Differentiating allylic and vinylic leaving groups for Pd catalysis. The use of vinyl iodide to facilitate room temperature activation of a vinyl C-X bond in the presence of allyl carbonate

Article abstract of DOI:10.1016/S0040-4039(03)00881-5

Ionization of allylic, stabilized leaving groups by Pd catalysis is a very facile process at or below room temperature, whereas oxidative addition of many vinyl or aryl C-X bonds requires heating. There are only a handful of examples in the literature where a vinyl leaving group can be activated in a competitive fashion in the presence of a suitable allylic one. In this report a series of polyfunctional olefin building blocks have been constructed that allow vinyl halides to be selectively and routinely activated in the presence of highly active allylic leaving groups. This differentiation is dependent solely on the bond strengths of the leaving groups involved and shows no temperature dependence to differentiate the two processes.

Full text of DOI:10.1016/S0040-4039(03)00881-5

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4403–4406
Differentiating allylic and vinylic leaving groups for Pd catalysis.
The use of vinyl iodide to facilitate room temperature activation
of a vinyl CꢀX bond in the presence of allyl carbonate
Michael G. Organ,* Elena A. Arvanitis, Anita Villani, Yvette Majkut and Stephen Hynes
The Department of Chemistry, York University, 4700 Keele Street, Toronto, Ontario, Canada M3J 1P3
Received 24 March 2003; revised 3 April 2003; accepted 3 April 2003
Abstract—Ionization of allylic, stabilized leaving groups by Pd catalysis is a very facile process at or below room temperature,
whereas oxidative addition of many vinyl or aryl CꢀX bonds requires heating. There are only a handful of examples in the
literature where a vinyl leaving group can be activated in a competitive fashion in the presence of a suitable allylic one. In this
report a series of polyfunctional olefin building blocks have been constructed that allow vinyl halides to be selectively and
routinely activated in the presence of highly active allylic leaving groups. This differentiation is dependent solely on the bond
strengths of the leaving groups involved and shows no temperature dependence to differentiate the two processes. © 2003 Elsevier
Science Ltd. All rights reserved.
Our research group is interested in the development of
small, polyfunctional olefin building blocks (templates)
for use in modular organic synthesis using transition
metal catalysis to affect sequential transformations of
one, or of more than one mechanism.1,2 For such olefin
compounds, allylic leaving groups are generally consid-
ered to be much more readily activateable than the
corresponding vinyl group (i.e. halides or pseudo
halides).3,4 For example the allylic bromide of 2,3-
dibromo-1-propene is activated cleanly in the presence
of the vinyl halide at rt and can be substituted with a
number of suitable nucleophiles. The remaining vinyl
halide can then be activated readily, albeit at elevated
temperature (e.g. refluxing THF), and cross coupled
with a variety of organometallic reagents.1
We demonstrated for the first time that this reactivity
profile can be reversed in a general, non-substrate spe-
cific manner.5 That is, an olefin substrate (1) was
designed with a vinyl halide that was activated prefer-
entially by Pd in the presence of a suitable allylic
leaving group (Scheme 1). In this case, the selectivity of
the catalyst toward the vinyl bromide of 1, when com-
pared with 2,3-dibromo-1-propene, can be reasoned by
the bond strengths of the leaving groups involved. This
can be made practical for the synthetic chemist by
considering the pKa values of their corresponding acids.
While the development of olefin template 1 allowed us
to change the order of Pd-mediated reactions involving
polyfunctional olefins as we desired, and to demon-
Scheme 1.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00881-5

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M. G. Organ et al. / Tetrahedron Letters 44 (2003) 4403–4406
strate the application of this methodology syntheti-
cally,5 the reactions still had to be monitored closely.
With compound 1, it was important that the tempera-
ture not exceed 60°C in the first step to ensure that
no undesired allylic ionization was occurring. We
sought to develop a second generation olefin template
that was equipped with a suitable allylic leaving
group such that the two competing Pd-mediated path-
ways (i.e. vinylic oxidative addition and allylic ioniza-
tion) were energetically well separated so that close
monitoring of temperature between reactions was not
necessary. This would make olefin template use
increasingly practical for the synthetic community.
stitution (9) or Suzuki coupling (11). Although an
exhaustive set of compounds has yet to be made, it
appears that simple alkyl groups are not electron rich
enough to allow Pd to adequately differentiate allylic
and vinylic leaving group activation.
The 2-bromo olefin template was re-equipped with
the more electron-rich 4-methoxyphenol substituent
(12) and subjected to an allylic substitution reaction
in refluxing 1,4-dioxane (Scheme 3). Under these con-
ditions, the phenol group did not ionize visibly and
the major product (13) arose from oxidative addition
of the vinyl bromide.7 Next, the Br in 12 was cross
coupled to give 14 in refluxing THF, again with no
apparent activation of the phenol moiety. Compound
14 was reacted subsequently at ꢀ100°C with mal-
onate (8) to provide 3. In a separate reaction, all
three components (i.e. 12, 8 and 10) were put into the
same flask in 1,4-dioxane at reflux and the reaction’s
progress followed by proton NMR spectroscopy. The
cross coupling completed first selectively in ꢀ20 min
(14), which was followed in situ by the allylic substi-
tution to give the final product (3). Thus, the reaction
components can assemble themselves in a controllable
fashion based on their inherent reactivities which can
prove very useful synthetically. This result confirmed
that a change in temperature was no longer necessary
to differentiate the reaction pathways as all events
took place in the same solvent at the same tempera-
ture.
In designing the new olefin template, there were two
possibilities: increase the electron richness of the leav-
ing group (i.e. increase the pKa of its’ conjugate acid)
or decrease the bond strength of the vinyl substituent.
In light of our initial success with phenoxide leaving
groups, we opted first to adjust the substituent(s) on
the phenol ring to diminish its leaving group ability.
Olefin template 4 was prepared and treated to Suzuki
coupling conditions6 (Scheme 2). From the product
distribution, and by monitoring the reaction’s pro-
gress by NMR spectroscopy, it is clear that vinyl Br
activation is the first event that takes place. However,
ionization of the 2,4-dimethylphenoxide group and
coupling of the Br are a closely related process
energetically resulting in the formation of 6 and 7
from 5. The phenol moiety on 5 was then activated
by Pd to give either the product of nucleophilic sub-
Scheme 2.

M. G. Organ et al. / Tetrahedron Letters 44 (2003) 4403–4406
4405
Scheme 3.
While the reaction pathways were now well differenti-
ated electronically, we still wanted to have an allylic
group that could be activated at a lower temperature to
improve the method’s general application. Thus, we
turned our attention to the functional group on the
olefin and replaced the bromide with an iodide. We
discovered that we could now differentiate the vinyl
position from the allylic position at rt (Scheme 4).
When 15a or 15b were reacted under allylic substitution
conditions, it appeared as though no reaction took
place despite that fact that carboxylates and carbonates
ionize at, or well below 0°C. In fact, oxidative addition
had taken place and we identified intermediate 16 by
proton and carbon NMR spectroscopy and mass spec-
troscopy.8 In the absence of a suitable organometallic
partner (i.e. not sodium malonate), the reaction could
proceed no further. When we tried to cross couple 15b
at rt, metal–metal exchange was now the rate-limiting
step and no reaction took place. However, heating to
reflux allowed smooth conversion to 17 which was
subsequently reacted with malonate (8) and substituted
at the allylic position to yield 3. Thus, once again we
have a template in hand that not only allows us to
change the order of reactivity of the catalyst from
allylic ionization to oxidative addition of a vinyl halide,
but to do so under very mild reaction conditions. It is
interesting to note that when the leaving group of 15
was modified to a halide (i.e. 18) that reactivity was
then switched back to the allylic site, once again at rt.
In summary, we have developed a series of difunctional
olefin templates that allow us to switch the regioselec-
tivity of the Pd catalyst from the allylic site to the
vinylic site of these useful 3-carbon building blocks.
The selectivity is solely on the basis of electronic fea-
tures, i.e. bond strength and anion stability. Hence, the
pairings of functional groups will provide reliable reac-
tivity when applied to other related systems.
Acknowledgements
Support for this research came from NSERC (Canada)
and the Ontario Research and Development Challenge
Fund (Ontario).

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M. G. Organ et al. / Tetrahedron Letters 44 (2003) 4403–4406
Scheme 4.
References
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2. For a related approach using dihaloethylenes in sequential
cross coupling reactions, see: (a) Zeng, F.; Negishi, E.-i. Org.
Lett. 2001, 3, 719–722; (b) Negishi, E.-i.; Hata, M.; Xu, C.
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4. For substrate specific examples where a vinyl halide or
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6. All compounds in this report were characterized by proton
and carbon NMR spectroscopy, infrared spectroscopy and
high-resolution mass spectroscopy and/or combustion anal-
ysis.
7. Reduction product 13 was substituted subsequently with
malonate under the identical reaction conditions which
suggests that the malonate in the initial reaction was
consumed in the reduction of 12.
8. There are many examples of such stable Pd(II) complexes
which can be reviewed on the Cambridge Crystallographic
Data Base.