Synthesis of Isomerically Pure (Z)-Alkenes from Terminal Alkynes and Terminal Alkenes: Silver-Catalyzed Hydroalkylation of Alkynes

Article abstract of DOI:10.1021/jacs.9b09336

Alkenes are an important class of compounds common among biologically active molecules and often are used as intermediates in organic synthesis. Many alkenes exist in two stereoisomeric forms (E and Z), which have different structures and different properties. The selective formation of the two isomers is an important synthetic goal that has long inspired the development of new synthetic methods. However, the efficient synthesis of diastereopure, thermodynamically less stable, Z-alkenes is still challenging. Here, we demonstrate an efficient synthesis of diastereopure Z-alkenes (Z:E > 300:1) through a silver-catalyzed hydroalkylation of terminal alkynes, using alkylboranes as coupling partners. We also describe the exploration of the substrate scope, which reveals the broad functional group compatibility of the new method. Preliminary mechanistic studies suggest that a 1,2-metalate rearrangement of the silver borate intermediate is the key step responsible for the stereochemical outcome of the reaction.

Full text of DOI:10.1021/jacs.9b09336

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Synthesis of Isomerically Pure (Z)‑Alkenes from Terminal Alkynes
and Terminal Alkenes: Silver-Catalyzed Hydroalkylation of Alkynes
Mitchell T. Lee,† Madison B. Goodstein,† and Gojko Lalic*
Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
synthesis of Z-alkenes,5 such as alkyne semireduction,6 cross-
coupling reactions,7 alkene cross metathesis,8 or alkene
ABSTRACT: Alkenes are an important class of com-
pounds common among biologically active molecules and
isomerization.9
often are used as intermediates in organic synthesis. Many
alkenes exist in two stereoisomeric forms (E and Z),
which have different structures and different properties.
The selective formation of the two isomers is an important
synthetic goal that has long inspired the development of
new synthetic methods. However, the efficient synthesis of
diastereopure, thermodynamically less stable, Z-alkenes is
still challenging. Here, we demonstrate an efficient
synthesis of diastereopure Z-alkenes (Z:E > 300:1)
through a silver-catalyzed hydroalkylation of terminal
alkynes, using alkylboranes as coupling partners. We also
describe the exploration of the substrate scope, which
reveals the broad functional group compatibility of the
new method. Preliminary mechanistic studies suggest that
a 1,2-metalate rearrangement of the silver borate
intermediate is the key step responsible for the stereo-
chemical outcome of the reaction.
We were intrigued by the idea that hydroalkylation of
alkynes is one reaction that may allow us to accomplish all
three goals of Z-alkenes synthesis. Hydroalkylation has already
proven effective in the synthesis of E-alkenes through reductive
coupling of terminal alkynes with alkyl iodides10 or alkyl
triflates (Scheme 1a).11 The same approach is also effective
Scheme 1. Hydroalkylation of Alkynes
lkenes serve as important intermediates in organic
Asynthesis and are often found among pharmaceuticals
and other biologically active compounds. The key feature of
alkenes is the presence of a π bond, which hinders the rotation
about the carbon−carbon σ-bond1 and confers structural
rigidity to alkenes. The hindered rotation also leads to two
distinct stereoisomeric forms of disubstituted alkenes, denoted
as E and Z.2 An efficient synthesis of thermodynamically less
stable Z-alkenes presents a complex set of challenges that
continues to inspire the development of new synthetic
methods.
The efficient synthesis of Z-alkenes must accomplish three
important goals. The most basic goal is to form a double bond.
The synthesis should also exert complete control over the
double bond geometry, so that only the Z isomer of the alkene
is formed. The synthesis of diastereopure products is
particularly important considering the difficulties often
encountered in the separation of alkene isomers. Finally, a Z-
alkene should be constructed from two smaller fragments
through the formation of a new C−C σ-bond.3 Such a
convergent approach to synthesis has long been recognized as
key for the efficient buildup of molecular complexity.4 Ideally,
all three goals of Z-alkene synthesis (π-bond formation,
formation of only one isomer, and C−C σ-bond formation)
should be accomplished in a single reaction. Unfortunately, this
is difficult to achieve using standard catalytic methods for the
when applied to the synthesis of 1,1-disubstituted alkenes
(Scheme 1b).12 Still, hydroalkylation reactions had limited
success targeting Z-alkenes. Z-Selectivity has, so far, been
achieved only in an iron-catalyzed radical hydroalkylation,
reported by Hu et al. in 2015 (Scheme 1c). This method is
limited to reactions of aryl acetylenes and yields mixtures of E-
and Z-alkenes with varying selectivity.13
Unfortunately, other mechanistic paradigms used to
accomplish hydroalkylation favor the formation of E-alkenes.
