Regiocontrol in catalytic reductive couplings through alterations of silane rate dependence

Article abstract of DOI:10.1021/ja511778a

Combinations of ligand, reducing agent, and reaction conditions have been identified that allow alteration in the rate- and regioselectivity-determining step of nickel-catalyzed aldehyde-alkyne reductive couplings. Whereas previously developed protocols involve metallacycle-forming oxidative cyclization as the rate-determining step, this study illustrates that the combination of large ligands, large silanes, and elevated reaction temperature alters the rate- and regiochemistry-determining step for one of the two possible product regioisomers. These modifications render metallacycle formation reversible for the minor isomer pathway, and σ-bond metathesis of the metallacycle Ni-O bond with the silane reductant becomes rate limiting. The ability to tune regiocontrol via this alteration in reversibility of a key step allows highly regioselective outcomes that were not possible using previously developed methods.

Full text of DOI:10.1021/ja511778a

Article
pubs.acs.org/JACS
Regiocontrol in Catalytic Reductive Couplings through Alterations of
Silane Rate Dependence
Evan P. Jackson and John Montgomery*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
ABSTRACT: Combinations of ligand, reducing agent, and
reaction conditions have been identified that allow alteration in
the rate- and regioselectivity-determining step of nickel-catalyzed
aldehyde−alkyne reductive couplings. Whereas previously devel-
oped protocols involve metallacycle-forming oxidative cyclization
as the rate-determining step, this study illustrates that the
combination of large ligands, large silanes, and elevated reaction
temperature alters the rate- and regiochemistry-determining step for one of the two possible product regioisomers. These
modifications render metallacycle formation reversible for the minor isomer pathway, and σ-bond metathesis of the metallacycle
Ni−O bond with the silane reductant becomes rate limiting. The ability to tune regiocontrol via this alteration in reversibility of a
key step allows highly regioselective outcomes that were not possible using previously developed methods.
into the factors that govern regioselectivity have been
provided.7
INTRODUCTION
■
Reductive couplings of two π-components have been widely
developed for numerous substrate combinations utilizing many
transition metals across the periodic table.1,2 Numerous highly
effective processes have been described that provide control of
both regiochemistry, stereoselectivity, and enantioselectivity
across a broad range of substrates, but the ability to reverse the
regiochemical biases inherent to a particular substrate class is
still quite challenging and rare.3 As a result, most regioselective
reductive coupling processes employ electronically or sterically
biased π-components that naturally favor a single regioisomer.
In these cases, access to the opposite regioisomer without
modification of the substrate typically cannot be achieved. In
the rare cases where regiochemical reversal may be achieved,
the most commonly employed strategies involve (a) special
alkyne structures that allow directed additions, where the
directing effect may be turned on and off by ligands employed,
or (b) ligand structures that allow access to either product
regioisomer through the development of steric interactions in
the oxidative cyclization step.
Irrespective of strategy employed, the mechanism in all of the
prior work on nickel-catalyzed aldehyde−alkyne reductive
couplings appears to involve oxidative cyclization of a Ni(0)−
aldehyde−alkyne complex 1 to form a five-membered metal-
lacycle 2 as the rate- and regiochemistry-determining step
(Scheme 1). σ-Bond metathesis of the silane with the Ni−O
bond of 2 then affords intermediate 3 in a fast reaction that
follows rate-determining metallacycle formation, and reductive
elimination of 3 then provides the observed silyl-protected
Scheme 1. Mechanism of Prior Protocols
The nickel-catalyzed reductive coupling of aldehydes and
alkynes is a representative reaction class where regiochemical
reversals have been demonstrated by these two strategies.4 In
alkene-directed reactions reported by Jamison, the ligand
environment on nickel may be tuned to allow the directing
group either to complex the catalyst or be effectively displaced
by altering the ligand structure and concentration. By this
strategy, the regiochemical outcome may be reversed.5 In work
from our laboratory, rate-determining formation of an
oxametallacyclic intermediate is highly sensitive to ligand
sterics, and regiochemistry reversals may be directly observed
across a range of substrates simply by ligand alteration.6
Computational studies from Houk have been conducted on
both of these nickel-catalyzed methods, and significant insight
Received: November 16, 2014
Published: December 22, 2014
© 2014 American Chemical Society
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DOI: 10.1021/ja511778a
J. Am. Chem. Soc. 2015, 137, 958−963

Journal of the American Chemical Society
Article
allylic alcohol product. Both detailed kinetics studies and
computational studies have provided evidence in support of this
generalization.7,8
couplings using SIPr as ligand surprisingly displayed a much
more pronounced influence on silane structure (Table 1,
entries 7−11). With SIPr as ligand, couplings proceeded in
58:42 regioselectivity with Et3SiH, whereas increasing the silane
size resulted in an increase in regioselectivity up to >98:2
selectivity favoring regioisomer 5 with t-Bu2MeSiH as
reductant. This outcome provides a highly selective procedure
that completely reverses the outcome seen with more typical
protocols, which strongly prefer the production of regioisomer
6.
We initially rationalized this unexpected finding as potentially
being derived from a change in rate-determining step, where
metallacycle formation becomes reversible (i.e., the 1 to 2
conversion, Scheme 1),9 and participation of the silane
becomes rate-determining (i.e., the 2 to 3 conversion, Scheme
1) as the silane size increases. This hypothesis further suggested
additional opportunities for altering the relative rates of
metallacycle formation and σ-bond metathesis, thus providing
additional experimental handles for adjusting regiocontrol. For
example, lowering the concentration of silane should slow the
rate of the silane σ-bond metathesis while not affecting the rate
of metallacycle formation, therefore favoring the pathway
involving reversible metallacycle formation. Additionally, the
previous computational studies illustrated a significant entropic
penalty associated with the σ-bond metathesis step.7c,d Such a
penalty would be maximized at high temperature, suggesting
that increasing temperature would provide another handle for
favoring the reversible metallacycle formation pathway. Using
the benchmark example of the benzaldehyde−phenylpropyne
coupling process, we conducted a series of experiments to
evaluate these hypotheses.
As would be expected for a sequence involving rate- and
regiochemistry-determining oxidative cyclization, silane struc-
ture and concentration generally has no effect on the
regioselectivity outcome. Whereas ligand control or directing
group effects influence the regioselectivity outcome, the
involvement of silane structural influences on the σ-bond
metathesis step has not been developed as a regiocontrol
strategy. Herein, we disclose that an interplay of silane
structure, ligand structure, and temperature leads to alteration
of the kinetic behavior of this system, and the insights provide a
new strategy for regiochemistry reversals in this class of
reactions.
RESULTS AND DISCUSSION
■
Experimental Factors That Influence Regioselectivity.
The nickel-catalyzed coupling of benzaldehyde with phenyl
propyne has been reported with a broad range of protocols.
Using the most widely used phosphines (i.e., PCy3) or N-
heterocyclic carbene ligands (i.e., IMes), near-perfect regiose-
lectivities for structure 6 are typically observed irrespective of
reducing agent employed, including a broad range of silanes or
Et3B (which provides the free hydroxyl of 6). The outcomes of
couplings using IMes or SIMes as ligand with Et3SiH or (i-
Pr)3SiH as the reductant are provided as representative
examples (Table 1, entries 1−4). In these cases, highly
regioselective production of 6 was observed with no influence
of silane structure on regioselectivity. Couplings using the
bulkier ligand IPr provided nearly equivalent quantities of
regioisomers 5 and 6, and a small influence of the silane
structure was noted (Table 1, entries 5 and 6). However,
As expected for a protocol where metallacycle formation is
rate-determining, the silane concentration should not affect the
regiochemical outcome. Using the standard protocol with SIPr
as the ligand and Et3SiH as the reductant, this outcome was
documented, where a 5-fold increase in silane concentration
afforded identical outcomes in regioselectivity (Table 2, entries
1 and 2). However, a marked contrast was observed in
reactions involving SIPr as ligand but utilizing a bulkier silane
(i-Pr)3SiH as reductant (Table 2, entries 3−6). Characteristic
a
Table 1. Ligand and Silane Structural Effects
a
Table 2. Concentration Effects
entry
ligand
R3SiH
Et3SiH
5:6 (% yield)
1
IMes
IMes
SIMes
SIMes
IPr
<2:98 (84)
<2:98 (83)
2
(i-Pr)3SiH
Et3SiH
b
3
4:96
b
4
(i-Pr)3SiH
Et3SiH
4:96
b
5
44:56
b
6
IPr
(i-Pr)3SiH
Et3SiH
56:44
b
entry
silane (equiv)
conc (M)
5:6 (% yield)
7
SIPr
SIPr
SIPr
SIPr
SIPr
58:42 (65)
60:40 (83)
77:23 (86)
83:17 (89)
>98:2 (61)
1
2
3
4
5
6
Et3SiH (2.0)
0.125
0.125
0.125
0.125
0.125
58:42 (65)
58:42 (32)
95:5 (57)
8
t-BuMe2SiH
t-BuPh2SiH
(i-Pr)3SiH
(t-Bu)2MeSiH
Et3SiH (10.0)
9
(i-Pr)3SiH (1.1)
(i-Pr)3SiH (2.0)
(i-Pr)3SiH (10.0)
(i-Pr)3SiH (2.0)
10
11
83:17 (89)
68:32 (93)
>98:2 (82)
a
c
0.0125
Ni(COD)2 (0.06 mmol), ligand·HCl (0.05 mmol), and t-BuOK (0.05
mmol) were stirred with 2 mL of THF. Benzaldehyde (0.5 mmol),
phenylpropyne (0.5 mmol), and silane (1.0 mmol) were combined,
diluted to a total volume of 2 mL, and added to the reaction mixture
via syringe drive over 1 h at rt. IMes·Cl = 1,3-bis(mesityl)imidazolium
chloride; SIMes·HCl = 1,3-bis(mesityl)-4,5-dihydroimidazolium chlor-
ide; IPr·HCl = 1,3-bis(2,6-diisopropylphenyl)imidazolium chloride;
SIPr·HCl = 1,3-bis(2,6-diisopropyl-phenyl)-4,5-dihydroimidazolium
a
Ni(COD)2 (0.06 mmol), SIPr·HCl (0.05 mmol), and t-BuOK (0.05
mmol) were stirred with 2 mL of THF. Benzaldehyde (0.5 mmol),
phenylpropyne (0.5 mmol), and silane were combined, diluted to a
total volume of 2 mL, and added to the reaction mixture via syringe
drive over 1 h at rt. Concentration refers to the final molarity of the
aldehyde and alkyne starting components. The catalyst was prepared
b
c
b
chloride. Isolated yield not determined.
in 38 mL of THF.
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Journal of the American Chemical Society
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improvements in regioselectivity compared with small ligand−
small silane protocols were seen as silane concentration was
lowered (Table 2, entries 3−5). When 10 equiv of (i-Pr)3SiH
was employed, regioselectivities began to approach the lower
selectivities observed with Et3SiH (Table 2, entry 5). Even
without altering silane stoichiometry, simply diluting the
reaction mixture led to significant improvements in regiose-
lectivity in reactions of (i-Pr)3SiH with SIPr as ligand (Table 2,
entry 6). It should be noted that yields of protected allylic
alcohol products were higher when the aldehyde, alkyne, and
silane were all added by syringe drive to the catalyst mixture.
Therefore, concentrations vary over the course of the reaction,
but the impacts of stoichiometry and concentration were
nonetheless essential variables as Table 2 illustrates.
Table 4. Reaction Scope with Optimized Protocol
a
entry
R1
R2
Ph
R3
method
5:6 (% yield)
b
1
Ph
Me
Me
Me
Me
Et
A
>98:2 (82)
93:7 (85)
>98:2 (77)
>98:2 (90)
94:6 (86)
93:7 (66)
68:32 (56)
93:7 (76)
>98:2 (78)
>98:2 (75)
>98:2 (61)
95:5 (69)
2
4-FC6H4
n-Hept
c-Hex
Ph
Ph
A
A
A
A
A
A
A
A
A
B
B
3
Ph
4
Ph
5
i-Bu
i-Bu
n-Pr
n-Pr
i-Pr
i-Pr
i-Pr
n-Hex
6
n-Hept
Ph
Et
Next, to explore the impact of changing temperature,
modified outcomes can be judged against the observation
that reactions using IMes with (i-Pr)3SiH illustrated no impact
of temperature on regioselectivity (Table 3, entries 1 and 2).
7
Et
8
2-furyl
Ph
Me
Me
Me
H
9
10
11
12
c-Hex
Ph
a
Table 3. Temperature Effects
Ph
H
a
Method A: i-Pr3SiH as reductant, reaction conducted at 0.125 M in
the aldehyde and alkyne at 50 °C. Method B: t-Bu2MeSiH as
reductant, reaction conducted at 0.0125 M in the aldehyde and alkyne
b
with 22 mol % Ni(COD)2 at rt. Conducted at 0.0125 M in the
aldehyde and alkyne.
commercially available (t-Bu)2MeSiH and diluted reaction
conditions while maintaining a room temperature protocol.
Using optimized method A, phenyl propyne was coupled
with a variety of aromatic and aliphatic aldehydes to produce
regioisomer 5 with high selectivity in all instances (Table 4,
entries 1−4). Steric influences in the homopropargylic position
were sufficient to allow for excellent regiocontrol (Table 4,
entries 5 and 6). However, when steric branching was
decreased in the homopropargylic position (i.e., comparing
ethyl to n-propyl), a large erosion in regioselectivity was
observed (Table 4, entry 7). This very challenging case defines
the limits of the current strategy where very modest biases in
alkyne substitution are present.
entry
NHC ligand
temp (°C)
5:6 (% yield)
1
2
3
4
5
6
IMes
IMes
SIPr
SIPr
SIPr
SIPr
rt
50
0
<2:98 (84)
<2:98 (77)
68:32 (81)
83:17 (89)
94:6 (73)
rt
50
95
b
98:2 (57)
a
Ni(COD)2 (0.06 mmol), NHC•HCl (0.05 mmol), and t-BuOK
(0.05 mmol), were stirred with 2 mL of THF. Benzaldehyde (0.5
mmol), phenylpropyne (0.5 mmol), and silane (1.0 mmol) were
combined, diluted to a total volume of 2 mL, and added to the reaction
mixture via syringe drive over 1 h. Toluene was used as the reaction
solvent.
b
Not surprisingly, when the steric differences were increased
closer to the alkyne, excellent selectivity was maintained. For
example, internal alkynes bearing a methyl substituent were
well controlled as the aldehyde and large alkyne substituent
were varied (Table 4, entries 8−10). Terminal alkynes, which
previously required the use of a noncommercial ligand to
obtain regioisomer 5 in high selectivity, could be coupled
efficiently using commercially available SIPr (Table 4, entries
11 and 12), although catalyst loading needed to be increased to
achieve good chemical yields. It should be noted that for all of
the illustrations in Table 4 regioisomer 6 would be expected
using standard protocols, as has been previously reported for a
number of the cases described.
Origin of Regioselectivity Reversals. As documented
above, experimental conditions were identified that provide a
new handle for regioselectivity reversals across a broad range of
substrates. The unique capabilities of this regioselectivity
reversal strategy are well illustrated in couplings of aromatic
alkynes. Phenyl propyne, for example, can now be converted to
either regioisomer with very high selectivity as the above
optimization studies illustrate (Tables 1−3). The simplest
explanation for the effects is that the rate-determining step for
the standard protocol involves metallacycle formation (1 to 2,
Scheme 2a) leading to the preferred formation of 6, whereas
However, by using the combination of (i-Pr)3SiH with SIPr, a
significant temperature effect was seen, with regioselectivities
jumping from 68:32 at 0 °C up to 98:2 at 95 °C (Table 3,
entries 3−6). Whereas high temperatures provided the best
regioselectivities, this comes at the expense of chemical yield,
and more modest temperature increases in combination with
the concentration effects noted above provide the best strategy
for optimizing both yield and regioselectivity.
While previous efforts had shown some successes in
regioselectivity reversals of aldehyde−alkyne reductive cou-
plings, we sought to evaluate the above findings against a
broader range of substrate combinations that led to modest
regioselectivities or required noncommercial ligands in prior
studies. To address this goal of a more general and convenient
regioselective process, two optimized protocols were developed
that could be applied to a wide range of alkynes. As shown in
Tables 1−3, several different conditions could be used to access
high regioselectivity with internal alkynes; however, heating the
reaction to 50 °C and using (i-Pr)3SiH (method A, Table 4)
proved most efficient and versatile. With terminal alkynes,
excellent regioselectivities upon heating came at the expense of
chemical yield. Therefore, a second general procedure (method
B, Table 4) was developed for terminal alkynes using
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Journal of the American Chemical Society
Article
Scheme 2. Initial Mechanistic Hypothesis
the rate-determining step for the new protocols using a large
ligand, large silane, high temperature, and low concentration
involves silane σ-bond metathesis (2 to 3, Scheme 2b) leading
to the preferred formation of 5. In related processes, the
reversibility of metallacycle formation has been demonstrated,
which would be required for the σ-bond metathesis step to be
rate-determining.9 This hypothesis of changing rate-determin-
ing step between the different experimental protocols suggested
the evaluation of the experimental variations described above
(Tables 1−3).
Figure 1. (a) Initial rates for formation of 5. (b) Initial rates for
formation of 6. (c) Ratio (6/5) of initial rates.
Given that silane σ-bond metathesis had not been previously
documented to be rate-determining in any of the prior
experimental or computational studies of this reaction type,
we sought to gain direct evidence for this mechanistic feature.
Kinetic isotope effects using (i-Pr)3SiH and (i-Pr)3SiD in the
above protocols were small and were little changed between
protocols.10 However, initial rates experiments involving
variations of silane concentration provide much more useful
information in this context.11
The dependence of initial rates on silane concentration was
thus conducted with the experimental protocol described in this
work following method A (Table 4), except at an overall
concentration of 0.0125 M and without slow addition of any
reagents. To our surprise, initial rates for the generation of
products illustrated only a small rate dependence on the silane
concentration. However, the origin of this effect became clear
by analyzing the silane dependence in the generation of
regioisomers 5 and 6 separately. As the plots of the rates of
formation of the major product 5 (Figure 1a) and minor
product 6 (Figure 1b) depict, the rate dependence varied
sharply between the two product regioisomers. Upon varying
silane concentration from 2.0 to 6.0 equiv at constant volume,
the increase in rate of formation of the major regioisomer 5 was
very small, with a near-zero rate dependence. Alternatively,
upon tracking the initial rates of the formation of the minor
isomer 6, a significant rate dependence was noted with a near-
first-order rate dependence. Plotting the ratios of initial rates of
the product formation (initial rate of 6/initial rate of 5) across
the range of silane concentrations provides a clear demon-
stration of the changes in rate dependence for each regioisomer
(Figure 1c). Furthermore, the trend visible in this latter graph
shows that regioselectivity should increase as silane concen-
tration decreases, which explains the observation that syringe
drive addition protocols and experiments at high dilution lead
to exceptionally high regiocontrol.
The above initial rate data suggests, at least for the fast
addition protocols, that the origin of the effects described above
(Tables 1−3) is that the rate-determining step is different for
the two regioisomeric pathways (Scheme 3). The formation of
major regioisomer 5 follows the previously observed mecha-
nistic feature of rate-determining metallacycle formation (1a to
2a), while the minor regioisomer 6 follows a mechanism that
involves rate-determining σ-bond metathesis (2b to 3b). This
difference in behavior of 2a and 2b can be explained by the
more crowded nickel center of 2b, due to the proximal position
of the bulkier alkyne substituent (Ph in this case). The
concentration effects described above (Table 2) can be
rationalized by a mechanism involving different rate-determin-
ing steps for the major and minor isomers (Scheme 3), since
only formation of product 6 strongly depends on silane
concentration. Similarly, the temperature effects (Table 3) can
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Journal of the American Chemical Society
Article
silane participates in the rate- and regiochemistry-determining
step of the reaction for minor regioisomer production. This
methodology possesses broad scope and improves the
regioselectivity outcome for numerous substrate combinations
by selecting for addition to the more hindered alkyne terminus.
Scheme 3. Mechanism Invoking Different Rate-Determining
Steps for Production of 5 and 6
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details, kinetics analysis, and analytical data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*jmontg@umich.edu
be rationalized, since the rate-determining step for the
production of 5 (i.e., 1a to 2a) is a unimolecular rearrangement,
whereas the rate-determining step for the production of 6 (i.e.,
2b to 3b) is a bimolecular process involving two bulky
components (metallacycle 2b and (i-Pr)3SiH), which thus
proceeds with a large entropic penalty. The modification of
reaction kinetics for only one of two regioisomeric products
thus provides an unusual but effective handle for rational
reversal of regioselectivity in a catalytic process.
While we are unaware of direct precedent for this
regiocontrol strategy in reductive couplings, Ohmura and
Suginome demonstrated a strategy with reversal of regiose-
lectivity in alkyne silaborations by switching between reversible
and irreversible alkyne insertion pathways using ligand
control.3a In other conceptually related advances, Waymouth
demonstrated control in the reversibility of metallacycle
formation as a strategy for controlling diastereoselectivity of
zirconocene-catalyzed diene cyclomagnesiations.12 However,
the simultaneous operation of differing kinetic descriptions for
two regioisomeric pathways in a single reaction has not
previously been described in reactions of this type.
While it is conceivable that a completely different mechanism
involving direct oxidative additive of silane to Ni(0) could
explain the silane rate dependence, several pieces of evidence
argue against this. First, the increasing silane bulk required to
introduce the silane rate dependence would disfavor silane
oxidative addition on steric grounds.13 Second, the differing
kinetic descriptions for formation of the two regioisomers, as
documented in Figure 1, would not be expected by mechanisms
involving silane oxidative addition to nickel. Third, silane
oxidative addition pathways typically afford the products of
aldehyde hydrosilylation8,14a or alkyne hydrosilylation,14b but
not three-component coupling of the aldehyde, alkyne, and
silane. The hydrosilylation of neither the aldehyde nor the
alkyne proceeds efficiently under the conditions (Table 4,
method A) where the three-component coupling efficiently
occurs. Finally, the aldehyde hydrosilylation processes proceed
with a significant inverse kinetic isotope effect,8 which is not
seen under the conditions developed in this study. For these
reasons, the data reported herein are best interpreted as
described as following the mechanism outlined in Scheme 3.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Hasnain Malik, Dr. Grant Sormunen, and Prof.
Ryan Baxter for helpful suggestions and discussions. We are
grateful to the National Institutes of Health (GM57014) for
financial support.
REFERENCES
■
(1) For processes involving nickel catalysis: (a) Montgomery, J.
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3829.
CONCLUSIONS
■
In summary, this study illustrates that a rational change in the
regioselectivity- and rate-determining step of aldehyde−alkyne
reductive couplings for one of the two possible regioisomers
leads to a significantly improved regiocontrol strategy using
commercially available ligands and silanes. The improvement in
selectivity arises from a change in mechanism such that the
962
DOI: 10.1021/ja511778a
J. Am. Chem. Soc. 2015, 137, 958−963

Journal of the American Chemical Society
Article
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(11) Previous computational work7c illustrated that the σ-bond
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coordination of silane to nickel, followed by the development of an
interaction between silicon and oxygen during the transition state.
During these processes, the Si−H bond length is only very slightly
elongated, and cleavage of the Si−H bond occurs after the transition-
state energy maximum. For this reason, even if the silane is involved in
the rate-determining step, a primary kinetic isotope effects would be
expected to be small. If the silane is involved in the rate-determining
step, the concentration of the silane will influence the initial rates
irrespective of the extent and timing of Si−H cleavage during the σ-
bond metathesis. For this reason, evaluating initial rates avoids the
limitations of KIE experiments.
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DOI: 10.1021/ja511778a
J. Am. Chem. Soc. 2015, 137, 958−963