Mechanism of Copper-Catalyzed Hydroalkylation of Alkynes: An Unexpected Role of Dinuclear Copper Complexes

Article abstract of DOI:10.1021/jacs.5b03086

This article describes a mechanistic study of copper-catalyzed hydroalkylation of terminal alkynes. Relying on the established chemistry of N-heterocyclic carbene copper hydride (NHCCuH) complexes, we previously proposed that the hydroalkylation reaction proceeds by hydrocupration of an alkyne by NHCCuH followed by alkylation of the resulting alkenylcopper intermediate by an alkyl triflate. NHCCuH is regenerated from NHCCuOTf through substitution with CsF followed by transmetalation with silane. According to this proposal, NHCCuH must react with an alkyne faster than with an alkyl triflate to avoid reduction of the alkyl triflate. However, we have determined that NHCCuH reacts with alkyl triflates significantly faster than with terminal alkynes, strongly suggesting that the previously proposed mechanism is incorrect. Additionally, we have found that NHCCuOTf rapidly traps NHCCuX (X = F, H, alkenyl) complexes to produce (NHCCu)₂(μ-X)(OTf) (X = F, H, alkenyl) complexes. In this article, we propose a new mechanism for hydroalkylation of alkynes that features dinuclear (NHCCu)₂(μ-H)(OTf) (X = F, H, alkenyl) complexes as key catalytic intermediates. The results of our study establish feasible pathways for the formation of these intermediates, their ability to participate in the elementary steps of the proposed catalytic cycle, and their ability to serve as competent catalysts in the hydroalkylation reaction. We also provide evidence that the unusual reactivity of the dinuclear complexes is responsible for efficient hydroalkylation of alkynes without concomitant side reactions of the highly reactive alkyl triflates. (Figure Presented).

Full text of DOI:10.1021/jacs.5b03086

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Article
Mechanism of Copper-Catalyzed Hydroalkylation of
Alkynes: An Unexpected Role of Dimeric Copper Complexes
Alison M Suess, Mycah R Uehling, Werner Kaminsky, and Gojko Lalic
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.5b03086 • Publication Date (Web): 04 Jun 2015
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Mechanism of Copper-Catalyzed Hydroalkylation of Alkynes: An
Unexpected Role of Dinuclear Copper Complexes
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Alison M. Suess,≠ Mycah R. Uehling, ≠ Werner Kaminsky, and Gojko Lalic*
The Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
ABSTRACT: This article describes a mechanistic study of copper-catalyzed hydroalkylation of terminal alkynes. Relying on the
established chemistry of N-heterocyclic carbene copper hydride (NHCCuH) complexes, we previously proposed that the hydroalkyl-
ation reaction proceeds by hydrocupration of an alkyne by NHCCuH, followed by alkylation of the resulting alkenyl copper interme-
diate by an alkyl triflate. NHCCuH is regenerated from NHCCuOTf through substitution with CsF, followed by transmetalation with
silane. According to this proposal, NHCCuH must react with an alkyne faster than with an alkyl triflate to avoid reduction of the alkyl
triflate. However, we have determined that NHCCuH reacts with alkyl triflates significantly faster than with terminal alkynes, strongly
suggesting that the previously proposed mechanism is incorrect. Additionally, we have found that NHCCuOTf rapidly traps NHCCuX
(X = F, H, alkenyl) complexes to produce (NHCCu)2(-X)(OTf) (X = F, H, alkenyl) complexes. In this article we propose a new
mechanism for hydroalkylation of alkynes that features dinuclear (NHCCu)2(-H)(OTf) (X = F, H, alkenyl) complexes as key cata-
lytic intermediates. The results of our study establish feasible pathways for the formation of these intermediates, their ability to
participate in the elementary steps of the proposed catalytic cycle, and their ability to serve as competent catalysts in the hydroalkyl-
ation reaction. We also provide evidence that the unusual reactivity of the dinuclear complexes is responsible for efficient hydroal-
kylation of alkynes without concomitant side reactions of the highly reactive alkyl triflates.
electrophiles to allenes,14 reductions of alkyl triflates to al-
kanes,15 or the semi-reduction of alkynes to alkenes.16 NHC
copper hydride complexes have proven to be particularly im-
portant in the development of hydrofunctionalization reactions
that are postulated to proceed through the hydrocupration of un-
saturated compounds. NHC copper hydride complexes have
been invoked as intermediates in hydrocarboxylation,17 hydrob-
oration,18 hydrobromination,19 and hydroalkylation of al-
kynes.20
Introduction
Copper hydride complexes have been known since 1844 when
Wurtz described a preparation of copper(I) hydride.1 However,
the modern chemistry of copper hydrides can be traced back to
a study of the stability and reactivity of copper hydride com-
plexes, reported by Whitesides in 1969.2 Soon after, in 1971,
the synthesis of a thermally stable and well-characterized
[CuH(PPh3)]6 complex was reported by Osborn and Churchill.3
The first application of the Osborn complex in organic synthesis
followed in 1988, when Stryker published a series of papers de-
scribing mild and selective reductions of activated alkenes.4 The
Osborn complex became known in the synthesis community as
Stryker’s reagent. In 1998, following the initial reports by Brun-
ner,5 Mori,6 and Hosomi,7 Lipshutz introduced the use of silanes
as a terminal hydride source in reactions catalyzed by Stryker’s
reagent.8 The basic reactivity pattern established by Stryker and
Lipshutz led to the development of a wide range of transfor-
mations featuring copper hydride complexes as key catalytic in-
termediates.9
The first direct evidence for NHC copper(I) hydride com-
plexes invoked as intermediates in these transformations was
provided by Sadighi and coworkers in a seminal 2004 paper.21
They demonstrated the synthesis of a stable and isolable
IPrCuH (2) by transmetalation of IPrCuOt-Bu complex (1) with
a silane (Scheme 1, eq 1). They also showed that in the solid
state IPrCuH exists as a dimer with bridging hydride ligands.
However, there are no indications that the dimer is stable in so-
lution, and a recent experimental and theoretical study suggests
that the monomeric form is the reactive species in reduction of
ketones.22 Further stoichiometric studies with IPrCuH provided
evidence for the feasibility of key elementary steps of known
catalytic reactions. For example, Sadighi has demonstrated the
ability of IPrCuH to effect facile hydrocupration of alkynes (eq
2),21 which has been proposed as the key elementary step in
copper-catalyzed hydrofunctionalization reactions. Overall, re-
actions catalyzed by NHC copper complexes in the presence of
a silane have generally been assumed to involve intermediates
analogous to the IPrCuH complex originally described by Sadi-
ghi.
Critical for the successful development of copper hydride
chemistry was an early realization that properties of the ancil-
lary ligand(s) can have dramatic effects on both the selectivity
and reactivity of copper hydride complexes.10 While excellent
results have been obtained using a range of phosphine ligands,
the introduction of N-heterocyclic carbene (NHC) ligands had
a particularly significant impact on the chemistry of copper hy-
dride complexes. In 2003, Buchwald and Sadighi reported the
first example of a catalytic reaction in which an NHC copper
hydride complex was proposed as a key catalytic intermediate.11
Since this seminal report, NHC copper hydride complexes have
been invoked as intermediates in a wide range of transfor-
mations performed in the presence of a silane as a terminal hy-
dride donor. Most common are reduction reactions, such as 1,4-
reductions of unsaturated carbonyls,11 1,2-reductions of ke-
tones,12 reduction of carbon dioxide,13 reduction of propargylic
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Scheme 1. IPrCuH - Formation and Reaction with Alkyne
produce IPrCuH rather than fluorinate the alkyl triflate. In this
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article, we describe our exploration of the mechanism by which
hydroalkylation of alkynes is accomplished without concomi-
tant reduction or fluorination of alkyl triflates (eq 4 and 5). We
present the results of our study and propose a new mechanism
of the hydroalkylation reaction that explains this remarkable se-
lectivity.
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Scheme 3. Proposed Mechanism of Hydroalkylation
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For the past several years our group has actively pursued the
development of new transformations based on the chemistry of
NHC copper hydride complexes.16b,19,15 As a result of our ef-
forts, we have recently developed copper-catalyzed hydroalkyl-
ation of terminal alkynes.20 As shown in Scheme 2, we found
that terminal alkynes and alkyl triflates can undergo a reductive
cross-coupling in the presence of IPrCuOTf as a catalyst,
(Me2HSi)2O as a hydride donor, and CsF as a turnover reagent
(eq 3). Relying on the well-established chemistry of NHCCuH
complexes21 and previous studies of related hydrofunctionaliza-
tion reactions16a,16b,19 we proposed that the hydroalkylation of
terminal alkynes proceeds according to the mechanism shown
in Scheme 3. According to this proposal the hydroalkylation re-
action involves 1) formation of the copper hydride complex (2),
2) hydrocupration of an alkyne, and 3) alkylation of an alkenyl
copper intermediate (6).
Results
Reactions of IPrCuH With Alkynes and Alkyl Triflates
The feasibility of the originally proposed mechanism of hy-
droalkylation (Scheme 3) hinges on the relative rates of the re-
action of IPrCuH with the alkyl triflate and the alkyne. The re-
action of the copper hydride complex with the alkyne has to be
faster than its reaction with the alkyl triflate. We found that both
a terminal alkyne and an alkyl triflate react very quickly in a
stoichiometric reaction with IPrCuH (Scheme 4, eq 6 and 7). In
a reaction with a terminal alkyne 51% yield of the alkenyl cop-
per complex 7 is formed in just four seconds. Complete conver-
sion of the IPrCuH was achieved after less than five minutes,
with the concomitant formation of 95% of alkenyl copper com-
plex 7. In a stoichiometric reaction with an alkyl triflate, com-
plete consumption of the IPrCuH is achieved in less than four
seconds. Surprisingly, only 0.5 equivalents of the alkyl triflate
were consumed. While the results of these experiments did not
allow us to definitively establish the relative rates of IPrCuH
reaction with a terminal alkyne and an alkyl triflate, they did
suggest that the reaction with alkyl triflates may be faster.
Scheme 2. Copper-Catalyzed Reactions of Alkyl Triflates
To further explore this possibility, we performed a competition
experiment in which IPrCuH was exposed to a mixture of an
alkyl triflate and an alkyne (eq 8). The complete consumption
of the IPrCuH was accompanied by the consumption of 0.5
equiv of the alkyl triflate and the formation of 0.5 equiv of the
alkane. At the same time, >95% of the alkyne was still present
in the reaction mixture.26 The results of this competition exper-
iment allow us to conclude that the reaction of IPrCuH with an
alkyl triflate is significantly faster than the reaction with a ter-
minal alkyne. Importantly, these results allow us to conclude
that the originally proposed mechanism of hydroalkylation is
incorrect.
This mechanism raised interesting questions about the selec-
tivity exhibited by IPrCuF and IPrCuH intermediates consider-
ing that same complexes have also been implicated in two other
transformations of alkyl triflates (eq 4 and 5).23,15 Under reac-
tion conditions that are essentially the same as those used in the
hydroalkylation reaction, but in the absence of a terminal al-
kyne, we observe an efficient reduction of the alkyl triflate to
an alkane (eq 4).24 If we omit both the silane and the alkyne
from the reaction mixture we observe facile formation of an al-
kyl fluoride (eq 5).25
Considering the three transformations of alkyl triflates shown
in Scheme 2, we were intrigued by the selectivity of the hy-
droalkylation reaction, as neither the alkane nor the alkyl fluo-
ride are formed in appreciable amount (<5% yield) during the
reaction. For the proposed hydroalkylation mechanism to be
correct, IPrCuH must selectively react with an alkyne rather
than reduce the highly electrophilic alkyl triflate present in the
reaction mixture. Similarly, IPrCuF must react with silane to
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Scheme 4. Relative Rates of IPrCuH Reactions
Scheme 5. Formation and Reactivity of (IPrCu)2(μ-H)(OTf)
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Formation and Reactivity of (IPrCu)2(μ-H)(OTf)
The first indication of an alternative mechanism of hydroal-
kylation emerged when we tried to understand the unusual stoi-
chiometry of the reaction between IPrCuH and alkyl triflate.
This reaction results in the consumption of only half an equiva-
lent of the alkyl triflate, and yet leads to the consumption of a
full equivalent of IPrCuH (Scheme 4, eq 7). We determined that
another major product of the reaction is (IPrCu)2(-H)(OTf)27
complex (8) (Scheme 5, eq 9).28 One possible explanation for
the formation of the hydride-bridged complex 8 is that
IPrCuOTf formed in the reduction of the alkyl triflate sequesters
IPrCuH before it can be fully consumed by the alkyl triflate. As
shown in Scheme 5 (eq 10), we found that the reaction between
IPrCuH and IPrCuOTf happens rapidly at room temperature to
cleanly produce (IPrCu)2(-H)(OTf). Considering that only 0.5
equivalents of the alkyl triflate are consumed (eq 9), we can
conclude that the formation of the dinuclear complex is signifi-
cantly faster than the reaction of IPrCuH with alkyl triflates.
As shown in Scheme 5, (IPrCu)2(-H)(OTf) (8) can be formed
in a stoichiometric reduction of alkyl triflate by IPrCuH. How-
ever, in the catalytic hydroalkylation reaction, alkane is formed
in only trace amounts (<5%), which suggests that the reduction
of alkyl triflates is not a relevant method for the formation of
the key catalytic intermediate. We also found that IPrCuOTf
does not react directly with the silane, and decided to explore
other ways in which dinuclear hydride 8 can be formed from
IPrCuOTf in the presence of a silane and CsF.
Scheme 6. Formation and Reactivity of (IPrCu)2(μ-F)(OTf)
The results of the experiment shown in equation 9 clearly show
that the hydride-bridged complex 8 is stable in the presence of
an alkyl triflate. This raises the possibility that complex 8 is re-
sponsible for the selective hydrocupration of the alkyne in the
presence of the alkyl triflate. In agreement with similar obser-
vations recently made by Sadighi,28 we found that the dinuclear
hydride reacts with an alkyne to form (IPrCu)2(-alkenyl)(OTf)
complex 9 in good yield (eq 11). The product precipitates from
the reaction mixture to yield colorless crystals suitable for X-
ray crystallography, which allowed us to fully characterize this
complex.29 The competition experiment shown in equation 12
demonstrates efficient hydrocupration of an alkyne even in the
presence of an alkyl triflate. This result suggests that the atten-
uated reactivity of complex 8 may be responsible for the cross-
coupling of alkyl triflates in the hydroalkylation reaction (eq 3)
without their concomitant reduction. Furthermore, this result al-
lows us to conclude that hydrocupration of an alkyne by
(IPrCu)2(-H)(OTf) does not proceed through dissociation and
subsequent reaction of IPrCuH with the alkyne. If IPrCuH were
involved, we would expect only the reduction of the alkyl tri-
flate according to the results of the experiment shown in eq 8.
We previously demonstrated the formation of the NHCCuF
from corresponding triflate complexes in the presence of alkali
metal fluorides in 1,4-dioxane.23 We have found that like
IPrCuH, IPrCuF also readily reacts with IPrCuOTf to form
(IPrCu)2(-F)(OTf) (10) (Scheme 6, eq 13). This suggests that
the fluoride-bridged complex is likely present at partial conver-
sions of IPrCuOTf to IPrCuF. We have also found that the flu-
oride-bridged complex 10 rapidly and quantitatively converts to
the hydride-bridged complex 8 after addition of (Me2HSiO)2 (eq
14). This reaction sequence provides a plausible pathway for
the formation of the key catalytic intermediate (IPrCu)2(-
H)(OTf) (8) under the conditions relevant to the catalytic hy-
droalkylation reaction (see Scheme 2, eq 3).
With complex 8 as a plausible intermediate responsible for se-
lective hydrocupration of an alkyne in the presence of an alkyl
triflate, we explored ways in which this key intermediate could
be formed in a catalytic hydroalkylation reaction.
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Reactivity of IPrCuF and (IPrCu)2(-F)(OTf) Towards Al-
kyl Triflates
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In the light of the reaction shown in eq 5, we found it surprising
that fluorination of the alkyl triflate does not occur in the hy-
droalkylation reaction. We previously showed that the key step
in the catalytic fluorination (eq 5) is a fast reaction of IPrCuF
with alkyl triflates.23 We surmised that in the hydroalkylation
reaction the formation of the less reactive (IPrCu)2(-F)(OTf)
may prevent the fluorination of the alkyl triflate. We have found
that (IPrCu)2(-F)(OTf) does react with alkyl triflates (Scheme
7, eq 15), albeit at the significantly lower rate than IPrCuF.23
The reaction shown in eq 14 suggests that transmetalation of
(IPrCu)2(-F)(OTf) with a silane may be faster than its reaction
with alkyl triflate. To more firmly establish the relative rates of
the two reactions we performed the competition experiment
shown in eq 16. When (IPrCu)2(-F)(OTf) is exposed to a mix-
ture of (Me2HSi)2O and dodecyl triflate no alkyl fluoride is
formed.30 Instead, (IPrCu)2(-H)(OTf) is formed as the major
product. This finding confirms that (IPrCu)2(-F)(OTf) reacts
faster with (Me2HSi)2O than with alkyl triflates,31 and provides
a simple explanation for the selective cross-coupling of the al-
kyl triflates without competing formation of alkyl fluorides.
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Unfortunately, our attempts to promote the reaction between
alkenyl-bridged dinuclear complex and alkyl triflate by addition
of individual components of the catalytic reaction (alkyne,
silane, or CsF) were unsuccessful.29 However, excellent yield
of the cross-coupling product 11 can be obtained if 4-methoxy-
phenyl acetylene, CsF, and (Me2HSi)2O are added to the mix-
ture of an alkyl triflate and alkenyl-bridged complex 9. In this
experiment, product 11 is formed exclusively by the cross-cou-
pling of the alkenyl group of complex 9 with an alkyl triflate.
We also found that adding alkenyl-bridged complex 9 into an
ongoing catalytic reaction between 4-methoxyphenyl acetylene
and dodecyl triflate results in the formation of a cross-coupling
product 11 in 71% yield (Scheme 9, eq 20). While these exper-
iments do not unequivocally establish the nature of the species
involved in the C-C bond forming step of the reaction, they es-
tablish the feasibility of the cross-coupling of the alkyl triflate
and intermediate 9 under the reaction conditions, as well as the
feasibility of a catalytic cycle featuring 9 as an intermediate.
Scheme 7. Fluorination of Alkyl Triflates
Reactivity of (IPrCu)2(-alkenyl)(OTf)
Our next goal was to explore the reactivity of (IPrCu)2(-
alkenyl)(OTf) (9) and its potential role in the C-C bond-forming
step of the hydroalkylation reaction. The alkenyl-bridged com-
plex 9 does not react with dodecyl triflate under a variety of
conditions (Scheme 8, eq 17), indicating that direct alkylation
of 9 is unlikely. However, reaction of alkenyl copper complex
7 and dodecyl triflate results in complete consumption of 7 and
the formation of an equal amount of C-C coupled product 11
and alkenyl-bridged complex 9 (Scheme 8, eq 18). We propose
that IPrCuOTf formed in the coupling reaction sequesters the
unreacted IPrCu(alkenyl) before it can react with the remaining
alkyl triflate. As shown in eq 19, this reaction occurs readily at
room temperature.
Scheme 9. (IPrCu)2(-alkenyl)(OTf) in a Catalytic Reaction
These results suggest that dissociation of alkenyl-bridged
complex 9 under the conditions of the catalytic hydroalkylation
would be a viable way to accomplish the C-C bond formation.
The dissociation of the alkenyl-bridged dinuclear complex may
be promoted by the replacement of the triflate ligand with a
more electron-donating ligand. The same ligand exchange
could alternatively result in the formation of a more reactive
alkenyl-bridged dinuclear complex, which would react further
with the alkyl triflate.
Conditions a): 9 (0.1 equiv), CH3(CH2)11OTf (1.5 equiv), 4-
MeOC6H4CCH (1.0 equiv), (Me2HSi)2O (2.0 equiv), CsF (2.0
equiv), 1,4-dioxane, 45 °C. Conditions b): same as a) with IPrCuF
(10 mol %) added. c) 80% yield obtained using 15 instead of 9.
Reactivity of SIPr Copper Complexes
Previously, we found that IPrCuOTf was the optimal catalyst
for both the fluorination23 and reduction15 of alkyl triflates.
However, the best results in the hydroalkylation reaction were
obtained using SIPrCuOTf as a catalyst. The change in the cat-
alyst structure going from IPrCuOTf to SIPrCuOTf is relatively
Scheme 8. Reactivity of (IPrCu)2(-alkenyl)(OTf)
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Figure 1. Crystal structure ORTEP images of SIPr copper complexes with ellipsoids at 50% probability. For clarity, triflate counterion and
most hydrogen atoms are omitted. For clarity, methyl substituents of the isopropyl groups on 15 are also omitted. (alkenyl = (E)-
CH=CH(CH2)3Ph).
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small, and we found that in experiments shown in equations 7-
Discussion
20, SIPr and IPr complexes performed qualitatively in the same
way.29 We found that in general, SIPr complexes give lower
yields in stoichiometric reactions. At the same time, the SIPr
copper complexes proved easier to crystalize, which allowed us
to characterize all relevant complexes by X-ray crystallography
(see Figure 1).
One of the major questions about the mechanism of the cata-
lytic hydroalkylation reaction shown in equation 3 is the ques-
tion of selectivity: why do alkyl triflates selectively couple with
alkynes rather than undergo reduction or fluorination during the
course of the hydroalkylation reaction? Our attempts to under-
stand this aspect of the hydroalkylation reaction led us to con-
clude that the initially proposed mechanism of hydroalkylation
(Scheme 3) is incorrect. We found that the postulated IPrCuH
intermediate reacts with alkyl triflates significantly faster than
it does with terminal alkynes. Further studies of the reaction be-
tween alkyl triflates and IPrCuH led us to identify (IPrCu)2(-
X)(OTf) (X = H, F, alkenyl) complexes as a possible interme-
diates in the catalytic hydroalkylation reaction. These dinuclear
copper complexes are not unprecedented. Although in a differ-
ent context, the closely related (IPrCu)2(-X)(BF4) (X = H, F,
alkenyl) complexes have recently been prepared and character-
ized by Sadighi and coworkers.28,33 The same authors have also
demonstrated a stoichiometric hydrocupration of phenyl acety-
lene using (IPrCu)2(-H)(BF4).28 However, complexes of this
type have rarely been proposed as intermediates in catalytic re-
actions.34
While, in general, the reactivity of SIPr and IPr complexes is
quite similar, we found that (SIPrCu)2(-alkenyl)(OTf) (15)
performed better than the analogous IPr complex (9) in the C-C
bond forming experiment shown in equation 20 (80% vs 71%
yield, see Scheme 8). We also found that the hydrocupration of
the alkyne is significantly slower with SIPrCuH than with the
IPr analogue. The reaction of SIPrCuH with an alkyne took an
hour to complete (eq 21), while the same reaction using IPrCuH
took less than 5 min (eq 6). The reaction of SIPrCuH with alkyl
triflate was essentially instantaneous and produced
(SIPrCu)2(-H)(OTf). These findings further strengthen our
conclusion that the originally proposed mechanism for the hy-
droalkylation reaction is incorrect.32
The results of our study lead us to postulate a new mechanism
of the hydroalkylation reaction with (SIPrCu)2(-X)(OTf) (X =
H, F, alkenyl) complexes as key catalytic intermediates. Ac-
cording to the mechanism shown in Scheme 11, we propose that
SIPrCuOTf reacts with CsF to form SIPrCuF, which is imme-
diately trapped by remaining SIPrCuOTf to form (SIPrCu)2(-
F)(OTf) (14). The fluoride-bridged complex 14 reacts with
silane to quickly form hydride-bridged complex 13.
(SIPrCu)2(-H)(OTf) (13) does not react with alkyl triflates and
allows selective hydrocupration of terminal alkynes in the pres-
ence of these strong electrophiles. A reaction of alkenyl-bridged
complex 16 with an alkyl triflate leads to the formation of the
cross-coupling product. At the same time either fluoride- or hy-
dride-bridged dinuclear complex would be regenerated. The de-
tailed mechanism of the cross-coupling step and the catalyst
turnover remains to be elucidated. However, the results of ex-
periments shown in Scheme 9 provide strong evidence for the
feasibility of the cross-coupling of the alkenyl group of inter-
mediate 9 and an alkyl triflate, under the reaction conditions. At
the same time, results of the experiment shown in equation 18
suggest monomeric NHC copper alkenyl complex as the active
intermediate involved in the formation of the C-C bond .
To explore the relevance of dinuclear SIPr complexes in the
catalytic hydroalkylation performed under optimal reaction
conditions, we tested the ability of these complexes to catalyze
the hydroalkylation reaction (Figure 1).
Scheme 10. Proposed Intermediates as Catalysts in Hy-
droalkylation Reaction
We found that all the complexes were catalytically competent,
although the yield of the hydroalkylation was diminished in few
instances (Scheme 10). These results are consistent with the
idea that the bridged dinuclear complexes are intermediates in
the catalytic hydroalkylation reaction.
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The key aspect of the mechanism shown in Scheme 11 is the
intermediacy of (NHCCu)2(-X)(OTf) complexes (X = H, F,
alkenyl). In this new proposal, the intermediates of the initially
proposed catalytic cycle are all replaced by the related dinuclear
complexes. In light of the results presented in the previous sec-
tion this is not surprising. We showed that (NHCCu)2(-
X)(OTf) (X = H, F, alkenyl) are all readily formed in reactions
of corresponding NHCCuX with NHCCuOTf. Therefore, if
there is a sufficient amount of NHCCuOTf relative to other in-
termediates in the reaction mixture, the dinuclear complexes
will dominate. Our kinetics data suggest phase transfer of fluo-
ride from solid CsF as the turnover-limiting step,20 which would
ensure that a sufficient amount of NHCuOTf is available under
the reaction conditions.35 Furthermore, the feasibility of the pro-
posed elementary steps involving (NHCCu)2(-F)(OTf) and
(NHCCu)2(-H)(OTf) intermediates has been demonstrated
through stoichiometric reactions. It is important to point out that
the exact mechanism of the transformation of (NHCCu)2(-
alkenyl)(OTf) into the final product remains unclear.
reactivity of CsF prevents the direct fluorination of alkyl tri-
1
2
3
4
5
6
7
8
flates, and ensures that the only way fluoride can participate in
the reaction is through the formation of copper fluoride com-
plexes. The fact that phase transfer of fluoride is turnover-lim-
iting in catalytic hydroalkylation is essential for maintaining a
sufficiently high concentration of NHCCuOTf complex neces-
sary to sequester NHCCuH and prevent unwanted reduction of
the alkyl triflate. As a result, in a catalytic hydroalkylation re-
action performed with a more soluble and reactive source of
fluoride we would expect to see competing fluorination and re-
duction of alkyl triflates. Indeed, we found that catalytic hy-
droalkylation reactions performed with either TBAT (tetrabu-
tylammonium difluorotriphenylsilicate) or TMAF (tetrame-
thylammonium fluoride) instead of CsF, result in the formation
of alkyl fluorides, as well as in the reduction of the alkyl triflate
to alkanes.29
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
In conclusion, we believe that the new mechanism of the hy-
droalkylation reaction provides opportunities for better under-
standing of other transformations, as well as for the develop-
ment of new ones. For example, our study suggests that the
(IPrCu)2(-H)(OTf) complex is also a likely intermediate in the
catalytic reduction of alkyl triflates (eq 4). Additionally, the
unique reactivity of (NHCCu)2(-H)(OTf) opens the possibility
for the development of hydrofunctionalization reactions of al-
kynes using other strong electrophiles which are not compatible
with the IPrCuH intermediate.
Scheme 11. Proposed Mechanism of the Hydroalkylation
ASSOCIATED CONTENT
Supporting Information.
Experimental procedures and characterization of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
* lalic@chem.washington.edu.
Author Contributions
≠ These authors contributed equally to this work. The manuscript
was written through contributions of all authors.
Funding Sources
NSF CAREER award #1254636
While the mechanism of the hydroalkylation reaction shown
in Scheme 11 is closely related to the originally proposed mech-
anism (Scheme 3), the two mechanisms feature catalytic inter-
mediates that have profoundly different reactivities. The finely
tuned reactivity of the hydride-bridged dicopper complex (13)
and fluoride-bridged dicopper complex (14) is essential for the
selective transformation of alkyl triflates in the hydroalkylation
reaction. The (SIPrCu)2(-H)(OTf) complex is perfectly suited
for its role in the hydroalkylation reaction. It reacts with alkynes
to give the hydrocupration product 16, but unlike the SIPrCuH,
it does not react with alkyl triflates. Similarly, (SIPrCu)2(-
F)(OTf) reacts with silanes much faster than it reacts with alkyl
triflates. Overall, the reactivity of these two complexes explains
why reduction or fluorination of alkyl triflates does not occur
during the course of the hydroalkylation reaction.
ACKNOWLEDGMENT
Professor Forrest Michael is gratefully acknowledged for helpful
discussions and suggestions. We gratefully acknowledge Sarah E.
Flowers for assistance with X-ray crystallography. We thank the
reviewers for a number of helpful suggestions.
REFERENCES
(1) Wurtz, A. Ann. Chim. Phys. 1844, 11, 250.
(2) Whitesides, G. M.; San Filippo, J.; Stredronsky, E. R.; Casey, C.
P. J. Am. Chem. Soc. 1969, 91, 6542.
(3) (a) Churchill, M. R.; Bezman, S. A.; Osborn, J. A.; Wormald, J.
J. Am. Chem. Soc. 1971, 93, 2063; (b) Churchill, M. R.; Bezman, S. A.;
Osborn, J. A.; Wormald, J. Inorganic Chemistry 1972, 11, 1818.
(4) (a) Brestensky, D. M.; Huseland, D. E.; McGettigan, C.; Stryker,
J. M. Tetrahedron Lett. 1988, 29, 3749; (b) Mahoney, W. S.; Bresten-
sky, D. M.; Stryker, J. M. J. Am. Chem. Soc. 1988, 110, 291; (c) Ma-
honey, W. S.; Stryker, J. M. J. Am. Chem. Soc. 1989, 111, 8818; (d)
Brestensky, D. M.; Stryker, J. M. Tetrahedron Lett. 1989, 30, 5677; (e)
Koenig, T. M.; Daeuble, J. F.; Brestensky, D. M.; Stryker, J. M. Tetra-
hedron Lett. 1990, 31, 3237.
Another key feature of the catalytic cycle worth mentioning is
that the low solubility of the fluoride source is essential for the
success of the hydroalkylation reaction. The low solubility and
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Journal of the American Chemical Society
(5) Brunner, H.; Miehling, W. J. Organomet. Chem. 1984, 275, c17.
(6) Mori, A.; Fujita, A.; Nishihara, Y.; Hiyama, T. Chem. Commun.
1997, 2159.
(7) Ito, H.; Ishizuka, T.; Arimoto, K.; Miura, K.; Hosomi, A. Tetra-
hedron Lett. 1997, 38, 8887.
(8) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R. Tetrahedron Lett.
1998, 39, 4627.
(22) Vergote, T.; Nahra, F.; Merschaert, A.; Riant, O.; Peeters, D.;
Leyssens, T. Organometallics 2014, 33, 1953.
(23) Dang, H.; Mailig, M.; Lalic, G. Angew. Chem., Int. Ed. 2014,
53, 6473.
(24) The reaction conditions shown in eq 4 are different from opti-
mal conditions for the reduction of alkyl triflates. See reference 15 for
details.
1
2
3
4
5
(9) (a) Rendler, S.; Oestreich, M. Angew. Chem., Int. Ed. 2007, 46,
498; (b) Deutsch, C.; Krause, N.; Lipshutz, B. H. Chem. Rev. 2008,
108, 2916; (c) Egbert, J. D.; Cazin, C. S. J.; Nolan, S. P. Catal. Sci.
Technol. 2013, 3, 912.
(10) Lipshutz, B. H. Synlett 2009, 509.
(11) Jurkauskas, V.; Sadighi, J. P.; Buchwald, S. L. Org. Lett. 2003,
5, 2417.
(12) (a) Kaur, H.; Zinn, F. K.; Stevens, E. D.; Nolan, S. P. Organo-
metallics 2004, 23, 1157; (b) Albright, A.; Gawley, R. E. J. Am. Chem.
Soc. 2011, 133, 19680.
(13) (a) Zhang, L.; Cheng, J.; Hou, Z. Chem. Commun. 2013, 49,
4782; (b) Shintani, R.; Nozaki, K. Organometallics 2013, 32, 2459.
(14) Deutsch, C.; Lipshutz, B. H.; Krause, N. Angew. Chem., Int. Ed.
2007, 46, 1650.
(25) The reaction conditions used in eq 5 are different from the op-
timal conditions for the fluorination of alkyl triflates. See reference 23
for details.
(26) After a longer period of time the reaction proceeds according to
the reactions described in equations 9 and 11 (vide infra).
(27) A closely related hydride-bridged dicopper complex has re-
cently been described by Sadighi. See reference 28.
(28) Wyss, C. M.; Tate, B. K.; Bacsa, J.; Gray, T. G.; Sadighi, J. P.
Angew. Chem., Int. Ed. 2013, 52, 12920.
6
7
8
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
(29) See supporting information.
(30) Control experiments exclude the possibility that the initially
formed alkyl fluoride gets reduced under the reaction conditions.
(31) The analogous competition experiment with IPrCuF suggests
that transmetallation with (Me2HSi)2O is again faster than the reaction
with an alkyl triflate.
(32) It is interesting to point out that the different reactivity of
IPrCuH and SIPrCuH may explain performance of different catalysts
in other hydrofunctionalization reactions. We previously showed that
semire-duction of alkynes and hydrobromination of alkynes involve
hydrocu-pration of alkynes by IPrCuH. In both reactions, the IPr cop-
per cata-lyst performed significantly better than the closely related SIPr
copper catalyst.
(33) Wyss, C. M.; Tate, B. K.; Bacsa, J.; Wieliczko, M.; Sadighi, J.
P. Polyhedron 2014, 84, 87.
(34) Worrell, B. T.; Malik, J. A.; Fokin, V. V. Science 2013, 340,
457.
(35) Our attempts to determine the resting state of the catalyst using
NMR spectroscopy were hampered by the heterogeneous nature of the
reaction mixture
(15) Dang, H.; Cox, N.; Lalic, G. Angew. Chem., Int. Ed. 2014, 53,
752.
(16) (a) Semba, K.; Fujihara, T.; Xu, T.; Terao, J.; Tsuji, Y. Adv.
Synth. Catal. 2012, 354, 1542; (b) Whittaker, A. M.; Lalic, G. Org.
Lett. 2013, 15, 1112; (c) Wang, G.-H.; Bin, H.-Y.; Sun, M.; Chen, S.-
W.; Liu, J.-H.; Zhong, C.-M. Tetrahedron 2014, 70, 2175.
(17) Fujihara, T.; Xu, T.; Semba, K.; Terao, J.; Tsuji, Y. Angew.
Chem., Int. Ed. 2011, 50, 523.
(18) Lipshutz, B. H.; Bošković, Ž. V.; Aue, D. H. Angew. Chem.,
Int. Ed. 2008, 47, 10183.
(19) Uehling, M. R.; Rucker, R. P.; Lalic, G. J. Am. Chem. Soc.
2014, 136, 8799.
(20) Uehling, M. R.; Suess, A. M.; Lalic, G. J. Am. Chem. Soc. 2015,
137, 1424.
(21) Mankad, N. P.; Laitar, D. S.; Sadighi, J. P. Organometallics
2004, 23, 3369.
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