Enantioselective α-Arylation of Ketones via a Novel Cu(I)-Bis(phosphine) Dioxide Catalytic System

Article abstract of DOI:10.1021/jacs.0c13236

A novel catalytic system based on copper(I) and chiral bis(phosphine) dioxides is described. This allows the arylation of silyl enol ethers to access enolizable α-arylated ketones in good yields and enantiomeric excess up to 95%. Noncyclic ketones are amenable substrates with this method, which complements other approaches based on palladium catalysis. Optimization of the ligand structure is accomplished via rational design driven by correlation analysis. Preliminary mechanistic hypotheses are also evaluated in order to identify the role of chiral bis(phosphine) dioxides.

Full text of DOI:10.1021/jacs.0c13236

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Enantioselective α‑Arylation of Ketones via a Novel Cu(I)−
Bis(phosphine) Dioxide Catalytic System
Margarita Escudero-Casao,† Giulia Licini, and Manuel Orlandi*,†
Cite This: J. Am. Chem. Soc. 2021, 143, 3289−3294
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ABSTRACT: A novel catalytic system based on copper(I) and chiral bis(phosphine) dioxides is described. This allows the arylation
of silyl enol ethers to access enolizable α-arylated ketones in good yields and enantiomeric excess up to 95%. Noncyclic ketones are
amenable substrates with this method, which complements other approaches based on palladium catalysis. Optimization of the
ligand structure is accomplished via rational design driven by correlation analysis. Preliminary mechanistic hypotheses are also
evaluated in order to identify the role of chiral bis(phosphine) dioxides.
he Pd-catalyzed α-arylation of carbonyl compounds is a
fundamental reaction in transition metal catalysis, which
T
was first reported by the groups of Buchwald and Hartwig in
1997.1,2 Since then, this transformation has been successfully
employed in academia and industry.3 As a result, several groups
engaged in the development of enantioselective variants of this
transformation.4 However, despite several transformations
having been developed, the vast majority of these rely on the
formation of quaternary stereocenters.5−14 Only a few reports
have been published that allow for the formation of tertiary
stereocenters.15−21 This limitation is because of the facile
postreaction racemization via product enolization, which is
promoted by the strong bases typically required in these
reactions.
The first example to set an enolizable stereocenter was
reported by Zhou and co-workers in 2011,18 who developed the
enantioselective Pd-catalyzed α-arylation of esters (Figure 1A).
In this work, silyl ketene acetals were employed as substrates to
preactivate the carbonyl compound. This modification allowed
avoiding the use of strong bases and consequent racemization as
previously reported.22 Similarly, Gaunt and MacMillan showed
that TMS-enol ethers of imides are amenable of enantioselective
α-arylation by diaryliodonium salts in the presence of either
Cu(I)− or Cu(II)−BOX catalysts (Figure 1B).16,17 MacMillan
also demonstrated that aldehydes could be α-arylated via
enamine catalysis in the presence of diaryliodonium salts and
CuBr (Figure 1C).15
Although aldehydes could be activated via enamine catalysis
and carboxyl derivatives as TMS-enolates, the α-arylation of
ketones proved more challenging. Ketones are less prone to
condensation with an amine catalyst than aldehydes, and silyl
enol ethers are less nucleophilic than silyl ketene acetals.23
However, Zhou and co-workers found that the more
nucleophilic Bu3Sn-enolates react smoothly under their typical
conditions using Pd-catalysis and ligand 1b (Figure 1D).21 Sn-
enolates could be generated in situ from the corresponding
alkenyl acetate in the presence of stoichiometric Bu3SnOMe.
However, even though efficient for the α-arylation of cyclic
ketones, this method proved unsuitable for the arylation of
Figure 1. State of the art for the enantioselective α-arylation of carbonyl
compounds to set tertiary stereocenters.
Received: December 22, 2020
Published: February 26, 2021
© 2021 The Authors. Published by
American Chemical Society
https://dx.doi.org/10.1021/jacs.0c13236
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Figure 2. (A) Benchmark reaction and ligand screening. Yields are reported in the Supporting Information. (B) Single parameter correlation between
the measured enantioselectivity and the ligand PO stretching frequency for an unbiased ligands subset. (C) Multidimensional correlation between
the ligand structure and the observed enantioselectivity for a ligand set excluding 3t, 3m, and 3e. Tol = 4-Me-Ph, Xyl = 3,5-Me2-Ph, DMM = 4-OMe-
3,5-Me2, BTFM = 3,5-(CF3)2, DTBM = 4-OMe-3,5-tBu2.
noncyclic substrates. Therefore, a general procedure for the
enantioselective α-arylation of ketones is still missing. We herein
show that silyl enol ethers of noncyclic ketones can be arylated in
enantioselective fashion for the first time by means of a novel
Cu(I) catalytic system featuring chiral bis(phosphine) dioxides
as ligands (Figure 1E).
Having identified a suitable class of ligands, a number of
bis(phosphine) dioxides 3 were easily obtained from their
corresponding commercially available phosphines. The enantio-
selectivities obtained are summarized in Figure 2A (for reaction
yields, see the Supporting Information). In general, the
GARPHOSO (3i−3m) and SEGPHOSO (3n−3p) scaffolds
provided the best performances, with DMM-GARPHOSO 3l
being the best commercially available candidate tested (er
86:14). Electron-poor ligands such as 3m gave low reactivity,
and increasing the steric hindrance of the aryl groups was
detrimental for the enantioselectivity (see DTBM-SEGPHOSO
3p). Even though 3a−3u did not give acceptable selectivity, we
reasoned that an optimal ligand structure could be accessed via
correlation analysis, assuming that a proper descriptor could be
found. This would be preferable to a trial-and-error approach
and would reduce the effort toward the synthesis of new
candidates.
Initially, silyl enol ether 4a was found to react smoothly with
diaryliodonium salt 5a to give the corresponding racemic α-
arylated product 6a in the presence of Cu(OTf)2 in DCM. In an
effort to render this transformation enantioselective, we found
that adding (R)-BINAP under aerobic conditions provided the
desired product in 72% yield and 74:26 er. Given the propensity
of phosphines to be oxidized and of Cu to undergo redox events,
several combinations of (R)-BINAP, (R)-BINAP(O) (mon-
oxide of (R)-BINAP), or (R)-BINAPO 3a with Cu(OTf)2 or
(CuOTf)2·Tol were tested under an inert atmosphere (see the
Supporting Information). Although chiral bis(phosphine)
dioxides are well-known Lewis base catalysts,24,25 to the best
of our knowledge, only three reports exist about their use in
combination with transition metal catalysis.26−28 Therefore, we
were surprised to find that the reaction was indeed promoted by
a combination of Cu(I) and chiral bis(phosphine) dioxides 3a. A
number of other classes of ligands were tested that proved
unsuitable for this transformation (see the Supporting
Information). Complexes 2 previously used for the arylation
of silyl ketene imides (Figure 1B)16,17 were among those that
showed no conversion.
The structures of ligands 3a−3u were optimized at the M06-
2X/6-31G(d) level. The vibrational analysis was performed at
the same level of theory to access a number of frequencies that
could be relevant descriptors for the electronic properties of the
ligand. These included υPOas, the frequency of the asymmetric
PO bonds stretching.
Interestingly, when reducing the data set by removing
candidates affected by strong steric or structural biases (i.e.,
3e−3h, 3p, 3s, and 3t), the correlation in Figure 2B was
obtained (blue dots). This relates the reaction enantioselectivity
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Figure 3. Reaction scope. Yields and selectivity are expressed according with the formula NMR y(isol. y)%, er. Conditions: diaryliodonium salt 5 (0.1
mmol), silyl enol ether 4 (0.2 mmol), (CuOTf)2·Tol (4 mol %), 3x (12 mol %), DCM (0.5 mL). (a) 3.0 equiv of silyl enol ether 4 was used. (b) ent-3z
was used instead of 3x. (c) Reaction time: 6 h. (d) Reaction time: 24 h. (e) The er was determined on the corresponding alcohol after reduction with
LiAlH4.
(expressed as ΔΔG⧧ in kcal/mol) with υPOas, suggesting
important effects induced by the electronics of the ligand at
the diastereomeric transitions states. Due to additivity of the
Hammett σ parameters, a simple comparison of the selectivity
for 3i−3l would indicate 3v as a promising ligand. On the other
hand, virtual evaluation and predictions given by the correlation
in Figure 2B suggested 3v to be average (predicted er: 80:20)
and identified 3x as the best candidate (predicted er: 90:10).
Ligands 3v, ent-3z, and 3x were therefore synthesized to test our
model. Pleasingly, the correlation was found to be obeyed
(orange dots in Figure 2b), with 3x providing product 6a in 94:6
er and 58% yield.
Adding 3v, ent-3z, and 3x to the whole data set, the selectivity
range was extended to ca. 1.5 kcal/mol, allowing for more
statistically sound multidimensional linear regression analysis to
be performed.29−32 This would allow accounting for additional
steric and structural effects. Other descriptors acquired for the
ligands included: (i) B1, B5, and L, Verloop Sterimol
parameters33 accounting for the minimum width, maximum
width, and length of the whole Ar group; (ii) B1x, B5x, and Lx
(where x = m or p), Verloop Sterimol parameters accounting for
the minimum width, maximum width, and length of the meta- or
para-substituents of the Ar group; (iii) %Vx (where x = m or p),
buried volume34 of a 3.5 Å sphere placed on the meta- or para-
substituent of the Ar group; dPO, PO bond length; and φ,
dihedral angle of the scaffold biaryl moiety. When applying the
multivariate linear regression procedure, the model in Figure 2C
was obtained. In addition to υPOas, parameters B1, B1m, and φ
appeared in the model, the former two with opposite coefficient
sign. Since also φ is likely affected by the size of the Ar groups,
this suggests that a fine balance between steric hindrance and
geometrical features is required in order to achieve optimal
selectivity. The model presents a good quality of fit with R2 =
0.94 and was proven to be robust by leave-one-out cross
validation (LOO Q2 = 0.83).
With the optimized ligand 3x, the reaction scope was
evaluated (Figure 3). Silyl enol ethers bearing electron-donating
substituents in meta- or para-positions were found to react
smoothly to access good yields and er ≥95:5 (6b−6e, 6h, 6j).
Despite good reactivity, 6i gave lower selectivity (er 83:17)
likely due to the geometrical bias provided by the ortho-OMe
group. Decreasing the nucleophilicity of the Si-enolate resulted
in diminished chemical activity (6f, 6g). However, we found that
changing the ligand to ent-3z for these substrates was beneficial.
Despite the lower pKa of 6g due to the CF3 group, the er at 6 and
24 h was conserved (92:8 er).
Substrates with a longer α-substituent also resulted in high
enantioselectivity, with products 6k and 6l being obtained in
96.5:3.5 and 97.5:2.5 er, respectively. iPr or Bn groups onto the
nucleophilic α-carbon are detrimental for the reactivity likely
due to steric hindrance (6m, 6n). Tetralone 6z can be obtained
in 94:6 er even though with modest yield, while the use of 4aa
resulted in high yields but lower selectivity. Therefore, this
method is synthetically complementary to previous work by
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Zhou.21 Notably, linear dialkyl ketones were also suitable
reaction partners with only slightly diminished efficiency (6ac−
6af), which is unprecedented in enantioselective α-arylations.
Moreover, methyl propionate ent-6ab was obtained in 50% yield
and 90:10 er (with ligand ent-3z) showing that also esters are
amenable to arylation under our catalytic conditions. Diary-
liodonium salts 5 featuring different electronic and steric
properties were also tested. Both electron-rich and electron-
poor aryl groups reacted in typically good yields and high er
(6o−6x) showing good generality. Steric hindrance next to the
reaction site was detrimental, as the ortho-tolyl-substituted
ketones 6y and 6n could not be obtained. Finally, a comparison
of the optical rotation with products previously reported allowed
the establishment that (R)-ligands lead to the formation of (S)-
products. It should be noted that enantioenriched α-arylated
noncyclic ketones of the type reported herein were only
accessible via Kumada-type couplings from α-halogenated
ketones or by photocatalytic acylation of benzyl radicals.35−38
Alternatively, a multistep strategy would need to be followed.39
Phosphine oxides are generally believed to be labile ligands in
transition metal catalysis.40−45 Moreover, they are also known as
excellent Lewis bases.24,25 As such, this class of compounds is
capable of binding hypervalent iodine compounds with binding
constant K ≃ 50−200 M−1 in DCM.46 Therefore, the question
follows whether ligands 3 would operate as ancillary ligands at
the Cu metal center (Figure 4B), or by activation of the arylating
reaction rate constant 1/kobs against the concentration of
bis(phosphine) dioxides 3a resulted in a straight line (R2 = 0.98)
with positive slope. The kinetic order −1 suggests that 3a is
involved in a pre-equilibrium that requires it to dissociate from
its acidic partner before the reaction can proceed. As phosphine
oxides and diaryliodonium salts 5 form 1:1 complexes, the
hypothesis that their combination would result in catalytic
activity is in contrast with this kinetic data (Figure 4A). On the
contrary, this data is consistent with a scenario where an inactive
off-cycle complex [Cu(3a)2Xn] is formed in the presence of a
large excess of ligand. This complex would require a ligand
molecule to dissociate before the catalytically active species
[Cu(3a)Xn] can enter into the catalytic cycle (Figure 4B).
Clearly, this does not exclude the formation of Lewis complexes
in solution. Therefore, even though phosphine oxides act as
labile ligands in transition metal catalysis with soft second- and
third-row metals,40−45 this work adds to precedents showing
that these bind to first row transition metals such as Fe26−28 or
Cu.47,48
In summary, we showed that a novel catalytic system featuring
Cu(I) and bis(phosphine) dioxides 3 efficiently promotes the
unprecedented enantioselective α-arylation of noncyclic silyl
enol ethers. Oxides of commercially available bisphosphines
provided selectivity up to 86:14 er. Therefore, ligand 3x was
identified by means of correlation analyses and synthesized in
the enantiomerically pure form. This was found to outperform
other ligands providing er up to 97.5:2.5. After evaluation of the
reaction scope, we turned our attention to the role of 3 in
catalysis. We found that, contrarily to common opinions,
bis(phosphine) dioxides efficiently bind to the Cu center to
promote the reaction as a ligand rather than as a Lewis base. In
this instance, this transformation is an example of how new
classes of ligands could give access to new reactivity thus
underpinning the continuously increasing interest for the use of
abundant base metals.49−51 Further investigations into the
mechanism of this novel catalytic system and extension to other
transformations are currently ongoing in our laboratories and
will be reported in due course.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c13236.
Experimental and computational details and character-
ization of all compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Manuel Orlandi − Department of Chemical Sciences and
̀
CIRCC−Consorzio Interuniversitario per le Reattivita
Figure 4. Preliminary mechanistic considerations. Bis(phosphine)
dioxides 3 promote the reaction as the ligand to the Cu center rather
than as a Lewis base.
Chimiche e la Catalisi, University of Padova, 35131 Padova,
Italy; orcid.org/0000-0002-0569-6719;
Email: manuel.orlandi@unipd.it
Authors
Margarita Escudero-Casao − Department of Chemical Sciences
agent 5 by formation of a hypervalent Lewis acid−base adduct
(Figure 4A).24 Preliminary clarification of the role of 3 in the
reaction mechanism would help understand this novel catalytic
system setting the basis for its future deployment in other
transformations. Therefore, this was investigated in our
benchmark reaction via initial rate kinetic analysis giving the
plot in Figure 4. The plot of the reciprocal of the observed
̀
and CIRCC−Consorzio Interuniversitario per le Reattivita
Chimiche e la Catalisi, University of Padova, 35131 Padova,
Italy
Giulia Licini − Department of Chemical Sciences and
CIRCC−Consorzio Interuniversitario per le Reattivita
̀
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Selectivity, Oxidation State, and Room-Temperature Reactions. J. Am.
Chem. Soc. 2011, 133, 16330.
Chimiche e la Catalisi, University of Padova, 35131 Padova,
Italy; orcid.org/0000-0001-8304-0443
(14) Xie, X.; Chen, Y.; Ma, D. Enantioselective Arylation of 2-
Methylacetoacetates Catalyzed by CuI/trans-4-Hydroxy-l-proline at
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Aldehydes via the Productive Merger of Iodonium Salts and
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(16) Bigot, A.; Williamson, A. E.; Gaunt, M. J. Enantioselective α-
Arylation of N-Acyloxazolidinones with Copper(II)-bisoxazoline
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Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c13236
Author Contributions
†M.E.-C. and M.O. contributed equally. All authors have given
approval to the final version of the manuscript.
Funding
The Department of Chemical Sciences of the University of
Padova is thankfully acknowledged for the grant P-DiSC#08-
BIRD2019.
Notes
(18) Huang, Z.; Liu, Z.; Zhou, J. An Enantioselective, Intermolecular
α-Arylation of Ester Enolates To Form Tertiary Stereocenters. J. Am.
Chem. Soc. 2011, 133, 15882.
The authors declare no competing financial interest.
(19) Kobayashi, K.; Yamamoto, Y.; Miyaura, N. Pd/Josiphos-
Catalyzed Enantioselective α-Arylation of Silyl Ketene Acetals and
Mechanistic Studies on Transmetalation and Enantioselection. Organo-
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(20) Huang, Z.; Chen, Z.; Lim, L. H.; Quang, G. C. P.; Hirao, H.;
Zhou, J. Weak Arene C-H···O Hydrogen Bonding in Palladium-
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ACKNOWLEDGMENTS
■
We thank Prof. S. E. Denmark and Dr. J. Ruchti for useful
discussions and insights. Samples of (R)-BITIAMPO 3s and
(R)-BITIOPO 3t were graciously gifted by Prof. T. Benincori
̀
(Universita dell’Insubria). Computations were performed at the
HPC facility of the Computational Chemistry Community of
Padova (C3P).
(21) Huang, Z.; Lim, L. H.; Chen, Z.; Li, Y.; Zhou, F.; Su, H.; Zhou, J.
Arene CH-O Hydrogen Bonding: A Stereocontrolling Tool in
Palladium-Catalyzed Arylation and Vinylation of Ketones. Angew.
Chem., Int. Ed. 2013, 52, 4906.
(22) Liu, X.; Hartwig, J. F. Palladium-Catalyzed Arylation of
Trimethylsilyl Enolates of Esters and Imides. High Functional Group
Tolerance and Stereoselective Synthesis of α-Aryl Carboxylic Acid
Derivatives. J. Am. Chem. Soc. 2004, 126, 5182.
(23) Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.; Janker,
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https://dx.doi.org/10.1021/jacs.0c13236
J. Am. Chem. Soc. 2021, 143, 3289−3294