Lewis Acid Enabled Copper-Catalyzed Asymmetric Synthesis of Chiral β-Substituted Amides

Article abstract of DOI:10.1021/jacs.7b07344

Here we report that readily available silyl- and boron-based Lewis acids in combination with chiral copper catalysts are able to overcome the reactivity issues of unactivated enamides, known as the least reactive carboxylic acid derivatives, toward alkyla

Full text of DOI:10.1021/jacs.7b07344

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Lewis Acid Enabled Copper-Catalyzed Asymmetric Synthesis of
Chiral β‑Substituted Amides
Mamen Rodríguez-Fernandez,†,§ Xingchen Yan,†,§ Juan F. Collados,†,§ Paul B. White,‡
́
and Syuzanna R. Harutyunyan*,†
†Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG Groningen, The Netherlands
‡Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
S
* Supporting Information
ABSTRACT: Here we report that readily available silyl- and
boron-based Lewis acids in combination with chiral copper
catalysts are able to overcome the reactivity issues of
unactivated enamides, known as the least reactive carboxylic
acid derivatives, toward alkylation with organomagnesium
reagents. Allowing unequaled chemo-reactivity and stereo-
control in catalytic asymmetric conjugate addition to
enamides, the method is distinguished by its unprecedented
reaction scope, allowing even the most challenging and
synthetically important methylations to be accomplished with good yields and excellent enantioselectivities. This catalytic
protocol tolerates a broad temperature range (−78 °C to ambient) and scale up (10 g), while the chiral catalyst can be reused
without affecting overall efficiency. Mechanistic studies revealed the fate of the Lewis acid in each elementary step of the copper-
catalyzed conjugate addition of Grignard reagents to enamides, allowing us to identify the most likely catalytic cycle of the
reaction.
not suffer from noncatalyzed additions at high temperatures.5
The challenge faced in the development of efficient and
stereoselective alkylations of simple enamides has led to the
development of several alternative approaches, with the most
common ones based on specific enamide substrates activated by
placing an electron-withdrawing group at the N-atoms (Scheme
INTRODUCTION
■
Conjugate addition (CA) reactions of hard carbon nucleophiles
to α,β-unsaturated carbonyl derivatives that forge carbon−
carbon (C−C) bonds rank among the most fundamental
reactions in chemical synthesis.1,2 Chiral copper-based catalysts
have proven to permit asymmetric conjugate additions (ACA)
1c) to allow electronic activation and/or bidentate coordination
to various Michael acceptors (Scheme 1a).2 Deemed one of the
with the chiral catalyst.5−7 Another nondirect method to β-
most important structural motifs in organic chemistry, amides
are found in a plethora of natural products and bioactive
substituted chiral amides is based on 1,4-addition to α,β-
compounds, such as proteins and pharmaceuticals.3 However,
unsaturated esters, followed by quenching of the reaction
mixture with the corresponding amines.8 Intriguingly, the only
despite almost 80 years of intensive research in the field of
reported direct addition to simple enamides makes use of
copper promoted CA reactions, a general solution for catalytic
Grignard reagents, but the limited scope of the resulting chiral
ACA to simple α,β-unsaturated amides (enamides) has not
been found.2,4 The challenges associated with catalytic ACA to
β-alkyl substituted amides and the modest enantioselectivities
led the authors to switch to a chiral auxiliary strategy.9
α,β-unsaturated amides are due to the sluggish resonance
activation of the olefin moiety via the adjacent carboxamide
group (Scheme 1b). The high degree of nitrogen lone-pair
delocalization, resulting from the orbital overlap with the
Thus, despite the advances realized, the conjugate alkylation
of unactivated enamides still constitutes a daunting, so far
unsolved, challenge.
Whereas the resonance stabilization impedes the reactivity of
antibonding orbital of the carbonyl group, makes carboxamide
the least electron-deficient carboxylic acid derivative.3a Thus,
enamides, it also gives rise to a pronounced Lewis basicity of
the amide carbonyl oxygen atom. We hypothesized that
contrary to aldehydes, ketones, and esters, the lowest
coordination of a strong LA to the oxygen atom should
unoccupied molecular orbital (LUMO) of the corresponding
significantly enhance the electrophilicity of the adjacent olefinic
enamide is not sufficiently enhanced toward nucleophilic
moiety toward nucleophilic addition10,11 thus activating the
addition at the β-position. As a result of this low reactivity,
addition of hard organometallics was only possible at
temperatures above −78 °C, at which noncatalyzed blank
reactions outcompete the catalytic enantioselective pathway.
enamides in situ (Scheme 1d). This in turn could allow direct
additions of hard alkyl nucleophiles, namely Grignard reagents,
Therefore, the only reported examples of catalytic ACA to
Received: July 17, 2017
simple enamides are confined to Rh-catalyzed arylations that do
© XXXX American Chemical Society
A
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a
Scheme 1. Catalytic ACA of Hard Carbon Nucleophiles to α,β-Unsaturated Carbonyl Compounds: State-of-the-Art
a
(a) Cu-catalyzed ACA has been investigated for over the last 70 years. (b) Progress in the development of ACA depending on the reactivity of
various conjugated carbonyls is contrasted to the lack of examples for direct ACA to the less reactive conjugated amides (enamides) which could lead
to an array of valuable chiral molecules. (c) ACA has been developed only for activated amides or imides. (d) Strategy that was initially aimed at
overcoming the intrinsically low reactivity of the enamide through enhancement of its LUMO by coordination with a Lewis acid.
a
Table 1. Selected Optimization Data for the Cu-Catalyzed Alkylation of Enamide 1a with EtMgBr
b
c
b
c
Entry
L1/Cu(I)
LA
T [°C ]
Conv. [%]
ee [%]
Entry
L1/Cu(I)
LA
T [°C]
Conv. [%]
ee [%]
1
2
3
4
5
6
−
−
−
−
−
−
−
−78
−78
−78
0
0
0
−
−
−
−
0
7
−
−
−
−50
−50
−78
−78
−78
−78
12
20
0
0
5
Cu(I)
L1/Cu(I)
−
8
L1/Cu(I)
0
9
−
−
BF3·Et2O
TMSOTf
BF3·Et2O
−
−
97
97
42
79
10
11
12
50
94
92
Cu(I)
0
L1/Cu(I)
L1/Cu(I)
0
0
L1/Cu(I)
TMSOTf
92
a
b
Reaction conditions: 0.1 M of 1a in CH2Cl2, LA (2.0 equiv), EtMgBr (2.0 equiv). For details see SI. Conversion was determined by NMR of
reaction crude. Enantiomeric excess was determined by HPLC on a chiral stationary phase. Absolute configuration was assigned by analogy with
c
literature data (see SI).
to simple unactivated enamides without the need for specific
substrates, while rendering the reaction enantioselective by
using chiral catalysts.
regardless of whether copper salt or chiral ligand L1 were
present (Table 1, entries 1−3). Raising the temperature to 0 °C
resulted in substrate conversion, but unfortunately the reaction
with chiral ligand yielded racemic product, and the non-
catalyzed reaction was faster than the one promoted by the
copper catalyst (entries 4−6). At −50 °C the catalyzed reaction
rate started to surpass that of the noncatalytic reaction, but still
racemic product was obtained (entries 7 and 8).
These results indicate that the chiral copper catalyst L1/
Cu(I) is not capable of either outcompeting the noncatalyzed
racemic addition to simple enamides, or of providing CA with
enantiodiscrimination. This is a striking difference from the
RESULTS AND DISCUSSION
■
We started exploring this concept by evaluating the reactivity of
simple trans N,N-dimethyl enamides 1a toward addition of
EtMgBr in different reaction conditions. The initial experiments
confirmed the inherently poor reactivity of acyclic α,β-
unsaturated amides relative to typical Michael acceptors. No
addition of the highly reactive EtMgBr to enamide 1a was
observed when performing the reaction in CH2Cl2 at −78 °C,
B
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Scheme 2. Product Scope of Lewis Acid Promoted Copper-Catalyzed ACA Methodology
a
Isolated yields for all the products are shown. Absolute configuration was assigned by analogy with literature data (see SI). Reaction conditions (for
b
details see SI). 2.0−3.0 equiv of BF3·Et2O were used as LA at (−78) °C. In this case 10 mol % of CuBr·SMe2 and 12 mol % of L1 were used.
c
d
e
Weinreb amide was used in this case, and it underwent demethoxylation. Without LA at (−50) °C. 2.0−3.0 equiv of TMSOTf was used as LA at
(−50) °C.
overwhelming literature precedence on Cu-catalyzed asym-
metric additions of organometallics to enones and enoates.1,2
At this point we introduced LA to explore the activation of
enamides toward additions at low temperature (−78 °C).
In the absence of copper salt, no significant product was
formed when using BF3·Et2O. Instead, we observed trans-
metalation (by NMR spectroscopy, see mechanistic studies
below) of the latter with the Grignard reagent, thus effectively
destroying the nucleophile in the reaction (entry 9). With the
more reactive trimethylsilyl trifluoromethanesulfonate
(TMSOTf), 50% of product was formed (entry 10), but also
some transmetalation of TMSOTf with EtMgBr was observed.
However, combining either BF3·Et2O or TMSOTf with chiral
copper catalyst led to an immense acceleration of the ACA
reaction. Importantly, apart from outcompeting the non-
catalyzed addition of EtMgBr, the catalytic pathway provided
the ACA product for the first time with excellent
enantioselectivity (entries 11 and 12). Further LA, solvent,
chiral ligand, and copper salt screening (see SI) failed to
improve these already excellent results, thus establishing the
following optimized conditions: 2.0−3.0 equiv of either of these
LAs and 2.0 equiv of Grignard reagents in the presence of 6
mol % of chiral ligand L1 and 5 mol % of CuBr·SMe2, with
CH2Cl2 as solvent and in a temperature range from −50 to −78
°C.12
C
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Figure 1. Practical aspects and application of the methodology. (a) Temperature dependence and 10 g scale reaction. (b) Scale-up reaction
procedure. (c) ACA product transformations. (d) ACA to trifluoromethylated enamide 1y for further applications in the synthesis of a drug
candidate. (e) Effect of the nature of the LA on the structure of the final ACA product.
With the optimized set of conditions in hand, we investigated
the generality of this methodology (Scheme 2), testing both
BF3·Et2O and TMSOTf as LA. Although both LA’s enable ACA
to almost all tested enamides, TMSOTf generally works best
for relatively unreactive and unhindered enamides, while BF3·
Et2O is the LA of choice for relatively reactive, both hindered or
unhindered, enamides.
2j, succeeded. Interestingly, no Lewis acid was required in this
case, most likely due to the higher reactivity of cyclic Michael
acceptors toward nucleophiles compared to linear analogues.
Carrying out the reaction in the presence of BF3·Et2O or
TMSOTf led to side reactions, and the CA product 2j was
obtained with an ee of 79% due to the competing background
reaction. Low conversions and racemic products were obtained
when primary or secondary amides were used as Michael
acceptors.
Having established that our catalytic system tolerates a broad
scope of variations at the N-atom, we subsequently explored
α,β-unsaturated amides with different substitution patterns at
the β-position. We were delighted to find that excellent results
are obtained with substrates featuring linear as well as branched
carbon chains (2a, b, k, l), aromatic rings (2m−2r),
heteroaromatic substituents (2s−2v), and functional groups
such as halogen and unprotected hydroxyl (2w, x).
It should be noted that the reactivity of the chiral copper
catalyst was not affected by the presence of heteroatoms. The
consistently first-rate enantioselectivities and good to excellent
yields observed during these experiments highlight the
prominent role of the catalyst and the LA in the CA to
unreactive α,β-unsaturated enamides.
Next, the scope of the reaction in terms of Grignard reagents
was examined.13 It is remarkable that most of the assessed
Grignard reagents were suitable partners for this catalytic
system, with the exception of PhMgBr, which provided low
First, we evaluated various substituents at the nitrogen atom
and found that a wide variety can be used, allowing efficient
transformation to the corresponding β-chiral amides. ACA to
N-diallyl, N-dibenzyl, and N-di(p-methoxylbenzyl) groups, with
possible subsequent deprotection in mind, are well-tolerated
and give the corresponding CA products (2c−2e) with good
yields and excellent (98%) enantiomeric excess (ee). Addition
of EtMgBr to enamide with a N-phenyl-N-methyl group led to
CA product 2f with 77% ee. Notably, CA to highly activated
enamide with N-tosyl-N-methyl groups, a substrate that
provides the CA product with a dramatic 36% of ee in the
absence of a LA (see SI), now yielded product 2g with a high ee
of 86%. Addition to Weinreb-type enamide proceeded with
excellent chemo- and enantioselectivity and led to the
secondary amide product 2h, resulting from demethoxylation.
Gratifyingly, CA to morpholine-substituted enamide leading to
product 2i, amenable to further synthetic transformations,
proceeded with 75% of isolated yield and 96% of ee. Finally,
even addition of EtMgBr to the six-membered α,β-unsaturated
lactam bearing an endocyclic double bond, resulting in product
D
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Figure 2. Mechanistic studies. (a) Undesired reaction pathways in the CA of Grignard reagents to enamides in the presence of LA followed by NMR
spectroscopy in CD2Cl2 at −80 °C. (b) Reaction scheme for the sections c, d. Reaction conditions: 0.1 M 1a in CH2Cl2, LA (2.0 equiv), RMgBr (2.0
equiv) at −78 °C, 18 h. (c) Effect of different LAs in the Cu-catalyzed CA of EtMgBr to 1a. (d) Cu-catalyzed CA of MeMgBr to (E)- or (Z)-1a. (e)
31P NMR spectra of: L1-CuBr (red), L1-CuBr and 2.0 equiv of MeMgBr (species 10, orange), L1-CuBr and 10 equiv of TMSOTf (green) or BF3·
1
Et2O (purple), addition of MeMgBr to L1-CuBr prior mixed with TMSOTf (blue). (f) H NMR spectra of LA-enamide complexes: free enamide
(red), with TMSOTf (orange), BF3·Et2O (purple), with MeMgBr (blue), the reaction media before completion (green). (g) Types of enolates
formed as end product of the CA of MeMgBr to enamide (for detailed discussion see SI) in the reaction using TMSOTf (blue), BF3·Et2O (green),
and in the absence of LA (red) determined by TOCSYs experiments. (h) Proposed catalytic cycle.
conversion and racemic product.14 It was particularly gratifying
that, where previous reports on additions to conjugated
enamides were restricted to arylations, our catalytic system
enabled the addition of a wide variety of alkyl Grignard reagents
(linear as well as α-, β- and γ-substituted and functionalized)
with excellent regio- and enatioselectivities (Scheme 2,
products 2a, 3a−3g). Because of the utmost synthetic relevance
of methylated chiral centers in pharmaceuticals, the addition of
MeMgBr deserves a special note. Despite the formidable
advances realized in copper-catalyzed additions of organo-
metallics, the methylation of the more reactive α,β-unsaturated
esters is still considered a notoriously difficult transformatio-
n.1a,2,15 Therefore, we anticipated that the addition of MeMgBr,
the least reactive among all alkyl Grignard reagents, to
enamides, a substrate far less reactive than ester, would be
very challenging.
However, to our delight, the addition of this reagent was
successful, providing the β-substituted amide 3h in 50% yield
E
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and nearly absolute stereocontrol (99% ee, see SI). Remarkably,
the yield was greatly improved to 93% by using TMSOTf as
LA, while retaining the enantioselectivity of 99% (Scheme 2,
product 3h).
the intermediate silyl enolate, providing cyclic product trans-7
with contiguous stereocenters and as a single diastereoisomer.
To gain more detailed insight into this catalytic system, and
particularly clarify the role of the LA, we carried out
mechanistic studies (Figure 2, more details are in SI). It is
generally assumed that the mechanism of the Cu-catalyzed
enantioselective CA of organometallic compounds follows
similar principles as proposed for the noncatalytic organo-
cuprate addition, involving an oxidative addition-reductive
elimination pathway.2,21−24 However, the necessary presence
of LA to accomplish enantioselective CA to enamides adds
another level of mechanistic complexity. LA additives have been
known for decades to accelerate the CA of organometallics to
various α,β-unsaturated carbonyl derivatives.22 In particular, the
use of very weak TMSCl became common practice in CA of
various hard organometallics.21a,23 In contrast, relatively strong
LAs, such as BF3·Et2O, have been used only in CA of
stoichiometric organocopper reagents.21a,24
Tests on the temperature tolerance provided a final
testament to the robustness and power of our methodology.
High levels of selectivity in the ACA of hard organometallics to
Michael acceptors are typically possible at temperatures below
0 °C.2,15 From an industrial perspective, this requirement is a
major restriction for large-scale applications.1a To challenge our
catalytic system further, we carried out the CA reactions to
enamide 1a at higher temperatures, using both EtMgBr and the
relatively less reactive MeMgBr (Figure 1a). We were pleased
that these experiments produced high levels of regio- and
enantioselectivity, unprecedented for hard organometallics
under these conditions. The corresponding CA products were
obtained with good yields and ee’s above 90% at 0 °C in case of
the addition of EtMgBr and at both 0 and 25 °C for the
addition of MeMgBr (Figure 1a, entries 1−3).
These results convincingly demonstrate the synergistic power
of the chiral copper catalyst and the LA, allowing them to
outcompete the noncatalyzed reaction at relatively high
temperatures for this chemistry. The nature of the LA is
critical to the success of these reactions at high temperatures,
with TMSOTf found to be superior in terms of yield and ee.
This catalytic protocol is scalable and operationally simple, as
we corroborated by performing the addition of MeMgBr to
enamide 1a at 0 °C on a preparative scale (10 g, 71 mmol),
using 5 mol % of chiral catalyst (L1-CuBr). Full conversion was
reached once the addition of the last reaction component,
MeMgBr, to the reaction mixture was completed (within few
minutes, Figure 1b). The CA product 3h was obtained with
excellent yield and enantioselectivity (entry 3) with no need for
special equipment. The catalyst was recovered with 80% yield
and reused for another ACA reaction with similar performance
(see SI).
β-Alkyl-substituted chiral secondary amides as well as β-alkyl
substituted chiral amines are interesting synthetic targets as
these structures are present in various pharmaceutically active
ingredients16−18 including Cyclotheonamide E5 and Orbicula-
mide A, both known for their cytotoxic activities.17 Similarly, β-
alkyl-substituted chiral amines, and in particular trifluoromethy-
lated ones, are known precursors in the synthesis of leukotriene
receptor antagonists used, for instance, to treat asthma.18 To
showcase the utility of our catalytic protocol, we demonstrated
that chiral β-substituted amide 2e can easily be transformed
into a number of corresponding valuable molecules (Figure 1c).
Deprotection19 of 2e afforded chiral β-ethyl amide 4, which in
turn can be used for the synthesis of the chiral γ-ethyl chiral
amine 5 via reduction of the carbonyl moiety or to β-ethyl
chiral amine 6 through Hoffman rearrangement.20 We have also
applied our ACA methodology for the methylation of
trifluoromethylated enamide 1y, leading to β-methyl-substi-
tuted amide product 3j with 99% ee (Figure 1d). When
subjected to deprotection and Hoffman rearrangement, this
product could lead to a direct precursor of the drug candidate
ZENECA ZD 3523.18 Another synthetically important trans-
formation in which this catalytic system can be engaged is the
trapping of the product enolate (Figure 1e). To demonstrate
this, we performed the CA reaction to Br-substituted enamide
1w. When BF3·Et2O is used as LA, conjugate addition product
2w is obtained. However, switching to TMSOTf as LA allows
the CA reaction to be followed by intramolecular trapping of
In our case, the presence of a strong LA together with only
few percent of chiral Cu(I)-catalyst and highly reactive
Grignard reagents makes for a complex system. The outcome
of the reaction depends critically not only on the relative rates
of the desired catalyzed and the undesired noncatalyzed
pathways but also on those of several competing processes,
indicated in Figure 2a.
We expect the catalytic cycle (Figure 2h) to be initiated by
the formation of species 8 through transmetalation of chiral
catalyst L1-CuBr by Grignard reagents. However, the chiral
ligand L1, reversibly bound to copper, is Lewis basic, and thus a
strong LA competes with copper for binding to L1, potentially
destroying the chiral catalyst (Figure 2a, e). This was confirmed
by a control experiment that saw the formation of a mixture of
unidentified species lacking bidentate coordination to copper
(singlets versus doublets in 31P NMR) upon addition of either
LA to chiral copper complex L1-CuBr. Remarkably though,
addition of MeMgBr to this mixture resulted in an immediate
recovery of either the L1-CuBr or the transmetalated copper
complex 8, depending on the remaining amount of Grignard
reagent in the media. Similarly, adding an excess of LA to the
transmetalated copper complex did not affect its structure. Even
when adding copper salt and Grignard after combining LA with
L1, species 8 is formed, demonstrating its remarkable formation
rate and stability. Furthermore, transmetalation of the LA by
the Grignard reagent can deplete both components. NMR
guided control experiments, in the absence of enamide or L1-
CuBr complex, performed in CD2Cl2 at −80 °C confirmed all
indicated in Figure 2a pathways occur (see SI). Fortunately, the
excellent results observed for our system constitute evidence
that these processes are outcompeted by the catalyzed reaction.
Following the formation of transmetalated copper complex 8,
the next step in the catalytic cycle is π-complexation with the
activated enamide to form species 11 or 11′, followed by the
formation of σ-complex intermediates 12 or 12′ (silyl enolate
in case of TMSOTf and boron enolate in case of BF3·Et2O).
We anticipated the activated enamide to be an LA-enamide
complex (9), the formation of which was indeed observed by
1H NMR spectroscopy when using either BF3·Et2O or
TMSOTf (Figure 2h, f). However, subsequent addition of a
stoichiometric amount of MeMgBr led to the formation of a
new species corresponding to MeMgBr-enamide complex 10.
On the one hand it seems reasonable to assume that π-
complexation of species 8 with the relatively more stable
activated enamide 10 would occur next, forming π-complex 11
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in step 1. On the other hand, based on the Curtin−Hammett
principle, direct formation of π-complex 11′ in step 1 cannot be
excluded.
Thus, the main question is at which stage the LA is involved
in the catalytic cycle: before, during, or after oxidative addition
step or during or after reductive elimination step.
makes our methodology by far the most general strategy for CA
to carbonyl-based Michael acceptors. The demonstrated
temperature tolerance, scalability, and possibilities for catalyst
recovery add to its attractiveness. Our mechanistic studies and
experimental data support the notion that the role of the Lewis
acid is in the enhancement of the copper-catalyzed pathway. As
a result, LA allows both the ACA to occur as well as to
outcompete the blank reactions that occur at higher temper-
atures. Furthermore, the experimental data point to a very
similar mechanistic behavior for both Lewis acids employed in
this ACA of Grignard reagents to enamides, namely BF3·Et2O
and TMSOTf. Finally, the unexpected compatibility observed
in our catalytic system between highly reactive Grignard
reagents, Lewis acids, and phosphine ligands was found to be
due to the remarkable stability of the active catalyst toward the
deleterious effect of Lewis acids.
Based on the E−Z isomerizations of α,β-unsaturated
carbonyl substrates often observed in copper-catalyzed CA
reactions and specific isotope effects observed, the oxidative
addition step is thought to be reversible, with the rate
enhancement upon addition of TMSCl attributed to making
the oxidative step irreversible.2,21,23
To verify whether this holds true for the role of BF3·Et2O
and TMSOTf in our reaction, two more sets of experiments
were executed (Figure 2b−d). A number of different LAs were
tested varying in strength and sterics (Figure 2b, c). The results
reveal clearly that the strength of the LA is crucial for our
catalytic cycle, with the very weak TMSCl producing <7%
conversion, the relatively stronger TMSBr a poor 44%, and the
stronger TMS-, TBS- and TBDPS- substituted triflates as well
as BF3·Et2O providing excellent results, both in terms of
reactivity and selectivity. Furthermore, the nearly identical ee’s
given by the three sterically varying triflates imply that the LA
does not affect the enantiodiscrimination step. The differences
observed in the ee’s using various LA are explained by different
rates between the enantioselective Cu-catalyzed and the
noncatalyzed racemic CA reactions.
Double-bond isomerization of the enamide substrate ((Z)-1a
to the more stable (E)-1a) was studied as well (Figure 2b, d).
Copper-catalyzed CA of MeMgBr to (Z)-1a led to the final
products with absolute configuration opposite to that obtained
with (E)-1a and with ee’s of 99% and 46% when using BF3·
Et2O and TMSOTf, respectively. Analysis of substrate samples
obtained during the reaction confirmed that no isomerization
to the more stable (E)-1a takes place, consistent with the
interpretation that step 2 (or 3′) of the catalytic cycle is not
reversible.
Combining the results on the strength of the LA, its lack of
effect on the enantiodiscrimination, the lack of isomerization
and Cu-catalyzed ACA in the absence of LA, and all the
discussed experimental data, we believe that the LA is almost
certainly involved in one of the steps preceding reductive
elimination (step 4), making the oxidative addition overall
irreversible. Strong LA is either required to increase the π-
acidity of the π-complex (as in π-complex 11′ formed in step
2′) or to trap the magnesium enolate σ-complex 12 into the
more stable silyl or boron enolate σ-complex 12′ (step 3). In
both scenarios, that cannot be distinguished with the current
data, the resulting more stable silyl or boron enolate σ-complex
12′ is expected to undergo faster reductive elimination than the
magnesium enolate σ-complex 12. Further support for the
formation of σ-complex 12′ comes from the fact that only Mg-
activated enamide 10 and silyl or boron enolates of the CA-
addition products (Figure 2g) are observed, with no traces of 9
or Mg-enolate of the CA-product throughout the reaction.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.7b07344.
■
S
Experimental procedures, product characterizations, and
details on mechanistic studies (PDF)
Copies of all NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
*S.Harutyunyan@rug.nl
■
ORCID
Syuzanna R. Harutyunyan: 0000-0003-2411-1250
Author Contributions
§These authors contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from The Netherlands Organization for
Scientific Research (NWO-ECHO to S.R.H.), the China
Scholarship Council (CSC, to X.Y.), and the Ministry of
Education, Culture and Science (Gravity program 024.001.035
to S.R.H.) is acknowledged. We thank M. Veenstra for few
additional experiments. Solvias is acknowledged for the supply
for chiral ferrocenyl diphosphine ligands
REFERENCES
■
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CONCLUSIONS
■
We have presented a versatile approach to ACA reactions of
readily available Grignard reagents to α,β-unsaturated amides,
aided by LAs and chiral copper catalysts. The broad scope of
substrates as well as Grignard reagents allows even the most
challenging and synthetically important methylations to be
achieved with good yields and excellent enantioselectivities and
̀ ́
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(12) CH2Cl2 was found to be the optimal solvent. The presence of
even traces of THF is detrimental for the reaction conversion and
enantioselectivity (see SI). On the other hand, copper salts other than
CuBr can be used as well, as long as the halide in the Grignard reagent
is a bromide (RMgBr).
(13) Grignard reagents must be used either in Et2O or tBuOMe.
THF must be avoided, even in a small quantities. For example, Cu(I)-
catalyzed conjugate addition of iPrMgBr in THF led to racemic
product, while in Et2O the same reaction afforded the product with
67% ee.
(14) Racemic product being obtained with PhMgBr is due to slower
reductive elimination of Cu from Ar-Cu species as compared to Alk-
Cu, resulting in a slower copper-catalyzed reaction, which con-
sequently is outcompeted by the direct, noncatalytic addition of
PhMgBr. The low conversion obtained with PhMgBr is the direct
consequence of its high reactivity, since this causes the reaction with
the LA to be faster than the desired CA.
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DOI: 10.1021/jacs.7b07344
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX