The effect of vicinyl olefinic halogens on cross-coupling reactions using Pd(0) catalysis

Article abstract of DOI:10.1016/j.tet.2004.08.006

(trans) 1-Chloro-2-iodoethylene (3), (trans) 1-bromo-2-iodoethylene (4), (trans) 1,2-diiodoethylene (5) and (cis and trans) 1,2-dibromoethylene (11) were reacted under Suzuki, Sonogashira and Negishi cross-coupling conditions using Pd catalysis to obtain mono coupled products. Only olefin template 3 provided the desired coupling products reliably under all reaction conditions. Compound 5 did not provide cross coupled products under any of the reaction conditions used. The Negishi reaction was the only one that worked for templates 4 and 11. Studies indicate that oxidative addition of the most reactive carbon-halogen bond to Pd(0) is followed by elimination of the second halide, when the second halide is a bromide or an iodide. This happens to a much lesser degree when the second halogen is a chloride. Graphical Abstract.

Full text of DOI:10.1016/j.tet.2004.08.006

Tetrahedron 60 (2004) 9453–9461
The effect of vicinyl olefinic halogens on cross-coupling reactions
using Pd(0) catalysis
*
Michael G. Organ, Haleh Ghasemi and Cory Valente
The Department of Chemistry, York University, 4700 Keele Street, Toronto, Ont., Canada M3J 1P3
Received 4 May 2004; revised 6 July 2004; accepted 3 August 2004
Available online 3 September 2004
Abstract—(trans) 1-Chloro-2-iodoethylene (3), (trans) 1-bromo-2-iodoethylene (4), (trans) 1,2-diiodoethylene (5) and (cis and trans) 1,2-
dibromoethylene (11) were reacted under Suzuki, Sonogashira and Negishi cross-coupling conditions using Pd catalysis to obtain mono
coupled products. Only olefin template 3 provided the desired coupling products reliably under all reaction conditions. Compound 5 did not
provide cross coupled products under any of the reaction conditions used. The Negishi reaction was the only one that worked for templates 4
and 11. Studies indicate that oxidative addition of the most reactive carbon–halogen bond to Pd(0) is followed by elimination of the second
halide, when the second halide is a bromide or an iodide. This happens to a much lesser degree when the second halogen is a chloride.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
1-bromo-2-iodoethylene (4) employed in the coupling of
organozinc reagents (i.e., the Negishi coupling).6 His group
has demonstrated remarkable selectivity with these coup-
lings at the iodide site of 4, after which they have then gone
on to couple the bromide site with a different organozinc
reagent to create unsymmetrical olefins. The benefit of using
template 4 is that the bromide is quite reactive toward
oxidative addition, once the iodide has reacted already.
However, organozinc couplings are much more facile than
other analogous transformations such as the Stille, Suzuki,
or Sonogashira reactions.
We,1 and others,2 have been developing small, polyfunc-
tional olefin building blocks (templates) for use in modular
organic synthesis using transition metal catalysis. The
premise here is to use the template as a linchpin to ‘stitch’
two or more pieces (that have been prepared separately) of
the target molecule together, thus making the synthesis
convergent and highly efficient. In many cases, the
functional groups are the same, such as cis 1,2-dichloro-
ethylene (1a)2a,b or trans 1,2-dichloroethylene (1b)2c and
trans 1,2-di(trialkylstannyl)ethylenes (2).2f,g However, such
building blocks frequently suffer from poor selectivity in
oxidative addition to metals such as Pd with substrates like
13 or metal–metal exchange with substrates resembling 2,2f
resulting in significant bis coupling. Only with sterically
differentiated functional groups is there significant selectiv-
ity, such as is seen with geminal vinyl dibromides (e.g., 6) in
cross-coupling reactions.4 It is for this reason that we have
focused on the preparation of olefin templates that possess
electronically differentiated oxidative addition or metal–
metal exchange partners.
Many Negishi couplings are performed at or below room
temperature due to the relative ease of the Zn/Pd exchange.
Unfortunately, as reactions are heated (as would be the case
for the aforementioned transformations), the amount of
unwanted bromide oxidative addition, i.e. over coupling, in
the first step will necessarily increase due to simple reaction
kinetics. We were attracted to using 3 because we believed
that we could achieve absolute selectivity in oxidative
addition to the iodide, regardless of the reaction conditions.
Activation of the remaining chloride in the subsequent
coupling will be more sluggish, which, of course, is the
reason for the pronounced selectivity in the first oxidative
addition. However, there are many new highly reactive
catalysts available to alleviate this concern if necessary.7
We have demonstrated previously the selectivity and
synthetic usefulness of trans 1-chloro-2-iodoethylene (3)
as an effective olefin template to prepare trans 1,2-
disubstituted olefinic products.1,5 Negishi and his co-
workers have demonstrated also similar utility of trans
We have illustrated the use of template 3 as a lynch pin in
the synthesis of bupleurynol5a and (13E,15E,18Z,20Z)-1-
hydroxypentacosa-13,15,18,20-tetraen-11-yn-4-one1-acetate
(8).5b During the synthesis of the later, we discovered that
not only was 3 a selective and useful template, but in fact it
Keywords: Palladium; Catalysis; Cross coupling.
* Corresponding author. Tel.: C1-4167365313; fax: C1-4167365936;
e-mail: organ@yorku.ca
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.08.006

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M. G. Organ et al. / Tetrahedron 60 (2004) 9453–9461
was the only dihalo template that worked in the final
coupling sequence outlined in Figure 1. For instance, trans
1,2-diiodoethylene (5) did not appear to react at all and the
dimer of the boronic ester 9 was the only product isolated.
Further, we found in a separate study that while both of the
geminal dibromides on 6 could be reacted sequentially in
Suzuki reactions, the vicinyl bromides on 7 appeared not to
participate at all in these reactions. These results encouraged
us to look more closely into the effect of vicinyl halides on
oxidative addition and subsequent coupling with a variety of
organometallic partners.
was the boronic acid homo-coupled product 15 that was
minimal in reactions involving 3 indicating that this process,
presumably initiated by Pd(II), was slow relative to the
anticipated coupling.
In stark contrast, Suzuki couplings involving templates 4, 5
or 11 never provided the anticipated mono coupled products
13 (see Table 1). In every case, the dominant products were
the homo-coupled products 15 demonstrating that coupling
of the first halide on the templates appeared now to be a
slow process and not competitive with the dimerization of
boronic acids 12. That said, the yields of the dimerization
products were only about 10%. This may indicate that the
catalyst is not long lived in solution or that it is not readily
re-oxidized to Pd(II) to continue the boronic acid dimeriza-
tion process. It was observed visually that reactions with 3
remained light in colour for some time while reactions with
the other templates, especially 5 became almost black
(although not ‘blacked out’) within minutes. One other
interesting observation with these reactions is the presence
of the di coupled adduct 14 in the product mixture in
reactions not involving template 3, despite there being none
of compound 13 observed. This implies that while coupling
of the first halide is slow with templates 4, 5, and 11,
coupling of the remaining halide once the first one is gone is
not necessarily so.
2. Results and discussion
An array of experiments using Pd catalysis with templates 3,
4, 5 and 11 (as a 50:50 mixture of cis and trans isomers) and
boron-, zinc-, and copper-based organometallic coupling
partners was conducted and the results are outlined in the
following subsections.
2.1. Suzuki coupling reactions
Suzuki couplings were conducted between templates 3, 4, 5,
and 11 and a number of aryl- (12a–c) and alkenyl- (12d and
12e) boronic acids under identical reaction conditions
(Scheme 1, Table 1). When the couplings were performed
with template 3 at rt, there was no discernable activity.
However, when heated, all couplings proceeded until the
template was consumed and the dominant products were the
expected mono coupled compounds 13 (Table 1, entries 1,
5, 9, 13 and 16).
2.2. Sonogashira coupling reactions
The same four templates were then subjected to coupling
with the copper acetylide of hexyne (16), which is a simple
and very suitable coupling partner for such reactions1
(Scheme 2, Table 2). The results obtained from these
Sonogashira reactions were similar to those seen in the
Suzuki couplings. When compound 3 was used, the mono
coupled enyne 17 was produced, albeit in moderate
recovery (Table 2, entry 1), whereas it was not detected at
all in the product mixtures from templates 4, 5, and 11
(Table 2, entries 2–4). The formation of dimer 19 certainly
In some cases, there was over coupling that gave rise to 14
(Table 1, entries 1 and 9), but this was eliminated by simply
halting the reactions sooner. That is, all reactions were run
for the same time period with a slight excess of boronic acid
but if couplings were monitored and halted when 3 was
consumed, 13 was the sole product. The only other product
Figure 1. Structure of selected olefin templates and the use of template 3 in the synthesis of (13E,15E,18Z,20Z)-1-hydroxypentacosa-13,15,18,20-tetraen-11-
yn-4-one 1-acetate (8).

M. G. Organ et al. / Tetrahedron 60 (2004) 9453–9461
9455
Scheme 1.
Scheme 2.
Table 2. Sonogashira reaction between templates 3, 4, 5 and 11 with 1-
hexyne
is not a surprise as it is a common side product initiated by
Cu in Sonogashira couplings.3
Entry
Template
Yield (%)a
1
2
3
4
3
4
5
11
42 (17a)
62 (19)
51 (19)
42 (19)
2.3. Negishi cross-coupling reaction
While template 4 failed to provide the simple mono coupled
products under Sonogashira or Suzuki cross-coupling
conditions, it could be reacted selectively using Negishi
coupling conditions (Scheme 3, Table 2, entries 2 and 5).
This is consistent with results communicated by Negishi.6
As seen with Suzuki and Sonogashira results, template 3
also smoothly and selectively mono coupled. However,
template 5 did not appear to react and the dimer products 19
and 23 were the sole products (Table 3, entries 3 and 6). It
had been reported already that template 11 undergoes
Negishi coupling with aryl zinc reagents so these
a
Yields were determined following flash chromatography.
experiments were not repeated here.9 It is interesting to
note that the authors report that only the trans 1,2-
dibromoethylene isomer reacts in their coupling exper-
iments and the cis is usually recovered intact.
We are also doing work with trifunctionalized templates in
an attempt to devise convergent and general approaches to
Table 1. Reaction conditions and results from Suzuki coupling with a variety of boronic acids and olefin templates 3, 4, 5 and 11
Entry
Template
Boronic acid
Ratio of 13, 14 and 15a
Yield (%) of
13C14C15
1
2
3
4
5
6
7
8
3
4
5
11
3
4
5
11
3
4
5
11
3
4
5
3
12a
12a
12a
12a
12b
12b
12b
12b
12cb
12cb
12cb
12cb
12d
12d
12d
12e
12e
12e
86 (13a)
0
0
0
83 (13b)
0
3 (14a)
11 (14a)
10 (14a)
34 (14a)
0 (14b)
3 (14b)
5 (14b)
36 (14b)
7 (14c)
0 (14c)
45 (14c)
10 (14c)
0 (14d)
0 (14d)
10 (14d)
0 (14e)
45 (14e)
5 (14e)
11 (15a)
89(15a)
90 (15a)
66 (15a)
17 (15b)
97 (15b)
95 (15b)
64 (15b)
15 (15c)
100 (15c)
55 (15c)
90 (15c)
9 (15d)
80
10
10
11
62
10
10
20
26
10
10
10
54
10
10
51
108
10
0
0
78 (13c)
0
9
10
11
12
13
14
15
16
17
18
0
0
91 (13d)
0
0
95 (13e)
0
0
100 (15d)
90 (15d)
5 (15e)
55 (15e)
95 (15e)
4
5
a
Compounds 13 were readily isolable from 14 and 15 by flash chromatography. However, the latter two compounds were inseparable and relative ratios
were determined by 1H NMR spectroscopy.
4-Acetyl phenol was a major byproduct formed in this reaction.
b

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M. G. Organ et al. / Tetrahedron 60 (2004) 9453–9461
Scheme 3.
trisubstituted olefinic products. One result stood out, given
the results described above. Treatment of tribromoethyelene
(24) with Suzuki conditions smoothly led to the mono cross
coupled product 26 in good recovery (Scheme 4). Yet,
attempts to couple one of the remaining bromides, even
under Negishi conditions, failed and the product of apparent
elimination and homo coupling (27) prevailed along with
the simple homo-coupled product of phenylzinc iodide
(15b). Thus, geminal bromides appear to have an activating
effect on each other that overrides the presence of a vicinyl
bromide that appears to suppress the ‘normal’ catalytic
cycle associated with cross-coupling from all of the
previous results presented (vide supra).
the most reactive halide bond on 4, 5, or 11 could be
happening, but the superior leaving group ability of the
remaining Br or I, relative to Cl, would lead to elimination
of that halide producing acetylene, thus maintaining the
oxidation state of Pd (i.e., (PPh3)2PdXY, where X and YZ
Br or I).
To address these questions, we performed the same series of
coupling reactions, as discussed above, with E-4,5-dihalo-4-
octenes 28a and 28b. Assuming that no significant steric or
electronic perturbation would arise from the addition of the
two propyl chains, we were hoping that these substrates
would mimic 3 and 11, the difference being that there was
no possible HX elimination across the olefin. Thus, any
alkyne formation would have to be taking place via initial
oxidative addition of the C–X bond to Pd. Unfortunately
however, as we see in Scheme 5, the alkyl groups did exert a
significant effect. We did not observe much of the
anticipated mono- or di cross coupled products under
Suzuki, Sonogashira, or Negishi conditions with 28a, given
that 3 coupled very well under all of these conditions (vide
supra). Of interest though, we observed production of
4-octyne (31) suggesting that, while there was no observed
cross-coupling, there was oxidative addition taking place,
most notably with 28b. Although there are only the three
representative reactions given, many more examples were
conducted but the results were essentially identical.
It has been known for some time that all of the chlorides on
polychloroethyelenes (i.e., vicinyl chorides, even tetra-
chloroethylene) can be cross-coupled successively with no
apparent trouble.12 However, the present results clearly
show that when chloride is replaced by bromide, or iodide
especially, that cross-coupling becomes significantly
impaired. Of course, the fact that there are little, or none
of the cross coupled products with templates 4, 5, or 11
(other than Negishi coupling) does not necessarily mean that
oxidative insertion of the C–X bond does not occur. Rather,
it could be that addition is taking place, but other events are
now competitive with the metal–metal exchange that is
required to give the reductive elimination product. The
presence of 27 in the reaction of 26 suggests that one of two
likely explanations could be operative in this case and
therefore possibly applicable to the dihaloethylenes
examples. First, the basic reaction conditions could induce
elimination of the elements of HBr to yield 1-bromo-2-
phenylacetylene that is dimerizing in the presence of Pd. In
the case of substrates 4, 5, or 11, such elimination products
would be highly volatile, thus no coupling products would
be observed or recovered. Conversely, oxidative addition of
Table 3. Negishi cross-coupling reaction between templates 3, 4, and 5 and
alkynes 16 or 20
Entry
Template
Alkyne
Yield (%)
1
2
3
4
5
6
3
4
5
3
4
5
16
16
16
20
20
20
68 (17a)10
72 (17b)12
23 (19)
59 (21a)10
68 (21b)11
16 (23)
Scheme 4.

M. G. Organ et al. / Tetrahedron 60 (2004) 9453–9461
9457
Scheme 5.
For clarity, it should be noted that ratios were calculated in
such a way that the first four product mixture components
added up to 100%, being that they all are derived from either
28a or 28b. The simple dimer product 32 was listed as a
molar ratio relative to the other products, although there was
1.1 equiv of it used in each experiment. Alkyne formation
occurred to the greatest extent in the Suzuki reactions,
which are arguably the harshest and most basic conditions
(assuming that organozinc reagents are relatively non
basic). The next issue to be addressed was the effect that
the basic conditions might be having on this transformation.
Hence, two additional sets of control experiments were
carried out (Scheme 6).
catalyst, i.e. without boronic acid or base, a small amount of
conversion was observed with 28a. In the presence of both
base and catalyst, but no boronic acid, significant alkyne was
formedinthe caseof28a, although this was not mirrored in the
case of 28b. However, when 28b was reacted with a
stoichiometric amount of Pd, a steady conversion to 31 was
observed over 6 h. Although the control experiments with just
base showed no direct involvement of hydroxide in the
elimination, when it was present with stoichiometric Pd the
rate of elimination significantly increased. It may be possible
that the base plays a role in reducing the Pd(II) generated in the
oxidative addition/elimination, or that it is activating the
catalyst to oxidative addition, or perhaps both.
It is feasible that the alkyne could be formed via an
intermediate allenyl species formed by Pd activation of one
of the allylic hydrogen atoms. To explore this possibility,
E-dibromostilbene was reacted under Suzuki conditions.
While no cross-coupling was observed, diphenyl acetylene
(34) was obtained in good recovery demonstrating that it is
not necessary to invoke allenyl intermediates to account for
the X–Y eliminations observed in this report (Scheme 7).
Treatment of 28a or 28b with just base, i.e., without boronic
acid or catalyst, did not lead to any significant conversion to
31, which confirms that elimination is not a simple base-
mediated process. When the reaction was run with just
Thus, it appears that the reactivity profile of 1,2-dihalo-
alkenes toward Pd-catalyzed cross-coupling reactions is
quite variable and substrate specific. In general, when the
alkene substrate has chloride on it as one of the halides,
cross-coupling seems to proceed more smoothly and
reliably. When dibromo alkenes are the substrates for
cross-coupling, only Negishi coupling seems to work and
then only the trans 1,2-dibromoethylene has been reported
to couple.9 Interesting though, a recent report by Rathmore
and co-workers shows that E 4,5-dibromo-4-octene (com-
pound 28b used in this study which gave very little cross
coupled product) gave nearly quantitative cross-coupling at
both sites when reacted with pentamethylphenyl magnesium
bromide!13 Three additional pieces of information can be
gleaned from their study. Mono coupled product was never
seen. Even with limiting Grignard reagent, only the di
coupled product was isolated, which was also observed in
the present study in the Suzuki reaction with templates 4, 5
Scheme 6.

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M. G. Organ et al. / Tetrahedron 60 (2004) 9453–9461
Scheme 7.
and 11. Second, the only aromatic Grignard reagent that led
to coupled product had two ortho methyl groups flanking the
metal center, which seems counterintuitive. For example,
4-methylphenyl magnesium bromide led primarily to the
alkyne elimination product (31) and the homo-coupled
Grignard reagent. Finally, only the Z olefin product was
isolated (from the E dibromide) indicating that the
mechanism leading to the formation of the final product is
clearly far more involved than presently accepted cross-
coupling mechanistic dogma can explain.
(29.01 mmol) in 40 mL of HBr (48%) at 0 8C, after which
the temperature was then brought to rt and stirring continued
for 5 h. The reaction mixture was extracted with pentane
(2!) and the pooled organic layers washed successively
with brine and aqueous Na2S2O3. The organic layer was
dried over anhydrous Na2SO4 and concentrated in vacuo to
obtain 3.8 g of 4 (56% yield) as a colorless liquid. 1H NMR:
d 6.88 (d, JZ13.6 Hz, 1H), 6.76 (d, JZ13.6 Hz, 1H); 13C
NMR: d 110.1 (K), 76.8 (K). NMR data were consistent
with literature values.14
From evidence collected in the present report, it appears that
Pd catalyzed reactions that lead to elimination of the
dihalide are not base induced. Rather, oxidative addition
appears to take place followed by subsequent elimination of
good leaving groups, such as bromide or iodide. In the case
of reactions catalytic in Pd, the elimination does not proceed
too far which might be due to the lack of an efficient
reduction pathway to regenerate Pd(0) following elimin-
ation. It could be interpreted that metal–metal exchange is
now the rate-determining step in these transformations,
which allows elimination to become a strongly competing
process. Reactions involving 28a (E 4-chloro-5-iodo-4-
octene) clearly show a strong dependence on the substrate’s
structure, in addition to the structure of the metal coupling
partner as shown by Rathmore. While 3 coupled very nicely
in all of the reactions employed, 28a did not which might
imply that the increased steric hinderence of the propyl
group has slowed metal–metal exchange enough to make
chloride elimination now the kinetically favored event.
3.2. General procedure for Suzuki cross-coupling
reactions
To a solution of boronic acid 12 (1.1 equiv) in THF was
added a solution of 1 M KOH (2.1 equiv), (PPh3)4Pd
(0.05 equiv) and the olefin template (i.e., 3, 4, 5, or 11;
1.0 equiv). The reaction mixture was stirred at 60 8C for the
designated time or it was halted when the reaction was
judged complete by TLC analysis. Solid Na2SO3 was added
to the reaction mixture and the suspension was stirred for
5 min. The solvent was removed in vacuo and the crude
product was purified by column chromatography on silica
gel.
3.2.1. 1-[(1E)-2-Chloroethenyl]-4-methoxy benzene (13a).
The reaction mixture contained 100 mg of 12a (1.1 equiv,
0.66 mmol), 2 mL of THF, 1.2 mL of KOH (2.1 equiv,
0.68 mmol), 37 mg of (PPh3)4Pd (0.05 equiv, 0.032 mmol)
and 113 mg of 3 (1.0 equiv, 0.60 mmol). The crude product
was purified by column chromatography (RfZ0.9; 5% ether
in pentane) to obtain 81 mg of 13a (80% yield) along with a
1
3. Experimental
3.1. General
small amount of 14a and 15a. H NMR: d 7.23 (d, JZ
8.8 Hz, 2H), 6.86 (d, JZ8.8 Hz, 2H), 6.78 (d, JZ13.6 Hz,
1H), 6.50 (d, JZ13.6 Hz, 1H), 3.82 (s, 3H); 13C NMR: d
159.6 (C), 134.9 (K), 127.7 (C), 127.6 (K), 117.5 (K),
112.9 (K), 57.7 (K). NMR data were consistent with
literature values.15
All reactions were performed in a flame dried round bottom
flask equipped with magnetic stir bar. Reactions were
carried out under positive pressure of nitrogen gas that had
been pre dried through a Drieritew column. Tetrahydrofuran
3.2.2. [(1E)-2-Chloroethenyl] benzene (13b). The reaction
mixture contained 100 mg of 12b (1.1 equiv, 0.82 mmol),
2 mL THF, KOH (2.1 equiv, 1.55 mmol), 43 mg of
(PPh3)4Pd (0.05 equiv, 0.040 mmol) and 140 mg of 3
(1.0 equiv, 0.74 mmol). The crude product was purified by
column chromatography (RfZ0.95; pentane) to obtain
63 mg of 13b (62% yield) along with a small amount of
14b and 15b. 1H NMR: d 7.31 (m, 5H), 6.84 (d, JZ13.6 Hz,
1H), 6.65 (d, JZ13.6 Hz, 1H); 13C NMR: d 135.8 (K),
133.3 (K), 128.8 (K), 128.2 (K), 126.1 (K), 118.7 (K).
NMR data were consistent with literature values.16
1
was freshly distilled from sodium benzophenone ketyl. H
NMR and 13C NMR spectra were recorded using a Bruker
Avance 400 MHz NMR spectrometer (100 MHz for car-
bon). All 1H NMR and 13C NMR spectra were referenced to
7.26 and 77.23 ppm for chloroform solvent, respectively.
For 13C NMR APT spectra, positive peaks (indicated by C)
represent quarternary carbons as well as carbon atoms
attached to an even number of protons. Negative peaks
(indicated by K) represent carbon atoms attached to an odd
number of protons.
3.1.1. (E)-1-Bromo-2-iodoethene (4). Acetylene gas was
bubbled continuously for 1 h through a solution of 6 g of IBr
3.2.3. 1-[4-(E)(2-Chloroethenyl)phenyl] ethanone (13c).
The reaction mixture contained 110 mg of 12c (1.1 equiv,

M. G. Organ et al. / Tetrahedron 60 (2004) 9453–9461
9459
0.67 mmol), 2 mL THF, KOH (2.1 equiv, 1.22 mmol),
35 mg of (PPh3)4Pd (0.05 equiv, 0.030 mmol) and 115 mg
of 3 (1.0 equiv, 0.61 mmol). The crude product was purified
by column chromatography (RfZ0.9; 5% diethyl ether in
pentane) to obtain 28 mg of 13c (26% yield) along with a
The resultant Grignard was added to a second flask
containing the alkyne (i.e., 16 or 20; 0.9 equiv) and this
was stirred at rt for 3 h. To this was added a solution of
ZnCl2 in THF (1.2 equiv) after which the mixture was
stirred at rt for 30 min. At this time, the template (i.e., 3, 4,
or 5; 1.0 equiv) and (PPh3)4Pd (0.02 equiv) were added and
stirring continued for 10 h. The mixture was then passed
through a short silica gel pad and the filtrate concentrated in
vacuo. The crude product was purified by column
chromatography.
1
small amount of 14c and 15c. H NMR: d 7.92 (d, JZ
8.4 Hz, 2H), 7.38 (d, JZ8.4 Hz, 2H), 6.88 (d, JZ13.6 Hz,
1H), 6.79 (d, JZ13.6 Hz, 1H), 2.60 (s, 3H); 13C NMR: d
202.2 (C), 139.3 (C), 136.6 (C), 132.9 (K), 128.2 (K),
126.2 (K), 122.0 (K), 25.1 (K); HRMS calcd for
C10H9OCl 180.0342, found 180.0316.
3.3.1. (1E)-1-Chloro-3-yn-1-octen (17a). The reaction
mixture contained 18 mg of Mg (1.4 equiv, 0.740 mmol),
1.6 mL of THF, 70 mg of bromoethane (1.2 equiv,
0.64 mmol), 40 mg of 16 (0.9 equiv, 0.48 mmol, 56 mL),
0.64 mL of ZnCl2 (1.2 equiv, 0.64 mmol, 1 M solution in
THF), 100 mg of 3 (1.0 equiv, 0.53 mmol) and 12 mg of
(PPh3)4Pd (0.02 equiv, 0.01 mmol). The crude product was
purified by column chromatography (RfZ0.85; 2% ether in
pentane) to provide 51 mg of 17a (68% yield).6
3.2.4. [(1E,3E)-4-Chloro-1,3-butadienyl] benzene (13d).
The reaction mixture contained 100 mg of 12d (1.1 equiv,
0.68 mmol), 2 mL THF, KOH solution (2.1 equiv,
1.29 mmol), 35 mg of (PPh3)4Pd (0.05 equiv, 0.030 mmol)
and 116 mg of 3 (1.0 equiv, 0.62 mmol). The crude product
was purified by column chromatography (RfZ0.9; pentane)
to obtain 54 mg of 13d (54% yield) along with a small
amount of 14d and 15d. 1H NMR: d 7.35 (m, 5H), 6.67 (m,
3H), 6.33 (d, JZ12.8 Hz, 1H); 13C NMR: d 136.7 (C),
133.9 (K), 133.3 (K), 128.7 (K), 128.0 (K), 126.5 (K),
124.7 (K), 121.0 (K). NMR data were consistent with
literature values.17
3.3.2. (1E)-1-Bromo-3-yn-1-octen (17b). The reaction
mixture contained 30 mg of Mg (1.4 equiv, 1.20 mmol),
2 mL of THF, 112 mg of bromoethane (1.2 equiv,
1.63 mmol), 64 mg of 16 (0.9 equiv, 0.772 mmol, 90 mL),
1.03 mL of ZnCl2 (1.2 equiv, 1.03 mmol, 1 M solution in
THF), 200 mg of 4 (1.0 equiv, 0.86 mmol) and 20 mg of
(PPh3)4Pd (0.02 equiv, 0.02 mmol). The crude product was
purified by column chromatography (RfZ0.85; 2% ether in
pentane) to provide 115 mg of 17b (72% yield). 1H NMR: d
6.57 (d, JZ14.4 Hz, 1H), 6.20 (d, JZ14.4 Hz, 1H), 2.27 (t,
JZ7.6 Hz, 2H), 1.51 (m, 2H), 1.42 (m, 2H), 0.92 (t, JZ
7.6 Hz, 3H); 13C NMR: d 119.4 (K), 118.3 (K), 93.2 (C),
77.4 (C), 30.5 (C), 22.0 (C), 19.1 (C), 14.9 (K). NMR
data were consistent with literature values.20
3.2.5. (1E,3E)-1-Chloro-1,3-decadiene (13e). The reaction
mixture contained 50 mg of 12e (1.1 equiv, 0.32 mmol),
1.2 mL THF, KOH solution (2.1 equiv, 0.61 mmol), 17 mg
of (PPh3)4Pd (0.05 equiv, 0.014 mmol) and 55 mg of 3
(1.0 equiv, 0.29 mmol). The crude product was purified by
column chromatography (RfZ0.9; 2% diethyl ether in
pentane) to obtain 26 mg of 13e (51% yield) along with a
small amount of 14e and 15e. 1H NMR: d 6.42 (dd, JZ13.2,
10.8 Hz, 1H), 6.08 (d, JZ13.2 Hz, 1H), 5.97 (m, 1H), 5.70
(m, 1H), 2.07 (m, 4H), 1.36 (m, 6H), 0.89 (t, JZ6.8 Hz,
3H); 13C NMR: d 136.2 (K), 133.8 (K), 127.0 (K), 117.3
(K), 32.6 (C), 31.8 (C), 29.4 (C), 28.9 (C), 22.8 (C),
19.2 (K). NMR data were consistent with literature
values.18
3.3.3. [(3E)-4-Chloro-3-buten-1-ynyl] trimethyl silane
(21a). The reaction mixture contained 30 mg of Mg
(1.4 equiv, 1.20 mmol), 2 mL of THF, 112 mg of bromo-
ethane (1.2 equiv, 1.63 mmol), 75 mg of 20 (0.9 equiv,
0.77 mmol), 1.03 mL of ZnCl2 (1.2 equiv, 1.03 mmol, 1 M
solution in THF), 162 mg of 3 (1.0 equiv, 0.86 mmol) and
20 mg of (PPh3)4Pd (0.02 equiv, 0.02 mmol). The crude
product was purified by column chromatography (RfZ0.90;
2% ether in pentane) to provide 80 mg of 21a (59% yield).
1H NMR: d 6.58 (d, JZ13.6 Hz, 1H), 5.95 (d, JZ13.6 Hz,
1H), 0.20 (s, 9H); 13C NMR: d 131.4 (K), 113.7 (K), 99.4
(C), 97.5 (C), K0.3 (K). NMR data were consistent with
literature values.21
3.2.6. (1E)-1-Chloro-3-yn-1-octen (17a). To a solution of 3
(1.0 equiv, 0.53 mmol) in 2 mL THF was added 65 mg of 16
(1.5 equiv, 0.80 mmol), 0.1 mL piperidine (2.0 equiv,
1.1 mmol), 31 mg of (PPh3)4Pd (0.05 equiv, 0.026 mmol),
5 mg of CuI (0.05 equiv, 0.03 mmol) and the reaction
mixture was stirred at 60 8C for 5 h. When the reaction was
judged complete, it was quenched with saturated
ammonium chloride and the organic layer was separated.
The aqueous layer was extracted with diethyl ether and the
combined organic layers were dried over anhydrous
MgSO4. After filtering, the solvent was removed in vacuo
and the crude product was purified by column chromatog-
raphy (RfZ0.8; 5% ether in pentane) to provide 35 mg of
17a (42% yield) along with a trace amount of 18. 1H NMR:
d 6.41 (d, JZ13.6 Hz, 1H), 5.94 (d, JZ13.6 Hz, 1H), 2.28
(t, JZ6.2 Hz, 2H), 1.59 (m, 4H), 0.91 (t, JZ6.4 Hz, 3H).
NMR data were consistent with literature values.19
3.3.4. [(3E)-4-Bromo-3-buten-1-ynyl] trimethyl silane
(21b). The reaction mixture contained 30 mg of Mg
(1.4 equiv, 1.20 mmol), 2 mL of THF, 112 mg of bromo-
ethane (1.2 equiv, 1.63 mmol), 75 mg of 20 (0.9 equiv,
0.77 mmol), 1.03 mL of ZnCl2 (1.2 equiv, 1.03 mmol, 1 M
solution in THF), 200 mg of 4 (1.0 equiv, 0.86 mmol) and
20 mg of (PPh3)4Pd (0.02 equiv, 0.02 mmol). The crude
product was purified by column chromatography (RfZ0.90;
2% ether in pentane) to provide 118 mg of 21b (68% yield).
1H NMR: d 6.74 (d, JZ14.0 Hz, 1H), 6.22 (d, JZ14.0 Hz,
1H), 0.19 (s, 9H); 13C NMR: d 120.0 (K), 118.3 (K), 101.0
(C), 97.4 (C), 0.0 (K). NMR data were consistent with
literature values.22
3.3. General procedure for Negishi cross-coupling
reactions
To a suspension of Mg (1.4 equiv) in THF was added
bromoethane (1.2 equiv) and this was stirred at rt for 2 h.

9460
M. G. Organ et al. / Tetrahedron 60 (2004) 9453–9461
3.3.5. (cis)-a,b-Dibromostyrene (26). To a solution of 24
(1.0 equiv, 0.43 mmol, 113 mg) and Pd(PPh3)4 (0.07 equiv,
0.03 mmol, 35 mg) in 2.5 mL of THF was added 12b
(1.8 equiv, 0.75 mmol, 91 mg), CsF (3.3 equiv, 1.40 mmol,
213 mg) and 0.2 mL of water. After refluxing for 22 h, the
mixture was cooled to rt and 5 mL of water was added. The
layers were separated and the aqueous layer extracted with
ether (3!). The combined organic extracts were dried with
anhydrous MgSO4 and the solvent removed in vacuo. The
resulting crude product was purified by column chromato-
graphy (RfZ0.45; in pentane) providing 87 mg of 26 (78%
20.9 (C), 15.1 (K). Spectra were consistent with literature
data.26
3.3.9. (E)-1,2-Dibromo-1,2-diphenylethene (33). To a
solution of 0.3 g of diphenylacetylene (1.0 equiv,
1.7 mmol) in 8 mL of dichloromethane was added 0.3 g of
bromine (1.1 equiv, 1.9 mmol) and the reaction mixture was
stirred at rt for 1 h. When the reaction was judged complete
by 1H NMR analysis, it was filtered and the precipitate was
washed with dichloromethane to provide 0.52 g (90%) of
product as a white crystal. 1H NMR d 7.59 (m, 4H), 7.40 (m,
6H); mp 216–218 8C (lit. 215–216 8C).27
1
yield) as a pale yellow oil. H NMR: d 7.52 (t, JZ5.6 Hz,
2H), 7.37 (t, JZ5.6 Hz, 3H), 7.07 (s, 1H). 13C NMR: d
138.5 (C), 131.1 (C), 129.4 (K), 128.6 (K), 127.8 (K),
108.9 (K). NMR data were consistent with literature
values.23
Acknowledgements
This work was supported by funding from NSERC Canada
and the Ontario Research and Development and Challenge
Fund.
3.3.6. 1,4-Diphenyl-1,3-butadiyne (27). Phenyl iodide
(2.0 equiv, 0.46 mmol, 93.8 mg) was dissolved in 2.0 mL
of THF and the mixture was cooled to K78 8C. n-BuLi
(0.29 mL of 1.6 M solution in hexanes, 2.0 equiv,
0.46 mmol) was then added and the solution stirred for an
additional 30 min. To this reaction was added 0.92 mL of
0.5 M anhydrous ZnCl2 in THF (2.0 equiv, 0.46 mmol) after
which the solution was stirred for 40 min at rt. To a separate
flask was added 26 (1.0 equiv, 0.23 mmol, 60 mg),
Pd(PPh3)4 (0.05 equiv, 0.01 mmol, 13 mg) and 0.5 mL
THF, followed by the contents of the first flask. Reaction
was stirred for 18 h at rt and then for 24 h at 40 8C. Water
(5 mL) was added, the layers separated and the aqueous
layer was extracted with ether (3!). The combined organic
extracts were dried with anhydrous MgSO4 and the solvent
removed in vacuo. The crude product was purified by
column chromatography (RfZ0.5; in pentane) providing
34 mg of 27 (57% recovery), 9.1 mg (0.090 mmol) of bis-
coupled product 27 (39% yield) and 14.5 mg (0.094 mmol)
of biphenyl (15b). 1H NMR for 27: d 7.54 (d, JZ2 Hz, 2H),
7.35 (d, JZ2 Hz, 3H); 13C NMR: d 135.5 (K), 129.3 (K),
128.1 (K),121.9 (C), 81.7 (C), 73.9 (C). NMR data were
consistent with literature values.24
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2004.08.
006
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