Enantioselective 1,1-arylborylation of alkenes: Merging chiral anion phase transfer with pd catalysis

Article abstract of DOI:10.1021/jacs.5b00344

A palladium-catalyzed three-component coupling of α-olefins, aryldiazonium salts, and bis(pinacolato)diboron affords direct access to chiral benzylic boronic esters. This process is rendered highly enantioselective using an unprecedented example of cooperative chiral anion phase transfer and transition-metal catalysis.

Full text of DOI:10.1021/jacs.5b00344

Communication
pubs.acs.org/JACS
Enantioselective 1,1-Arylborylation of Alkenes: Merging Chiral Anion
Phase Transfer with Pd Catalysis
Hosea M. Nelson,‡ Brett D. Williams,‡ Javier Miro, and F. Dean Toste*
́
Department of Chemistry, University of California, Berkeley, California 94720, United States
Chemical Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, California 94720, United States
S
* Supporting Information
ABSTRACT: A palladium-catalyzed three-component
coupling of α-olefins, aryldiazonium salts, and bis-
(pinacolato)diboron affords direct access to chiral benzylic
boronic esters. This process is rendered highly enantiose-
lective using an unprecedented example of cooperative
chiral anion phase transfer and transition-metal catalysis.
enzylic boronic esters are attractive building blocks for
complex biologically active natural products and pharma-
B
ceuticals as they participate in several well-established stereo-
specific transformations that forge C−O, C−N, or C−C
bonds.1 Accordingly, there has been significant interest in
developing new enantioselective methods that afford these
motifs. Examples of catalytic enantioselective hydroboration,2
allylic borylation,3 conjugate borylation,4 reductive trans-
formations of vinyl boronates5 and 1,2-diborylation of aromatic
imines and styrenes have been reported.6 Furthermore, several
enantioselective borylation reactions utilizing stoichiometric
amounts of chiral auxiliaries have been disclosed.7 Recently,
several methods have been reported that rely on trans-
formations of 1,1-diborylated alkanes. For example, Hall8 and
Yun9 have reported the preparation of enantioenriched 1,1-
diborylated alkanes that undergo chemoselective coupling to
provide highly enantioenriched benzylic organoboronates
(Figures 1a and 1b). In a related contribution, Morken and
co-workers have disclosed an enantioselective Suzuki reaction
of 1,1-diboronates to provide highly enriched boronic esters
(Figure 1c).10 While these methods ultimately access valuable
enantioenriched benzylic boronates, they require a multistep
synthetic sequence. From the perspective of synthetic
divergence and step-economy, an ideal transformation would
involve one-step installation of both the boronate and aryl
functional groups (Figure 1d).
Figure 1. Recent examples of multistep enantioselective 1,1-
arylborylation by (a) Hall and co-workers, (b) Yun and co-workers,
(c) Morken and co-workers, and (d) the single-step 1,1-arylborylation
reported herein. dan = 1,8-diaminonaphthalene; pin = pinacolato.
continuous Coulombic attraction between the chiral anion and
a cationic metal center, we hypothesized that a chiral anion
phase-transfer (CAPT) strategy13−15 could enable association
of a chiral anion with the key cationic Pd(II) intermediates
involved in the enantiodetermining step. In this scenario, an
insoluble aryldiazonium salt (11, Figure 2) would undergo
phase transfer to provide soluble, chiral ion pair 12.16,17
Oxidative addition of the Pd(0) species followed by migratory
insertion of the olefinic coupling partner would yield chiral Pd
complex 14. Sequential β-hydride elimination and reinsertion
steps would yield enantioenriched benzylic Pd complex 15 that
is poised to undergo transmetalation and subsequent reductive
elimination to provide the desired benzylic boronic ester.
Importantly, the non-cationic Pd(0) species generated in this
process can be reoxidized by soluble diazonium chiral ion pair
12 to regenerate the chiral Pd(II) species 13. In this
Communication we report the successful execution of this
methodological hypothesis through the single-step 1,1-arylbor-
Inspired by seminal examples of Pd-catalyzed 1,1-diarylation
from Sigman and co-workers,11,12 we envisioned direct
formation of 1,1-arylborylated products (9) from unactivated
olefins (7) via a three-component Heck−Matsuda arylation/
Miyuara borylation cascade reaction (Figure 1d). In these initial
reports, efficient 1,1-difunctionalization required “ligand-free”
conditions, as efforts to induce enantioselectivity through
application of chiral ligands attenuated the desired three-
component reaction pathway.12 Cognizant of this limitation, we
were intrigued by the possibility of providing enantioinduction
via a chiral ion-pairing strategy. While the intermediacy of non-
cationic Pd(0) species presented a challenge due to the lack of
Received: January 12, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b00344
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
Table 2. Optimization of Enantioselective 1,1-
a b
,
Arylborylation
entry
cat.
solvent
base
additive ee (%) yield (%)
1
2
3
4
5
6
7
8
9
28
28
28
29
27
27
27
27
27
hexanes
THF
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
−
−
−
−
−
−
−
30a
−
<5
72
45
14
25
25
26
40
39
<5
33
<5
88
94
93
70
90
Figure 2. Proposed dual catalytic cycle for Pd-CAPT 1,1-
arylborylation.
Na3PO4
Na3PO4
Na3PO4
30b
a b
,
a
b
Table 1. Non-enantioselective Scope
Enantiomeric excess determined by chiral phase HPLC. Yield
determined by 1H NMR utilizing dimethyl sulfone as an internal
standard.
Given the lack of precedent for this transformation, we
sought to provide proof-of-principle with the development of a
non-stereoselective 1,1-arylborylation of α-olefins. We were
pleased to find that a room-temperature THF suspension of
catalytic Pd2(dba)3, phenyldiazonium tetrafluoroborate, allyl
methyl carbonate, and bis(pinacolato)diboron smoothly
provided racemic boronate 16 in 72% yield (Table 1). Both
electron-rich (17) and electron-poor aryldiazonium salts (18)
proved competent in the transformation of allyl methyl
carbonate to provide boronic esters 17 and 18 in 90% and
71% yield, respectively. Use of ortho-substituted aryldiazonium
cations also provided the product in good yield (19). Notably,
utilization of homoallylic carbonates (20), as well as protected
allylic amines, furnished the borylated products in good to
excellent yields (21,22). Further, a nitrile-substituted substrate
underwent smooth arylborylation in 99% yield, demonstrating
that substrates containing chelating groups did not impede the
reaction (23). As an important demonstration of scope,
electron poor alkenes were also effective under our reaction
conditions, providing the arylborylated products 24−26, albeit
in diminished yields.18
Having provided proof-of-principle for a single-step 1,1-
arylborylation reaction, we began work toward rendering the
process enantioselective via CAPT. Utilizing allyl methyl
carbonate and phenyldiazonium tetrafluoroborate, an extensive
study of reaction conditions was undertaken. In initial
experiments, nonpolar solvents such as hexanes provided
poor conversion (Table 2, entry 1), while THF allowed for
excellent conversion albeit with poor enantioselectivity (entry
2). Et2O was identified as optimal, furnishing the product in
33% ee and 45% yield (entry 3).19 Examination of commonly
employed CAPT catalysts (27−29) identified TCyP (27) as
superior in terms of enantioselectivity, providing the desired
product in 88% ee (entry 5). Further, Na3PO4 provided the
a
Conditions: ArN2BF4 (1 equiv), B2(pin)2 (1.2 equiv), Pd2(dba)3
b
(0.025 equiv), alkene (1 equiv), THF, 25 °C, 2−8 h. Isolated yields.
c
NMR yield.
ylation of α-olefins, with high levels of enantioselectivity
achieved via implementation of a CAPT strategy.
B
DOI: 10.1021/jacs.5b00344
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
a b
,
synthetically useful yields and good to excellent enantioselec-
tivities (Table 3a, 32 and 33). Alkyl substitution of the para- or
meta-positions also provided highly enantioenriched benzylic
boronic ester products (34−37). Finally, substitution with a
vinyl group at the para-position afforded enriched boronic ester
(38) in 40% yield and 98% ee.
Table 3. Enantioselective Scope
In addition to protected allylic alcohols, α,β-unsaturated
esters were utilized as an alternative olefinic precursor for the
enantioselective transformation (Table 3b). Notably, use of m-
CF3-dba (30b) was not required to achieve useful yields and
high enantioselectivities with acrylate coupling partners.
Utilization of phenyldiazonium tetrafluoroborate allowed for
formation of β,β-arylborylated ester 40 in 47% yield and 89%
ee. The aryl moiety of the diazonium salt was tolerant of
substitution of the para-position with heteroatom or alkyl
functional groups, providing a variety of β,β-arylborylated esters
in synthetically useful yields and excellent enantioselectivities
(41−44).
In conclusion, we have disclosed a modular and step-
economical method for the direct preparation of chiral benzylic
boronates from terminal alkenes. Furthermore, this process was
rendered enantioselective through the use of a chiral anion
phase-transfer strategy. We expect the coupling of CAPT and
Pd catalysis to have broad implications, as it provides an
alternative strategy for achieving enantioinduction in “ligand-
less” reaction manifolds where chiral ancillary ligands have a
deleterious effect.22
ASSOCIATED CONTENT
* Supporting Information
Procedures and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
*fdtoste@berkeley.edu
■
Author Contributions
‡H.M.N. and B.D.W. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the NIGMS (R01 GM104534) for
financial support. We acknowledge Prof. Matthew Sigman for
useful discussions and experimental advice. H.M.N. also
acknowledges the UNCF and Merck for generous funding.
J.M. thanks the University of Valencia for a predoctoral
fellowship.
a
b
Enantiomeric excess determined by chiral phase HPLC. Yield
determined by 1H NMR utilizing dimethyl sulfone as an internal
standard.
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D
DOI: 10.1021/jacs.5b00344
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX