Pd(II)-Catalyzed Enantioselective C(sp3)-H Borylation

Article abstract of DOI:10.1021/jacs.6b13389

Pd(II)-catalyzed enantioselective borylation of C(sp³)-H bonds has been realized for the first time using chiral acetyl-protected aminomethyl oxazoline ligands. This reaction is compatible with carbocyclic amides containing α-tertiary as well as α-quaternary carbon centers. The chiral β-borylated amides are useful synthons for the synthesis of chiral β-hydroxylated, β-fluorinated, and β-arylated carboxylic acids.

Full text of DOI:10.1021/jacs.6b13389

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Pd(II)-Catalyzed Enantioselective C(sp3)–H Borylation
Jian He, Qian Shao, Qingfeng Wu, and Jin-Quan Yu
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Feb 2017
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Pd(II)-Catalyzed Enantioselective C(sp3)–H Borylation
Jian He, Qian Shao,† Qingfeng Wu,† and Jin-Quan Yu*
Department of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037
different ligand scaffolds. Enantioselective C(sp3)–H cross-
coupling reactions via Pd(II)/Pd(0) catalysis have been developed
using MPAA and mono-N-protected α-amino-O-
methylhydroxamic acid (MPAHA) ligands, albeit with significant
limitations (Scheme 1, eqs 1 and 2).6,9 Notably, enantioselective
C(sp3)–H borylation has not been developed to date.10–12 Herein,
we report the first example of Pd(II)-catalyzed enantioselective β-
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ABSTRACT: Pd(II)-catalyzed enantioselective borylation of
C(sp3)–H bonds has been realized for the first time using chiral
acetyl-protected aminomethyl oxazoline ligands. This reaction is
compatible with carbocyclic amides containing α-tertiary as well as
α-quaternary carbon centers. The chiral β-borylated amides are
useful synthons for the synthesis of chiral β-hydroxylated, β-
fluorinated, and β-arylated carboxylic acids.
borylation
of
carboxylic
acid-derived
amides
with
bis(pinacolato)diboron using acetyl-protected aminomethyl
oxazoline (APAO) ligands (Scheme 1, eq 3). A range of cyclic
amides, including cyclopropanes, cyclobutanes, and cyclohexanes,
can be successfully borylated with high levels of enantioselectivity.
This reaction is compatible with amide substrates containing α-
tertiary as well as α-quaternary carbon centers. Notably, O2 is used
as the sole oxidant for this Pd(II)/Pd(0) catalysis.
Differentiation of prochiral C–H bonds through metal insertion
has recently emerged as a promising approach in asymmetric
catalysis.1,2
A number of Pd(0)-catalyzed enantioselective
intramolecular C(sp3)–H arylation and alkylation reactions have
been realized by the use of chiral N-heterocyclic carbene3 or
phosphine ligands.4,5 The feasibility of Pd(II)-catalyzed
enantioselective intermolecular C(sp3)–H activation was initially
demonstrated using mono-N-protected amino acid (MPAA)
ligands.6 Major advances have been recently made by using a
weakly coordinating monodentate substrate and a chiral bidentate
ligand. The design of chiral bidentate acetyl-protected aminoethyl
quinoline (APAQ) and mono-N-protected aminomethyl oxazoline
(MPAO) ligands for asymmetric induction have led to the
development of enantioselective intermolecular arylation of
methylene C(sp3)–H bonds and gem-dimethyl C(sp3)–H bonds,
respectively.7,8
We have previously developed C(sp3)–H borylation promoted
by a monodentate quinoline ligand (Scheme 2, eq 4).12f Since the
recently developed chiral APAQ ligands for enantioselective β-C–
H arylation also contain a quinoline moiety,7 we initiated our
investigation on the borylation of 1a using this type of ligands
(Scheme 2, eq 5). Although these bidentate quinoline ligands are
known to promote C(sp3)–H cleavage of amide substrates, they
failed to provide any desired borylated products under our
previously established conditions. It appears that this ligand
scaffold is not compatible with the transmetalation or the C(sp3)–B
reductive elimination step.
The development of these enantioselective C(sp3)–H activation
reactions involving Pd(II)/Pd(IV) redox catalysis calls into
question whether enantioselective C(sp3)–H activation reactions
with nucleophiles through Pd(II)/Pd(0) redox catalysis are
compatible with the APAQ and MPAO ligands. Although both
catalytic reactions proceed through the same asymmetric C–H
insertion intermediates, the transmetalation and reductive
elimination steps in Pd(II)/Pd(0) catalytic cycles may require
Scheme 2. Palladium-Catalyzed C(sp3)–H Borylation using
Quinoline-Based Ligands
Scheme 1. Enantioselective C(sp3)–H Activation via
Pd(II)/Pd(0) Catalysis
Considering the previously observed significant steric effect of
ligands on C(sp3)–H borylation,12f we replaced the quinoline motif
with a variety of heterocycles. We found acetyl-protected
aminomethyl oxazolines as the only effective ligands for this
unprecedented enantioselective C(sp3)–H borylation reaction. The
enantioenriched borylated product 2a was obtained in 82% 1H
NMR yield and 95.6% ee when reacting 1a with
bis(pinacolato)diboron in the presence of Pd(CH3CN)4(OTf)2 (10
mol%), bidentate oxazoline ligand (S,R)-L1 (30 mol%), and
K2HPO4 in the mixed solvent (CH3CN/DCE/H2O) at 80 °C under
O2 atmosphere for 15 h (Table 1, entry 1). Control experiments
revealed that the palladium catalyst and base were crucial for the
C(sp3)–H borylation to proceed (entries 2 and 3). Low reaction
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employed in C(sp3)–H borylation, the substituents on both chiral
Table 1. Effect of Reaction Parameters in Pd(II)-Catalyzed
Enantioselective C(sp3)–H Borylation of Cyclic Amide 1aa,b
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centers of the ligand backbone exert a synergistic effect in
asymmetric induction through the steric repulsion with the
cyclobutane ring, favoring five-membered palladacycle
Intermediate A over Intermediate B. Reducing the amount of
Pd(CH3CN)4(OTf)2 to 5 mol% gave 2a in 67% yield and 89.0% ee
(entry 13). The fine tuning of palladium sources, bases, and
solvents was also essential for achieving high levels of
enantioselectivity in this C(sp3)–H borylation (entries 14–18). A
similar ee value was obtained when conducting the reaction at
60 °C, but the yield was significantly lower (entry 19). The reaction
could also be carried out in air, affording the desired product in 61%
yield and 94.8% ee (entry 20).
Figure 1. The proposed asymmetric induction model in enantioselective C(sp3)–H
borylation of cyclobutanes.
With the optimal reaction conditions in hand, we then evaluated
the scope of cyclobutanecarboxylic acid-derived amides towards
Table 2. Substrate Scope for Enantioselective C(sp3)–H
Borylation of Cyclobutanecarboxylic Amidesa,b
aReaction conditions: substrate 1a, B2pin2 (2.0 equiv), Pd(CH3CN)4(OTf)2 (10 mol%),
APAO ligand (30 mol%), K2HPO4 (2.0 equiv), CH3CN/DCE/H2O (16:4:1), O2, 80 °C,
15 h. bThe yield was determined by 1H NMR analysis of the crude product using
CH2Br2 as the internal standard. The ee values were determined by HPLC analysis on
a chiral stationary phase. c(S,R)-L1 (15 mol%) was used.
conversion was observed in the absence of ligands (entry 4).
Decreasing the loading of (S,R)-L1 to 20 mol% slightly increased
the yield of 2a, but the ee dropped to 93.4% (entry 5). The use of
(S,S)-L1, the other diastereomer of the optimal ligand, drastically
decreased yield and ee to 24% and 50.4%, respectively (entry 6).
Changing the substituents on both the side chain and the oxazoline
moiety of (S,R)-APAO ligands did not have significant impact on
reactivity and enantioselectivity (entries 7–10). However, the chiral
oxazoline ligands lacking a stereocenter on either the side chain or
the oxazoline moiety gave poor enantioselectivity (entries 11 and
12), which speaks to the importance of both chiral centers on the
APAO ligand backbones for asymmetric induction. The observed
significant impact of both chiral centers on the enantioselectivity
can be explained by the potential structures of the C–H insertion
intermediates shown in Figure 1. When (S,R)-oxazoline ligands are
aReaction conditions: substrate 1a–1o, B2pin2 (2.0 equiv), Pd(CH3CN)4(OTf)2 (10
mol%), (S,R)-L4 (30 mol%), K2HPO4 (2.0 equiv), CH3CN/DCE/H2O (16:4:1), O2,
80 °C, 15 h. bIsolated yields. The ee values were determined by HPLC analysis on a
chiral stationary phase. c(S,R)-L1 (30 mol%) was used. d(S,R)-L5 (30 mol%) was used.
eCH3CN/DCE (4:1) was used as the mixed solvent. fPd(CH3CN)4(OTf)2 (5 mol%) and
(S,R)-L4 (15 mol%) were used.
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enantioselective C(sp3)–H borylation (Table 2). While (S,R)-L1
diastereomers, which is consistent with the ligand effect in the
enantioselective C(sp3)–H arylation of amide 7 with aryl iodides.8
The use of (S,S)-L8 (20 mol%) to activate cyclohexanecarboxylic
amide 5a gave the chiral borylated product as a cis- and trans-
mixture which was then oxidized to provide cis-6a and trans-6a in
92.4% and 93.2% ee, respectively. The borylation/oxidation ofboth
cis- and trans-4-substituted cyclohexane substrates furnished the
desired products (6b and 6c) with high levels of diastereoselectivity
(d.r. > 10:1) and enantioselectivity (95.2% and 91.7% ee,
respectively). The reaction conditions was also applied to the
asymmetric C(sp3)–H functionalization of the bicyclo[2.2.2]octane
(5d), giving the enantioenriched hydroxylated product (6d) in 70%
ee. With the aid of (S,S,S)-L9, desymmetrization of the isopropyl
group in isobutyric acid derivative 7 afforded 8 in moderate yield
(54%) and enantioselectivity (66% ee).
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was superior in the borylation of amide substrate 1a bearing an α-
hydrogen atom, (S,R)-L4 containing an isopropyl group on the
oxazoline moiety gave better enantioselectivity for substrates
containing α-quaternary carbon centers in general. Simple α-alkyl
substituted amides could be borylated in good yields with excellent
levels of enantioselectivity, ranging from 98.4% to 99.2% ee (2b–
2f). A variety of aromatic rings at the β- or γ-positions of the
exocyclic alkyl side chain were well tolerated (2h–2i). C(sp2)–H
borylation was not detected in the functionalization of these
substrates. (S,R)-L5 gave the highest enantioselectivity in the
borylation of amide 1h containing a simple benzyl group at the α-
position. Substrates with potentially coordinating heteroatoms such
as oxygen (1g, 1m, and 1n) and nitrogen (1o) on the α-substituents
were also compatible with this enantioselective C(sp3)–H
borylation. Even though water had to be excluded from the solvent
mixture to prevent hydrolysis of the phthalimido group, C(sp3)–H
borylation of β-amino acid substrate 1o still provided the desired
product 2o in a moderate yield. The absolute configuration of the
borylated compounds was confirmed by X-ray crystallographic
To further demonstrate the synthetic utility of this
enantioselective C(sp3)–H borylation reaction,13 we subjected the
chiral cyclobutylboronate ester 2a to various reaction conditions,
constructing a range of β-chiral centers containing carbon–
heteroatom or carbon–carbon bonds (Scheme 4). After reacting 2a
with hydrogen peroxide in THF and NaH2PO4 aqueous solution,
the desired β-hydroxylated product 9 could be obtained in 88%
yield and 95.8% ee. The combination of AgNO3 and Selectfluor in
CH2Cl2/H2O (1:1) converted 2a into chiral β-fluorinated
cyclobutanecarboxylic acid derivatives (cis-10 and trans-10) in a
total yield of 92% through a radical pathway.14 High ee values were
maintained in both diastereomers. Treatment of the borylated
product 2a with KHF2 in acetonitrile led to the formation of
trifluoroborate salt 11 in 95% yield after recrystallization. The
Suzuki-Miyaura cross-coupling between 1-chloro-4-nitrobenzene
and 11 provided the β-arylated product 12 in 99.3% ee with
retention of stereochemistry.15 The absolute configuration of 12
was also confirmed by X-ray crystallographic analysis. Removal of
the amide auxiliary by BF3·Et2O in methanol gave the
corresponding ester 13 in 90% yield without loss of enantiomeric
purity (Scheme 5).16
analysis
after
an
oxidation
sequence
(see
Supporting Information). To probe the efficiency of this catalytic
system, we also carried out the enantioselective C(sp3)–H
borylation in the presence of 5 mol% of Pd(CH3CN)4(OTf)2 and 15
mol% of (S,R)-L4, which provided the desired products (2d, 2f, and
2k) in 52–60% yield and 97.2–99.2% ee.
Under similar reaction conditions using (S,R)-L5 as the optimal
ligand, cyclopropanecarboxylic amide 3 was borylated in 32%
yield and 95.2% ee, while an unexpected diborylated product 4 was
also obtained in 20% isolated yield. Pd(CH3CN)4(OTf)2 was found
to promote the side product formation, but the detailed reaction
mechanism remains to be exploited. In the borylation of
cyclohexane and gem-dimethyl substrates (5a–5c and 7), (S,S)-
APAO ligands were substantially more effective than their (S,R)-
Scheme 3. Enantioselective C(sp3)–H Borylation of Other
Cyclic and Acyclic Amides
Scheme 4. Synthetic Applications of Enantioselective C(sp3)–H
Borylation
Scheme 5. Removal of the Amide Auxiliary
In summary, we have developed enantioselective C(sp3)–H
borylation of weakly coordinating carboxylic amides via a
Pd(II)/Pd(0) catalytic cycle. Pivotal to the success of this
asymmetric catalysis was the use of chiral bidentate APAO ligands.
This reaction is compatible with carbocyclic substrates containing
α-tertiary as well as α-quaternary carbon centers. The borylated
products can be converted into various chiral β-hydroxylated, β-
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effective chiral bidentate ligands to enable highly enantioselective
borylation of gem-dimethyl C(sp3)–H bonds is currently underway
in our laboratory.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and spectral data for all new compounds
(PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
AURHOR INFORMATION
Corresponding Author
*yu200@scripps.edu
Author Contributions
†Q.S. and Q.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
We gratefully acknowledge The Scripps Research Institute and the
NIH (NIGMS, 2R01GM084019) for financial support.
(16) He, J.; Li, S.; Deng, Y.; Fu, H.; Laforteza, B. N.; Spangler, J. E.; Homs, A.;
Yu, J.-Q. Science 2014, 343, 1216.
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Maleczka, R. E. Jr.; Smith, M. R. III. Science 2002, 295, 305.
(11) For representative examples of transition-metal-catalyzed non-directed
C(sp3)–H borylation, see: (a) Chen, H.; Hartwig, J. F. Angew. Chem., Int.
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