Stereoselective cyanation of β-bromo-β-fluorostyrenes using potassium cyanide and promoted by (CH3CN)4Cu+ BF4-

Article abstract of DOI:10.1016/j.tet.2011.10.111

A general method for the synthesis of α-fluorocinnamonitrile based on the stereoselective reaction between β-bromo-β-fluorostyrene and potassium cyanide, promoted by (CH₃CN)₄Cu⁺ BF₄^- in 1-methyl-2-pyr

Full text of DOI:10.1016/j.tet.2011.10.111

Tetrahedron 68 (2012) 603e607
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Stereoselective cyanation of
b-bromo-
b-fluorostyrenes using potassium cyanide
and promoted by (CH3CN)4Cuþ BF4ꢀ
,
,
Said Eddarir a b, Mohammed Kajjout a, Christian Rolando a
*
a
ꢀ
ꢁ
ꢀ
Universite de Lille 1, Sciences et Technologies, Miniaturisation pour l’Analyse, la Synthese & la Proteomique (MSAP), USR CNRS 3290 and Institut Michel Chevreul FR CNRS 2698,
59655 Villeneuve d’Ascq Cedex, France
b
ꢀ
ꢀ
ꢀ
Universite Cadi Ayyad, Faculte des Sciences et Techniques Gueliz, BP 549 Marrakech, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 20 August 2011
Received in revised form 30 October 2011
Accepted 31 October 2011
Available online 6 November 2011
A general method for the synthesis of a-fluorocinnamonitrile based on the stereoselective reaction be-
tween
pyrrolidinone (NMP), is described.
b-bromo-b
-fluorostyrene and potassium cyanide, promoted by (CH3CN)4Cuþ BF4ꢀ in 1-methyl-2-
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
reaction of fluorotribromethane with an aldehyde in the presence
of a tertiary phosphine according to the procedure developed for
the synthesis of dibromoolefins by Corey and Fuchs,5 adapted to
bromofluoroolefins by Burton et al.6 and improved by activating the
condensation step by diethylzinc as described by Pannecouke et al.7
Recently, Shastin et al. have introduced a new version of this last
reaction based on the treatment of N-unsubstituted hydrazones
with CFBr3 in the presence of a catalytic amount of CuCl.8 The
CoreyeBurton strategy is particularly convenient as it is compatible
with functionalized molecules like carbohydrates, nucleotides and
polyphenols.9 Furthermore, the kinetic resolution gives the pure
thermodynamic Z product starting from an E/Z mixture since the
(Z)-bromofluorolefin may be isomerized into the E isomer, which is
more reactive.10 The reaction may also be conducted on the crude E/
Z mixture and stopped when all the (E)-bromofluorolefin is con-
sumed, leading to pure Z products.10,11 The substitution of a bro-
mine atom located on a vinylic position by the cyanide anion was
decribed since the early 70s using various organometallic catalysts
based on derivatives of copper, nickel, cobalt or palladium alone or
with copper (I) as co-catalyst.12 We report a general method for the
Very few syntheses of a-fluoro-a,b-unsaturated nitriles 2 have
been described in the literature.1 The most common access is based
on the reaction of diethylcyanofluoromethanephosphonate with
the corresponding aldehydes or ketones.2 Diethylcyano-
fluoromethanephosphonate is synthesized either by fluorination of
diethylcyanomethanephosphonate, transformation of ethyl dieth-
ylphosphonofluoroacetate into the amide by ammonia, followed by
dehydration or by reaction of diethylchlorophosphate with a fluo-
roacetonitrile anion. These a-fluoro-a,b-unsaturated nitriles 2 may
serve as fluorinated building blocks since they can be further
transformed into 2-fluoroallylamines by reduction with DIBAL-H
and then into C-(1-fluorovinyl)nitrones.2i,j The wide availability of
cold-labelled (13C and 15N) or hot-labelled (14C) potassium cyanide
and the ease of manipulation of this reagent in small quantities in
comparison with gaseous carbon dioxide strengthen the interest of
the synthesis of a-fluoro-a,b-unsaturated nitriles 2 based on this
reagent. However, while the transformation of bromoolefins into
the corresponding cyanoolefins is a well-documented reaction, the
reaction between 1-bromo-1-fluoroalkenes and potassium cyanide
has received little attention. Only Nenajdenko et al. have reported
the synthesis of 2-fluoroacrylonitriles starting from 1-bromo-1-
fluoroalkenes by copper cyanide in DMF at 150 ꢁC.2k 1-Bromo-1-
fluoroalkenes are easily obtainable in several ways: (i) in configu-
rationally pure form by the addition of bromine to the corre-
synthesis of a-fluoro-a,b-unsaturated nitriles based on the reaction
between 1-bromo-1-fluoroalkenes and potassium cyanide (KCN)
promoted by (CH3CN)4Cuþ BF4ꢀ. The use of potassium cyanide as
a CN source allows a potentially easy labelling of the final product
without isolating copper cyanide.13
sponding
fluoroacrylate
followed
by
dehydrogenative
2. Results and discussion
decarboxylation;3 (ii) as an E/Z mixture by condensation with
LiCFBr2 on an aldehyde followed by water elimination;4 or (iii) by
First we tried to use the conditions originally described by
Yamamura et al.14 and recently employed for the synthesis of 13C
labelled cinnamonitrile.14b These conditions are based on the sol-
ubilisation of potassium cyanide by 18-crown-6 and palladium (0)
(Pd(PPh3)4, PPh3) as catalyst in benzene at reflux. For this
* Corresponding author. Tel.: þ33 320434977; e-mail address: christian.rolando@
univ-lille1.fr (C. Rolando).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.10.111

604
S. Eddarir et al. / Tetrahedron 68 (2012) 603e607
experiment we used almost stereochemically pure (Z)-
fluorostyrene (Z/E>95/5) 1a, Z obtained by dehydrogenative de-
carboxylation of (Z)- -fluorocinnamic acid. Unfortunately, under
these conditions -bromo- -fluorostyrene was recovered unreac-
ted, but not isomerized and no -fluorocinnamonitrile 2a could be
b-bromo-b-
X
X
X
a
Br
F
CN
F
b
b
a
detected (Table 1, entry a). This result was rather unexpected as the
conditions are close to those we previously described for the syn-
thesis of fluorinated dienes and enynes based on the palladium
catalyzed coupling of alkenes and alkynes starting from 1-bromo-
1-fluoroalkenes.3,15 The replacement of the palladium (0) catalyst
by a palladium (II) precursor (Pd(OAc)2, 3%; PPh3, 6%) did not lead to
any improvement (Table 1, entry b). Using triethylamine as a sol-
vent, which avoids the use of 18-crown-6 for solubilising potassium
cyanide, also failed (Table 1, entry c). 1-Methyl-2-pyrrolidinone
(NMP) was recently used as a solvent for the uncatalyzed sub-
stitution of 1-bromo-1-fluoroolefins by sodium benzene sulfinate
(CH3CN)4Cu+
H
H
H
H
1, Z
-
2, E
BF4
+ KCN
X
1-Methyl-
2-pyrrolidinone
150 °C, 18 h
F
F
Br
CN
1, E
2, Z
leading to a
-fluoro conjugated sulfones in good yields.16 But using
Scheme 1. Stereoselective cyanation of
b-bromo-b-fluorostyrene 1 using potassium
cyanide and promoted by (CH3CN)4Cuþ BFꢀ4 in 1-methyl-2-pyrrolidinone (NMP).
NMP as a solvent for palladium catalyzed substitution by potassium
cyanide also failed (Table 1, entry d). So we were delighted that the
conditions originally described by Bouas-Laurent et al.,12a which are
based on the use of copper (I) cyanide (CuCN) in 1-methyl-2-
tetrafluoroborate with KCN in 1-methyl-2-pyrrolidinone may lead
to the formation of a cuprate species,20 mostly Cu(CN)2ꢀ and
Cu(CN)23ꢀ, which are able to transfer the CN group.21 The enhanced
formation of reduction products in the presence of triphenylphos-
phine may be explained by the reactionwith water traces, which are
difficult toremovefroma dipolaraprotic solvent like NMP, leading to
triphenylphosphine oxide and reductive hydrogen species.
These results have prompted us to ascertain the kinetics of the
reaction (Table 2) and to look if the effect described by Burton for
palladium catalysis, in which the (E)-
by far more reactive, is also observed for copper catalysis. Starting
from -bromo-
-fluorostyrene 1a richer in the kinetic isomer Z10 (E/
Z ratio 26/74),3 the E/Z ratio of the remaining
-bromo- -fluo-
pyrrolidinone (NMP) led to
yield (94%; Table 1, entry e). In spite of the rather harsh conditions
(heating at 150 ꢁC for 6 h) the stereochemistry of the obtained
a-fluorocinnamonitrile 2a, E in good
a
-
fluorocinnamonitrile 2a was mainly E, as demonstrated by the
3
17 Hz value for the observed JHF coupling constant. This result
shows that the stereochemistry of the b-bromo-b-fluorostyrene 1a
reagent was well preserved, even when using an E, Z mixture
containing in majority the less stable Z precursor.10 The use of DMF
as a solvent as described by Friedman and Shechter17 also yielded
the desired product. However the results were slightly lower for
both yield and stereochemistry (Table 1, entry f).
b-bromo-b-fluorostyrene 1a is
b
b
b
b
Table 1
Cyanation of
b-bromo-b-fluorostyrene 1a with Z/E geometry better than 95/5 by copper and potassium cyanide
Entry
Catalyst and CNꢀ source
Solvent
T
ꢁC
Time (h)
Recovered 1a, Z %b
PhCH]CFCN 2a % (E/Z)b
a
b
c
d
e
f
g
h
i
Pd(PPh3)4, 3%; KCN (2 equiv); 18-crown-6a (8%)
Pd(OAc)2, 3%; PPh3, 6%; KCN (2 equiv); 18-crown-6a (8%)
Pd(OAc)2, 3%; PPh3, 6%; KCN (2 equiv)
Pd(OAc)2, 3%; PPh3, 6%; KCN (2 equiv)
CuCN (2 equiv)
Benzene
Benzene
Et3N
75
75
20
36
12
18
5
72
24
24
18
100
100
100
100
6
15
100
37
d
d
100
150
150
150
150
150
150
d
NMPa
NMP
d
94 (93/7)
85 (80/20)
Traces
63 (>95/5)
100 (>95/5)
CuCN (1.1 equiv)
DMF
NMP
NMP
NMP
CuCN (5%); KCN (2 equiv); 18-crown-6a (8%)
(PPh3)4Cuþ BF4ꢀ (1.5 equiv); NaCN (1.5 equiv)
(CH3CN)4Cuþ BF4ꢀ (1.5 equiv); KCN (1.5 equiv)
Traces
a
Abbreviations: 18-crown-6: 1,4,7,10,13,16-hexaoxacyclooctadecane; NMP: 1-methyl-2-pyrrolidinone.
Relative yield determined by GC/MS assuming the same factor response for both products and isomers.
b
In order to utilize labelled cyanide we tried to use a catalytic
amount of copper (I) cyanide in 1-methyl-2-pyrrolidinone in the
presence of potassium cyanide, but only traces of -fluo-
rostyrene 1a increases steadily to 12/88. This kinetics shows that the
Z kinetic isomer was not converted into the thermodynamic E iso-
mer in these reaction conditions and that the E isomer also has
a
rocinnamonitrile 2a were obtained (Table 1, entry g). The re-
placement of copper (I) cyanide by tetrakis(triphenylphosphine)
copper (I), tetrafluoroborate18 in 1-methyl-2-pyrrolidinone in the
Table 2
Kinetics and stereochemistry of the cyanation of b-bromo-b-fluorostyrene 1a using
potassium cyanide promoted by (CH3CN)4Cuþ BF4ꢀ in 1-methyl-2-pyrrolidinone
(NMP) at 150 ꢁC
presence of sodium cyanide (NaCN) led to (E)-a-fluorocinnamoni-
trile 2a in fair yield (63%) while still preserving an almost pure E
stereochemistry (E/Z better than 95/5; Table 1, entry h). An equiva-
lent result was obtained using potassium cyanide. However, a care-
Time
(mn)
Starting material 1a
PhCH]CFCN 2a
% Expa
% E/Z expa
% Expa
% E/Z expa
ful examination of the reaction mixture showed the presence of
b
-
(calcd)b
(calcd)b
(calcd)b
(calcd)b
fluorostyrene arising from the reduction of -bromo- -fluorostyr-
ene 1a. We also found that the proportion of the reduction product
increased when the reaction was performed on a substituted
b
b
0
100 (100)
80 (71)
53 (50)
28 (26)
12 (13)
26/74 (26/74)
23/77 (22/78)
20/80 (19/81)
18/82 (14/86)
12/88 (9/91)
d
d
30
60
120
180
20 (29)
47 (50)
72 (74)
88 (87)
73/27 (68/32)
80/20 (72/28)
78/22 (79/22)
83/17 (85/15)
b-bromo-b-fluorostyrene bearing either electron-donating or
electron-attracting groups. The use of tetrakis(acetonitrile)cop-
per(I), tetrafluoroborate19 under the same conditions (Scheme 1)
gave the substitution products cleanly and in a nearly quantitative
yield (Table 1, entry i). The mixing of tetrakis(acetonitrile)copper(I),
a
Relative yield determined by GC/MS assuming the same response factor for both
products and isomers.
b
Calculated values using the following first order kinetic constants (molꢀ1 minꢀ1
)
kE¼0.017, kZ¼0.010 for the reagents; kZ/E¼0.005 for the product (see text).

S. Eddarir et al. / Tetrahedron 68 (2012) 603e607
605
a slightly higher reactivity in the case of cyanation promoted by
Dimethylformamide (DMF) and 1-methyl-2-pyrrolidinone (NMP)
were distilled at reduced pressure before use. NMR spectra were
recorded on a Bruker (Wissembourg, France) AM 300 spectrometer
(300, 282 and 75 MHz, for 1H, 19F and 13C, respectively) using CDCl3
as solvent and TMS as internal standard; chemical shifts and cou-
pling constants J values are given in delta and hertz, respectively; C
and H are assigned according to Scheme 2. MS experiments: Gas
chromatography mass spectrometry experiments using electron
impact ionization (EI) spectra were carried out on a Polaris-Q ion
trap (Thermo Finnigan, San Jose, CA). High resolution mass spectra
were recorded on a JEOL MStation 700 double focussing mass
spectrometer using electron impact ionization (EI) by direct inlet
introduction. Starting E/Z mixtures of unsubstituted or substituted
(CH3CN)4Cuþ BFꢀ4 . Experimental data are well fitted by a first order
reaction
for
both
isomers
(kE¼0.017
molꢀ1
minꢀ1
;
kZ¼0.010 molꢀ1 minꢀ1). The stereochemistry of the product was in
majority E as expected for a specific substitution on each isomer of
the bromine atom bythe cyanide ion. However, the proportion of the
E isomer in the
time. The final ratio in favour of the E isomer was slightly higher than
the Z ratio in the starting -bromo- -fluorostyrene 1a. This may be
a-fluorocinnamonitrile 2a product increased with
b
b
explained by an isomerisation of the formed (Z)-2-fluoro-3-phenyl-
acrylonitrile 2a to the E isomer (kZ/E¼0.005 molꢀ1 minꢀ1). Calcu-
lated values using this set of kinetic constants are in good agreement
with experimental results and are given in brackets in Table 2.
In summary, this kinetic experiment demonstrates that (i) the
b-bromo-b-fluorostyrenes were obtained either enriched in E or Z
stereochemistry of the starting
b
-bromo-
b
-fluorostyrene 1 is pre-
isomer by bromine addition to the corresponding fluoroacrylate
followed by dehydrogenative decarboxylation,3 or as a roughly
equimolar E,Z mixture using the reaction of aromatic aldehyde with
fluorotribromomethane according to the Burton protocol.10
served and (ii) the E isomer corresponding to the bromine atom cis
to the hydrogen atom on the less crowded part of the olefin while
still fully conjugated with the aromatic ring has a greater reactivity.
We then performed preparative experiments with a series of
substituted
b-bromo-b-fluorostyrene 1 bearing either electron-
attracting groups (Table 3, entries bed), electron-donating groups
(Table 3, entry e) or mixed groups (Table 3, entry f). In all cases the
reaction proceeded very cleanly, giving only substitution products
in good chemical yields and with an almost complete conservation
of the stereochemistry of the starting product. The stereochemistry
g
h
f
i
e
b
d
of the obtained unsubstituted
a-fluorocinnamonitrile 2a was
a
c
mostly completely E (96%, Table 3, entry 1a). This higher amount
when compared to the kinetic experiment described above is due
to a longer heating time leading to a near complete isomerisation.
Scheme 2. Atom numbering for the description of NMR spectra.
Table 3
4.2. Procedure of the synthesis of 2-fluoro-3-phenyl-
acrylonitrile 2a using CuCN (Table 1, entry e)
Cyanation of substituted
b-bromo-b-fluorostyrene 1aef using potassium cyanide
promoted by (CH3CN)4Cuþ BF4ꢀ in 1-methyl-2-pyrrolidinone (NMP) at 150 ꢁ
C
1
Substituents
1 (E/Z)a
2, Isolated yield (%)
2 (E/Z)a
A
mixture of (2-bromo-2-fluorovinyl)-benzene (201 mg,
1 mmol), copper cyanide (179 mg, 2 mmol) in 3 ml NMP (1-methyl-
2-pyrrolidinone) was heated at 150 ꢁC under argon for 5 h. After
cooling, the organic phase was acidified with hydrochloric acid
(1 M, 10 ml) then extracted with pentane. The pentane phase was
washed with brine then dried over anhydrous MgSO4 and the
solvent was removed in vacuum, giving 120 mg of 2-fluoro-3-
phenyl-acrylonitrile as a clear oil.
meta
para
1a
1b
1c
1d
1e
1f
H
H
H
H
H
Br
H
F
Cl
Br
OMe
OMe
26/74
74/26
90/10
10/90
42/58
73/27
85
88
83
79
91
82
96/4
23/77
10/90
88/12
43/57
27/73
a
Relative yield of isomers determined by GC/MS assuming the same response
factor for both isomers. The values obtained are consistent with those determined
by 1H NMR.
4.3. Procedure of the synthesis of 2-fluoro-3-phenyl-
acrylonitrile 2a from NaCN using (PPh3)4CuD BF4L as catalyst
(Table 1, entry h)
3. Conclusion
A
mixture of (2-bromo-2-fluorovinyl)-benzene (1.05 g,
We report a convenient method for the conversion of
b-bromo-
5.00 mmol), sodium cyanide (0.36 g, 7.34 mmol) and tetrakis(-
triphenylphosphine)copper(I), tetrafluoroborate complex (8.94 g,
7.46 mmol) in 8 ml of 1-methyl-2-pyrrolidone was heated at 150 ꢁC
under argon for 24 h. After cooling, the organic phase was acidified
with hydrochloric acid (1 M, 10 ml) then extracted with pentane.
The pentane phase was washed with brine then dried over anhy-
drous MgSO4 and then the solvent was removed in vacuum, giving
782 mg of 2-fluoro-3-phenyl-acrylonitrile as a clear oil.
b
-fluorostyrenes 1 into the corresponding nitriles 2 using potas-
sium cyanide enabling easy labelling of the final product. The ste-
reochemistry of the starting 1-bromo 1-fluoroalkene is preserved:
b
-bromo-
reciprocally 1, E starting material afforded 2, Z product. As
-unsaturated nitriles 2 can be reduced into aldehydes by di-
isobytylaluminium hydride2d this new reaction opens the way to
labelled -fluoro-2-alkenals and 2-fluoroallylic alcohols.
b-fluorostyrene 1, Z gave
a
-fluorocinnamonitrile 2, E and
a-fluoro-
a,b
a
4. Experimental part
4.1. General
4.4. General procedure for the preparation of of 2-fluoro-3-
phenyl-acrylonitrile 2a from KCN using (CH3CN)4CuD BF4L as
catalyst (Table 1, entry i)
All commercially available products were purchased from
Aldrich (Saint-Quentin Fallavier, France) and used as received.
Deuterated solvents (99.9% or better) were purchased from Euriso-
Top (Saint-Aubain, France). Tetrahydrofuran (THF) was distilled
from sodium benzophenone ketyl under argon before use.
A
mixture of (2-bromo-2-fluorovinyl)-benzene (201 mg,
1.0 mmol), potassium cyanide (97.50 mg, 1.5 mmol) and tetraki-
s(acetonitrile)copper(I), tetrafluoroborate complex (474 mg,
1.5 mmol) in 3 ml of 1-methyl-2-pyrrolidone was heated at 150 ꢁC
under argon for 18 h. After cooling, the organic phase was acidified

606
S. Eddarir et al. / Tetrahedron 68 (2012) 603e607
3
3
with hydrochloric acid (1.0 M, 10 ml) then extracted with pentane.
The pentane phase was washed with brine then dried over anhy-
drous MgSO4 then the solvent was removed in vacuo, giving a clear
oil.
(d, JHeF¼35.4 Hz, 1H, Hc), 6.86 (d, JHeH¼8.9 Hz, 2H, Hf), 7.46 (d,
3JHeH¼8.9 Hz, 2H, He); 19F NMR (CDCl3): ꢀ130.3 (d, 3JHeF¼34.4 Hz,
1F); 13C NMR (CDCl3): 55.2 (OCH3), 113.8 (d, JCeF¼46.4 Hz, Ca),
2
114.3 (s, Ch), 123.2 (d, JCeF¼6.3 Hz, Cd), 125.7 (d, JCeF¼24.5 Hz,
2
2
Cc), 129.6 (d, 1JCeF¼253.2 Hz, Cb), 131.8 (d, JCeF¼8.5 Hz, Ce), 161.7
4
6
4.4.1. 2-Fluoro-3-phenyl-acrylonitrile 2a (Table 3, entry a)2f,i. (E)
Isomer: 1H NMR (CDCl3): 7.08 (d, 3JHeF¼16.7 Hz, 1H, Ha), 7.35e7.45
(d, JCeF¼3.4 Hz, Cg). (E) Isomer: 1H NMR (CDCl3): 3.79 (s, 3H,
OCH3), 6.97 (d, JHeF¼17.4 Hz, 1H, He), 6.88 (d, JHeH¼8.9 Hz, 2H,
3
3
(m, 3H), 7.57 (m, 2H); 19F NMR (CDCl3): ꢀ126.5 (d, JHeF¼16.7 Hz,
Hf), 7.47 (d, JHeH¼8.9 Hz, 2H, He); 19F NMR (CDCl3): ꢀ131.2 (d,
3
3
1F). 13C NMR (CDCl3): 113.0 (d, JCeF¼48.6 Hz, Ca), 126.1 (d,
3JHeF¼17.3 Hz, 1F). MS (EI) m/z (relative intensity): 177 (100, Mþꢂ),
162 (43), 147 (10), 134 (50), 107 (36). HRMS (EI) (E/Z) isomer
mixture (m/z): observed, 177.0593; calculated for C10H8OFN,
177.0590.
2
2JCeF¼24.0 Hz, Cc), 128.4 (d, 4JCeF¼3.2 Hz, Ce), 129.2 (s, Cg), 130.2 (d,
3JCeF¼7.7 Hz, Cd), 131.5 (d, 5JCeF¼1.7 Hz, Ch), 131.9 (d,
1JCeF¼257.1 Hz, Cb). (Z) Isomer: 1H NMR (CDCl3) 6.47 (d,
3JHeF¼34.6 Hz, 1H, Hc), 7.35e7.45 (m, 3H), 7.57 (m, 2H); 19F NMR
3
(CDCl3): ꢀ125.8 (d, JHeF¼34.6 Hz, 1F); MS (EI) m/z (relative in-
4.4.6. 2-Fluoro-3-(3-bromo-4-methoxyphenyl)acrylonitrile 2f (Table
3, entry f). (Z) Isomer: 1H NMR (CDCl3): 4.00 (s, 3H), 6.34 (d,
tensity): 147 (100, Mþꢂ), 146 (15), 128 (12), 127 (45), 121 (16), 120
(50), 105 (16), 100 (15), 96 (10), 94 (10), 86 (29). HRMS (EI) (E/Z)
isomer mixture (m/z): observed, 147.1548; calculated for C9H6FN,
147.1533.
3JHeF¼34.4 Hz, 1H, Hc), 6.92 (d, JHeH¼8.7 Hz, 1H, Hf), 7.50 (dd,
3
3JHeH¼8.7 Hz, 4JHeH¼2.2 Hz, 1H, He), 7.78 (d, 4JHeH¼2.2 Hz, 1H, Hi);
19F NMR (CDCl3): ꢀ127.8 (d, JHeF¼34.4 Hz, 1F); 13C NMR (CDCl3):
3
56.4 (OCH3), 112.0 (s, Ch), 112.3 (s, Cf), 118.1 (d, JCeF¼46.5 Hz, Ca),
2
2
3
4.4.2. 2-Fluoro-3-(4-fluorophenyl)acrylonitrile 2b (Table 3, entry
b). (Z) Isomer: 1H NMR (CDCl3): 6.44 (d, 3JHeF¼34.4 Hz,1H, Hc), 7.12
124.3 (d, JCeF¼25.2 Hz, Cc), 128.5 (d, JCeF¼3.0 Hz, Cd), 130.4 (d,
1JCeF¼237.8 Hz, Cb), 133.5 (s, Ce), 133.8 (s, Ci), 161.5 (Cg). (E) Isomer:
(dd, JHeF¼8.6 Hz, JHeH¼8.5 Hz, 2H, Hf), 7.56 (dd, JHeH¼8.6 Hz,
4JHeF¼5.4 Hz, 2H, He); 19F NMR (CDCl3): ꢀ127.0 (dd, 3JHeF¼34.4 Hz,
7JFeF¼2.7 Hz, 1F), ꢀ111.9 (m, 1F); 13C NMR (CDCl3): 116.3 (d,
2JCeF¼22.0 Hz, Cf), 116.4 (d, 2JCeF¼22.1 Hz, Cc), 117.4 (d,
1H NMR (CDCl3): 3.95 (s, 3H), 6.94 (d, JHeF¼16.5 Hz, 1H, Hc), 6.98
3
3
3
3
(d, 3JHeH¼8.6 Hz, 1H, Hf), 7.61 (dd, 3JHeH¼8.6 Hz, 4JHeH¼2.3 Hz, 1H,
He). 7.73 (d, JHeH¼2.3 Hz, 1H, Hi); 19F NMR (CDCl3): ꢀ128.3 (d,
4
JHeF¼16.6 Hz, 1F). MS (EI) m/z (relative intensity): 257 (100, Mþ
,
3
ꢂ
2JCeF¼46.7 Hz, Ca), 130.5 (d, JCeF¼269.2 Hz, Cb), 130.8 (dd,
81Br), 255 (100, Mþ
,
79Br), 242 (56), 240 (55), 214 (37), 212 (37), 176
1
ꢂ
3JCeF¼8.6 Hz, 4JCeF¼3.2 Hz, Cd), 132.3 (dd, 3JCeF¼8.5 Hz,
(11), 161 (13), 133 (65), 132 (20), 106 (10). HRMS (EI) (E/Z) isomer
mixture (m/z): observed, 254.9691; calculated for C10H7OBrFN,
254.9695.
4JCeF¼8.5 Hz, Ce), 163.4 (dd, JCeF¼253.5 Hz, JCeF¼2.9 Hz, Cg). (E)
1
6
Isomer: 1H NMR (CDCl3): 7.04 (d, JHeF¼16.5 Hz, 1H, Hc), 7.14 (dd,
3
3JHeF¼8.6 Hz, JHeH¼8.4 Hz, 2H, Hf), 7.56 (dd, JHeH¼8.4 Hz,
4JHeF¼5.4 Hz, 2H, He); 19F NMR (CDCl3): ꢀ126.9 (dd, 3JHeF¼16.5 Hz,
7JFeF¼4.8 Hz, 1F), ꢀ111.9 (m, 1F). MS (EI) m/z (relative intensity):
165 (100, Mþꢂ), 146 (13), 145 (59), 138 (38), 118 (13). HRMS (EI) (E/Z)
isomer mixture (m/z): observed, 165.0388; calculated for C9H5F2N,
165.0390.
3
3
Acknowledgements
ꢀ
This work was supported by the Conseil Regional Nord, Pas-
de-Calais, France. The NMR and Mass Spectrometry facilities used
in this study were funded by the European Community (FEDER),
ꢀ
the Region Nord-Pas de Calais (France), the CNRS, and the Uni-
4.4.3. 2-Fluoro-3-(4-chlorophenyl)acrylonitrile 2c (Table 3, entry
c). (Z) Isomer: 1H NMR (CDCl3): 6.43 (d, 3JHeF¼34.2 Hz,1H, Hc), 7.40
ꢀ
versite de Lille 1, Sciences et Technologies. S.E. thanks the Uni-
ꢀ
ꢀ
ꢀ
versite Cadi Ayyad, Faculte des Sciences et Techniques Gueliz,
Marrakech, Morocco, for a sabbatical leave and the Region Nord,
Pas-de-Calais for a position as invited professor. This work was
3
3
(d, JHeH¼8.5 Hz, 2H, Hf), 7.50 (d, JHeH¼8.5 Hz, 2H, He); 19F NMR
3
(CDCl3): ꢀ124.8 (d, JHeF¼34.2 Hz, 1F); 13C NMR (CDCl3): 117.8 (d,
2JCeF¼46.3 Hz, Ca), 124.3 (d, 2JCeF¼24.9 Hz, Cc), 129.4 (s, Cf), 129.6 (d,
3JCeF¼11.2 Hz, Cd), 131.3 (d, 4JCeF¼8.2 Hz, Ce), 131.6 (d,
1JCeF¼255.1 Hz, Cb), 136.7 (d, 6JCeF¼3.8 Hz, Cg). (E) Isomer: 1H NMR
ꢀ
performed in the frame of the CNRST-CNRS ‘Action concertee
ꢁ
ꢀ
Chimie 08/09 Synthese de sondes fluorescentes specifiques des
ꢀ
glyco et phopshopeptides pour l’analyse proteomique’. The au-
3
3
(CDCl3): 7.03 (d, JHeF¼16.3 Hz, 1H, Hc), 7.43 (d, JHeH¼8.4 Hz, 2H,
thors thank Dr. Maria van Agthoven for her help with editing this
manuscript.
Hf), 7.58 (d, JHeH¼8.4 Hz, 2H, He). 19F NMR (CDCl3): ꢀ125.4 (d,
3
JHeF¼16.3 Hz, 1F). MS (EI) m/z (relative intensity): 183 (24, Mþ
,
3
ꢂ
37Cl),181 (75, Mþ
,
35Cl),146 (100),126 (28), 99 (13). HRMS (EI) (E/Z)
ꢂ
Supplementary data
isomer mixture (m/z): observed, 181.0088; calculated for C9H5FClN,
181.0095.
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.10.111. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
4.4.4. 2-Fluoro-3-(4-bromophenyl)acrylonitrile 2d (Table 3, entry
d). (E) Isomer: 1H NMR (CDCl3): 6.98 (d, 3JHeF¼16.9 Hz,1H, Hc), 7.32
3
3
(d, JHeH¼8.5 Hz, 2H, Hf), 7.45 (d, JHeH¼8.5 Hz, 2H, He); 19F NMR
(CDCl3): ꢀ127.7 (d, JHeF¼16.4 Hz, 1F); 13C NMR (CDCl3): 116.5 (d,
3
References and notes
2JCeF¼47.6 Hz, Ca), 122.1 (d, 2JCeF¼24.5 Hz, Cc), 128.8 (s, Cf), 129.2 (s,
Cg), 129.4 (d, 3JCeF¼8.6 Hz, Cd), 130.7 (d, JCeF¼2.3 Hz, Ce), 131.2 (d,
4
1. (a) Landelle, G.; Bergeron, M.; Turcotte-Savard, M.-O.; Paquin, J.-F. Chem. Soc.
Rev. 2011, 40, 2867e2908; (b) Yanai, H.; Taguchi, T. Eur. J. Org. Chem. 2011, 2011,
5939-5954.
1JCeF¼247.5 Hz, Cb). (Z) Isomer: 1H NMR (CDCl3): 6.38 (d,
3JHeF¼34.4 Hz, 1H, Hc), 7.32 (d, JHeH¼8.6 Hz, 2H, Hf), 7.45 (d,
3
2. (a) Tronchet, J. M. J.; Martin, O. R. Helv. Chim. Acta 1977, 60, 585e589; (b)
Cousseau, J.; Albert, P. Bull. Soc. Chim. Fr. 1986, 910e915; (c) Tessier, J.; Demoute,
J. P.; Truong Van, T. Roussel-UCLAF. EP Patent 224417, 1987; (d) Baader, E.;
Bartmann, W.; Beck, G.; Below, P.; Bergmann, A.; Jendralla, H.; Kesseler, K.;
Wess, G. Tetrahedron Lett. 1989, 30, 5115e5118; (e) Beck, G.; Bartmann, W.;
Wess, G.; Granzer, E. Hoechst A.-G. DE Patent 3826814, 1990; (f) Patrick, T. B.;
Nadji, S. J. Fluorine Chem. 1990, 49, 147e150; (g) Barry, J. M.; Droux, S.; Gi-
gliotti, G. Roussel-UCLAF. EP Patent 474527, 1992; (h) Xu, Z. Q.; DesMarteau,
D. D. J. Chem. Soc., Perkin Trans. 1 1992, 313e315; (i) van Steenis, J. H.; van den
Nieuwendijk, A. M. C. H.; van der Gen, A. J. Fluorine Chem. 2004, 125, 107e117;
(j) Wang, Y.; Lugtenburg, J. Eur. J. Org. Chem. 2004, 5100e5110; (k)
3JHeH¼8.6 Hz, 2H, He); 19F NMR (CDCl3): ꢀ128.6 (d, 3JHeF¼34.4 Hz,
1F). MS (EI) m/z (relative intensity): 227 (40, Mþ, 81Br), 225 (41, Mþ
,
ꢂ
79Br), 197 (17), 195 (16), 146 (100), 126 (36), 116 (55), 99 (18), 89
(21). HRMS (EI) (E/Z) isomer mixture (m/z): observed, 226.0490;
calculated for C9H5BrFN, 226.0493.
4.4.5. 2-Fluoro-3-(4-methoxyphenyl)acrylonitrile 2e (Table 3, entry
e)2f,i. (Z) Isomer: 1H NMR (CDCl3): 3.79 (s, 3H, OCH3), 6.35

S. Eddarir et al. / Tetrahedron 68 (2012) 603e607
607
Nenajdenko, V. G.; Muzalevskiy, V. M.; Shastin, A. V.; Balenkova, E. S.; Haufe,
G. J. Fluorine Chem. 2007, 128, 818e826.
3. (a) Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C. Tetrahedron Lett. 1990,
31, 4449e4452; (b) Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C. Bull.
Soc. Chim. Fr. 1997, 134, 741e755.
12. (a) Lapouyade, R.; Daney, M.; Lapenue, M.; Bouas-Laurent, H. Bull. Soc. Chim. Fr.
