Mechanism of NHC-Catalyzed Conjugate Additions of Diboron and Borosilane Reagents to α,β-Unsaturated Carbonyl Compounds

Article abstract of DOI:10.1021/jacs.5b06745

Broadly applicable enantioselective C-B and C-Si bond-forming processes catalyzed by an N-heterocyclic carbene (NHC) were recently introduced; these boryl and silyl conjugate addition reactions (BCA and SCA, respectively), which proceed without the need f

Full text of DOI:10.1021/jacs.5b06745

Article
pubs.acs.org/JACS
Mechanism of NHC-Catalyzed Conjugate Additions of Diboron and
Borosilane Reagents to α,β-Unsaturated Carbonyl Compounds
Hao Wu, Jeannette M. Garcia, Fredrik Haeffner, Suttipol Radomkit, Adil R. Zhugralin,
and Amir H. Hoveyda*
Department of Chemistry, Merkert Chemistry Center, Boston College, Chestnut Hill, Massachusetts 02467, United States
S
* Supporting Information
ABSTRACT: Broadly applicable enantioselective C−B and C−Si bond-forming processes catalyzed by an N-heterocyclic
carbene (NHC) were recently introduced; these boryl and silyl conjugate addition reactions (BCA and SCA, respectively), which
proceed without the need for a transition-metal complex, represent reaction pathways that are distinct from those facilitated by
transition-metal-containing species (e.g., Cu, Ni, Pt, Pd, or Rh based). The Lewis-base-catalyzed (NHC) transformations are
valuable to chemical synthesis, as they can generate high enantioselectivities and possess unique chemoselectivity profiles. Here,
the results of investigations that elucidate the principal features of the NHC-catalyzed BCA and SCA processes are detailed.
Spectroscopic evidence is provided illustrating why the presence of excess base and MeOH or H2O is required for efficient and
enantioselective boryl and silyl addition reactions. It is demonstrated that the proton sources influence the efficiency and/or
enantioselectivity of NHC-catalyzed enantioselective transformations in several ways. The positive, and at times adverse, impact
of water (biphasic conditions) on catalytic enantioselective silyl addition reactions is analyzed. It is shown that a proton source
can facilitate nonenantioselective background reactions and NHC decomposition, requiring the catalyst to surpass such
complications. Stereochemical models are presented that account for the identity of the observed major enantiomers, providing a
rationale for the differences in selectivity profiles of BCA and SCA processes.
diboron to α,β-unsaturated carbonyl compounds (Scheme
1).16,17 Enantioselective variants18 including those promoted by
chiral phosphines19 and transformations involving a borosilyl
reagent (to give a C−Si bond)20 were subsequently introduced.
Phosphine-21 and NHC-catalyzed boryl additions to tosyli-
mines and ynones soon followed.22 Activation of B−B bonds by
an external23 and then a neighboring Lewis-basic alkoxide24
were later exploited to effect diboron additions to unactivated
alkenes, and related transformations involving propargyl
alcohols were outlined.25 Metal alkoxides have been shown to
catalyze reactions of silylboron reagents with organohalide
substrates, affording the corresponding silanes.26 In the
significant majority of Lewis-base-catalyzed boryl and silyl
additions, the presence of a proton source (typically MeOH) is
necessary; in many instances, excess base is needed for optimal
efficiency and/or stereoselectivity. Nonetheless, a rigorous
mechanistic basis for the latter requirements is lacking.
INTRODUCTION
■
The landscape of organic chemistry would be considerably
more limited were it not for the multifaceted attributes of
organoboron compounds. Also important are Si-containing
organic molecules, entities that have significantly impacted the
art of chemical synthesis. Accordingly, development of reliable
catalytic enantioselective processes that generate C−B1−7 or
C−Si8,9 bonds remains a compelling goal of research in modern
chemistry. One area of activity relates to boryl and silyl
conjugate addition (BCA and SCA, respectively) reactions that
are facilitated by different transition-metal species10 and, in
particular, Cu-based chiral complexes.11−13 For example, cyclic
β-hydroxyl carbonyl products as well as acyclic or cyclic variants
that contain a tertiary alcohol may be prepared by catalytic
BCA methods (after C−B bond oxidation); these entities,
which cannot be accessed through catalytic enantioselective
aldol addition or related approaches,14 facilitate synthesis of a
variety of biologically active molecules.
It was reported in 2009 that achiral N-heterocyclic
Received: May 12, 2015
carbenes15 (NHCs) can catalyze the addition of (pinacolato)-
© XXXX American Chemical Society
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number of questions regarding the details of the catalytic cycles
for C−B and C−Si bond formation (Scheme 1), including
those that are promoted by NHCs, remain unaddressed.27 An
appreciation of such attributes will be crucial to the success of
future endeavors regarding catalyst and method development in
this emerging area of research. Herein, we detail the results of
studies performed aimed at finding a plausible answer for the
above issues and various other questions relating to the inner
workings of NHC-catalyzed boryl and silyl conjugate additions.
Scheme 1. Catalytic Processes and the Key Mechanistic
Questions
BACKGROUND
■
The viability of Lewis-base-catalyzed BCA is manifested in the
manner with which initial activation of a B−B bond might
occur by the oxygen atom of an NHC− or phosphine−Cu−OR
complex (i → iii via ii, Scheme 2a).28 In addition to increasing
Cu Lewis acidity, according to the well-established tenets of
Lewis-base enhancement of Lewis acidity,29 the Lewis base
(e.g., an NHC) elevates the nucleophilicity of the alkoxide
ligand, facilitating the formation of ii, which is the principal
player in a Cu−boryl addition. The question would then be
whether efficient activation can be achieved directly by an
organic Lewis-basic molecule. This notion finds support in X-
ray crystallographic investigations showing that adducts derived
from association of bis(catecholato)diboron and bis-
(thiocatecholato)diboron with 4-methylpyridine and dimethyl-
Boryl and silyl conjugate additions that are facilitated by
transition-metal-free Lewis-base catalysts mark a new chapter in
organoboron and organosilicon chemistries; these are mecha-
nistically distinct reactions that offer complementary functional
group compatibility profiles (vs those promoted by organo-
metallic species). However, in addition to the aforementioned
̀
issues vis-a-vis the need for a proton source and excess base, a
a
Scheme 2. Discovery of NHC-Catalyzed Boryl Conjugate Addition
a
G = alkyl or aryl group; B(pin) = (pinacolato)boron.
B
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phenylphosphine, respectively, cause perceptible weakening of
B−B bonds.30,31
Scheme 3. Enantioselective NHC-Catalyzed Boryl Conjugate
Additions
a
We initially established that NHC·B2(pin)2 complexes can be
readily generated. Spectroscopic analysis pointed to the
formation of a Lewis-base-bound B atom (cf. 2 derived from
NHC 1, Scheme 2b), and calculations indicated B−B bond
lengthening. The validity of the originally suggested NHC·
diboron complex 2 was afterward substantiated by the notable
X-ray crystallographic studies of Marder and co-workers.32
While formation of a Lewis-base·diboron complex does not
guarantee a catalytic process, we soon discovered that NHCs
do promote BCA reactions. The multicomponent trans-
formation in Scheme 2c, affording 4 as a single stereoisomer,
is illustrative;16a this reaction underscores the functional group
compatibility of the NHC-catalyzed processes versus those
promoted by Cu-based complexes (vs 31% yield with NHC−
Cu species due to boryl addition to the aldehyde). We found
that phosphines are catalytically less active,18a and alkoxides
(e.g., NaOt-Bu) proved to be less capable promoters (e.g.,
compared to i).16a
Enantioselective boryl additions to α,β-unsaturated carbonyl
compounds (acyclic and cyclic enones, esters, Weinreb amides,
or enals) can be performed with chiral NHC catalysts and 1,8-
diazabicyclo[5.4.0]undec-7-ene (dbu) as the base (Scheme
3a).18a,33 The high er values are mechanistically revealing: they
clearly indicate that an NHC-bound chiral complex is
responsible for the C−B bond-forming process. Further,
enantioselective addition to the more challenging trisubstituted
enones is feasible; this is exemplified by the transformation
promoted by the enantiomerically pure NHC derived from 7b
(Scheme 3b).18b The BCA en route to natural product
crassinervic acid proceeded readily despite the presence of a
phenol and an aryl aldehyde, moieties that greatly diminish the
activity of phosphine− or NHC−Cu complexes.34 NHC-
catalyzed enantioselective BCA reactions afford products that
cannot be easily prepared otherwise in high enantioslectivity
(e.g., acetate aldol products that contain a Weinreb amide33 and
ketone aldol products such as 818b in Scheme 3b) and are
practical and robust; contrary to reactions with Cu complexes,
use of a drybox is not needed.
a
Mes =2,4,6-Me3-C6H2. The er values for some of the β-boryl ketones
in Scheme 3a correspond to reactions with NHC catalysts that are
slight structural variants of 7a; see ref 18 for details. The
stereoselectivity profiles, however, are as shown.
bond-forming reactions regardless of whether cyclic or linear
α,β-unsaturated carbonyl compounds are employed.
The above progress raises several fundamental questions. (1)
Why is it that, unlike additions promoted by achiral NHC
catalysts, the presence of MeOH is required for high conversion
in enantioselective BCA reactions? (2) Why is excess base
(dbu), beyond what is necessary for NHC formation, generally
needed for achieving high yields of the desired products? (3) If
the transferred boryl group is not the one that is associated with
the NHC catalyst then precisely how is a high degree of
stereochemical induction observed with the Lewis-base
promoter being at a relatively remote site? (4) Why is the
sense of addition to the acyclic substrates opposite to that of
the cyclic enones (cf. Scheme 3a)?
NHC-catalyzed silyl conjugate addition (SCA) with
dimethylphenylsilylpinacolatoboron [PhMe2Si−B(pin);
Scheme 4]35 further broadens the scope of the approach and,
on several fronts, is distinct from the related boryl additions.
Unlike the BCA processes, regardless of whether an achiral or a
chiral NHC is involved, there is minimal conversion without a
protic additive.20 Not only is a proton source needed in SCA
reactions, water is the superior choice (vs MeOH with BCA; cf.
Scheme 4). Similar to the boryl additions, excess dbu enhances
efficiency, but in further contrast to BCA processes, the same
sense of absolute stereochemistry is generated in the C−Si
RESULTS AND DISCUSSION
■
1. Probing the Possibility of a Radical-Based
Mechanism. We began by looking into whether the NHC-
catalyzed BCA or SCA reactions involve odd-electron
intermediates, a scenario that may find support in the
pioneering investigations of Curran, Malacria, and co-workers.
The latter researchers provided convincing evidence that
NHC−borane complexes are capable of facilitating a C−H
and C−C bond-forming transformations by radical-based
routes.36 We judged the possibility of a radical pathway to be
especially relevant because the calculated homolytic bond
dissociation energy (BDE) for B−B bonds in B2(pin)2 and
NHC·B2(pin)2 (NHC = 1,3-dimethylimidazol-2-ylidene) is 104
and 63 kcal/mol, respectively [at unrestricted B97D/6-
31+G(d,p) level of theory].37 The aforementioned values are
lower than those calculated36a for BDE of B−H bonds in
NHC−BH3 complexes (∼74−80 kcal/mol), which are within
the range measured for established radical precursors (e.g., 74
kcal/mol for n-Bu3Sn−H).38
Subjection of 3-cyclopropyl-cyclohexenone 9 to the BCA
conditions afforded β-boryl ketone 10 in 85% yield without any
detectable amounts of 11 (Scheme 5a), which would be formed
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change in the 11B NMR spectrum (6.0 h, 25 °C; Scheme 6);
this is in contrast to when achiral NHC 1 was employed, where
there was >98% conversion within just 5 min. In the case of the
chiral NHC, only after 30 equiv of MeOH and 6 equiv of dbu
were introduced were we able to detect 20−30% of a new signal
at 5.1 ppm (11B NMR), likely arising from NHC·diboron
complex 19a and/or 19b (Scheme 6). (As will be detailed
below, the aforementioned signal is not due to the derived
methoxy complex.)
Scheme 4. NHC-Catalyzed Silyl Conjugate Addition
Concurrent availability of base and MeOH likely causes one
of the pinacolato units of B2(pin)2 to rupture, producing a more
accessible boron center (Scheme 7a).42 With MeOH, but in the
absence of base, B2(pin)2 remains unaltered (Scheme 7b). The
structurally modified and sterically less hindered boron site can
readily associate with the more sizable chiral NHC (e.g., 7a−c).
Thus, with the smaller achiral NHC, complex formation and
B−B bond activation do not require a priori cleavage of the
pinacolato ring. Utilization of less congested diboron
derivatives [vs B(pin)] to boost reactivity is an established
strategy in organoboron chemistry;40 in situ conversion of a
B(pin) unit to a more accessible derivative was recently
illustrated.41 The B(pin) moiety within the BCA product is
more immune to reaction with MeOH probably because of the
shorter B−C bond (1.5 vs 1.7 Å for B−B bond) as well as the
presence of a neighboring sp3-hybridized C (vs an sp2-
hybridized B).
Spectroscopic analysis provided additional information about
the role of excess base and alcohol. Reaction of B2(pin)2 with
dbu and MeOH generated free pinacol, as indicated by analysis
42
1
of H NMR spectra of the unpurified mixtures, and resulted
in a peak at 7.5 ppm in the 11B NMR spectrum, a signal that
may be attributed to the methoxy-bound diboron species 23a-b
(peak a, Figure 1); the intensity of the signal increased with
time. Additionally, two broad peaks appeared between 25−35
ppm (b and c, Figure 1). The more upfield peak b may be
attributed to the B atom undergoing hybridization change due
to the rapid equilibrium between B2(pin)2 and 20. As the
sample was cooled to −10 °C, signal b shifted upfield toward
∼10 ppm, indicating an increasing preference for the formation
of borate 20 (Figure 1). The large and broad peak c almost
certainly corresponds to the sp2-hybridized B atoms of B2(pin)2
and other species such as 20, 22a-b, and 23a-b. The most
upfield small signal (marked by a blue box), which can only be
detected at ≤10 °C, is likely derived from association of the
more weakly Lewis-basic and larger dbu (vs methoxide) with
the diboron species (24a-b); thus, the more weakly held
complex is more readily dissociated. As will be described, the
amount of this latter entity increases in the presence of a highly
Lewis-basic NHC. Methoxide activation of a B−B bond via 20
or 23a-b points to the possibility of methoxide-catalyzed boryl
addition.23,24 Accordingly, treatment of enone 6a (Scheme 3)
with 1.1 equiv of B2(pin)2, 20 mol % of dbu, and 60 equiv of
MeOH generated ∼20% of the corresponding rac-β-boryl
ketone after 14 h (22 °C). The chiral NHC catalyst must
overcome this latter competitive background process since high
enantioselectivity can be attained.
if a carbon radical were generated at the carbon β to the
carbonyl group. A similar observation was made with the
cyclopropyl moiety positioned at the site adjacent to the CO
bond: 12 was isolated in 67% yield as a single stereoisomer
without any cyclopropyl cleavage. To ascertain that a radical
mechanism is not in effect, we examined the reactions of the
derived diphenylcyclopropane; here, the corresponding odd-
electron species would undergo cleavage at a rate that is above
the rate of diffusion-controlled processes.39 We did not detect
any 13, likely because of steric hindrance, but did obtain β-
boryl ketone 14 in 45% yield. Again, the product resulting from
rupture of the cyclopropyl moiety was not observed. The
identity of the BCA product was further substantiated by
determination of the crystal structure of 15, generated from
reaction of 14 with atmospheric oxygen (Scheme 5a). NHC-
catalyzed C−Si bond formation does not seem to involve odd-
electron intermediates either, as the conversion of 16 to β-silyl
ketone 17 and complete absence of 18 indicates (Scheme 5b).
2. Influence of Excess Base and MeOH on Boryl
Conjugate Additions. We then turned to addressing the
question of why BCA reactions with achiral NHCs can be
performed without MeOH (e.g., with 3a in Scheme 2c),
whereas when the corresponding chiral catalysts are used, an
excess amount of a proton source is required (cf. Scheme 3a).
When we made an inquiry regarding the possible association of
the chiral NHC derived from imidazolinium salt 7c with
B2(pin)2 in the absence of MeOH, we did not detect any
3. Details of the Formation of Chiral NHC·diboron
Complex. Spectroscopic studies with samples that contain
enantiomerically pure imidazolinium salt 7c shed light on the
interaction of various Lewis bases with in situ-generated
sterically accessible/more reactive diboron species (Figure 2).
Within 30 min at 25 °C, a peak at 7.5 ppm (c) and another at
6.5 ppm (b) could be detected. After 2 h, the two signals grew
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a
Scheme 5. Probing the Possibility of a Radical-Based Mechanism
a
Catalytic BCA reactions leading to 12 and 14 were performed with 20 mol % 3a and 22 mol % NaOtBu. See the Supporting Information for details.
Scheme 6. Probing the Effect of Base and MeOH on B−B Bond Activation
in strength and another upfield singlet emerged at 5.0 ppm (a).
In 6 h, the intensity of the three peaks (a−c) increased
extensively. The chemical shift at 7.5 ppm (c) corresponds to
the methoxy-bound B atoms of diboron species 23a-b, as
established by the experiments depicted in Figure 1, and the
signal at 5.0 ppm arises from the NHC·diboron complexes 19a-
b, based on the spectroscopic observations illustrated in
Scheme 6. The signal at 6.5 ppm (b, Figure 2) is attributable
to dbu·diboron complexes 24a-b; as before, though this
particular peak could not be detected at 25 °C in the absence
of the NHC (cf. Figure 1), it could be seen by cooling the
sample to below 10 °C (cf. Figure 1). The signal corresponding
to 24a-b also appears as a much smaller peak in the spectra in
Figure 1 recorded at ≤10 °C; this difference in signal intensity
is to be expected because the sterically less demanding
methoxide can more effectively compete with dbu (vs chiral
NHC). The increased abundance of 24a-b in the presence of
NHC suggests that the Lewis base accelerates B(pin)
cleavage,43 likely in the same manner as illustrated in Scheme
7a for a methoxide ion, to provide a higher concentration of the
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Lewis base (methoxy, dbu, or NHC) may begin to dissociate
from its diboron host. Accordingly, signals a and b disappeared
and peak d became visible at 40 °C, pointing to a shift in
equilibrium in favor of sp2-hybridized B atoms. Methoxide
complexes 23a-b (signal c) proved to be more resistant toward
dissociation (vs 19a-b or 24a-b), as the signal at 7.5 ppm
persisted at elevated temperatures. Such stability profiles may
be partly due to the smaller size of a methoxide (less steric relief
upon dissociation), which is congruent with the faster
appearance of the corresponding peak versus those that relate
to NHC- (a) or dbu-based diboron complexes (b) (cf. Figure 2
Scheme 7. Susceptibility of B2(pin)2 to Alcohol and Base
̀
at 0.5 and 2 h). As mentioned vis-a-vis peak b in Figure 1 for
MeO·diboron species 20, higher temperatures led to
conversion of Lewis-base·diboron complexes to the free
diboron species that contain only sp2-hybridized B atoms;
this is evidenced by the downfield movement of signal e in
Figure 3 when the sample was allowed to warm from −10 to 40
°C.
The above spectroscopic studies show that electronic
variations extend beyond changes in the chemical shift of the
B(pin) group that is directly bound to a Lewis base. Spectral
data point to increased Lewis acidity at the unbound boron site
(sp2 hybridized). Thus, there is a chemical shift change from
the B atoms of B2(pin)2 (30.1 ppm in 11B NMR) to the more
downfield signal for the uncoordinated sp2-hybridized B atom
of the NHC·diboron complex derived from carbene 1a (36.3
ppm; cf. Scheme 2b). The electronic influence of Lewis-base
activation is further manifested by the most downfield signals in
Figure 3 (a and b, red); these peaks may be attributed to the
sp2-hybridized B atoms of NHC-, methoxide-, and dbu-bound
dbu·diboron complex. The broad signals d−f in Figure 2 have
been already analyzed (cf. signals b and c, Figure 1).
Variable-temperature NMR experiments showed that if the
sample is allowed to warm from −10 to 40 °C (Figure 3), a
Figure 1. Effect of dbu on loss of pinacol and association of Lewis-basic groups with the more exposed B center.
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Figure 2. 11B NMR spectra for reaction of B2(pin)2 with 100 mol % of 7c with 6.0 equiv of dbu and 30 equiv of MeOH (thf-d8, 25 °C).
Figure 3. 11B NMR spectra at different temperatures for reaction of B2(pin)2, 100 mol % 7c with 6.0 equiv of dbu, and 30 equiv of MeOH after 6 h
(thf-d8).
complexes 19, 23, and 24. These findings are again consistent
with the principles of Lewis-base activation of Lewis acids,29,43
indicating that alteration of electron density extends to the
neighboring B(pin) unit as well (net increase at the more
electronegative O atoms). The increase in Lewis acidity of the
unbound boron atom, caused by association of a Lewis base to
the diboron compound, should not be expected to have an
adverse effect on the rate of a BCA process, as it is the electron
density of the more polarized B−B bond that likely kick-starts
that C−B bond-forming process. It might be suggested that the
enhancement in Lewis acidity of the uncoordinated boron
might cause it to associate with a Lewis base as well. However,
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Scheme 8. Influence of the Amount of Base on NHC-Catalyzed Boryl Additions
Figure 4. 11B NMR spectrum for reaction of (pin)B−SiMe2Ph with an achiral NHC in the presence of only dbu (thf-d8, 25 °C).
DFT calculations clearly indicate37 that a doubly coordinated
species would be substantially higher in energy probably as a
result of steric congestion (severe eclipsing interactions) caused
by vicinal fully substituted B atoms. Furthermore, the resulting
B−B bond would be less polarized, and the activation barrier
toward addition to an enone would be more energetically
demanding.
The above studies provide valuable clues regarding
optimization of the experimental conditions, namely, that
increasing the amount of Lewis base (e.g., dbu) should lead to
faster cleavage of a B(pin) unit of B2(pin)2. NHC·diboron
complex formation would then be facilitated, and B−B bond
activation and an increase in the efficiency of the BCA process
would ensue. Such expectations are supported by the
representative data in Scheme 8. Whereas with 20 mol % of
dbu there was 27% and 75% conversion to 29a and 29b,
respectively, after 14 h (22 °C) with 100 mol % of base the
BCA proceeded to full conversion. This enhancement in
enantioselectivity suggests that, at lower concentration of dbu
and with less efficient chiral NHC binding, there is likely
residual catalysis by an achiral Lewis base (most likely the
methoxide ion).23,24
reactions. Unlike boryl additions, there is no C−Si bond
formation without a protic additive despite involvement of a
smaller achiral NHC. Moreover, SCA reactions are less efficient
when carried out in the presence of MeOH; transformations
proceed readily when conducted in a water/thf mixture that is
turned emulsive due to the presence of the borosilane reagent.
It is therefore possible that activation of a more sterically
demanding borosilane [vs B2(pin)2] requires a more accessible
B(OH)2 unit and/or a medium that can better accommodate
the formation of polar intermediates and transition states.
Inefficient generation of a Lewis-base·borosilane complex is
not the reason why SCA processes are slow when they are
performed in the absence of a proton source. Treatment of
imidazolium salt 3c with (pin)B−SiMe2Ph at 25 °C with 1.05
equiv of dbu (without any H2O) led to complete loss of the
signal for the borosilane reagent (33.4 ppm, 11B NMR
spectrum) in 5 min (Figure 4); this time, a broad peak
appeared at 8.0 ppm that may be attributed to NHC·borosilane
complex 30.44 It is therefore more likely that because of the
bulkier dimethylphenylsilyl moiety [vs B(pin) of B2(pin)2],
efficient association of a species such as 30 with an enone
substrate requires the conversion of the pinacolato group to a
B(OH)2 unit.
