A Palladium-catalyzed three-component-coupling strategy for the differential vicinal diarylation of terminal 1,3-dienes

Article abstract of DOI:10.1021/ol502279u

A palladium-catalyzed intermolecular vicinal diarylation of terminal 1,3-dienes using aryldiazonium tetrafluoroborates and arylboronic acids is reported. Using this technology, two different arenes are regioselectively introduced in a vicinal fashion across the terminal alkene of a variety of terminal 1,3-dienes at ambient temperature. Through the action of a chiral bicyclo[2.2.2]octadienyl ligand at -20 °C, good enantioselectivity has also been achieved.

Full text of DOI:10.1021/ol502279u

Letter
pubs.acs.org/OrgLett
Open Access on 08/27/2015
A Palladium-Catalyzed Three-Component-Coupling Strategy for the
Differential Vicinal Diarylation of Terminal 1,3-Dienes
Benjamin J. Stokes, Longyan Liao, Aline Mendes de Andrade, Qiaofeng Wang, and Matthew S. Sigman*
Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, Utah 84112, United States
S
* Supporting Information
ABSTRACT: A palladium-catalyzed intermolecular vicinal
diarylation of terminal 1,3-dienes using aryldiazonium
tetrafluoroborates and arylboronic acids is reported. Using
this technology, two different arenes are regioselectively
introduced in a vicinal fashion across the terminal alkene of a variety of terminal 1,3-dienes at ambient temperature. Through
the action of a chiral bicyclo[2.2.2]octadienyl ligand at −20 °C, good enantioselectivity has also been achieved.
Scheme 1. Three-Component-Couplings of Terminal 1,3-
Dienes
number of intermolecular alkene diarylation reactions
Ahave been developed wherein 2 equiv of a single arene are
added to an alkene in a single step.1 Consequently, two
identical aryl groups are incorporated. In the interest of rapidly
generating complexity from simple feedstock starting materials,
there is a strong desire to develop single-step alkene diarylation
reactions wherein different arenes are added across an alkene
selectively in the presence of a palladium catalyst. While
norbornadiene,2 terminal allenes,3 and more recently simple
terminal alkenes4 have been used as substrates in three-
component diarylations, selective three-component diarylations
of terminal 1,3-dienes are not yet known. Three-component
couplings of terminal 1,3-diene substrates attracted our interest
because, unlike the aforementioned technologies, we envi-
sioned that the products could retain an alkene functional
group and also incorporate a chiral center.
Our approach to the vicinal difunctionalization of terminal
1,3-dienes is shown in Scheme 1A. Mechanistically, such
reactions are initiated upon oxidative addition of an sp2 carbon
electrophile to Pd(0). This generates a cationic Pd-alkyl species
A that may undergo migratory insertion and defer trans-
metalation if the leaving group is noncoordinating (Scheme
1B).5 The resultant Pd-alkyl B is stabilized as a π-allyl C that
resists β-hydride elimination.6 To complete the difunctionaliza-
tion sequence, transmetalation and reductive elimination of the
second sp2 coupling partner, R2, affords the product E. This
strategy was implicated in our previous vicinal alkenylarylation
of 1,3-dienes, which gave products of the type F (Scheme
1C).5a Unfortunately, our attempts to develop an analogous
three-component diarylation by using aryl triflates instead of
alkenyl triflates consistently failed, which is likely a result of the
relative inertia of aryl triflates.7 We now wish to report the
successful development of a three-component vicinal diary-
lation of 1,3-dienes, which employs aryldiazonium tetrafluor-
oborates and aryl boronic acids as coupling partners, affording
products of type G (Scheme 1D). We have also identified a
chiral bicyclo[2.2.2]octadienyl ligand that is capable of
delivering diarylation products with good levels of enantiomeric
enrichment.
We began the study by optimizing the coupling of trans-1-
(para-methoxyphenyl)-1,3-butadiene 1a with phenyldiazonium
tetrafluoroborate and phenylboronic acid (Table 1). Arenedia-
zonium tetrafluoroborates were chosen not only because they
readily oxidize Pd(0) but also because they afford the
aforementioned requisite cationic aryl-Pd intermediates re-
quired for migratory insertion (see A in Scheme 1B).4,8 Starting
with our previously reported alkenylarylation conditions,5a the
indicated Heck product predominated over both the desired
vicinal diarylation product 2a and the Suzuki product (entry 1).
Received: July 31, 2014
Published: August 27, 2014
© 2014 American Chemical Society
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Table 1. Optimization of the Three-Component-Coupling of
1a with Phenyl Diazonium Tetrafluoroborate and Phenyl
Boronic Acid
conv
a
yield
a
a
(%)
(%)
selectivity
entry
base
KF
solvent
DMA
of 1a
of 2a (2a/Suzuki/Heck)
1
2
3
4
5
6
7
8
70
8
04:04:92
50:50:tr
tr:50:50
tr:08:92
05:19:76
14:14:72
62:13:25
92:02:06
94:03:03
96:02:02
94:04:02
KF
1,4-dioxane
THF
100
100
100
100
100
100
93
14
tr
KF
KF
MeOH
tr
KF
EtOH
4
KF
i-PrOH
11
33
53
57
58
80
KF
t-BuOH
t-AmylOH
t-AmylOH
t-AmylOH
t-AmylOH
KF
b
9
KF
90
b
10
NaHCO3
NaHCO3
96
bc
,
11
100
a
Determined by GC analysis using dodecane as an internal standard
b
following response factor correction. This reaction was conducted at
room temperature. An additional 15 mol % of dba was added to this
c
reaction.
In contrast to N,N-dimethylacetamide (DMA), 1,4-dioxane
minimized Heck product formation but afforded an equimolar
ratio of 2a and the Suzuki product (entry 2). Interestingly,
another ethereal solvent, THF, afforded only trace amounts of
2a and an equimolar ratio of Suzuki and Heck products (entry
3). Next, alcoholic solvents, which have proven valuable in
differential geminal diarylations of terminal alkenes with
diazonium salts and boronic acids,4 were examined. While
trace amounts of 2a and mostly the Heck product were
observed in methanol (entry 4), increasingly bulky alcohols led
to improved yields of 2a at the expense of the Heck product
(entries 4−8). In particular, the use of tert-amyl alcohol
afforded superior selectivity for the desired diarylation product
over both Heck and Suzuki products (entry 8). Comparable
results were obtained when the reaction was carried out at
ambient temperature (entry 9) and with NaHCO3 in place of
KF (entry 10). The final breakthrough was the addition of
exogenous dibenzylideneacetone (dba), which improved the
yield significantly, presumably by preventing the detrimental
accrual of unligated Pd(0) (entry 11).9,10
Under the optimized conditions, we initially investigated
increasingly electron-deficient trans-1-phenyl-1,3-butadienes 1b
and 1c in order to directly compare 1-aryl-1,3-diene electronic
effects on vicinal diarylations (Figure 1). These substrates
afforded diminishing yields of the corresponding 1,3,4-triaryl-1-
butene products 2b (65%) and 2c (52%), although the
selectivity for the difunctionalization product remained >95% in
these cases and all subsequent ones. Next, trans-1-(para-
fluorophenyl)-1,3-butadiene 1d was found to react efficiently
with para-methoxyphenyldiazonium tetrafluoroborate and
phenylboronic acid, affording an 83% yield of 2d. Additionally,
the reaction between (E)-1-(1-naphthyl)-1,3-butadiene, 4-
nitrophenyldiazonium tetrafluoroborate, and phenyl boronic
Figure 1. Exploration of the scope of coupling partners in the three-
component diarylation of terminal 1,3-butadienes. The isolated yield
of each product is reported.
acid delivered the designated nitrophenyl-containing product
2e in 50% yield.
Having established the broad tolerance of electronically
disparate terminal 1,3-dienes and phenyldiazonium salts in 2a−
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2e, we turned our attention to functional group compatibility.
In addition to the aforementioned methylphenyl ether (2a),
trifluoromethylphenyl (2c), fluorophenyl (2d), and nitrophenyl
(2e) functional groups, a phenylacetamide group was
introduced to the substrate via the boronic acid component,
giving 2f in high yield. Functionalized phenyldiazonium salts
and phenylboronic acids also could be incorporated simulta-
neously, with installation of the diazonium component in the
homallylic position and the boronic acid component in the
allylic position of the product, as shown in 2g−2l. In addition
to the use of trifluoromethyl (2c and 2h), fluoro (2d and 2h),
and nitro (2e) arene substituents, other functional groups that
are well-tolerated include a ketone (2g and 2k), an aryl
bromide (2i), and even an aryl iodide (2k) in reactions with 1-
(para-methoxyphenyl)-1,3-butadiene.
substrate is itself a diene, which may confound effective
asymmetric catalysis). Under the optimized conditions
identified in Table 1 above, tetrahydropentalenyl ligand L1
afforded 1,3,4-triphenyl-1-butene 2b in just 3% enantiomeric
excess (Table 2, entry 1). A substantial improvement was
Table 2. Selected Ligand and Temperature Effects on
Asymmetric Induction in the Vicinal Diphenylation of (E)-1-
Phenyl-1,3-butadiene
With respect to the phenylboronic acid component, both
electron-rich and -poor examples are well-tolerated (compare,
for example, para-CF3-containing product 2j and para-OMe-
containing product 2l). The boronic acid can also be sterically
hindered, as an ortho-tolyl group can be added to the allylic
position (see 2i). Conversely, ortho-tolyldiazonium tetrafluor-
oborate can be used to install the group in the homoallylic
position (2j).11
Alkyl 1,3-dienes were also tested as substrates under the
optimized conditions. To this end, a protected alcohol-
containing 1,3-diene coupled efficiently to para-methoxyphenyl
and para-(trifluoromethyl)phenyl groups, giving 2m. In
contrast, a trisubstituted alkene-containing substrate afforded
a diminished yield of 2n when coupled to the indicated arenes.
These results are consistent with the requirement of a large
substituent at the 1-position of the 1,3-diene to avoid σ−π−σ
isomerization of the Pd-allyl intermediate (C, Scheme 1), which
would afford 1,4-diarylation products.12 These examples,
combined with those of 2a−2l, make clear that a wide variety
of electronically and sterically diverse 1,3-dienes and arenes
may be combined under these conditions.
The development of a catalytic enantioselective route to the
diarylation products 2 is of interest because these products are
precursors to pharmaceutically important enantioenriched α-
arylpropionic acids,13 and their asymmetric synthesis has not
yet been achieved.14 Thus, a catalytic asymmetric route starting
from terminal 1,3-dienes, which are prepared in one step, would
streamline the access to enantioenriched variants of 2. We
therefore sought to identify a suitable chiral ligand that would
deliver 2 in high enantiomeric excess (ee) and yield.
Unfortunately, the addition of privileged nucleophilic ligands
for cross-coupling reactions, such as phosphines (including
phosphoramidites), N-heterocyclic carbenes, and bidentate
amines, afforded Suzuki cross-coupling as the major reaction
outcome; the diene substrates were not consumed (see the
Supporting Information for details). This may be due to the
fact that Lewis basic ligands change the electrophilic nature of
the Pd-alkenyl adduct (intermediate A, Figure 1) so as to favor
transmetalation over alkene insertion. This problem is
encountered in all of our three-component-coupling methods
(sp2−sp2 Suzuki coupling partners are present but must not
react with one another) and is the likely reason why each of
these optimized reactions perform best under “ligandless”
conditions.5
a
Determined by GC analysis using dodecane as an internal standard
b
following response factor correction. Determined by SFC analysis.
observed through the use of bicylo[2.2.2]octadienyl ligand L2,
which afforded 2b in 29% ee (entry 2). Focusing on the
bicyclo[2.2.2]octadienyl core, we found that the pseudo C2-
symmetric (R)-(−)-carvone-derived ligand L3 delivered 2b in
51% ee (entry 3), while (R)-(−)-α-phellandrene-derived L4
performed the best under these conditions, affording a
promising 65% ee (entry 4).16 A brief temperature profile
revealed that the enantioselectivity could be improved by
decreasing the temperature, albeit at the expense of the reaction
yield. At −8 °C, just above the freezing point of tert-AmylOH,
83% ee was observed, albeit with a low 10% yield of 2b (entry
5). Conversely, increasing the temperature to 40 °C resulted in
an improved yield (51%) but a diminished ee (55%, entry 7).
Our final aim was to improve the yield of the asymmetric
diphenylations using L4 while preserving enantiomeric
excesses. To this end, 1,2-dichloroethane (DCE) was selected
as the solvent, enabling the reaction to be carried out at −20
°C, while a slight excess of 1,3-diene substrates and increases in
catalyst, ligand, and base loading were also employed (Figure
2). Under these conditions, terminal dienes 1a−1c could be
converted to the corresponding (R) enantiomers17 in 75−82%
ee and in isolated yields of 25−30%. Neither the yield nor the
selectivity was found to depend significantly on the electronic
nature of the diene, with electron-rich (1a), electron-neutral
(1b), and electron-deficient (1c) substrates behaving similarly.
This asymmetric variant resisted our best efforts to increase the
yield by changing the conditions or the technical procedure.
In summary, we have developed a highly regioselective
vicinal diarylation reaction of terminal 1,3-dienes that
incorporates two different aryl groups from diazonium salts
and boronic acids. The reaction is conducted under mild
conditions, incorporates a variety of functionalized arenes, and
can be rendered enantioselective through the use of a chiral
bicyclo[2.2.2]octadienyl ligand, albeit in low yield. New
Given that dba, an achrial diene, is well-tolerated in each of
our three-component-coupling reactions, we looked to
commercially available chiral dienes for suitability as non-
nucleophilic ligands15 (although it should be noted that the
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Organic Letters
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(7) Elevated temperatures and phosphine ligands are typically
required to oxidize Pd(0) with aryl triflates in nonpolar solvents. For
leading references, see: (a) Jutand, A.; Mosleh, A. Organometallics
1995, 14, 1810. (b) Alcazar-Roman, L. M.; Hartwig, J. F. Organo-
metallics 2002, 21, 491. (c) Jutand, A.; Negri, S. Organometallics 2003,
22, 4229.
(8) For a review, see: (a) Taylor, J. G.; Moro, A. V.; Correia, C. R. D.
Eur. J. Org. Chem. 2011, 2011, 1403. For leading references, see:
(b) Callonnec, F. o. L.; Fouquet, E.; Felpin, F. o.-X. Org. Lett. 2011,
13, 2646. (c) Werner, E. W.; Sigman, M. S. J. Am. Chem. Soc. 2011,
133, 9692. (d) Werner, E. W.; Mei, T.-S.; Burckle, A. J.; Sigman, M. S.
Science 2012, 338, 1455. (e) Oliveira, C. C.; Angnes, R. A.; Correia, C.
R. D. J. Org. Chem. 2013, 78, 4373. (f) Oger, N.; Le Callonnec, F.;
Jacquemin, D.; Fouquet, E.; Le Grognec, E.; Felpin, F.-X. Adv. Synth.
Catal. 2014, 356, 1065.
(9) The addition of exogenous dba has been effective in improving
yields in alkene difunctionalization reactions. See: Saini, V.; Sigman,
M. S. J. Am. Chem. Soc. 2012, 134, 11372.
(10) Geminal diarylation was not observed in these studies.
(11) NMR NOE analyses of 2i and 2j, in which the phenyl methyl
group of each product was irradiated, confirmed the diazonium-
derived arene is installed at the homoallylic position, while the boronic
acid derived arene is installed at the allylic position.
Figure 2. Reoptimized enantioselective diphenylations of (E)-1-aryl-
1,3-dienes at −20 °C. The isolated yield and enantiomeric excess (as
determined by SFC) for each product are reported.
approaches to asymmetric three-component-coupling reactions
are currently under investigation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimetal procedures, full spectroscopic data for new
compounds, and chiral separations. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) For a study of the steric inhibition of σ−π−σ isomerization of
similar Pd-allyl intermediates, see: Liao, L.; Sigman, M. S. J. Am. Chem.
Soc. 2010, 132, 10209.
(13) For example, see: Thalen
́
, L. K.; Sumic, A.; Bogar
́
, K.; Norinder,
AUTHOR INFORMATION
Corresponding Author
J.; Persson, A. K. Å.; Backvall, J.-E. J. Org. Chem. 2010, 75, 6842.
̈
■
(14) Stereospecific palladium-catalyzed arylations of enantiomerically
enriched secondary styrenyl carbonates are challenging when a
homostyrenyl arene is present because the carbonate is easily
eliminated to give 1,4-diaryl-1,3-dienes. See: Zhao, J.; Ye, J.; Zhang,
Y. J. Adv. Synth. Catal. 2013, 355, 491.
*E-mail: sigman@chem.utah.edu.
Notes
The authors declare no competing financial interest.
(15) For a review on the use of chiral olefins as ligands in asymmetric
transition metal catalysis, see: Defieber, C.; Grutzmacher, H.; Carreira,
E. M. Angew. Chem., Int. Ed. 2008, 47, 4482.
(16) Ligand L4 was used as purchased from Sigma-Aldrich (product
# 723673).
(17) The (R) configuration was assigned by converting (R)-2c into a
compound of known absolute configuration, namely 2,3-diphenyl-
propanoic acid, using an oxidative cleavage reaction. See the
Supporting Information for details.
̈
ACKNOWLEDGMENTS
■
The research reported in this publication was supported by the
National Institute of General Medical Science of the National
Institutes of Health under Award Numbers R01GM063540 and
F32GM099254 (B.J.S.), and a Science Without Borders
undergraduate scholarship from the National Council for
Scientific and Technological Development of Brazil (CNPq) to
A.M.A.
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