Accessing Both Retention and Inversion Pathways in Stereospecific, Nickel-Catalyzed Miyaura Borylations of Allylic Pivalates

Article abstract of DOI:10.1021/jacs.6b07396

We have developed a stereospecific, nickel-catalyzed Miyaura borylation of allylic pivalates, which delivers highly enantioenriched α-stereogenic γ-aryl allylboronates with good yields and regioselectivities. Our complementary sets of conditions enable access to either enantiomer of allylboronate product from a single enantiomer of readily prepared allylic pivalate substrate. Excellent functional group tolerance, yields, regioselectivities, and stereochemical fidelities are observed. The stereochemical switch from stereoretention to stereoinversion largely depends upon solvent and can be explained by competitive pathways for the oxidative addition step. Our mechanistic investigations support a stereoretentive pathway stemming from a directed oxidative addition and a stereoinvertive pathway that is dominant when MeCN blocks coordination of the directing group by binding the nickel catalyst.

Full text of DOI:10.1021/jacs.6b07396

Article
pubs.acs.org/JACS
Accessing Both Retention and Inversion Pathways in Stereospecific,
Nickel-Catalyzed Miyaura Borylations of Allylic Pivalates
Qi Zhou,†,‡ Harathi D. Srinivas,‡,§ Songnan Zhang, and Mary P. Watson*
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, United States
S
* Supporting Information
ABSTRACT: We have developed a stereospecific, nickel-
catalyzed Miyaura borylation of allylic pivalates, which delivers
highly enantioenriched α-stereogenic γ-aryl allylboronates with
good yields and regioselectivities. Our complementary sets of
conditions enable access to either enantiomer of allylboronate
product from a single enantiomer of readily prepared allylic
pivalate substrate. Excellent functional group tolerance, yields,
regioselectivities, and stereochemical fidelities are observed. The stereochemical switch from stereoretention to stereoinversion
largely depends upon solvent and can be explained by competitive pathways for the oxidative addition step. Our mechanistic
investigations support a stereoretentive pathway stemming from a directed oxidative addition and a stereoinvertive pathway that
is dominant when MeCN blocks coordination of the directing group by binding the nickel catalyst.
with allylic transposition.2d,6 These powerful allylic trans-
position reactions make such allylic boronates highly valuable
intermediates.
INTRODUCTION
■
α-Stereogenic allylic boronates are powerful synthetic inter-
mediates.1 Allylic transposition reactions of these versatile
Given their utility, it is not surprising that robust methods
molecules enable construction of C−C bonds with exquisite
have been developed to prepare these highly useful compounds.
control over product stereochemistry.2 In particular, allylbora-
Matteson homologations and related reactions enable access to
tion of aldehydes and imines gives rise to homoallylic alcohols
a wide range of enantioenriched allylic boronates.2f,h,7 However,
and amines that have found wide use in the preparation of
these routes require use of Grignard or lithium reagents, and
natural products, pharmaceuticals, and other bioactive com-
typically stoichiometric chiral agents. Although alternative
pounds. As illustrated by the examples in Figure 1, numerous
methods, including catalytic variants, have been developed for
bioactive molecules contain a homobenzylic alcohol or amine
fragment,3 which are accessible via aldehyde or imine
the preparation of α-stereogenic allylic boronates with terminal
alkenes,8,5 relatively few catalytic methods for the preparation
hydroboration using α-stereogenic γ-aryl allylic
boronates.2d,i,4,5 α-Stereogenic γ-substituted allylic boronates
of enantioenriched γ-substituted α-stereogenic allylic boronates
have been reported. The majority of these methods deliver only
can also be elaborated to a range of arylated products via
γ-alkyl allylic boronates.9 Most closely related to this report, Ito,
stereospecific palladium-catalyzed cross-couplings that occur
Kawakami, and Sawamura have elegantly demonstrated a
stereospecific, copper-catalyzed borylation of allylic carbonates
to deliver highly enantioenriched γ-alkyl allylic boronates
(Scheme 1A),9a but such methodology is absent for the
preparation of γ-aryl allylic boronates. Only three catalytic
methods deliver enantioenriched γ-aryl allylic boronates, all of
which rely on 1,3-dienes as substrates and have limited scope in
the preparation of γ-aryl products (Scheme 1B).4a,9b,10
Given these limitations, as well as the high synthetic value of
these γ-aryl allylic boronates, we endeavored to develop an
efficient, catalytic route to their preparation. We recently
developed a stereospecific, nickel-catalyzed arylation of γ-aryl
allylic pivalates11 and envisioned that such a strategy may
enable a stereospecific Miyaura borylation to deliver γ-aryl α-
stereogenic allylic boronates.12 Herein, we report the successful
development of a stereospecific borylation of allylic pivalates to
Received: July 22, 2016
Figure 1. Bioactive homobenzylic alcohol and amine derivatives.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.6b07396
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Article
a
Scheme 1. Catalytic Preparation of Enantioenriched α-
Stereogenic γ-Substituted Allylic Boronates
Table 1. Optimization of Stereoinvertive Borylation
b
b
c
d
entry
mol % [Ni]
yield (%)
α/γ
ee (%)
es (%)
1
2
5
2
93
94
11:1
18:1
83
86
85
88
a
Conditions: 1a (98% ee, 0.2 mmol, 1.0 equiv), B2pin2 (2.0 equiv),
Ni(cod)2, BnPPh2 (ratio of Ni(cod)2/BnPPh2 = 1:2.2), K3PO4 (2.0
b
1
equiv), MeCN (0.4 M), rt, 24 h. Determined by H NMR analysis
using 1,3,5-trimethoxybenzene as internal standard. ee’s of the
c
subsequent alcohol (3a), formed via oxidation with H2O2 and
NaOH. Determined by high-performance liquid chromatography
d
(HPLC) analysis using a chiral stationary phase. es = eeproduct
/
eestarting material
.
configuration (Table 2, entry 1). To obtain high levels of
stereochemical fidelity with retention of configuration,
a
Table 2. Optimization of Stereoretentive Borylation
b
b
c
d
entry
ligand (mol %)
yield (%)
α/γ
ee (%) es (%)
e
1
BnPPh2 (11)
89
90
95
55
99
>20:1
>20:1
>20:1
>20:1
>20:1
49
94
95
75
95
50
96
97
77
97
2
3
4
5
P(o-Tol)3 (4.4)
t-BuXPhos (4.4)
dppb (2.2)
t-BuXantPhos (2.2)
deliver highly enantioenriched α-stereogenic γ-aryl allylic
boronates (Scheme 1C). This method harnesses readily
prepared, enantioenriched secondary allylic alcohol derivatives
to deliver a wide range of γ-aryl allylic boronates with broad
functional group tolerance. Excitingly, largely by optimization
of reaction solvent, we discovered complementary conditions
that result in either stereoinversion or stereoretention, thereby
enabling efficient access to either enantiomer of allylic boronate
product from a single enantiomer of starting material.13 Our
mechanistic investigations suggest that the primary role of
solvent over the stereochemical outcome stems from a dual role
of MeCN as both solvent and ligand.14
a
1a (98% ee, 0.2 mmol, 1.0 equiv), B2pin2 (2.0 equiv), Ni(cod)2,
b
ligand, K3PO4 (2.0 equiv), PhMe (0.4 M), rt, 24 h. Determined by 1H
NMR analysis using 1,3,5-trimethoxybenzene as internal standard.
c
ee’s of the subsequent alcohol (3a), formed via oxidation with H2O2
and NaOH. Determined by HPLC analysis using a chiral stationary
phase. es = eeproduct/eestarting material. 5 mol % Ni(cod)2.
d
e
optimization of the ligand proved critical. Use of P(o-Tol)3
resulted in high yield and a dramatic increase in stereochemical
fidelity (entry 2). However, the small amount of remaining
pivalate 1a proved difficult to separate from allylic boronate 2a.
To enable effective purification of boronate 2, we further
optimized the ligand to achieve quantitative conversion. t-
BuXPhos provided some increase in yield (entry 3), but t-
BuXantPhos proved superior, delivering nearly quantitative
yield of 2a (entry 5). Notably, other bidentate ligands proved
inferior (e.g., entry 4).
A wide range of γ-aryl allylic pivalates underwent borylation
under both sets of conditions (Scheme 2). In general, the
regioselectivity and stereochemical fidelity were slightly higher
under the stereoretentive conditions (e.g., 2a). However,
synthetically useful yields, regioselectivities, and stereospecific-
ities were generally observed under both sets of conditions with
each substrate. Borylation of 1a proceeded to give high isolated
yields of boronate 2a. Further, this reaction was performed on a
5 mmol scale with nearly identical yield, regioselectivity, and
stereochemical fidelity. A variety of functional groups were well-
tolerated on the γ-aryl substituent, including thioether (2c),
fluoro (2d), chloro (2e), and ether (2f). Products with both
electron-rich (2b, 2c, 2g, 2i, and 2j) and electron-poor (2d−2f)
RESULTS AND DISCUSSION
■
We began by examining the borylation of pivalate 1a. Such
pivalates are derived from allylic alcohol precursors, which are
readily prepared in high enantiomeric excess via either CBS
reduction or kinetic resolution.15 Using conditions similar to
the optimal conditions for the stereospecific allylic arylation
(Ni(cod)2, BnPPh2, K3PO4, and MeCN), high yield and
stereochemical fidelity were observed in the borylation (Table
1, entry 1). Consistent with the arylation, the major product
resulted from inversion of absolute configuration. Optimization
of these conditions revealed that reduction of the catalyst
loading to 2 mol % Ni(cod)2 and 4.4 mol % BnPPh2 led to
similar yields with slightly higher regioselectivity and
enantiospecificity (entry 2).
However, when PhMe replaced MeCN as solvent, a
remarkable switch in stereospecificity was observed; the major
product was formed in 49% ee via retention of absolute
B
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a
Scheme 2. Scope of Allylic Borylation
a
Retention conditions: 1 (0.4 mmol, 1.0 equiv), B2pin2 (2.0 equiv), Ni(cod)2 (2 mol %), t-Bu-XantPhos (2.2 mol %), K3PO4 (2.0 equiv), PhMe (0.4
M), rt, 24 h. Inversion Conditions: 1 (0.4 mmol, 1.0 equiv), B2pin2 (2.0 equiv), Ni(cod)2 (2 mol %), BnPPh2 (4.4 mol %), K3PO4 (2.0 equiv),
1
MeCN (0.4 M), rt, 32 h. Average isolated yields, α/γ ratios (determined by H NMR of isolated allylic boronates 2), and ee’s (of the subsequent
b
alcohol 3 formed via oxidation with H2O2 and NaOH, determined by HPLC analysis using a chiral stationary phase) of two duplicate runs. Five
c
d
e
mmol scale, single experiment. Five mol % Ni(cod)2, 11 mol % BnPPh2. Five mol % Ni(cod)2, 5.5 mol % t-Bu-XantPhos. Single experiment.
f
g
h
i
Scale: 0.3 mmol. Forty °C. Ratio of subsequent alcohol (3p). ee of p-nitrobenzoate of alcohol 3p.
aryl substituents were formed in high yields, regioselectivities,
and ee’s. In addition, pivalates with sterically bulky o-tolyl (2g),
as well as 2-naphthyl (2h), substituents reacted well. Heteroaryl
groups can also be incorporated. Under stereoretentive
conditions, both benzothiofuran 2i and furan 2j were formed
in excellent regioselectivity and high es’s, albeit in somewhat
lower yields. Under stereoinvertive conditions, however, the
yields of these heteroaryl products, as well as the stereo-
chemical fidelity of furan 2j, were diminished. With respect to
the alkyl substituent (R in Scheme 2), high yields and
stereochemical fidelity were observed with increased steric
hindrance (Et and i-Pr, 2k and 2l). However, lower
regioselectivity was observed, particularly in the formation of
2l. Boronates with both phenethyl (2m) and allylic (2n) groups
were prepared in high yields. Notably, borylation of allyl-
substituted 1n resulted in lower levels of stereochemical fidelity
(77 and 88% ee), whereas prenol 1o reacted to give 2o in much
higher levels of stereochemical fidelity. This contrast suggests
that the vinyl group of 1n may bind to the nickel catalyst,
changing the mechanism of the stereospecific reaction and/or
accelerating an epimerization pathway. In addition to γ-aryl
allylic boronates, this method can be used to prepare γ-alkyl
allylic boronates in high yields, regioselectivities, and
enantiopurities, as long as there is a significant steric difference
between the α- and γ-alkyl substituents. For example,
cyclohexyl-substituted allylic boronate 2p was formed in 90%
yield, 13:1 regioselectivity, and 91% es under the stereo-
retentive conditions.
In addition to the wide scope in the pivalate partner, various
diboranes can be employed (Scheme 3). The use of
bis(neopentyl glycolato)diboron led to high yields under both
stereoretentive and stereoinvertive conditions. Bis(hexylene
glycolato)diboron proved to be more sensitive to reaction
conditions, only resulting in high yields under the stereo-
retention conditions. However, these boronates proved more
difficult to isolate due to decomposition upon purification by
silica gel chromatography, limiting the utility of borylations
C
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a
minimal loss in enantiopurity. Similarly, trifluoroborate (R)-4q
was formed in 83% yield and 79% ee via borylation using the
stereoinvertive conditions, followed by conversion to the
trifluoroborate.
Scheme 3. Alternative Diboranes
In addition to the allylic transposition reactions, these allylic
boronates can be reduced to highly enantioenriched secondary
alkyl boronates. Reduction of boronate 2a and subsequent
conversion to trifluoroborate 7 proceeded in 81% yield with no
loss of enantiopurity (eq 1). Via stereospecific, palladium-
catalyzed cross-couplings with aryl chlorides, trifluoroborate 7
can be converted to a number of highly enantioenriched
products with tertiary benzylic stereocenters.17
With respect to the mechanism of this reaction, we were
intrigued by the strong stereochemical dependence on solvent.
Examples of switchable stereospecificity have been reported
with both allylic and benzylic electrophiles. In their copper-
catalyzed alkylation of allylic phosphates, Ohmiya, Sawamura,
and co-workers observed a stereospecificity switch dependent
on base and solvent.13b Kurosawa’s group reported a solvent-
controlled stereochemical switch in the oxidative addition of
Pd2(dba)3 into allylic chlorides.13c In their nickel-catalyzed
arylation of benzylic carbamates, Jarvo and co-workers observed
that ligand identity could flip the stereochemical outcome.13a,e
These groups all attribute the stereoretention to a mechanism
in which the metal catalyst is directed to the allylic or benzylic
fragment by the leaving group (phosphate, chloride, or
carbamate). The inversion product is hypothesized to arise
via a nondirected SN2′ addition. Support for these mechanistic
proposals lies largely in the comparison of reaction parameters
for the two pathways; no systematic study to support the dual
role of the leaving group as also a directing group has been
published. We thought that this allylic borylation would provide
a suitable platform for such studies, particularly given the fact
that solvent was providing our stereospecificity switch.
a
Retention conditions: 1a (0.2 mmol, 1.0 equiv), B2X2 (2.0 equiv),
Ni(cod)2 (2 mol %), t-Bu-XantPhos (2.2 mol %), K3PO4 (2.0 equiv),
PhMe (0.4 M), rt, 24 h. Inversion Conditions: 1 (0.2 mmol, 1.0
equiv), B2pin2 (2.0 equiv), Ni(cod)2 (2 mol %), BnPPh2 (4.4 mol %),
K3PO4 (2.0 equiv), MeCN (0.4 M), rt, 32 h. Yields and α/γ ratios
1
determined by H NMR analysis using 1,3,5-trimethoxybenzene as an
internal standard. ee’s of the subsequent alcohol 3 formed via
oxidation with H2O2 and NaOH, determined by HPLC analysis using
a chiral stationary phase.
with these diboranes to cases where the allylic boronate can be
used directly without purification.
In some cases, purification of the allylic boronate esters was
hindered due to their decomposition on silica gel. This problem
was overcome by conversion of the boronate ester to a
potassium trifluoroborate salt.16 For example, borylation of
nitrile 1q under the stereoretentive conditions produced (S)-2q
in 84% ee (Scheme 4). Although 2q could not be purified via
silica gel chromatography, the subsequent trifluoroborate (4q)
was cleanly isolated in 84% yield as a single regioisomer with
To begin our mechanistic study, we first hypothesized that
the reaction proceeds via a π-allyl nickel intermediate. The
observation of minor amounts of the γ-regioisomer is consistent
with this hypothesis (see Scheme 2 above). In addition, we
subjected pivalate 1r to the borylation conditions. Boronate 2r
was formed as a 9:1 ratio of regioisomers, with the major
isomer mirroring that formed when pivalates 1a−1w are used
(Scheme 5). The styrenyl isomer is likely favored due to
conjugation of the olefin with the aryl group. Similar
regioselectivity and support for a π-allyl intermediate were
Scheme 4. Formation of Allylic Potassium Trifluoroborate
Salts
Scheme 5. Regioselective Borylation Consistent with π-Allyl
Nickel Intermediate
D
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also obtained in the analogous arylation of γ-aryl allylic
pivalates.11
Scheme 6. Proposed Mechanism of Allylic Borylation with
Retention and Inversion
We next investigated the dramatic solvent effect. By
performing the borylation of 1a under the conditions optimized
for retention of configuration in a variety of solvents, we
observed a general trend that the stereochemical fidelity of the
reaction decreases as the polarity of the solvent increases, as
N
shown in Figure 2, where ET is an empirical parameter of
single pathway (path A or B, Scheme 6). We can then use the
enantiomeric ratio to reflect the relative rates between path A
and B. To probe the directing ability of the carboxylate, we
replaced pivalate with a series of substituted benzoates in the
borylation under conditions that lead to stereoretention (Figure
3). Under these conditions, higher stereochemical fidelity was
N
Figure 2. Plot of log (er) vs ET
.
solvent polarity.18 Similar trends are observed using other
solvent parameters, including εr and the Kirkwood function.
Notably, however, the result in MeCN falls distinctly off this
trend, suggesting that MeCN’s role goes beyond a medium
effect.
Consistent with previous hypotheses for stereoretentive
oxidative addition into benzylic and allylic electrophiles,13a,c
we propose that the pivalate leaving group directs the nickel
catalyst in the oxidative addition when the reaction is run in
nonpolar solvents, such as PhMe (Scheme 6A). Two 7-
membered-ring, chairlike structures must be considered for this
closed transition state. In TS1, the nickel catalyst adds to the re
face of the alkene. Via rotation around the C1−C2 bond, the
nickel catalyst adds to the si face in TS2. We propose that TS1
will be favored, because both the phenyl and methyl
substituents reside in pseudoequatorial positions. This oxidative
addition leads to overall retention of stereochemistry. In more
polar solvents, an undirected, SN2′-type oxidative addition,
which proceeds via the charge-separated intermediate B, begins
to compete with path A (Scheme 6B). However, it is only when
MeCN is used as solvent that the stereochemical outcome flips
from stereoretention to stereoinversion. Given MeCN’s
propensity to act as a ligand for transition metals,14 we
hypothesize that MeCN coordinates nickel, prohibiting the
directed oxidative addition. In this case, two open transition
states are possible. We propose that TS3 will be favored,
because of destabilizing A1,3 strain between methyl and
hydrogen in TS4. Oxidative addition via TS3 leads to the
observed inversion of configuration.
Figure 3. Hammett correlation between benzoate substituents and
enantiomeric ratio.
observed for benzoates with more electron-donating groups.
This trend is consistent with coordination of the carboxylate to
the nickel catalyst in the stereoretentive pathway; more strongly
coordinating carboxylates lead to higher stereochemical fidelity.
We hypothesize that the moderate R2 value may be due to the
fact that the carboxylate is both a directing group and a leaving
group. Changing the leaving group identity affects both path A
and path B.
To support this mechanistic hypothesis, we undertook a
series of experiments to probe the role of both carboxylate
leaving group and nitrile additive. For these experiments, we
have assumed that each enantiomer of product forms via a
E
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We also investigated the importance (and geometry) of
nitrile coordination. Under the conditions optimized for
stereoretention (Ni(cod)2, t-Bu-XantPhos, K3PO4, and
PhMe), we added para-substituted benzonitriles (3.0 equiv)
to probe their effect on the stereochemical fidelity (Figure 4).
Experimental details and data (PDF)
AUTHOR INFORMATION
Corresponding Author
*mpwatson@udel.edu
■
Present Addresses
†Adesis, Inc., 27 McCullough Drive, New Castle, DE 19720.
§Inogent Laboratories Private Limited, IDA Nacharam,
Hyderabad 500076, India.
Author Contributions
‡Q.Z. and H.D.S. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
NIH (R01 GM111820) is gratefully acknowledged. NMR and
other data were acquired at UD on instruments obtained with
assistance of NSF and NIH funding (NSF CHE0421224,
CHE1229234, CHE0840401, and CHE1048367; NIH
P20GM104316, P20 GM103541, and S10OD016267).
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CONCLUSION
■
In conclusion, we have developed complementary reaction
conditions to enable the borylation of secondary allylic pivalates
to deliver either enantiomer of highly enantioenriched α-
stereogenic γ-aryl allylic boronates. This reaction harnesses
allylic pivalates that are readily prepared in high enantiopurity,
as well as commercially available nickel sources and ligands.
Excellent scope and functional group tolerance were observed.
The dramatic solvent effect over the stereospecificity appears to
arise from competitive oxidative addition mechanisms. Support
for the directing ability of the carboxylate, as well as the
importance of nitrile coordination, was gained via a series of
Hammett correlations. This is the first example of the synthesis
of enantioenriched α-stereogenic γ-aryl allylic boronates via
borylation of an allylic electrophile, and it offers an efficient
route to these versatile synthetic intermediates.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.6b07396.
■
S
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