Stereoselective synthesis of (E)-chloroenynes or (E,E)-chlorodienes starting from a stereoisomeric mixture of 1,2-dichloroethylenes

Article abstract of DOI:10.1016/S0040-4039(02)00412-4

Under palladium or nickel catalysis, a stereomeric mixture 1:1 of (Z) and (E)-1,2-dichloroethylene readily reacts with 1-alkynes, vinyl alanes or vinyl boranes to afford selectively the corresponding (E)-coupling product in good to excellent isolated yiel

Full text of DOI:10.1016/S0040-4039(02)00412-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 3007–3009
Stereoselective synthesis of (E)-chloroenynes or
(E,E)-chlorodienes starting from a stereoisomeric mixture of
1,2-dichloroethylenes
Mouaˆd Alami,* Jean-Franc¸ois Peyrat and Jean-Daniel Brion
Laboratoire de Chimie The´rapeutique associe´ au CNRS (ESA 8076, BIOCIS), Faculte´ de Pharmacie, rue J.B. Cle´ment,
92296 Chaˆtenay Malabry Cedex, France
Received 14 January 2002; accepted 27 February 2002
Abstract—Under palladium or nickel catalysis, a stereomeric mixture 1:1 of (Z) and (E)-1,2-dichloroethylene readily reacts with
1-alkynes, vinyl alanes or vinyl boranes to afford selectively the corresponding (E)-coupling product in good to excellent isolated
yields. The selectivity of this coupling reaction is discussed. © 2002 Elsevier Science Ltd. All rights reserved.
Chloroenynes are quite interesting intermediates which
undergo a variety of synthetically useful transforma-
tions to give unsaturated compounds (e.g. enynes, 1,3-
diynes, chloropolyenes, enediynes and polyenes).1 By
far, the most convenient and simple method for the
synthesis of (E)- and (Z)-chloroenynes is the stereospe-
cific palladium-copper catalyzed cross-coupling reaction
of terminal alkynes with (E)- and (Z)-1,2-
dichloroethylene.2 This procedure is of great interest
since the preparation of organometallic acetylide spe-
cies is not required and it allows a huge range of
functionalized 1-alkynes to couple chemoselectively
under very mild conditions.
therefore interesting to attempt a stereoselective synthe-
sis of chloroenynes by coupling the easily available
mixture of (Z)- and (E)-1,2-dichloroethylene with ter-
minal alkynes in less than molar amounts. The results
of this study are reported now.
As expected, it was found that under suitable condi-
tions,3 the reaction of the commercially available
stereomeric mixture (E/Z:1/1) of 1,2-dichloroethylenes
with hept-1-yne 1a in the presence of Pd(PPh3)4, CuI
and piperidine in benzene afforded selectively the
desired (E)-chloroenyne 2a in good yield (90%) together
with a small amount of the (Z)-isomer (E/Z=90/10).
In order to favour the selective obtention of the (E)-iso-
mer and to avoid the formation of the disubstituted
products, an excess of (Z,E)-1,2-dichloroethylenes is
needed (5 equiv.). It should be noted that this selectivity
was enhanced in favour of the (E)-isomer when
diethylether was used instead of benzene (Table 1, entry
1: E/Z, 98/2 in Et2O instead of C6H6/E/Z, 90/10). The
results presented in Table 1 show that under similar
conditions, various 1-alkynes have been used success-
fully. In most cases, good yields of (E)-chloroenynes 2
were obtained and the reaction was highly stereoselec-
tive: the E-stereomeric purity was higher than 95%,
except in the case of alkyne 1b (entry 2).
During our studies on this palladium-catalyzed cou-
pling reaction, it was observed that the reactivity of
(E)-1,2-dichloroethylene was higher than with the cor-
responding (Z)-isomer when the reaction was per-
formed in piperidine, whereas in the presence of
butylamine, the (Z)-1,2-dichloroethylene was more
reactive than the corresponding (E)-isomer.3 These
results show that when a stereomeric mixture of 1,2-
dichloroethylenes is reacted, the expected selectivity of
the coupling reaction may be a function of the amine
used. Moreover, it was also reported that in the pres-
ence of Pd(PPh3)4, the rate constant of the oxidative
step for (Z)-1,2-dichloroethylene was ca. four times
larger than the (E)-isomer (kZ/kE=3.6).4 It appeared
Next, the cross-coupling reaction of alkyne 1 and a
mixture of (E)- and (Z)-1,2-dichloroethylenes in the
presence of n-butylamine was studied. Under these
conditions, (Z)-1,2-dichloroethylene is expected to be
more reactive than the (E)-isomer3 and therefore the
coupling should produce selectively (Z)-chloroenynes 2.
Keywords: palladium; copper; alkynes; chloroenynes; chlorodienes.
* Corresponding author. Fax: +33(1) 46835828; e-mail: mouad.alami@
cep.u-psud.fr
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00412-4

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M. Alami et al. / Tetrahedron Letters 43 (2002) 3007–3009
Table 1. Stereoselective synthesis of (E)-chloroenynes 2
from a mixture of (Z) and (E)-1,2-dichloroethylenesa
tion metal-catalyzed coupling reaction of bromoolefins
or 1,2-dibromoethylenes with organometallic reagents.5
R
R
1a-i
Cl
Finally, it should be noted that the selectivity observed
in the case of 1,2-dichloroethylenes is not dependent on
the nature of nucleophiles.4 Thus, selective nickel- or
palladium-catalyzed cross-coupling of vinyl alane 5 or
vinyl borane 6 with a mixture of (Z)- and (E)-1,2-
dichloroethylene according to the procedure developed
by Linstrumelle6 and Millar,7 respectively resulted in
Cl
Pd(PPh3)4, CuI, piperidine
Et2O
Cl
2a-i
E/Z> 95/5
excess
E/Z: 50/50
Entry
R
Yieldsb of 2 (%)
E/Zc
1
2
3
4
5
6
7
8
9
a: C5H11
b: C6H5
c: HO(CH2)9
d: HO(Me)2C
e: C5H11CH(OH)
f: Me2NCH2
g: HO(C5H11)CHCH2 71
h: HOCH2CH2
i: HO(C6H5)CH
90
80
85
90
70
75
98/2d
90/10
97/3
98/2
95/5
95/5
98/2
95/5
95/5
the formation of (E,E)-chlorodiene
7 having a
stereomeric purity higher than 95%8.
88
78
a All reactions were performed in the presence of
5 mol% of
Pd(PPh3)4, 10 mol% of CuI, 1,2-dichloroethylene (5 equiv., E/Z:1/
1), piperidine (2 equiv.) in Et2O at room temperature. All of the
reported compounds exhibited spectral data in full accord with
assigned structures.
b Yields are given for pure isolated products.
c Ratios were determined by 1H NMR spectra in the crude reaction
mixture.
The initial step of the mechanism of this reaction is
presumably a coordination step followed by oxidative
addition of (E)- and (Z)-1,2-dichloroethylene to the
low-ligated Pd(0) complex to afford a mixture of s-
vinyl palladium species 3 and 4 (Scheme 1). Despite the
higher reactivity of (Z)-1,2-dichloroethylene than of the
(E)-isomer in the oxidative addition step,4 the overall
coupling reaction is the selective formation of (E)-
chloroenynes 2. It seems reasonable to conclude that
the high selectivity of the reaction is due to the fact that
the resulting s-vinyl palladium species 3 and 4 exhibit
different reactivity toward nucleophiles and that there-
fore the 4-(E)-trans probably undergoes the transmetal-
lation step much faster than 3-(Z)-trans in the catalytic
cycle.
d A 90/10 ratio was obtained when the reaction was performed in
C6H6.
Thus, when performing the coupling with oct-1-yn-3-ol
1e in diethylether in the presence of n-butylamine and
Pd(PPh3)4–CuI, a mixture of (E)- and (Z)-chloroenynes
2e was obtained in which the (E)-isomer is predominat-
ing (entry 10, Table 2). Attempts to improve this selec-
tivity by using other palladium catalysts including
Pd(OAc)2, Pd(dba)2, PdCl2(PPh3)2 either with or with-
out added triphenylphosphine met with no success. The
effect of various amines was also studied and had no
significant change on the selectivity of this reaction as
summarized in Table 2. These results clearly demon-
strate that, whatever the conditions used (nature of the
amine or the catalyst), the (E)-isomer is remarkably
more reactive than the (Z)-isomer. Such trends in selec-
tivity have been already observed in the case of transi-
In summary, we have shown that the coupling reaction
of an excess of stereomeric mixture of (Z)- and (E)-1,2-
dichloroethylenes with a terminal alkyne under appro-
priate conditions affords selectively (E)-chloroenynes in
good yields. Moreover, when a vinyl alane or vinyl
borane was used instead of 1-alkyne, the (E,E)-chloro-
diene was obtained with a high stereomeric purity.
These results show that although the coupling reaction
is cleaner with the pure trans dichloroethylene (avail-
able commercially at Lancaster at a reasonable price), it
can nevertheless be very well carried out with the usual
cis–trans mixture. The observed selectivity may be
assumed to be controlled by the rate of the transmetal-
lation step in the catalytic cycle.
Table 2. Effects of amines on selectivity of the coupling
of 1e with stereoisomeric mixture (1/1) of 1,2-
dichloroethylenea
Entry
Amine
Yield (%)b
E/Zc
10
11
12
13
14
BuNH2
Et3N
Et2NH
iPr2NH
Pyrrolidine
90
84
73
32
65
85/15
82/18
76/24
95/5
92/8
Typical procedure for the preparation of 2c: CuI (20
mmol, 40 mg) was added at room temperature to a
solution of dichloroethylenes (E/Z:1/1, 10 mmol, 670
mL), alkyne 1c (2 mmol, 334 mg), piperidine (4 mmol,
396 mL), and Pd(PPh3)4, (0.1 mmol, 116 mg) in Et2O (5
mL). After consumption of the starting material (4 to 6
a All reactions were performed in the presence of
5
mol% of
Pd(PPh3)4, 10 mol% of CuI, 1,2-dichloroethylene (5 equiv., E/Z:1/
1), amine (2 equiv.) in diethylether at room temperature.
b Yields of isolated product.
c Ratios were determined by 1H NMR spectra in the crude reaction
mixture.

M. Alami et al. / Tetrahedron Letters 43 (2002) 3007–3009
3009
Cl
Cl
E/Z
Cl
L
L
fast
Nu
Cl
Pd
Cl
Pd
Cl
Pd
Cl
Cl
Nu
PdL4
L
L
L
slow
L
Cl
3-(Z)-trans
Nu
3-(Z)-cis
ClCH=CHCl, Pd(0)
Cl
L
Cl
Cl fast
L
Cl
4-(E)-trans
L
Nu
Nu
Pd
Pd
Pd
Nu
Cl
fast
L
L
L
4-(E)-cis
Scheme 1.
h), the dark brown reaction mixture is concentrated in
vacuo. The ratio E/Z is determined by H NMR spec-
2. (a) Ratovelomanana, V.; Linstrumelle, G. Tetrahedron
Lett. 1981, 22, 315–318; (b) Alami, M.; Gueugnot, S.;
Domingues, E.; Linstrumelle, G. Tetrahedron 1995, 51,
1209–1220.
3. Chemin, D.; Linstrumelle, G. Tetrahedron 1994, 50, 5335–
5344.
1
tra in the crude reaction mixture. Purification by flash
chromatography on silica gel (AcOEt/cyclohexane: 40/
1
60) gave 390 mg (85%) of 2c (E/Z: 97/3). H NMR
(200 MHz, CDCl3): l 6.42 (d, J=13.4 Hz, 1H), 5.90
(dt, J=13.4 and 2.2 Hz, 1H), 3.63 (t, J=6.7 Hz, 2H),
2.28 (td, J=6.9 and 2.2 Hz, 2H), 1.56–1.49 (m, 4H),
1.30 (m, 10H). 13C NMR (50 MHz, CDCl3): l 128.6,
114.3, 93.5, 75.6, 63.0, 32.7, 29.3 (×2), 29.0, 28.8, 28.4,
25.7, 19.3.
4. Amatore, C.; Azzabi, M.; Jutand, A. J. Am. Chem. Soc.
1991, 113, 1670–1677.
5. For the reactivity of bromoolefins, see: (a) Fauvarque, J.
F.; Jutand, A. J. Organomet. Chem. 1981, 209, 109–111;
(b) Rossi, R.; Carpita, A. Tetrahedron Lett. 1986, 27,
2529–2532; (c) Carpita, A.; Rossi, R.; Scamuzzi, B. Tetra-
hedron Lett. 1989, 30, 2699–2702. For the reactivity of
1,2-dibromoethylenes, see: (d) Carpita, A.; Rossi, R. Tet-
rahedron Lett. 1986, 27, 4351; (e) Andreini, B. P.; Benetti,
M.; Carpita, A.; Rossi, R. Tetrahedron 1987, 43, 4591–
4600; (f) McNaughton-Smith, G. A.; Taylor, R. J. K.
Tetrahedron 1996, 52, 2113–2124.
Acknowledgements
The CNRS is gratefully thanked for support of this
research. We would like to thank Guillaume Sassi for
carrying out some experiments.
6. Ratovelomanana, V.; Linstrumelle, G. Tetrahedron Lett.
1984, 25, 6001–6004.
7. Chen, C.; Millar, J. G. Synthesis 2000, 113–118.
8. Stereomeric puriy of 7 was determined by GC analysis
(capillary column SGE 50 QC 2/BP5 0.25). The spectral
properties of 7 were in good agreement with those
reported in the literature, see: Ref. 2b.
References
1. For a review, see: Alami, M.; Peyrat, J. F.; Brion, J. D.
Synthesis 2000, 1499–1518.