Palladium-catalyzed 1,4-difunctionalization of butadiene to form skipped polyenes

Article abstract of DOI:10.1021/ja3110544

A palladium-catalyzed 1,4-addition across the commodity chemical 1,3-butadiene to afford skipped polyene products is reported. Through a palladium σ → π → σ allyl isomerization, two new carbon-carbon bonds are formed with high regioselectivity and trans s

Full text of DOI:10.1021/ja3110544

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Communication
Palladium-Catalyzed 1,4-Difunctionalization
of Butadiene to Form Skipped Polyenes
Matthew Scott McCammant, Longyan Liao, and Matthew S Sigman
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/ja3110544 • Publication Date (Web): 08 Mar 2013
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Matthew S. McCammant, Longyan Liao, and Matthew S. Sigman*
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Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT, 84112
E-mail: sigman@chem.utah.edu
Supporting Information Placeholder
tion of the allyl complex22 (Figure 1c, →→C with subse-
ABSTRACT: A palladium-catalyzed 1,4-addition across
the commodity chemical 1,3-butadiene to afford skipped
polyene products is reported. Through a palladium
σ→π→σ allyl isomerization, two new carbon-carbon
bonds are formed with high regio- and trans stereochemi-
cal selectivity of the newly formed alkene. The utility of
this method is highlighted by the successful synthesis of
the ripostatin A skipped triene core.
quent cross-coupling of C with a boronic acid derivative. A
key previous report suggests that this isomerization is facile
(Figure 1d). Specifically, a systematic study of substituent
effects in the hydroarylation of terminal 1,3-dienes, which
proceeds through a similar π-allyl species, reveals a linear
free-energy relationship between Charton steric parameters
and the logarithm of the ratio of 1,2 and 1,4-regioisomers.21e
If 1,3-butadiene was employed, extrapolation of the Charton
relationship would achieve >20:1 selectivity for the 1,4-
addition reaction. However, the use of a Pd-Ar rather than a
Pd-H species to initiate the alkene functionalization, as well
as the likely requirement of different reaction conditions
than those used in the hydroarylation reaction, makes the
outcome of this reaction less predictable.
The four-carbon feedstock, 1,3-butadiene, is a product of
petroleum cracking on a >10 million ton scale annually,1
which makes it an especially attractive candidate for convert-
ing into more complex building blocks for synthesis. In this
regard, we envisioned using this simple and symmetric
diene2 in a similar approach to that of the venerable Diels-
Alder reaction by forming carbon‒carbon bonds at both ter-
mini with the preservation of a single alkene in the product.
In contrast to cycloadditions of 1,3-butadiene with dieno-
philes, we wanted to controllably form the carbon-carbon
bonds using two distinct reaction partners through a 1,4-
difunctionalization process (Figure 1a). This would efficient-
ly generate significant molecular complexity from a simple
feedstock. In considering possible coupling partners, a spe-
cific goal was to ultimately form skipped diene and triene
products as these are common motifs in various natural
products3-15 and often challenging to prepare.16-19 Herein we
present the development of a Pd-catalyzed 1,4-addition of
vinyl electrophiles and boronic acid derivatives across 1,3-
butadiene to access these important structural motifs high-
lighted by the synthesis of the skipped triene core of ri-
postatin A.3
To accomplish a 1,4-difunctionalization of butadiene using
a three-component coupling strategy, several important se-
lectivity issues needed to be considered.20-21 We recently
reported a three-component coupling of substituted 1,3-
dienes, vinyl triflates, and boronic acids wherein selective
formation of the 1,2-addition product is observed (Figure
1b).21d The use of vinyl triflates is proposed to account for the
high selectivity of the three-component coupling product
rather than either the Heck or Suzuki products presumably
due to the cationic nature of intermediates along the reac-
tion path. The use of these and related reagents is an obvi-
ous starting point for reaction development. Achieving a 1,4-
addition rather than a 1,2-addition across butadiene after
oxidative addition to form A requires a σ→π→σ isomeriza-
Figure 1. Proposed 1,4-difunctionalizaion of 1,3-butadiene
with vinyl triflates and boronic acids
To explore the possibility of a 1,4-difunctionalization of 1,3-
butadiene, vinyl triflate 1 and phenyl boronic acid 3 were
chosen for reaction optimization (Table 1). The initial reac-
tion conditions tested were those found optimal for the
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Table 2. Scope of 1,4-vinylarylation of 1,3-butadiene
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dure where a >20:1 selectivity for the 1,4-addition product
Table 1. Optimization of three-component coupling with
1,3-butadiene
and a 92:8 ratio for the desired trans alkene is observed (en-
try 5). It should be noted that some of the enhancement of
the observed selectivity is from consumption of the unde-
sired terminal alkene product 5 with the excess vinyl triflate.
Therefore, an improvement of selectivity and ease of purifi-
cation comes with a cost of overall yield. Finally, the vinyl
triflate can be replaced with the more economical vinyl no-
naflate,24 which produces nearly identical results (entry 6).
Using the optimal conditions, the scope of this 1,4-
vinylarylation of 1,3-butadiene was assessed, which was ini-
tially focused on a variety of substituted arenes and hetero-
cyclic vinyl triflates/nonaflates resulting in excellent selectiv-
ity for the 1,4-addition product. Electronic effects of the aryl
boronic acid had little influence on product yields (7a-f),
although a lower regioselectivity was observed for the more
electron rich aryl group installed in 7c. Examining the steric
influence of o-tolyl boronic acid, 7g, resulted in good selec-
tivity and good yield. When larger arenes, including several
heteroaromatic groups, were examined, the yield and selec-
tivity of the process were not significantly influenced (7h-k).
Unfortunately, boronic acids incorporating more Lewis basic
heteroatoms (e.g., pyridine) fail to yield the three-
component coupling product in an appreciable amount.
Acyclic Z-vinyl triflates derived from β-dicarbonyls were suc-
cessfully used, yielding 7l and 7m without isomerization of
alkene geometry suggesting that a wide variety of skipped
dienes can be accessed using this method. Finally, the use of
a simple E-vinyl triflate (6n) resulted in the desired product
(7n), again, without loss of stereochemical integrity originat-
ing from the vinyl triflate (Eq. 1). It should be noted that the
internal alkene derived from butadiene is formed in a >8:1
ratio favoring the trans configuration in all cases, which is
consistent with other difunctionalization reactions of this
substrate. 20k,22c,h-j
previously reported three-component coupling.21d While the
three-component coupling products were formed in an ex-
cellent yield, the product distribution was suboptimal with a
3:1 ratio of the desired 1,4-addtion product 4 to the 1,2-
addition product 5 as an inseparable mixture (entry 1). Ini-
tially, butadiene was introduced in the gaseous phase via a
balloon, where the stoichiometry cannot be easily controlled.
Therefore, we moved to a standard, commercial solution as
the source of 1,3-butadiene (15 wt% in n-hexane). Upon this
change, a significant improvement in selectivity for the 1,4-
addition product is observed albeit at the cost of yield. An
origin for this improvement may be inhibition of σ→π→σ
isomerization when 1,3-butadiene is in substantial molar
excess as it may act as a ligand on Pd. Modest concentration
deviations of the diene had negligible effects.23 Further im-
provement of both selectivity and yield is observed upon
either performing the reaction at higher overall concentra-
tion (entry 3) or adding an excess of the vinyl triflate (entry
4). Combining these changes provides an optimized proce-
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To showcase the utility of this method, the skipped diene
core of ripostatin A, a bacterial RNA-polymerase inhibitor,3
was targeted. To our delight, the desired product (9e) was
formed with the appropriate display of the skipped triene
core and necessary functional groups for further manipula-
tion. This example effectively illustrates the synthetic poten-
tial of this method by incorporating a simple feedstock
chemical between two relatively complex fragments.
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Encouraged by the successful vinylarylation three-
component coupling reactions, we sought to explore a three-
component vinylvinylation of 1,3-butadiene to form skipped
trienes (Table 3). A styrenyl boronic acid can be coupled
with a cyclic and an acyclic boronic acid with 1,3-butadiene
to effectively form skipped trienes 9a and 9b in modest to
good yields. A simple acyclic vinyl boronic is also an effec-
tive substrate in the synthesis of the skipped triene 9c. The
use of a considerably more complex organometallic coupling
partner requires the use a higher catalyst loading to prepare
9d. In this case, the pinacol boronic ester was used as it was
more easily accessed (9d-9e). In these cases, the alkene ge-
ometry in both the vinyl triflate and the boronic ester remain
intact. Additionally, the alkene derived from1,3-butadiene is
again formed in the trans configuration suggesting a trans σ-
allyl intermediate as depicted in C in Figure 1. The selectivity
for 1,4-addition relative to 1,2-addition is diminished relative
to the vinylarylation process but the 1,4-addition product of
the skipped dienes can be accessed by re-exposing the mix-
ture to the reaction conditions, which selectively consumes
the terminal alkene.
In summary, we have developed a new method for the effi-
cient access to skipped polyenes. This process takes ad-
vantage of the simplicity of 1,3-butadiene and the ability to
selectively and independently functionalize both terminal
alkenes. Additionally, the reaction proceeds with high stere-
ochemical integrity of the alkenes formed wherein the geom-
etry of the starting materials is relayed into the product and
the alkene fashioned from 1,3-butadiene is mainly of the
trans geometry. The scope of the method is highlighted by
the synthesis of the skipped triene core structure of ri-
postatin A in only three linear steps from simple starting
materials. Many mechanistic questions arise when consider-
ing substituted terminal 1,3-dienes where more highly func-
tionalized skipped polyene products can be envisioned. Fu-
ture work is focused on examining these effects and expand-
ing the scope of coupling partners.
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Supporting Information. Experimental procedures and
characterization data for new substances. This material is
available free of charge via the Internet at
http://pubs.acs.org.
Table 3. Scope of 1,4-vinylvinylation of 1,3-butadiene
sigman@chem.utah.edu
This work was supported by the National Institutes of Health
(NIGMS RO1 GM3540).
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