CuX2-Mediated Halogenation of Alkylidenecyclopropanes: A Highly Efficient and Stereoselective Method for the Preparation of Z-2, 4-Dihalobutenes

Article abstract of DOI:10.1055/s-2003-41480

A convenient and efficient method for the synthesis of (Z)-2,4- dihalobutenes, a useful building block in organic synthesis, was reported in good yield by the reaction of alkylidenecyclopropanes and CuX₂ (or CuI/I₂).

Full text of DOI:10.1055/s-2003-41480

2080
LETTER
CuX2-Mediated Halogenation of Alkylidenecyclopropanes: A Highly Efficient
and Stereoselective Method for the Preparation of Z-2, 4-Dihalobutenes
C
uX -Mediate
d
H
a
o
logenation
o
n
f
A
lkylidene
g
c
yclopropan
w
es ei Zhou,a Xian Huang,*a,b Wanli Chena
2
a
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, P. R. China
b
State Key Laboratory of Oganometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. China
E-mail: huangx@mail.hz.zj.cn
Received 8 July 2003
R2
Abstract: A convenient and efficient method for the synthesis of
(Z)-2,4-dihalobutenes, a useful building block in organic synthesis,
was reported in good yield by the reaction of
alkylidenecyclopropanes and CuX2 (or CuI/I2).
HX
X
R2
R1
R1
R2
ref 4a
MXn
X
ref 4b
Key words: copper-mediated, halogenation, alkylidenecyclo-
propane, stereoselective, (Z)-2,4-dihalobutene
R1
Scheme 2
2,4-Dihalobutenes have attracted considerable attention
because of their versatility as a building block or starting
substrate in organic synthesis1 and in the pharmaceutical
industries.2 However, the synthesis of 2,4-dihalobutenes
is limited by the lack of a general synthetic route.
Especially, the stereoselective synthesis of unsymmetrical
(Z)-2,4-dihalobutenes is not easy. During the last decades,
methylenecyclopropanes (MCPs), served as useful
building blocks in organic synthesis, have been studied
with numerous synthetic interests because the relief of
ring strain provides a potent thermodynamic driving
force.3
conditions.5 This interesting result stimulated us to further
investigate the CuX2-mediated reactions of alkylidene-
cyclopropanes. Herein we wish to report the ring-opening
reactions of MCPs 1 promoted by copper halides under
mild conditions in which (Z)-2,4-dihalobutenes can be
obtained stereoselectively in good to excellent yields.
At the first attempt, we examined the reaction of
benzylidenecyclopropanes (1a) with 4 equivalents of
CuBr2 in aqueous acetonitrile at 85 °C. The reaction was
completed within 4 hours to afford 1-phenyl-1,2,2,4-tetra-
bromobutane in 82% yield (Scheme 3).6
Early in 1970s, Hanack has reported a dibromination
reaction of bromide with alkylidenecyclopropanes and
(1,2-dibromo-1-methylene)cyclopropane was obtained 3s,t
(Scheme 1).
Br Br Br
Ph
CuBr2 (4 equiv)
Br
85 °C, 4h
82%
Ph
Scheme 3
Br
Br
R
Br2 (1 equiv)
Considering the possibility of bromination of alkene in the
presence of CuBr2 [6], we used 2 equivalents of CuBr2 as
bromizating agent and luckily, (Z)-1-phenyl-2, 4-
dibromobutene (2a) was obtained with high stereo-
selectivity in 52% yield. Further screening demonstrated
anhydrous acetonitrile was more suitable reaction
medium and the reaction could be carried out at the lower
reaction temperature (65 °C) affording a good yield of 2a
(Scheme 4).
R
R=Ar, Alkyl
Scheme 1
Recently, Yamamoto has reported a stereoselective ring-
opening reaction of HX with MCPs and Shi observed an
MXn-mediated ring-opening reaction to afford (E)-4-
halobutenes and a quantity of byproducts (Z)-4-ha-
lobutenes (Scheme 2).4
CuBr2 (2equiv)
Br
During our study of MCPs, we have found CuX2-
mediated cyclization reaction of cyclopropylideneacetic
acids and esters to give 4-substitued-2-(5H)furanones and
3,4-substituted-5,6-dihydro-2H-pyran-2-ones under mild
65 °C, 14h
82%
Br
2a
Ph
Ph
1a
Scheme 4
SYNLETT 2003, No. 13, pp 2080–2082
1
6
.1
0
.2
0
0
3
In order to extend this result, we further examined the
halogenation reaction of 1a with CuCl2 or CuI/I2. The
Advanced online publication: 08.10.2003
DOI: 10.1055/s-2003-41480; Art ID: U12803ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
CuX2-Mediated Halogenation of Alkylidenecyclopropanes
2081
chloride and iodide were readily obtained in high yield, (Z)-2,4-Dihalobutenes, containing a homoallylic halogen
respectively, and no tetrachlorobutane or tetraiodobutane and a vinyl halogen, which may react with various re-
was observed even an excess of CuCl2 or CuI/I2 was used agents respectively, can obviously be applied for useful
(Scheme 5).
building block in organic synthesis. We examined a nu-
cleophilic substitution and a Sonogashira cross-coupling
reaction for the synthesis of polysubstituted alkenes
(Scheme 6).
65 °C, 16h
Cl
Cl
Ph
2b
The substituted MCPs 1 are readily available by the
reaction of aldehydes/ketones with 3-bromopropyl-
phosphonium bromide (Scheme 7).9 It should be noted
that we do not need to take care of the stereochemical
problem at the stage of the preparation of 1 as perfect
stereocontrol is accomplished during the addition of CuX2
to 1.
CuCl2 (2 eq) 89%
CuCl2 (4 eq)
85%
Ph
65 °C, 16h
CuI(0.1eq)
1a
I
I
Ph
2c
I2 (2.0 eq)
91%
88%
I2 (4.0 eq)
R2
R1
R2
R1
t-BuOK
Scheme 5
+
O
Br
PPh3Br
1
With this trend in hand, a series of alkylidenecyclo-
propanes were chosen as substrates and (Z)-2,4-di-
halobutenes were obtained highly selectively in good
yields7 and the stereochemistry of the resulting products
Scheme 7
In conclusion, we have developed a convenient and
efficient method for the synthesis of (Z)-2,4-diha-
lobutenes, a useful building block in organic synthesis, in
good yield by the reaction of alkylidenecyclopropanes
and CuX2 (or CuI/I2) in acetonitrile. The reaction
mechanism and synthetic application of this methodology
are being carried out in our laboratory.
1
has been established on the basis of H NMR as well as
from NOESY experiments (Table 1).8
Table 1 Synthesis of (Z)-2,4-Dihalobutenesa
R2
R2
CuX2 (2equiv)
65 °C
X
R1
X
R1
2
1
Acknowledgment
Entry R1
R2
X
Time (h) Product
(yield, %)
This work was supported by the National Natural Science
Foundation of China (20272050) and the Doctoral Foundation of
the National Education Ministry of China.
1
p-Br-Ph
p-Br-Ph
H (1b)
H (1b)
H (1b)
Cl
Br
I
16
14
16
15
12
15
10
8
2d (89)
2e (82)
2f (91)
2g (87)
2h (80)
2i (89)
2j (93)
2k (90)
2l (94)
2
3
4
5
6
7
8
9
References
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Ph
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R1SO2Na
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H
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I
EtOH
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18h
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Et3N/CH3CN
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R=H, R1=Ph
Scheme 6
Synlett 2003, No. 13, 2080–2082 © Thieme Stuttgart · New York

2082
H. Zhou et al.
LETTER
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(7) General Procedure for the Synthesis of 2: Condition A:
A solution of 1a (130 mg, 1.0 mmol) with CuBr2 (450 mg,
2.0 mmol) in 5 mL of CH3CN was stirred at 65 °C for 14 h.
The mixture was then diluted with 30 mL of sat. NH4Cl and
extracted three times with n-hexane. The organic phases
were combined and dried over MgSO4. After evaporation,
the residues were purified via chromatography on silica gel
with n-hexane as the eluent to afford 254 mg (82%) of 2a.
Condition B. A solution of 1a (130 mg, 1.0 mmol) with I2
(510 mg, 2.0 mmol) and CuI (20 mg, 0.1 mmol) in 10 mL of
CH3CN was stirred at 65 °C for 16 h. The mixture was then
diluted with 30 mL of sat. Na2S2O3 and extracted three times
with n-hexane. The organic phases were combined and dried
over MgSO4. After evaporation, the residues were purified
via chromatography on silica gel with n-hexane as the eluent
to afford 349 mg (91%) of 2c.
(8) Selected Data of Compounds 2c and 2g:
(a)Spectral and analytical data for 2c: IR(neat): 1491 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.48–7.46 (m, 2 H), 7.37–
7.31 (m, 3 H), 6.80 (s, 1 H), 3.41–3.38 (t, J = 7.0 Hz, 2 H),
3.16–3.12 (t, J = 7.0 Hz, 2 H). 13C NMR (100 MHz, CDCl3):
d = 137.9, 136.9, 128.6, 128.2, 128.1, 105.0, 49.9, 5.18. MS
(EI): m/z (%) = 384 (21.41) [M+], 257 (12.16), 130(100).
Anal. Calcd for C10H10I2: C, 31.28; H, 2.62. Found: C, 31.55;
H, 2.39.
(b)Spectral and analytical data for 2g: IR(neat): 1504 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.36–7.32 (m, 52 H), 7.28–
7.21 (m, 3 H), 3.80& ndash;3.77 (t, J = 6.8 Hz, 2 H), 2.98–
2.95 (t, J = 6.8 Hz, 2 H), 2.09 (s, 3 H). 13C NMR (100 MHz,
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39.0. MS (EI): m/z (%) = 217 (1.98) [M+ + 3], 216 (16.67)
[M+ + 2], 215 (3.93) [M+ + 1], 214 (25.64) [M+], 129(100).
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Synlett 2003, No. 13, 2080–2082 © Thieme Stuttgart · New York