Diastereodivergent Reductive Cross Coupling of Alkynes through Tandem Catalysis: Z- and E-Selective Hydroarylation of Terminal Alkynes

Article abstract of DOI:10.1021/jacs.8b05113

A diastereodivergent hydroarylation of terminal alkynes is accomplished using tandem catalysis. The hydroarylation allows highly selective synthesis of both E and Z diastereoisomers of aryl alkenes, from the same set of starting materials, using the same combination of palladium and copper catalysts. The selectivity is controlled by simple changes in the stoichiometry of the alcohol additive. The hydroarylation has excellent substrate scope and can be accomplished in the presence of various classes of compounds, including esters, nitriles, alkyl halides, epoxides, carbamates, acetals, ethers, silyl ethers, and thioethers. The Z-selective hydroarylation is accomplished using a new approach based on tandem Sonogashira coupling and catalytic semireduction. The E-selective hydroarylation involves an additional catalytic isomerization of the Z-alkene. Our explorations of the reaction mechanism explain the role of individual reaction components and how the subtle changes in the reaction conditions influence the rates of specific steps of the hydroarylation. Our studies also show that, although the Z- and E-selective hydroarylation reactions are mechanistically closely related, the roles of the palladium and copper catalysts in the two reactions are different.

Full text of DOI:10.1021/jacs.8b05113

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Diastereodivergent Reductive Cross Coupling of Alkynes through
Tandem Catalysis: Z- and E‑Selective Hydroarylation of Terminal
Alkynes
Megan K. Armstrong,† Madison B. Goodstein,† and Gojko Lalic*
Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
ABSTRACT: A diastereodivergent hydroarylation of termi-
nal alkynes is accomplished using tandem catalysis. The
hydroarylation allows highly selective synthesis of both E and
Z diastereoisomers of aryl alkenes, from the same set of
starting materials, using the same combination of palladium
and copper catalysts. The selectivity is controlled by simple
changes in the stoichiometry of the alcohol additive. The
hydroarylation has excellent substrate scope and can be
accomplished in the presence of various classes of compounds, including esters, nitriles, alkyl halides, epoxides, carbamates,
acetals, ethers, silyl ethers, and thioethers. The Z-selective hydroarylation is accomplished using a new approach based on
tandem Sonogashira coupling and catalytic semireduction. The E-selective hydroarylation involves an additional catalytic
isomerization of the Z-alkene. Our explorations of the reaction mechanism explain the role of individual reaction components
and how the subtle changes in the reaction conditions influence the rates of specific steps of the hydroarylation. Our studies also
show that, although the Z- and E-selective hydroarylation reactions are mechanistically closely related, the roles of the palladium
and copper catalysts in the two reactions are different.
Scheme 1. Stereoselectivity in Cross Coupling
INTRODUCTION
■
Alkenes play an important role in organic chemistry, both as
common structural elements of organic molecules and as
intermediates in organic synthesis. The preparation of the E
and Z isomers of an alkene generally requires the synthesis of
two different sets of precursors,1 often using different synthetic
routes. For example, in extensively used cross-coupling
reactions, the stereochemistry of the alkene product is
determined by the stereochemistry of the starting material.1b
As a result, the synthesis of E- and Z-aryl alkenes involves
separate cross-coupling reactions of two diastereomeric alkene
fragments with a functionalized arene (Scheme 1a).
Although rare, stereodivergent methods that allow the
synthesis of both alkene isomers from the same starting
materials are known. For example, both isomers can be formed
by the semireduction of an alkyne.2 Whereas this approach
allows control over the double bond geometry and stereo-
divergence, no new carbon−carbon bond is formed. A more
efficient approach is offered by alkene cross metathesis,3 which
leads to fragment coupling through the formation of a new
double bond and allows the control of the double bond
geometry. The stereochemistry of the product is primarily
determined by the catalyst used in the reaction.3b,4 The
downside of this approach is that the selective formation of the
desired cross metathesis product often necessitates the use of
specific combinations of substrates and/or a large excess of one
of the substrates.
Like the alkene cross metathesis reaction, these trans-
formations are responsible both for the formation of a new
C−C bond and for setting the stereochemistry of the alkene
product. Therefore, in principle, a single hydroarylation
reaction could provide access to both diastereoisomers of an
aryl alkene from a single alkyne substrate (Scheme 1b).
Despite the development of numerous reactions for the
Reductive cross-coupling reactions of alkynes also provide
an excellent opportunity for stereodivergent alkene synthesis.
Received: May 16, 2018
© XXXX American Chemical Society
A
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hydroarylation of alkynes, diastereodivergent methods remain
rare.5
diarylation are often formed. Finally, it is important to note
that all three mechanistic approaches to hydroarylation shown
in Scheme 3 (a and b) have been difficult to apply to reactions
of terminal alkynes, making hydroarylation of this important
class of substrates particularly challenging.13
Recently, a diastereodivergent hydroalkylation of aryl
alkynes (Scheme 2) was reported by Nishikata et al.,6
Seeking to exploit the full potential of hydroarylation
chemistry, we were interested in developing a diastereodi-
vergent hydroarylation of terminal alkynes that would provide
access to both Z- and E-aryl alkenes. Considering the
diastereospecific nature of current hydroarylation methods,
we decided to explore a fundamentally different approach
based on tandem catalysis.
Scheme 2. Diastereodivergent Reductive Alkylation
Tandem catalysis has recently received a lot of attention as
an efficient strategy for the development of new catalytic
transformations.14 Performing two or more catalytic reactions
in the same flask enables a more economical use of energy and
time, and minimizes the use of reaction workup and product
purification.14a At the same time, tandem catalysis allows the
development of transformations that are difficult to accomplish
relying on a single catalytic cycle.15
We reasoned that the Z-selective hydroarylation could be
achieved using tandem Sonogashira coupling16 and Z-selective
semireduction.2c On the basis of the seminal work by Sadighi
et al.17 and the subsequent work by Tsuji18 and our group,19
we planned to use the same NHC copper catalyst to promote
Sonogashira coupling and to achieve semireduction in the
presence of a silane and an alcohol (Scheme 3c). E-Alkenes
could be accessed using the same catalyst system through
Sonogashira coupling and semireduction, followed by isomer-
ization of the Z product. E-Styrenes are known to be
significantly more stable than Z isomers, and several distinct
mechanisms for palladium-catalyzed isomerization have been
established.20
demonstrating the feasibility of diastereodivergent reductive
cross coupling. Although no detailed mechanistic analysis was
reported, the diastereodivergence seems to result from
fundamentally different mechanisms for the two reactions.
The Z-products are proposed to be formed through radical
bromoalkylation, followed by the reduction of alkenyl bromide.
The formation of E-alkenes, on the other hand, likely involves
hydroboration followed by Suzuki cross coupling.
Mechanistic analysis of known hydroarylation reactions
suggests why stereodivergence has been difficult to achieve.
Most current methods are based on syn-stereospecific carbo-7
or hydrometalation8 of alkynes, which forces the syn-selective
hydroarylation and prevents the formation of the other isomer
(Scheme 3a).
Scheme 3. Methods for Hydroarylation of Alkynes
RESULTS AND DISCUSSION
■
Z-Selective Hydroarylation of Alkynes. On the basis of
our general strategy outlined in Scheme 3c, we initially
explored Z-selective hydroarylation and found that Sonoga-
shira coupling under a variety of known conditions followed by
in situ copper-catalyzed semireduction was an ineffective
method for hydroarylation. The best result (27% yield) was
obtained using modified Fu−Buchwald Sonogashira condi-
tions21 with conditions for the semireduction previously
reported by our group19 (eq 1, see the Supporting Information
for details).
These results demonstrate the major challenge in tandem
catalysis of ensuring that the catalytic reactions involved in the
process are mutually compatible. Cross-talk between compo-
nents of different catalytic cycles often leads to side reactions
and catalyst deactivation or decomposition.14 In our case, the
major concern was the ability of palladium catalysts to react
with silanes and unsaturated compounds in a variety of ways.
For example, previously, when the product of a Sonogashira
reaction was treated with a silane in situ, exclusive formation of
To our knowledge, the only approach to catalytic anti-
selective hydroarylation was developed by Fujiwara in 2000
(Scheme 3b).9,10 Using a palladium or platinum catalyst, anti-
selective hydroarylation is accomplished through electrophilic
activation of alkynes.11 Unfortunately, the Friedel−Crafts
mechanism12 of this reaction limits the scope to highly
electron-rich arenes and electrophilic alkynes, such as
propiolates. Furthermore, products of dialkenylation and
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the alkane product was observed,22 consistent with the general
propensity of palladium complexes to promote over-reduction
of aryl alkynes.2c,23 Palladium catalysts have also been shown
to promote isomerization of Z-alkenes24 in the presence of
hydride donors, such as tin hydrides and silanes.25
Furthermore, palladium-catalyzed hydrosilylation of alkenes26
and alkynes27 is also known. Overall, even though both
Sonogashira and semireduction reactions are well-established,
merging them into a single process presents significant
challenges, and requires a catalyst system that will selectively
promote the desired combination of reactions and suppress
other well-established reaction pathways.
On the basis of this analysis, we focused on finding a
combination of a palladium catalyst and a silane that would
minimize the possible side reactions. Considering our previous
work on the Z-selective semireduction of alkynes, we focused
on exploring various combinations of IPrCuOt-Bu and
palladium catalysts in the presence of a silane and an alkoxide
(Table 1). We observed a wide range of reactions promoted by
significantly higher selectivity for the desired alkene product
than the closely related SPhos (entries 4 vs 5). The use of L1
eliminated the aryl bromide reduction and suppressed
hydrosilylation of the alkynes, resulting in increased yield of
the hydroarylation product (entry 5). Hydrosilylation was
further suppressed by switching to dimethylisopropylsilane
(Me2i-PrSiH), resulting in clean formation of the Sonogashira
product and a slow semireduction (entry 6). Full conversion of
the Sonogashira product was achieved only after 72 h, and the
product was obtained in 87% yield and 28:1 Z:E selectivity.
The semireduction was dramatically faster when 1.5 equiv of
MeOH was added after the Sonogashira coupling was
completed (entry 7). Within 2 h of the MeOH addition, we
observed the formation of the desired Z alkene in 94% yield
and 19:1 Z:E selectivity. Once the terminal alkyne (1) has
been consumed, the timing of the MeOH addition is not
critical. The same results were obtained with MeOH added 2
or 24 h after the start of the reaction.
In a control experiment, we discovered that adding the silane
at the beginning of the reaction was beneficial. Under standard
conditions described in entry 7 (Table 1), 99% of the
Sonogashira product was formed after 2 h, while in the absence
of the silane, only 24% of the coupling product was formed at
the same time point.30 Another interesting aspect of our
Sonogashira reaction is the tolerance of a copper cocatalyst.
Previously, Buchwald et al. have documented the deleterious
effect of copper cocatalysts in a Sonogashira reaction promoted
by a closely related palladium catalyst stabilized by XPhos
ligand.31
Table 1. Reaction Development
Having established the reaction conditions for the Z-
selective hydroarylation of terminal alkynes (Table 1, entry
7), we explored the scope of the reaction (Table 2). Alkynes
containing reductively labile functional groups such as an alkyl
chloride (12), alkyl bromide (11), ester (9), and nitrile (8)
were compatible with this reaction. In addition, the reaction
could be successfully performed in the presence of epoxides
(16), silyl ethers (15), and protected amines (10). Notably,
both electron-rich and electron-deficient aryl alkynes were
competent coupling partners in this reaction (17 and 18).
