Catalytic Anti-Markovnikov Hydroallylation of Terminal and Functionalized Internal Alkynes: Synthesis of Skipped Dienes and Trisubstituted Alkenes

Article abstract of DOI:10.1021/jacs.7b02104

We have developed catalytic anti-Markovnikov hydroallylation of terminal and functionalized internal alkynes. In this article, we describe the development of the reaction, exploration of the substrate scope, and a study of the reaction mechanism. Synthesis of skipped dienes through the hydroallylation of terminal alkyl and aryl alkynes with simple allyl phosphates and 2-substituted allyl phosphates is described. The hydroallylation of functionalized internal alkynes leads to the formation of skipped dienes containing trisubstituted alkenes. We demonstrate that the hydroallylation of internal alkynes can be used in the regio- and diastereoselective synthesis of complex trisubstituted alkenes. A mechanism of the hydroallylation reaction is proposed, and experimental evidence is provided for the key steps of the catalytic cycle. Stoichiometric experiments demonstrate an unexpected role of lithium alkoxide in the carbon-carbon bond-forming step of the reaction. A study of the hydrocupration of internal alkynes provides new insight into the structure, stability, and reactivity of alkenyl copper intermediates, as well as insight into the source of the regioselectivity in reactions of internal alkynes.

Full text of DOI:10.1021/jacs.7b02104

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Article
Catalytic Anti-Markovnikov Hydroallylation of Terminal and Functionalized
Internal Alkynes: Synthesis of Skipped Dienes and Trisubstituted Alkenes
Melrose Mailig, Avijit Hazra, Megan K Armstrong, and Gojko Lalic
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 28 Apr 2017
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Journal of the American Chemical Society
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Catalytic Anti-Markovnikov Hydroallylation of Terminal and
Functionalized Internal Alkynes: Synthesis of Skipped Dienes
and Trisubstituted Alkenes
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Melrose Mailig,† Avijit Hazra,† Megan K. Armstrong, and Gojko Lalic*
Department of Chemistry, University of Washington, Seattle, Washington 98195
ABSTRACT: We have developed catalytic anti-Markovnikov hydroallylation of terminal and functionalized internal alkynes. In
this article, we describe the development of the reaction, exploration of the substrate scope, and a study of the reaction mechanism.
Synthesis of skipped dienes through the hydroallylation of terminal alkyl and aryl alkynes with simple allyl phosphates and 2-
substituted allyl phosphates is described. The hydroallylation of functionalized internal alkynes leads to the formation of skipped
dienes containing trisubstituted alkenes. We demonstrate that the hy-
droallylation of internal alkynes can be used in the regio- and diastere-
oselective synthesis of complex trisubstituted alkenes. A mechanism of
the hydroallylation reaction is proposed, and experimental evidence is
provided for the key steps of the catalytic cycle. Stoichiometric exper-
iments demonstrate an unexpected role of lithium alkoxide in the car-
bon-carbon bond-forming step of the reaction. A study of the hydrocu-
pration of internal alkynes provides new insight into the structure, stability, and reactivity of alkenyl copper intermediates, as well
as insight into the source of the regioselectivity in reactions of internal alkynes.
functionalized. Furthermore, this approach allows the prepara-
Introduction
tion of highly substituted skipped dienes, which may be diffi-
cult to prepare using other methods. One drawback of the hy-
droalkenylation approach is that a mixture of diastereoisomers
is often obtained,8b although high diastereoselectivity can be
achieved.10
Skipped or 1,4-dienes are found in a number of natural prod-
ucts.1 The importance of this class of compounds and the chal-
lenges associated with their preparation2 have spurred the de-
velopment of numerous methods for their synthesis. Some rely
on reactions commonly used in preparation of simple alkenes.3
Others have been specifically designed for the synthesis of
skipped dienes. One example of such a method, and at the
same time one of the best stoichiometric methods for the syn-
thesis of skipped dienes, is titanium-mediated coupling of
allylic alcohols with alkynes, developed by Micalizio et al.4
Over the last ten years, the focus has mostly been on the de-
velopment of new catalytic reactions that yield skipped dienes.
These catalytic reactions generally belong to one of the three
major classes: 1) Cross-coupling reactions of alkenyl organo-
metallic reagents with electrophiles, 2) hydroalkenylation of
1,3-dienes, and 3) hydroallylation of alkynes (Scheme 1).
Transition metal catalyzed cross-coupling reactions of various
organometallic reagents with a variety of electrophiles have
been used to access skipped dienes.5 The most notable exam-
ples of this approach are catalytic enantioselective reactions of
alkenylboron6 and alkenylaluminum7 compounds with allylic
electrophiles. Another excellent method, developed by Sigman
et al., is based on a variation of the cross-coupling approach,
and involves palladium-catalyzed reaction of 1,3-butadiene
with enol triflates and alkenylboron compounds.2,5n
Scheme 1. Catalytic reactions for the synthesis of skipped
dienes.
Finally, skipped dienes can also be prepared by hydroallyla-
tion of alkynes.11 While less common than cross-coupling and
hydroalkenylation reactions, hydroallylation methods have
proven to be highly effective. Recently, Montgomery et al.
reported an excellent method for the synthesis of skipped
dienes shown in Scheme 2a.11d In this formal hydroallylation
reaction, alkynes are reductively coupled with enones in the
presence of a nickel catalyst, a silane, and a stoichiometric
Hydroalkenylation of 1,3-dienes also provides skipped dienes
and can be accomplished using Co,8 Ni,9 or Fe10 catalysts. A
major advantage of hydroalkenylation methods over cross-
coupling reactions is that substrates do not need to be pre-
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amount of Ti(Oi-Pr)4. Excellent regio- and diastereoselectivity of hydrofunctionalization reactions with excellent anti-
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was observed with a wide range of substrates, together with a
good functional group compatibility. The reaction works par-
ticularly well with symmetrical internal alkynes and alkyl aryl
alkynes.
Markovnikov regioselectivity and E diastereoselectivity (eq
1). Using this approach, Tsuji et al. developed a catalytic hy-
drocarboxylation of alkynes,18 while our group developed
catalytic methods for the hydrobromination19 and hydroalkyla-
tion of alkynes.20 We anticipated that the same approach could
be used to accomplish an anti-Markovnikov hydroallylation of
alkynes.
Several methods for Markovnikov hydroallylation of alkynes
are known.12 The most general is the ruthenium-catalyzed
hydroallylation of terminal alkynes reported by Trost et al. in
1998 (Scheme 2b).11a,11b The reaction proceeds with excellent
Markovnikov selectivity (with respect to the alkyne) and has
exceptional substrate scope and functional group compatibil-
ity. This method has been successfully used with complex
substrates and as a key step in the synthesis of natural prod-
ucts.5o,11a,13 Lee and Trost have later shown that good regiose-
lectivity can also be obtained using boro-,14 silyl-,15 and al-
kynyl-substituted16 internal alkynes. Overall, this reaction is
one of the most well-developed and broadly applicable meth-
ods for the synthesis of skipped dienes.17
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Stoichiometric experiments shown in Scheme 3 demonstrate
that both allyl chloride and allyl phosphate are competent elec-
trophiles in a reaction with isolated alkenyl copper complex
5.21 The less reactive electrophiles, such as allyl acetate and
allyl carbonate provide the desired product in less than 10%
yield. Using these results as a starting point we were able to
develop a method for the catalytic hydroallylation of terminal
alkynes, shown in Table 1. The best results were obtained
using IPrCuOt-Bu as a catalyst, polymethylhydrosiloxane
(PMHS) as a hydride source, and LiOt-Bu as a turnover rea-
gent. The reaction is performed in toluene and is completed
after 16 h at 45 °C. During our efforts to identify the best con-
ditions for the hydroallylation reaction, we made several ob-
servations summarized in Table 1.
Scheme 2. Alkynes in the synthesis of skipped dienes.
Scheme 3. Stoichiometric allylation of an alkenyl copper
complex
Even though both allyl chloride and allyl phosphate gave high
yields in the stoichiometric reaction with the alkenyl copper
complex, in the catalytic reaction, allyl phosphate provided a
significantly higher yield of the desired product (entries 1 and
2). NHC copper(I) tert-butoxide performed better than NHC
copper(I) chloride as a catalyst precursor (entries 1 and 3). As
in other catalytic transformations that involve hydrocupration
of alkynes,19-20,22 we found that copper complexes supported
by IPr or SIPr ligands are the most effective catalysts. Closely
related ligands shown in entries 5, 6, and 7 gave significantly
lower yields of the desired product. Although the exact reason
for the superior performance of these two ligands is not clear,
we suspect that it is related to the lower aggregation and high-
er stability of copper hydride complexes supported by these
sterically hindered ligands.23 Finally, a wide range of copper
complexes supported by phosphine ligands were completely
ineffective as catalysts in the hydroallylation reaction (see SI
for details). Surprisingly, the catalytic system commonly used
in hydrofunctionalization of styrenes, including hydroallyla-
tion, was also completely ineffective.24 This observation fur-
ther supports our observations that the NHC-copper complex-
es are uniquely effective in hydrofunctionalization of alkynes.
High yields in the hydroallylation reaction were obtained in
both aromatic hydrocarbon solvents, such as toluene and chlo-
robenzene, and in ethereal solvents such as THF and 1,4-
dioxane (entries 8, 9, and 10). Surprisingly, isooctane was also
an effective solvent (entry 11). Silane choice proved to be
essential for the success of the reaction. PMHS and
(Me2HSi)2O both performed well (entries 1 and 12). However,
In this article, we describe the development of a direct hy-
droallylation of terminal alkynes (Scheme 2c) with regioselec-
tivity opposite from the Markovnikov selectivity of Trost’s
method. We also demonstrate that nonsymmetrical dialkyl-
substituted alkynes can be used as substrates to provide trisub-
stituted alkene products with excellent regioselectivity. This
class of substrates has not been previously used in the synthe-
sis of skipped dienes, or in any other copper-catalyzed hydro-
functionalization reaction. We demonstrate that hydroallyla-
tion can be used in synthesis of complex trisubstituted alkenes.
Finally, we also describe our investigation of the reaction
mechanism, which suggests a new role of the alkoxy turnover
reagent and provides a new insight into the structure, stability,
and reactivity of the β-functionalized alkenyl copper complex-
es.
Results and Discussion
Reaction development. In the last several years, our group
has focused on the development of a general approach to the
hydrofunctionalization of alkynes. Several groups, including
ours, have shown that syn-diastereospecific hydrocupration of
alkynes, followed by electrophilic functionalization of the
alkenyl copper intermediate can be used to accomplish a range
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with benzyl substituted electrophile 24, we observed a com-
highly reactive (EtO)3SiH (entry 14) gave significantly lower
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yield of the desired product, while a variety of other di and
trialkyl substituted silanes also provided very little of the de-
sired hydroallylation product (entries 13 and 15).
plete conversion of the starting alkyne within 16 h (Table 3).
However, the desired hydroallylation product was a minor
product of the reaction (Table 3, entry 1). Furthermore, all
other identifiable products (desired hydroallylation product,
reduced alkyne, and reductive homo-coupling of the alkyne)
accounted for less than half of the starting material consumed.
Table 2. Hydroallylation of terminal alkynesa
Hydroallylation of terminal alkynes. Hydroallylation of a
wide range of terminal alkynes can be accomplished using the
optimized reaction conditions (Table 2). In all cases, a single
regioisomer and E-diastereoisomer of the desired product is
obtained. The observed selectivity is in line with the results of
the stoichiometric hydrocupration of terminal alkynes, which
is syn-diastereospecific and selective for the anti-Markovnikov
product.22 Furthermore, the reaction can be performed in the
presence of a wide range of functional groups. Electrophilic
carboxylic acid derivatives, such as esters and nitriles, are
compatible with the reaction conditions (compounds 11 and
12). Surprisingly, ketones are also tolerated, despite reports of
rapid reduction of ketones under similar reaction conditions
(compound 13).25 Alkyl electrophiles such as alkyl chlorides,
bromides, and tosylates (compounds 14, 15, 23), as well as
aryl fluoride and aryl iodide (compounds 9 and 10), are also
compatible with the reaction conditions and provide function-
alized skipped dienes.
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Table 1. Reaction development
The failure to obtain the desired product with substituted
phosphates led us to explore conditions that in our preliminary
reaction optimization provided promising results. We found
that isooctane gave results superior to those obtained in tolu-
ene (Table 3, entry 1 vs. 3). Surprisingly, while increasing the
reaction temperature to 60 °C marginally effected the yield of
the desired product, a further increase to 90 °C resulted in the
formation of the desired product in 90% yield (entries 4 and
5).26 A similar increase in temperature with toluene as the sol-
vent was not productive (entry 2).
Table 3. Solvent and temperature effects in reactions with
2-substituted allylic electrophilesa
Variation of the electrophilic components of the hydroallyla-
tion reaction proved to be significantly more challenging. Sub-
stitution at the central carbon of the allylic electrophile led to a
dramatic decrease in reactivity. In fact, from a range of 2-
substituted allylic electrophiles we explored, only phenyl- and
methyl-substituted substrates provided the desired products in
significant yields under the standard reaction conditions de-
scribed in Table 1. These two electrophiles reacted with a va-
riety of alkynes, as shown in Table 2 (entries 18-23).
Using the reaction conditions shown in entry 5 of Table 3, we
were able to perform hydroallylation reaction with various
substituted allylic phosphates (Table 4). Sterically hindered
substituents and functionalized alkyl substituents are well-
With electrophiles containing other substituents at the 2 posi-
tion, we observed significantly lower yields. For example,
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tolerated (compounds 26, 28, and 31). Chloro- and bromo- withdrawing and electron-donating substituents on the arene
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substituted electrophiles provide functionalized products
which can be further derivatize (compounds 27 and 30).
Table 4. Reactions of 2-substituted allylic electrophilesa
were tolerated (32 and 35). However, somewhat lower yield of
35 suggests that the with highly acidic aryl alkynes the for-
mation of the acetylide may be a problem. Finally, in all reac-
tions only one diastereoisomer is formed and good anti-
Markovnikov regioselectivity is observed (>10:1).
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Hydroallylation of internal alkynes. One of the major chal-
lenges in the hydroallylation of alkynes is the reactivity of
nonsymmetrical internal alkynes. To achieve good regioselec-
tivity with this class of substrates, the existing methods require
significant electronic or steric differentiation of the alkyne
substituents. As a result, the use of internal alkynes in the syn-
thesis of skipped dienes has been generally limited to reactions
of aryl-,11d alkynyl-,16 and silyl-substituted17b alkyl acetylenes.
In the light of these constraints, we were interested in explor-
ing the reactivity of differentially functionalized dialkyl al-
kynes. We found that good regioselectivity (~10:1) can be
obtained with substrates containing a polar functional group in
the propargylic position. With minor changes in the standard
reaction conditions, we were able to accomplish the regio- and
diastereoselective synthesis of skipped dienes that contain a
trisubstituted alkene (Table 6).
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Table 6. Hydroallylation of internal alkynesa
Hydroallylation of aryl alkynes. Aryl alkynes are often poor
substrates for reactions catalyzed by late transition metal com-
plexes. The increased acidity of the alkynes makes the for-
mation of the metal acetylide difficult to avoid, especially in
the presence of a strong base such as LiOt-Bu. Furthermore,
the presence of the aryl substituent can influence the regiose-
lectivity of the hydrometallation step.
Table 5. Reactions of aryl alkynesa
Derivatives of propargylic alcohols, amines, and thiols were
all effective in controlling the regioselectivity of the hydroal-
lylation (compounds 39-41). In all cases, the allylation oc-
curred at the position closer to the functional group (FG, in
Table 6). With substrates in which both sides of the alkyne
contain a polar functional group, the one closer to the alkyne
had a dominant effect and controlled the selectivity (com-
pounds 45-48). As the examples of hydroallylation reaction
shown in Table 6 demonstrate, the overall scope of the reac-
tion with internal alkynes generally mimics the scope observed
Our initial attempts to achieve hydroallylation of aryl alkynes
using the standard reaction conditions were not successful.
However, the change of the solvent to THF and the increase of
the reaction temperature to 60 °C allowed hydroallylation of
several aryl and heteroaryl alkynes (Table 5). Both electron-
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with terminal alkynes. It is worth noting that the trisubstituted
alkene products shown in Table 6 are isolated as a single re-
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gio- and diastereoisomer after purification by silica gel col-
umn chromatography.
Hydroallylation of internal alkynes in the synthesis of
complex trisubstituted alkenes. The hydroallylation of inter-
nal alkynes is also interesting in the context of the synthesis of
trisubstituted alkenes. Selective synthesis of this class of al-
kenes is still a major challenge, as detailed in reviews and
recent publications by Negishi et al.27 The transformation of
internal alkynes into trisubstituted alkenes is a potentially effi-
cient and appealing synthetic strategy. However, it is difficult
to achieve transformations of internal alkynes to trisubstituted
alkenes with high regio- and diastereoselectivity. Recently,
Engle et al. reported a breakthrough in this area, using
homopropargylic picolinamide directing group to achieve se-
lective hydroarylation of internal alkynes (Scheme 4a).28 The
best method for the hydroalkylation of internal alkynes relies
on the cross coupling of alkenyl iodides prepared by Corey’s
selective hydroalumination of propargylic alcohols (Scheme
4b).29
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However, one observation called into question the proposed
mechanism. We noticed that the stoichiometric reaction of
alkenyl copper complex 5 with 1 equiv of allyl phosphate
takes more than 24 h to complete (see SI for details), while
under the same reaction conditions the catalytic reaction is
completed in 16 h. This observation indicates that the pro-
posed allylation of the alkenyl copper complex is kinetically
incompatible with the proposed mechanism of the hydroallyla-
tion reaction.
Scheme 4. Synthesis of trisubstituted alkenes from internal
alkynes.
Scheme 6. Proposed mechanism of hydroallylation
The hydroallylation of internal alkynes described in Table 6
allows the regio- and diastereoselective synthesis of trisubsti-
tuted alkenes from internal alkynes. Considering that the reac-
tion is syn-selective and the allylation occurs proximal to the
directing group, our method provides an excellent complement
to the existing methods shown in Scheme 4. The terminal al-
kene of the hydroallylation products is a versatile synthetic
handle that can be used to access a variety of more complex
trisubstituted alkenes. We demonstrated that the terminal al-
kene of the hydroallylation products can be selectively elabo-
rated through oxidation, hydration, hydroamination, and hy-
droarylation (Scheme 5).
Mechanism of the hydroallylation reaction. Previous work
on copper-catalyzed hydrofunctionalization reactions makes
the general mechanism shown in Scheme 6 plausible. Elemen-
tary steps I, II, and III have strong precedent in the literature in
the form of stoichiometric experiments that demonstrate their
feasibility.18,22-23,30 Stoichiometric reactions shown in Scheme
3 also demonstrate the feasibility of the elementary step IV
(Scheme 6).
To resolve this apparent paradox, we explored the effect of
individual components of the catalytic reaction on the rate of
allylation of the alkenyl copper complex (Scheme 7). In the
presence of LiOt-Bu, the initial rate of the stoichiometric al-
lylation of alkenyl copper complex 5 was 4.7 times higher
than in its absence (see SI for details). To separate the effect of
lithium ions and of the alkoxide we measured the rate of the
reactions in the presence of both 12-crown-4 and LiOt-Bu.
The crown ether has only a minor effect on the initial rate (see
SI for details), indicating that the alkoxide is likely responsible
for the observed rate increase. We also found that the effect is
solvent dependent, and was much smaller in THF (1.6-fold
acceleration with LiOt-Bu vs 4.7 in benzene) (see SI for de-
tails).
In related catalytic transformations, it has been shown that the
identity of the metal alkoxide turnover reagent can have a sig-
nificant effect on the overall rate of the reaction.24a,31 In in-
stances in which the NHC ligand used to support the copper
catalyst contains a sulfonate group, the identity of the sul-
fonate counterion derived from the metal alkoxide has been
shown to effect the selectivity of the reaction between the or-
ganocopper intermediate and the electrophile.32 However, the
Scheme 5. Elaboration of trisubstituted alkenes prepared
by hydroallylation.
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results shown in Scheme 7 provide the first direct evidence for
participation of the alkoxide anion in the electrophilic func-
tionalization of the organocopper intermediate.
Scheme 7. Effect of base on the allylation of an alkenyl
copper complex
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The result of the competition experiment shown in Scheme 8
provides evidence that selective hydrocupration of the alkyne
is feasible. The alkene product 55, which is obtained by the
protonation of the alkenyl copper complex, is formed about
two times faster than 56, which is formed by phosphate reduc-
tion. The competitive reduction of the phosphate is consistent
with the fact that more than one equivalent of an allylic phos-
phate is generally required for the complete consumption of an
alkyne in the hydroallylation reaction.
Hydrocupration of internal alkynes. Nonsymmetrical inter-
nal alkynes have not previously been used as substrates in
copper-catalyzed hydrofunctionalization reactions. As a result,
we were interested in the inherent regioselectivity of the hy-
drocupration of these substrates, as well as in the source of the
regioselectivity. We were also curious about the apparent re-
sistance of the resulting alkenyl copper complexes to β-
elimination of the polar functional groups. Such β-elimination
reactions from alkenyl copper intermediates are well-
documented in catalytic reductions of propargylic electro-
philes37-39 and in copper-catalyzed alkylation and arylation of
propargylic phosphates.31d,40
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One plausible explanation for the rate increase in the presence
of the alkoxide is the formation of alkoxycuprate (53)
(Scheme 7), which acts as the reactive nucleophile in the reac-
tion with allyl phosphates. Alkoxycuprates have been postu-
lated as reactive intermediates in asymmetric reactions of alkyl
lithium reagents performed in the presence of a stoichiometric
amount of copper and chiral alkoxide.33 There are also exam-
ples of isolated and characterized alkoxycuprates.34 Recently,
Sawamura et al, have proposed a related phenoxycuprate as a
reactive species in several copper-catalyzed reactions.35 The
proposed phenoxycuprate is formed by an intramolecular addi-
tion of the phenoxide, which is a part of the NHC ligand that
supports the copper catalyst.
We investigated the interaction of the alkenyl copper 5 with
LiOt-Bu using in situ 1H and 13C NMR and found no evidence
for the cuprate formation. Nevertheless, if the reversible for-
mation of the alkoxycuprate is unfavorable under the reaction
conditions, we would not observe the cuprate by NMR. In that
case, the cuprate could still contribute to the increased rate of
the allylation in a typical Curtin-Hammett scenario (low equi-
librium concentration and high reactivity).
The third step of the proposed catalytic cycle also required
additional verification, as it was not consistent with our previ-
ous work on copper-catalyzed hydrofunctionalizations of al-
kynes. One of the key features of (NHC)CuH complexes is
that they quickly reduce a range of organic electrophiles in-
cluding alkyl iodides,36 alkyl triflates,36 propargylic
epoxides,37 and carbonates.38 As a result, in both hydroalkyla-
tion and hydrobromination of alkynes selective hydrocupration
in the presence of the electrophile was not possible. Instead,
hydroalkylation was shown to proceed through a different
mechanism that involves a series of dinuclear analogues of the
intermediates proposed in Scheme 6. In the hydrobromination
reaction, on the other hand, slow addition of the electrophile
was necessary in order to avoid its reduction. In contrast to
these two hydrofunctionalization reactions, the mechanism of
the hydroallylation (Scheme 6) requires selective hydrocupra-
tion of alkynes by IPrCuH in the presence of the allyl phos-
phate.
To explore the regioselectivity of the hydrocupration and the
stability of the alkenyl copper complex, we performed the
stoichiometric hydrocupration of OTBS-substituted alkyne 57
1
(Scheme 9). H NMR analysis of the crude reaction mixture
indicated that hydrocupration proceeds with excellent regiose-
lectivity (rs >25:1). We were able to obtain an X-ray crystal
structure of hydrocupration product 58, and thus unambigu-
ously establish the regioselectivity of the hydrocupration (see
Fig. 1).
Scheme 9. Stoichiometric hydrocupration of internal al-
kynes
Alkenyl copper complex 58 proved to be quite stable in C6D6
solution at 45 °C: after 1 h, 99% of material remained intact,
while after 24 h, 79% of the material was still present in solu-
tion (see SI for details). On the other hand, the hydrocupration
product obtained from thioether substituted alkyne 59 was
significantly more prone to elimination. We could identify a
small amount of the expected alkenyl copper complex 60 by
1H NMR analysis of the reaction mixture. However, attempts
to isolate 60 yielded only IPrCuSPh, the expected product of
the β-thiolate elimination. The formation of the hydroallyla-
tion product 40 (Table 6) suggests that the allylation of the
Scheme 8. Hydrocupration of alkynes in the presence of
allyl phosphate
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viable substrates in the catalytic hydroalkylation reaction.
alkenyl copper intermediate can outcompete the β-thiolate
elimination.
1
These results also emphasize the unique potential of the hy-
droallylation reaction as a method for the regio- and diastere-
oselective synthesis of trisubstituted alkenes from internal
alkynes.
Scheme 10. Allylation and alkylation of alkenyl copper
complex 58
2
3
4
5
6
7
8
9
The stoichiometric hydrocupration of OTBS-substituted al-
kyne 57, also provides important information about the source
of the regioselectivity in the hydrocupration. The oxygen atom
in ROTBS moiety is significantly less basic than oxygen atom
in dialkyl ethers,41 and has been shown not to coordinate even
highly electrophilic metal complexes, such as TiCl4.42 Fur-
thermore, the X-ray structure of the alkenyl copper complex
58 (Figure 1) reveals no interaction between the OTBS and
copper (Cu-O distance is 3.22 Å). Based on these considera-
tions, we conclude that the regioselectivity is not a result of a
direct interaction between OTBS and the catalyst. Instead, the
likely explanation is that the inductive effect of the OTBS
substituent causes polarization of the alkyne and results in the
observed regioselectivity. Similar electronic effects were re-
cently invoked by Hartwig et al.43 to rationalize regioselectivi-
ty in the hydroamination of alkenes containing homoallylic
directing groups.
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59
60
Conclusion
We have developed a new method for the anti-Markovnikov
hydroallylation of alkynes. The hydroallylation is syn-
stereospecific and highly regioselective, which in most cases
leads to the formation of a single product. The reaction can be
performed in the presence of a wide range of functional
groups, including esters, nitriles, ketones, sulfonate esters,
alkyl halides, aryl halides, sulfonamides, thioethers, and silyl
ethers. The new method provides stereoselective access to a
range of skipped dienes from readily available starting materi-
als. The method also allows regio- and stereoselective synthe-
sis of trisubstituted alkenes from functionalized internal al-
kynes. This is a major advantage of the hydroallylation reac-
tion over the recently reported copper-catalyzed hydroalkyla-
tion reaction, which was limited to transformations of terminal
alkynes. Our studies of the key steps of the proposed catalytic
cycle suggest that divergent reactivity of the alkenyl copper
intermediate with alkyl triflates and allyl phosphates is respon-
sible for this major difference in scope of the two reactions.
These studies also suggest an unexpected role of LiOt-Bu in
allylation step of the catalytic cycle. We have also uncovered
unexpected resistance of alkenyl copper complexes to β-
elimination of polar functional groups and interesting differ-
ences in the reactivity of alkenyl copper complexes derived
from internal alkynes toward allylic and alkyl electrophiles.
Figure 1. ORTEP presentation of the crystal structure of alkenyl
copper complex 58, with thermal ellipsoids at the 50% probability
level. Disorder omitted for clarity (see SI for details).
Allylation vs. alkylation of alkenyl copper complexes 58.
After exploring the structure and stability of 58, we examined
its reactivity. We performed stoichiometric reactions with two
carbon based electrophiles that can produce trisubstituted al-
kenes (Scheme 10). In the reaction with allyl phosphate (8),
we observed the formation of the desired product in 90% yield
within 1 h at 25 °C. It is interesting to note that this allylation
reaction is significantly faster than the reaction of terminal
alkenyl copper complex (5) with the same electrophile
(Scheme 3).
ASSOCIATED CONTENT
Supporting Information. Experimental procedures and charac-
terization of new compounds. The Supporting Information is
available free of charge on the ACS Publications website at DOI:
AUTHOR INFORMATION
Corresponding Author
The alkylation of alkenyl copper complexes with alkyl triflates
is the key step in the catalytic hydroalkylation of alkynes pre-
viously developed in our lab.20 With terminal alkenyl copper
complexes, the stoichiometric alkylation reaction proceeds
quickly to produce the alkylation product in 50% yield, to-
gether with the formation of half an equivalent of the dinuclear
alkenyl copper complex.20 In the reaction of the alkenyl copper
complex 58 with alkyl triflate 61, we observed elimination
product 62 in 89% yield. The unexpected elimination reaction
shows the dramatic effect the electrophile has on the reactivity
of alkenyl copper complexes derived from internal alkynes
and may explain why internal alkynes, such as 57, are not
*lalic@chem.washington.edu
Author Contributions
† These authors contributed equally. The manuscript was written
through contributions of all authors. All authors have given ap-
proval to the final version of the manuscript.
Funding Sources
Financial support by NSF is acknowledged (NSF CAREER
Award 1254636)
ACKNOWLEDGMENT
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(16) Trost, B. M.; Koester, D. C.; Herron, A. N. Angew. Chem., Int.
Ed. 2015, 54, 15863.
(17) Cho, E. J.; Lee, D. J. Am. Chem. Soc. 2007, 129, 6692.
We thank Maike Blakely and Werner Kaminsky for assistance
with X-ray crystallography.
1
2
3
4
(18) (a) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew.
Chem., Int. Ed. 2005, 44, 6630; (b) Trost, B. M.; Cregg, J. J. J. Am.
Chem. Soc. 2015, 137, 620.
ABBREVIATIONS
(19) Fujihara, T.; Xu, T.; Semba, K.; Terao, J.; Tsuji, Y. Angew.
Chem., Int. Ed. 2011, 50, 523.
(20) Uehling, M. R.; Rucker, R. P.; Lalic, G. J. Am. Chem. Soc.
2014, 136, 8799.
(21) (a) Uehling, M. R.; Suess, A. M.; Lalic, G. J. Am. Chem. Soc.
2015, 137, 1424; (b) Suess, A. M.; Uehling, M. R.; Kaminsky, W.;
Lalic, G. J. Am. Chem. Soc. 2015, 137, 7747.
5
6
7
8
REFERENCES
(1) An extensive list of natural products featuring skipped dienes
and exam-ples of problems associated with the synthesis of skipped
dienes is provided by Sigman et al. in the next reference.
(2) McCammant, M. S.; Liao, L.; Sigman, M. S. J. Am. Chem. Soc.
2013, 135, 4167.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(22) (a) Rona, P.; Tokes, L.; Tremble, J.; Crabbe, P. J. Chem. Soc.
D: Chem. Commun. 1969, 43; (b) Alexakis, A.; Bäckvall, J. E.;
Krause, N.; Pàmies, O.; Diéguez, M. Chem. Rev. 2008, 108, 2796.
(23) Whittaker, A. M.; Lalic, G. Org. Lett. 2013, 15, 1112.
(24) Jordan, A. J.; Lalic, G.; Sadighi, J. P. Chem. Rev. 2016, 116,
8318.
(25) (a) Wang, Y.-M.; Buchwald, S. L. J. Am. Chem. Soc. 2016,
138, 5024; (b) For a related reaction of alkenyl boronates, see: Han, J.
T.; Jang, W. J.; Kim, N.; Yun, J. J. Am. Chem. Soc. 2016, 138, 15146.
(26) (a) Díez-González, S.; Kaur, H.; Zinn, F. K.; Stevens, E. D.;
Nolan, S. P. J. Org. Chem. 2005, 70, 4784; (b) Kaur, H.; Zinn, F. K.;
Stevens, E. D.; Nolan, S. P. Organometallics 2004, 23, 1157.
(27) At the reviewer's suggestion, we also explored the reaction in
heptane, and obtained very similar results (see SI for details).
(28) (a) Negishi, E.-i.; Wang, G.; Rao, H.; Xu, Z. J. Org. Chem.
2010, 75, 3151; (b) Negishi, E.-i.; Huang, Z.; Wang, G.; Mohan, S.;
Wang, C.; Hattori, H. Acc. Chem. Res. 2008, 41, 1474; (c) Xu, S.;
Lee, C.-T.; Rao, H.; Negishi, E.-i. Adv. Synth. Catal. 2011, 353, 2981.
(29) Liu, Z.; Derosa, J.; Engle, K. M. J. Am. Chem. Soc. 2016, 138,
13076.
(30) Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am.
Chem. Soc. 1967, 89, 4245.
(31) Mankad, N. P.; Laitar, D. S.; Sadighi, J. P. Organometallics
2004, 23, 3369.
(32) (a) Wang, Y.-M.; Bruno, N. C.; Placeres, Á. L.; Zhu, S.;
Buchwald, S. L. J. Am. Chem. Soc. 2015, 137, 10524; (b) Shido, Y.;
Yoshida, M.; Tanabe, M.; Ohmiya, H.; Sawamura, M. J. Am. Chem.
Soc. 2012, 134, 18573; (c) Yoshida, M.; Ohmiya, H.; Sawamura, M.
J. Am. Chem. Soc. 2012, 134, 11896; (d) Uehling, M. R.; Marionni, S.
T.; Lalic, G. Org. Lett. 2012, 14, 362.
(33) (a) Shi, Y.; Hoveyda, A. H. Angew. Chem., Int. Ed. 2016, 55,
3455; (b) Shi, Y.; Jung, B.; Torker, S.; Hoveyda, A. H. J. Am. Chem.
Soc. 2015, 137, 8948.
(34) (a) Corey, E. J.; Naef, R.; Hannon, F. J. J. Am. Chem. Soc.
1986, 108, 7114; (b) Tanaka, K.; Ushio, H.; Kawabata, Y.; Suzuki, H.
J. Chem. Soc., Perkin Trans. 1 1991, 1445.
(35) Zanardi, A.; Novikov, M. A.; Martin, E.; Benet-Buchholz, J.;
Grushin, V. V. J. Am. Chem. Soc. 2011, 133, 20901.
(36) (a) Harada, A.; Makida, Y.; Sato, T.; Ohmiya, H.; Sawamura,
M. J. Am. Chem. Soc. 2014, 136, 13932; (b) Yasuda, Y.; Ohmiya, H.;
Sawamura, M. Angew. Chem., Int. Ed. 2016, 55, 10816.
(37) Cox, N.; Dang, H.; Whittaker, A. M.; Lalic, G. Tetrahedron
2014, 70, 4219.
(38) Deutsch, C.; Lipshutz, B. H.; Krause, N. Angew. Chem., Int.
Ed. 2007, 46, 1650.
(39) Deutsch, C.; Lipshutz, B. H.; Krause, N. Org. Lett. 2009, 11,
5010.
(40) Zhong, C.; Sasaki, Y.; Ito, H.; Sawamura, M. Chem. Commun.
2009, 5850.
(41) Ohmiya, H.; Yokobori, U.; Makida, Y.; Sawamura, M. Org.
Lett. 2011, 13, 6312.
(3) (a) Schnermann, M. J.; Romero, F. A.; Hwang, I.; Nakamaru-
Ogiso, E.; Yagi, T.; Boger, D. L. J. Am. Chem. Soc. 2006, 128,
11799; (b) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123,
10772; (c) Xu, S.; Zhu, S.; Shang, J.; Zhang, J.; Tang, Y.; Dou, J. J.
Org. Chem. 2014, 79, 3696.
(4) (a) Diez, P. S.; Micalizio, G. C. J. Am. Chem. Soc. 2010, 132,
9576; (b) Kolundzic, F.; Micalizio, G. C. J. Am. Chem. Soc. 2007,
129, 15112; (c) Macklin, T. K.; Micalizio, G. C. Nat. Chem. 2010, 2,
638; (d) Reichard, H. A.; McLaughlin, M.; Chen, M. Z.; Micalizio, G.
C. Eur. J. Org. Chem. 2010, 391.
(5) (a) Kacprzynski, M. A.; Hoveyda, A. H. J. Am. Chem. Soc.
2004, 126, 10676; (b) Taguchi, H.; Ghoroku, K.; Tadaki, M.; Tsu-
bouchi, A.; Takeda, T. J. Org. Chem. 2002, 67, 8450; (c) Li, H.;
Alexakis, A. Angew. Chem., Int. Ed. 2012, 51, 1055; (d) Huang, Y.;
Fananas-Mastral, M.; Minnaard, A. J.; Feringa, B. L. Chem. Commun.
2013, 49, 3309; (e) Kabalka, G. W.; Al-Masum, M. Org. Lett. 2006,
8, 11; (f) Dey, R.; Chattopadhyay, K.; Ranu, B. C. J. Org. Chem.
2008, 73, 9461; (g) Kong, W.; Che, C.; Kong, L.; Zhu, G. Tetrahe-
dron Lett. 2015, 56, 2780; (h) Castaño, A. M.; Echavarren, A. M.
Tetrahedron Lett. 1996, 37, 6587; (i) Crawforth, C. M.; Burling, S.;
Fairlamb, I. J. S.; Taylor, R. J. K.; Whitwood, A. C. Chem. Commun.
2003, 2194; (j) Kayaki, Y.; Koda, T.; Ikariya, T. Eur. J. Org. Chem.
2004, 4989; (k) Kabalka, G. W.; Venkataiah, B.; Dong, G. Org. Lett.
2003, 5, 3803; (l) Yang, B.; Wang, Z.-X. J. Org. Chem. 2016, DOI:
10.1021/acs.joc.6b02564; (m) Sarkar, S. M.; Uozumi, Y.; Yamada, Y.
M. A. Angew. Chem., Int. Ed. 2011, 50, 9437; (n) McCammant, M.
S.; Sigman, M. S. Chem. Sci. 2015, 6, 1355; (o) Gutierrez, A. C.;
Jamison, T. F. Org. Lett. 2011, 13, 6414.
(6) (a) Hart, D. W.; Blackburn, T. F.; Schwartz, J. J. Am. Chem.
Soc. 1975, 97, 679; (b) Hamilton, J. Y.; Sarlah, D.; Carreira, E. M. J.
Am. Chem. Soc. 2013, 135, 994.
(7) (a) Akiyama, K.; Gao, F.; Hoveyda, A. H. Angew. Chem., Int.
Ed. 2010, 49, 419; (b) Gao, F.; McGrath, K. P.; Lee, Y.; Hoveyda, A.
H. J. Am. Chem. Soc. 2010, 132, 14315; (c) Lee, Y.; Akiyama, K.;
Gillingham, D. G.; Brown, M. K.; Hoveyda, A. H. J. Am. Chem. Soc.
2008, 130, 446.
(8) McCammant, M. S.; Sigman, M. S. Chem. Sci. 2015, 6, 1355.
(9) (a) Arndt, M.; Dindaroğlu, M.; Schmalz, H.-G.; Hilt, G. Org.
Lett. 2011, 13, 6236; (b) Hilt, G.; du Mesnil, F.-X.; Lüers, S. Angew.
Chem., Int. Ed. 2001, 40, 387; (c) Page, J. P.; RajanBabu, T. V. J. Am.
Chem. Soc. 2012, 134, 6556; (d) Sharma, R. K.; RajanBabu, T. V. J.
Am. Chem. Soc. 2010, 132, 3295.
(10) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128, 54.
(11) Moreau, B.; Wu, J. Y.; Ritter, T. Org. Lett. 2009, 11, 337.
(12) (a) Trost, B. M.; Probst, G. D.; Schoop, A. J. Am. Chem. Soc.
1998, 120, 9228; (b) Trost, B. M.; Pinkerton, A. B.; Toste, F. D.;
Sperrle, M. J. Am. Chem. Soc. 2001, 123, 12504; (c) Hilt, G.; Treut-
wein, J. Angew. Chem., Int. Ed. 2007, 46, 8500; (d) Todd, D. P.;
Thompson, B. B.; Nett, A. J.; Montgomery, J. J. Am. Chem. Soc.
2015, 137, 12788.
(13) (a) Yadav, J. S.; Reddy, B. V. S.; Reddy, P. M. K.; Gupta, M.
K. Tetrahedron Lett. 2005, 46, 8411; (b) C. Ranu, B.; Majee, A.
Chem. Commun. 1997, 1225.
(14) (a) Trost, B. M.; Papillon, J. P. N.; Nussbaumer, T. J. Am.
Chem. Soc. 2005, 127, 17921; (b) Gutierrez, A. C.; Jamison, T. F.
Org. Lett. 2011, 13, 6414.
(42) (a) Shambayati, S.; Schreiber, S. L.; Blake, J. F.; Wierschke,
S. G.; Jorgensen, W. L. J. Am. Chem. Soc. 1990, 112, 697; (b) Wein-
hold, F.; West, R. J. Am. Chem. Soc. 2013, 135, 5762.
(43) Evans, D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J.
Am. Chem. Soc. 2001, 123, 10840.
(15) Hansen, E. C.; Lee, D. J. Am. Chem. Soc. 2005, 127, 3252.
8
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(44) (a) Xi, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2016, 138, 6703;
(b) Xi, Y.; Butcher, T. W.; Zhang, J.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2016, 55, 776.
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