4. Influence of Excess Base and H2O on NHC-
Catalyzed Silyl Conjugate Additions. There are several
key differences between NHC-catalyzed BCA and SCA
Hydrolysis of the B(pin) group is likely to be equally (if not
more) critical when the more sizable chiral NHC catalysts are
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involved. In the presence of chiral imidazolinium salt 7c and
excess amounts of dbu (6.0 equiv) and 6.0 equiv of H2O, the
borosilane reagent was completely consumed in 1 h. Still, a
signal corresponding to the NHC·borosilane complex could not
be detected (Scheme 9).42
another at 7.6 ppm is because of the tetravalent B atom of 32b;
these complexes may form by pathways similar to those shown
in Scheme 7a [involving B2(pin)2 and MeOH].
Through another experiment, summarized in Scheme 10b,
we established that although (pin)B−SiMe2Ph is relatively
stable in aqueous media, soon after the addition of dbu it is
swiftly consumed and SCA takes place efficiently (34%
conversion in 2 min and 86% conversion in 30 min to β-silyl
ketone 33b). Moreover, we were able to isolate and obtain the
X-ray crystal structure of borate complex 34, resulting from the
loss of the pinacol group, an event that likely leads to a more
reactive borosilane derivative (e.g., 32b) and facile SCA,
regardless of whether an achiral (cf. 3b, Scheme 4) or a larger
chiral NHC (cf. 7c, Scheme 4) is involved. These observations
illustrate that a highly effective enantioselective SCA catalyst
must be sufficiently active to overcome the somewhat rapid
background processes that afford racemic β-silylcarbonyl
compounds.
Scheme 9. Probing the Association of Chiral NHC with
(pin)B−SiMe2Ph
We resorted to spectroscopic analysis (11B NMR) in our
quest to gain information regarding the details of borosilyl
activation by a chiral NHC. A mixture of (pin)B−SiMe2Ph
together with an equivalent of chiral imidazolinium salt 7c, 6.0
equiv of dbu, and 6.0 equiv of H2O, shown in Figure 5, led to
generation of different products, many of which contain an sp3-
hybridized B atom (peaks a and b relating to 35a-b and 32b,
respectively). The assignment of the signals at 4.4 and 7.7 ppm
are based on formerly reported values44 and the experiment
performed in the absence of an NHC (cf. Scheme 10a),
To gain insight regarding the possible influence of water on
NHC-borosilane association, we first examined the fate of
(pin)B−SiMe2Ph when treated with 6.0 equiv of dbu and H2O
in thf at 22 °C. Within 30 min, the reagent was entirely
consumed and two types of B-containing species were
generated (Scheme 10a). A signal at 21.5 ppm is likely due
to formation of boronate 31, Me2PhSiH (characteristic peak in
1H NMR spectrum at 4.4 ppm), and complex 32 [in
equilibrium with (pin)B−SiMe2Ph, H2O, and dbu], while
a
Scheme 10. Influence of Base and H2O on (pin)B−SiMe2Ph and SCA Reactions
a
See the Supporting Information for details.
I
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Figure 5. 11B NMR spectra for reaction of (pin)B-SiMe2Ph with a chiral NHC in the presence of H2O and dbu (thf-d8, 25 °C).
Figure 6. 11B NMR spectrum for reaction of (MeO)2B−SiMe2Ph with a chiral NHC (thf-d8, 25 °C).
respectively; that is, a distinct signal that may be confidently
attributed to NHC·borosilane complex 36 could not be formed.
Considering the differences in the electron donor abilities of an
OH and an NHC ligand and the aforementioned influence of
such characteristics on the chemical shift for the signals of the
associated boron atoms, the possibility that the signal for 36
might be hidden behind the peak at ∼8 ppm is remote. It is
noteworthy that the NHC·borosilane complex that is
responsible for promoting SCA reactions with high enantiose-
lectively in the face of a somewhat swift background process
J
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and at significantly lower concentrations (e.g., 5.0 vs 100 mol
%) is difficult to observe. It is reasonable to suggest, however,
that the lifetime of the borosilyl reagent or 36 is substantially
increased under biphasic conditions (i.e., 3:1 H2O/thf vs 6.0
equiv of H2O in thf), as these species probably spend much of
their time in the organic layer. Otherwise, extended reaction
times (e.g., 12 h in Scheme 4) would not be productive.
To detect a chiral NHC·borosilane complex spectroscopi-
cally, we prepared dimethylphenylsilyl(dimethoxy)boron 37
(confirmed by HRMS), a species that is easier to synthesize and
handle than the corresponding bis(hydroxy)boron derivative.
Treatment of a sample of 37, after filtration to remove solid
residues, with 1.0 equiv of imidazolinium salt 7c and 1.0 equiv
of potassium hexamethyldisilazide (KHMDS, to ensure rapid
and complete kinetic deprotonation) at 25 °C in thf-d8 for 30
min led to the appearance of a singlet in the 11B NMR
spectrum at −0.4 ppm (Figure 6). This signal likely belongs to
complex 39, and its broad shape indicates a rapid equilibrium
between the chiral NHC·borosilane complex and the unbound
borosilane. To ensure that the aforementioned peak does not
originate from association of the NHC with trimethoxyborane
used for preparation of 37, we obtained the 11B NMR spectrum
of the suspected complex (40), establishing that the associated
peak appears at 1.4 ppm. Furthermore, when the dimethox-
yborosilane reagent 37 was reacted with the achiral NHC
derived from bis(mesityl)imidazolium salt 3c, the resulting
NHC·boryl species (41) manifested itself with a signal at 0.1
ppm. Control experiments indicate that the reason for
Scheme 11. Probing the Formation of a Chiral NHC·
Borosilane Complex by Spectroscopic Analysis of a 13C-
a
Labeled Chiral NHC
a
See the Supporting Information for details.
PhMe2Si−B(pin) (to emulate catalytic reaction conditions)
caused the aqueous thf mixture to become biphasic, and 7c
remained unaltered (Scheme 12); however, when 3.0 equiv of
dbu was added, there was ∼20% decomposition to acyclic
formamide 43 (Scheme 12). When 7c was first treated with 1.0
equiv of potassium hexamethyldisilazide (KHMDS, thf) before
being placed in an aqueous thf solution that does not contain
either the borosilane reagent or any dbu (monophasic),
complete conversion to 43 occurred in less than 2 h. The
above experiments demonstrate that whereas the imidazolinium
salt precursors are relatively stable, the NHC species, formed
upon addition of dbu, can slowly decompose under the reaction
conditions. Formamide 43 promotes SCA but nonenantiose-
lectively (Scheme 12). Facile and highly enantioselective silyl
additions therefore imply that the biphasic nature of the
medium retards the rate of formamide generation, and an
NHC·borosilane complex is probably longer living than an
unbound NHC.
5. Effect of Hydroxide Ion Permeability on Efficiency
and Enantioselectivity of Conjugate Silyl Additions.
Through the studies described above we demonstrated that the
presence of water can have a positive [increasing activity by
B(pin) hydrolysis] or a deleterious effect (NHC and/or
borosilane decomposition) on NHC-catalyzed SCA reactions,
and the degree and nature of the influence of water depends on
the amount of dbu present (cf. Scheme 10b). With a better
understanding of such factors, we can rationalize the origin of
otherwise perplexing observations, and conditions may be
modified leading to significant improvement in reaction
outcomes. One noteworthy case relates to SCA to p-
trifluoromethylphenyl-substituted enone 6c, which proved to
be notoriously inefficient despite the substrate’s significant
electrophilicity. Indeed, in our initial disclosure, we reported
that the expected β-silyl ketone could not be observed after 3 h
in the biphasic 3:1 mixture of H2O and thf (Scheme 13).20 We
reasoned that the presence of three fluorine atoms might cause
enhanced phase separation, diminishing the concentration of
the hydroxide in the organic phase (cf. Scheme 10b) needed to
facilitate B(pin) removal, NHC·borosilane complex formation,
and efficient SCA. Indeed, as shown in Scheme 13, when
reaction with 6c was performed with only 3.3 equiv of H2O in
thf (monophasic), we were able to obtain 33c in 86% yield after
formation of the NHC·borosilyl complex is not the use of a
stronger base (i.e., KHMDS vs dbu) as opposed to the
availability of a more sterically accessible borosilane partner;
treatment of 7c, KHMDS (1.0 equiv), and (pin)B−SiMe2Ph
does not lead to any detectable amounts of a chiral NHC·
1
borosilane complex (400 MHz H NMR analysis).
To explore the formation of the chiral NHC·borosilyl
complex 39 further, we prepared a 13C-labeled sample of
imidazolinium salt 7c and converted it to the corresponding
NHC·BF3 complex 42 by the addition of 1.0 equiv of KHMDS
at 22 °C in thf-d8 for 30 min (Scheme 11). At ambient
temperature, trifluoroboron species 42 may be identified by
peaks at 164.2 and −0.9 ppm in the 13C and 11B NMR spectra,
respectively.45 The latter signal is broad, indicative of rapid
equilibrium between the free carbene and the BF3 complex.
Subsequent addition of 1.0 equiv of bis(methoxy)borosilane 37
to the sample containing 42 resulted in the formation of 39,
which was marked by the appearance of a new signal at 181.2
ppm in the 13C NMR spectrum (11B NMR signal at −0.4 ppm).
The above findings imply that the catalytically active NHC·
borosilane is probably formed and capable of promoting
substantial amounts of transformation prior to its decom-
position.
Imidazolinium salt 7c is stable in monophasic 3:1 H2O/thf
solution (spectroscopic analysis). Incorporation of 22 equiv of
K
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a
Scheme 12. Decomposition of an Imidazolinium Salt in an Aqueous Medium
a
See the Supporting Information for details.
Scheme 13. Influence of Ratio of Water/thf on the Efficiency of NHC-Catalyzed SCA
only 3 h. We must note that the latter conditions do not
translate to efficient SCA with other, less electrophilic,
enonesit is in the case of highly active substrates that a
relatively small amount of water is sufficient to generate enough
B(pin) hydrolysis for efficient silyl conjugate addition.
Another notable implication of the biphasic reaction medium
and the role of in-situ-generated hydroxide in facilitating a
catalytic SCA process is that the optimal base must be
adequately soluble in the aqueous as well as the organic phase.
The base (e.g., dbu) can then penetrate the aqueous phase to
generate the appropriate amount of hydroxide salt (e.g.,
H+dbu·−OH) that is lipophilic enough to enter the organic
layer and promote B(pin) hydrolysis. The findings in Scheme
14 shed light on these issues.
Firstly, with 100 mol % of dbu, SCA with trifluoromethyl-
phenyl-substituted enone 6c proceeded to >98% conversion,
affording 33c enantioselectively (87:13), even in biphasic 3:1
H2O/thf (Scheme 14); this is in stark contrast to <2%
conversion when 22.5 mol % of dbu was used (cf. Scheme 13).
Secondly, efficiency variations with amine bases that possess
different solubility properties indicate that with a more
lipophilic base or one that has higher hydrophilicity than dbu,
SCA efficiency suffers [(∼10% and 70% conversion with (n-
Bu)2NH (log P = 2.8346) and pyrrolidine (log P = 0.46),
respectively, vs >98% conversion with dbu (log P = 1.31)].
Thirdly, enantioselectivity is higher when an amine base that is
less water soluble is present [94:6 er for (n-Bu)2NH] or when a
base that is more hydrophilic than dbu is used (93:7 er for
L
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Scheme 14. Effect of Solubility of Different Amine Bases on the Efficiency of Catalytic SCA Reactions
pyrrolidine vs 87:13 er with dbu). In either instance, the
concentration of hydroxide in the organic layer, where 6c can
be found, would be lower (vs with dbu), resulting in reduced
generation of rac-33c (cf. Scheme 10b). For SCA with (n-
Bu)2NH, there is insufficient base penetration into the aqueous
layer, and with pyrrolidine there would be less partitioning of
the ammonium hydroxide into the organic layer.
Higher efficiency of exchange between the phases is not
caused by the nature of the amine base only. The presence of a
suitably polar organic molecule can accelerate an otherwise
inert enone as well. As previously mentioned (cf. Scheme 13),
there was <2% conversion when 6c was subjected to 7.5 mol %
of 7c, 1.1 equiv of (pin)B−SiMe2Ph, and 22.5 mol % of dbu in
3:1 H2O/thf after 12 h. Nevertheless, with an equal amount of
phenyl-substituted enone 6a simultaneously present (identical
catalyst loading for total enone concentration; cf. eq 1), the
more lipophilic trifluoromethylphenyl-substituted enone 6c was
fully consumed in 5 h and 33c was obtained in 96:4 er. The
higher er in the latter transformation (vs 87:13 er, Scheme 13)
is due to the presence of 6a, which can increase hydroxide ion
concentration enough so that SCA is facilitated but not to the
extent that would lead to production of rac-33c (due to NHC
rationale for the observed stereochemical outcomes of NHC-
catalyzed enantioselective BCA and SCA processes.
decomposition; cf. Scheme 12).
6. Kinetic Studies and Stereochemical Models. Initial
rate measurements involving representative enantioselective
NHC-catalyzed BCA and SCA reactions indicate that trans-
formations are first order in the NHC, the α,β-unsaturated
carbonyl substrate, as well as B2(pin)2 and (pin)B−SiMe2Ph
reagents, respectively; no dependence on dbu was observed.47
With the assumption that NHC·diboron and NHC·borosilane
complex formation are rapidly reversible under the reaction
conditions (22 °C; steady state approximation), a premise
supported by the broad signals in the 11B NMR spectra (see
above) that may be sharpened at lower temperatures,16b,32a the
latter findings point to the C−B and C−Si bond-forming steps
as turnover limiting. Accordingly, we set out to develop a
To begin with, several general scenarios for BCA and SCA
reactions were explored by means of DFT calculations [B97D/
6-31+G(d,p) level of theory], most of which entailed initial B−
B or B−Si bond activation by an NHC catalyst.37 Among the
pathways examined were those proceeding via intermediates
derived from NHC insertion into the B−B or B−Si bonds.48
These investigations indicated that the originally suggested
route, namely, the addition of polarized NHC·diboron or
NHC·borosilane complexes to unsaturated carbonyl com-
pounds, is energetically the more favorable possibility.
Model for Additions to Acyclic Substrates. The lowest
energy transition state structures for boryl and silyl conjugate
additions to an acyclic enone are presented in Figure 7. For the
M
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Figure 7. Transition state models for NHC-catalyzed enantioselective BCA and SCA reactions of acyclic enones obtained by DFT calculations.
Figure 8. Transition state models for NHC-catalyzed enantioselective BCA and SCA reactions of cyclic enones obtained by DFT calculations.
BCA reactions, unlike I, complex II suffers from a destabilizing
steric repulsion between the alkenyl substituent of the
electrophile and the NAr moiety of the chiral NHC. This is
consistent with experimental findings, indicating that the size of
the meta substituent of the NAr group influences BCA
enantioselectivity (Me in I and II, i-Pr in the optimal catalyst
derived from 7a; cf. Scheme 3). A larger ortho substituent
within the NAr unit can cause the aromatic plane to tilt, so that
the coordinating substrate is more readily accommodated (e.g.,
Mes in 7a vs Ph in I and II).49
aforementioned NAr group and the enone substituent (Ph in
II). The transition states calculated for SCA transformations,
III and IV, generally resemble those obtained for the BCA
processes; the same arguments provided for I and II apply here
as well. Widening of the N−C−B angle is less in the case of the
borosilane complexes (124°/129° in III/IV vs 123°/133° in I/
II) perhaps because the longer B···Si engenders a lower degree
of steric repulsion with the NHC. A difference between silyl
and boryl additions is the possibility of H-bonding interactions
between the B−OH within the NHC·borosilane ensemble and
the substrate carbonyl group in III and IV. Such interactions
alleviate the accumulation of electron density at the carbonyl
oxygen that is developed after conjugate addition; the same
DFT calculations point out that the N−C−B angle in the less
favorable II is bent by ∼10° (133° vs 123° in I); this allows
minimization of the destabilizing interactions between the
N
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type of stabilization may be provided externally by a protonated
dbu or a MeOH molecule in the NHC-catalyzed boryl
additions (cf. I and II); the zero-order rate dependence on
dbu suggests that either MeOH, which is available in great
excess, largely serves as the proton source or association with
Hdbu+ is fast and precedes the turnover-limiting step.
borosilane complex generation and a more rapid
initiation of a catalytic cycle.
(e) For the silyl addition processes, the chiral NHC must be
sufficiently active to overcome borosilane reagent
decomposition as well as its own breakdown, which
can yield a catalytically active but nonenantioselective
acyclic formamide derivative.
Model for Additions to Cyclic Substrates. As mentioned
before, unlike transformations involving acyclic substrates, BCA
and SCA reactions with cyclic enones proceed with the opposite
sense of enantioselectivity. DFT calculations50 support the
experimentally observed trend, indicating that whereas mode of
addition V (Figure 8) is preferred for the C−B bond-forming
processes (vs VI), those that afford β-silyl carbonyl compounds
probably proceed via VII (vs VIII). One reason for this
distinction might be the size differences among the B(pin), the
Hdbu-bound substrate, and the especially larger Me2SiPh
moiety. Another factor could be the shorter B···B versus B···Si
distance in the transition state structure (e.g., 2.21 vs 3.37 Å in
V and VII, respectively). It is therefore plausible that the B(pin)
moiety would be preferentially situated in the vicinity of the
sterically less demanding front/left-hand quadrant of the chiral
complex V. In the SCA process, on the other hand, the
Me2SiPh group would be situated more distally from the
aforementioned N−Ar group, reducing the degree of repulsion
between the NHC’s N−Ar unit and the dbuH- or MeOH-
bound enone. Another feature of the structures shown in Figure
8 is the absence of internal H bonding between the B(OH)2
and the carbonyl unit (cf. III and IV in Figure 7);51 such
interactions would be a great deal more geometrically
demanding in cyclic α,β-unsaturated carbonyl compounds,
which are locked into a s-cis conformation (vs s-trans
conformers in Figure 7).
(f) The positive role of dbu in an NHC-catalyzed SCA is a
culmination of a sensitive balance achieved regarding the
solubility of the base in two phases of the reaction
mixture (typically, 3:1 H2O/thf; biphasic nature caused
by the borosilane reagent). Hydroxide ions must be
transported into the organic layer in the form of
Hdbu+·−OH in amounts that are sufficient for converting
the B(pin) group of the silylboron reagent to its derived
B(OH)2, which is critical for NHC activation of the B−Si
bond. At the same time, the base must not cause too high
an increase in hydroxide ion concentration in the organic
layer or a substantial degree of reagent and catalyst
decomposition results.
(g) Initial rate studies and DFT calculations demonstrate
that the opposite sense of enantioselectivity for BCA
reactions involving cyclic enones versus SCA trans-
formations originate from the larger size of a Me2SiPh
moiety and a more elongated B−Si bond in the
corresponding transition states.
Lewis-base-catalyzed reactions involving an NHC, a
phosphine, or an alkoxide species, particularly those that
generate a C−B bond, have emerged as a potentially significant
set of transformations that provide reactivity, functional group
compatibility, and stereoselectivity profiles and/or levels that
are complementary to the more widely examined transition-
metal-catalyzed systems. An understanding of the key
mechanistic factors that facilitate such processes and/or render
them highly selective allows for a more clear analysis of the
existing data and is crucial if future initiatives in this burgeoning
area are to achieve maximal success. The findings described
above offer some of this needed insight.
CONCLUSIONS
■
The investigations detailed herein shed light on the following
key mechanistic principles in regard to NHC-catalyzed
enantioselective boryl and silyl conjugate addition reactions,
which we show do not involve single-electron pathways.
(a) Excess base MeOH and dbu are needed for BCA
reactions promoted by the larger chiral NHC catalysts
because conversion of the relatively hindered B(pin) unit
to a more accessible B(OMe)2 or B(OMe) (OC-
Me2CMe2OH) facilitates diboron bond activation and
NHC·diboron complex formation.
(b) Initial rate studies and DFT calculations have resulted in
the development of models that provide a plausible
rationale for the different stereoselectivity profiles for
boryl addition processes.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b06745.
■
S
Cyrstallographic information (CIF)
Cyrstallographic information (CIF)
Cyrstallographic information (CIF)
Experimental details for all reactions and analytic details
for all enantiomerically enriched products (PDF)
(c) The lack of efficiency of silyl conjugate additions with the
more diminutive achiral NHC (vs the corresponding
BCA processes) in the absence of water is not because
the necessary Lewis-base·borosilane species cannot be
generated. Rather, it might be due to the resulting NHC·
B(pin) complex being too hindered, rendering approach
by an α,β-unsaturated carbonyl compound energetically
prohibitive.
(d) The origin of high efficiency in SCA reactions in water
with excess dbu is rapid hydrolysis of the sterically
demanding B(pin) unit, allowing for the formation of a
more sterically accessible and thus more reactive
borosilane; this results in the more efficient NHC·
AUTHOR INFORMATION
Corresponding Author
*amir.hoveyda@bc.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by the NIH (GM-57212).
■
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(34) Such observations (substantial difference between reactions
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reactions are indeed NHC catalyzed and do not involve trace amounts
of transition-metal impurities that might accompany a reagent and, in
particular, sodium alkoxides (it should be noted that dbu is an equally
effective base). It merits mention that altering the amount of NaOt-Bu
does not lead to any change in reaction efficiency (see below for
representative data); such would not be the case if the metal impurities
contained within the alkali metal salt were playing an important role.
The possibility of trace amounts of transition-metal salts playing a role
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addressed as well (cf. ref 19a).
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(50) We selected to focus on carrying out DFT calculations on BCA
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(37) See the Supporting Information for further information on the
DFT calculations.
(38) Chatligialoglu, C.; Newcomb, M. In Advances in Organometallic
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(39) Newcomb, M. Tetrahedron 1993, 49, 1151−1176.
(40) For representative cases where replacing a B(pin) group of a
reagent to a less hindered derivative leads to reaction rate
enhancement, see: (a) Brown, H. C.; Racherla, U. S.; Pellechia, P. J.
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(41) For representative cases where in situ rupture of a B(pin) group
results in an increase reaction rates, see: (a) Chen, J. L.-Y.; Scott, H.
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(42) See the Supporting Information for details.
(43) Association of a Lewis base, such as a methoxy group or the
strongly σ-donating NHC, to a B(pin) unit can lead to a substantial
increase in the electron density of the oxygen atoms of the pinacolato
unit (see ref 29), increasing the probability of its protonation and
subsequent rupture of the B-based heterocycle.
(44) Two NHC·borosilane complexes have been prepared and
characterized through X-ray crystallography, see: Kleeberg, C.; Borner,
C. Eur. J. Inorg. Chem. 2013, 2013, 2799−2806. These investigators
report that treatment of the NHC·borosilane complexes with benzyl
bromide, methyl iodide, and trimethylsilyl chloride does not lead to
any reaction. We also find that NHC-catalyzed boryl or silyl addition
cannot be readily extended to alkylation processes. As stated in our
original report in 2009 (refs 16a and b), the relatively high
polarizability of an α,β-unsaturated carbonyl substrate is key to the
efficiency of a Lewis-base-catalyzed C−B or C−Si addition process.
(45) For spectral data on NHC·BF3 and NHC·B(Et)3 complexes,
respectively, see: (a) Arduengo, A. J.; Davidson, F.; Krafczyk, R.;
Marshall, W. J.; Schmutzler, R. Monatsh. Chem. 2000, 131, 251−265.
(b) Yamaguchi, Y.; Kashiwbara, T.; Ogata, K.; Miura, Y.; Nakamura,
Y.; Kobayashi, K.; Ito, T. Chem. Commun. 2004, 2160−2161.
(46) log P, a partition coefficient, is the ratio of concentrations of a
species in a mixture of two immiscible phases at equilibrium. The log P
values mentioned here involve water and n-octane; thus, log P = log
Poct/H O = log([solute]oct/[solute]un‑ionized water). For a comprehensive
2
list of log P values, see: Sangster, J. J. Phys. Chem. Ref. Data 1989, 18,
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(47) See the Supporting Information for details of the kinetic
measurements and the calculation of rate equations leading to the
conclusions regarding the identity of the turnover-limiting steps.
(48) Although, to the best of our knowledge, there are no reports of
compounds derived from NHC insertion into a B−B or a B−Si bond,
entities resulting from reactions with H−H, C−Zr, B−H, Be−H, P−
H, and Si−H bonds have been disclosed, see: (a) Frey, G. D.; Lavallo,
R
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