching by addition of a saturated NH4Cl solution.
After extraction with diethyl ether, the organic phases were washed
with water, dried (MgSO4) and concentrated in vacuo. After puri-
fication by chromatography on silica gel, the product 15 was iso-
lated as white crystals (38 mg, 73% yield). Mp: 83e85 ꢂC. Rf¼0.23
1H NMR (CDCl3, 400 MHz)
d, ppm: 2.33 (s, 6H); 7.10e7.15 (m, 1H);
7.29e7.47 (m, 9H); 7.48e7.49 (m, 2H). 13C NMR (CDCl3, 100 MHz)
d
,
1
ppm: 19.4; 19.8; 119.8; 120.6 (t, JCF¼242.3 Hz); 124.5; 124.6 (t,
3
3
5JCF¼2.4 Hz); 127.8 (t, JCF¼5.4 Hz); 128.2 (t, JCF¼7.0 Hz); 129.0;
129.8; 130.8 (t, 2JCF¼27.2 Hz); 131.5; 133.5 (t, 3JCF¼3.3 Hz); 136.2 (t,
(Et2O/pentane, 20/80). 1H NMR (CDCl3, 400 MHz)
d, ppm: 2.17 (d,
2JCF¼28.3 Hz); 137.6; 138.8; 139.5 (t, JCF¼1.7 Hz); 166.9. 19F NMR
1H, J¼4.2 Hz); 2.29 (s, 3H); 2.34 (s, 3H); 2.53 (d, 1H, J¼2.2 Hz); 5.58
5
(CDCl3, 282 MHz)
d
, ppm: ꢁ83.08 (s). HRMS (ESI) calcd for
(dd, 1H; J¼4.2, 2.2 Hz); 7.24 (s, 1H); 7.32e7.34 (m, 2H); 7.54e7.56
C22H18NOF279BrNa: [MþNa]þ: m/z 452.0438. Found: m/z 452.0440
(m, 2H); 7.72 (s, 1H). 13C NMR (CDCl3, 100 MHz)
d, ppm: 19.5; 19.6;
4
1
(1 ppm).
60.4 (t, JCF¼3.7 Hz); 74.2; 83.5; 121.0 (t, JCF¼241.0 Hz); 124.9
5 3 3
(t, JCF¼2.4 Hz); 127.8 (t, JCF¼7.7 Hz); 127.9 (t, JCF¼5.0 Hz); 130.2
2
3
4.13. {2-[(4-Bromophenyl)difluoromethyl]-4,
5-dimethylbenzaldehyde 13
(t, JCF¼26.2 Hz); 130.3; 131.7; 136.1 (t, JCF¼1.9 Hz); 136.3 (t,
2JCF¼28.5 Hz); 137.2; 140.1 (t, JCF¼1.6 Hz). 19F NMR (CDCl3,
5
282 MHz)
d
, ppm: ꢁ81.67 (d, J¼268. 6 Hz), ꢁ80.63 (d, J¼268.5 Hz,
To a solution of IBX (252 mg, 0.90 mmol, 1.5 equiv) in DMSO
(3 mL), was added a solution of alcohol 10 (205 mg, 0.60 mmol) in
THF (2 mL) and the reaction mixturewasstirredat 40ꢂC for 1 h. After
coming back to room temperature, ice cold water (10 mL) was
added. The reaction mixture was filtered and the solid residue
washed with ether (10 mL). The organic phase was separated and
washed with water, dried (MgSO4) and concentrated in vacuo. After
purification by flash chromatography on silica gel, the aldehyde 13
was isolated as white crystals (190 mg, 92% yield). Mp: 78e80 ꢂC.
AB system). HRMS (ESI) calcd for C18H15OF279BrNa: [MþNa]þ: m/z
387.0172. Found: m/z 387.0175 (1 ppm).
4.16. {2-[(4-Bromo-phenyl)-difluoro-methyl]-4,5-dimethyl-
phenyl}-phenyl-methanol 16
To a solution of aldehyde 13 (50 mg, 0.15 mmol) in anhydrous THF
(1 mL) was added, dropwise under magnetic stirring and under ni-
trogen at ꢁ70 ꢂC, a 1.5e1.7 M solution of phenyl lithium in a 70/30
mixture of cyclohexane and ether (0.11 mL, 1.2 equiv). The mixture
was stirred for 2 h at this temperature, before quenching by addition
of a saturated NH4Cl solution. After extraction with diethyl ether, the
organic phases were washed with water, dried (MgSO4) and con-
centrated in vacuo. After purification by silica gel chromatography,
the alcohol 16 was isolated as white crystals (50 mg, 81% yield). Mp:
85e87 ꢂC. Rf¼0.38 (Et2O/pentane, 20/80). 1H NMR (CDCl3, 300 MHz)
Rf¼0.33 (Et2O/pentane, 2/98). 1H NMR (CDCl3, 300 MHz)
d, ppm:
2.36 (s, 6H); 7.30e7.35 (m, 2H); 7.37 (s, 1H); 7.54e7.60 (m, 2H); 7.84
(s,1H); 10.14 (t,1H, J¼2.0 Hz).13C NMR (CDCl3, 75 MHz)
d, ppm: 19.5;
1
5
20.3; 120.5 (t, JCF¼242.0 Hz); 125.1 (t, JCF¼2.4 Hz); 127.7 (t,
3
3
3JCF¼5.0 Hz); 128.2 (t, JCF¼7.9 Hz); 130.1; 131.6 (t, JCF¼1.9 Hz);
2
2
131.9; 134.9 (t, JCF¼27.6 Hz); 136.6 (t, JCF¼28.1 Hz); 139.8 (t,
5JCF¼1.5 Hz); 143.2; 190.3 (t, 4JCF¼3.7 Hz).19F NMR (CDCl3, 282 MHz)
d
, ppm: ꢁ78.62(s). HRMS (ESI) calcd for C16H13OF279BrNa: [MþNa]þ:
d
, ppm: 2.06 (s, 1H); 2.26 (s, 3H); 2.31 (s, 3H); 6.03 (s, 1H); 7.19e7.39
m/z 361.0015. Found: m/z 361.0020 (1 ppm).
(m, 9H); 7.53e7.58 (m, 2H). 13C NMR (CDCl3, 75 MHz)
d, ppm:
4
1
19.5; 19.7; 70.6 (t, JCF¼2.7 Hz); 121.1 (t, JCF¼241.4 Hz); 124.7
5
3
4.14. {2-[(4-Bromo-phenyl)-difluoro-methyl]-4,5-dimethyl-
benzyl}-phenyl-amine 14
(t, JCF¼2.5 Hz); 126.3; 127.0; 127.4; (t, JCF¼8.1 Hz); 127.9 (t,
3JCF¼4.9 Hz); 128.1; 130.8; 130.9 (t, 2JCF¼25.7 Hz); 131.7; 136.2; 136.9
(t, 2JCF¼28.5 Hz); 139.5 (t, 3JCF¼2.1 Hz); 139.7 (t, 5JCF¼1.6 Hz); 143.0.
A solution of aldehyde 13 (60 mg, 0.18 mmol), aniline (20
mL,
19F NMR (CDCl3, 282 MHz)
d, ppm: ꢁ82.25 (d, J¼266.0 Hz), ꢁ79.83
1.2 equiv) and a 1 M solution of zinc chloride (0.23 mL, 1.3 equiv) in
THF was stirred at room temperature for 3 h before addition of
ethanol (0.5 mL) and sodium cyanoborohydride (33 mg, 3 equiv).
The reaction mixturewas stirred at roomtemperatureovernight and
then quenched by addition of water. The inorganic precipitate was
filtered and washed with ethanol. The organic phases were con-
centrated in vacuo. The crude product was dissolved in ethyl acetate,
filtered to remove the remaining inorganic solids and concentrated
in vacuo. After purification by flash chromatography on silica gel, the
amine 14 was isolated as white crystals (64 mg, 87% yield). Mp:
114e116 ꢂC. Rf¼0.37 (Et2O/pentane, 4/96).1H NMR (CDCl3, 400 MHz)
(d, J¼266.0 Hz, AB system). HRMS (ESI) calcd for C22H19OF279BrNa:
[MþNa]þ: m/z 439.0485. Found: m/z 439.0485 (0 ppm).
4.17. 3-{2-[(4-Bromo-phenyl)-difluoro-methyl]-4,5-dimethyl-
phenyl}-(E)-acrylic acid methyl ester (17a) and 3-{2-[(4-
bromo-phenyl)-difluoro-methyl]-4,5-dimethyl-phenyl}-(Z)-
acrylic acid methyl ester 17b
A solution of aldehyde 13 (50 mg, 0.15 mmol) and Ph3PCHCO2Me
[100 mg, 2 equiv in benzene (1 mL)] was stirred at 50 ꢂC for 6 h. The
reaction mixture was filtered on a short pad of silica gel to remove
large part of triphenylphosphine oxide, the residues washed with
ether and the solution concentrated in vacuo. The alkenes 17a and
17b, obtained in an 8/1 ratio by NMR analysis, were separated
by chromatography on silica gel (47 mg, 81% combined yield).
d, ppm: 2.28 (s, 3H); 2.32 (s, 3H); 3.86 (br s); 4.18 (s, 2H); 6.40e6.43
(m, 2H); 6.68e6.72 (m,1H); 7.10e7.14 (m, 2H); 7.34 (s,1H); 7.35e7.38
(m, 2H); 7.39 (s,1H); 7.52e7.56 (m, 2H).13C NMR (CDCl3,100 MHz)
ppm: 19.5; 19.7; 45.2 (t, JCF¼3.2 Hz); 112.8; 117.5; 121.2 (t,
d,
4

3886
A. Khalaf et al. / Tetrahedron 67 (2011) 3881e3886
Compound 17a: white crystals (42 mg, 72% yield). Mp: 122e124 ꢂC.
was filtered on silica gel, and concentrated in vacuo. The twoisomers
19a and 19b were obtained as a 2/1 mixture by NMR analysis. The,
inseparable mixture, of 19a and 19b was isolated as yellow oil by
chromatography on silica gel (115 mg, 97% yield). The analysis of the
spectral data could be done on this purified reaction mixture. 19a:
Rf¼0.49 (Et2O/pentane, 20/80). 1H NMR (CDCl3, 400 MHz)
d, ppm:
2.31 (s, 3H); 2.32 (s, 3H); 3.74 (s, 3H); 6.19 (d, 1H, J¼15.8 Hz);
7.30e7.33 (m, 2H); 7.38 (s, 1H); 7.39 (s, 1H); 7.51e7.54 (m, 2H); 7.83
(dt,1H, JHH¼15.8 Hz, JHF¼1.9 Hz). 13C NMR (CDCl3,100 MHz)
d, ppm:
1
19.5; 19.8; 51.6; 119.5; 120.6 (t, JCF¼242.4 Hz); 124.6 (t,
Rf¼0.42 (Et2O/pentane, 10/90). 1H NMR (CDCl3, 400 MHz)
d, ppm:
3
3
5JCF¼2.3 Hz); 127.8 (t, JCF¼5.1 Hz); 127.9 (t, JCF¼7.9 Hz); 129.1;
1.26 (t, 3H, J¼7.1 Hz); 2.45 (s, 3H), 4.25 (q, 2H, J¼7.1 Hz); 7.45e7.50
3
2
130.6 (t, JCF¼2.5 Hz); 131.7; 132.5 (t, JCF¼26.0 Hz); 136.6 (t,
(m, 2H); 7.57e7.60 (m, 2H). 13C NMR (CDCl3, 100 MHz)
d, ppm: 11.4;
2JCF¼28.7 Hz); 138.6; 139.3; 142.1 (t, JCF¼2.6 Hz); 166.8. 19F NMR
13.9; 61.5; 111.2 (t, JCF¼1.4 Hz); 114.8 (t, JCF¼246.0 Hz); 125.6 (t,
3 2
4
3
1
(CDCl3, 376 MHz)
d,
ppm: ꢁ83.87 (s). HRMS calcd for
5JCF¼2.3 Hz); 127.2 (t, JCF¼5.5 Hz); 131.8; 133.0 (t, JCF¼26.9 Hz);
158.8 (t, 4JCF¼1.2 Hz); 160.8 (t, 4JCF¼0.7 Hz); 166.3 (t, 2JCF¼36.4 Hz).
C19H17O2F279BrNa: [MþNa]þ: m/z 411.0278. Found: m/z 417.0280
(1 ppm). Compound 17b: White crystals (5 mg, 9% yield). Mp:
63e65 ꢂC. Rf¼0.66 (Et2O/pentane, 20/80).1H NMR (CDCl3, 500 MHz)
19F NMR (CDCl3, 282 MHz)
d
, ppm: ꢁ92.27 (s). 19b: Rf¼0.42 (Et2O/
pentane, 10/90). 1H NMR (CDCl3, 400 MHz)
d, ppm: 1.27 (t, 3H,
d
, ppm: 2.29 (s, 3H); 2.31 (s, 3H); 3.55 (s, 3H); 5.78 (d,1H, J¼12.0 Hz);
J¼7.1 Hz); 2.40 (t, 3H, J¼1.9 Hz); 4.29 (q, 2H, J¼7.1 Hz); 7.41e7.43 (m,
7.04 (d, 1H, J¼12.0 Hz); 7.08 (s, 1H); 7.29e7.33 (m, 2H); 7.36 (s, 1H);
2H); 7.54e7.58 (m, 2H). 13C NMR (CDCl31, 100 MHz)
d, ppm: 11.6 (t,
7.47e7.50 (m, 2H). 13C NMR (CDCl3, 125 MHz)
d
, ppm: 19.5; 19.7;
4JCF¼3.1 Hz); 13.7; 62.7; 117.3 (t, JCF¼240.2 Hz); 119.1 (t,
51.1; 120.5; 120.7 (t, 1JCF¼241.8 Hz); 124.4 (t, 5JCF¼2.3 Hz); 127.3 (t,
2JCF¼34.3 Hz); 125.1 (t, JCF¼2.4 Hz); 127.1 (t, JCF¼5.4 Hz); 131.8;
5
3
3
2
3JCF¼7.5 Hz); 128.1 (t, JCF¼5.0 Hz); 130.8 (t, JCF¼25.2 Hz); 131.4;
135.0 (t, 2JCF¼27.9 Hz); 156.1 (t, 3JCF¼1.2 Hz); 158.0 (t, 3JCF¼4.8 Hz);
131.5; 132.0 (t, 3JCF¼3.0 Hz); 136.5 (t, 2JCF¼28.5 Hz); 136.7; 138.4 (t,
160.0 (t, 4JCF¼0.9 Hz). 19F NMR (CDCl3, 282 MHz)
, ppm: ꢁ83.89 (s).
d
4JCF¼1.4 Hz); 143.0; 165.7.19F NMR (CDCl3, 376 MHz)
d, ppm: ꢁ86.03
HRMS (19aþ19b) (ESI) calcd for C14H12NO3F279BrNa: [MþNa]þ: m/z
(s). HRMS (ESI) calcd for C19H17O2F279BrNa: [MþNa]þ: m/z 411.0278.
381.9866. Found: m/z 381.9868 (0 ppm).
Found: m/z 417.0276 (0 ppm).
Acknowledgements
4.18. 3-Benzyl-5-[(4-bromophenyl)-difluoromethyl]-3H-
[1,2,3]triazole-4-carboxylicacid ethyl ester 18a and 1-benzyl-
5-[(4-bromo-phenyl)-difluoromethyl]-1H-[1,2,3]triazole-4-
carboxylicacid ethyl ester 18b
We thank CNRS and MESR for financial support. We thank
CRMPO (Rennes) for the mass spectral analyses. We thank Drs. P.
Van de Weghe and M. Capet for very fruitful discussions.
The difluoro-propargylicester5 (195 mg, 0.64 mmol,1 equiv) and
benzyl azide (0.12 mL, 1.5 equiv) were stirred, neat, at 60 ꢂC for 6 h.
The adducts 18a and 18b, obtained in a 1/2 ratio by NMR analysis,
were separated by chromatography on silica gel (251 mg, 90% com-
bined yield). Compound 18a (83 mg, 30% yield) was obtained as
white crystals. Mp: 50e52 ꢂC. Rf¼0.41 (Et2O/pentane, 1/9). 1H NMR
References and notes
1. For a very interesting recent literature coverage on corresponding molecules
€
see: Jung, N.; Brase, S. Eur. J. Org. Chem. 2009, 4494e4502 and references cited
therein.
2. For a short selection of representative examples see: Fenoprofen (NSAID),
Triclosan (antibacterial-antifungal); Levothyroxine (hypothyroidism); Bumeta-
mide (diuretic); Deltamethrin (insecticide); Quizalofop-ethyl (herbicide).
3. For a short selection of representative examples see: Ketoprofen (NSAID);
Tolcapone (Parkinson); Fenofibrate (hypolipidaemic); Flubendazole (anthel-
mintics); Amiodarone (antiarrhythmic, cardiovascular system); Enoximone
(cardiotonic).
4. (a) Ojima, I., McCarthy, J. R., Welch, J. T. Biomedical Frontiers in Fluorine
Chemistry; ACS Symposium Series 639: Washington, DC, 1996. (b) Welch, J. T.;
Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; Wiley Interscience: New
York, NY, 1991; (c) Welch, J. T. Tetrahedron 1987, 43, 3123e3197; (d) Isanbor, C.;
O’Hagan, D. J. Fluorine Chem. 2006, 127, 303e319; (e) Begue, J.-P.; Bonnet-Del-
pon, D. J. Fluorine Chem. 2006, 127, 992e1012; (f) Kirk, K. L. J. Fluorine Chem.
2006, 127, 1013e1029 and references cited therein.
5. Kitazume, T.; Kamazaki, T. Experimental Methods in Organic Fluorine Chemistry;
Gordon and Breach Science: Tokyo, 1998.
(CDCl3, 300 MHz)
d, ppm: 1.22 (t, 3H, J¼7.1 Hz); 4.27 (q, 2H, J¼7.1 Hz);
5.87(s, 2H); 7.28e7.36 (m, 5H); 7.44e7.46 (m, 2H); 7.56e7.59(m, 2H).
13C NMR (CDCl3, 75 MHz)
d, ppm: 13.7, 54.1; 62.6; 116.3 (t,
5
3
1JCF¼240.9 Hz); 124.8 (t, JCF¼2.3 Hz); 126.4; 127.6 (t, JCF¼5.6 Hz);
2
128.0; 128.6; 128.8; 131.5; 134.2; 134.9 (t, JCF¼27.1 Hz); 145.4 (t,
2JCF¼34.4 Hz); 157.7. 19F NMR (CDCl3, 282 MHz)
, ppm: ꢁ87.72 (s).
d
HRMS (ESI) calcd for C19H16N3O2F279BrNa: [MþNa]þ: m/z 458.0292.
Found: m/z 458.0288 (1 ppm). Compound 18b (168 mg, 60% yield)
was obtained as white crystals. Mp: 86e88 ꢂC. Rf¼0.40 (Et2O/pen-
ꢀ
ꢀ
tane, 2/8). 1H NMR (CDCl3, 300 MHz)
d, ppm: 1.26 (t, 3H, J¼7.1 Hz);
4.27 (q, 2H, J¼7.1 Hz); 5.76 (s, 2H); 7.01e7.05 (m, 2H); 7.12e7.15 (m,
2H); 7.22e7.31 (m, 3H); 7.35e7.39 (m, 2H). 13C NMR (CDCl3, 75 MHz)
6. Chang, Y.; Terawi, A.; Adi, A.-I.; Bae, C. Tetrahedron 2008, 64, 9837e9842 and
references cited therein.
d
, ppm: 13.9; 54.9 (t, 3JCF¼4.5 Hz); 61.8,116.7 (t,1JCF¼242.7 Hz); 125.5
7. For reviews on the chemistry of propargylic fluorides see: (a) Prakesch, M.;
5
3
ꢀ
ꢀ
(t, JCF¼2.5 Hz); 127.1 (t, JCF¼5.0 Hz); 127.7; 128.7; 128.8; 131.6;
Gree, D.; Gree, R. Acc. Chem. Res. 2002, 35, 175e181; (b) Pacheco, M. C.; Purser,
S.; Gouverneur, V. Chem. Rev. 2008, 108, 1943e1981 and references cited
therein.
2
2
133.1 (t, JCF¼26.9 Hz); 133.8, 134.0 (t, JCF¼34.7 Hz); 139.3 (t,
3JCF¼2.0 Hz); 159.6. 19F NMR (CDCl3, 282 MHz)
, ppm: ꢁ83.185 (s).
d
ꢀ
ꢀ
8. (a) Kerouredan, E.; Prakesch, M.; Gree, D.; Gree, R. Lett. Org. Chem. 2004, 1,
78e80; (b) Pujari, S. A.; Kaliappan, K. P.; Valleix, A.; Gree, D.; Gree, R. Synlett
2008, 2503e2507.
9. Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980, 45, 28e29.
10. For a rationalization of the higher reactivity of propargylic systems in nucleo-
philic fluorination see: Prakesch, M.; Kerouredan, E.; Gree, D.; Gree, R.; De
Chancie, J.; Houk, K. N. J. Fluorine Chem. 2004, 125, 537e541.
11. Danishefsky, S. J.; Kitahara, T. J. Am. Chem. Soc. 1974, 96, 7807e7808.
12. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457e2483.
13. Heck, R. F.; Nolley, J. P. J. Org. Chem. 1972, 37, 2320e2322.
HRMS (ESI) calcd for C19H16N3O2F279BrNa: [MþNa]þ: m/z 458.0292.
ꢀ
ꢀ
Found: m/z 458.0293 (0 ppm).
4.19. 5-[(4-Bromo-phenyl)-difluoro-methyl]-3-methyl-
isoxazole-4-carboxylic acid ethyl ester (19a) and 4-[(4-bromo-
phenyl)-difluoro-methyl]-3-methyl-isoxazole-5-carboxylic
acid ethyl ester (19b)
ꢀ
ꢀ
14. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508e524.
15. For some previous examples of Pd-catalyzed coupling reactions on heterocycles
A solution of fluoro-alkyne 5 (100 mg, 0.33 mmol), C2H5NO2
ꢀ
ꢀ
with fluorinated side chains see: Blayo, A.-L.; Le Meur, S.; Gree, D.; Gree, R. Adv.
Synth. Catal. 2008, 350, 471e476 and references cited therein.
16. Mukaiyama, T.; Hishino, T. J. Am. Chem. Soc. 1960, 82, 5339e5342.
(70
mL, 3 equiv), PhNCO (110 mL, 3 equiv) and three drops of Et3N in
toluene (5 mL) was stirred, at 50 ꢂC during 3 h. The reaction mixture