As a result, to achieve the synthesis of pure Z-alkenes we need
a fundamentally new approach to hydroalkylation of alkynes.
Here, we describe a catalytic method for the synthesis of
diastereopure Z-alkenes through the coupling of terminal
alkynes and alkylboranes. The development of this method was
Received: August 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b09336
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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inspired by a 1975 report from H. C. Brown (Scheme 2a).14 In
the report, Brown showed that lithium acetylides readily add to
Scheme 3. Proposed Catalytic Cycle
Scheme 2. New Approach to Hydroalkylation
b
Table 1. Development of Hydroalkylation Reaction
alkylboranes to form borate complexes. Further reaction of the
borate with a Brønsted acid leads to a 1,2-metalate shift15,16
and the formation of both isomers of alkenyl borane, with Z
being the major isomer. The stereochemical outcome has been
attributed to the nature of the 1,2-metalate shift, which is
proposed to proceed through a carbocation intermediate.14c
Subsequent protodeboration provides a mixture of Z- and E-
alkenes.14c,17
We reasoned that in the 1,2-metalate shift described by
Brown, the Brønsted acid could be replaced by a cationic
complex of a coinage metal (Scheme 2b). The 1,2-metalate
shift promoted by π-acid coordination18,19 to the alkyne has
been shown to require antiperiplanar orientation of the π-acid
and the migrating group20 and would allow exclusive formation
of the Z-alkene product. Furthermore, the coinage metal
complex could be delivered in the form of a metal acetylide
that would replace the lithium acetylide used in the reaction
sequence described by Brown. Ultimately, these simple
changes would allow us to develop a catalytic process that
results in the exclusive formation of Z-alkenes.
Scheme 3 shows the postulated mechanism of such a
catalytic reaction. In the presence of an alkoxide base, a
coinage metal catalyst promotes acetylide formation, which is
followed by addition to the alkyl borane. Upon addition, the
metal counterion coordinates to the alkyne and promotes the
1,2-metalate shift through π-activation of the alkyne. Finally,
alkene formation is accomplished by protodeboration and
protodemetalation of the intermediate in the presence of an
alcohol additive.
a
Isooctane was used instead of toluene. Ar = methyl-4-benzoate.
Only Z-alkene was detected in crude reaction mixtures by GC and
b
1H NMR analysis. The standard reaction conditions are bolded in red.
Crucially, only the Z isomer of alkene product 3 was formed in
the reaction. Through further optimization of the reaction
parameters, we found that a triazole carbene ligand and a
nonpolar solvent provided the highest yield of the Z-alkene
product. Under optimized conditions, complete conversion
was achieved using a modest excess (1.3−1.5 equiv) of the
alkylborane, which was prepared in situ from an alkene.
Standard control experiments confirmed that the catalyst, base,
and methanol were all necessary for the reaction (see the SI).
The new transformation proved to be remarkably general,
providing Z-alkenes as exclusive products with a wide range of
substrates (Table 2). Functionalized alkyl alkynes could be
successfully used in the reaction together with both electron-
rich and electron-poor aryl alkynes. Alkylboranes prepared in
situ from a variety of terminal alkenes, including 1,1-
disubstituted alkenes, could be used as substrates. Further-
more, a wide range of functional groups was tolerated. Alkene
products were formed in the presence of alcohols, aldehydes,
ketones, esters, nitriles, alkenes, Boc-protected primary and
secondary amines, anilines, alkyl bromides, alkyl chlorides, aryl
With the broad strategy outlined in Scheme 3 in mind, we
explored the reaction of alkyne 1 with alkylborane 2 in the
presence of a copper, silver, or gold catalyst (Table 1).
Surprisingly, the silver catalyst performed the best, even
though silver complexes are expected to be the least π-acidic.21
B
DOI: 10.1021/jacs.9b09336
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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d
Table 2. Reaction Scope
a
b
Conditions: IPrAgCl (10 mol %), alkyl borane (1.5 equiv), LiOt-Bu (2.0 equiv), MeOH (1.1 equiv), toluene (5 mL), 60 °C, 16 h. R =
c
d
1
propylbenzene. Yield determined by H NMR. Reactions were performed on a 0.5 mmol scale. Reported are yields of isolated products after
purification by silica gel chromatography. In all reactions, the Z:E ratio of products was estimated to be >300:1 (see text). Alkylboranes were
prepared in situ by stirring the corresponding alkene (1 equiv) and 9-borabicyclo[3.3.1]nonane dimer (0.45 equiv) in toluene (2 M) at 60 °C.
Reaction conditions: TriAgCl (10 mol %), alkylborane (1.3 equiv), LiOt-Bu (1.5 equiv), MeOH (1.1 equiv), isooctane (5 mL), 45 °C, 16 h.
C
DOI: 10.1021/jacs.9b09336
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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Journal of the American Chemical Society
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iodides, aryl bromides, aryl boronic esters, epoxides, acetals,
and alkyl and silyl ethers. Heterocycles such as pyridine,
thiazole, benzimidazole, benzopyrazine, pyrimidine, pyridazine,
thiophene, and furan were also compatible with the reaction
conditions. The reaction could be performed on a preparative
scale, yielding 1 g of alkene 3. Finally, in the synthesis of alkene
4, careful analysis of the crude reaction mixture by GC and
GC/MS using authentic samples of Z and E isomers of the
alkene revealed the presence of a very small amount of the E
isomer (Z:E = 570:1). Similar GC analysis of crude reaction
mixtures obtained in the synthesis of 3, 17, 35, 39, and 41, in
all cases, indicated the Z:E ratio was greater than 300:1.22
Several limitations in the scope of the hydroalkylation
reaction were noted. While primary alkyl groups participate in
the 1,2-metalate shift, secondary and tertiary alkyl, alkenyl, and
aryl groups do not. Free amines, carboxylic acids, and
carboxylates are not compatible with the reaction. We also
noticed that the presence of an electron-withdrawing group
two carbons away from the boron in alkyl boranes significantly
lowers the yield of the reaction.
accomplished by preparing alkene 60 in 93% yield and 100%
Z-selectivity. Falcarindiol has been shown to have a range of
pharmacologically useful properties, including anticancer
activity in breast cancer cells.26
To probe the mechanism of the reaction, we explored the
feasibility of the elementary steps in our postulated catalytic
cycle (Scheme 5). In a stoichiometric reaction, we found that
Scheme 5. Experiments Probing the Reaction Mechanism
We have explored the application of the new method in the
synthesis of biologically active compounds. Zucapsaicin is used
in the treatment of osteoarthritis and neuropathic pain
(Scheme 4a).23 The formal synthesis24 of this synthetic
analogue of capsaicin was accomplished by the synthesis of
57 in 82% yield as a single isomer. A formal racemic synthesis
of the natural product falcarindiol25 (Scheme 4b) was
the silver catalyst, in the presence of an alkoxide, readily reacts
with a terminal alkyne 61 to produce silver acetylide 62
(Scheme 5). The acetylide rapidly reacts with alkyl borane 2 to
produce borate complex 63. The X-ray structure of this
complex (Figure 1) indicates that the silver cation associated
Scheme 4. Applications
Figure 1. X-ray structure of borate complex 63 with thermal ellipsoids
at 50% probability. Disorder in one phenyl group and one isopropyl
group has been omitted for clarity.
with the borate is coordinated to the alkyne and is therefore
poised to promote the 1,2-metalate shift. However, the
unfavorable orientation of the migrating alkyl group is
consistent with the observed stability of this intermediate. In
a control experiment, we confirmed that the silver borate
complex is a viable catalyst for the hydroalkylation reaction
(see the SI).
These experimental observations provide direct support for
some of the key aspects of the proposed reaction mechanism
shown in Scheme 3 (M = Ag). Further studies are necessary to
D
DOI: 10.1021/jacs.9b09336
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX