Enantioselective, Palladium-Catalyzed Conjugate Additions of Arylboronic Acids to Form Bis-benzylic Quaternary Stereocenters

Article abstract of DOI:10.1021/acs.orglett.7b01825

We report enantioselective, palladium-catalyzed conjugate additions of arylboronic acids to β-aryl, β,β-disubstituted enones to generate ketones containing bis-benzylic quaternary stereocenters. A catalyst generated from palladium trifluoroacetate and (S)-4-tert-butyl-2-(2-pyridyl)oxazoline ligand ((S)-t-BuPyOx) promotes conjugate additions of a wide range of arylboronic acids to a variety of β-aryl, β,β-disubstituted enones. Iterative addition of the arylboronic acid to minimize undesired protodeboronation pathways leads to efficient formation of the corresponding ketones containing bis-benzylic quaternary stereocenters in up to 92% yield and up to 93% enantioselectivity.

Full text of DOI:10.1021/acs.orglett.7b01825

Letter
pubs.acs.org/OrgLett
Enantioselective, Palladium-Catalyzed Conjugate Additions of
Arylboronic Acids to Form Bis-benzylic Quaternary Stereocenters
Abhishek A. Kadam, Arkady Ellern, and Levi M. Stanley*
Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
S
* Supporting Information
ABSTRACT: We report enantioselective, palladium-catalyzed
conjugate additions of arylboronic acids to β-aryl, β,β-
disubstituted enones to generate ketones containing bis-benzylic
quaternary stereocenters. A catalyst generated from palladium
trifluoroacetate and (S)-4-tert-butyl-2-(2-pyridyl)oxazoline li-
gand ((S)-t-BuPyOx) promotes conjugate additions of a wide
range of arylboronic acids to a variety of β-aryl, β,β-disubstituted enones. Iterative addition of the arylboronic acid to minimize
undesired protodeboronation pathways leads to efficient formation of the corresponding ketones containing bis-benzylic
quaternary stereocenters in up to 92% yield and up to 93% enantioselectivity.
ompounds containing bis-benzylic quaternary centers are
present in an array of biologically active compounds1
(Figure 1) and are a structural motif found in the cardo class of
organometallic nucleophiles to β-aryl β,β-disubstituted enones to
generate compounds containing bis-benzylic quaternary stereo-
centers are limited to copper-catalyzed additions to acyclic
electrophiles.
C
In 2013, Hoveyda and co-workers reported copper-catalyzed
conjugate additions of arylaluminum compounds to β-aryl β,β-
disubstituted acyclic enones to form acyclic ketones containing
bis-benzylic quaternary stereocenters with good-to-excellent
enantioselectivity (Scheme 1A).5c In this report, however,
Scheme 1. Enantioselective, Conjugate Additions of Aryl
Nucleophiles to β-Aryl β,β-Disubstituted Enones
Figure 1. Biologically active compounds containing bis-benzylic
quaternary centers.
polymers.2 Enantioselective, transition metal-catalyzed conju-
gate addition reactions of organometallic nucleophiles to β,β-
disubstituted enones are a powerful approach to form quaternary
stereocenters.3 Despite recent advances in enantioselective,
transition metal-catalyzed conjugate additions of organometallic
nucleophiles, asymmetric additions to β-aryl β,β-disubstituted
enones to form bis-benzylic quaternary stereocenters remain
challenging.
Over the past decades, enantioselective conjugate additions of
arylzinc,4 arylaluminum,5 arylmagnesium,6 and arylboron7
nucleophiles to β,β-disubstituted enones in the presence of
chiral copper, rhodium, and palladium catalysts have been
developed as practical methods to synthesize compounds
containing benzylic quaternary stereocenters. In particular,
Stoltz and co-workers developed enantioselective conjugate
additions of arylboronic acids to a variety of β-substituted cyclic
enones to form quaternary stereocenters in the presence of
Pd(II) complexes of a chiral, nonracemic pyridine-oxazoline
ligand ((S)-t-BuPyOx).7d,f,h−k However, examples of enantiose-
lective, transition metal-catalyzed conjugate additions of aryl
there are no examples of additions of arylaluminum nucleophiles
to β-aryl β,β-disubstituted cyclic enones. In addition, these
copper-catalyzed conjugate addition reactions use air and
moisture sensitive arylaluminum nucleophiles and have low
functional group compatibility.
We recently reported palladium-catalyzed conjugate additions
of bench stable and commercially available arylboronic acids to
β,β-disubstituted enones in aqueous media to form an array of
ketones with bis-benzylic quaternary centers in moderate-to-high
yields (54−74%).8,9 However, efforts from our group and others
Received: June 15, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01825
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
to develop enantioselective variants of these reactions have been
limited by modest enantioselectivity in aqueous media, poor
reactivity in organic solvents,7i and competing decomposition of
the arylboronic acid nucleophile. We now report catalytic,
enantioselective additions of arylboronic acids to β-aryl β,β-
disubstituted cyclic enones that occur in up to 92% yield with
high enantioselectivity and minimize undesired pathways for
nucleophile decomposition (Scheme 1B).
Early efforts to identify an enantioselective catalyst for
conjugate addition of phenylboronic acid to 3-(4-methoxyphen-
yl)-cyclohexen-2-one in aqueous reaction media led to modest
yields of the corresponding ketone product and relatively low
enantioselectivity (see Table S1 in the Supporting Information).
After an initial evaluation of palladium(II) catalysts generated
from chiral, nonracemic pyridine-oxazoline and bisoxazoline
ligands, we identified reactions conducted in 1,2-dichloroethane
and a catalyst generated in situ from palladium trifluoroacetate
(Pd(TFA)2) and (S)-t-BuPyOx7k as leads for further reaction
optimization.7d,f,h−k
have hindered the development of conjugate additions to form
bis-benzylic quaternary stereocenters. The addition of 4 equiv of
4-tolylboronic acid to 1a led to protodeboronation of 43% of the
total tolylboronic acid, formation of 2% of the homocoupling
byproduct 4,4′-dimethyl-1,1′-biphenyl, and oxidation of 1a to
form 4% 3-(4-methoxyphenyl)phenol. When the model reaction
was conducted with 1 equiv of 4-tolylboronic acid, the reaction
generated 2a in 45% yield and 89% ee. The formation of 25%
toluene through protodeboronation and small amounts (<5%) of
4,4′-dimethyl-1,1′-biphenyl and 3-(4-methoxyphenyl)-phenol
were also observed.
The absolute configuration of ketone 2a was determined after
conversion to the corresponding 2,4-dinitrophenylhydrazone.
The absolute configuration was determined to be 3S by X-ray
crystallographic analysis (see the SI for details).
We next studied the impact of reaction temperature on the
relative rate of protodeboronation to conjugate addition (Table
1, entries 2−5). The amount of toluene generated decreases with
lower reaction temperature. The best ratios of ketone 2a/toluene
3a (4.2−4.7:1) are observed at 60−80 °C, and the reactions
generate 2a in 42% yield and 89−91% ee (entries 3−4).
Increasing the reaction time (entry 6) and the reaction
concentration (entry 7) led to modest improvement in the
yield of 2a without increasing the rate of protodeboronation. To
increase the yield of 2a, we adopted an iterative addition strategy
to maintain low concentrations of tolylboronic acid and hence a
low rate of protodeboronation (entries 8−11). These reactions
were conducted by starting the reaction with 1 equiv of 4-
tolylboronic acid and adding additional equivalent(s) at 3 or 6 h
intervals. This approach to arylboronic acid addition led to
significantly higher yields of ketone 2a (64−83%) and high
enantioselectivities without a dramatic increase in the rate of
protodeboronation. The model reaction occurs to form 2a with
similar yields and enantioselectivities in the presence and absence
of 2,6-di-tert-butylpyridine (compare entries 11 and 12)
suggesting that residual TFA is not required for product
formation. We chose to evaluate the scope of the conjugate
addition reaction using the conditions in entry 11 as a practical
combination of reactivity, enantioselectivity, and relative rates of
productive versus unproductive reaction pathways.
Studies to establish the scope of additions of a variety of
arylboronic acids to 3-(4-methoxyphenyl)-cyclohex-2-enone 1a
are summarized in Scheme 2. Additions of electronically diverse,
para- and meta-substituted arylboronic acids occurred to
generate the corresponding ketone products 2a−2k in 18−
92% yields with 82−91% enantioselectivities. Additions of para-
substituted electron-rich, electron-neutral, and halogenated
arylboronic acids to 1a formed ketones 2a−2e in moderate-to-
high yields (49−92%) with high enantioselectivities (82−91%
ee). However, the addition of electron-deficient arylboronic
acids, which are less nucleophilic, generated 2f and 2g in 39% and
38% yields. Additions of electron-rich meta-substituted arylbor-
onic acids to 1a formed 2h and 2i in 60% and 88% yield with 90%
ee. In contrast, additions of meta- and ortho-halogenated
arylboronic acids generate ketones 2j−2l in low yields but with
good enantioselectivities (81−84% ee).
We then selected the addition of 4-tolylboronic acid to 3-(4-
methoxyphenyl)-cyclohex-2-enone 1a in the presence of 5 mol %
of the catalyst generated from Pd(TFA)2 and (S)-t-BuPyOx as a
model reaction (Table 1) that would facilitate straightforward
a
Table 1. Identification of Reaction Conditions
b
c
d
entry
temp (°C)
x
yield 2a (%)
yield 3a (%)
ee (%)
e
1
90
90
80
60
40
60
60
60
60
60
80
80
4
1
1
1
1
1
1
2
3
3
3
3
46
45
42
42
24
49
55
70
82
64
83
80
43
25
10
9
89
89
89
91
94
91
92
91
91
91
89
87
2
3
4
5
6
f
6
10
12
11
14
9
f g
7 ,
g
,
,
h
h
8
9
g
g
g
g
,
,
,
i
i
i
10
11
12
21
,
j
k
nd
a
Reaction conditions: 1a (1.0 equiv), 4-tolylboronic acid (x equiv)
Pd(TFA)2 (5 mol %), (S)-t-BuPyOx (6 mol %), 1,2-dichloroethane
b
c
(0.5 M), 3 h. Isolated yields. GC yield, calculated based on the total
number of equiv of 4-tolylboronic acid. Determined by chiral HPLC
d
e
f
g
analysis. Reaction time = 24 h. Reaction time = 6 h. [1a] = 2 M.
h
i
Addition of 4-tolylboronic at 6 h intervals. Addition of 4-tolylboronic
j
at 3 h intervals. Reaction run in the presence of 10 mol % 2,6-di-tert-
butylpyridine. nd = not determined.
k
These reactions also encompass additions of a variety of di-
and trisubstituted arylboronic acids. The corresponding ketone
products 2m−2q are generated in moderate-to-good yields (36−
67%) with good-to-high enantioselectivities (78−90%). How-
ever, additions of 2-methoxyphenylboronic acid, 3-furylboronic
acid, and 6-indolylboronic acid, which are more susceptible to
protodeboronation,10a,11 were unsuccessful.
analysis of reaction products and byproducts. The addition of 4
equiv of 4-tolyboronic acid to 1a at 90 °C formed 3-(4-
methoxyphenyl)-3-(4-tolyl)cyclohexanone 2a in 46% yield with
89% ee (entry 1). Palladium-catalyzed conjugate additions of
arylboronic acids are often plagued by protodeboronation
reactions that can occur through multiple pathways7g,10 and
B
DOI: 10.1021/acs.orglett.7b01825
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Enantioselective, Pd-Catalyzed Conjugate
Additions of Arylboronic Acids to 1a
Scheme 3. Enantioselective Pd-Catalyzed Conjugate
a
Additions of Arylboronic Acids to β-Aryl β,β-Disubstituted
a
Enones
a
Reaction conditions: 1a (1.0 equiv), arylboronic acid (3.0 equiv),
Pd(TFA)2 (10 mol %), (S)-t-BuPyOx (12 mol %), 1,2-dichloroethane
b
(2 M). Reaction run in the presence of 5 mol % of the palladium
c
catalyst. Values in parentheses are for a 1.00 mmol scale experiment
a
Reaction conditions: 3-arylcyclohex-2-enone (1.0 equiv), arylboronic
d
in the presence of 5 equiv of water. Reaction performed in the
acid (3.0 equiv), Pd(TFA)2 (10 mol %), (S)-t-BuPyOx (12 mol %),
1,2-dichloroethane (2 M). Reaction performed in the presence of 5
presence of 5 equiv of water.
b
equiv of water.
To further expand the scope of these reactions, we studied
additions of arylboronic acids to a variety of β-aryl β,β-
disubstituted enones. These results are summarized in Scheme
3. Additions of 4-tolylboronic acid to 3-arylcyclohex-2-enones
containing electron-neutral, halogenated, electron-deficient, and
electron-rich aryl groups generated 2r−2v in moderate-to-good
yields (36−74%) with high enantioselectivities (87−93%). The
additions of 4-tolylboronic acid to β,β-disubstituted enones
containing either an ortho-substituted aryl unit or a heteroarene
enables the formation of ketones 2w and 2x, products that cannot
be formed by addition of the corresponding ortho-substituted
arylboronic acid or heteroarylboronic acid. To demonstrate the
addition of meta-substituted arylboronic acids to an additional
enone, we conducted the reaction of 3-methylphenylboronic acid
with 3-phenylcyclohex-2-enone to generate 2y in 76% yield with
88% ee. The addition of phenylboronic acid to 3-(4-
methylphenyl)cyclohex-2-enone and 4-methoxyphenylboronic
acid to 3-phenylcyclohex-2-enone generated (ent)-2r and (ent)-
2b in 40−77% yield and 80−88% ee. We also studied the
addition of 4-tolylboronic acid to cyclic enones with different
ring sizes and to an acyclic enone. Addition of 4-tolylboronic acid
to 3-(4-methoxyphenyl)cyclopent-2-enone generated 2z in 60%
yield and 91% ee. However, addition of 4-tolylboronic acid to 3-
phenylcyclohept-2-enone and (E)-4-phenylpent-3-en-2-one
generated the corresponding ketone products in less than 15%
yield.
arylboronic acids to β-aryl β,β-disubstituted cyclic enones. A
catalyst generated in situ from Pd(TFA)2 and (S)-t-BuPyOx
catalyzes enantioselective conjugate additions of electronically
and structurally diverse arylboronic acids to a variety of β-aryl
β,β-disubstituted enones. These reactions generate cyclic ketone
products containing bis-benzylic quaternary carbon stereo-
centers in up to 92% yield and up to 93% ee by iterative addition
of the arylboronic acid nucleophile to minimize protodeborona-
tion.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01825.
Experimental procedures, characterization data, NMR
spectra, and HPLC traces for new compounds (PDF)
Crystallographic data (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: lstanley@iastate.edu.
ORCID
In summary, we have developed the first examples of
enantioselective, palladium-catalyzed conjugate additions of
Levi M. Stanley: 0000-0001-8804-1146
C
DOI: 10.1021/acs.orglett.7b01825
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Funding
Letter
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We thank the Research Corporation for Science Advancement,
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank Dr. Ryan Van Zeeland (Alcami Corporation) for
valuable discussions related to this study.
■
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DOI: 10.1021/acs.orglett.7b01825
Org. Lett. XXXX, XXX, XXX−XXX