A wide range of aryl bromides could also be used as
substrates (Table 2). Both electron-rich (3 and 21) and
electron-poor (19, 22 and 30) aryl bromides were viable
substrates, as were heteroaryl bromides. A variety of functional
groups were tolerated on the arene substrate, including
thioethers (23), acetals (24), and alkenes (26). Finally,
products derived from ortho-, meta-, and para-substituted aryl
bromides were isolated in high yields and good to excellent
diastereoselectivities (27−29).
To demonstrate the utility of the new method, we prepared
3 on a gram scale. We also used the hydroarylation reaction in
the synthesis of biologically relevant compounds shown in
Table 2. These applications allow us to make a direct
comparison to other methods previously used to accomplish
the synthesis of aryl alkenes. Compound 32 was used in the
synthesis of caffeic acid derivative 33, which showed selective
antiproliferative activity in certain highly metastatic carcinoma
cell lines.32 The compound was originally prepared using a
Wittig reaction (25% yield and 3.3:1 Z:E selectivity).32 More
recently, Hu et al. prepared 32 by Z-selective hydroalkylation
of aryl acetylenes using 3 equiv of the alkyl iodide (44% yield
and 7.6:1 Z:E selectivity).13a The hydroarylation of terminal
alkyne shown in Table 2 provided 32 in 81% yield and 16:1
Z:E selectivity. Compounds 34 and 35 are among the most
various Cu/Pd catalyst combinations, including alkyne
homocoupling, reduction of the aryl bromide,22 and hydro-
silylation of the terminal and internal alkynes (see the
Supporting Information for details).26a
The performance of various phosphine ligands in the
hydroarylation reaction revealed some general trends that
guided further reaction development. Homocoupling of the
alkyne was a major product with common bidentate ligands,
such as BINAP (Table 1, entry 1). Monodentate trialkyl
phosphine ligands, such as PCy3, fully suppressed the
homocoupling, but greatly decreased conversion (entry 2).
With dialkylbiaryl phosphine ligands,28 such as XPhos and
SPhos, full consumption of the starting material was achieved,
although hydrosilylation and reduction of the starting materials
dominated (entries 3 and 4). Interestingly, ligand L129 showed
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Table 2. Scope and Applications of Z-Selective Hydroarylation
a
Reactions performed on 0.5 mmol scale. Reported are isolated yields of purified mixtures of product diastereoisomers. Z:E ratios of products
determined by GC analysis of crude reaction mixtures are reported in parantheses. Conditions: IPrCuCl (10 mol %), Pd(OAc)2 (5 mol %), L1 (10
b
mol %), Me2i-PrSiH (2 equiv), NaOt-Bu (2 equiv), toluene, 45 °C, 2 h. Reaction conditions: IPrCuCl (10 mol %), Pd(OAc)2 (5 mol %), L1 (10
c
mol %), Me2i-PrSiH (2 equiv), LiOt-Bu (2 equiv), toluene, 45 °C, 3 h, then MeOH (4 equiv) and NaOt-Bu (2 equiv), 60 °C. i-BuOH was used
d
e
instead of MeOH. Reaction performed at 0 °C. t-BuOH was used instead of MeOH, and the semireduction was performed at 60 °C after
f
addition of alcohol. Reaction was monitored by GC.
active analogues of natural product Combretastatin A4, which
is a potent inhibitor of tubulin polymerization.33 Like many
other analogues, these have been prepared with relatively low
Z-selectivity using Wittig reaction.34 Using our hydroarylation
reaction, both compounds were prepared in high yield (>80%)
and with excellent Z-selectivity (>30:1).
Table 3. Change in Z-Selectivity over Timea
To ensure high Z-selectivity in synthesis of compounds
shown in Table 2, we monitored the reaction progress by TLC,
and stopped the reactions when the products of the
Sonogashira coupling were consumed. Careful monitoring of
the reaction progress by gas chromatography (GC) established
that in several representative cases, high Z selectivity (10:1)
can be achieved in a 20 min window within the first hour after
the addition of MeOH (Table 3). In the absence of MeOH,
isomerization is significantly slower and good Z selectivity is
observed even 24 h after the complete consumption of the
Sonogashira product (Table 1, entry 6: after 96 h, we obtained
the Z-alkene in 87% yield and Z:E = 11:1).
a
b
Reported selectivities of crude reaction mixture. i-BuOH used
c
instead of MeOH. Reaction mixture contains <10% of alkyne.
d
Combined yields of Z and E isomers.
We found it convenient that the rate of the semireduction
additive. The semireduction of internal alkynes containing an
can be adjusted by varying the temperature and the alcohol
electron-deficient arene was slow in the presence of MeOH
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and significantly faster in the presence of isobutanol (i-BuOH).
For example, with MeOH as an additive, the syntheses of
compounds 19 and 25 required more than 24 h, while with i-
BuOH the reductions were completed in less than 2 h.
Conversely, under the standard reaction conditions, the
reduction of the Sonogashira products with electron-rich aryl
bromides (21) was completed in several minutes, which made
monitoring the reaction progress difficult and resulted in low Z
selectivity. At a lower temperature, the reduction was
completed in 6 h. Finally, in syntheses of several products
shown in Table 2, we used LiOt-Bu instead of NaOt-Bu. We
noticed that this was required with more acidic alkynes that
contain electron-withdrawing groups. In these reactions, NaOt-
Bu was completely ineffective in promoting Sonogashira
coupling, and we could recover the starting materials.
Monitoring reactions between different alkynes and the two
bases by in situ 1H NMR did not reveal any clear differences in
these reactions.
Table 4. Isomerization of the Aryl Alkene Product
E-Selective Hydroarylation of Alkynes. Next, we
explored the development of E-selective hydroarylation of
alkynes. The formation of the E isomer would involve the
execution of the following three catalytic processes in tandem:
Sonogashira coupling, semireduction, and alkene isomerization
(Scheme 3c). The feasibility of this approach was supported by
the strong thermodynamic preference for the E isomer of aryl
alkenes. For example, the equilibrium constant for isomer-
ization of Z-1-phenyl-1-propene to the E isomer is 32.2.20
Furthermore, several mechanisms for palladium-catalyzed
alkene isomerization have been established through detailed
mechanistic studies.20
Despite numerous documented mechanisms for palladium-
catalyzed isomerization of aryl alkenes, previous efforts to
develop a preparatively useful method for this transformation
encountered significant problems. Spencer et al. have shown
that (MeCN)2PdCl2 promotes alkene isomerization through a
cationic intermediate.24 Good yields and selectivities are
obtained under mild reaction conditions. However, the
reaction is limited to electron-rich aryl alkenes that can
support the formation of the carbenium intermediate. A more
general method based on reversible hydropalladation of
alkenes was later developed by Jung et al.25 However, they
found that if silane is used as a hydride source, a significant
amount of alkane product is formed well before the
thermodynamic E:Z ratio of alkenes can be reached. To
avoid the reduction of alkenes, Jung et al. used n-Bu3SnH (2.2
equiv) as a hydride source.
On the basis of Jung’s report and our observation that
isomerization of the Z-alkene occurs after the Sonogashira
product is completely consumed, we explored the formation of
E-alkenes using the standard reaction conditions and a range of
phosphine ligands (Table 4). QPhos and DavePhos provided
promising initial results and showed fast isomerization to the
E-isomer. Unfortunately, after 24 h, the reaction with QPhos
ligand afforded the alkene mixture with an E:Z ratio of only
5.2:1.
In the reaction with DavePhos, we observed a significant
amount of hydrosilylation products before E-alkene was the
dominant component in the mixture. L1, which was initially
optimized for the formation of Z isomer, led to the slowest
isomerization of the Z-alkene, but with no side reactions. Even
after 6 days, 95% of the alkene was present as a mixture of the
two isomers (E:Z = 2:1) (entry 6).
Prompted by the excellent combined yield of the alkene
obtained with L1, we explored the effect of other reaction
parameters on isomerization hoping to identify a perturbation
of the standard reaction conditions that would allow us to
achieve full isomerization of Z-alkenes. Surprisingly, we found
that E-alkenes could be obtained using the standard conditions
for Z-selective hydroarylation with one simple change in
reaction stoichiometry. With a larger excess of MeOH additive
(5 equiv), isomerization proceeds within 24 h to provide E-
alkenes in excellent yield and high selectivity (E:Z > 100:1)
(entry 7). In contrast to the Z-selective hydroarylation, strict
monitoring of the reaction progress was not necessary, as we
generally observed <5% yield of the alkane over-reduction
product after 24 h.
The addition of excess MeOH allowed the synthesis of a
wide range of E-aryl alkenes in yields and diastereoselectivities
that were comparable to those observed in the synthesis of Z-
alkenes (Table 5). We observed a similar functional group
compatibility and general scope of the reaction. Nitriles, esters,
epoxides, alkyl halides, tertiary amines, acetals, and silyl ethers
were all compatible with the reaction conditions. Both aryl and
alkyl alkynes were, again, viable substrates.
We have also used the E-selective hydroarylation in the
synthesis of biologically active compounds or their precursors.
Electrophile 56 was previously used in the synthesis of
LY223982, a Leukotriene B4 antagonist developed by Ely Lilly
& Co.35 56 was originally prepared in three steps and 5% yield
and was used in alkylation of a phenol en route to the target
molecule.35 We have prepared an alternative electrophile 55 in
one step from commercially available materials, in 88% yield
and in excellent selectivity (>100:1). We have also prepared 57
in 85% yield and >100:1 selectivity. In the context of an SAR
study of Combretastatin A4,33 57 was previously prepared
using Wittig reaction in 71% yield as a mixture of E and Z
isomers (E:Z = 1:2.5).
Overall, the two hydroarylation reactions shown in Tables 2
and 5 allow us to access both Z- and E-aryl alkenes, using one
set of starting materials and reagents, and one catalyst system.
Mechanism of Hydroarylation Reactions. Considering
the established mechanisms of the Sonogashira coupling16b
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Table 5. Scope and Applications of E-Selective Hydroarylation
a
Reactions performed on 0.5 mmol scale. Reported are isolated yields of purified mixtures of product diastereoisomers. E:Z ratios reported in
b
parantheses were determined by GC analysis of crude reaction mixtures. See Table 2. Reaction conditions: Same as conditions A, except LiOt-Bu
instead of NaOt-Bu, then after 3 h, NaOt-Bu (2 equiv), MeOH, 60 °C. i-BuOH used instead of MeOH. Reaction placed at 60 °C after addition
of alcohol. Pd(OAc)2 (10 mmol %), L1 (20 mol %). 0.5 equiv of Me2i-PrSiH added after 2 h in addition to 5.0 equiv of MeOH. t-BuOH used
c
d
e
f
g
instead of MeOH.
and the copper-catalyzed semireduction,18,19 a plausible
Scheme 5. Role of Pd and Cu Catalysts in the
mechanism for the Z-selective hydroarylation is presented in
Scheme 4. Monitoring the reaction progress confirmed that the
starting materials (I and II) are fully converted to the
Sonogashira product III before the semireduction.
Semireduction
Scheme 4. Plausible Mechanism of Z-Selective
Hydroarylation
a
Pd(OAc)2 (5 mol %), L1 (10 mol %), IPrCuOt-Bu (10 mol %),
Me2i-PrSiH (2 equiv), NaOt-Bu (1 equiv), t-BuOH (1 equiv),
b
toluene, 45 °C. Yield after 24 h. R = Ph(CH2)3.
In the context of this general mechanism, we were interested
in understanding the relative contributions of the two catalysts
to the individual steps of the reaction. First, we explored the
role of the palladium catalyst in the semireduction and found
evidence that under certain reaction conditions the semi-
reduction of the Sonogashira product is more complicated than
Scheme 4 suggests. Experiments presented in Scheme 5a show
that both palladium and copper catalysts independently
promote selective semireduction. These results suggest that
in the catalytic hydroarylation both catalysts likely contribute
to the semireduction of intermediate III.36 However, in the
absence of the copper catalyst, palladium-catalyzed semi-
reduction does not result in complete conversion, and the
maximum yield of the semireduction product was 41% after 24
h (see the Supporting Information). Furthermore, the relative
contributions of the palladium and copper catalysts to the
semireduction depend on the alcohol additive used in the
reaction.
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When i-BuOH is used instead of MeOH, the contribution of
the palladium catalyst is significantly reduced, and the
semireduction is mostly effected by the copper catalyst
(Scheme 5b). Control experiments presented in Table S8
confirm that palladium contribution depends on the alcohol
additive and not the substrate of the reaction.
presence of MeOH and i-BuOH (Scheme 7). The experiment
confirmed that the reaction is faster in the presence of i-BuOH.
Scheme 7. i-BuOH in Semireduction
We were also interested in understanding the role of the
alcohol additive and the reasons for the changes to the
standard conditions that were necessary with certain substrates.
Initially, we explored the mechanism behind the significant
acceleration of the semireduction in the presence of MeOH
additive, which we observed in both E- and Z-selective
hydroarylation reaction. We found that the rate of the
stoichiometric hydrocupration is significantly higher using
IPrCuOMe versus IPrCuOt-Bu (Scheme 6a) (see the
Scheme 6. Effect of MeOH on Semireduction
In both reactions, we observed a significant amount of the
alkenyl copper intermediate (61) throughout the course of the
reaction (18−20% of alkenyl copper in the reaction with 20
mol % loading of IPrCuOt-Bu; see the Supporting Information
for details). These results suggest that the resting state of the
catalyst in the reaction of electron-deficient alkynes is the
alkenyl copper intermediate and that the turnover limiting step
is the protonation of this intermediate. Somewhat surprisingly,
these results indicate that the protonation of the alkenyl copper
intermediate is significantly faster with i-BuOH than with
MeOH.
Finally, we also explored aspects of the reaction mechanism
specific to the conditions employed in the synthesis of E-aryl
alkenes. In this case, the relative contributions of palladium
and copper catalysts to the semireduction were dramatically
different from their contributions in the Z-selective reaction.
With 5 equiv of MeOH, copper-catalyzed semireduction of the
Sonogashira product provides only 10% of the desired product
and 10% conversion. The data in Scheme 8a show the impact
the increasing amounts of methanol have on the copper-
catalyzed semireduction. These results are consistent with
Supporting Information for complete kinetics data), although
IPrCuOMe is only partially soluble in toluene. Considering
that the alkoxide group plays no role in the hydrocupration of
the alkyne, this observation implies a significant difference in
the rate of IPrCuH formation from IPrCuOR and a silane.
These results are consistent with a computational study, which
attributed a high activation barrier for the reaction between
NHCCuOR and trialkylsilanes to significant steric repulsion in
the transition state.37 Surprisingly, this effect has not been
experimentally observed in reactions mediated by NHCCuH.
The rate of protonation of the alkenyl copper intermediate
60 was also significantly higher with MeOH than with t-BuOH,
as demonstrated by the stoichiometric experiment shown in
Scheme 6b. Consistent with stoichiometric experiments, we
found that the catalytic semireduction of 58 was significantly
faster in the presence of MeOH than in the presence of t-
BuOH (Scheme 6c). Significant concentration of the alkenyl
copper intermediate 60 was observed during copper-catalyzed
semireduction in the presence of either alcohol. This result
indicates that the protonation of the intermediate is at least
partially rate limiting. Overall, it is likely that MeOH
accelerates the semireduction by facilitating both the formation
of the IPrCuH and the protonation of the alkenyl copper
intermediate.
Scheme 8. Role of Pd Catalyst and MeOH in E-Selective
Hydroarylation
a
To understand the effect of i-BuOH additive in reactions
with electron-deficient aryl bromides, we did initial rate
measurements for the semireduction performed in the
Conditions: IPrCuOt-Bu (10 mmol %), Pd(OAc)2 (5 mol %), L1
(10 mol %), NaOt-Bu (1 equiv), t-BuOH (1 equiv), toluene 45 °C.
b
No further progress observed after 24 h.
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competitive protonation of IPrCuH by methanol we previously
observed in the semireduction reaction.19
complete exchange of the same deuterium label, suggesting
that the mechanism remains the same in the presence of
methanol. The extent of deuterium exchange in the presence of
MeOH suggests fast exchange between Pd−H and MeOH.40
In summary, our exploration of the reaction mechanism
provided insight into the roles of the two catalysts and the
effects that alcohol additives and various changes from the
standard reaction conditions have on the reaction. The most
interesting finding is that the alcohol additive changes the role
of each of the two catalysts in the hydroarylation. i-BuOH
inhibits palladium-catalyzed semireduction, while excess
MeOH suppresses copper-catalyzed semireduction and
promotes both the palladium-catalyzed semireduction and
the alkene isomerization. This complementary reactivity of the
two metal catalysts is essential for the success of the
hydroarylation.
The major implication of these results is that under
conditions used in E-selective hydroarylation, the semi-
reduction is predominantly mediated by the palladium catalyst
and is promoted by excess MeOH. Experiments shown in
Scheme 8b confirm the more prominent role of the palladium
catalyst and the key role of MeOH in E-selective hydro-
arylation.
We were also interested in understanding the mechanism of
alkene isomerization in the E-selective hydroarylation. On the
basis of available precedents, isomerization through reversible
hydrocupration of aryl alkenes seems unlikely under the
conditions employed in our reaction.2b,38 Control experiments
shown in Schemes 8b and 9a demonstrate that isomerization
Scheme 9. Palladium-Catalyzed Alkene Isomerization
CONCLUSION
■
We have developed a diastereodivergent method for hydro-
arylation of terminal alkynes. The new method involves a
sequence of catalytic reactions promoted by a combination of
palladium and copper catalysts operating in tandem. The Z-
selective hydroarylation is achieved through Sonogashira
coupling of alkynes and aryl bromides, followed by semi-
reduction. The E-selective hydroarylation involves an addi-
tional isomerization of the Z-aryl alkene. The new hydro-
arylation reactions allow access to both isomers of aryl alkenes
using the same set of starting materials, and the same
combination of catalysts. The hydroarylation reactions have
excellent substrate scopes and functional group compatibility
and provide the desired products in high yields and with high
diastereoselectivity. Mechanistic experiments indicate different
roles of palladium and copper catalysts in Z- and E-selective
hydroarylation reactions. While both are involved in the
Sonogashira coupling, the semireduction is predominantly
promoted by a copper catalyst in the Z-selective reaction, while
the palladium catalyst is necessary for both the semireduction
and the isomerization in the E-selective reaction.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b05113.
requires both the palladium catalyst and the silane.
Furthermore, we found that isomerization can be effectively
accomplished using only the palladium catalyst and a
substoichiometric amount of a silane (Scheme 9b). Interest-
ingly, in contrast to the results reported by Jung,25 we did not
observe the formation of the alkane products. On the basis of
observations we made during the development of the reaction,
we believe that both the ligand and the silane used in the
reaction are responsible for this difference.
Considering the conditions necessary for isomerization, it
seems likely that the formation of E-aryl alkene proceeds
though a reversible hydropalladation of the alkene, one of the
established mechanisms for alkene isomerization. Further
evidence for this mechanism was provided by isotope
incorporation experiments (Scheme 9c). With 10 mol % of
silane, we observed selective and full incorporation of a proton
into d2-3. The position of the proton incorporation is
consistent with the established regioselectivity of styrene
hydropalladation.39 In the presence of MeOH, we observed the
Experimental procedure and product characterization
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*lalic@chem.washington.edu
ORCID
Gojko Lalic: 0000-0003-3615-3423
Author Contributions
†M.K.A. and M.B.G. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by NIH and by the University of
Washington.
H
DOI: 10.1021/jacs.8b05113
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Article
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DOI: 10.1021/jacs.8b05113
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX