Copper-catalyzed hydroalkylation of terminal alkynes

Article abstract of DOI:10.1021/ja5124368

We have developed a copper-catalyzed hydroalkylation of terminal alkynes using alkyl triflates as coupling partners and (Me₂HSi)₂O as a hydride donor. The hydroalkylation proceeds with excellent anti-Markovnikov regioselectivity and provides exclusively (E)-alkenes. We have demonstrated that both alkyl- and aryl-substituted alkynes can be used as substrates, together with 1° alkyl and benzylic triflates. Finally, the transformation can be accomplished in the presence of a wide range of functional groups. Overall, the new hydroalkylation reaction allows highly efficient and diastereospecific synthesis of (E)-alkenes from readily available terminal alkynes and alkyl triflates. On the basis of a preliminary mechanistic study, we propose that the hydroalkylation reaction involves copper hydride formation, hydrocupration of an alkyne, and alkylation of an alkenyl copper intermediate.

Full text of DOI:10.1021/ja5124368

Communication
pubs.acs.org/JACS
Copper-Catalyzed Hydroalkylation of Terminal Alkynes
Mycah R. Uehling, Alison M. Suess, and Gojko Lalic*
The Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
triflates as electrophiles. We describe the reaction development,
our exploration of the reaction scope, and the results of a
preliminary study of the reaction mechanism.
We and others have recently disclosed methods for catalytic
semireduction,16 hydrocarboxylation,17 and hydrobromination18
of alkynes using a general approach outlined in Scheme 1. All of
ABSTRACT: We have developed a copper-catalyzed
hydroalkylation of terminal alkynes using alkyl triflates as
coupling partners and (Me2HSi)2O as a hydride donor.
The hydroalkylation proceeds with excellent anti-Markov-
nikov regioselectivity and provides exclusively (E)-alkenes.
We have demonstrated that both alkyl- and aryl-
substituted alkynes can be used as substrates, together
with 1° alkyl and benzylic triflates. Finally, the trans-
formation can be accomplished in the presence of a wide
range of functional groups. Overall, the new hydro-
alkylation reaction allows highly efficient and diastereo-
specific synthesis of (E)-alkenes from readily available
terminal alkynes and alkyl triflates. On the basis of a
preliminary mechanistic study, we propose that the
hydroalkylation reaction involves copper hydride forma-
tion, hydrocupration of an alkyne, and alkylation of an
alkenyl copper intermediate.
Scheme 1. General Approach to Catalytic
Hydrofunctionalization of Alkynes
these reactions involve hydrocupration of an alkyne,19 followed
by electrophilic functionalization of the alkenyl copper
intermediate (3). We were intrigued by the idea that, at least
in principle, we could accomplish hydroalkylation of alkynes
using the same general approach.
To identify an appropriate electrophile for such a hydro-
alkylation reaction, we explored the reactivity of the presumed
alkenyl copper intermediate 5 with a range of alkyl electrophiles
(Scheme 2). We observed no reaction with alkyl iodide or alkyl
(E)-Alkenes are ubiquitous in organic chemistry and numerous
methods for their synthesis have been developed over the years.
Traditional methods, such as dissolving metal reduction of
alkynes,1 Schlosser modification of the Wittig reaction,2 or the
Julia-Kocienski reaction,3 are still commonly used. Several
catalytic methods are also available. In addition to the Heck
reaction,4 the most commonly used are numerous trans-
formations based on cross-coupling of functionalized (E)-
alkenes, such as alkenyl halides or alkenyl metal reagents,5 and
those based on the E-selective reduction of internal alkynes.6
A particularly efficient approach to the synthesis of alkenes is
intermolecular hydroalkylation of alkynes. This transformation
leads to an increase in both structural (new C−C bond is
formed) and stereochemical (double bond geometry) complex-
ity and offers potential for complete control of both regio- and
diastereoselectivity. Furthermore, terminal alkynes and alkyl
electrophiles are readily available starting materials. Despite the
great potential of hydroalkylation as a method for synthesis of
(E)-alkenes, there are still no catalytic methods for simple
hydroalkylation of terminal alkynes. While there are several
excellent methods for reductive cross-coupling of internal7
alkynes with π electrophiles, such as aldehydes,8,9 formamides,10
ketones,11 enones,12 and imines,13 reductive cross-coupling
reactions with alkyl (σ) electrophiles are exceedingly rare. The
most general example of such a reaction is a reductive coupling of
internal alkynes with epoxides, reported in 2003.14,15 To the best
of our knowledge, catalytic hydroalkylation of alkynes using alkyl
halides or sulfonate esters as electrophiles has not been reported.
In this communication, we describe the development of an E-
selective catalytic hydroalkylation of terminal alkynes using alkyl
Scheme 2. Reaction of Alkenyl Copper Complex with Alkyl
Electrophiles
tosylate, over a wide range of temperatures. However, the alkyl
triflate provided the desired alkylation product at room
temperature in ∼50% yield and led us to focus our efforts on
this class of electrophiles.
The choice of alkyl triflates as electrophiles introduced
additional challenges. The turnover reagents previously used in
copper-catalyzed hydrofunctionalization reactions (alkoxides,16
phenoxides,18 and carboxylates17) are not compatible with alkyl
triflates. Therefore, we needed a turnover reagent that is
compatible with alkyl triflates but is still able to promote the
formation of copper hydride. An even bigger concern was the
reduction of alkyl triflates in the presence of a silane and an NHC
copper catalyst, recently reported by our group.20 The efficiency
Received: December 9, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja5124368
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Journal of the American Chemical Society
Communication
of the reduction suggested that, in the proposed hydroalkylation
reaction, it may be difficult to avoid the unwanted reduction of
the alkyl triflate electrophile.
Despite these challenges, we were able to develop hydro-
alkylation of terminal alkynes shown in Table 1. Essential for the
The standard reaction conditions shown in Table 1 proved
effective in the hydroalkylation of various types of alkynes
including alkyl-substituted alkynes, α-branched alkyl alkynes, and
aryl acetylenes (see Table 2). The hydroalkylation can be
a
Table 2. Catalytic Hydroalkylation of Alkynes
a
Table 1. Development of Hydroalkylation Reaction
a
b
c
R =Ph(CH2)3; R1 = CH3(CH2)9. Used 1.0 equiv of CsF. Thirty-six
hours.
a
All reactions were performed on 0.5 mmol scale. Yields of isolated
success of the reaction is the use of CsF, which is compatible with
alkyl triflates and can also function as an effective turnover
reagent. As shown in Table 1, the best results are obtained using
SIPrCuOTf as a catalyst, (Me2HSi)2O as a hydride source, and
1,4-dioxane as a solvent. Surprisingly, these reaction conditions
are remarkably similar to the reaction conditions we previously
developed for the reduction of alkyl triflates. Nevertheless, the
product of alkyl triflate reduction was formed in less than 5%
yield, demonstrating the excellent selectivity of the catalytic
system.
During the development of the hydroalkylation reaction we
made several observations. The choice of catalyst is crucial for the
success of the reaction. SIPr- and IPrCuOTf catalyze the desired
reaction efficiently (Table 1, entries 1 and 2), while other NHC
ligands that are similar to SIPr electronically,21 but differ
sterically, afford little or no hydroalkylation product (entry 3).
We found that excess alkyl triflate is necessary for efficient
cross coupling (entry 4). Similarly, lower yield of the cross-
coupling product was obtained when 0.6 equiv of the silane was
used (entry 5). In that case, in addition to the cross-coupling
product, the dodecyl fluoride was formed in 20% yield.22,23 The
copper-catalyzed formation of alkyl fluoride was effectively
eliminated when 2 equiv of the silane was used. Other common
silanes did not perform nearly as well as (Me2HSi)2O under the
optimized conditions (entries 6−8). With one equivalent of CsF
the observed decrease in yield is not significant (entry 9), but
there is a substantial decrease in the rate of the reaction.24 Finally,
the reaction proceeds in other common organic solvents (entries
10−12), but at a substantially lower rate.
products after column chromatography are reported.
accomplished with a variety of primary alkyl triflates, including
benzylic triflates (compounds 21 and 22, Table 2). It is
important to note that all triflates used in Table 2 are prepared
in high purity and in good yield from the corresponding
alcohols.25 The mild reaction conditions allow successful
hydroalkylation of alkynes in the presence of a wide range of
functional groups. Silyl ethers, alkyl bromides, alkyl tosylates,
esters, ethers, aryl bromides, sulfonamides, and nitro arenes are
all compatible with the standard reaction conditions. In all
examples described in Table 2, a single regio- and diaster-
eoisomer of the product is formed.
During the explorations of the substrate scope, we have also
identified some limitations of the new method. We found that
when α-branched alkyl triflates or electron-deficient aryl
acetylenes are used as substrates, the hydroalkylation products
are obtained in significantly lower yields.26 In addition, when
internal alkynes are used as substrates in reactions performed
under standard reaction conditions, the formation of the
hydroalkylation products was not observed.
On the basis of the result of the stoichiometric reaction shown
in Scheme 2 and previous work on the mechanism of related
hydrofunctionalization reactions,16−18 we propose that the
hydroalkylation proceeds according to the mechanism shown
in Scheme 3. The SIPrCuOTf catalyst reacts with CsF to form
SIPrCuF, which after transmetalation with silane forms
SIPrCuH. Subsequent hydrocupration of an alkyne, followed
B
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J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Scheme 3. Proposed Catalytic Cycle
In further kinetics experiments we established that the rate of
the reaction does not depend on the concentration of the alkyne,
silane, or the alkyl triflate.25 These results, together with the stir-
rate dependence of the reaction rate, strongly suggest that the
phase transfer of fluoride ultimately determines the rate of the
hydroalkylation reaction. In the context of the proposed
mechanism, that would make the formation of SIPrCuF the
turnover-limiting step of the catalytic cycle.
As previously pointed out alkyl triflates can be transformed
into alkyl fluorides23 or alkanes20 under reaction conditions that
are remarkably similar to the conditions used in the hydro-
alkylation reaction. In that light, the selectivity of the hydro-
alkylation reaction is surprising, and a more detailed study aimed
at understanding this selectivity is under way.
We have developed copper-catalyzed hydroalkylation of
terminal alkynes using alkyl triflates as electrophiles and
(Me2HSi)2O as a hydride donor. The hydroalkylation proceeds
with complete control of both regio- and diastereoselectivity and
allows an efficient synthesis of (E)-alkenes from readily available
starting materials. We have demonstrated that both alkyl- and
aryl-substituted alkynes can be used as substrates, together with a
range of primary alkyl triflates. We propose that the hydro-
alkylation reaction involves hydrocupration of the alkyne
followed by electrophilic functionalization of the alkenyl copper
intermediate. A preliminary study of the reaction mechanism
suggests that the formation of the SIPrCuF intermediate is the
turnover-limiting step of the catalytic cycle.
by alkylation of the alkenyl copper intermediate with alkyl triflate
forms the product and regenerates SIPrCuOTf.
The feasibility of all the elementary steps in the proposed
catalytic cycle is supported by experimental evidence. Recently,
we demonstrated the formation of the NHCCuF from
corresponding triflate complexes in the presence of alkali metal
fluorides.23 The hydrocupration of alkynes by NHC-copper
hydride complexes is well established.19 The stoichiometric
experiment described in Scheme 2 demonstrates the feasibility of
the key step responsible for the formation of the carbon−carbon
bond. Finally, the proposed transmetalation from silane to
copper is supported by the stoichiometric experiment shown in
eq 1. We found that SIPrCuF reacts with (Me2HSi)2O almost
instantly at room temperature to generate SIPrCuH in
quantitative yield.27 SIPrCuH was stable under N2 in C6D6 for
over 30 min.
2 equiv (Me2HSi)2O
SIPrCuF ⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯⎯→⎯ SIPrCuH
C6D6, 25 °C
(1)
In an effort to provide further insight into the reaction
mechanism and explore the relative rates of elementary steps
involved in the catalytic cycle, we examined the kinetics of the
hydroalkylation reaction. Initial experiments revealed a surpris-
ing induction period (see Figure 1, conditions A and B).
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, kinetic plots, and full spectroscopic
data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*lalic@chem.washington.edu
■
Notes
Figure 1. Reaction profiles demonstrating catalyst and stir rate
dependence for conditions A (SIPrCuOTf, 300 rpm), B (SIPrCuOTf,
1500 rpm), and C (SIPrCuF, 1500 rpm) as described in eq 2 (data was
not fitted).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Professor Forrest Michael is gratefully acknowledged for helpful
discussions and suggestions during the preparation of the
manuscript. We thank the NSF (CAREER award #1254636) for
funding.
Furthermore, we found that both the induction period and the
rate of the reaction strongly depend on the rate at which the
reaction mixture is stirred (Figure 1, conditions A and B). We
speculated that phase transfer of fluoride may limit the rate at
which copper fluoride is initially formed and, in that way, cause
the induction period. Indeed, when SIPrCuF was used as a
catalyst there was no induction period (Figure 1, condition C).
The induction period could also be reduced by vigorously stirring
CsF in the heated reaction solvent for 25 min before addition of
the other reagents.
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D
DOI: 10.1021/ja5124368
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX