Versatile Transformations of α,β-Dibromoesters and Ketones in Basic Media under Microwave Irradiation

Article abstract of DOI:10.1055/s-2003-41054

Depending on the reaction medium, α,β-dibromoesters under microwave irradiation may selectively lead to α-bromoalk-enes, to alkenes or to (E)-β-bromostyrenes. The corresponding ketones give selectively the α-bromoketones.

Full text of DOI:10.1055/s-2003-41054

PAPER
2185
Versatile Transformations of , -Dibromoesters and Ketones in Basic Media
under Microwave Irradiation
T
J
ransform
a
a
tions of
,
c
-Dibromo
k
estersand
K
etone sH amelin,* Aïcha Saoudi, Hadj Benhaouab
c
a,b
a
b
c
Centre Universitaire de Saïda, Bp 138, Route de Mascara, Nasr, Saïda, 20000 Algérie
Institut de chimie, Université d’Oran, 31000 Algérie
Synthèse et Electrosynthèse Organiques 3, UMR 6510, Université de Rennes 1 et CNRS, Campus de Beaulieu, 35042 Rennes, France
Fax +33(2)23236374; E-mail: jack.hamelin@univ-rennes1.fr
Received 23 June 2003
For this purpose, we chose methyl or ethyl-2,3-dibromo-
-phenylpropanoate (RS,SR), 2,3-dibromo-4-phenylbu-
tanone (RS,SR) and their p-substituted phenyl derivatives.
Abstract: Depending on the reaction medium, , -dibromoesters
under microwave irradiation may selectively lead to -bromoalk-
enes, to alkenes or to (E)- -bromostyrenes. The corresponding ke-
tones give selectively the -bromoketones.
3
We found that in the presence of piperidine or Et N with-
3
Key words: dehydrobromination, debromination, solvent-free re- out solvent, under thermal or microwave activation
action, microwaves
(MWI), the , -dibromoesters lead exclusively to -bro-
moalkenes 4-(Z) and 4-(E) (Scheme 3) with very good
yields in very short times (5–15 min) (Tables 1 and 2).
We have previously reported the synthesis of functiona-
1
lised aziridines starting from , -dibromoesters or ke-
tones 1 and primary amines over bentonite as solid
support. This first study has shown that coupling of this
reaction with microwave irradiation promoted the forma-
tion of -bromoalkenes 4 (Scheme 1).
H
R
H
X
R
H
H
Br
X
H
Bentonite
R
+
+
HCR C(X)Br
H
X
Scheme 3
N
R
N
R
1
Br
R NH2
1
1
1
2
3
4
All the compounds are already described in the literature
resulting from various methods which need longer reac-
tion times, are less straightforward and involve less eco-
friendly procedures.3
X: ester or ketone
Scheme 1
–7
Although the yields were quantitative with both amines, it
is noteworthy that the Z selectivity was higher with pipe-
ridine and that higher temperatures promote isomerisa-
tion.
In order to form selectively the -bromoalkenes, we stud-
ied the behaviour of these , -dibromo compounds under
various conditions and we found that treatment with KF
2
supported on alumina under microwave irradiation led to
an elimination reaction which produced functionalised - We realised a comparison between microwave activation
bromoalkenes in fair yields, but at high temperatures the and conventional heating by using an oil bath previously
formation of the debrominated alkenes 5 competed set at the temperature used under irradiation and found no
(
Scheme 2).
difference between the two activation modes. Neverthe-
less the microwave experiments are much easier to set up.
These results led us to extend the investigation related to
these eliminations in various conditions with the aim of We were also interested in the debromination reactions for
getting better selectivities.
the synthesis of alkenes. This reaction is known in the lit-
9
–11
erature using DMF coupled with a reducing agent
or as
shown later with DMF alone.1
2–14
In the latter case, the
H
Br
X
Br
X
H
KF/Al O3
R
R
R
temperature was usually 150–160 °C under N during 90
minutes.
2
2
R
+
+
Br
X
Br
4(E)
X
MWI
1
4(Z)
5
We readily achieved the debromination using 8.5 equiva-
lents of DMF under microwave irradiation at a monitored
temperature of 150 °C. In these conditions, we could ob-
serve the formation of the alkenes 5 in 5–15 minutes in
good yields (Scheme 4 and Table 3).
X: ester or ketone
Scheme 2
Synthesis 2003, No. 14, Print: 02 10 2003. Web: 28 08 2003.
Art Id.1437-210X,E;2003,0,14,2185,2188,ftx,en;Z08503SS.pdf.
DOI: 10.1055/s-2003-41054
It is noteworthy that an electron-donating substituent on
the phenyl group (1c and 2c) leads to a lower yield of 5
©
Georg Thieme Verlag Stuttgart · New York

2
186
J. Hamelin et al.
PAPER
Table 1 Dehydrobromination with Piperidine
H
Br
Br
Ar
Ar
DMF, MWI
Ar
Ar
Br
CO2R1
+
+
1
CO R1
d
H
CO R
Br
Sub-
strate (°C)
T
t
Yield 4-(Z) 4-(E) Yield 4 Bp
2
2
a
b
(%)c (%)c
(min) (%)
(°C/mbar)
or mp (°C)
1
5
6
4(Z+E)
Ar: a: C6H5
b: pClC6H4
c: pMeOC6H4
1: R = CH3
2: R = C2H5
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
a
a
a
a
b
b
b
c
80
80
5
15
5
89
78
80
78
80
80
70
90
90
80
99
99
96
99
100
91
82
90
90
90
86
93
85
88
80
82
77
85
94
89
88
90
82
85
89
93
82
88
92
90
14
07
15
12
20
18
23
15
06
11
12
10
18
15
11
07
18
12
08
10
85
115/0.076,7
Scheme 4
100
100
80
and favours the formation of 4-(Z,E). A longer reaction
time or larger excess of DMF does not change the results
significantly.
15
5
80
80
90
64–664,6
Then our interest was focused on the formation of the (E)-
bromostyrene 6. These compounds are often used as
starting materials for the synthesis of substituted al-
kenes.
the literature,1
-dibromoesters. After some trials, we found out that
this could be readily achieved by coupling Et N and DMF
under irradiation with a monitored temperature of 150 °C
-
80
15
15
5
100
80
15–21
Although various syntheses are described in
9,22–26
115/0.065–7
none to our knowledge starting from
,
c
80
15
15
5
3
c
100
80
(
Scheme 5). The results are given in Table 4.
a
a
a
a
b
b
b
c
90/0.064,7
Br
H
Ar
Br
Et N/DMF
Ar
Ar
Ar
Br
3
+
+
80
15
5
CO2CH3 MWI
Br
CO2CH3
CO2CH3
4(Z+E)
H
100
100
80
1
6
5
15
5
6 5
Ar: a: C H
+
Ar
b: pClC6H4
c: pMeOC H
90–95/0.058
120/0.078
7
81
75
6
4
80
15
15
5
Scheme 5
100
80
Starting from the isomeric mixture of 4-(Z,E), we could
demonstrate that the (E)- -bromostyrene 6 was formed by
demethoxycarbonylation of the former by Et N according
3
c
80
15
15
Table 3 Debromination with DMF Alone
c
100
a
b
c
d
Temperature monitored by the oven and measured with an IR captor.
Yield of crude reaction mixture.
Ratio estimated by H NMR.
Substrate T
(°C)
t
Yield
5
(%)
6
(%)
4-(Z,E)
(%)
(%)a
b
b
b
(min)
1
c
1a
100
140
140
150
150
150
150
150
150
150
150
150
10
5
–
–
–
Isolated yield.
1
1
a
a
100
100
80
85
73
78
80
26
33
84
84
84
34
37
–
–
Table 2 Dehydrobromination with Triethylamine at 80 °C
7
16
13
10
–
11
09
10
74
67
06
10
11
66
63
Substrate
t (min)
5
Yield (%)a 4-(Z) (%)b
4-(E) (%)b
1a
1b
1c
1c
2a
2a
2b
2c
5
1
1
1
1
2
2
2
2
a
a
b
c
90
90
64
64
67
37c
59
59
67
43
36
36
33
55
41
41
33
57
5
90
15
15
15
5
7
85
100
100
90
15
5
85
–
90
–
a
a
b
c
7
80
06
05
–
15
15
15
100
82
7
87
7
100
100
100
2c
10
–
a
b
c
a
Yield of crude reaction mixture.
Ratio estimated by H NMR.
Reaction was not quantitative.
Yield of crude reaction mixture.
Ratio estimated by H NMR.
No reaction.
1
b
c
1
Synthesis 2003, No. 14, 2185–2188 © Thieme Stuttgart · New York

PAPER
Transformations of
-Dibromoesters and Ketones
2187
Table 4 Formation of the (E)- -Bromostyrene 6 Starting from , -
Dibromoesters
Table 5 Debromination of 8 by DMF Alone under MWI
Sub- T
t
Yield 9
10
11
Yield Bp (°C/mbar)
Sub-
strate (°C)
T
t
Yield
6
(%)
5
(%)
4-(Z,E) Yield 6c
(%)
strate (°C) (min) (%)a (%) (%) (%)
d
9
or Mp (°C)
(min) (%)a
b
b
b
b
8
8
8
8
8
8
8
a
a
a
a
a
a
b
80
5
–
–
–
1a
1a
1a
1a
1b
1c
130
150
150
150
150
150
45
45
30
15
37
45
86
57
60
64
83
80
69
87
82
40
76
–
3
1
1
4
3
–
28
80 15
80 30
80 45
92
92
92
92
64 28
76 21
83 13
58 33
8
3
4
9
12
17
56
10
–
44d,26
83 108–110/0.0328,32
150
5
150 15
80 15
80 45
68d,15,26
52d,26
60c 40 35
25
14
4
90
87
99
86
81
96
66
90
81
36 50
85
a
b
c
d
Yield of crude reaction mixture.
Ratio estimated by H NMR.
Isolated yield.
1
8b
9
64 106
The alkyne 7 is also formed: 7a has a bp of 142 °C and is not recov- 8b 150
5
74 19
60 30
49 43
71 19
72 18
80 16
69 23
7
1
ered; 7b and 7c (low yield) were characterized by H NMR in the
crude mixture.
8
8
8
8
b
c
c
c
150 15
10
8
80
5
2
7
to the mechanism already known. When the mixture 4-
Z,E) was placed in the reaction conditions, we got 25%
of (E)- -bromostyrene 6 after 30 minutes, together with
1% of remaining 4-(Z,E) and 16% of methyl cinnamate
5). We repeated this experiment with two drops of bro- 8c
80 15
80 30
80 45
10
10
4
(
6
(
63 79–8027
mine and in this case we obtained 61% of 6 after the same
time, together with the isomerised mixture of 4-(Z,E)
(
8
c
150
5
8
25% Z and 5% E). It may be concluded that the isomeri- 8c 150 15
66c 47 35
18
sation of the mixture 4-(Z,E) into the E-isomer catalysed
by bromine, favours the demethoxycarbonylation as it is
the case when the reaction is starting from the dibro-
moester.
a
b
c
d
Yield of crude reaction mixture.
No reaction.
Degradation of crude mixture.
Isolated yield.
During this synthesis of -bromostyrene we could ob-
serve the formation of small amounts of the correspond-
ing alkynes 7 and the selective formation of 7 is actually
under study.
tetrabromocyclohexa-2,5-dienone,29 2-bromo-2-cyano-
N,N-dimethylacetanide (BCDA)31 or trimethylbromosi-
lane–dimethylsulfoxide (TMBS–DMSO).32
It appears that microwave irradiation at 80 °C for 45 min
is much more simple. The formation of 9 results from bro-
mination of the alkene 10 via the enolic form and this ex-
plains the regioselectivity of bromine as is already
demonstrated in the literature in different reaction me-
dia. In order to make sure of this, we have realised the fol-
In order to broaden the scope of the debromination reac-
tion by DMF alone, we studied this reaction starting from
the , -dibromoketones 8 (SR,RS) (Scheme 6).
The reaction leads to the major formation of the -bro-
moketones 9. The optimal conditions and the results are
reported in Table 5.
32
lowing experiments: starting from pure 10, the addition of
Compounds 9 are interesting intermediates in the synthe- bromine in DMF at r.t. leads to 9–11. Under the same con-
2
9
sis, which are usually prepared according to two main ditions (DMF, 80 °C, 45 min), 2,3-dibromo-1,3-diphenyl-
processes: either by Wittig–Horner reaction of a bromi- propanone (which is non-enolisable) remains unchanged.
3
0
nated ylid, or via bromination of an , -unsaturated ke-
tone with various brominating agents such as, 2,4,4,6-
We have set up selective routes for the debromination and
the dehydrobromination/demethoxycarbonylation of , -
H
Ar
Ar
Ar
Br
Br
COCH3
H
DMF, MWI
Ar
+
+
Br
COCH2Br
COCH3
COCH3
8
9
10
11
Ar: a: C6H5
b: pClC6H4
c: pMeOC6H4
Scheme 6
Synthesis 2003, No. 14, 2185–2188 © Thieme Stuttgart · New York

2
188
J. Hamelin et al.
PAPER
C NMR (300 MHz, CDCl , 25 °C): = 33.19 (t, J = 151.38 Hz,
3
1
3
1
dibromoesters. Starting from , -dibromoketones, we
were able to prepare -bromoketones. These various se-
lective methods use very simple reagents and rather short
reaction times under microwave irradiation.
1
1
CH ), 122.57 (d, J = 158.56 Hz, CH), 129.36 (dd, J = 167.45 Hz,
2
2
1
2
J = 4.95 Hz, CH), 129.79 (dt, J = 161.75 Hz, J = 6.12 Hz, C ),
32.45 (s, C ), 137.08 (s, C ), 143.83 (dt, J = 155.6 Hz, J = 4.72
Hz, C ), 190.78 (sq, J = 3.47 Hz, CO) ppm.
m
1
2
1
q
q
2
o
+
HRMS: m/z calcd for C H OClBr (M ): 257.94470; found:
1
0
8
NMR spectra were run on a Bruker FTAM 200 spectrometer using
257.9450.
CDCl as solvent and TMS as internal standard. HRMS (EI) was
3
performed at the Centre de Mesures Physiques de l’Ouest, Rennes
on a Varian MAT 311 spectrometer. Microwave irradiations were References
®
realised in a Synthewave 402 oven (Prolabo). The temperatures
(
1) Saoudi, A.; Hamelin, J.; Benhaoua, H. J. Chem. Res., Synop.
996, 492.
2) Saoudi, A.; Hamelin, J.; Benhaoua, H. Tetrahedron Lett.
998, 39, 4035.
were measured with a built in IR captor. The maximum power was
00 W and the cylindrical reactors were 1.8 cm diameter for analyt-
1
3
(
ic reactions and 4 cm diameter for quantitative reactions (isolation
of products). The distillations were carried out in a Kugelröhr (Bü-
chi GKR-50). Unless otherwise stated all the compounds were iden-
tified by comparison with literature data.
1
(
(
3) Marsura, A.; Luu-Duc, C.; Gellon, G. Synthesis 1985, 537.
4) Rossi, R.; Bellina, F.; Bechini, C.; Mannina, L.; Vergamini,
P. Tetrahedron 1998, 54, 135.
(
5) Dai, W. M.; Wu, J.; Fong, K. C.; Lee, M. Y. H.; Lau, C. W.
Dehydrobromination of , -Dibromoester by Amines Leading
to the -Bromoesters 4 (Z and E)
J. Org. Chem. 1999, 64, 5062.
(6) Tago, K.; Kogen, H. Tetrahedron 2000, 56, 8825.
(7) Tago, K.; Kogen, H. Org. Lett. 2000, 2, 1975.
(8) Huang, Z.; Yu, X. J. Org. Chem. 2002, 67, 8261.
(9) Matai, M.; Schug, K.; Miller, S. I. J. Org. Chem. 1970, 35,
For analytical purpose, amine (2 equiv) [piperidine (0.25 g) or Et N
3
(0.3 g)] were added to the , -dibromoesters (1 equiv, 1.5 mmol).
The mixture was then irradiated in the microwave oven with moni-
toring of the temperature. According to the reaction time, the as-
signed temperature was reached after 2–5 min and then maintained
for the appropriate time. After cooling, the crude reaction mixture
was extracted with CH Cl washed with water and dried over
1733.
(
(
(
(
10) Matai, M.; Miller, S. I. J. Org. Chem. 1970, 35, 3416.
11) Fukunaga, K. Synthesis 1980, 879.
12) Khurana, J. M.; Maikap, G. C. J. Org. Chem. 1991, 56, 2582.
13) Khurana, J. M.; Maikap, G. C.; Sahoo, P. K. Synthesis 1991,
2
2
MgSO . After removal of the solvent, the product was purified by
4
distillation. For isolation and purification needs, the quanitities of
substrates were multiplied by 10.
827.
(
(
(
14) Khurana, J. M.; Sehgal, A. Synth. Commun. 1996, 26, 3791.
15) Loar, M. K.; Stille, J. K. J. Am. Chem. Soc. 1981, 103, 4174.
16) Ogawa, T.; Hayami, K.; Iyama, H.; Suzuki, H. Chem. Lett.
990, 937.
17) Ogawa, T.; Kiji, K.; Hayami, K.; Suzuki, H. Chem. Lett.
991, 1443.
18) Ogawa, T.; Usuki, N.; Ono, N. J. Chem. Soc., Perkin Trans.
. 1998, 2953.
(19) Herz, H. G.; Queiroz, M. J. R. P.; Maas, G. Synthesis 1999,
013.
Debromination by DMF to form the Alkenes 5
DMF (8.5 equiv, 1 mL) was added to the , -dibromoester (1 equiv,
1
1
.5 mmol) and the solution was irradiated in the microwave oven.
(
(
The monitored temperature of 150 °C was reached in 2 min and
maintained for the appropriated time. After cooling, CH Cl was
1
2
2
added and the solution was washed with water (4 ×) and then dried
1
over MgSO . After removal of CH Cl under vacuum, the crude
4
2
2
1
mixture was analysed by H NMR.
1
(
(
(
(
20) Vassilikogiannakis, G.; Hatzimarinaki, M.; Orfanopoulos,
M. J. Org. Chem. 2000, 65, 8180.
21) Lebedev, Y.; Izmer, V. V.; Kazyul’Kin, D. N. Org. Lett.
(
E)- -Bromostyrene 6 from , -Dibromoesters in the Presence
of Et N in DMF
In the cylindrical reactor (1.8 cm or 4 cm diameter) was placed Et N
3
3
2
002, 4, 623.
22) Matsumoto, M.; Kuroda, K. Tetrahedron Lett. 1980, 21,
021.
23) Naskar, D.; Chowdhury, S.; Roy, S. Tetrahedron Lett. 1998,
9, 699.
(24) Hee Kim, S.; Wei, H.; Willis, S.; Li, G. Synth. Commun.
999, 29, 4179.
25) Kuang, C.; Senboku, H.; Tokuda, M. Tetrahedron Lett.
001, 42, 3893.
26) Kuang, C.; Senboku, H.; Tokuda, M. Tetrahedron 2002, 58,
491.
27) Texier, F.; Marchand, E.; Carrié, R. Tetrahedron 1974, 30,
185.
(
3 equiv, 0.45 mL) in a mixture of DMF (8.5 equiv, 1 mL) and the
dibromoester (1 equiv). With a power of 300 W, the temperature of
50 °C was reached in 5 min and then maintained for 30–45 min.
After cooling, CH Cl was added and the solution was washed with
4
1
2
2
3
water (4 ×). After drying over MgSO and removal of CH Cl under
4
2
2
1
vacuum, the crude mixture was analysed by H NMR and then the
product was purified either by distillation or by flash chromatogra-
phy over SiO2.
1
(
(
(
(
(
(
2
-
Bromoketones 9 Starting from , -Dibromoketones
The , -dibromoketone (1 equiv, 1.5 mmol) was added to of DMF
8.5 equiv, 1 mL) and irradiated with a monitored temperature of 80
C which was reached after 5 min and maintained for 45 min. The
1
(
°
3
28) Ashraf, S. A.; Hill, J.; Ikhlef, F.; M’Hamedi, A.; Zenzer, H.
J. Chem. Res., Synop. 1993, 7, 1731.
product was purified as above. Compound 9b was not found in the
literature; mp 106 °C (petroleum ether, bp = 35–60°C).
29) Calo, V.; Lopez, L.; Pesce, G.; Todesco, P. E. Tetrahedron
1973, 29, 1625.
30) Le Corre, M. Bull. Soc. Chim. Fr. 1974, 9-10, 1951.
1
H NMR (300 MHz, CDCl 25 °C): = 4.08 (s, 2 H, CH ), 6.62 (d,
3
,
2
2
2
J = 16.02 Hz, 2 H, CH) and 7.64 (d, J = 16.02 Hz, 2 H, CH), 7.37
2
2
(
d, J = 8.52 Hz, 2 H, CH ), 7.50 (d, J = 8.52 Hz, 2 H, CH ).
a
r
a
r
(31) Sekiya, M.; Ito, K.; Suzuki, K. Tetrahedron 1975, 31, 231.
(
32) Bellesia, F.; Ghelfi, F.; Grandi, R.; Pagnoni, U. M. J. Chem.
Res., Synop. 1986, 428.
Synthesis 2003, No. 14, 2185–2188 © Thieme Stuttgart · New York