1973, 720e721; (b) Funabiki, T.; Yoshida, S.; Tarama, K. J. Chem. Soc., Chem.
Commun. 1978, 1059e1061; (c) Prochazka, M.; Siroky, M. Collect. Czech. Chem.
Commun. 1983, 48, 1765e1773; (d) Murahashi, S.-I. J. Organomet. Chem. 2002,
653, 27e33; (e) Alterman, M.; Hallberg, A. J. Org. Chem. 2000, 65, 7984e7989;
4. (a) Kuroboshi, M.; Yamada, N.; Takebe, Y.; Hiyama, T. Tetrahedron Lett. 1995, 36,
6271e6274; (b) Shimizu, M.; Yamada, N.; Takebe, Y.; Hata, T.; Kuroboshi, M.;
Hiyama, T. Bull. Chem. Soc. Jpn. 1998, 71, 2903e2921.
(f) Takagi, K. Palladium-catalyzed cross-coupling involving
substituted organometals: palladium-catalyzed cross-coupling Involving metal
cyanides In. Handbook of Organopalladium Chemistry for Organic Synthesis;
a-hetero-
5. Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 3769e3772.
Negishi, E.-I., Ed.; John Wiley & Sons, Inc.: New York, USA, 2002; Vol.1,
6. (a) Vanderhaar, R. W.; Burton, D. J.; Naae, D. G. J. Fluorine Chem. 1972, 1,
381e383; (b) Van Hamme, M. J.; Burton, D. J. J. Fluorine Chem. 1977, 10, 131e143.
7. Lei, X.; Dutheuil, G.; Pannecoucke, X.; Quirion, J.-C. Org. Lett. 2004, 6,
2101e2104.
pp 657e672; http://dx.doi.org/10.1002/0471212466.ch30.
13. (a) Andersson, Y.; Langstroem, B. J. Chem. Soc., Perkin Trans. 1 1994, 1395e1400;
(b) Ponchant, M.; Hinnen, F.; Demphel, S.; Crouzel, C. Appl. Radiat. Isot. 1997, 48,
755e762.
8. Shastin, A. V.; Muzalevsky, V. M.; Balenkova, E. S.; Nenajdenko, V. G. Mendeleev
Commun. 2006, 179e180.
14. (a) Yamamura, K.; Murahashi, S. Tetrahedron Lett. 1977, 4429e4430;
(b) Zippi, E. M.; Kamperman, E. J. Labelled Compd. Radiopharm. 2002, 45,
103e106.
15. Eddarir, S.; Mestdagh, H.; Rolando, C. Tetrahedron Lett. 1991, 32, 69e72.
16. Shastin, A. V.; Nenajdenko, V. G.; Muzalevskiy, V. M.; Balenkova, E. S.; Froehlich,
R.; Haufe, G. Tetrahedron 2008, 64, 9725e9732.
9. (a) Lee, H. H.; Hodgson, P. G.; Bernacki, R. J.; Korytnyk, W.; Sharma, M. Carbo-
hydr. Res. 1988, 176, 59e72; (b) Wnuk, S. F.; Mao, Y.; Yuan, C.-S.; Borchardt, R. T.;
Andrei, G.; Balzarini, J.; De Clercq, E.; Robins, M. J. J. Med. Chem. 1998, 41,
3078e3083; (c) Wnuk, S. F.; Yuan, C.-S.; Borchardt, R. T.; Robins, M. J. Nucleo-
sides Nucleotides 1999, 18, 595e596; (d) Eddarir, S.; Abdelhadi, Z.; Rolando, C.
Tetrahedron Lett. 2001, 42, 9127e9130.
17. Friedman, L.; Shechter, H. J. Org. Chem. 1961, 26, 2522e2524.
18. Reichle, W. T. Inorg. Chim. Acta 1971, 5, 325e332.
10. Xu, J.; Burton, D. J. Tetrahedron Lett. 2002, 43, 2877e2879.
11. (a)Zhang, X.; Lu, L.; Burton, D. J. Collect. Czech. Chem. Commun. 2002, 67,1247e1261;
(b) Xu, J.; Burton, D. J. J. Org. Chem. 2005, 70, 4346e4353; (c) Xu, J.; Burton, D. J. J. Org.
Chem. 2006, 71, 3743e3747;(d)Dutheuil, G.;Lei, X.; Pannecoucke, X.; Quirion, J.-C. J.
Org.Chem.2005, 70,1911e1914;(e)Dutheuil, G.;Paturel, C.;Lei, X.;Couve-Bonnaire,
S.; Pannecoucke, X. J. Org. Chem. 2006, 71, 4316e4319.
19. Kubas, G. J. Inorg. Synth. 1979, 19, 90e92.
20. Hanson, P.; Rowell, S. C.; Taylor, A. B.; Walton, P. H.; Timms, A. W. J. Chem. Soc.,
Perkin Trans. 2 2002, 1126e1134.
21. (a) Kronenburg, C. M. P.; Amijs, C. H. M.; Wijkens, P.; Jastrzebski, J. T. B. H.; van
Koten, G. Tetrahedron Lett. 2002, 43, 1113e1115; (b) Zanon, J.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 2890e2891.