Stereoselective synthesis of 1-bromo-1-fluorostyrenes

Article abstract of DOI:10.1070/MC2006v016n03ABEH002282

The effective and stereoselective one-pot synthesis of 1-bromo-1- fluorostyrenes from aromatic aldehydes based on a catalytic olefination reaction was elaborated.

Full text of DOI:10.1070/MC2006v016n03ABEH002282

Mendeleev Commun., 2006, 16(3), 178–180
Stereoselective synthesis of 1-bromo-1-fluorostyrenes
Aleksey V. Shastin,a Vasiliy M. Muzalevsky,b Elizabeth S. Balenkovab and Valentine G. Nenajdenko*b
a Institute of Problems of Chemical Physics, Russian Academy of Sciences, Chernogolovka, 142432 Moscow Region,
Russian Federation
b Department of Chemistry, M. V. Lomonosov Moscow State University, 119992 Moscow, Russian Federation.
Fax: +7 495 932 8846; e-mail: nen@acylium.chem.msu.ru
DOI: 10.1070/MC2006v016n03ABEH002282
The effective and stereoselective one-pot synthesis of 1-bromo-1-fluorostyrenes from aromatic aldehydes based on a catalytic
olefination reaction was elaborated.
Organofluorine compounds are of interest due to their bio-
logical activity.1 For example, monofluorostilbenes ArCH=CFAr
are the analogues of the natural polyhydroxylated stilbene
resveratrol and are very interesting as potential enzyme inhibi-
tors.2 An approach to the synthesis of such stilbenes is the
palladium-catalysed cross-coupling reaction of 1-bromo-1-fluoro-
styrenes with organoboron and organotin compounds.3 The
general methods for the synthesis of 1-bromo-1-fluorostyrenes
include the decarboxylation of 2,3-dibromo-2-fluoro-3-aryl-
propanoic acids,4 modifications of Wittig reaction2,5–7 and a
method suggested by Hiyama8 who used LiCFBr2 and carbonyl
compounds.
We propose a new reaction of the catalytic olefination of car-
bonyl compounds.9 It was found that N-unsubstituted hydrazones
of carbonyl compounds can be converted to the corresponding
olefins when treated with polyhaloalkanes in the presence of a
catalytic amount of CuCl.
This reaction was used for the synthesis of 1-bromo-1-fluoro-
styrenes. Hydrazone of 4-nitrobenzaldehyde was used as the
model substrate to find optimum reaction conditions. The highest
yields of the target alkenes were obtained when ethanol was
used as the solvent and ethylenediamine was used as the base,
like in the synthesis of alkenes from Freons.10 It is sufficient to
use 1.5 equiv. of CBr3F and 1 mol% CuCl. The high activity of
this compound compared to CCl4 is in agreement with quantum
calculation global electrofilicity index for CBr3F (the measure
of polyhaloalkane olefination activity11) and with experimental
data. Competitive reactions of 4-chlorobenzaldehyde hydrazone
with a mixture of CCl4 and CBr3F give corresponding 1-bromo-
1-fluorostyrene and 1,1-dichlorostyrene in a 5.9:1 ratio.
Under optimal reaction conditions, we investigated conver-
sion of aromatic aldehydes 1 containing electron-donating and
electron-withdrawing groups (one-pot method12) into 1-bromo-
1-fluorostyrenes. We found that the reaction products can be
prepared in high yields (Scheme 1, Table 1).†
Note that the reaction proceeds stereoselectively and the most
unhindered (E)-isomer is obtained: for example, in the case of
†
IR spectra were recorded on a UR 20 spectrophotometer (Nujol).
1H and 13C NMR spectra were recorded on a Bruker AMX 400 spectro-
meter (400 and 100 MHz, respectively) in CDCl3 with Me4Si as the
internal standard. TLC was carried out with Merck 60 F254 plates;
Merck silica gel (63–200 mesh) was used for column chromatography.
Synthesis of bromofluorostyrenes (general procedure). A solution of
2 mmol of the corresponding aldehyde in 8 ml of ethanol was added
dropwise to the solution of 0.11 ml (2.1 mmol) of hydrazine hydrate in
4 ml of ethanol with intense stirring. After completion of hydrazone
formation (TLC monitoring), 0.2 ml (1.5 equiv.) of ethylenediamine
and 0.002 g (1 mol%) of CuCl were added. The reaction mixture was
cooled to 0 °C and 0.3 ml (1.5 equiv.) of CBr3F was added dropwise
with stirring. The reaction mixture was stirred for 4–48 h at room tem-
perature to the completion (TLC monitoring) and 50 ml of a 5% aqueous
HCl solution was added (in the cases of pyridine-2-carbaldehyde, only
water was added). The reaction products were extracted with CH2Cl2
(3×30 ml) and the extract was dried with Na2SO4. The solvent was
evaporated and the residue was purified by column chromatography on
SiO2 (hexane–CH2Cl2 mixture as an eluent). The (E)- and (Z)-alkene
isomers cannot be separated by column chromatography.
1H NMR spectra of compounds 3a,b,e,i,j,6 3c,4(a) 3d7 are in agreement
with published data.
1-(2-Bromo-2-fluorovinyl)-2-bromobenzene 3f: colourless oil, obtained
as a mixture of Z/E isomers, 1:4. IR (n/cm–1): 1650 (C=C). (E)-isomer:
1H NMR (CDCl3) d: 6.41 (d, 1H, ArCH=C, 3JHF 31.69 Hz), 7.16 (t, 1H,
3
3
CH-5, J 7.83 Hz), 7.33 (t, 1H, CH-4, J 7.83 Hz), 7.60 (d, 1H, CH-6,
3J 7.83 Hz), 7.68 (d, 1H, CH-3, 3J 7.83 Hz). 13C NMR (CDCl3) d: 111.86
(d, ArCH=C, 2J 5.13 Hz), 127.60 (C-5), 129.27 (C-4), 130.02 (C-2), 130.34
(d, C-6, J 2.19 Hz), 132.2 (d, C-1, 3J 5.12 Hz), 132.91 (C-3), 135.32
(d, C–F, 1J 331.5 Hz). (Z)-isomer: 1H NMR (CDCl3) d: 6.78 (d, 1H,
3
ArCH=C, 3JHF 13.69 Hz), 7.21 (t, 1H, CH-5, J 8.21 Hz). Other signals
are identical to those for (E)-isomer. 13C NMR (CDCl3) d: 111.69 (d,
ArCH=C, 2J 25.62 Hz), 127.23 (C-5), 129.56 (C-4), 132.68 (C-3), 137.17
(d, C–F, 1J 317.0 Hz). Other signals are identical to those for (E)-isomer.
Found (%): C, 34.20; H, 1.70; Calc. for C8H5Br2F (%): C, 34.32; H, 1.80.
1-(2-Bromo-2-fluorovinyl)-4-iodobenzene 3g: yellowish crystals,
obtained as a mixture of Z/E isomers, 1:4. IR (n/cm–1): 1650 (C=C).
(E)-isomer: 1H NMR (CDCl3) d: 5.93 (d, 1H, ArCH=C, 3JHF 32.47 Hz),
7.15 (d, 2H, CH-3,5, 3J 8.22 Hz), 7.69 (d, 2H, CH-2,6, 3J 8.22 Hz).
13C NMR (CDCl3) d: 93.53 (C-4), 112.27 (d, ArCH=C, 2J 5.85 Hz),
129.67 (d, C-2,6, 4J 7.32 Hz), 131.96 (d, C-1, 3J 4.39 Hz), 134.62 (d,
C–F, 1J 332.2 Hz), 137.85 (C-3,5). (Z)-isomer: 1H NMR (CDCl3) d: 6.60
(d, 1H, ArCH=C, 3JHF 14.67 Hz) 7.24 (d, 2H, CH-3,5, 3J 8.61 Hz) 7.71
(d, 2H, CH-2,6, 3J 8.61 Hz). 13C NMR (CDCl3) d: 110.97 (d, ArCH=C,
2J 24.88 Hz), 130.09 (d, C-2,6, 4J 3.66 Hz), 137.63 (C-3,5). Other signals
are identical to those for (E)-isomer. Found (%): C, 29.55; H, 1.63. Calc.
for C8H5BrFI (%): C, 29.39; H, 1.54.
R
H
R
H
R
H
F
H2NNH2
CBr3F
CuCl
O
N
NH2
Br
1
2
3
Scheme 1
Table 1 Synthesis of 1-bromo-1-fluorostyrenes 3a–m.
Yield of
alkenes 3 (%)
Compound
R
E/Z
1-(2-Bromo-2-fluorovinyl)-4-methylbenzene 3h: colourless oil, obtained
3a
3b
3c
3d
3e
3f
3g
3h
3i
4-NO2C6H4
2-NO2C6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
87
86
86
86
85
85
86
90
85
95
60
95
48
3.5
3.3
6
4
5
as a mixture of Z/E isomers, 1:5.5. IR (n/cm–1): 1650 (C=C). (E)-isomer:
3
1H NMR (CDCl3) d: 2.40 (s, 3H, Me), 6.0 (d, 1H, ArCH=C, JHF
33.06 Hz), 7.21 (d, 2H, CH-3,5, 3J 8.02 Hz), 7.35 (d, 2H, CH-2,6,
3J 8.02 Hz). 13C NMR (CDCl3) d: 21.37 (Me), 113.12 (d, ArCH=C,
2J 6.59 Hz), 128.10 (d, C-2,6, 4J 7.32 Hz), 129.50 (C-3,5), 129.86 (d,
C-1, 3J 4.39 Hz), 133.29 (d, C–F, 1J 330.06 Hz), 137.93 (d, C-4, 6J 2.19 Hz).
(Z)-isomer: 1H NMR (CDCl3) d: 2.41 (s, 3H, Me), 6.68 (d, 1H, ArCH=C,
3JHF 15.26 Hz), 7.23 (d, 2H, CH-3,5, 3J 8.22 Hz), 7.44 (d, 2H, CH-2,6,
3J 8.22 Hz). 13C NMR (CDCl3) d: 111.67 (d, ArCH=C, 2J 23.42 Hz),
128.39 (d, C-2,6, 4J 2.93 Hz), 129.29 (C-3,5), 134.47 (d, C–F, 1J 314.70 Hz),
138.05 (C-4). Other signals are identical to those for (E)-isomer. Found
(%): C, 50.38; H, 3.84. Calc. for C9H8BrF (%): C, 50.26; H, 3.75.
2-BrC6H4
4-IC6H4
4
4
4-MeC6H4
4-MeOC6H4
4-MeO2CC6H4
3,4-(MeO)2C6H3
2-Py
5.5
5
3.5
4.5
1.8
21
3j
3k
3l
3m
2,6-Cl2C6H3
Mendeleev Commun. 2006 179

Mendeleev Commun., 2006, 16(3), 178–180
2,6-dichlorobenzaldehyde, the amount of a minor isomer is less
an excess of phosphorus or organometallic compounds are not
required for the catalytic olefination.
Thus, we elaborated a new stereoselective one-pot method
for the synthesis of 1-bromo-1-fluorostyrenes using commercially
available starting materials. The target alkenes are formed in
high yields and stereoselectively.
than 5%. It is in good agreement with the earlier proposed
reaction mechanism.10,12 It was shown previously that the forma-
tion of the most unhindered isomer is preferable. High E/Z ratio
of isomers is a significant advantage of our approach to 1-bromo-
1-fluorostyrenes in comparison with the Wittig reaction. In the
case of CBr3F, Wittig olefination proceeds nonstereoselectively
to give target alkenes as a mixture of almost equal amounts of
(E)- and (Z)-isomers.2,5–7 Moreover, an inert atmosphere and
This work was supported by the Russian Foundation for
Basic Research (project nos. 03-03-32052a and 06-03-32303)
and the Russian Science Support Foundation.
1-(2-Bromo-2-fluorovinyl)-3,4-dimethoxybenzene 3k: colourless oil,
obtained as a mixture of Z/E isomers, 1:4.5. IR (n/cm–1): 1650 (C=C).
(E)-isomer: 1H NMR (CDCl3) d: 3.87 (s, 3H, MeO), 3.88 (s, 3H, MeO),
References
3
3
5.90 (d, 1H, ArCH=C, JHF 33.06 Hz), 6.81 (d, 1H, CH-5, J 8.21 Hz),
6.92 (dd, 1H, CH-6, 3J 8.21 Hz, 4J 1.96 Hz), 6.97 (d, 1H, CH-2, 4J 1.96 Hz).
13C NMR (CDCl3) d: 55.77 (2MeO), 110.93 (C-2), 111.03 (d, ArCH=C,
1
2
3
M. Hudlicky and A. Pavlath, Chemistry of Organic Fluorine Com-
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(a) C. Chen, K. Wilcoxen, N. Strack and J. R. McCarthy, Tetrahedron
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2J 5.13 Hz), 112.75 (d, C-6, J 5.89 Hz), 121.47 (d, C-5, 5J 6.59 Hz),
4
125.44 (d, C-1, 3J 4.39 Hz), 132.32 (d, C–F, 1J 329.34 Hz), 148.79 (C-4),
148.84 (C-3). (Z)-isomer: 1H NMR (CDCl3) d: 3.88 (s, 3H, MeO), 3.89
(s, 3H, MeO), 6.60 (d, 1H, ArCH=C, 3JHF 15.46 Hz), 6.85 (d, 1H, CH-5,
3J 8.42 Hz), 7.02 (dd, 1H, CH-6, J 8.42 Hz, J 1.96 Hz), 7.08 (d, 1H,
CH-2, 4J 1.96 Hz). 13C NMR (CDCl3) d: 121.47 (d, C-5, 5J 3.66 Hz),
123.82 (d, C-1, 3J 8.05 Hz), 133.67 (d, C–F, 1J 313.96 Hz), 148.71 (C–OMe).
Other signals are identical to those for (E)-isomer. Found (%): C, 45.85;
H, 3.78. Calc. for C10H10O2BrF (%): C, 46.00; H, 3.86.
3
4
4
5
6
(a) D. J. Burton, J. Fluorine Chem., 1983, 23, 339; (b) D. J. Burton,
Z.–Y. Yang and W. Qiu, Chem. Rev., 1996, 96, 1641; (c) C. Galli,
A. Guarnieri, H. Koch, P. Mencarelli and Z. Rappoport, J. Org. Chem.,
1997, 62, 4072.
X. Lei, G. Dutheuil, X. Pannecoucke and J. Quirion, Org. Lett., 2004,
6, 2101.
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M. Kuroboshi and T. Hiyama, Bull. Chem. Soc. Jpn., 1998, 71, 2903.
A. V. Shastin, V. N. Korotchenko, V. G. Nenajdenko and E. S. Balenkova,
Tetrahedron, 2000, 56, 6557.
2-(2-Bromo-2-fluorovinyl)pyridine 3l: colourless oil, obtained as a
mixture of Z/E isomers, 1:1.8. IR (n/cm–1): 1650 (C=C). (E)-isomer:
3
1H NMR (CDCl3) d: 6.20 (d, 1H, PyCH=C, JHF 32.47 Hz), 7.06–7.09
(m, 1H, CH-5), 7.46 (d, 1H, CH-3, 3J 8.02 Hz), 7.55–7.60 (m, 1H, CH-4),
8.48–8.49 (m, 1H, CH-6). 13C NMR (CDCl3) d: 114.51 (d, PyCH=C,
3
2J 4.59 Hz), 122.21 (C-5), 123.23 (d, C-3, J 11.71 Hz), 136.48 (C-4),
7
8
137.13 (d, C–F, 1J 332.99 Hz), 149.46 (C-6), 151.66 (d, C-2, 3J 5.86 Hz).
(Z)-isomer: 1H NMR (CDCl3) d: 6.74 (d, 1H, ArCH=C, 3JHF 15.06 Hz),
7.09–7.12 (m, 1H, CH-5), 7.53 (d, 1H, CH-3, 3J 8.02 Hz), 7.57–7.61
(m, 1H, CH-4), 8.52–8.54 (m, 1H, CH-6). 13C NMR (CDCl3) d: 112.54
9
2
3
(d, PyCH=C, J 24.15 Hz), 122.39 (C-5), 123.07 (d, C-3, J 3.66 Hz),
1
136.11 (C-4), 135.78 (d, C–F, J 318.35 Hz), 149.54 (C-6), 151.27 (d,
C-2, J 12.44 Hz). Found (%): C, 41.83; H, 2.62. Calc. for C7H5NBrF
10 V. N. Korotchenko, A. V. Shastin, V. G. Nenajdenko and E. S. Balenkova,
Tetrahedron, 2001, 57, 7519.
11 V. G. Nenajdenko, V. N. Korotchenko, A. V. Shastin, D. A. Tyurin and
E. S. Balenkova, Zh. Org. Khim., 2004, 40, 1801 (Russ. J. Org. Chem.,
2004, 40, 1750).
12 V. G. Nenajdenko, A. V. Shastin, V. N. Korotchenko and E. S. Balenkova,
Izv. Akad. Nauk, Ser. Khim., 2001, 1003 (Russ. Chem. Bull., Int. Ed.,
2001, 50, 1047).
3
(%): C, 41.62; H, 2.49.
1-(2-Bromo-2-fluorovinyl)-2,6-dichlorobenzene 3m: colourless oil,
obtained as a mixture of Z/E isomers, 1:21. IR (n/cm–1): 1660 (C=C).
(E)-isomer: 1H NMR (CDCl3) d: 6.09 (d, 1H, ArCH=C, 3JHF 31.35 Hz),
7.22 (t, 1H, CH-4, 3J 8.21 Hz), 7.36 (d, 2H, CH-3,5, 3J 8.21 Hz). 13C NMR
(CDCl3) d: 107.69 (d, ArCH=C, 2J 11 Hz), 128.01 (C-3,5), 129.68 (C-4),
129.99 (C-1), 134.99 (C-2,6), 135.2 (d, C–F, 1J 330.06 Hz). (Z)-isomer:
1H NMR (CDCl3) d: 6.52 (d, ArCH=C, 3JHF 10.0 Hz). Other signals are
identical to those for (E)-isomer. All 13C NMR signals are identical to
those for (E)-isomer. Found (%): C, 35.74; H, 1.55. Calc. for C8H4BrCl2F
(%): C, 35.60; H, 1.49.
Received: 29th November 2005; Com. 05/2624
180 Mendeleev Commun. 2006