Asymmetric Conjugate Addition of Organoboron Reagents to Common Enones Using Copper Catalysts

Article abstract of DOI:10.1021/jacs.5b11441

Copper complexes of phosphoramidites efficiently catalyzed asymmetric addition of arylboron reagents to acyclic enones. Importantly, rare 1,4-insertion of arylcopper(I) was identified which led directly to O-bound copper enolates. The new mechanism is fundamentally different from classical oxidative addition/reductive elimination of organocopper(I) on enones.

Full text of DOI:10.1021/jacs.5b11441

Communication
pubs.acs.org/JACS
Asymmetric Conjugate Addition of Organoboron Reagents to
Common Enones Using Copper Catalysts
Chunlin Wu,† Guizhou Yue,‡ Christian Duc-Trieu Nielsen,† Kai Xu,† Hajime Hirao,*,†
and Jianrong (Steve) Zhou*,†
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
‡College of Science, Sichuan Agricultural University, Ya’an, Sichuan, China 625014
S
* Supporting Information
ABSTRACT: Copper complexes of phosphoramidites
efficiently catalyzed asymmetric addition of arylboron
reagents to acyclic enones. Importantly, rare 1,4-insertion
of arylcopper(I) was identified which led directly to O-
bound copper enolates. The new mechanism is funda-
mentally different from classical oxidative addition/
reductive elimination of organocopper(I) on enones.
symmetric conjugate additions of organometallic reagents
constitute an important class of carbon−carbon bond-
such as α-cyanoacrylates and acroylimidazoles were used.
A
forming reactions.1 In particular, rhodium catalysts were
extensively developed in addition reactions of air-stable
organoboron reagents, due to efforts by Miyaura, Hayashi,
Lin, and others. Thus, the reaction has been applied in kilogram
synthesis of drug candidates.2 In general, dienes and other
weakly donating ligands produced more active rhodium
catalysts than bisphopshines.3 In the past decade, this reaction
has also been extensively developed with palladium catalysts.4
In particular, Stoltz et al. recently reported efficient nitrogen-
based catalysts for highly asymmetric addition to hindered
cyclic enones.5 In both Rh and Pd catalysis, experiments and
DFT calculations supported 1,2-insertion of arylmetal species
to olefins to form C-bound enolates as key steps.6
Recently, organocatalytic conjugate addition of vinylboron
reagents also emerged by activation of enones, but the arylation
afforded rather unsatisfactory ee.15
We envisioned to combine the best of two worlds, i.e., air-
stable organoboron reagents and cheap copper catalysts in
conjugate reaction (Table 1). Unfortunately, when we
attempted a model reaction of a chalcone derivative and
phenylboronic acid, no product was detected with many
different catalysts and conditions. Accidentally, we found that
phenylboronic acid underwent spontaneous dehydration to
form phenylboroxine during storage in a drybox. The latter was
very active and afforded the adduct in good yield and 94% ee, in
the presence of a copper/L1 catalyst.16 In comparison,
PhB(pin) and PhBF3K did not react at all, while PhB(neop)
gave only 10% conversion of the enone under similar
conditions. Moreover, only weakly basic acetates such as
KOAc and NaOAc efficiently promoted this reaction, while
stronger bases (e.g., KOtBu, NaOH, and KOH) surprisingly
inhibited it. Notably, when the amount of KOAc was reduced
to 20 mol %, 90% conversion of the enone was seen after 3 days
at 70 °C, so the acetate was not consumed during catalysis (see
the Supporting Information (SI)).
In the beginning, we found that a commercially available
spiro-phosphoramidite L217 afforded promising results with
87% ee (Table 1). Changing its phenethyl group to a tetralinyl
ring (L3) helped to improve the ee to 91%. Subsequent
alteration of the other phenethyl group to cyclohexylethyl led
to our optimal ligand L1. Notably, ligand L4 bearing a
cyclododecyl group was also very stereoselective. Later, we tried
to “invert” the configuration of cyclohexylethylamine in L1, and
Copper, an abundant base metal, is over thousands-fold
cheaper than rhodium and palladium. Historically, chiral copper
catalysts were extensively developed in conjugate addition of
reactive organometallic reagents, even for the formation of
quaternary centers.7 However, air-sensitive organometallic
reagents of Li,8 Mg,9 Al,10 Zn,11 and Zr12 must be used in
those reactions. Only recently, conjugate addition using air-
stable organoboron reagents was reported by Shintani/
Hayashi13 and Sawamura14 using copper/NHC catalysts (eqs
1 and 2). In both cases, only highly activated Michael acceptors
Received: November 2, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b11441
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Journal of the American Chemical Society
Communication
(Scheme 1a). Enones bearing β aliphatic groups were less
reactive and needed 10% copper catalyst to reach good
conversion. In reactions of two dienones, only 1,4-adducts were
detected without any trace amount of 1,6-adducts. Moreover,
enones carrying both α′ aryl and heteroaryl groups reacted very
efficiently (Scheme 1b). Those carrying α′ alkyl groups,
however, required 10% catalyst loading to give good conversion
(Scheme 1c). A model reaction was easily scaled up to give
more than 1 g of a product at 1% copper loading (Scheme 1d).
Notably, the reaction was not very sensitive to air. It still gave
70% yield and 91% ee even after the mixture was exposed to air
for 5 min before heating (see SI). α,β-Unsaturated esters and
aldehydes remained unreactive. We also tested α-cyanocinna-
mates and N-methyl-2-acroylimidazole. The former afforded
very low conversion (<10%), while the latter gave 30% yield
and 13% ee.
Table 1. Ligand Screening for Conjugate Addition to a
Model Chalcone
Other arylboroxines with diverse electronic demands and a
thienyl derivative reacted smoothly (Scheme 2). We found that
alkenylboroxines gave only partial conversion under similar
conditions.
Scheme 2. Examples of Copper-Catalyzed Conjugate
Addition of Other Organoboroxines
the resulting ligand L1a was slightly less selective (88% ee). We
also tried to “mutate” the spiro chirality in L1. The new ligand
L1b led to the opposite enantiomer as the major product in the
model reaction. Thus, the spiro chirality had dominant
influence on the stereoselectivity. In comparison, Feringa
ligand L5 built on a binaphthyl skeleton gave only 38% ee.
When 1:1 or 1:2 molar ratios of the CuOTf complex and L1
were added, almost the same reaction rates and ee values were
seen in the model reaction (at 5% Cu loading). However, when
the ratio was reduced to 1:0.5, the reaction rate decreased
significantly, although the ee remained constant (see the SI).
Therefore, the 1:1 complex of (L1)arylcopper(I) is most likely
the active species during insertion. We noticed that other
copper salts (e.g., CuCl, CuBr, and CuOAc) led to slightly
slower conversion in comparison.
The ketone group in a product was readily converted to an
ester and an amide by simple manipulation (Scheme 3). It was
also readily deoxygenated by Pd/C catalyzed hydrogenolysis.
No erosion of 99% ee was seen in all cases.
We have considered a few possible pathways for the key C−
C bond formation in the conjugate addition. Classical conjugate
addition of diorganocuprates involved a sequence of oxidative
The copper/L1 catalyst was applicable to chalcones carrying
β aryl and heteroaryl groups with diverse electronic properties
Scheme 1. Examples of Copper-Catalyzed Conjugate Addition of Phenylboroxine
B
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with the observed 95% ee (R) from the model reaction. The
overall insertion barrier leading to the major (R )-enantiomer
was 13 kcal/mol, as the two ground-state structures can
interconvert easily.
Scheme 3. Product Derivatization
In 1,4-insertion, the enones must assume an s-cisoid reactive
conformation, which is consistent with the fact that cyclic
enones, e.g., 2-cyclohexenone and indenone, did not react
under this condition. Furthermore, 1,4-insertion predicted a
C12/C13 KIE value of 1.02 at β carbon of the chalcone, which
was confirmed by natural-abundance C13 KIE experiments
(Scheme 4d).22
We also modeled 1,4-insertion pathways of (L1)2(phenyl)
copper (Scheme 4e),23 but the insertion barriers were too high,
around 21−25 kcal/mol, to be considered as the main
pathways.
addition and reductive elimination at β position of enones.18 In
2006, Feringa et al. proposed a similar mechanism involving
(bisphosphine)arylcopper(I) in conjugate additions of
Grignard reagents (Scheme 4a).19 Importantly, Lewis acidic
Scheme 4. Mechanistic Studies
The calculated transition structures revealed how a
monoligated copper complex formed a good chiral pocket
around the copper center. L1 assumed a specific conformation
to minimize steric repulsion between two large groups on the
nitrogen (Figure 1). The cyclohexylethyl group pointed up and
Figure 1. Transition states TS-R (left) and TS-S (right) for 1,4-
insertion of (L1)phenylcopper(I) to p-methylchalcone. L1 is shown in
a space-filling model, and reacting ligands and copper are in ball-and-
stick. Copper is in blue, while Cu-bound phenyl ring is in pink. The
carbon atoms of chalcone are in green, while its oxygen is in red.
shielded the top-right quadrant, while an indanyl ring extended
out in the bottom-left space. Consequently, the top-left
quadrant was left widely open for the C−C bond formation.
In comparison, the bottom-right space was slightly more
congested, and thus the C−C bond formation thereby had
higher barriers.
Interestingly, we identified that in TS-R leading to the major
enantiomer, there was weak hydrogen bonding between two
aromatic C−H bonds of ligand L1 and the oxygen atom of the
chalcone, which was absent in TS-S. Each of the CH hydrogen
atoms had a partial charge of +0.2. Thus, weak attractive
interactions provided additional charge stabilization of the
developing enolate during insertion. The CH···O hydrogen
bonding can provide stabilizing energy of 0.5−4 kcal/mol
depending on the acidity of CH bonds and the topology of
bonds.24 Recently, examples of this kind are emerging in
transition metal catalysis.25
We conducted DFT calculation on transmetalation from
(L1)Cu(enolate) to phenylboroxine (Scheme 4f). Relatively
high activation barriers were identified (23−25 kcal/mol),
indicating that the transmetalation was rate-limiting in a
catalytic cycle. Modeling of transmetalation using phenyl-
boronic acid, however, suggested even higher barriers (27−30
kcal/mol). Putting all the results together, we conclude that
phenylboronic acid and boron ester derivatives did not react,
due to prohibitively slow transmetalation.
metal ions, such as lithium, magnesium and zinc, played a key
role in stabilizing enolate structures during oxidative addition.
Potassium ion is insufficiently Lewis acidic to serve this role to
stabilize enolates. Furthermore, reversible oxidative addition
can lead to cis-to-trans isomerization of unreacted starting
material, which was not detected under our conditions.
We then conducted DFT calculations20 to simulate insertion
of (L1)phenylcopper(I) to p-methylchalcone. To our surprise,
classical 1,2-insertion was not found (Scheme 4b). Instead, a
rare 1,4-insertion pathway was identified, in which a six-
membered transition state led directly to an O-bound copper
enolate (Scheme 4c).21 During insertion, we believe the Cu−O
coordination helped to dissipate the negative charge of
enolates. The energy gap of two transition states TS-R and
TS-S was determined to be 2.3 kcal/mol, in good agreement
In summary, we report here copper catalysts ligated by
phosphoramidites for asymmetric addition of organoborons to
C
DOI: 10.1021/jacs.5b11441
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Journal of the American Chemical Society
Communication
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b11441.
Experimental details (PDF)
NMR spectra (PDF)
DFT calculations (PDF)
Crystallographic data (CIF)
(13) Takatsu, K.; Shintani, R.; Hayashi, T. Angew. Chem., Int. Ed.
2011, 50, 5548.
(14) (a) Ohmiya, H.; Yoshida, M.; Sawamura, M. Org. Lett. 2011, 13,
482. (b) Yoshida, M.; Ohmiya, H.; Sawamura, M. J. Am. Chem. Soc.
2012, 134, 11896.
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129, 4908. (b) Turner, H. M.; Patel, J.; Niljianskul, N.; Chong, J. M.
Org. Lett. 2011, 13, 5796.
AUTHOR INFORMATION
■
Corresponding Authors
*jrzhou@ntu.edu.sg
*hirao@ntu.edu.sg
Notes
The authors declare no competing financial interest.
(16) Copper/bipy-catalyzed addition of arylboroxines to α,β-
unsaturated ketones: Liao, Y.-X.; Hu, Q.-S. J. Org. Chem. 2011, 76,
7602.
(17) Xie, J.-H.; Zhou, Q.-L. Acc. Chem. Res. 2008, 41, 581.
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ACKNOWLEDGMENTS
■
We thank Singapore Ministry of Education Academic Research
Fund (MOE2013-T2-2-057 and MOE2014-T1-001-021) for
financial support and Chinese Scholarship Counsel for financial
support of G.Y. C.D.-T.N. thanks Imperial College London for
the undergraduate exchange programme. H.H. acknowledges
the computer resources of the High-Performance Computing
Centre at NTU. We thank Dr. Yongxi Li for X-ray analysis of a
product.
(19) Harutyunyan, S. R.; Lopez, F.; Browne, W. R.; Correa, A.; Pena,
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(20) Gaussian 09 was used for DFT calculations. See the SI for
details of DFT calculations.
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DOI: 10.1021/jacs.5b11441
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX